D L Kendler*1, H G Bone2, F Massari3, E Gielen4, S Palacios5, J Maddox6, C Yan7, C Libanati8, S Yue6 and A Grauer6
1University of British Columbia, Vancouver, BC, Canada, 2Michigan Bone and Mineral Clinic, Detroit, MI, 3Instituto de Investigaciones Metabólicas, Buenos Aires, Argentina, 4UZ Leuven, Leuven, Belgium, 5Instituto Palacios, Madrid, Spain, 6Amgen Inc., Thousand Oaks, CA, 7Amgen Ltd, Cambridge, United Kingdom, 8UCB Pharma, Brussels, Belgium

 

Introduction

Romosozumab (Romo) has a dual effect of increasing bone formation and decreasing bone resorption and is associated with vertebral and clinical fracture risk reduction within 12 months (1). We present the results of 12-months Romo retreatment in subjects initially treated with Romo followed by placebo (Pbo) or denosumab (DMAb).

Methods

Postmenopausal women with a lumbar spine (LS), total hip (TH), or femoral neck (FN) T score ≤−2.0 and ≥−3.5 were enrolled in a phase 2 study (2) (NCT00896532). A total of 139 subjects entered the 12-month Romo 210 mg QM retreatment phase at month 36 after being randomized to various Romo doses from baseline (BL) to month 24, followed by Pbo or DMAb (month 24‒36). Here we report the results of retreatment for the group that was initially randomized to Romo 210 mg QM (n=35).

 

Results

Romo retreatment after Pbo resulted in bone mineral density (BMD) increases at the LS, TH, and FN comparable to the initial Romo treatment. BMD increased by 12.7% from month 36‒48 (12.0% BL‒month 12; 17.6% BL‒month 48) at the LS, 5.8 % (5.5% BL‒month 12; 7.1% BL‒ month 48) at the TH, and 6.3% (5.4% BL‒month 12; 8.6% BL‒month 48) at the FN. In subjects initially treated with Romo followed by DMAb for 12 month, then retreated with Romo, BMD increased by 2.8% from month 36‒48 (12.6% BL‒month 12; 22.1% BL‒month 48) at the LS, while no further BMD increase was noted at TH (7.3% BL‒month 36 and BL‒month 48) or FN (6.3% BL‒month 36; 6.7% BL‒month 48) in the retreatment phase. Bone formation (P1NP) and bone resorption (CTX) patterns were similar in Romo retreatment subjects after Pbo to subjects who received Romo in the first 12 months. In subjects who had received DMAb, reduced levels of both P1NP and CTX increased gradually after Romo retreatment to 52.1% and 16.5%, respectively, at month 48 from BL. The safety profile of Romo retreatment was generally consistent with Romo treatment from BL‒month 24. Of the 140 subjects initially exposed to Romo, 2 subjects previously antibody negative developed binding antibodies during retreatment, none had neutralizing activity; 6 subjects had neutralizing antibodies at the start of retreatment, 1 subject remained positive at the end of retreatment.

Conclusion

After a 12-month treatment-free period, Romo retreatment increased BMD at the spine and hip to an extent similar to initial Romo treatment. Romo retreatment after DMAb resulted in further increases in BMD at the spine and maintenance of BMD at the hip. Safety findings were similar to the initial Romo treatment.

 

Disclosure: DLK: Data Safety Advisory Board, Merck & Co., Principal Investigator, Astra Zeneca, Principal Investigator, Astellas, Speaker, Eli Lilly & Company, Principal Investigator, Eli Lilly & Company, Consultant, Eli Lilly & Company, Speaker, Amgen, Principal Investigator, Amgen, Consultant, Amgen. HGB: Consultant, Amgen, Speaker, Amgen, Investigator, Amgen, Data and Safety Monitoring Board Member, Grunenthal, Consultant, Merck & Co., Investigator, Merck & Co., Consultant, Radius, Consultant, Shire, Speaker, Shire, Consultant, Sucampo. SP: Advisory Group Member, Novo Nordisk, Speaker, Servier, Speaker, Daiichi Sankyo, Speaker, MSD, Advisory Group Member, Gedeon Richter, Speaker, Gedeon Richter, Advisory Group Member, Procare Health, Speaker, Procare Health, Advisory Group Member, Shionogi, Speaker, Shionogi, Speaker, Teva, Principal Investigator, Pfizer, Inc., Principal Investigator, Amgen, Principal Investigator, Gedeon Richter, Principal Investigator, Exeltis, Principal Investigator, Daiichi Sankyo, Speaker, Novo Nordisk, Speaker, Bayer Schering Pharma. JM: Employee, Amgen, Employee, Amgen. CY: Employee, Amgen, Employee, Amgen. CL: Employee, UCB Pharma, Employee, UCB Pharma. SY: Employee, Amgen, Employee, Amgen. AG: Employee, Amgen, Employee, Amgen. Nothing to Disclose: FM, EG

OR08-1 29273 1.0000 A Retreatment with Romosozumab after 12 Months of Placebo Demonstrates Similar BMD Efficacy Compared with Initial Romosozumab Treatment 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 1:15:00 PM OR08 9439 11:30:00 AM Insights into Skeletal Metabolism and Osteoporosis Therapies Oral


M R McClung*1, M A Bolognese2, J P Brown3, J-Y Reginster4, B L Langdahl5, J Maddox6, C Yan7, S Yue6, P D Meisner8 and A Grauer6
1Oregon Osteoporosis Center, Portland, OR, 2Bethesda Health Research Center, Bethesda, MD, 3Laval University and CHU de Québec (CHUL) Research Centre, Québec City, QC, Canada, 4University of Liège, Liège, Belgium, 5Aarhus University Hospital, Aarhus, Denmark, 6Amgen Inc., Thousand Oaks, CA, 7Amgen Ltd, Cambridge, United Kingdom, 8UCB Pharma, Brussels, Belgium

 

Introduction

Romosozumab (Romo) increased bone mineral density (BMD) and bone formation, and decreased bone resorption, resulting in vertebral and clinical fracture risk reduction within 12 months in postmenopausal women with osteoporosis (1). Here we report the efficacy and safety of transitioning to zoledronic acid (Zol) following Romo.

Methods

A phase 2 trial (2) (NCT00896532) enrolled postmenopausal women with a lumbar spine (LS), total hip (TH), or femoral neck (FN) T-score ≤−2.0 and ≥−3.5. In this analysis, women received various Romo doses or placebo (Pbo) from baseline (BL) to month 24, were re-randomized to denosumab (DMAb) or Pbo (month 24‒36), and then all received Romo (210 mg QM) for 12 months (month 36‒48). At month 48, subjects on active treatment (Romo/DMAb/Romo) for 48 months were assigned to no intervention, unless they had a fracture from month 24‒48 or a T-score ≤–2.5 at LS, TH, or FN at month 48 and were subsequently assigned to Zol (5 mg IV). All other subjects received Zol and both groups were followed for 24 months to month 72.

Results

After Romo treatment (month 36‒48), 141 women (90 Zol, 51 no intervention) continued in the study. In the Zol group, LS BMD was maintained through month 48‒72 (percentage change from month 48: ‒0.8%; percentage change from BL at month 72: 12.8%). Similar patterns were observed at the TH (0.1% and 4.2%, respectively) and FN (0.5% and 4.4%, respectively). After no intervention, LS BMD decreased from month 48‒72 (‒10.8%), although remained above BL at month 72 (percentage change from BL at month 72: 4.2%). At the TH and FN, BMD decreased by 6.4% and 5.9% respectively from month 48‒72, reaching values close to BL at month 72. In the Zol group, both median P1NP and CTX levels decreased initially, then moved towards BL by month 72. In the no intervention group, PINP decreased while CTX increased initially and gradually returned towards BL. During month 48‒72, adverse events (AEs) were reported in 83.9% of subjects receiving Zol and 72.5% assigned to no intervention; serious AEs were reported in 13.8% and 15.7% of subjects, respectively. Fragility fractures were reported in 2 Zol (1 radius, 1 rib) and 2 no intervention (1 radius; 1 fibula) subjects, and 1 fatal event occurred in a no intervention subject.

Conclusion

BMD gains at the LS, TH, and FN with prior Romo treatment were generally maintained over 24 months with a single dose of Zol. In women who received no further intervention, BMD decreased, but remained above (LS) or near BL (TH, FN) from month 48‒72.

 

Disclosure: MRM: Consultant, Radius, Consultant, Merck & Co., Speaker Bureau Member, Amgen, Speaker, Amgen, Consultant, Amgen. MAB: Speaker Bureau Member, Amgen, Clinical Researcher, Amgen. JPB: Scientific Board Member, Merck & Co., Speaker Bureau Member, Eli Lilly & Company, Scientific Board Member, Eli Lilly & Company, Principal Investigator, Eli Lilly & Company, Speaker Bureau Member, Amgen, Principal Investigator, Amgen, Scientific Board Member, Amgen. JYR: Consultant, Asahi, Consultant, UCB, Consultant, IBSA-Genevrier, Consultant, Servier, Speaker, Dairy Research Council, Speaker, Pharmevo, Speaker, IBSA-Genevrier, Speaker, Cniel, Speaker, Meda, Speaker, Danone, Speaker, Servier, Speaker, Merck & Co., Investigator, IBSA-Genevrier, Investigator, Cniel, Investigator, Meda, Investigator, Danone, Investigator, Pfizer, Inc., Investigator, Servier, Investigator, Eli Lilly & Company, Investigator, Amgen, Investigator, Merck & Co., Consultant, Radius Health, Consultant, Meda, Consultant, Pierra Fabre. BLL: Advisory Group Member, Amgen, Advisory Group Member, UCB, Speaker, Eli Lilly & Company, Speaker, Merck & Co., Speaker, Amgen, Researcher, Eli Lilly & Company, Researcher, Novo Nordisk, Researcher, Orkla, Advisory Group Member, Eli Lilly & Company, Advisory Group Member, Merck & Co.. JM: Employee, Amgen, Employee, Amgen. CY: Employee, Amgen, Employee, Amgen. SY: Employee, Amgen, Employee, Amgen. PDM: Employee, UCB Pharma, Employee, UCB Pharma. AG: Employee, Amgen, Employee, Amgen.

OR08-2 29272 2.0000 A Transition to Zoledronic Acid after Romosozumab Treatment Maintains Bone Mineral Density Gains 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 1:15:00 PM OR08 9439 11:30:00 AM Insights into Skeletal Metabolism and Osteoporosis Therapies Oral


Serge Ferrari*1, Jacques P Brown2, Nico Pannacciulli3, Nigel Gilchrist4, Christian Roux5, Ove Törring6, Ivo Valter7, Rachel B Wagman3, Andrea T Wang3 and Steven R Cummings8
1Geneva University Hospital, Geneva, Switzerland, 2Laval University and CHU de Québec (CHUL), Québec City, QC, Canada, 3Amgen Inc., Thousand Oaks, CA, 4The Princess Margaret Hospital, Christchurch, New Zealand, 5Paris Descartes University, Paris, France, 6Karolinska Institutet, Södersjukhuset, Stockholm, Sweden, 7Center for Clinical and Basic Research, Tallinn, Estonia, 8San Francisco Coordinating Center, CPMC Research Institute, San Francisco, CA

 

Purpose: Discontinuation of denosumab (DMAb), a reversible RANKL inhibitor, is associated with increases in bone turnover markers and decreases in lumbar spine and total hip bone mineral density (BMD) to baseline levels, and increases in vertebral Fx (VFx) incidence to rates comparable with placebo (PBO). Isolated cases of multiple VFx (MVF) after DMAb cessation have recently been reported (1). Furthermore, we previously observed that (a) subjects who sustained new VFx after DMAb cessation had a greater incidence of MVF than after PBO cessation and (b) prior VFx was the major determinant of off-treatment (Tx) VFx (2). This analysis further characterizes off-Tx VFx, including MVF, and associated factors in subjects who discontinued DMAb.

Methods: Subjects who discontinued investigational product (IP; PBO or DMAb 60 mg SC Q6M) from the 3-year FREEDOM trial and its 7-year Extension (Ext) were included in this analysis. Subjects receiving DMAb from FREEDOM or Ext were analyzed together. Off-Tx period was defined as 7 mo after last dose of IP through the end of study. Analyses assessed off-Tx new or worsening VFx; MVF were defined as ≥ 2 off-Tx new and/or worsening VFx.

Results: This analysis included 470 PBO and 1001 DMAb subjects. VFx were sustained by 6.6% subjects off PBO and 5.6% off DMAb, with 2.6% PBO and 3.4% DMAb sustaining MVF (including 0.9 and 1.6% with clinical MVF). Median follow-up time was 1.4/1.4 years (PBO/DMAb) and 0.5/0.3 years (PBO/DMAb) for those who did and did not sustain off-Tx VFx, respectively. More subjects who discontinued PBO (43%) than DMAb (15%) initiated alternative OP therapy. Subjects who initiated OP therapy before single VFx or MVF began OP therapy a median 4.4 or 6.3 months after last dose of PBO and 6.3 or 10.2 months after DMAb, respectively. Among those who initiated OP therapy, 5.0 and 4.0% from PBO and 4.1 and 9.0% from DMAb sustained a single VFx and MVF, respectively. Among subjects with available off-Tx BMD data (N = 297 PBO, N = 466 DMAb), mean annualized percent change in total hip BMD was +0.6% and –1.9% after stopping PBO and DMAb, respectively, for those with no off-Tx VFx; –1.3% and –2.2% for single VFx; and –1.2% and –3.5% for MVF.

Conclusion: This analysis confirms and expands previous results showing discontinuation of DMAb is associated with an increase in VFx rate, particularly clinical and morphometric MVF, whose incidence remained low and comparable to that of PBO. Fewer subjects who discontinued DMAb than PBO transitioned to alternative OP treatment, and transitioned later, suggesting that delaying a substitute therapy after DMAb may be detrimental. This is further corroborated by off-Tx BMD loss, which was greatest among subjects who sustained MVF and greater among those who sustained single VFx than those with no off-Tx VFx. Those who discontinue DMAb should transition to another OP therapy after the 6-mo dosing interval.

 

Disclosure: SF: Speaker, Eli Lilly & Company, Consultant, Eli Lilly & Company, Speaker, MSD, Consultant, MSD, Principal Investigator, MSD, Speaker, UCB, Consultant, UCB, Consultant, Amgen, Speaker, Amgen, Principal Investigator, Amgen. JPB: Scientific Board Member, Merck & Co., Speaker Bureau Member, Eli Lilly & Company, Scientific Board Member, Eli Lilly & Company, Principal Investigator, Eli Lilly & Company, Speaker Bureau Member, Amgen, Principal Investigator, Amgen, Scientific Board Member, Amgen. NP: Employee, Amgen, Employee, Amgen. CR: Board Member, Alexion, Speaker, Eli Lilly & Company, Board Member, UCB, Board Member, MSD, Board Member, Amgen. RBW: Employee, Amgen, Employee, Amgen. ATW: Employee, Amgen, Employee, Amgen. SRC: Consultant, Radius, Consultant, Amgen. Nothing to Disclose: NG, OT, IV

OR08-3 29266 3.0000 A Vertebral Fracture Incidence after Discontinuation of Denosumab Treatment: Analysis from Freedom and Its Extension 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 1:15:00 PM OR08 9439 11:30:00 AM Insights into Skeletal Metabolism and Osteoporosis Therapies Oral


David L Kendler*1, A Chines2, M L Brandi3, S Papapoulos4, E M Lewiecki5, J-Y Reginster6, C Roux7, M Munoz Torres8, A Wang2 and H G Bone9
1University of British Columbia, Vancouver, BC, Canada, 2Amgen Inc., Thousand Oaks, CA, 3University of Florence, Florence, Italy, 4Leiden University Medical Center, Leiden, Netherlands, 5New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, 6University of Liège, Liège, Belgium, 7Paris Descartes University, Paris, France, 8Hospital Universitario San Cecilio, Granada, Spain, 9Michigan Bone and Mineral Clinic, Detroit, MI

 

Osteoporosis is a common, progressive condition leading to increased bone fragility and susceptibility to fracture (fx). Although osteoporosis therapy decreases fx risk, fx while on treatment can occur and does not necessarily represent treatment failure. It is therefore of interest to assess whether patients who fx on denosumab (DMAb; FREEDOM and FREEDOM Extension) experience a lower risk of subsequent fx continuing on therapy than those on placebo (Pbo) who have fx.

During FREEDOM, postmenopausal women with osteoporosis were randomized to Pbo or DMAb for 3 years. During the 7-year Extension, all participants were allocated to receive DMAb. In this analysis, we report subsequent osteoporotic fx (new vertebral or nonvertebral) in subjects who received ≥ 2 doses of DMAb during FREEDOM or the Extension, had an osteoporotic fx while on treatment, and continued treatment post-fx, compared with subsequent fx in FREEDOM Pbo subjects. These subsequent fx were analyzed as recurrent events using the stratified Cox model with the robust variance estimation adjusting for prior fx. The analysis was repeated in subgroups of subjects with or without prevalent vertebral fx, defined at treatment baseline, without adjusting for prior fx.

During FREEDOM, 438 Pbo and 272 DMAb subjects had an osteoporotic fx (mean age at first on-study fx: 74.1 and 74.5 years, respectively). Of these, there were 54 (12.3%) and 24 (8.8%) subjects who had ≥ 1 subsequent fx in the Pbo and DMAb groups, respectively. Adjusted subject incidence per 100 patient-years was lower for DMAb (6.7) vs Pbo (10.1). Combining all subjects on DMAb from FREEDOM and the Extension for up to 10 years (Combined-DMAb), 794 (13.7%) subjects had an osteoporotic fx while on DMAb (mean age at first on-study fx: 76.5 years); of these, one or more subsequent fx occurred in 144 (18.1%) subjects, with an adjusted subject incidence of 5.8 per 100 patient-years, similar to FREEDOM DMAb (6.7 per 100 patient-years). Among subjects with ≥ 1 subsequent fx, 90% had only 1 fx; vertebral fx was the most frequent. The risk of having subsequent on-study osteoporotic fx was lower in the Combined-DMAb group vs Pbo (HR 0.59 [95% CI: 0.43–0.81]; p = 0.0012), adjusting for prior fx. In this analysis, 33% of subjects had prevalent vertebral fx at treatment baseline. The effect of DMAb treatment on reduction of subsequent on-study fx was statistically greater in subjects with prevalent vertebral fx (Pbo = 17.4 vs Combined-DMAb = 7.8 per 100 patient-years; HR 0.41 [95% CI: 0.26–0.65]; p < 0.0001) compared with subjects without prevalent vertebral fx (Pbo = 6.8 vs Combined-DMAb = 4.9 per 100 patient-years; HR 0.81 [95% CI: 0.50, 1.30]; p = 0.3728), with an interaction p = 0.0347. In both subgroups, spine fx was the most frequent subsequent fx. These data demonstrate that DMAb decreases the risk of subsequent fx and a fx sustained while on DMAb is not necessarily indicative of treatment failure.

 

Disclosure: DLK: Principal Investigator, Amgen, Speaker, Amgen, Consultant, Eli Lilly & Company, Principal Investigator, Eli Lilly & Company, Speaker, Eli Lilly & Company, Principal Investigator, Astellas, Principal Investigator, Astra Zeneca, Data Safety Advisory Board, Merck & Co., Consultant, Amgen. AC: Employee, Amgen, Employee, Amgen. MLB: Speaker, Amgen, Principal Investigator, Amgen, Speaker, Abiogen, Principal Investigator, Abiogen, Speaker, Eli Lilly & Company, Principal Investigator, Eli Lilly & Company, Speaker, Alexion, Principal Investigator, Alexion, Speaker, Shire, Principal Investigator, Shire. SP: Ad Hoc Consultant, UCB, Speaker, Amgen, Advisory Group Member, Merck & Co., Speaker, Merck & Co., Ad Hoc Consultant, Axsome, Advisory Group Member, Mereo Biopharma, Advisory Group Member, Amgen. EML: Study Investigator, Amgen, Medical Advisory Board Member, Merck & Co., Study Investigator, Merck & Co., Medical Advisory Board Member, Eli Lilly & Company, Study Investigator, Eli Lilly & Company, Medical Advisory Board Member, Radius, Medical Advisory Board Member, Amgen. JYR: Speaker, IBSA-Genevrier, Speaker, Cniel, Speaker, Meda, Speaker, Danone, Speaker, Servier, Speaker, Merck Sharp & Dohme, Investigator, IBSA-Genevrier, Investigator, Cniel, Investigator, Meda, Investigator, Danone, Investigator, Pfizer, Inc., Investigator, Servier, Investigator, Lilly, Investigator, Amgen, Investigator, Merck Sharp & Dohme, Speaker, Pharmevo, Speaker, Dairy Research Council, Consultant, Servier, Consultant, IBSA-Genevrier, Consultant, UCB, Consultant, Asahi, Consultant, Radius Health, Consultant, Meda, Consultant, Pierre Fabre. CR: Board Member, MSD, Board Member, UCB, Speaker, Eli Lilly & Company, Board Member, Alexion, Board Member, Amgen. MM: Medical Advisory Board Member, Amgen, Study Investigator, Eli Lilly & Company. AW: Employee, Amgen, Employee, Amgen. HGB: Consultant, Sucampo, Speaker, Shire, Consultant, Shire, Consultant, Radius, Investigator, Merck & Co., Consultant, Merck & Co., Data and Safety Monitoring Board, Grunenthal, Investigator, Amgen, Speaker, Amgen, Consultant, Amgen.

OR08-4 29153 4.0000 A The Risk of Subsequent Osteoporotic Fractures Is Decreased in Patients Experiencing Fracture While on Denosumab: Results from the Freedom and Freedom Extension Studies 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 1:15:00 PM OR08 9439 11:30:00 AM Insights into Skeletal Metabolism and Osteoporosis Therapies Oral


Sean J. Iwamoto*1, Micol S. Rothman1, Shenghui Duan2, Steven Mumm2, Kelsey Burr1 and Michael P. Whyte3
1University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, 2Washington University School of Medicine at Barnes-Jewish Hospital, Saint Louis, MO, 3Shriners Hospital for Children, Saint Louis, MO

 

Background: With better access to mutation analysis, diagnosis of rare genetic diseases has improved. Examples include the monogenic disorders of receptor activator of nuclear factor kappa-B ligand (RANKL), its receptor RANK, and osteoprotegerin. Specifically, heterozygous 12-, 15-, 18-, and 27-base pair insertional duplications are known within exon 1 of TNFRSF11A, the gene that encodes the signal peptide of RANK. These autosomal dominant mutations cause remarkably different skeletal diseases called panostotic expansile bone disease, expansile skeletal hyperphosphatasia (ESH), familial expansile osteolysis (FEO), and early-onset Paget’s disease of bone (PDB2), respectively (1-3). Mechanistically, they constitutively increase RANK activity and promote high-turnover bone disease via osteoclast formation and activation.

Clinical Case: A 48-year-old Mexican man with HIV was evaluated for severely low BMD and multiple atraumatic fractures starting in adulthood, including bilateral femur fractures. His viral load was suppressed on HAART. Transient hypercalcemia had followed hip surgery. He lost teeth at age 28. He had difficultly hearing the TV but never had formal audiometry. He did not report familial bone disease, but his father had short stature and multiple fractures. Physical exam noted a height of 5’2”, edentulous mouth, subjective right > left decreased hearing, white sclerae, thoracic kyphosis, enlarged fingers, and anteriorly bowed tibias. Serum alkaline phosphatase (ALP) was 330 U/L (n: 39-117 U/L) and bone-specific ALP was 87.6 ug/L (n: 6.5-20.1 ug/L), whereas PTH, Ca, Vit D and phosphorus were normal. Bone turnover markers were strikingly elevated: serum CTX 2477 pg/mL (n: 60-700 pg/mL) and osteocalcin 281 ng/mL (n: 11-50 ng/mL). DXA spine BMD was 0.488 g/cm2 with Z-score -5.5. Skeletal survey showed remarkably lucent bones with vertebral compression fractures, calvarial lucencies, and thinned long bone cortices. We identified a unique, heterozygous 27-base pair duplication (77dup27) in exon 1 of TNFRSF11A. Alendronate 70 mg/week modestly decreased bone turnover markers in 6 weeks. Family investigation is planned.

Conclusion: Our patient’s high-turnover bone disease involves a novel 27-base pair duplication in TNFRSF11A, the gene encoding the signal peptide of RANK. Similar duplications have been identified in Japanese (75dup27) and Chinese (78dup27) PBD2 cohorts, although they seem to predict the same 9-amino acid duplication (4). Our patient shares features of their PDB2 with presentation in his late 20s, painless enlarged fingers, transient hypercalcemia, and absence of childhood tooth or hearing loss. Bisphosphonate therapy improves bone turnover markers in PBD2 patients. Our experience supports mutation analysis in the diagnosis and management of high-turnover bone diseases, including those involving constitutively active RANK.

 

Nothing to Disclose: SJI, MSR, SD, SM, KB, MPW

OR08-5 31200 5.0000 A High Turnover Bone Disease Due to a Novel 27-Base Pair Tandem Duplication in TNFRSF11A leading to Constitutively Active RANK 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 1:15:00 PM OR08 9439 11:30:00 AM Insights into Skeletal Metabolism and Osteoporosis Therapies Oral


Christine Swanson*1, Steven A Shea2, Pamela Wolfe1, Sheila Markwardt2, Charles A Czeisler3, Orfeu Marcello Buxton4 and Eric S Orwoll5
1University of Colorado, Aurora, CO, 2Oregon Health & Science University, Portland, OR, 3Brigham and Women's Hospital, Boston, MA, 4Pennsylvania State University, University Park, PA, 5Oregon Health & Sciences Univ, Portland, OR

 

Long and short sleep durations have both been associated with low BMD, but underlying mechanisms are unknown. We investigated the impact of combined circadian disruption with sleep loss, akin to the stresses endured during rotating shift work, on biomarkers of bone metabolism in 10 healthy men (age groups: 20-27y, n = 6; 55-65yo, n = 4). We hypothesized that sleep/circadian disturbance would negatively alter bone balance.

Four bone biomarkers (CTX = bone resorption; PINP = bone formation; sclerostin/FGF-23 = osteocyte function) were measured on q2h plasma samples over a 24-h interval at baseline and after a 3-wk intervention of sleep restriction (5.6h sleep/24-h) with concurrent circadian disruption (recurring 28-h ‘day’). Post-intervention samples were obtained when participants were at a similar circadian phase compared to the baseline samples.

Maximum likelihood estimates for repeated measures were obtained to assess the effects of sleep/circadian disruption and of age, on bone biomarker levels across a 24-h interval.

Except FGF-23, bone biomarker levels varied significantly by age at baseline (CTX/PINP higher in younger men (p = 0.01 and 0.02, respectively); sclerostin higher in older men (p = 0.005). This is consistent with higher bone (re)modeling rates in younger men during their consolidation phase and a nadir in BTMs in 50-60yo men. PINP levels were significantly lower post intervention compared to baseline; the decrease in PINP occurred at every time point and this decline was greater for the younger men with higher bone turnover at baseline (-27% or -20.73 ± 1.38 mcg/L, p<0.001), compared to older men (-18% or -10.01 ± 1.70 mcg/L, p<0.001). These decreases were of similar magnitude to the early increase seen with teriparatide treatment and occurred independently of changes in CTX (Δ = 2-4%, p = 0.56). Sclerostin levels were significantly higher post-intervention in the younger men only (Δ +25% or 5.92 ± 1.84 pmol/L, p=0.002) compared to older men (Δ +2.3% or 0.90 ± 2.26 pmol/L, p=0.69). Post intervention, FGF-23 levels were 6.5% lower (-2.46 ± 0.96 pg/mL; p = 0.01).

These results suggest that 3 weeks of sleep loss with circadian disruption can lead to an uncoupling of bone turnover and a potential “catabolic window,” wherein bone formation is decreased but bone resorption is unchanged. These data further suggest that sleep disruption may be most detrimental to bone during high bone turnover states (i.e. bone modeling, menopause). These changes could be due to direct effects on diurnal bone remodeling (either related to sleep restriction, or prior circadian disruption), indirect effects via changes in sex-hormone status, inflammation and/or sympathetic tone induced by sleep disruption, or less likely, the decreased physical activity inherent in study conditions. Further studies are needed to confirm these data independent of study conditions and to explore sex differences and mechanisms.

 

Disclosure: CAC: , Merck & Co., , Quest Diagnostics. Nothing to Disclose: CS, SAS, PW, SM, OMB, ESO

OR08-6 29839 6.0000 A Lower Bone Formation after 3 Weeks of Sleep Restriction with Circadian Disruption: A Mechanism for Sleep-Related Bone Loss 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 1:15:00 PM OR08 9439 11:30:00 AM Insights into Skeletal Metabolism and Osteoporosis Therapies Oral


Michael R McClung*1, Gregory C Williams2, Gary Hattersley2, Lorraine A Fitzpatrick3, Yamei Wang4 and Paul D Miller5
1Oregon Osteoporosis Center, Portland, OR, 2Radius Health, Inc, Waltham, MA, 3Radius Health, Inc, Wayne, PA, 4Radius Health, Inc, Parsippany, NJ, 5Colorado Center for Bone Research, Lakewood, CO

 

Regional heterogeneity has been observed in fracture risk, and geography may impact the efficacy of osteoanabolic agents. Abaloparatide-SC (ABL-SC) is an investigational, novel, selective activator of the PTH 1 receptor signaling pathway. In the global, phase 3 ACTIVE trial of 2463 postmenopausal women with osteoporosis, ABL-SC significantly reduced the risk of vertebral and nonvertebral fractures compared to placebo, and reduced the risk of major osteoporotic fractures compared to teriparatide. Prespecified exploratory analyses of ACTIVE were completed to investigate, across geographic subgroups (North America, South America, Europe, Asia), both the heterogeneity of fracture risk at baseline and the consistency of effect of ABL-SC versus placebo treatment on fracture risk reduction. A post hoc analysis of consistency of effect of ABL-SC versus placebo was also conducted for women of Hispanic/Latino ethnicity versus other women enrolled in ACTIVE.

Country-specific FRAX models were used to calculate 10-year absolute fracture risks at baseline. Relative risk reductions for new vertebral fractures (VF) and hazard ratios for nonvertebral (NVF), clinical (CF), and major osteoporotic (MOF) fractures were calculated for each geographic and ethnic subgroup, and Forest plots were constructed to assess treatment-by-subgroup interactions.

Prevalent VF were observed at baseline in 20.0%, 18.0%, 25.3%, and 18.5% of total (placebo and ABL-SC) patients from North America, South America, Europe, and Asia, and at least one prior NVF was reported in 80.0%, 40.1%, 58.5%, and 32.2%, respectively. Mean FRAX 10-year probabilities were 16.5%, 8.8%, 13.9%, and 17.7% for MOF. The effects of ABL-SC versus placebo on the risks of VF, NVF, CF, and MOF did not differ significantly across geographic regions, as well as for Hispanic/Latino versus other ethnicities, with no significant treatment-by-region interactions (p=0.57, 0.89, 0.83, 0.76, respectively, for geographic subgroups; p=0.35, 0.57, 0.33, and 0.65, respectively, for Hispanic/Latino versus other ethnicities).

In conclusion, despite limitations of subgroup analyses and geographic variability in fracture incidence and risk at baseline, these analyses suggest that the effects of ABL-SC versus placebo on reducing the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures were consistent across prespecified geographic subgroups. Additionally, a post hoc analysis suggests that the effects of ABL-SC versus placebo on fracture risk were also similar for women of Hispanic/Latino ethnicity compared to other women enrolled in ACTIVE.

 

Disclosure: MRM: Consultant, Radius Health, Inc, Consultant, Amgen, Speaker, Amgen. GCW: Employee, Radius Health, Inc, Employee, Radius Health, Inc.. GH: Employee, Radius Health, Inc, Employee, R. LAF: Employee, Radius Health, Inc, Employee, Radius Health, Inc.. YW: Employee, Radius Health, Inc, Employee, Radius Health, Inc.. PDM: Medical Advisory Board Member, Amgen, Medical Advisory Board Member, AgNovos, Medical Advisory Board Member, Lilly USA, LLC, Medical Advisory Board Member, Merck & Co., Medical Advisory Board Member, Radius Health, Inc., Medical Advisory Board Member, Roche Pharmaceuticals, Medical Advisory Board Member, Ultragenix, Researcher, Alexion, Researcher, Amgen, Researcher, Boehringer Ingelheim, Researcher, Immunodiagnostics, Researcher, Eli Lilly & Company, Researcher, Merck & Co., Researcher, Merck Serono, Researcher, National Bone Health Alliance, Researcher, Novartis Pharmaceuticals, Researcher, Radius Health, Inc, Researcher, Roche Diagnostics, Researcher, Regeneron, Researcher, Daiichi Sankyo, Researcher, Ultragenyx.

1 Saturday, April 1st OR08-7 33167 7.0000 A Comparison of the Geography of Fracture Incidence in Postmenopausal Women with Osteoporosis Treated with Abaloparatide-SC Versus Placebo during the ACTIVE Trial 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 1:15:00 PM OR08 9439 11:30:00 AM Insights into Skeletal Metabolism and Osteoporosis Therapies Oral


Jens Øllgaard*1, Peter Gæde1, Peter Rossing2, Hans Henrik Parving3 and Oluf Pedersen4
1Slagelse Hospital, Denmark, 2Steno Diabetes Center, Denmark, 3Rigshospitalet, Denmark, 4University of Copenhagen, Copenhagen, Denmark

 

Introduction: Intensified multifactorial intervention for 7.8 years in patients with type 2 diabetes mellitus and microalbuminuria reduced risk of macro- and microvascular complications. Here we seek to investigate the durability of this approach with a total of 21 years follow-up in a post hoc analysis including endpoints as recommended in FDA-guidelines.

Methods: 160 patients with type 2 diabetes and microalbuminuria were assigned to conventional or intensified, multi-factorial therapy targeting multiple risk factors. Mean treatment duration was 7.8 years. After 7.8 years the study continued as an observational follow-up with all patients treated as the original intensive-therapy group. Time to event was modelled using Cox-regressions adjusted for age and sex.

The primary endpoint was survival time after randomization and survival time before first CVD event.

The secondary endpoint was the relative risk reduction in a 3 point MACE defined as death of CVD, coronary artery disease (CAD: non-fatal or fatal acute myocardial infarction or cardiac revascularization) and cerebrovascular disease (defined as non-fatal and fatal ischemic or hemorrhagic stroke) analyzed both as a composite- and separate endpoints.

Results: Overall median survival time was 7.9 [95% CI 2.2 – 9.6; p = 0.005] years longer in the original intensive-therapy group compared to standard treatment. Time before first CVD-event was 8.1 [4.0 – 12.6; p = 0.001] years longer in the intensive therapy group.

Hazard rates of both the composite and separate secondary endpoints were all decreased with intensified therapy. HR of the composite endpoint was 0.36 [95 % CI 0.23 – 0.57; p < 0.001], of CAD 0.43 [0.23 – 0.77; p = 0.005] and cerebrovascular disease 0.26 [0.12 – 0.55; p < 0.001]. In addition, the risk of recurrent events was significantly decreased in the intensive-therapy group (p = 0.049 for CAD and p = 0.003 for stroke).

Conclusions: At 21.2 years of follow up of 7.8 years of intensified, multifactorial, target driven treatment of type 2 diabetes mellitus with microalbuminuria, we demonstrate significantly increased life span and reduced risk of macrovascular complications.

(ClinicalTrials.gov number, NCT00320008.)

 

Disclosure: JØ: , Novo Nordisk. Nothing to Disclose: PG, PR, HHP, OP

OR11-1 32556 1.0000 A Increased Survival and Reduced Macrovascular Disease with 7.8 Years of Intensified, Multifactorial Intervention in Patients with Type 2 Diabetes and Microalbuminuria in the Steno-2 Study 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 1:00:00 PM OR11 9442 11:30:00 AM Clinical Dilemmas and Outcomes in Diabetes Oral


Tali Cukierman-Yaffe*1, Jung Hyejung2, Jackie Bosch3, Zubin Punthakee4 and Hertzel C Gerstein5
1Sheba Medical Center, Tel-Aviv university, Israel, Population Health Research Institute, McMcaster university, Canada, 2Population Health Research Institute, McMaster university, Hamilton, Canada, 3Population Health Research Institute, McMaster university, Hamilton Canada, 4Population Health Research Institute, McMaster university, Hamilton, ON, CANADA, 5Population Health Research Institute, McMaster University

 

Epidemiological studies have reported that recurrent severe hypoglycemia is associated with dementia and cognitive dysfunction in middle-aged and older people with type 2 diabetes. Cognitive dysfunction may precede or follow severe hypoglycemia in people with type 2 diabetes who are at risk for both conditions. The relationship between incident hypoglycemia and incident cognitive dysfunction was therefore analyzed using prospectively collected data in the outcome reduction with an initial glargine intervention (ORIGIN) trial. Methods:This prospective cohort analysis of data from a randomized controlled trial included individuals with dysglycemia (88% diabetes) who all had additional cardiovascular risk and a Mini Mental State Examination (MMSE) score equal to or above 24/30 (N=11495). Hypoglycemia (severe and non-severe) events were collected prospectively through-out the study (median follow-up 6.2 years). Non-severe hypoglycemia was defined as an event associated with symptoms of hypoglycemia, confirmed by a capillary glucose of <=54 mg/dl (3 mmol/L) and not requiring assistance from another person. Severe hypoglycemia was defined as a symptomatic hypoglycemic event requiring the assistance of another person and either 1) prompt recovery after oral carbohydrate, IV glucose, or glucagon and/or 2) documented self- measured or lab measured plasma glucose of <= 36mg-dl (2mmol/L). Incident cognitive dysfunction was defined as either newly reported dementia or a MMSE score of below 24 during follow-up. The relationship between severe and non-severe hypoglycemia (included as time-varying covariates) and incident cognitive dysfunction was determined using Cox proportional hazard models after adjusting for several variables and a propensity score for hypoglycemia.

Results: There was no relationship between severe hypoglycemia and incident cognitive impairment after adjusting for baseline CVD, diabetes status, treatment allocation, a propensity score for severe hypoglycemia and the interaction of treatment allocation and severe hypoglycemia (HR 1.28, 95% 0.8, 2.05). Those individuals who experienced at least one episode of non-severe hypoglycemia were less likely to develop cognitive dysfunction than were those that did not, after adjustment for baseline CVD, diabetes status, treatment allocation, a propensity score for non-severe hypoglycemia and the interaction of treatment allocation and hypoglycemia (HR 0.71, 95% 0.56, 0.9).

To conclude: Among 11,495 individuals ~63 years of age with dysglycemia, after accounting for the risk factors of hypoglycemia, hypoglycemia itself was not associated with an increased incidence of cognitive dysfunction over 6.2 years.

 

Disclosure: TC: Speaker, Eli Lilly & Company, Speaker, Astra Zeneca, Speaker, Merck & Co., Speaker, Novo Nordisk, Speaker, Sanofi, Speaker, BI, Advisory Group Member, Sanofi. ZP: Investigator, Amgen, Advisory Group Member, Animas, Advisory Group Member, Astra Zeneca, Speaker, Astra Zeneca, Speaker, Astra Zeneca, Investigator, Astra Zeneca, Advisory Group Member, BI, Speaker, BI, Investigator, BI, Advisory Group Member, Bristol-Myers Squibb, Speaker, Bristol-Myers Squibb, Investigator, Bristol-Myers Squibb, Advisory Group Member, Eli Lilly & Company, Speaker, Eli Lilly & Company, Investigator, Eli Lilly & Company, Investigator, Lexicon Pharmaceuticals, Inc., Advisory Group Member, Merck & Co., Speaker, Merck & Co., Investigator, Merck & Co., Advisory Group Member, Novo Nordisk, Speaker, Novo Nordisk, Investigator, Novo Nordisk, Advisory Group Member, Pfizer, Inc., Speaker, Pfizer, Inc., Advisory Group Member, Serono, Speaker, Serono, Advisory Group Member, Sanofi, Consultant, Sanofi, Investigator, Sanofi. HCG: Ad Hoc Consultant, Sanofi, Principal Investigator, Sanofi, Speaker, Sanofi, Advisory Group Member, Eli Lilly & Company, Advisory Group Member, Astra Zeneca, Advisory Group Member, Merck & Co., Advisory Group Member, Amgen, Advisory Group Member, Novo Nordisk, Advisory Group Member, Abbott Laboratories, Advisory Group Member, Berlin Chemie, Advisory Group Member, BI, Advisory Group Member, Kaneq Bioscience, Principal Investigator, Eli Lilly & Company, Principal Investigator, Astra Zeneca, Principal Investigator, Merck & Co.. Nothing to Disclose: JH, JB

OR11-2 29310 2.0000 A Hypoglycemia & Incident Cognitive Dysfunction: A Post-Hoc Analysis from the Origin Trial 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 1:00:00 PM OR11 9442 11:30:00 AM Clinical Dilemmas and Outcomes in Diabetes Oral


Sunee Saetung*1, Megan M Hood2, Hataikarn Nimitphong3, Nantaporn Siwasaranond4, Stephanie J Crowley2 and Sirimon Reutrakul5
1Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 2Rush University Medical Center, Chicago, IL, 3Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 4Faculty of Medicine Ramathibodi Hospital, Bangkok, Thailand, 5Faculty of Medicine Ramahibodi Hospital, Bangkok, Thailand

 

The circadian system plays a role in the sleep/wake cycle and metabolism. Individuals vary in their circadian preference or chronotype, i.e. morning or evening type. Chronotype has been shown to be related to psychological functioning, i.e. more evening preference (later chronoytpe) has been associated with greater depressive symptoms in general population. In addition, sleep disturbances, more prevalent in evening types, have been associated with depression. Depression is common in type 2 diabetes (T2D) patients and related to worse outcomes. Little data exist describing whether chronotype is related to depressive symptoms in T2D, independent of sleep disturbances and other confounders. In addition, chronotype may differ by geographic locations (more morning preference near the equator). We aimed to explore the association between chronotype and depressive symptoms in T2D patients from two different geographic areas.

Cross sectional studies in T2D patients were conducted separately in Chicago (latitude 42N) (n=194) and Thailand (latitude 13N) (n=282). Demographics, diabetes history and complications were collected. Depressive symptoms were assessed by the Center for Epidemiologic Studies Depression scale (CES-D). Chronotype was assessed using the Morningness-Eveningness Questionnaire (MEQ) in the Chicago cohort, and the Composite Score of Morningness (CSM) in the Thailand cohort. Sleep quality was assessed using the Pittsburg Sleep Quality Index (PSQI). HbA1c values were retrieved from medical records.

In the Chicago cohort, mean age was 58.3±13.0 years, 69.6% were female and 28.4% were whites. Higher CES-D scores (more depressive symptoms) were associated with later chronotype (lower MEQ score, r= -0.242, p=0.001), as well as younger age (p=0.005), female sex (p=0.047), non-whites (p=0.003), insulin use (p<0.001), higher HbA1c levels (p=0.005), poorer sleep quality (p <0.001). After adjusting for age, sex, ethnicity, HbA1c, insulin use and PSQI score, later chronotype was significantly associated with higher CES-D scores (B=-0.112, p=0.045). In Thailand cohort, mean age was 55.7±11.6 years and 57.4% were female. Higher CES-D scores were associated with later chronotype (lower CSM score, r= -0.227, p<0.001), as well as younger age (p=0.019), female sex (p=0.004), and poorer sleep quality (p<0.001). After adjusting for age, sex and PSQI score, later chronoytpe was significantly associated with higher CES-D score (B= -0.114, p=0.045).

In this study of two different ethnic cohorts, later chronotype was found to be independently associated with depressive symptoms in T2D. These data support an association between circadian regulation and psychological functioning in individuals with T2D. Intervention studies targeting circadian timing should be explored to determine whether altering circadian functioning may improve depressive symptoms in T2D patients.

 

Disclosure: SR: , Medtronic Minimed, , Novo Nordisk, , Merck & Co., , Sanofi. Nothing to Disclose: SS, MMH, HN, NS, SJC

OR11-3 29541 3.0000 A Later Chronotype Is Associated with Greater Depressive Symptoms in Type 2 Diabetes Patients: A Study in Two Different Ethnic Cohorts 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 1:00:00 PM OR11 9442 11:30:00 AM Clinical Dilemmas and Outcomes in Diabetes Oral


Ekasitt Wanitcharoenkul*1, Boonsong Ongphiphadhanakul2, Naricha Chirakalwasan3, Somvang Amnakkittikul4, Suranut Charoensri5, Sunee Saetung6, Punyu Panburana4, Sommart Bumrungphuet5 and Sirimon Reutrakul4
1Faculty of Medicine Ramathibodi hospital, Bangkok, Thailand, 2Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 3Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, 4Faculty of Medicine Ramahibodi Hospital, Bangkok, Thailand, 5Faculty of Medicine Ramathibodi Hospital, Bangkok, Thailand, 6Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

 

Background: Obstructive sleep apnea (OSA) has been shown to be associated with gestational diabetes (GDM) and adverse pregnancy outcomes including preeclampsia, caesarean section and premature delivery. However, the data on the effect of continuous positive airway pressure treatment (CPAP) on pregnancy outcomes were lacking. We previously reported an improved insulin secretion as a result of a 2-week CPAP treatment in women with diet-controlled GDM and OSA in the third trimester. The aim of this study was to report pregnancy outcomes in these women, and compare them with GDM women without OSA.

Methods: Obese pregnant women (pre-pregnancy BMI >=25 kg/m2) with diet-controlled GDM were asked to participate. OSA was screened using an overnight home monitor. Those diagnosed with OSA were randomized to receive CPAP treatment for 2 weeks or be wait-list controls. After randomization period ended, all women were offered CPAP treatment until delivery. Pregnancy outcomes were collected in all women from medical records.

Results: Of the 82 women screened at a median gestational age (GA) of 29 weeks, 43 had OSA (apnea hypopnea index >=5). Of these, 28 had CPAP treatment and 15 did not. Pregnancy outcomes were available in 78 women (38 in No-OSA group, 28 in OSA/CPAP group and 11 OSA/no-CPAP group).

When comparing women among the three groups; No-OSA vs. OSA/CPAP vs. OSA/No-CPAP, there were no significant differences their age, pre-pregnancy BMI, gravida and para. There were also no significant differences in the pregnancy outcomes including subsequent rates of insulin use, preterm delivery (<37 weeks), preeclampsia, unplanned caesarean section, birth weight (3164±489 gm vs. 3099±509 gm vs. 3196±608, p=0.821), Apgar score at 1 minute and 5 minutes, or the rate of small for gestational age and large for gestational age.

Of the 28 women exposed to CPAP, 23 had used CPAP for >=2 weeks. There was no significant difference in GA at CPAP start between those using CPAP >=2 vs. <2 weeks (30.7±3.0 vs. 30.0 ± 3.7 weeks, p=0.619). Those using CPAP >=2 weeks used the device on average for 37±16 days and for 74±18% of the days.

When comparing women in No-OSA group (n=38) vs. OSA with CPAP use >=2 weeks (n=23) and OSA with CPAP use <2 weeks (n=16), the rate of preterm delivery was significantly less in those who used CPAP >=2 weeks (13.1% vs. 0% vs. 31.2%, p=0.017). In addition, unplanned caesarean section was also significantly less (34.2% vs. 13.0% vs 52.0%, p=0.026). Other pregnancy outcomes were similar among groups.

Conclusion: CPAP use in pregnant women with diet-controlled GDM and OSA was safe. CPAP use for >=2 weeks in the third trimester was associated with a significantly less risk for premature delivery and unplanned caesarean section. This information supported the benefits of CPAP treatment in this patient group and should be confirmed in a larger study.

 

Nothing to Disclose: EW, BO, NC, SA, SC, SS, PP, SB, SR

OR11-4 29547 4.0000 A Continuous Positive Airway Pressure Treatment in Gestational Diabetes Women with Obstructive Sleep Apnea: Effects on Pregnancy Outcomes 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 1:00:00 PM OR11 9442 11:30:00 AM Clinical Dilemmas and Outcomes in Diabetes Oral


Sarah C. Nyirjesy1, Saba Sheikh2, Denis Hadjiliadis1, Diva D. De Leon2, Amy J. Peleckis1, Jack N. Eiel1, Christina Kubrak2, Darko Stefanovski3, Ronald C. Rubenstein2, Michael R. Rickels1 and Andrea Kelly*2
1Hospital of the University of Pennsylvania, Philadelphia, PA, 2Children's Hospital of Philadelphia, Philadelphia, PA, 3University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA

 

Patients with pancreatic insufficient cystic fibrosis (PI) who are defined as having normal glucose tolerance (PI-NGT) according to current clinical guidelines display impaired β-cell secretory capacity and early phase insulin secretion defects compared to pancreatic sufficient cystic fibrosis (PS) individuals and healthy controls. To better identify PI patients with early defects in insulin secretion, we sought evidence of impaired β-cell secretory capacity, a measure of functional β-cell mass, using a more stringent parameter for characterizing indeterminate glucose tolerance (PI-IDGT): a 1-hour plasma glucose ≥ 155mg/dL. Metabolic tests, including the mixed-meal tolerance test (MMTT), glucose potentiated arginine (GPA) test, and continuous glucose monitoring (CGM) were conducted across groups of patients with PI categorized by an oral glucose tolerance test (OGTT) as normal (1-hour plasma glucose < 155 and 2-hour < 140 mg/dL; n = 13), indeterminate (1-hour ≥ 155 and 2-hour < 140 mg/dL; n = 13), impaired (PI-IGT: 2-hour ≥ 140 and < 200 mg/dL; n = 8), and diabetic (CFRD: 2-hour ≥ 200 mg/dL; n = 8), and in PS participants (n = 9). PI-IDGT had elevated post-prandial glucose (AUCglu) during the MMTT compared to PS and those with more stringently defined normal glucose tolerance (PI-NGT; P < 0.05 for both). PI-IDGT also exhibited impaired post-prandial insulin responses (AUCins/AUCglu; P < 0.05 vs. PS and PI-NGT) as well as impaired acute insulin and C-peptide responses to glucose-potentiated arginine (P < 0.01 vs. PS and PI-NGT), measures of β-cell secretory capacity derived from the GPA test. Elevated proinsulin secretory ratios were observed under hyperglycemic clamp conditions in PI-IDGT (P < 0.05 vs. PS), suggesting the reduced functional β-cell mass is under excessive β-cell secretory demand resulting in impaired proinsulin processing. PI-IDGT displayed comparable glucose control by CGM to both PS and PI-NGT with increased glucose variability and excursions seen in PI-IGT and CFRD participants (P < 0.05 vs. PS for both). These results indicate that PI patients with 1-hour OGTT glucose as low as 155 mg/dL can already be identified with early impairments in β-cell secretory capacity that is further taxed by increased insulin secretory demand suggestive of increased endoplasmic reticulum stress during exposure to hyperglycemia. Future studies should address whether dietary and/or pharmacological interventions to reduce pancreatic β-cell stress in PI-IDGT may delay progression to development of CFRD.

 

Nothing to Disclose: SCN, SS, DH, DDD, AJP, JNE, CK, DS, RCR, MRR, AK

OR11-5 32162 5.0000 A New Criteria for Indeterminate Glucose Tolerance in Pancreatic Insufficient Cystic Fibrosis Based on Defects in β-Cell Secretory Capacity 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 1:00:00 PM OR11 9442 11:30:00 AM Clinical Dilemmas and Outcomes in Diabetes Oral


Rasa Pelanis*1, Marianne Andersen2, Inger Sundström Poromaa3, Pernille Ravn2, Laure Morin-Papunen4, Terhi Piltonen4, Johanna Puurunen5, Angelica Lindén Hirschberg6, Juha Tapanainen7, Dorte Glintborg2 and Jan Mellembakken1
1Oslo University Hospital, Oslo, Norway, 2Odense University Hospital, Odense, Denmark, 3Uppsala University, Uppsala, Sweden, 4University of Oulu and Oulu University Hospital, Medical Research Center, PEDEGO Research Unit, Oulu, Finland, 5Oulu University Hospital, University of Oulu, Oulu, Finland, 6Karolinska Institute, Stockholm, Sweden, 7Helsinki University Hospital and University of Helsinki, Finland

 

Abstract: Insulin resistance in polycystic ovary syndrome (PCOS) is associated with an increased prevalence of type 2 diabetes (T2D) and prediabetes. Guidelines from the Endocrine Society recommend an oral glucose tolerance test (OGTT) upon diagnosis. Previous studies have shown that women with PCOS are more insulin resistant than controls, and that the risk of T2D and prediabetes are closely linked to obesity, certain ethnicities and older age.

Aim: To investigate the risk of T2D and prediabetes in lean women with PCOS, and whether to use age, ethnicity and androgen concentration as additional screening criteria.

Design:Cross-sectional study in 1068 premenopausal Scandinavian women with PCOS. All included women underwent a 2h OGTT measuring baseline fasting glucose and 2h glucose. T2D and prediabetes were diagnosed according to American Diabetes Association’s recommendations. 839 women were white-European (WE), 69 were Indian-Pakistani and 160 were of other ethnicities. None had previously been diagnosed with T2D, were pregnant, or had other serious endocrine diseases. Testosterone was measured using mass spectrometry.

Results: 0/356 (0%) lean women (BMI<25 kg/m2) with PCOS in our study had T2D, and 47/356 (13.2%) had prediabetes. In women with BMI 25-30 kg/m2, 4/271 (1.5 %) had T2D and 76/271 (27.8%) had prediabetes. In women with BMI >30 kg/m2, 28/438 (6.4%) had T2D and 148/438 (54.6%) had prediabetes.

BMI and waist to hip ratio (WHR) were significantly associated with the risk of T2D and prediabetes. Indian-Pakistani women had a 3.2 higher relative risk of T2D (p=0.006) and 1.7 higher relative risk of prediabetes (p=0.002) compared to WE women (mean BMI 28.8 kg/m2 for both ethnicities). Age and androgen concentration (measured by both total testosterone and free androgen index) were not associated with the prevalence of T2D although older age and lower testosterone were significantly associated with the prevalence of prediabetes.

Conclusion: No women with PCOS and BMI<25 kg/m2 had T2D. Our data suggest that OGTT is not necessary in normal-weight women with PCOS. The present data underline the need for prospective studies in well described study cohorts with PCOS.

 

Nothing to Disclose: RP, MA, IS, PR, LM, TP, JP, ALH, JT, DG, JM

OR11-6 32086 6.0000 A Is Oral Glucose Tolerance Test Necessary in Lean Women with Polycystic Ovary Syndrome? 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 1:00:00 PM OR11 9442 11:30:00 AM Clinical Dilemmas and Outcomes in Diabetes Oral


Lindsey Starr Trevino*, Cristian Coarfa, Jianrong Dong, Charles E Foulds, Morgan Gallo and Cheryl Lyn Walker
Baylor College of Medicine, Houston, TX

 

Early life exposure to endocrine-disrupting chemicals (EDCs) can lead to obesity and metabolic syndrome in adulthood. Although this is thought to occur via developmental reprogramming of the epigenome, the molecular mechanisms underlying this developmental reprogramming are not well defined. The liver plays a central role in whole body fat metabolism and obesity, and is a target for environmental exposures that contribute to development of non-alcoholic fatty liver disease (NAFLD). We observed that rats exposed postnatally to the EDC bisphenol A (BPA), when fed a high fat diet (HFD) as adults, had increased liver weight, increased serum triglycerides, increased serum LDL/VLDL, and increased serum free cholesterol. These data are consistent with the hypothesis that BPA had developmentally reprogramed the liver, making exposed rats prone to a NAFLD phenotype.

To test this hypothesis, we combined RNA-seq and ChIP-seq analyses in liver tissue from vehicle- and BPA-exposed animals. RNA-seq identified a unique cassette of genes that were induced in response to HFD only in the livers of BPA-reprogrammed rats. Of these reprogrammed genes, the top pathways identified by gene set enrichment analysis (GSEA) were involved in fatty acid and/or lipid metabolism and are known to play a role in NAFLD. We have previously shown that acute, neonatal exposure to EDCs can reprogram the epigenome of developing tissues by increasing the activity of mixed lineage leukemia (MLL), the histone methyltransferase in the COMPASS complex responsible for methylation of histone H3 at lysine 4 (H3K4), an active chromatin mark. To determine the underlying mechanism responsible for the observed change in response to HFD, we performed ChIP-seq for histone modifications associated with active (H3K4me3, H3K4me1, H3K27ac) and repressive (H3K27me3) histone marks. The epigenome of 178 reprogrammed genes exhibited new H3K4me1, H3K4me3 and/or H3K27ac marks at their promoters. Importantly, these novel, active chromatin marks 1) appeared in the neonatal liver in response to BPA; 2) persisted into adulthood; and 3) were not associated with any change in gene expression in the absence to HFD (i.e. their persistence was not a consequenceof altered gene expression). Therefore, the neonatal BPA exposure resulted in an altered epigenetic landscape that persisted into adulthood and preceded the increase in gene expression seen in the reprogrammed rats in response to HFD.

H3K4me1 and H3K27ac marks are generally associated with active enhancer regions, and their presence at promoters is indicative of so-called “super promoters”. Together, these data suggest that early life EDC exposure modulates the activity of the COMPASS complex to reprogram the developing epigenome and generate new “super promoters” that are responsive to later life stimuli, such as HFD, resulting in a liver phenotype that is prone to NAFLD and metabolic disease.

 

Nothing to Disclose: LST, CC, JD, CEF, MG, CLW

OR15-1 32206 1.0000 A Early Life Environmental Exposure Creates “Super-Promoters” By Developmentally Reprogramming the Epigenome of Genes Associated with NAFLD 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Endocrine Disruptors Saturday, April 1st 1:00:00 PM OR15 9446 11:30:00 AM Endocrine Disrupting Chemicals (Including Phytoestrogens and Xenoestrogens) Oral


Katie Marie Aleck*, Kelly Marie Hallman, Brigitte Dwyer, Victoria Lloyd, Monica Szmyd, Tyler Bedgood, Ann Fuelle and Sumi Dinda
Oakland University, Rochester, MI

 

Bisphenol-S (BPS), a substitute for bisphenol-A (BPA), has been suggested to be an endocrine disrupting compound interfering with normal hormonal activity. This bisphenol analogue is found in plastic substitutes, paper currency, and most products marked “BPA-free.” Despite hopes for a safer alternative, studies have shown BPS to exhibit similar estrogenic activity due to its structural commonalities with its analogue BPA. Generally, bisphenols have been shown to disrupt proper estrogen receptor alpha (ERα) functioning in breast cancer cells. Given that a mutated BRCA1 gene will likely develop into hereditary breast cancer in 55-65% of people, determining the estrogenic effects of BPS in both genes is essential. This study focused on the effects of BPS, alone and in combination with hormones and anti-hormones, to examine the expression of ERα and BRCA1 in T-47D and MCF-7 breast cancer cells via Western Blot analyses, cellular viability, and RT-qPCR analyses. Western blot analysis revealed alterations in the expression of ERα and BRCA1 protein levels after 24 hours of treatment with varying concentrations of BPS (4-20 µM). A concentration-dependent decrease of ERα protein levels was observed in both cell lines, with a 49% reduction occurring with 8 µM BPS as compared to control. BRCA1 levels portray continued expression through concentrations of 20 µM BPS, found similarly in both cell lines. To gain further insight into possible similarities between BPS and other known effectors of ERα, the optimal concentration of BPS (8 μM) was used in combination with hormones and anti-hormones. Down-regulation of ERα protein levels was observed after 24-hour co-treatment of T-47D and MCF-7 cells with 8µM BPS and 10 nM E2. BPS with ICI showed significant down-regulation as compared to BPS alone, and BPS with TAM portrayed no significant differences. A similar trend in the effects on BRCA1 expression was depicted in T-47D and MCF-7 cells. Image cytometric analysis with propidium iodide staining was utilized to quantify cell values and viability changes to further portray the effects of BPS on T-47D and MCF-7 cellular growth. Following a six-day treatment with 4 µM to 20 µM BPS, cellular proliferation showed a 12-60% increase in both cell lines. The proliferative effect of E2 and BPS in cells was reversed when treated in combination with anti-estrogens. Gene analysis showed a transcriptional expression of ESR1 mRNA levels that correlate with the translational data obtained via western blot analyses on BPS. This study may contribute to the understanding of the molecular effects in breast cancer cells exhibited by endocrine disrupting compounds, specifically BPS, on tumor suppressor proteins and steroid receptors.

 

Nothing to Disclose: KMA, KMH, BD, VL, MS, TB, AF, SD

OR15-2 32425 2.0000 A Regulation of Estrogen Receptor (ER) and BRCA1 By Bisphenol-S (BPS) in Breast Cancer Cells 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Endocrine Disruptors Saturday, April 1st 1:00:00 PM OR15 9446 11:30:00 AM Endocrine Disrupting Chemicals (Including Phytoestrogens and Xenoestrogens) Oral


Gabriela Cavati Sena*1, Eduardo Merlo2, Priscila Lang Podratz2, Julia F P Araújo2, Leandro C Freitas-Lima2, Poliane A A Brandão2, Maria TWD Carneiro2, Marcelo M Morales3, Ana Paula S S Oliveira3, Leandro Miranda Alves3, Ian Victor Silva2 and Jones B Graceli4
1Federal University of Espirito Santo, Vitória, BRAZIL, 2Federal University of Espirito Santo, Vitoria, Brazil, 3Federal University of Rio de Janeiro, 4Federal University of Espirito Santo, Vitoria, BRAZIL

 

Tributyltin chloride (TBT) is a xenobiotic used as a biocide in antifouling paints that has been demonstrated to induce endocrine-disrupting effects, such as obesity and reproductive abnormalities. An integrative metabolic control in the hypothalamus-pituitary-gonadal (HPG) axis was exerted by leptin. Obesity is associated with abnormal hypothalamic leptin action, affecting the reproductive function. Studies that have investigated the obesogenic TBT effects in the HPG axis are especially rare. We describe the reproductive and metabolic characterization as result of TBT exposure in female rats. To study whether obesity as result of TBT disrupted HPG function, we administered vehicle (CON, 0.4% ethanol) and TBT (TBT, 100 ng/kg/day) in the Wistar female rats for 15 days via gavage. TBT rats displayed a tin ovary accumulation (CON:3.97±0.58 vs TBT:48.70±9.72µg.kg−1; p≤0.05; n=5). TBT rats exhibited abnormal estrous cyclicity, showing fewer days in the proestrus phase (CON:0.95±0.04 vs TBT:0.50±0.05 d; p≤0.05, n=8-10) and predominately remained in a persistent metestrus-diestrus phase (CON:1.74±0.19 vs TBT:3.10±0.40 d; p≤0.05). TBT rats had lower surge serum LH levels (CON:19.84 ± 0.08 vs TBT:16.02 ± 0.09 mU/mL; p≤0.01; n=5-6). The GnRH mRNA was approximately 45% lower in the TBT hypothalamus (p≤0.01; n=4). Kisspeptin (Kiss) stimulation test was also performed. Interestingly, an approximately 25% decreased responsiveness to Kiss was identified in the TBT vs CON rats (CON: 2.39±0.06 vs CON-treated Kiss: 6.80 ± 0.11 mU/mL; TBT:1.51 ± 0.21 vs TBT-treated Kiss: 4.43±0.16 mU/mL; p≤0.001; n=5-6). Impaired fertility was noted with reduced number of pups/litter and corpora lutea in the female TBT rats (p≤0.05; n=6). TBT rats had higher testosterone (CON:0.20±0.01 vs TBT:0.35±0.03 ng/mL; p≤0.05; n=5-6) and lower estrogen levels (CON: 16.47±0.57 vs TBT:12.34±0.49 pg/mL; p≤0.01; n=5-6). Ovary and uterus atrophy, fibrosis and apoptosis was observed in TBT rats, as well the uterine inflammation (p≤0.05; n=4-8). The serum LH levels in the OVX control rats and OVX TBT rats were increased (p≤.001; n=5). There was an approximately 18% lower increase in the serum LH levels in the OVX TBT rats vs OVX CON rats (p≤0.05; n=5). Similarly, there was an approximately 50% lower increase in the GnRH mRNA levels in the OVX TBT rats (p≤0.01; n=4). An increased body weight gain was identified in the TBT rats (p≤0.01; n=10), as well as a hyperinsulinemia, hyperleptinemia and hypoadiponectinemia (p≥0.05; n=5). Increased values for the glucose tolerance test at 15 min (p ≤ 0.05; n=8) and the insulin sensitivity test at 30 min (p ≤ 0.05; n=8) were identified in the TBT rats. Thus, TBT disrupted proper functioning of the HPG axis as a result of obesity and abnormal leptin/kisspeptin signalling. This work supports the hypothesis that TBT impairs the normal metabolic control in the HPG axis.

 

Nothing to Disclose: GCS, EM, PLP, JFPA, LCF, PAAB, MTC, MMM, APSSO, LMA, IVS, JBG

OR15-3 31167 3.0000 A Environmental Obesogen Tributyltin Chloride Leads to Abnormal Hypothalamic-Pituitary-Gonadal Axis Function By Disruption in Leptin/Kisspeptin Signalling in Female Rats 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Endocrine Disruptors Saturday, April 1st 1:00:00 PM OR15 9446 11:30:00 AM Endocrine Disrupting Chemicals (Including Phytoestrogens and Xenoestrogens) Oral


Bassem M. Shoucri*1, Timothy J. Abreo1, Victor T. Hung1, Eric S. Martinez1, Toshi Shioda2 and Bruce Blumberg1
1University of California, Irvine, Irvine, CA, 2MGH Cancer Ctr, Charlestown, MA

 

Accumulating evidence links developmental exposure to endocrine disrupting chemicals (EDCs) to the obesity epidemic. These "obesogens" can promote adiposity by stimulating fat cell development, thus increasing total fat cell number, a strong predictor of obesity in adults. We previously showed that tributyltin (TBT) is such an obesogen, acting through the peroxisome proliferator-activated receptor γ (PPARγ) and the retinoid X receptor (RXR) to bias mesenchymal stem cells (MSCs) towards the formation of fat at the expense of bone (1, 2). Mice treated prenatally with environmentally-relevant levels of TBT display increased adipose depot weights, hepatic steatosis, and MSCs reprogrammed to favor the adipose lineage, effects that persist in the F1, F2, and F3 progeny of exposed F0 mothers (2, 3). Importantly, undifferentiated MSCs from these mice already have a pro-adipogenic gene expression profile, suggesting that TBT can act early in MSC fate specification.

Current in vitro approaches to studying EDCs mechanistically during adipogenesis are limited in that they combine chemical exposures with an adipogenic induction cocktail, creating difficulties in distinguishing obesogens that act early during MSC lineage commitment from those that might promote terminal differentiation. To overcome this limitation, we developed an in vitro assay to screen for obesogens that act during the commitment step whereby MSCs are pretreated with chemical ligands prior to being differentiated with a standard cocktail. Using this new approach, we found that TBT commits MSCs to the adipose lineage in a PPARγ-independent, RXR-dependent manner. Transcriptomic profiling of MSCs treated with TBT revealed genome-wide changes in gene expression that were replicated by an RXR agonist, but not a PPARγ agonist. Pathway analysis of altered transcripts indicated an enrichment of gene targets of the repressive histone modifier Enhancer of Zeste 2 (EZH2), which led us to explore how TBT acts through RXR to reshape the epigenome of unspecified MSCs. Taken together, our data show a critical and unreported role for RXR in early MSC specification. Furthermore, we have shown for the first time that TBT induces adipogenesis in two distinct phases: first during lineage commitment through RXR, and subsequently during differentiation through PPARγ and RXR.

 

Nothing to Disclose: BMS, TJA, VTH, ESM, TS, BB

OR15-4 30696 4.0000 A The Endocrine Disruptor Tributyltin Commits Mesenchymal Stem Cells to the Adipose Lineage Via the Retinoid X Receptor 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Endocrine Disruptors Saturday, April 1st 1:00:00 PM OR15 9446 11:30:00 AM Endocrine Disrupting Chemicals (Including Phytoestrogens and Xenoestrogens) Oral


Jing Liu*1, Xiaoqing Ye2, Feixue Li3 and Weiping Liu2
1Zhejiang University, China, 2Zhejiang University, 3Hangzhou Normal University, China

 

Exposure to endocrine-disrupting chemicals (EDCs) has been associated with shifting pubertal timing which increases the risk for diseases later in adult life (1). Pyrethroids, one of the most ubiquitous pesticides that account for greater than 30% of currently global insecticide usage, have been identified as EDCs (2). However, little data regarding pyrethroid exposure and puberty are available, and the mechanism(s) by which pyrethroids affect puberty remains poorly understood.

Here, we recognize pyrethroids as a new environmental contributor to the observed secular trend toward earlier male sexual maturity. For the first time to our knowledge, this work reveal a highly significant and positive association between pyrethroids exposure and gonadotropins levels in 463 Chinese boys (p<0.001), in which a 10% increase in 3-PBA (a common urinary metabolite of pyrethroids) is associated with an approximate 4% increase in LH and FSH. Boys with increased urinary levels of 3-PBA have a significantly increased risk of earlier pubertal onset, in which the odds of being in an advanced pubertal stage are increase by 73% to 110%.

Because it is difficult to test the direct causality of environmental risk factors in humans, this investigation further sought to identify the mechanism(s) by which the pyrethroids act to alter the onset of puberty using in vitro and in vivo experimental rodent models. Consistent with the human data, our animal study shows that postnatal exposure to a widely used pyrethroid pesticide, cypermethrin (CP), can accelerate pubertal timing and induce circulating levels of gonadotropins and testosterone in male mice. We demonstrate that the acceleration of puberty onset by CP is independent of hypothalamic responsiveness and that the induction of gonadotropins and testosterone results from the direct effects of CP on pituitary gonadotropes and testis. CP regulates gonadotropins synthesis and the expression of gonadotropin subunit genes through the Ca2+/PKC/ERK/IEGs transduction pathways in pituitary gonadotropes. CP induces testosterone synthesis and steroidogenesis-related gene expression in testicular Leydig cells via interference with voltage-gated calcium channels (VGCCs) pathway. Our findings reveal the activation of VGCCs in pituitary gonadotropes and testicular Leydig cells as a newly discovered mechanism of pyrethroid-induced early puberty onset in the male.

In conclusion, this is the first study to provide evidence that environmental exposure to pyrethroids at levels actually present in human is associated with measurable effects on male pubertal development. Given the growing use of pyrethroid insecticides, our findings have important implications for the assessment of children’s health risk from these insecticides. More broadly, this study significantly expands the understanding of the possible mechanisms involved in humans.

 

Nothing to Disclose: JL, XY, FL, WL

OR15-5 30272 5.0000 A Pyrethroids Exposure Accelerates Male Pubertal Development 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Endocrine Disruptors Saturday, April 1st 1:00:00 PM OR15 9446 11:30:00 AM Endocrine Disrupting Chemicals (Including Phytoestrogens and Xenoestrogens) Oral


Sheba M J MohanKumar*1, Coral K Hahn-Townsend1, Hannah A Garver2, Joseph E Henriquez2, Gregory D Fink2 and Puliyur S MohanKumar1
1University of Georgia, Athens, GA, 2Michigan State University, E. Lansing, MI

 

Pregnant women are frequently exposed to endocrine disrupting chemicals (EDCs) such as bisphenol A (BPA) and diethyl hexyl phthalate (DEHP) and these chemicals are known to cross the placental barrier and "program" the fetus for adult disorders such as hypertension. When programmed female offspring are exposed to estrogenic compounds in adulthood (as in oral contraceptives), we hypothesize that it will hasten the onset and exacerbate the increase in blood pressure. These effects are most likely mediated through oxidative-stress related pathways in the brain. To test this hypothesis, we used pregnant Sprague Dawley rats and dosed them orally with vehicle, 5 µg/kg BW of BPA, 7.5 mg/kg BW of DEHP or a combination of both (B+D) from day 6-21 of gestation. Female offspring were allowed to reach 3 months of age and were implanted with a radio telemeter and also received an estradiol pellet capable of releasing 20 ng of estradiol 17ß (E2) per day for 90 days. Blood pressure changes were monitored for 90 days and the animals were sacrificed. The brain stem was sectioned and the rostral ventrolateral medulla (RVLM) was microdissected and analyzed for superoxide dismutase (SOD) activity. Treatment with E2 in adulthood increased average diastolic blood pressure (DBP) and mean arterial pressure (MAP). Prenatal exposure to EDCs in combination with E2 exposure in adulthood increased average systolic (SBP), DBP and MAP. Prenatal exposure to the combination of BPA and DEHP produced the most marked increase in blood pressure profiles. Analysis of the RVLM revealed that SOD activity decreased significantly with adult E2 exposures. Moreover, prenatal exposure to EDCs followed by adult exposure to E2 produced even further reductions in SOD activity. Since SOD is involved in scavenging free radicals, a reduction in SOD activity would indicate an increase in oxidative stress. These data suggest that prenatal EDC exposure could possibly increase the risk for development of hypertension most probably through oxidative stress related mechanisms in the brain.

 

Nothing to Disclose: SMJM, CKH, HAG, JEH, GDF, PSM

OR15-6 32737 6.0000 A Prenatal Exposure to Endocrine Disruptors Followed By Adult Exposure to Estradiol-17 Beta Increases Blood Pressure in Female Rats 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Endocrine Disruptors Saturday, April 1st 1:00:00 PM OR15 9446 11:30:00 AM Endocrine Disrupting Chemicals (Including Phytoestrogens and Xenoestrogens) Oral


Gudmundur Johannsson*1, Ulla Feldt-Rasmussen2, Ida Holme Håkonsson3, Henrik Biering4, Patrice Rodien5, Shigeyuki Tahara6, Andrew Toogood7 and Michael Højby Rasmussen8
1Institute of Medicine at Sahlgrenska Academy, University of Gothenburg and The Department of Endocrinology-Diabetes-Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden, 2Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, 3Novo Nordisk A/S, Søborg, DENMARK, 4MediCover Berlin-Mitte MVZ, Berlin, Germany, 5CHU Angers - Centre Hospitalier Universitaire, Angers, France, 6Nippon Medical School, Tokyo, Japan, 7Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom, 8Novo Nordisk A/S, Søborg, Denmark

 

Background: Daily subcutaneous injections of GH may be inconvenient for many patients with AGHD, leading to noncompliance, reduced efficacy and increased healthcare costs. Short-term trials have shown that somapacitan (Novo Nordisk A/S, Denmark), a once-weekly GH derivative, is well tolerated in healthy adults and in patients with AGHD. Somapacitan is a peptide produced by DNA recombinant technology, with more than 99% homology to human GH. The treatment satisfaction, tolerability and safety of once-weekly somapacitan administered in a prefilled pen device vs. once-daily GH (Norditropin® FlexPro®, Novo Nordisk A/S) were investigated in patients with AGHD in a multinational, multicenter, randomized (2:1), open-label, active-controlled trial (NCT02382939; REAL 2).

Methods: Ninety-two patients (diagnosed with AGHD, male/female, 18–79 years, previously treated with GH for ≥6 months) were randomized to once-weekly somapacitan (n=61) or once-daily Norditropin® FlexPro® (n=31). Somapacitan and Norditropin® FlexPro® doses were titrated for the first 8 weeks based on serum insulin-like growth factor-I (IGF-I) to achieve serum IGF-I standard deviation scores (SDS; within the normal range [preferably 0–2 SDS]). Doses were fixed for the remaining 18 weeks. Convenience, effectiveness and global treatment satisfaction were assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9), with an increase in scores signifying an increase in treatment satisfaction. A mixed model for repeated measurements was used to estimate treatment differences in TSQM-9 scores.

Results: Serum IGF-I levels were maintained in both treatment arms after dose titration. Mean (SD) serum IGF-I SDS scores at week 25 were 0.22 (0.89) and 0.35 (0.82) for somapacitan and Norditropin® FlexPro®, respectively. No safety issues were identified with somapacitan; the pattern and rate of adverse events (AEs) and serious AEs were similar with the two treatments. More than 1500 somapacitan injections were administered; two mild, transient injection-site reactions were observed. No anti-somapacitan or anti-GH antibodies were detected. Mean (SD) convenience score increased from 68.3 (18.3) to 83.8 (12.9) with somapacitan, and from 71.7 (17.5) at baseline to 75.8 (19.1) at end of treatment with Norditropin® FlexPro®; estimated between-treatment difference in change from baseline to end of treatment (somapacitan–Norditropin® FlexPro®) was 8.22 (95% CI: 1.51; 14.93, P=0.0171), with somapacitan being more convenient than Norditropin® FlexPro®. Effectiveness and global satisfaction scores were not statistically significantly different between treatment arms.

Conclusions: As a once-weekly GH treatment for AGHD, somapacitan was well tolerated with no detected safety issues and may be more convenient for patients than once-daily treatment.

 

Disclosure: GJ: Consultant, Viropharma, Speaker, Novo Nordisk, Speaker, Merck Serono, Speaker, Pfizer, Inc., Speaker, Ipsen, Consultant, Astra Zeneca, Consultant, Shire, Speaker, Novartis Pharmaceuticals, Speaker, Otsuka. UF: Consultant, Pfizer, Inc., Consultant, Novo Nordisk. IHH: Employee, Novo Nordisk. PR: Speaker, Merck Serono, Speaker, HRA Pharma. AT: Speaker, Pfizer, Inc., Principal Investigator, Novo Nordisk. MHR: Employee, Novo Nordisk. Nothing to Disclose: HB, ST

OR22-1 29358 1.0000 A Convenience of the Once-Weekly Growth Hormone (GH) Derivative Somapacitan in Adult GH Deficiency (AGHD): Results from a 26-Week Randomized, Controlled, Phase 3 Trial 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Neuroendocrinology and Pituitary Saturday, April 1st 1:00:00 PM OR22 9453 11:30:00 AM Emerging Treatments for Pituitary, Adrenal, and Neuroendocrine Disorders Oral


Beverly M.K. Biller*1, Daniela Rogoff2, Trish Rice3, Shelby A Young2, R. William Charlton2, Bert Bakker2, Maria Koltowska-Häggström2, Eric Humphriss2, Timothy S Bailey4, Kimvir Singh Dhillon5, Ken Ho6, Laurence Katznelson7, Kylie McLachlan8, Shlomo Melmed9, Samer Nakhle10, Duncan J Topliss11, Whitney W. Woodmansee12, Kevin C.J. Yuen13, Martin Bidlingmaier14 and Christian J Strasburger15
1Massachusetts General Hospital, Boston, MA, 2Versartis, Inc., Menlo Park, CA, 3Premier Research, Naperville, IL, 4AMCR Institute Inc., Escondido, CA, 5Therapeutic Research Institute of Orange County, Laguna Hills, CA, 6Princess Alexandra Hospital/ University of Queensland, Brisbane, Australia, 7Stanford University School of Medicine, Stanford, CA, 8St. Vincent's Hospital, Melbourne, Australia, 9Cedars-Sinai Medical Center, Los Angeles, CA, 10Palm Research Center, Las Vegas, NV, 11Alfred Hospital, Melbourne, Australia, 12Mayo Clinic, Jacksonville, FL, 13Swedish Neuroscience Institute, Seattle, WA, 14Klinikum der Universität München, München, Germany, 15Charité-Universitätsmedizin, Berlin, Germany

 

Daily rhGH injections for AGHD represent a treatment burden associated with noncompliance and loss of treatment effect in 65% of adult patients (1). Some AGHD patients opt not to initiate therapy due to the onus of daily injections, thereby missing the opportunity to mitigate consequences associated with GHD. Somavaratan is a novel long-acting rhGH under development for treatment of GHD in adults and children. A Phase 1 PK/PD study of somavaratan in AGHD demonstrated an extended elimination t1/2, as well as durable IGF-I response after a single dose (2). Here we present preliminary data from VITAL, an open-label, international, multicenter, Phase 2 study evaluating safety, starting dose, and dose titration for monthly somavaratan administration in AGHD. Eligible subjects were adults aged 24–70 years, with documented GHD. Subjects were stratified into 3 cohorts with different starting doses based on expected requirements for rhGH: Cohort A) 0.6 mg/kg/month for subjects ≥ 35 years of age; Cohort B) 0.8 mg/kg/month for subjects < 35 years of age; and Cohort C) 1.0 mg/kg/month for female subjects on oral estrogen, regardless of age. Subjects received 5 monthly SC doses of somavaratan, with 4 dose adjustments permitted until 2 consecutive means of pre-dose and Day 8 IGF-I SDS values were within the target range of 0 to 1.5. Results are presented as mean ± SD. Of 36 subjects enrolled in the study (18 female and 18 male; mean age, 46.1 ± 13.1 years), 33 completed all 5 doses. Somavaratan was well tolerated; most adverse events (AEs) were mild or moderate in severity, and no severe AEs were deemed related to somavaratan. The most common related AEs were injection site reactions (19.4%) and headache (11.1%). Mean IGF-I SDS increased from -1.32 ± 1.73 at baseline to 2.31 ± 2.54 at 7 days after the first dose in the study (Day 8 IGF-I SDS: 3.45 ± 1.85, 1.37 ± 3.01, -0.10 ± 1.99 for Cohorts A, B, and C, respectively). Although all subjects within a cohort received the same weight-based starting dose (mg/kg), subjects who received higher total doses (mg) tended to have higher IGF-I responses (r2 = 0.43, 0.71, and 0.12 for Cohorts A, B, and C, respectively). Following the last study dose, IGF-I SDS returned to pre-dose values by Day 22 (P = 0.18, 0.13, and 0.39 for Cohorts A, B, and C). In conclusion, somavaratan was well tolerated and induced a robust IGF-I response in AGHD, with sustained effect for at least 2 weeks. More frequent, twice-monthly administration of a lower, non-weight-based starting dose may allow for optimal individual patient titration, while providing adequate drug exposure throughout the dosing interval. Starting somavaratan dose and administration frequency are being investigated further in the extension study (NCT02719990) and will be used in a new Phase 3 study.

 

Disclosure: BMKB: Principal Investigator, Novo Nordisk, Ad Hoc Consultant, Novo Nordisk, Ad Hoc Consultant, Pfizer, Inc., Principal Investigator, Opko, Principal Investigator, Versartis, Inc., Ad Hoc Consultant, Versartis, Inc.. DR: Employee, Versartis, Inc., Employee, Versartis, Inc.. TR: Employee of CRO, Versartis, Inc.. SAY: Employee, Versartis, Inc., Employee, Versartis, Inc.. RWC: Employee, Versartis, Inc., Employee, Versartis, Inc.. BB: Employee, Versartis, Inc., Employee, Versartis, Inc.. MK: Consultant, Versartis, Inc.. EH: Employee, Versartis, Inc., Employee, Versartis, Inc.. TSB: Investigator, Dexcom, Investigator, Elcelyx, Investigator, Glysens, Investigator, Insulet, Investigator, Jansen Pharmaceuticals, Investigator, Lexicon Pharmaceuticals, Inc., Investigator, Lifescan, Investigator, Eli Lilly & Company, Investigator, Medtronic Minimed, Investigator, Merck & Co., Investigator, Novo Nordisk, Investigator, Sanofi, Investigator, Senseonics, Investigator, Versartis, Investigator, Yofimeter, Ad Hoc Consultant, Ascensia, Ad Hoc Consultant, Astra Zeneca, Ad Hoc Consultant, BD, Ad Hoc Consultant, Calibra, Ad Hoc Consultant, Eli Lilly & Company, Ad Hoc Consultant, Medtronic Minimed, Ad Hoc Consultant, Novo Nordisk, Ad Hoc Consultant, Sanofi, Speaker, Abbott Laboratories, Speaker, Insulet, Speaker, Medtronic Minimed, Speaker, Novo Nordisk, Speaker, Sanofi, Investigator, Companion Medical, Investigator, Boehringer Ingelheim, Investigator, BD, Investigator, Ascensia, Investigator, ACON, Investigator, Abbott Laboratories. KH: Medical Advisory Board Member, Pfizer, Inc., Medical Advisory Board Member, Versartis, Inc, Speaker Bureau Member, Ipsen, Speaker Bureau Member, Novartis Pharmaceuticals, Speaker Bureau Member, Pfizer, Inc., Investigator, Novo Nordisk, Investigator, Versartis, Inc.. LK: Medical Advisory Board Member, Pfizer, Inc., Medical Advisory Board Member, Versartis, Inc., Investigator, Versartis, Inc.. KM: Investigator, Novo Nordisk, Investigator, Pfizer, Inc.. SM: Ad Hoc Consultant, Novartis Pharmaceuticals, Planning Group Member, Ipsen, Principal Investigator, Pfizer, Inc., Advisory Group Member, chiasma, Ad Hoc Consultant, ionis. SN: Investigator, Novo Nordisk, Investigator, Versartis, Inc.. DJT: Medical Advisory Board Member, Eisai, Medical Advisory Board Member, Genzyme Corporation, Educational Seminar, Eli Lilly & Company, Principal Investigator, Eisai, Principal Investigator, Janssen-Cilag, Principal Investigator, Novo Nordisk, Principal Investigator, Versartis, Inc.. WWW: Investigator, Novo Nordisk, Investigator, Versartis, Inc., Medical Advisory Board Member, Ipsen, Medical Advisory Board Member, Chiasma, Medical Advisory Board Member, Versartis, Inc.. KCJY: Investigator, Pfizer, Inc., Investigator, Opko, Investigator, Novo Nordisk, Investigator, Versartis, Medical Advisory Board Member, Pfizer, Inc., Medical Advisory Board Member, Novo Nordisk, Medical Advisory Board Member, Sandoz, Medical Advisory Board Member, Versartis, Inc.. MB: Investigator, Pfizer, Inc., Investigator, OPKO, Investigator, Genexine, Investigator, IDS, Speaker, Pfizer, Inc., Speaker, Sandoz, Speaker, Diasorin, Ad Hoc Consultant, Versartis, Inc., Ad Hoc Consultant, OPKO, Ad Hoc Consultant, Sandoz, Ad Hoc Consultant, Genexine. CJS: Medical Advisory Board Member, Versartis, Inc., Investigator, Versartis, Inc.. Nothing to Disclose: KSD

OR22-2 31263 2.0000 A Somavaratan, a Long-Acting Recombinant Human Growth Hormone (rhGH), for the Treatment of Adults with Growth Hormone Deficiency (AGHD): Results of VITAL, an Open-Label, Dose-Finding, International, Phase 2 Study (NCT02526420) 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Neuroendocrinology and Pituitary Saturday, April 1st 1:00:00 PM OR22 9453 11:30:00 AM Emerging Treatments for Pituitary, Adrenal, and Neuroendocrine Disorders Oral


Helene Lasolle1, Christine Cortet2, Frederic Castinetti3, Lucie Cloix4, Philippe Caron5, Rachel Desailloud6, Brigitte Delemer7, Cristel Jublanc8, Jean-Louis Sadoul9, Nathalie Bourcigaux10, Olivier Chabre11, Philippe Chanson12, Cyril Garcia13, Magalie Haissaguerre14, Yves Reznik15, Franck Schillo16, Guillaume Assie17 and Gérald Raverot*18
1hospices Cicils de Lyon, lyon, France, 2Lille University Hospital, Lille cedex, France, 3La Conception Hospital, Marseille, France, 4Hôpital Bretonneau, CHRU de Tours, Tours, France, 5CHU Larrey, Toulouse, France, 6CHRU Amien, Amiens, France, 7CHU Reims, Reims, France, 8AP-HP, 9CHU Nice, Nice Cedex, France, 10AP-HP, Paris, 11Grenoble University Hospital, Grenoble, France, 12Assistance publique Hôpitaux de Paris- Hôpital Bicêtre-Université Paris-Sud Paris, France, 13Hopital Instruction des Armées, Saint Mande, FRANCE, 14University Bordeaux 2/Hopital Haut Leveque, Pessac, France, 15Caen University Hospital, Caen, France, 16CHU Besancon, Besancon, France, 17Assistance Publique Hôpitaux de Paris, Paris, France, 18Hospices Civils de Lyon, Lyon Cedex 03, France

 

Objectives: Some case-reports and limited retrospective studies have reported the successful use of temozolomide (TMZ) in pituitary tumors (PT), with an efficacy rate of around 50% depending on studied criteria. However, the long term survival of patients treated with TMZ has rarely been evaluated. We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival.

Design: Multicenter retrospective study by members of the French Society of Endocrinology.

Methods: Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (n=23) or lactotroph (n=13), and 14 were carcinomas. Clinical/pathological characteristics of PT as well as data from treatment evaluation and at the last follow-up were recorded. A partial response was considered if the maximal tumor diameter had decreased by more than 30% and/or the hormonal rate by more than 50% at the end of treatment.

Results: The median treatment duration was 6.5 cycles (range 2-24), using a standard regimen for most and combined radiotherapy for six. Twenty-three patients (53.5%) were considered as responders. Silent tumor at diagnosis, though not MGMT expression, was associated with a poor response at multivariate analysis. The median follow-up after the end of treatment was 16 months [0-72] at which time 18 patients had deceased, 13 of whom were non-responders. Overall survival was significantly higher among responders (p=0.002) however ten patients relapsed 5 months (ranges 0-57) after the end of TMZ treatment, five in whom TMZ was reinitiated but without success.

Discussion: Patients in our series showed a 53.5% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.

 

Nothing to Disclose: HL, CC, FC, LC, PC, RD, BD, CJ, JLS, NB, OC, PC, CG, MH, YR, FS, GA, GR

OR22-3 30570 3.0000 A Temozolomide Treatment Can Improve Overall Survival in Aggressive Pituitary Tumors and Pituitary Carcinomas 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Neuroendocrinology and Pituitary Saturday, April 1st 1:00:00 PM OR22 9453 11:30:00 AM Emerging Treatments for Pituitary, Adrenal, and Neuroendocrine Disorders Oral


Brent S. Abel*, Caroline Sedmak, Mary F. Walter, Phillip Gorden, Ranganath Muniyappa and Rebecca J. Brown
NIDDK, NIH

 

Women with lipodystrophy suffer from infertility associated with hypogonadotrophic hypogonadism and hyperandrogenism (1). Treatment of lipodystrophy patients for two weeks with recombinant human leptin (metreleptin) increases nocturnal LH secretion (2). However, the long-term effects of metreleptin treatment on LH secretion in lipodystrophy patients remain unknown. Eight lipodystrophy patients (6 female, 2 generalized, 6 partial) undergoing initiation of metreleptin treatment were enrolled in a clinical trial that included assessment of LH nocturnal secretory dynamics at baseline (PRE) and 6 months (POST) after initiation. The dose of metreleptin was titrated to 9.5 ± 1.4 mg per day (mean ± SD) during the first six months to balance metabolic improvement against excessive weight loss. LH nocturnal secretory dynamics were assessed by 10 minute sampling from 23:00 to 07:00 and analyzed by multiparameter deconvolution. FSH, estradiol (E2), total testosterone (T), and sex hormone binding globulin (SHBG) were measured from samples collected at the end of each sampling. Data from baseline and 6 months were compared by paired t-test or Wilcoxon signed rank test based on normality. Neither mean (PRE: 3.3 ± 1.0 U/L, POST: 3.66 ± 1.8, p=0.63) nor integrated nocturnal LH concentrations (PRE: 1616 ± 495 U·L-1·min-1, POST: 1795 ± 889, p=0.585) were significantly different after treatment. LH burst frequency (PRE: 0.61 ± 0.26 hr-1, POST: 0.50 ± 0.31, p=0.56) and secretory burst mass (PRE: 7.6 ± 13.9 U/L, POST: 6.5 ± 4.8, p=0.30) were also similar. Consequently, neither basal secretion of LH (PRE: 18 ± 24 U·L-1·8hr-1, POST: 19 ± 7, p=0.47) nor pulsatile production rate (PRE: 34 ± 56 U·L-1·8hr-1, POST: 40 ± 19, p=0.47) changed after treatment. FSH levels were also similar (PRE: 4.4 ± 4.9 U/L, POST: 5.3 ± 4.7, p=0.16). In females, E2 (PRE: 40 ± 32 pg/mL, POST: 49 ± 33, p=0.73), T (PRE: 33 ± 19 ng/dL, POST: 34 ± 17, p=0.92), and SHBG (PRE: 12 ± 6 nmol/L, POST: 19 ± 12, p=0.09) levels did not change. These findings suggest that the stimulatory effect of leptin on the hypothalamic-pituitary-gonadal (HPG) axis is acute and does not persist long-term. Possible explanations for the differences between our observations and those changes measured after 2 weeks of metreleptin treatment include a smaller sample size, preponderance of partial lipodystrophy patients, and fewer controlled variables.

 

Nothing to Disclose: BSA, CS, MFW, PG, RM, RJB

OR22-4 32690 4.0000 A Long-Term Effects of Recombinant Human Leptin (Metreleptin) on Nocturnal LH Secretion in Lipodystrophy Patients 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Neuroendocrinology and Pituitary Saturday, April 1st 1:00:00 PM OR22 9453 11:30:00 AM Emerging Treatments for Pituitary, Adrenal, and Neuroendocrine Disorders Oral


Rosario Pivonello*1, Betul Hatipoglu2, Mark E Molitch3, Xavier Bertagna4, Nathalie Barbier5, Nicholas Sauter6, Beverly M.K. Biller7 and Jacques Young8
1Università Federico II di Napoli, Naples, Italy, 2Cleveland Clinic, Cleveland, OH, 3Northwestern University, Chicago, IL, 4Hôpital Cochin, Paris, France, 5Novartis Pharma AG, Basel, Switzerland, 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, 7Massachusetts General Hospital, Boston, MA, 8Assistance Publique Hôpitaux de Paris, Paris, France

 

Background: Osilodrostat (LCI699) is a potent oral 11β-hydroxylase inhibitor. In the 22-week (wk) LINC-2 study, osilodrostat normalized urinary free cortisol (UFC) levels in 78.9% (15/19) of patients (pts) with Cushing’s disease (CD). Sixteen pts entered an extension to LINC-2, with 68.8% (11/16) achieving normalized UFC at month (mo) 19. The most common AEs during the 22-wk study were nausea, diarrhea, asthenia, and adrenal insufficiency (n=6 each). This work reports 31-mo efficacy and safety results from the extension.

Methods: Pts receiving clinical benefit at wk 22 could enter the extension and continue on the same dose of osilodrostat. Dose adjustments were permitted during the extension. Response rate (RR; defined as the proportion of pts with UFC≤ULN [controlled; C] or UFC>ULN but ≥50% decrease from baseline [BL] [partially controlled; PC]) was assessed with last observation carried forward (LOCF; imputation of missing values using the last available measurements) and observed measurements at 31 mo. Safety was assessed from core BL until the last pt reached mo 31 (maximum follow-up = 40.3 mo).

Results: Of the 16 pts (11 females) who entered the extension, 12 remained on treatment at mo 31. The overall RR (LOCF) for pts who entered the extension was 93.8% (C, 93.8% [15/16]) at wk 22 and 100% (C, 87.5% [14/16]; PC, 12.5% [2/16]) at mo 31. RR was lower at mo 31 when missing values were not imputed: 56.3% (C, 50.0% [8/16]; PC, 6.3% [1/16]). No pts had escape from response (UFC>ULN at ≥2 consecutive visits on maximum tolerated dose after initial UFC normalization) during the extension. Mean (SD) changes in clinical signs of CD from BL to mo 31 (n=11) were: SBP, –3.4 (18.5) mmHg; DBP, –5.4 (9.9) mmHg; weight, –4.5 (5.7) kg; and BMI, –1.8 (2.3) kg/m2. The most common clinical AEs were diarrhea (n=6), headache, asthenia, and nausea (n=5 each). Six pts reported hypocortisolism-related AEs. Three pts discontinued from the extension; 1 other patient did not wish to participate. Mean (SD) plasma ACTH increased from 20.0 (10.4) pmol/L (normal 1.8–9.2; n=15) at BL to 80.5 (145.5) pmol/L (n=15) at wk 22 and 54.0 (35.1) pmol/L (n=10) at mo 31. Mean (SD) 11-deoxycortisol and 11-deoxycorticosterone increased from 4.5 (5.3) nmol/L (normal 0–3.92; n=15) and 0.3 (0.3) nmol/L (normal 0.1–0.4; n=13), respectively, at BL to 44.7 (39.5) nmol/L (n=15) and 4.8 (6.6) nmol/L (n=13) at wk 22, and 24.5 (18.8) nmol/L (n=9) and 2.0 (1.5) nmol/L (n=6) at mo 31. Mean (SD) aldosterone decreased from 168.1 (255.4) pmol/L (normal 55–250; n=15) at BL to 44.5 (72.0) pmol/L (n=15) at wk 22 and 19.0 (35.4) pmol/L (n=8) at mo 31.

Conclusion: Osilodrostat maintained normal UFC levels for >2.5 years in a majority of pts with CD, with a long-term safety profile similar to that after 22 wks; no new safety signals emerged. Osilodrostat is being evaluated in two ongoing Phase III studies in pts with CD.

 

Disclosure: RP: Principal Investigator, Novartis Pharmaceuticals, Coinvestigator, Novartis Pharmaceuticals, Clinical Researcher, Shire, Consultant, Shire, Speaker, Novartis Pharmaceuticals, Speaker, Novartis Pharmaceuticals, Speaker, Shire, Principal Investigator, Ipsen, Principal Investigator, Pfizer, Inc.. BH: Consultant, Merck & Co., Speaker, Merck & Co., Consultant, Novo Nordisk, Speaker, Novo Nordisk. MEM: Investigator, Novartis Pharmaceuticals, Investigator, Chiasma, Investigator, Ipsen, Investigator, Novo Nordisk, Investigator, Bayer, Inc., Consultant, Novartis Pharmaceuticals, Consultant, Chiasma, Consultant, Novo Nordisk, Consultant, Pfizer, Inc., Consultant, Merck Janssen. XB: Advisory Group Member, Novartis Pharmaceuticals. NB: Employee, Novartis Pharmaceuticals. NS: Employee, Novartis Pharmaceuticals. BMKB: Principal Investigator, Novartis Pharmaceuticals, Principal Investigator, Cortendo, Ad Hoc Consultant, Cortendo, Ad Hoc Consultant, Ipsen, Ad Hoc Consultant, Novartis Pharmaceuticals. JY: Investigator, Novartis Pharmaceuticals, Investigator, Jansen Pharmaceuticals, Investigator, HRA Pharma.

OR22-5 32394 5.0000 A Osilodrostat Can Provide Control of Urinary Free Cortisol for over 2.5 Years in Patients with Cushing's Disease: Results from an Extension to the Linc-2 Study 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Neuroendocrinology and Pituitary Saturday, April 1st 1:00:00 PM OR22 9453 11:30:00 AM Emerging Treatments for Pituitary, Adrenal, and Neuroendocrine Disorders Oral


Kwadwo Antwi1, Melpomeni Fani1, Tobias Heye1, Guillaume P Nicolas2, Elmar Merkle3, Jean Claude Reubi4, Beat Gloor5, Damian Wild1 and Emanuel R Christ*6
1University Hospital of Basel, Basel, Switzerland, 2UniversityHospital of Basel, Basel, Switzerland, 3University of Basel Hospital, Basel, Switzerland, 4University of Bern, Bern, Switzerland, 5University Hospital of Bern, Inselspital, Bern, Switzerland, 6University Hospital of Berne, Berne, Switzerland

 

Purpose:

The aim of our study is to compare the detection rate of GLP-1R PET/CT, GLP-1R SPECT/CT and standardized contrast enhanced 3T MRI in patients with a biochemically proven endogenous hyperinsulinemic hypoglycemia highly suspicious for an insulinoma. Preliminary results of an ongoing study are reported. 

Methods:

40 patients (31 females, 9 males, age range 18-80 years, mean 48 years) with neuroglycopenic symptoms due to endogenous hyperinsulinemic hypoglycemia were enrolled (ClinicalTrials.gov, NCT02127541). A standardized contrast enhanced 3T MRI was performed. Afterwards the patients received a SPECT/CT at 4 and 72 hours after injection of 111In-DOTA-exendin-4 and a PET/CT 2,5 hours after injection of 68Ga-DOTA-exendin-4 in a randomized order. Three independent blinded nuclear medicine physicians and three independent blinded radiologists reviewed the scans. Standard of comparison was the histological diagnosis after surgery. 

Results:

Previously performed cross-sectional imaging (CT/MRI) was negative or not conclusive in 27/40 (68%) of patients.

29 patients have been operated. In this collective, the histological diagnosis of a benign insulinoma was confirmed in 25 patients, 1 patient had adult islet cell hyperplasia. In 1 patient both intraoperative palpation as well as the histological diagnosis did not confirm an insulinoma. In 2 patient symptoms of endogenous hypoglycemia ceased postoperative but histological diagnosis did not confirm the diagnosis of a benign insulinoma or nesidioblastosis. Only these two patients were excluded from evaluation as the final diagnosis remained unclear.
Two patients refused surgery. Three patients are awaiting surgery. In five patients PET/CT, SPECT/CT as well as the previous performed conventional imaging did not find any suspicious lesion and were thus not operated up to date. One patient showed signs of malignancy in contrast enhanced MRI, thus did not meet the inclusion criteria and did not receive surgery up to date.
In this interim analysis of 27 operated patients PET/CT patients showed an overall pooled sensitivity of 92%, SPECT/CT at 72 hours an overall pooled sensitivity of 71% and contrast enhanced standardized 3T MRI an overall pooled sensitivity of 76%.  

Conclusion:

1) These preliminary data suggest that PET/CT performs better as standardized MRI imaging and SPECT/CT at lower irradiation dose and much shorter investigation time than the latter.

2) GLP-1R PET/CT will be a useful diagnostic tool in patients in which an insulinoma is suspected.

 

Nothing to Disclose: KA, MF, TH, GPN, EM, JCR, BG, DW, ERC

OR22-6 31688 6.0000 A Localization of Benign Insulinomas Using Glucagon-like Peptide-1 Receptor (GLP1-R) SPECT/CT and PET/CT and MRI in a Prospective Clinical Study 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Neuroendocrinology and Pituitary Saturday, April 1st 1:00:00 PM OR22 9453 11:30:00 AM Emerging Treatments for Pituitary, Adrenal, and Neuroendocrine Disorders Oral


Aleisha M Moore*1, Kathryn A Moore1, Robert L. Goodman2, Lique M Coolen3 and Michael N Lehman3
1University of Mississippi Medical Centre, Jackson, MS, 2West Virginia University School of Medicine, Morgantown, WV, 3University of Mississippi Medical Center, Jackson, MS

 

Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons of the arcuate nucleus play a key role in the hypothalamic regulation of fertility. The ability to study changes in the expression and connections of KNDy neurons across reproductive states is essential for understanding the function of the population. Recently developed protocols for optical tissue clearing has permitted three-dimensional (3D) imaging of complete neuronal populations. 3D imaging has the potential to reveal novel features of cell populations, however, these techniques have largely been reported in the mouse brain. We aimed to adapt the 3Disco (Ertürk et al. , Nature Protoc., 2012) and iDisco (Renier et al., Cell, 2014) protocols for imaging of intact neuronal networks in larger mammalian species. Here, we report preliminary data for 3D imaging of the complete arcuate kisspeptin population in the ewe. Hypothalamic blocks (1.5cm x 1.5cm x 1cm) were prepared from perfusion fixed brains (4% paraformaldehyde) of ovariectomized adult Suffolk ewes (n=3) and immunolabelled with rabbit anti-kisspeptin (1:250, kindly gifted by A. Caraty) and Alexa Fluor 647 (1:100, Life Technologies) antibodies. Dehydration of the tissue using tetrahydrofuran was optimized from the original iDisco protocol and brains were rendered transparent by incubation in dichloromethane and dibenzyl ether. Cleared brains were imaged using a bidirectional light-sheet microscope (LaVison BioTec) with a 2X/0.5NA objective. Stacks of images were collected using InspectorPro software at 6.3x zoom with a 4μm optical interval. Mosaic stacks of images were stitched together using Fiji software and projected with IMARIS software to provide 3D visualization of the complete population of arcuate kisspeptin cell bodies and their projections throughout the hypothalamus and preoptic area. Using this approach, kisspeptin cells were observed as a continuum throughout the entire rostral-caudal extent of the arcuate nucleus. Large populations of kisspeptin neurons were observed in caudal arcuate nucleus, which may have been underestimated using traditional approaches. In conclusion, this study expands the use of optical tissue clearing in multiple mammalian models, providing versatile analysis and comparison of the KNDy neuronal network across species. Future studies will expand the immunolabelling technique to include co-expressed peptides and markers of cell activation to study changes in the KNDy neuronal network across reproductive states and in disease.

 

Nothing to Disclose: AMM, KAM, RLG, LMC, MNL

OR23-1 32652 1.0000 A Visualization of the Complete Arcuate Kisspeptin Neuronal Population in the Ovine Hypothalamus Using Optical Tissue Clearing 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Neuroendocrinology and Pituitary Saturday, April 1st 1:00:00 PM OR23 9454 11:30:00 AM Neuroendocrine Control of Reproduction Oral


Roberta Araujo-Lopes1, Siew H Yip2, Juneo F Silva1, Raquel GL Bernardes1, Fernanda LM Bello1, Patricia C Henriques1, Laisa TM Hipolito1, Maristela O Poletini1, Celso R Franci3, David R Grattan2 and Raphael E Szawka*1
1Universidade Federal de Minas Gerais, Brazil, 2University of Otago, New Zealand, 3Universidade de Sao Paulo, Brazil

 

Kisspeptin, neurokinin and dynorphin (KNDy) neurons in the arcuate nucleus (ARC) are implicated in luteinizing hormone (LH) pulsatility. Previous evidence has also shown that KNDy neurons have extensive projections onto tuberoinfundibular dopaminergic (TIDA) neurons that are involved in prolactin (PRL) secretion. In rodents, estradiol (E2) induces concurrent preovulatory surges of LH and PRL. We aimed to test the hypothesis that KNDy neurons are major player in regulating this release of PRL. The activity of KNDy neurons was evaluated using double-label immunohistochemistry to c-Fos and kisspeptin in the ARC. The number of kisspeptin-immunoreactive (ir) neurons was lower on proestrus and estrus compared with diestrus (P < 0.01). Nevertheless, the percentage of kisspeptin-ir neurons expressing c-Fos was increased on proestrous afternoon by the time of LH and PRL surges (P < 0.05), confirmed using 2 anti-c-Fos antibodies (Ab-5, Calbiochem; K-25, Santa Cruz). Male rats displayed fewer kisspeptin-ir neurons in the ARC than diestrous females with unchanged coexpression of c-Fos during the day. The effects of E2 were evaluated in the positive-feedback model of ovariectomized (OVX) rats treated with E2 (OVX+E2). The number of kisspeptin-ir neurons in the ARC was reduced in OVX+E2 compared with OVX rats (P < 0.05). Similarly to proestrus, however, the percentage of kisspeptin-ir neurons expressing c-Fos was increased in OVX+E2 rats at 18 h (P < 0.01). This response, as well as the LH surge, was blocked by the anti-estrogen tamoxifen. Moreover, the activation of kisspeptin neurons was inversely correlated with the expression of phosphorylated tyrosine hydroxylase (TH) in the median eminence (P < 0.01), used as an index of TIDA neuron activity. The effects of E2 on expression of KNDy genes in the ARC were determined using qPCR. E2 inhibited the expression of Kiss1 and had no effect on Nkb mRNA. In contrast, OVX+E2 rats displayed an increased expression of Pdyn mRNA at 18 h (P < 0.05), coinciding with E2-induced LH and PRL surges. We then used transgenic rats expressing Cre-recombinase under the TH promoter to fill the cell bodies and dendrites of TIDA neurons with GFP, allowing investigation of dynorphin and kisspeptin inputs onto these cells by confocal microscopy. OVX+E2 rats displayed more dynorphin-ir neurons in the ARC in opposition to less kisspeptin cells compared to OVX (P < 0.05). E2 also increased the number of dynorphin inputs on the soma and dendrites of TIDA neurons whereas decreased the kisspeptin ones (P < 0.05). Thus, we provide evidence of a dual effect of E2 on the regulation of KNDy neurons. E2 reduces kisspeptin expression as part of the negative-feedback effect on LH. Concurrently, E2 induces an afternoon rise in the activity of KNDy neurons, higher expression of dynorphin and increased dynorphin inputs on TIDA neurons. These findings reveal a role for KNDy neurons in E2-induced PRL secretion.

 

Nothing to Disclose: RA, SHY, JFS, RGB, FLB, PCH, LTH, MOP, CRF, DRG, RES

OR23-2 30854 2.0000 A Estradiol Induces a Functional Switch in Arcuate Kndy Neurons from Kisspeptin to Dynorphin to Facilitate Prolactin Secretion 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Neuroendocrinology and Pituitary Saturday, April 1st 1:00:00 PM OR23 9454 11:30:00 AM Neuroendocrine Control of Reproduction Oral


Karen Jill Tonsfeldt*, Erica L Schoeller, Liza E Brusman and Pamela L Mellon
University of California, San Diego, La Jolla, CA

 

The preovulatory luteinizing hormone (LH) surge is temporally gated, but the origin of the timing cue is unknown. Estrogen primes kisspeptin (Kiss1) neurons in the anteroventral periventricular nucleus (AVPV) to secrete kisspeptin, which potently activates gonadotropin-releasing hormone (GnRH) neurons to release a bolus of GnRH, eliciting a surge of LH to prompt ovulation. Genomic deletion of the critical circadian clock component, Bmal1, results in infertility in females. Bmal1 KO females ovulate, but an LH surge has never been detected in these mice. We sought to determine if neuroendocrine disruption contributes to the absence of the LH surge in these animals. Corroborating previous studies, we found no difference in the LH response to 1 µg/kg GnRH 10 minutes after administration between wildtype (WT) and Bmal1 KOs (LH increase of 2.61 ± 0.25 ng/µl vs 2.51 ± 0.50 ng/µl, n=6). Interestingly, Bmal1 KO female mice had a significantly increased response to 30 nmole kisspeptin after 10 minutes (LH increase of 1.19 ± 0.34 ng/µl vs. 3.08 ± 0.56 ng/µl, n = 6, p<0.05). In addition to having an increased LH response to a kisspeptin challenge, the knockout mice showed greater area under the curve in response to kisspeptin during a 45-minute time course (38.99 ± 4.69 vs 163.30 ± 16.88 ng/min/µl, n=3-4, p<0.005). A dose response curve indicated no difference in ED50 (0.144 ± 0.048 vs. 0.085 ± 0.048 mg/kg, n=4) despite the increased maximal effect, indicating kisspeptin is more efficacious in eliciting LH in Bmal1 knockout females. Since the sex-specific expression of Kiss1 in the AVPV is critical for regulating ovulation in females, we hypothesized that this population may be absent in Bmal1 KO females. However, we found no differences in Kiss1 mRNA expression between WT and Bmal1 KO females (1.08 ± 0.25 vs 1.03±0.29-fold change, n=4). Overall, our results suggest disruption of the hypothalamic and pituitary regulation of fertility in the Bmal1 KO females, specifically in responsiveness to kisspeptin. This suggests that circadian cues may be important for regulating the temporal release of hypothalamic peptides that regulate fertility, possibly to optimize the timing of maximal fertility.

 

Nothing to Disclose: KJT, ELS, LEB, PLM

OR23-3 32447 3.0000 A Bmal1 Knockout Females Demonstrate Altered Kisspeptin Responsiveness 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Neuroendocrinology and Pituitary Saturday, April 1st 1:00:00 PM OR23 9454 11:30:00 AM Neuroendocrine Control of Reproduction Oral


Nicole H Bellefontaine*1, Marina Augusto Silveira2, Beatriz de Carvalho Borges1, David Garcia Galiano1, Thais T Zampieri2, Kevin W Williams3, Renata Frazao2 and Carol F Elias4
1University of Michigan, Ann Arbor, MI, 2University of Sao Paulo, Sao Paulo, Brazil, 3University of Texas Southwestern Medical Center, Dallas, TX, 4Univ of Michigan, Ann Arbor, MI

 

Neural networks controlling sexual maturation and fertility require signals from metabolic hormones, such as the adipocyte-derived hormone leptin. Leptin receptor signaling in the ventral premammillary nucleus (PMv) of the hypothalamus is sufficient to drive puberty and fertility in mice otherwise null for the leptin receptor. The specific cell populations and mechanisms by which the PMv contributes to the metabolic control of reproduction remains unknown. Within the PMv, leptin activates or inhibits neuronal activity suggesting the existence of two distinct populations sensitive to leptin. In this study we describe a leptin sensitive population within the PMv that expresses the dopamine transporter (DAT). DAT PMv cells appear to be sexually dimorphic, as females show higher levels of DAT mRNA within the PMv when compared to males. DAT PMv neurons are also developmentally regulated in females. Prepubertal females display higher levels of DAT mRNA expression compared to adult diestrus female (P<0.05, t=3.012, df=10). These developmental changes may be independent from changes in estrogen levels as DAT mRNA is not different between intact, ovariectomized (OVX), and OVX females with estradiol replacement (Diestrus n=5, OVX n=4, OVX+E2 n=5, p = 0.1266). Approximately, 35-40% of DAT PMv neurons are responsive to leptin as measured by leptin-induced P-STAT3-ir colocalization in DAT-Cre;R26tdTomato reporter mice. Electrophysiological recordings in DAT PMv cells revealed that leptin hyperpolarizes approximately 30% of DAT neurons (4 of 14 cells), whereas the other 70% of cells remained unresponsive. To assess the role for DAT-PMv neurons in reproductive functioning, we utilized the activating form of DREADDs to temporally activate DAT neurons specifically within the PMv. Activation of DAT-PMv neurons, through addition of clozapine-N-oxide (CNO; 2.5mg/100mL) into the drinking water, suppressed reproductive function by prolonging the number of days spent in the diestrus phase of the reproductive cycle. This effect was completely reversible with the removal of CNO from the drinking water (Water+DMSO (days 0-14) = 10.17 days, CNO diluted in DMSO (days 15-29) = 12.67, Water+DMSO (days 30-44) = 10.17 days, P= 0.007). Together these data show a novel leptin sensitive population within the PMv that suppress reproductive function. Moreover, these data reveal that the architecture of the PMv is far more complex than originally proposed.

 

Nothing to Disclose: NHB, MAS, BDCB, DG, TTZ, KWW, RF, CFE

OR23-4 32112 4.0000 A Pmv Neurons That Express the Dopamine Transporter Are Sensitive to Leptin and Suppress Reproduction 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Neuroendocrinology and Pituitary Saturday, April 1st 1:00:00 PM OR23 9454 11:30:00 AM Neuroendocrine Control of Reproduction Oral


Cadence True*1, Cloe Moctezuma2, Paul Kievit1 and Kevin L. Grove3
1Oregon National Primate Research Center, Beaverton, OR, 2Oregon National Primate Research Center, 3Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR

 

Negative energy balance is associated with inhibition of female reproductive function at the level of gonadotropin-releasing hormone (GnRH) neurons in nearly all mammals studied to date. Shortly upon exit of negative energy balance GnRH function is restored and examination of this critical window could reveal novel regulatory signals. The current study examined hormonal, metabolic and reproductive profiles during a 3-week calorie restriction (CR) followed by a resumption of ad libitum refeeding (RF). Intact female Wistar rats were either fed ad libitum or CR to achieve a 20-25% weight loss in a 3-week period. All groups were then fed ad libitum for 2-4 weeks and blood was collected at the following timepoints: at the end of CR, 24 hours RF, 48 hours RF, 7 days RF and 28 days RF. A subgroup of animals underwent indirect calorimetry during the same time course. Restoration of weight to initial levels was rapid following CR and occurred by 4 days RF. Serum luteinizing hormone (LH) levels were significantly decreased with CR, but had recovered by 24 hours RF indicating a rapid restoration of the GnRH pulse generator. Leptin levels followed a similar time course of suppression with CR and rapid restoration by 24 hours RF even when body weights had not fully recovered to initial starting weights. Estrous cycles were abnormal but not halted by a 3-week CR. Interestingly, estrous cycles remained abnormal in the 14-day RF period examined. Ovaries examined at 14 days RF had significantly fewer corpora lutea compared to controls (t-test, p<0.05), suggesting a persistent problem in ovulation. These findings indicate that although the GnRH pulse generator recovered quickly, inhibition of the GnRH surge mechanism persisted. Most changes in metabolic hormones normalized by 48 hr RF, except for insulin, which remained elevated at 7 days RF and normalized at 28 days RF. Indirect calorimetry revealed an elevated respiratory quotient (RQ) in CR+RF animals that persisted at 7 days RF but had normalized by 28 days RF. Elevated RQ at 7 days RF could indicate lipogenesis and fat storage remain elevated even after body weight has been restored. The current study reveals that separate signals may convey metabolic information to the neuroendocrine circuits controlling the GnRH pulse generator, which recovers rapidly, and the GnRH surge mechanism, which requires a longer period to recover even after weight has normalized. We provide evidence that changes in the adipokine leptin may provide immediate signals to restore GnRH pulsatility, while persistent changes in insulin signaling and lipogenesis may contribute to the delayed recovery of the GnRH surge mechanism. These processes are hypothesized to be regulated by two distinct kisspeptin populations in the rodent and future studies will examine changes at these neurons with CR and RF.

 

Disclosure: KLG: , Novo Nordisk. Nothing to Disclose: CT, CM, PK

OR23-5 32746 5.0000 A The Gonadotropin-Releasing Hormone Pulse Generator and Surge Mechanisms Are Restored on Distinct Time Courses Following Recovery from Negative Energy Balance 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Neuroendocrinology and Pituitary Saturday, April 1st 1:00:00 PM OR23 9454 11:30:00 AM Neuroendocrine Control of Reproduction Oral


Lorena Guimaraes Lima Amato*1, Luciana Ribeiro Montenegro2, Antonio M Lerario3, Priscila Sales Barroso1, Caroline Schnoll2, Alessandra Covallero Renck2, Berenice B Mendonca1, Ana Claudia Latronico2 and Leticia Ferreira Gontijo Silveira2
1Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, SAO PAULO, Brazil, 2Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 32Departament of Internal Medicine, University of Michigan, Michigan

 

Background: Loss-of-function mutations were recently identified in IGSF10 in six families with self-limited delayed puberty, by whole exomic sequencing. IGSF10 is expressed in the embryonic nasal mesenchyme in mice during GnRH neuronal migration to the hypothalamus. IGSF10 knockdown affected neuronal migration in vitro and in vivo. Rare predicted damaging variants in IGSF10 were also identified in patients with functional and congenital isolated hypogonadotropic hypogonadism (IHH) (1). However the definitive role of this gene in the pathogenesis of congenital IHH remains to be determined. Hypothesis: To further investigate the association of IGSF10 and congenital IHH, we investigated the presence of IGSF10 rare variants in this group of patients. Experimental design: Genomic DNA of 143 patients with normosmic IHH (n=84) and Kallmann syndrome (KS) (n=59) was analyzed by targeted Next Generation Sequencing (NGS), with a panel of 36 selected candidate genes, using the Illumina MiSeq 2500 platform. Variants were considered potentially pathogenic according to the following criteria: frequency ≤ 1% in the population bases 1000Genomes and Exome Aggregation Consortium, non-synonymous exonic or splicing variants, GERP score > 2.5 and determined damaging or likely damaging by more than three bioinformatic prediction models (SIFT, PolyPhen2, Mutation Taster, Mutation Assessor, FATHMM, PROVEAN, VEST and CADD). Results: Nine potentially pathogenic variants were identified in IGSF10 (p.E161K, p.T1266S, p.A2406V, p.T1538I, p.T1370I, p.P746R, p.G709V, p.Q433fs, p.D1802V), in 15 patients: 5 with KS (5 men) and 10 with normosmic IHH (4 women, 6 men). All patients had heterozygous variants, except one men with normosmic IHH, who displayed a compound heterozygous variant (p.D2277G/p.T1538I). This patient preseted with reversal of the hypogonadism for 3 yrs, with posterior relapse. Among the affected patients, the age at diagnosis varied from 16 to 27 years, 3 patients had a family history of pubertal delay, 5 men had unilateral or bilateral cryptorchidism, and all had micropenis at diagnosis. The initial testosterone values in men ranged from <12 to 28 ng/dL (240 - 810ng/dL), all women had undetectable estradiol levels at diagnosis (2.2 - 57.2ng/dL); LH values ranged from <0.1 to 1.7IU/L (1.7 - 8.6 IU/L) and FSH from <1 to 4.8IU/L (1.5 - 12.4 IU/L). No patient with IGSF10 variants had any other potentially pathogenic variant. Conclusion: We identified predicted damaging IGSF10 variants in 10.5% of our congenital IHH cohort. The current series shows that IGSF10 is an important gene related to congenital IHH and allows the expansion of knowledge about the role of this gene in IHH.

 

Nothing to Disclose: LGLA, LRM, AML, PSB, CS, ACR, BBM, ACL, LFGS

OR23-6 32125 6.0000 A Rare Allelic Variants in the IGSF10 Gene in Patients with Isolated Hypogonadotropic Hypogonadism with and without Olfactory Abnormalities 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Neuroendocrinology and Pituitary Saturday, April 1st 1:00:00 PM OR23 9454 11:30:00 AM Neuroendocrine Control of Reproduction Oral


Suriyan Ponnusamy1, Robert H Getzenberg2, Luke Selth3, Thirumagal Thiyagarajan1, Dong-Jin Hwang1, Yali He1, Iain J McEwan4, Carolyn Watt5, Wayne D Tilley6, Duane Miller1 and Ramesh Narayanan*7
1University of Tennessee Health Science Center, 2GTx, Inc., 3University of Adelaide & Hanson, Alelaide, Australia, 4University of Aberdeen, Scotland, United Kingdom, 5University of Aberdeen, 6University of Adelaide, Adelaide, Australia, 7University of Tennessee Health Science Center, Memphis, TN

 

Introduction and Objective: The androgen receptor (AR) is stabilized by its ligands thereby making it difficult to develop potent and specific degraders. Degrading the AR is important to ensure that the AR is not continually activated in prostate cancer through alternate mechanisms such as kinases, over-expression of coactivators, or generation of mutant or ligand binding domain (LBD)-null constitutively active splice variants (AR-SV). The clinical success of new AR-targeted therapies in patients with castration-resistant prostate cancer (CRPC) emphasizes the continued importance of the AR signaling axis in the disease. Despite the use of this new generation of therapies, some men with CRPC do not respond and resistance to these therapies typically develops for those that do. The objective of this work is to develop selective androgen receptor degraders (SARDs) that degrade all forms of the AR and provide advanced treatment options to men with CRPC.

Results: This report details a novel series of highly potent SARDs with unique pharmacology that selectively bind to the AR-LBD and inhibit transactivation at nanomolar concentrations. The SARDs antagonize the AR with an IC50 of ~50-250 nM in comparison to enzalutamide with an IC50 of ~500 nM. The SARDs are selective for the AR with the only significant observed cross-reactivity being with the PR. In addition to their antagonistic activity, the SARDs degrade full length AR (AR-FL) in the high (100-500 nM) nanomolar range and variant AR around 1-5 μM. The SARDs inhibit the proliferation of AR-FL and AR-SV- dependent PCa cells with potencies better than that of the comparators. The SARDs robustly inhibit the growth of the LNCaP androgen-dependent prostate cancer (PCa) xenograft, the 22RV1 CRPC xenograft, and AR- and AR-SV- positive CRPC patient-derived xenografts (PDX). NMR analysis as well fluorescence quenching support an interaction between the SARDs and the AR activation function domain (AF-1), making these molecules first-in-class dual-interacting AR antagonists and degraders. SARDs prevent AR-FL nuclear translocation and export the constitutively nuclear AR-SV. Mechanistic studies indicate that these SARDs re-program the interaction of the AR with DNA elements (ChIP-Seq) and proteins.

Conclusions: These novel highly potent SARDs that interact with both the AF-1 and LBD of the AR represent potential next-generation treatment options for advanced prostate cancer. Clinical development of these compounds is ongoing.

 

Disclosure: RHG: Employee, GTx, Inc.. RN: Consultant, GTx, Inc.. Nothing to Disclose: SP, LS, TT, DJH, YH, IJM, CW, WDT, DM

OR25-1 29884 1.0000 A Discovery and Characterization of Selective Degraders of Full Length and Splice Variant Androgen Receptors (SARDs) for the Treatment of Advanced Prostate Cancer 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Nuclear Receptors and Steroid Hormone Action Saturday, April 1st 1:00:00 PM OR25 9456 11:30:00 AM Androgen Receptor Signaling Oral


Shoulei Jiang*1, Sulgi Park1, Pawel Osmulski2, Jodie Cropper1, Maria Gaczynska2, Caleb Killer2, Chung Seog Song3 and Bandana Chatterjee3
1South Texas Veterans Health Care System, 2Molecular Medicine Department, UT Health San Antonio, Texas, 3South Texas Veterans Health Care System and Molecular Medicine Department, UT Health San Antonio, Texas

 

Context: The activated androgen receptor (AR) drives metastatic castration-resistant prostate cancer (mCRPC) to a lethal, non-curable disease. New-generation AR antagonists and androgen synthesis blockers are clinically effective against mCRPC as second-line inhibitors of the AR axis, although responses are short-lived. Alternate targets up or down the AR axis are likely to afford new options for management of the disease. The oxysterol-inducible nuclear receptors liver X receptors (LXR-a, LXR-b) inhibited prostate cancer cells in culture and in xenograft tumors (1), and LXRa/b-double knockout mice on high-cholesterol diet developed prostate intraepithelial neoplasia (PIN). A similar feeding condition did not induce PIN in wild type or single isoform (LXRa or LXRb) deleted mice (2).

Results: We report that the activated LXR significantly reduced AR mRNA and protein levels in C4-2 human CRPC cells upon treatment with a synthetic LXR ligand (T0901317 or GW3965) at low micro molar concentrations. Similar doses of the ligand strongly abated proliferation of C4-2 cells and their foci formation in culture. Reduced AR expression paralleled decreased AR activity, since androgen-induced expression of the AR target genes PSA and NKX3.1 diminished markedly. Activation of LXR in ligand-treated cells was confirmed from marked induction of ABCG1, a transporter-encoding gene and LXR target. We engineered C4-2 cells in which the endogenous AR gene was fused in-frame at its 3’UTR with the NanoLuc reporter cDNA by genome editing with CRISPR/Cas9. NanoLuc luciferase activity in the tagged C4-2 cells was markedly reduced upon LXR activation, indicating that LXR-mediated antagonism of AR expression was at least partly due to transcriptional suppression of the genomic AR. Cells were examined by atomic force microscopy (AFM) to analyze nanomechanical properties, which can reveal cell’s invasive potential (3). Ligand-activated LXR reduced the invasive phenotype of C4-2 cells in a dose dependent manner, since the AFM parameters demonstrated enhanced adhesion and higher young modulus –the latter indicating greater rigidity or lessened elasticity. Using DNAse1 footprinting and chromatin immunoprecipitation of the human AR promoter, we identified an LXR-responsive region, which was occupied by both LXR isoforms. Upon activation, LXR in C4-2 cells was associated with an HDAC1- and NCoR-associated corepressor complex. Molecular insights into the interplay of LXR with corepressors and various epigenetic modulators at the AR promoter can potentially unveil new anti-AR strategies, which, in a therapy setting, can stem prostate cancer progression.

 

Nothing to Disclose: SJ, SP, PO, JC, MG, CK, CSS, BC

OR25-2 31136 2.0000 A Liver x Receptor Antagonizes Androgen Receptor Expression and Activity in Prostate Cancer Cells 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Nuclear Receptors and Steroid Hormone Action Saturday, April 1st 1:00:00 PM OR25 9456 11:30:00 AM Androgen Receptor Signaling Oral


Basil Paul*1, Badrajee Piyarathna2, Zheng Xia1, Wei Li2, Cristian Coarfa1 and Nancy L Weigel1
1Baylor College of Medicine, Houston, TX, 2Baylor College of Medicine

 

Prostate cancer (PCa) is androgen-dependent and the first choice of treatment for metastatic PCa is androgen deprivation therapy (ADT). Although the tumors respond initially, they usually become resistant and are termed castration-resistant PCa (CRPC). These tumors remain androgen receptor (AR) dependent. There are multiple mechanisms for reactivation of AR including expression of constitutively active AR splice variants, which lack the hormone binding domain. These include the variant termed AR-V7 (AR3). Some studies suggest that variants, which activate many of the same genes as AR, also have unique targets, while others support the idea that the variant is a “weak” AR. To address this question, we have used our previously generated LNCaP cell line that expresses AR-V7 in response to doxycycline to compare the activities of the two isoforms and to identify the mechanistic basis for differential regulation of target genes. The transcriptomes for AR and AR-V7 were identified using RNA-Seq. A complete set of DNA-bound AR isoform locations at near single nucleotide resolution was mapped using ChIP-exo in LNCaP and LNCaP AR-V7 cells. Bioinformatics, qPCR, siRNA, and ChIP approaches were used to characterize the differences and to begin to elucidate mechanisms for differential regulation. We compared the transcriptomes for AR and AR-V7 using RNA-seq in the LNCaP and LNCaP AR-V7 cells. Although more than a thousand genes were regulated by both isoforms, a sub-set of genes were regulated only by AR or by AR-V7 and 67 were regulated in the opposite direction. An integrated analysis was performed to identify whether the unique gene signatures translate into unique cistrome interactions. We found that although the AR isoforms have common DNA binding domains and bind many of the same sites, there are also AR and AR-V7 specific sites. In general the AR specific sites are distal to the promoter whereas unique AR-V7 sites often are in regulatory regions close to the target genes. These AR-V7 binding sites are characterized by promoter elements and histone marks of transcriptional regulation. Bioinformatic analysis of the binding sites revealed transcription factors or interacting proteins required for common and unique activities of AR variants. As expected FOXA1 a known pioneering factor was a prominent factor predicted in a motif analysis of AR binding sites. Whereas some of the differentially regulated genes are those that are reported to be FOXA1 sensitive for AR dependent expression, we have also identified a number of genes preferentially regulated by AR-V7 which are insensitive to FOXA1 expression suggesting other mechanisms for differential regulation. These results indicate that although AR-V7 can substitute for AR, it also has unique actions and that many of these are regulated by differential binding to chromatin. These new actions may provide new therapeutic targets

 

Nothing to Disclose: BP, BP, ZX, WL, CC, NLW

OR25-3 32255 3.0000 A The Androgen Receptor Splice Variant AR-V7 Induces Unique Genes, in Part through Preferential Binding to Unique Promoter Proximal Sites in the Chromatin 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Nuclear Receptors and Steroid Hormone Action Saturday, April 1st 1:00:00 PM OR25 9456 11:30:00 AM Androgen Receptor Signaling Oral


Manqi Zhang*1, Judy Rieger2, Lubov Nathanson3, Nancy L Weigel4 and Irina U Agoulnik5
1Florida International University, miami, FL, 2Florida International University, 3Nova Southeastern University, Fort Lauderdale, FL, 4Baylor College of Medicine, Houston, TX, 5Herbert Wertheim College of Medicine, Florida International University, Miami, FL

 

Inositol polyphosphophate 4-phosphatase type II (INPP4B), is a dual phosphatase and functions as a tumor suppressor in prostate cancer. We and others have shown that INPP4B suppresses pro-oncogenic PI3K/Akt and PKC signaling pathways in multiple cell models. INPP4B protein levels and mRNA expression are reduced in primary and notably metastatic prostate cancers. Due to a key role of AR in prostate cancer progression, we investigated reciprocal regulation of INPP4B and AR signaling. We have previously shown that INPP4B expression is directly induced by AR. Remarkably, AR splice variant AR-V7 is unable to increase INPP4B expression. The knockdown of INPP4B did not alter AR protein level. We conducted microarray experiments to investigate transcriptional changes caused by androgens and INPP4B depletion. GSEA analysis suggested that INPP4B loss alters AR transcriptional output. INPP4B was also required for AR-V7 specific transcriptional activity. Using PI3K/Akt and PKC inhibitors, AZD5363, LY294002, and BIM-I, we tested whether they would phenocopy the effect of INPP4B on the AR target gene expression. The results revealed that inhibition of PI3K/Akt and PKC signaling did account for a portion of the INPP4B-induced changes in AR signaling. Further, we investigated AR signaling in prostates of male Inpp4b-/- mice. All prostate lobes were present in both wild-type and Inpp4b-/- mice. Consistent with our findings in human cell lines, AR expression and protein level in mouse prostate was not changed by the depletion of INPP4B. Remarkably, expression of several AR target genes such as Msmb, Apof, and Nkx3.1 was significantly reduced in Inpp4b-/- mice. Using Western blotting we compared Akt and PKC signaling in anterior (AP), dorsal/lateral (DLP) and ventral (VP) prostate lobes of the wild-type and Inpp4b-/- mice. Loss of INPP4B activated Akt signaling in DLP and VP and activated PKC ζ and β II pathways in AP and DLP. We determined that levels of PTEN protein were unchanged in Inpp4b-/- mouse prostates suggesting that Akt signaling was elevated exclusively due to Inpp4b loss. Taken together, INPP4B modulates transcriptional activity of both full length AR and AR-V7 splice variant without altering AR protein levels in prostate cancer cell lines and normal mouse prostate. INPP4B suppresses Akt and PKC signaling in benign mouse prostate and is required for optimal AR transcriptional activity.

 

Nothing to Disclose: MZ, JR, LN, NLW, IUA

OR25-4 32726 4.0000 A INPP4B Regulation of AR Transcriptional Activity and Cell Signaling in Prostate Cancer Cells and in Mouse Prostate 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Nuclear Receptors and Steroid Hormone Action Saturday, April 1st 1:00:00 PM OR25 9456 11:30:00 AM Androgen Receptor Signaling Oral


Frank A. Claessens*1, Martha Nadal2, Stefan Prekovic1, Biswajyoti Sahu3, Olli A Janne3, Adriaan B Houtsmuller4, Martin van Royen4, Pablo Fuentes-Prior2, Eva Estebanez-Perpina2 and Christine Helsen1
1KU Leuven, Belgium, 2University Barcelona, Spain, 3University Helsinki, Finland, 4Erasmus MC, Rotterdam, Netherlands

 

Dimerization of androgen and glucocorticoid receptors (AR and GR) happens at the level of two domains. The dimerization of the DNA binding domains (DBD) of the AR and GR is very similar but distinct. We developed a mouse model in which we swapped the second zinc finger of the AR for that of the GR. This so-called SPARKI model revealed clear effects on androgen responses in testis, prostate, kidney and epidydimis which correlated with changes in the AR ChIPseq data and in vitro AR DNA binding.

For most nuclear receptors (including the estrogen receptor) a dimerization at the level of the ligand binding domain (LBD) has been demonstrated. However, for the oxysteroid receptors (AR, GR, MR and PR) the dimerization via the LBD has been controversial.

Here, we show the crystal structure of the AR-LBD homodimerization interface (1,000-Å2) of the agonist-coactivator peptide-bound LBD. This interface is different from the one described for other nuclear receptors (including the estrogen receptor) and would not prevent coactivator binding or N/C interactions. In fluorescence resonance energy transfer (FRET) experiments this AR-LBD dimerization is disrupted by a mutation described in an androgen insensitivity syndrome (AIS) patient although it does not disrupt ligand binding. In fact up to 40 mutations described in AIS or prostate cancer that were unexplained before reside in this new LBD dimer surface. Clinical data thus strongly corroborate our AR-LBD dimer model. FRET assays further demonstrated that the dimerization of the AR-LBD is inducible by androgen agonists but not by antagonists. Importantly, mutations that disrupt the FRET signal (dimerization) did not disrupt ligand binding so dimerization is dependent on hormone, but hormone binding does not dependent on dimerization. Mutations that are predicted to disrupt the AR-LBD dimerization were introduced in the full size AR. They disrupted its transactivation properties on reporter genes clearly demonstrating the crucial role of dimerization in transactivation.

In conclusion, we described a new dimerization surface in the AR-LBD with a crucial role in transactivation.

 

Nothing to Disclose: FAC, MN, SP, BS, OAJ, ABH, MV, PF, EE, CH

OR25-5 32601 5.0000 A Dimerization of Androgen Receptor and Glucocorticoid Receptors 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Nuclear Receptors and Steroid Hormone Action Saturday, April 1st 1:00:00 PM OR25 9456 11:30:00 AM Androgen Receptor Signaling Oral


Jose Donato Jr.*1, Isadora C Furigo2, Gabriel Orefice2, Angela M Ramos-Lobo2, Carlos RJ Soares3, Edward O List4 and John J Kopchick4
1University of Sao Paulo, Sao Paulo - SP, Brazil, 2University of Sao Paulo, Sao Paulo, Brazil, 3IPEN-CNEN/SP, 4Ohio University, Athens, OH

 

Growth hormone (GH) responsive neurons are extensively distributed in many hypothalamic nuclei that also have leptin receptor (LepR)-expressing cells (1). However, whether GH affects metabolic functions regulated by leptin remains unknown. In the present study, we initially performed a co-localization study and confirmed that a large percentage of LepR-expressing neurons are directly responsive to peripherally injected GH in different brain nuclei. Then, we generated mice lacking GH receptor (GHR) specifically in LepR-expressing cells (LepR GHR KO mice). Although LepR GHR KO mice exhibited a similar body weight, food intake, energy expenditure, glucose tolerance and leptin sensitivity compared to control mice, we observed a lower adiposity in mutant mice. LepR GHR KO mice also showed a lower capacity to recover from insulin-induced hypoglycemia and a blunted counterregulatory response evoked by 2-deoxyglucose (2DG) administration. Co-infusion of 2DG with sympathetic blockers, but not parasympathetic blockers, was able to abolish the differences observed between groups. Remarkably, while control mice adapted to a 60% food deprivation period by progressively saving energy, LepR GHR KO mice exhibited a blunted metabolic adaptation to starvation, which led to hypoglycemia and an increased lethality rate, energy expenditure and weight loss, compared to control animals. In order to identify the specific neuronal populations responsible for the observed responses, we generated mice lacking GHR in steroidogenic factor-1 (SF1) cells, which comprises the ventromedial nucleus of the hypothalamus (VMH). SF1 GHR KO mice exhibited a similar metabolic phenotype in the basal condition, compared to littermate controls. On the other hand, SF1 GHR KO mice also showed a lower capacity to recover from insulin-induced hypoglycemia and a blunted counterregulatory response evoked by 2DG. However, metabolic adaptations to starvation were not affected by SF1-specific GHR deletion, which suggests that VMH does not mediate these latter changes. In summary, GHR expression in the brain is required to properly regulate glycemia and energy balance, especially during situations in which GH is highly secreted (e.g., hypoglycemia and food restriction). In addition, our findings revealed a previously unrecognized role of GH to coordinate, together with leptin, the metabolic adaptations to starvation in order to ensure survival, via the same neurocircuitry.

 

Nothing to Disclose: JD Jr., ICF, GO, AMR, CRS, EOL, JJK

OR26-1 30199 1.0000 A GH Controls Glycemia and Metabolic Adaptations to Starvation Via Neurons That Express the Leptin Receptor 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Obesity, Adipocyte Biology and Appetite Saturday, April 1st 1:00:00 PM OR26 9457 11:30:00 AM Central Regulation of Feeding and Body Weight Oral


Brigitte DeLashmette*, Gabrielle Page-Wilson, Sunil K. Panigrahi, Richard M. Smiley and Sharon L. Wardlaw
Columbia University College of Physicians & Surgeons, New York, NY

 

Glucocorticoids exert potent effects on appetite, body composition and metabolism that are mediated in part by central mechanisms but there is little information about central cortisol levels or brain cortisol metabolism with respect to human energy balance. The enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), which regulates cortisol activity through interconversion with cortisone (which is inactive), is widely expressed in brain. We postulated that cortisol (F) and cortisone (E) levels in CSF would reflect brain glucocorticoid exposure and that the ratio of F/E in CSF could be used to assess brain 11β-HSD1 activity. We therefore measured F and E levels in CSF of healthy human subjects (BMI 18-41). The relationship of these parameters to BMI, adiposity and to levels of hormones and neuropeptides that regulate energy balance was examined. CSF was collected by lumbar puncture in the morning after an overnight fast in 55 subjects (28 M, 27F) ages 19-50 yrs. 30 were lean (L) (mean BMI 22.5) and 25 were overweight/obese (O) (mean BMI 31.1). Mean CSF F and E levels were 5.6 ± 0.2 and 2.6 ± 0.1 ng/ml respectively; the mean ratio of F/E in CSF was 2.2 ± 0.1. CSF F was higher in females (p=0.01) and did not correlate with BMI or leptin. In contrast, CSF E correlated negatively with BMI (r = -0.41) and leptin (r = -0.29) (p<0.05) and was not affected by gender. However, the CSF F/E ratio was higher in O vs L subjects (2.5 vs 2.0; p<0.01) and this was independent of gender. Strong positive correlations were observed between the CSF F/E ratio and BMI (r=0.42), adiposity (r = 0.53), plasma leptin (r = 0.41) and CSF leptin (r = 0.42) (p<0.005). We next examined the relationship between CSF glucocorticoids and the melanocortin neuropeptides, proopiomelanocortin (POMC) and agouti-related protein (AgRP), that play reciprocal roles in regulating energy balance and neuroendocrine function. POMC-derived peptides and AgRP can inhibit and stimulate the HPA axis respectively and glucocorticoids can directly interact with these neurons. There was a strong negative correlation between CSF F and CSF POMC (r = - 0.46; p<0.001) that remained significant when the genders were analyzed separately. In contrast, CSF F correlated positively with CSF AgRP (p = 0.03). The CSF POMC to AgRP ratio (calculated as a measure of melanocortin activity) correlated negatively with CSF F (r= - 0.47; P<0.001). In summary, glucocorticoid levels in CSF and the ratio of F to E are strongly correlated with BMI, adiposity and leptin. The extent to which the CSF F/E ratio reflects brain 11β-HSD1 activity remains to be determined but our results highlight the central role of glucocorticoids in human energy balance and confirm a relationship between brain melanocortin neuropeptides and glucocorticoids. The bidirectional interactions between melanocortin peptides and the HPA axis and their relationship to energy balance deserve further study.

 

Nothing to Disclose: BD, GP, SKP, RMS, SLW

OR26-2 30370 2.0000 A Cerebrospinal Fluid Corticosteroid Levels and Assessment of Brain 11β-HSD1 Activity: Correlations with BMI, Leptin and Melanocortin Neuropeptides 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Obesity, Adipocyte Biology and Appetite Saturday, April 1st 1:00:00 PM OR26 9457 11:30:00 AM Central Regulation of Feeding and Body Weight Oral


Samantha R Spierling*, Alison D Kreisler and Eric P Zorrilla
The Scripps Research Institute, La Jolla, CA

 

In rats, intermittent access to a preferred high-sucrose, chocolate-flavored diet (“P”) has been used to model dieting behavior and leads to binge-like intake. The present study tested the hypothesis that metabolic hormones implicated in energy homeostasis are linked to compulsive palatable food self-administration during intermittent access. Female Wistar rats, matched for food intake and body composition, were assigned to 1 of 4 groups (n=7-10/group): 1) ad lib chow (C) 2) ad lib P 3) intermittent P for either 30 min or 4) 24 hr on 3 non-consecutive days/week, with C available otherwise. On intermittent P access days, rats performed operant self-administration for food on a fixed-ratio 1 (FR) or progressive-ratio (PR) schedule. Rats receiving intermittent access to P, but not ad lib access to C or P, showed increased PR breakpoint and FR self-administration despite footshock punishment, both consistent with compulsive self-administration. Rats with ad lib, but not intermittent, access to P developed greater body weight and % body fat with less % lean mass. However, both body mass and % fat composition correlated significantly with compulsivity – higher PR breakpoints and FR responding despite footshock – uniquely in intermittent rats. These relations were seen not only cross-sectionally (week 16), but also prospectively, with greater baseline weight/fat predicting the development of compulsive-like responding (rs = 0.46 - 0.56). Using the Luminex Rat Metabolic Analyte Kit, plasma levels of ghrelin, glucagon-like peptide-1 (GLP-1), insulin, leptin, and pancreatic polypeptide (PP) were assessed in briefly fasted subjects in the withdrawal phase (24-48 hr, pre-access) of their diet schedule. Linear discriminant function analysis of plasma hormone concentrations in relation to the above diet classifications (ad lib C, ad lib P, intermittent low-responder, or intermittent high-responder) revealed two independent relations of adipose-hormone profiles to compulsive-like eating behavior. First, one endocrine profile that reflected jointly higher GLP-1 (r = -0.74) and PP (r = -0.66) with lower ghrelin (r = 0.5), was seen and correlated directly with the intermittent high (“compulsive-like”) classification. A second discriminant function that strongly correlates with leptin concentrations (r = 0.89), was directly related to PR performance, FR performance in the punishment setting, and baseline body fat in the compulsive-like intermittent high-, but not low-, responder rats. The results support the hypothesis that adiposity and metabolic hormone profiles are linked, the former even prospectively, to the compulsivity of eating palatable food when access is intermittent.

 

Nothing to Disclose: SRS, ADK, EPZ

OR26-3 31159 3.0000 A The Sweet Link Between Metabolic Profile and Compulsive Self-Administration of Palatable Food 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Obesity, Adipocyte Biology and Appetite Saturday, April 1st 1:00:00 PM OR26 9457 11:30:00 AM Central Regulation of Feeding and Body Weight Oral


Hillary Woodworth*1, Bethany Genelle Beekly2, Gizem Kurt1, Hannah Marie Batchelor1, Raluca Bugescu1, Juliette Anne Brown1 and Gina Marie Leinninger1
1Michigan State University, East Lansing, MI, 2Gonzaga University, Seattle, WA

 

Mesolimbic dopamine (DA) neurons in the ventral tegmental area (VTA) modify ingestive and locomotor behaviors that impact body weight, and may be useful targets to treat or prevent obesity. We sought to understand how the neuropeptide neurotensin (Nts) engages this mesolimbic system and if it may be useful to support weight loss. Previous pharmacologic studies demonstrate that intra-VTA administration of Nts activates DA neurons expressing the Gq-coupled neurotensin receptor 1 (NtsR1), suppresses feeding and promotes locomotor activity (1-3). To determine the physiological source of Nts to the VTA, we injected a retrograde tracer into the VTA of NtsCre;GFP reporter mice. This method revealed that Nts neurons in the lateral hypothalamic area (LHA) provide significant Nts input to the VTA. We therefore hypothesized that activation of the LHA Nts→VTA DA circuit promotes weight loss behaviors, and that Nts action via NtsR1 is crucial for this effect. To investigate this, we used DREADDs to specifically activate LHA Nts neurons in wild-type (WT) mice and mice that lack NtsR1 (NtsR1KO mice). Activation of LHA Nts neurons increased locomotor activity and energy expenditure in WT and NtsR1KO mice, which was blunted by a DA receptor 1 (DR1) antagonist, confirming the requirement of DA signaling for promoting energy expenditure via this circuit. However, pretreatment with a NtsR1 antagonist did not blunt physical activity, indicating that LHA Nts neurons induce locomotor behavior via a NtsR1-independent mechanism. Interestingly, activation of LHA Nts neurons in WT mice promotes physical activity and energy expenditure without a compensatory increase in feeding which may promote weight loss over time. Indeed, repeated activation of the LHA Nts→VTA DA circuit in WT mice induced a net energy deficit and weight loss in these mice. By contrast, activation of LHA Nts neurons in NtsR1KO mice or in WT mice pre-treated with a NtsR1 antagonist increased food intake, suggesting that Nts action via NtsR1 is required to restrain compensatory feeding. Together, these data reveal that activation of the LHA Nts→VTA DA circuit promotes weight loss behaviors via both Nts-dependent and Nts-independent mechanisms. We therefore tested the translational potential of this circuit for treating obesity by activating LHA Nts neurons in diet-induced obese mice. Contrary to our hypothesis, repeated activation of LHA Nts neurons did not induce weight loss behaviors in severely obese mice, indicating that the LHA Nts→VTA DA circuit is dysfunctional in late-stage obesity. Collectively, these data suggest that therapeutic enhancement of LHA Nts signaling may be useful to support behaviors that prevent the development of obesity.

 

Nothing to Disclose: HW, BGB, GK, HMB, RB, JAB, GML

OR26-4 30892 4.0000 A Lateral Hypothalamic Neurotensin Neurons Engage the Mesolimbic Dopamine System to Promote Weight Loss Behaviors 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Obesity, Adipocyte Biology and Appetite Saturday, April 1st 1:00:00 PM OR26 9457 11:30:00 AM Central Regulation of Feeding and Body Weight Oral


Bethany Genelle Beekly*1, Hillary Lauren Woodworth2 and Gina Marie Leinninger2
1Gonzaga University, Seattle, WA, 2Michigan State University, East Lansing, MI

 

Neurons in the lateral hypothalamic area (LHA) act in concert with ventral tegmental area dopamine (VTA DA) neurons to either promote or suppress feeding. Distinguishing the precise LHA/VTA circuits that restrain feeding would be useful to develop targeted strategies to support weight loss and treat obesity. We sought to determine how LHA neurons expressing the anorectic neuropeptide neurotensin (Nts) engage the VTA, and whether activation of this neuronal circuit can suppress feeding behavior. As a first step, we determined which VTA cells express Neurotensin Receptor-1 (NtsR1) and/or -2 (NtsR2), and hence can be directly regulated by Nts. Using mice that express green fluorescent protein (GFP) in NtsR1 or NtsR2 neurons, we found that numerous VTA DA neurons express NtsR1, while NtsR2 is predominantly observed on glia. These data confirm that NtsR1 is the predominant receptor isoform expressed on VTA DA neurons, and mediates Nts actions in the VTA. We therefore hypothesized that LHA Nts neurons act via VTA NtsR1 neurons to suppress feeding, and that Nts action via NtsR1 is essential for this effect. To examine this, we used DREADD technology (Designer Receptors Activated by Designer Drugs) to selectively activate LHA Nts neurons in mice with intact NtsR1 (hence referred to as WT mice) or in mice lacking NtsR1 (referred to as NtsR1KO mice). Acute activation of LHA Nts neurons did not alter food intake or body weight in sated, energy-replete WT and NtsR1KO mice. We next investigated whether LHA Nts neurons alter feeding behavior in a fasted state, when the homeostatic drive to consume food is increased. After overnight food-deprivation, activation of LHA Nts neurons significantly reduced chow re-feeding and body weight recovery in WT and NtsR1KO mice. These data indicate that LHA Nts neurons suppress homeostatic re-feeding via an NtsR1-independent mechanism. Next, we investigated whether activation of the LHA Nts neurons modifies the incentive salience and intake of palatable foods (sucrose pellets). Acute activation of LHA Nts neurons did not alter responding for sucrose in sated, energy replete WT or NtsR1KO mice, consistent with our previous findings. By contrast, activation of LHA Nts neurons in fasted mice significantly blunts operant responding for sucrose in WT mice, but not in NtsR1KO mice. Thus, Nts signaling via NtsR1 is required to restrain intake of palatable food during enhanced motivational states (e.g. food deprivation). Together, these data demonstrate that activation of LHA Nts neurons suppresses re-feeding in food-deprived animals, including of palatable, calorie dense foods that promote overconsumption and weight gain. Strategies to enhance LHA Nts signaling may therefore be useful to restrain feeding during states of energy deprivation such as dieting, and could enhance diet-induced weight loss.

 

Nothing to Disclose: BGB, HLW, GML

OR26-5 30494 5.0000 A Activation of Lateral Hypothalamic Neurotensin Neurons Restrains Motivated Feeding 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Obesity, Adipocyte Biology and Appetite Saturday, April 1st 1:00:00 PM OR26 9457 11:30:00 AM Central Regulation of Feeding and Body Weight Oral


Cadence True*1, Anam Arik1, Elinor Louise Sullivan2, Kevin L. Grove1 and Paul Kievit1
1Oregon National Primate Research Center, Beaverton, OR, 2Oregon National Primate Research Center, Portland, OR

 

Exposure to a high-fat diet (HFD) in utero has been shown to impact the metabolism of nonhuman primate offspring later in life. These metabolic changes are linked to fetal changes in the brain melanocortin and serotonin pathways, which are implicated in the homeostatic regulation of feeding. Appetite is also regulated by a hedonic pathway that consists in part of dopaminergic neurons receiving metabolic feedback from melanin-concentrating hormone (MCH) and orexin neurons of the lateral hypothalamus. The current study examined MCH and orexin cell density in the lateral hypothalamus and axonal input to the ventral tegmental area (VTA), where dopamine neurons are found, to determine whether maternal and/or post-weaning exposure to a HFD also affects this reward-based feeding pathway in nonhuman primates. Japanese macaque dams were fed a control diet with 16% of calories derived from fat or a HFD with 36% of calories derived from fat. Dams were maintained on this diet at least 2 years prior to pregnancy and throughout both pregnancy and lactation. Offspring were weaned at 7 months of age and were either maintained on the same diet as their mother or switched to the opposing diet creating four groups: maternal and post-weaning control diet (CTR/CTR, n=9), maternal control diet and post-weaning HFD (CTR/HFD, n=8), maternal HFD and post-weaning control diet (HFD/CTR, n=8) and maternal and post-weaning HFD (HFD/HFD, n=8). Immunohistochemistry for MCH, orexin and tyrosine hydroxylase, a rate limiting enzyme in the production of dopamine, was performed on brains from 13-month old offspring. No differences in the quantity of MCH cells in lateral hypothalamus were observed across the four treatment groups. There was a modest but significant effect of post-weaning HFD diet exposure to increase orexin cell quantity in the lateral hypothalamus (two-way ANOVA, p<0.01). In the VTA, MCH fibers were rarely observed in the vicinity of dopamine neurons, indicating that this neuronal pathway may develop later in adulthood in the primate or be less prominent than the projections observed in rodents. Orexin fibers were abundant in the VTA and there was a surprising trend towards decreased orexin fiber density with either maternal or post-weaning exposure to a HFD. These findings indicate that the hedonic orexin input to dopamine neurons may be decreased with either prenatal or postnatal exposure to a HFD. Reduction in this input could result in a decreased sense of reward for calories consumed, requiring animals to overeat to achieve the same sense of reward.

 

Disclosure: KLG: , Novo Nordisk. Nothing to Disclose: CT, AA, ELS, PK

OR26-6 32682 6.0000 A Maternal and Post-Weaning Diet Effects on the Neuronal Pathways Regulating Hedonic Reward in Juvenile Nonhuman Primates 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Obesity, Adipocyte Biology and Appetite Saturday, April 1st 1:00:00 PM OR26 9457 11:30:00 AM Central Regulation of Feeding and Body Weight Oral


Anna Hjorth-Hansen*1, Torbjørn Eggebø2, Kjell Åsmund Salvesen3, Eszter Vanky4 and Rønnaug Ødegård5
1Dept. of Internal Medicine, Levanger Hospital, Norway, Levanger, Norway, 2National Center of Fetal Medicine, Trondheim, Institute of Laboratory Medicine, Children’s and Women’s Health, NTNU, Trondheim, 3Dept. of Obstetrics and Gynecology, St. Olav’s Hospital, Trondheim University Hospital, 4Dept. for Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway, 5Trondheim University Hospital, Trondheim, Norway

 

Metformin is used in pregnancy to treat GDM and polycystic ovary syndrome (PCOS). We know little about its long-term impact on metabolism or neural development in the offspring. Here we analyze ultrasound measurements in utero and revisit head size and growth at birth of children from the PregMet study [1]. We hypothesized that the effect of metformin on head size is traceable already in utero, and that babies born to mothers with PCOS may have a different body composition compared to normative data, expressed in z-score.
The present study was a post hoc analysis of data collected in an RCT, the “Metformin treatment in pregnant PCOS women” (The PregMet1) study, in which 273 women with PCOS were randomized to metformin 2g daily or placebo from first trimester to delivery. In all 258 babies were included in this study. Three women had miscarriages and 12 women dropped out. Compliance was good or acceptable in 85% of the participants.Bi-parietal diameter (BPD) and mean abdominal diameter (MAD) were measured at gestational weeks (gw) 19 and 32. Head circumference, length and weight were measured at birth. Gestational age and gender-adjusted z-scores were calculated based on standard values from a large Swedish population2.
At gw 19 we found no difference in BPD or MAD between the metformin and placebo groups. At gw 32 the metformin exposed fetuses had a larger BPD compared to those exposed to placebo (86.1 ± 3.1 mm vs. 85.2 ± 3.3 mm) (p=0.003). No difference was observed in MAD. 
At birth, compared to placebo, metformin exposed babies had a larger head circumference (HC), (35.6 ± 1.6 cm vs. 35.1 ± 1.6 cm) (p=0.007). We found no difference in birth weight and birth length between the groups.
Gestational age- and gender-adjusted z-score for head circumference showed that both metformin and placebo exposed babies tended to have larger head size z-score HCmet = 0.60 (95% CI 0.36 to 0.73), and z-score HCplac = 0.24 (95% CI -0.31 to 0.02) compared to the standard population. In contrast, in both groups, z-score for length tended to be lower than the population mean; z-score length(met) = - 0.25 (95% CI -0.41 to -0.9) and z-score length(plac) = - 0.12 (95% CI -0.31 to 0.02), whereas birth weight did not differ from the standard population.
Large head size has been reported to correlate to good cardio-vascular health, and is also directly correlated to brain volume. Brain volume is positively associated with cognitive function. We can only speculate on long-term effects of these findings.
In conclusion, in an RCT setting, metformin treatment of pregnant women with PCOS resulted in larger head size of the offspring, traceable already in utero. Compared to normative data, children born to mothers with PCOS had larger head and tended to be shorter at birth

* EV and RØ have shared last authorship


 

Nothing to Disclose: AH, TE, KÅS, EV, RØ

OR33-1 31101 1.0000 A Head Size and Growth in Utero and at Birth in Metformin Exposed Children Born to Mothers with PCOS – a Randomized Controlled Trial 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 1:00:00 PM OR33 9464 11:30:00 AM Female Reproductive Endocrinology: From Pregnancy to Menopause Oral


Rebecca Fleur Goldstein*1, Sally K. Abell1, Marie Louise Misso1, Sanjeeva Ranasinha1, Jacqueline Boyle1, Mary Helen Black2, Nan Li3, Gang Hu4, Francesco Corrado5, Line Rode6, Young Ju Kim7, Margaretha Haugen8, Won O Song9, Min Hyoung Kim10, Annick Bogaerts11, Roland Devlieger12, Judith Chung13 and Helena J. Teede1
1Monash University, Melbourne, Australia, 2Kaiser Permanente Southern California, Pasadena, CA, 3Tianjin Women’s and Children’s Health Center, Tianjin, China, 4Pennington Biomedical Research Center, Baton Rouge, Louisiana, 5University Hospital, Messina, Italy, 6Copenhagen University Hospital, Righospitalet, 7Department of Obstetrics and Gynecology, School of Medicine, Ewha Womans University, Seoul, Republic of Korea, 8Norwegian Institute of Public Health, Oslo, Norway, 9Michigan State University, MI, USA, 10Dankook University College of Medicine, Seoul, Korea, 11Department of Development and Regeneration KU Leuven, University of Leuven, Leuven, Belgium; Faculty of Medicine and Health Sciences, Centre for Research and Innovation in Care (CRIC), University of Antwerp, Belgium; Faculty of Health and Social Work, res, 12Department of Obstetrics and Gynaecology, University Hospitals KU Leuven, Belgium; Department of Obstetrics, Gynaecology and Fertility, GZA campus Sint-Augustinus, Wilrijk, Belgium;, 13University of California, Irvine, California

 

Importance: Institute of Medicine (IOM) gestational weight gain (GWG) guidelines are inconsistently used worldwide. Whilst comprehensively developed, they are not underpinned by systematic review or meta-analysis, lack ethnic diversity and are not informed by the most contemporary maternal data. This is relevant as obesity rates and rising GWG are well documented.

Objective: We performed a systematic review, meta-analysis and meta-regression to evaluate 2009 IOM guidelines in contemporary maternal populations across all weight categories and broad ethnic groups to validate the guidelines.

 

Data Sources: EMBASE, All EBM Reviews, Medline and Medline in-process were searched from 1st January 1999-28th January 2016.

Study selection: Inclusion required observational studies stratify by prepregnancy body mass index (BMI) category and total pregnancy GWG. Authors were contacted for re-analysis given data heterogeneity. Odds ratios (OR) used recommended GWG within each BMI category as the reference. PROSPERO registration CRD42015023325.

Data extraction and synthesis: Data were extracted by two independent reviewers. OR were calculated using a random-effects model. Heterogeneity was assessed using I². Methodological quality was assessed using Monash Centre for Health Research and Implementation Evidence Synthesis appraisal.

Main outcomes and measures: Outcomes were small for gestational age (SGA), preterm birth, large for gestational age (LGA), macrosomia, caesarean section and gestational diabetes.

Results: 5354 studies were identified, 19 studies (n=1,137,464 women) met inclusion criteria. GWG was below, at or above guidelines in 20, 29 and 51% of pregnancies respectively. GWG below recommended had higher SGA [(OR) 1.49; 95% CI 1.39,1.61] and preterm birth (1.37;1.21,1.55), and lower LGA (0.62;0.57,0.67) and macrosomia (0.65; 0.57 0.73) compared to recommended GWG. GWG above recommended had lower SGA (0.65;0.62,0.68) and preterm birth (0.77;0.68,0.88) and higher LGA (1.89;1.79,2.01), macrosomia (1.83;1.69,1.99) and caesarean (1.29;1.23,1.35). Subgroup analyses stratified by obesity class I-III found similar risks for SGA, LGA, macrosomia and caesarean.

Conclusions: In this review of over 1,000,000 pregnancies in a contemporary population with high mean BMI and diverse ethnicity, GWG outside 2009 IOM recommendations is associated with greater maternal and infant adverse effects. This work attests the broad applicability of 2009 IOM guidelines and highlights the need to implement these GWG recommendations broadly across maternity care.

 

Nothing to Disclose: RFG, SKA, MLM, SR, JB, MHB, NL, GH, FC, LR, YJK, MH, WOS, MHK, AB, RD, JC, HJT

OR33-2 29861 2.0000 A Gestational Weight Gain Outside Institute of Medicine Guidelines: Systematic Review and Meta-Analysis of Maternal and Infant Outcomes in over One Million Women 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 1:00:00 PM OR33 9464 11:30:00 AM Female Reproductive Endocrinology: From Pregnancy to Menopause Oral


Nozomi Takahashi*1, Miyuki Harada1, Jerilee MK Azhary1, Yasushi Hirota1, Osamu Yoshino2, Osamu Hiraike1, Tomoyuki Fujii1 and Yutaka Osuga1
1The University of Tokyo, Tokyo, Japan, 2The University of Toyama, Toyama, Japan

 

Obesity in reproductive-aged women is associated with shorter luteal phase and lower progesterone levels (1). Lipid accumulation in follicles of obese women compromises endoplasmic reticulum (ER) function, activating ER stress in granulosa cells (2). ER stress results in activation of a group transduction cascade, the unfolded protein response (UPR), affecting a wide variety of cellular functions. In previous studies, we demonstrated that ER stress in granulosa cells influences the regulation of cellular functions (3,4). We hypothesized that ER stress activated in granulosa lutein cells (GLCs) modulates progesterone production and contributes to obesity-associated progesterone deficiency. To test this hypothesis, we investigated the effect of ER stress on progesterone production in cultured human GLCs in vitro, as well as in rodents in vivo. First, to confirm the activation of ER stress in the ovary of obese individuals, the mRNA expression levels of UPR genes in the ovary of Ob/Ob mice (Lepob/ Lepob) were compared to control lean mouse (Lepob/+) by real-time quantitative PCR (qPCR). The mRNA expression of UPR genes, XBP1(S), ATF4, ATF6, and HSPA5, were upregulated in the ovary of Ob/Ob mice. Next, we investigated the effect of ER stress on hCG-induced progesterone production in cultured human GLCs in vitro by EIA. Pretreatment with tunicamycin (Tm) and thapsigargin, ER stress inducers, decreased hCG-stimulated progesterone secretion in human GLCs. To elucidate the underlying mechanism by which ER stress interferes with progesterone production, we examined the effect of Tm on the mRNA expression of hCG-stimulated steroidogenesis-related genes and LH/hCG receptor (LHR) in human GLCs by qPCR. Pretreatment with Tm inhibited hCG-stimulated StAR and 3β-HSD mRNA expression, without affecting the level of P450scc, aromatase, and LHR mRNA. Pretreatment with Tm also inhibited StAR protein and 3β-HSD enzyme activity in human GLCs, as determined by Western blot analysis and EIA. Pretreatment with Tm did not affect hCG-induced intracellular cAMP accumulation, while affecting the cAMP-stimulated expression of StAR, P450scc, and 3β-HSD mRNA similarly to stimulation with hCG. Furthermore, Tm attenuated hCG-induced protein kinase A and ERK activation, as determined by Western blot analysis. Finally, we examined the in vivo effect of ER stress on progesterone production. Administration of Tm to PMSG-treated immature mice prior to hCG treatment inhibited hCG-stimulated rise in serum progesterone levels and hCG-induced expression of StAR and 3β-HSD mRNA in the ovary without affecting serum estradiol levels or the number of corpora lutea. Our findings indicate that ER stress in the follicles of obese women contributes to progesterone deficiency by inhibiting hCG-induced progesterone production in GLCs.

 

Nothing to Disclose: NT, MH, JMA, YH, OY, OH, TF, YO

OR33-3 29489 3.0000 A Endoplamic Reticulum (ER) Stress Inhibits Progesterone Production in Human Granulosa Cells: A Potential Role for ER Stress in Progesterone Deficiency in Obese Women 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 1:00:00 PM OR33 9464 11:30:00 AM Female Reproductive Endocrinology: From Pregnancy to Menopause Oral


Ali Abbara*1, Sophie A Clarke1, Rumana Islam2, Julia K Prague1, Alexander N Comninos1, Shakunthala Narayanaswamy1, Deborah A Papadopoulou1, Rachel E Roberts1, Chioma Izzi-Engbeaya1, Risheka Ratnasabapathy1, Alexander Nesbitt1, Sunitha Vimalesvaran1, Rehan Salim2, Stuart A Lavery2, Stephen R Bloom1, Les Huson1, Geoffrey H Trew2 and Waljit S Dhillo1
1Imperial College London, London, United Kingdom, 2Hammersmith Hospital, London, United Kingdom

 

Aims:

IVF is an effective therapy for infertility, but can result in the potentially life-threatening complication ovarian hyperstimulation syndrome (OHSS). We have previously reported that a single injection of kisspeptin results in an LH-surge of ~12-14hrs duration, sufficient to safely trigger oocyte maturation in women at high risk of OHSS. We investigated whether increasing the duration of LH-exposure by administering a second dose of kisspeptin could further optimise oocyte maturation.

Methods:

We conducted a phase2 single-blinded randomised placebo-controlled trial of 62 women at high risk of OHSS. Following a standard recFSH/GnRH-antagonist IVF protocol, all patients received a subcutaneous injection of kisspeptin-54(9.6nmol/kg) 36hrs prior to oocyte retrieval. Patients were then randomized 1:1 to receive either a second dose of kisspeptin 10hrs later (D;Double), or saline placebo (S;Single). IVF physicians, embryologists and participants were blinded to the randomization. Retrieved oocytes were assessed for maturation and fertilized by ICSI. Elective single embryo transfer (eSET) was carried out in all patients with at least one high quality blastocyst.

Outcomes:

Primary Outcome: Proportion of patients achieving a satisfactory oocyte yield (% of mature oocytes retrieved from follicles ≥14mm in diameter) of ≥60%.

Secondary Outcomes: Implantation Rate and occurrence of OHSS.

Discussion:

A second injection of kisspeptin at 10hrs following the first induced a significant further mean fold-rise in LH-secretion at 4hrs (S:3.3, D:14.7;P<0.0001) and 10hrs (S:1.5, D:3.1;P=0.0002) thereafter when compared to pre-trigger levels. The proportion of patients achieving a satisfactory oocyte yield was improved following two doses of kisspeptin (S:45%, D:71%; RD 25.8%, CI 2.1-49.5%). There was a trend towards a higher implantation rate following 2 doses of kisspeptin (S:23.3%; D:37.1%; P=0.20), but no difference in the frequency of OHSS.

Conclusion:

Prolonging the duration of LH-exposure by administering a second dose of kisspeptin safely improves oocyte yield in women at high risk of developing OHSS undergoing IVF treatment.

 

Nothing to Disclose: AA, SAC, RI, JKP, ANC, SN, DAP, RER, CI, RR, AN, SV, RS, SAL, SRB, LH, GHT, WSD

OR33-4 30682 4.0000 A A Second Injection of Kisspeptin-54 Safely Improves Oocyte Maturation during in Vitro Fertilisation Therapy in Women at High Risk of Ovarian Hyperstimulation Syndrome 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 1:00:00 PM OR33 9464 11:30:00 AM Female Reproductive Endocrinology: From Pregnancy to Menopause Oral


Sophie A Clarke*1, Ali Abbara1, Rumana Islam2, Georgios Christopoulos2, Alexander N Comninos1, Stuart A Lavery2, Geoffrey H Trew2 and Waljit S Dhillo1
1Imperial College London, London, United Kingdom, 2Hammersmith Hospital, London, United Kingdom

 

Aim and Objectives:

Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic condition predominantly related to the mode of triggering oocyte maturation during IVF treatment. Kisspeptin is a novel trigger which stimulates the physiological release of GnRH from the hypothalamus. Kisspeptin has recently been shown to safely trigger oocyte maturation in a population at high risk of OHSS, but has yet to be directly compared with other triggers. Ovarian volume and ascitic fluid are commonly used to categorise the severity of OHSS in diagnostic guidelines. We therefore investigated these parameters in women undergoing IVF treatment with 3 different triggers of oocyte maturation in women at high risk of OHSS.

Method and Outcomes:

Women at high risk of OHSS (antral follicle count ≥23), aged <35yrs, BMI <30 kg/m2 with both ovaries intact, were screened sonographically and for symptoms of OHSS at 2-5 days following oocyte retrieval. Patient outcomes were determined when patients were triggered with human chorionic gonodotrophin (hCG) (n=8), GnRH agonist (GnRHa) (n=54) or kisspeptin (n=122). Statistical analysis was performed using Kruskal-Wallis test with post-hoc Bonferroni correction.

Discussion:

Median ovarian volume (MOV) following GnRHa trigger (74.8mls) was significantly lower than in patients triggered with hCG (143.3mls; p <0.05). MOV following kisspeptin trigger (44.0mls) was significantly lower still when compared with GnRHa trigger (p <0.001).

Median ascitic volume was lower after GnRHa (2mls; p<0.01) and kisspeptin (0mls; p<0.001) when compared with hCG (42mls). Symptoms of OHSS were more frequently reported following GnRHa use than kisspeptin and more frequently still following hCG.

 Relevance / Impact:

Increased ovarian volume and ascitic fluid volume consistent with OHSS were less frequent following kisspeptin than GnRHa or hCG in a population undergoing IVF treatment at high risk of OHSS. Kisspeptin was also associated with less frequent reporting of symptoms of OHSS. Kisspeptin may thus present a safer alternative than GnRHa or hCG triggering in patients undergoing IVF treatment at high risk of OHSS.

 

Nothing to Disclose: SAC, AA, RI, GC, ANC, SAL, GHT, WSD

OR33-5 31442 5.0000 A Kisspeptin - a Safer Alternative for Triggering Oocyte Maturation during IVF Treatment to Reduce the Risk of Ovarian Hyperstimulation Syndrome? 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 1:00:00 PM OR33 9464 11:30:00 AM Female Reproductive Endocrinology: From Pregnancy to Menopause Oral


Anqi Fu*1, Sydney Oberholzer1, Stefan Bagheri-Fam2, Jessica Muszynski1, Chi-chung Hui3, Dagmar Wilhelm2 and Joan Susan Jorgensen1
1University of Wisconsin - Madison, Madison, WI, 2The University of Melbourne, Parkville, Australia, 3University of Toronto, Toronto, ON, Canada

 

Ovarian follicle integrity and healthy development depends on appropriate communication between somatic cells and the oocyte within the follicle. Previously, we reported that global knockout (KO) of two Iroquois homeobox transcription factors, Irx3 and Irx5 (Irx3/5, Irx3ΔIrx5EGFP/Irx3ΔIrx5EGFP) caused abnormal follicle morphology with disrupted somatic cell – oocyte contacts that led to massive oocyte death. The objective of the current study was to characterize Irx3/5 expression profiles over time and investigate their roles in fertility. We hypothesized that cell- and time-specific expression of both Irx3/5 is required to promote follicle integrity for optimal fertility. Whole mount in situ hybridization results supported previous data indicating robust Irx3/5 RNA expression in mouse ovaries during development (embryonic day, E15.5 – postnatal day, P0), which diminished after P3. Further, immunofluorescence results showed that IRX3 and IRX5 were co-expressed within the pre-granulosa cell sub-population of ovarian somatic cells during development. After birth, IRX3 and IRX5 were co-expressed in both pre-granulosa cells and oocytes in primordial follicles, but their expression patterns diverged as follicles matured. From mature primordial to pre-antral follicle stages, IRX5 was restricted to granulosa cells while IRX3 was expressed exclusively in oocytes. Based on these patterns, we hypothesized that IRX3 and IRX5 play distinct roles in follicle health. To investigate the role of somatic cell-specific expression of Irx3/5 during ovary development, we used Sf1-Cre to generate mice with somatic cell deletion of Irx3 in the context of the Irx5 global knockout [Sf1Cre+/-; Irx3floxIrx5EGFP/Irx3floxIrx5EGFP (Irx3/5 sFF)]. Breeding studies were conducted to compare fertility between Irx3/5 sFF, Irx5EGFP/EGFP (NoCre; Irx3/5 sFF, = global Irx5 KO) and Irx3LacZ/LacZ (global Irx3 KO) mice. After 6-months, Irx3/5 sFF, Irx5EGFP/EGFP and Irx3LacZ/LacZ females produced significantly fewer pups per litter than their respective controls (9 vs. 11, P<0.01; 8 vs. 11, P<0.01; and 7 vs. 13, P<0.01). Notably, there was no significant difference in fertility between Irx3/5 sFF and Irx5EGFP/EGFP females (9 vs. 8, P>0.05). Based on these results, we concluded that somatic cell expression of Irx3 was dispensable; however, Irx3LacZ/LacZ females were also subfertile suggesting that Irx3 expression in germ cells was important. Experiments are currently underway to validate the requirement for germ cell-specific Irx3 expression using Ddx4-Cre. Understanding the requirement of cell type – specific expression of Irx3/5 in ovary will shed light on the mechanism of Irx3/5 function within developing follicles that ensures their integrity and, ultimately, fertility.

 

Nothing to Disclose: AF, SO, SB, JM, CCH, DW, JSJ

OR33-6 32411 6.0000 A Distinct Spatio-Temporal Expression Profiles of Irx3 and Irx5 in the Mouse Ovary Is Required to Maintain Follicle Integrity 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 1:00:00 PM OR33 9464 11:30:00 AM Female Reproductive Endocrinology: From Pregnancy to Menopause Oral


Oleg Varlamov*1, Cadence True1, Mithila Handu1, Diana Lynn Takahashi1, Judy L Cameron2, Richard L Stouffer3 and Charles T Roberts Jr.1
1Oregon National Primate Research Center, Beaverton, OR, 2University of Pittsburgh, Pittsburgh, PA, 3Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR

 

Hyperandrogenemia in females, principally in the context of polycystic ovary syndrome (PCOS), is often associated with metabolic disease. However, the relative contributions of excess androgen versus increased BMI often seen in women with PCOS, to insulin resistance and related features of the metabolic syndrome are difficult to discern in clinical studies. To evaluate the separate and combined effects of androgens and obesity, we have developed a preclinical model of female rhesus macaques maintained on a control or high-fat/calorie-dense western-style diet (WSD) in the presence or absence of chronically elevated testosterone (T) levels similar to those in young women predisposed to PCOS. Specifically, four groups of peripubertal females (C, control diet; T; WSD; WSD+T; n=10/group) were started at 2.5 years of age and maintained on treatment for three years until the current analysis at 5.5 years of age. After 3-years of treatment, only the WSD+T group exhibited significant change in percentage weight gain (p<0.01) and percentage body fat (p < 0.05), with a trend toward increased android fat, consistent with previous findings in women with PCOS. Ex vivo analysis of white adipose tissue (WAT) biopsies revealed that WSD+T visceral (OM, omental) adipocytes were significantly (p<0.05) enlarged, while WSD+T subcutaneous (SC) adipocytes showed a trend toward larger sizes compared to all other groups. Beta-adrenergic stimulation of OM-WAT lipolysis was blunted significantly in the T group (p<0.05), while beta-adrenergic stimulation of SC-WAT lipolysis was inhibited (p<0.001) in the T, WSD, and WSD+T groups. The T, WSD, and WSD+T groups displayed a trend toward reduced capillary density in both WAT depots compared to the C group. In addition to WAT dysfunction and increased body fat, WSD+T animals were also insulin-resistant based on HOMA-IR but remained relatively euglycemic due to increased insulin secretion. In summary, while T and WSD separately altered lipolysis in SC adipocytes, only the combination of WSD+T resulted in the cumulative phenotype of weight gain, increased (android) fat mass, enlarged visceral and subcutaneous adipocytes, insulin resistance, and hyperinsulinemia. Given that neither WSD nor T alone resulted in significant metabolic changes from controls during the three-year treatment period, we conclude that the combination of hyperandrogenemia and excess nutrition accelerates the development of metabolic disease and WAT dysfunction.

 

Nothing to Disclose: OV, CT, MH, DLT, JLC, RLS, CTR Jr.

OR34-1 31346 1.0000 A Combined Androgen Excess and Western-Style Diet Accelerates Metabolic Dysfunction in Young Adult, Female Nonhuman Primates 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 1:00:00 PM OR34 9465 11:30:00 AM Female Reproductive Endocrinology: Hyperandrogenism Oral


Fady Hannah-Shmouni*1, Rachel Morissette2, Ninet Sinaii2, Meredith Elman2, Toni R. Prezant3, Ann Pulver4 and Deborah P. Merke5
1Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 2National Institutes of Health, Bethesda, MD, 3Laboratory Corporation of America® Holdings, Calabasas, CA, 4Johns Hopkins School of Medicine, Baltimore, MD, 5NIH, Bethesda, MD

 

Objectives: Based on a 1985 HLA-B linkage study of 314 families, nonclassic CAH (NCCAH) is estimated to be common, with a prevalence of 0.1% in the general Caucasian population, and 3.7% (30.9% carrier rate) in Ashkenazi Jews (1). However, epidemiological and genetic studies have not been done to confirm these remarkable rates.

Methods: Genotyping was performed in 200 unrelated healthy subjects of Ashkenazi Jewish descent (defined as having 4 Ashkenazi Jewish grandparents) and 200 healthy Caucasians who did not self-identify as a specific ethnicity. DNA was collected from The Foundation for Jewish Genetic Medicine (Ashkenazi Jews), and the Coriell Institute for Medical Research Biorepository (Caucasians). CYP21A2 was analyzed using multiplex minisequencing, real time PCR and junction site analysis. Proportions and comparisons between groups were analyzed using the binomial and Fisher’s exact tests, respectively.

Results: Of the 200 Ashkenazi Jews screened, 15% (95% CI: 10.4 - 20.7) were NCCAH carriers, and 2.5% (95% CI: 0.8 - 5.7) were classic CAH carriers. Of the Caucasians screened, 9.5% (95% CI: 5.8 - 14.4) were NCCAH carriers, and 1.5% (95% CI: 0.3 - 4.3) were classic CAH carriers. One subject in each cohort (0.5%, 95% CI: 0.01-2.8) had a genotype consistent with being affected with NCCAH. p.Q318X in the setting of gene duplication was not considered pathogenic. The proportion of Ashkenazi Jewish NCCAH carriers (0.15 vs. 0.309, P < .0001) and disease affected (0.005 vs. 0.037, P = .009) were not as high as previously reported and did not differ from our random sample of Caucasians (0.15 vs. 0.095, P = .13). Our study also suggests that nonclassic CAH is commonly found in general Caucasian populations, with an estimated prevalence of 1 in 200 (0.5%, 95% CI: 0.01-2.8).

Conclusion: Our study is the first to demonstrate, through state-of-the-art CYP21A2 analysis, that NCCAH is less common in Ashkenazi Jews than previously suggested. Our estimates of disease rates in the general U.S. Caucasian population argue for universal screening of NCCAH in the setting of female infertility or hyperandrogenism, regardless of ethnicity. These results have important implications with preconception and infertility counseling.

 

Disclosure: DPM: Principal Investigator, Diurnal, Principal Investigator, Millendo Therapeutics. Nothing to Disclose: FH, RM, NS, ME, TRP, AP

OR34-2 29787 2.0000 A Revisiting the Prevalence of Nonclassic Congenital Adrenal Hyperplasia in U.S. Ashkenazi Jews and Caucasians 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 1:00:00 PM OR34 9465 11:30:00 AM Female Reproductive Endocrinology: Hyperandrogenism Oral


Carlos Eduardo Seraphim*1, Julliana dos Santos Frassei1, Fernanda Cavalieri Costa1, Mirela Costa de Miranda1, Larissa Garcia Gomes1, Guiomar Madureira1, Berenice B Mendonca2 and Tania A Bachega1
1Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 2Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, SAO PAULO, Brazil

 

Background: Treatment of classical forms of CAH is based on glucocorticoid (GC) and mineralocorticoid replacements. However, there is no consensus about which GC should be used at adulthood and several studies reported increased frequency of metabolic syndrome (MS) in patients in comparison with normal population. Dexamethasone (DEX) presents a long half-life allowing once-daily dosing, which improves adherence, and could be a good choice to treat adult patients. There is no longitudinal study in the literature regarding the long-term metabolic effects of DEX in CAH patients.

Objective: To analyze the metabolic impact of DEX therapy in adult CAH patients followed in a single tertiary center.

Patients and Methods: 60 well-controlled CAH patients (41M/30SW) received DEX therapy after the achievement of final height. All patients had adequate androgen levels and normal serum electrolytes. Mean daily DEX doses/m2was evaluated. Clinical and laboratorial data were compared before DEX introduction and at the last evaluation. Frequency of MS components were assessed as proposed by the NCEP-ATPIII criteria. Statistical analysis included paired t-tests, Wilcoxon signed-rank tests, Chi-square and regression analyses when appropriated.

Results: mean age at the last evaluation and mean duration of DEX therapy were 31.9 ± 9.6 yrs and 11.5 ± 4.9 yrs, respectively; mean daily DEX dose was 0.17±0.07mg/m2. No significant differences were found regarding BMI-SDS, LDL-cholesterol, glucose and triglycerides levels before and after DEX therapy. A decrease in HDL-cholesterol levels (57 ± 12.8 vs 53.5 ± 13.6; p=0.008) and an increase in HOMA-IR (2.5 ± 1.3 vs 2.8 ± 1.7; p=0.03) were observed. Obesity prevalence remained unchanged before and after DEX and was lower than a previous study comprising a large cohort receiving different GCs (1) (26.7% vs 41%, respectively; p=0.042). However, waist to height ratio (WHtR) increased from 0.54 ± 0.08 to 0.56 ± 0.1 after DEX (p=0.001), although final waist circunference (WC) values were similar to the ones described in patients on different GCs (2). Regression analysis showed no correlation between duration/dose of DEX therapy and WC gain. Frequency of MS and hypertension remained similar before and after DEX (6.7% vs. 10%, p=0.7; and 15% vs 13.3%, p=0.8, respectively).

Conclusions: In our cohort, the use of dexamethasone didn’t lead to increased frequency of obesity and MS, although undesirable body fat distribution can occur. DEX appears to be a good option for the CAH treatment in adulthood.

 

Nothing to Disclose: CES, JDSF, FCC, MCDM, LGG, GM, BBM, TAB

OR34-3 30694 3.0000 A Low Impact of Long Term Dexamethasone Therapy on Metabolic Profile of Adult Patients with Classical Forms of CAH Due to 21-Hydroxylase 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 1:00:00 PM OR34 9465 11:30:00 AM Female Reproductive Endocrinology: Hyperandrogenism Oral


Raiane Pina Crespo1, Thaís Machado Pagliaro Rocha*1, Viviane dos Reis Vieira1, Berenice Bilharinho Mendonca2 and Larissa Garcia Gomes2
1Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil, 2Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

 

Postmenopausal ovarian hyperandrogenism is a rare condition, most frequently caused by ovarian hyperthecosis (OH) followed by ovarian androgen-secreting tumors (OAST). There is a positive association between androgen levels and insulin resistance in premenopausal hyperandrogenic women. However, there are limited data regarding the prevalence of metabolic abnormalities in postmenopausal hyperandrogenic women and the impact of testosterone levels normalization after bilateral oophorectomy on the metabolic profile.

Objectives: To assess the prevalence of obesity, diabetes, hypertension and dyslipidemia in postmenopausal hyperandrogenic women before and after testosterone levels normalization by bilateral oophorectomy.

Patients and Methods: 30 hyperandrogenic postmenopausal women, mean age at diagnosis of 57.5 + 7.8 yrs and submitted to bilateral oophorectomy were selected. All patients had elevated total testosterone (T) levels, mean 305 + 321 ng/dL, (IFMA, reference value < 98 ng/dl) before oophorectomy, and normalized T levels after surgery. Ovarian histopathology confirmed OH in 19/30 and OAST in 11/30 cases. Physical and biochemical parameters including BMI, blood pressure, glucose, A1c, cholesterol and triglycerides levels were assessed before and 2 years after oophorectomy. T-test, Mann-Whitney, Qui-square tests were performed for statistical analysis.

Results: There was an elevated prevalence of obesity (53.3%), diabetes (70%), hypertension (70%) and dyslipidemia (56.6%) in these patients. Despite the difference in T levels between the OH (median 173 ng/dl) and the OAST groups (median 448 ng/dl), p = 0.002, there were no differences between OH and OAST patients in the prevalence of obesity (58% x 66%, p = 0.24), diabetes (74% x 64%, p = 0.13) and hypertension (69% x 73%, p = 0.53). However, the prevalence of dyslipidemia was higher in the OAST (82%) than in the OH group (42%), p < 0.001. The mean glycated hemoglobin (A1c) levels in the diabetic patients was 7.0%, with no difference between OH (mean 7.4%) and OAST group (mean 7.0%), (p = 0.61). The A1c levels after oophorectomy did not change (mean 6.9%), (p = 0.81), and so did not the triglycerides (p = 0.51), LDL (p = 0.77) and HDL (p = 0.71) levels before and after treatment. There was no difference in the BMI before and 2 years after bilateral oophorectomy (p = 0.34).

Conclusion: Women with postmenopausal ovarian hyperandrogenism have a very high prevalence of insulin resistance and metabolic syndrome risk factors. Hyperinsulinemia might contribute to the ovarian hyperandrogenism by directly stimulating ovarian testosterone synthesis. The normalization of androgen levels did not improve the metabolic profile suggesting no impact of androgen excess in insulin resistance in postmenopausal hyperandrogenism.

 

Nothing to Disclose: RPC, TMPR, VDRV, BBM, LGG

OR34-4 32478 4.0000 A Metabolic Profile in Postmenopausal Hyperandrogenic Women before and after Normalization of Testosterone Levels By Bilateral Oophorectomy 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 1:00:00 PM OR34 9465 11:30:00 AM Female Reproductive Endocrinology: Hyperandrogenism Oral


Anu Sharma*1, Ekta Kapoor1, Alice Y Chang1, Ravinder J. Singh2 and Dana Erickson1
1Mayo Clinic, Rochester, MN, 2Mayo Clinic

 

Introduction

The evaluation of clinical hyperandrogenism in women often includes the measurement of circulating concentrations of total testosterone (TT). Additional evaluation for androgen producing tumors (APTs) in women is generally recommended for TT greater than 200ng/dL. However, this is largely based on data using immunoassays to measure TT. Liquid chromatography/mass spectroscopy (LC/MS) assays are considered the gold standard for measuring TT due to its higher specificity. We hypothesized that a lower TT threshold for further APT evaluation might increase the detection of APTs without increasing evaluation of false negatives. To date, there have been no large series published regarding TT concentrations in women with APTs as measured by LC-MS.

Aim

To determine the best discriminatory threshold for TT concentrations measured by LC/MS to screen for APTs in women.

Methods

A retrospective analysis was conducted of all women with a TT concentration ≥ 100 ng/dL by LC-MS at the Mayo Clinic in Rochester, MN from 2004-2012(since assay availability). Medical records were reviewed to determine clinical presentation, laboratory and radiographic findings, diagnosis and treatment.

Results

A total of 366 adult female patients had TT concentrations ≥100ng/dL. Two hundred and eighty women were excluded from analysis (184 on exogenous testosterone, 22 liver failure, 12 gender dysphoria, 13 congenital adrenal hyperplasia/androgen insensitivity, 12 pregnant, 8 pediatric, 7 adrenocortical carcinoma and 22 had no further evaluation). Out of 86 who underwent final analysis, 55 women (64%) had polycystic ovarian syndrome (PCOS), 12 (14%) had ovarian hyperthecosis (OH) and 19 (22%) had an APT as the cause for hyperandrogenism. The mean age at presentation was 28±7 years in the PCOS group, 61±8 years in the OH group and 51±18 years in the APT group (p<0.001). APT patients had a significantly rapid onset of their symptoms (PCOS 60±7 months vs OH 35±15 months vs APT 19 ± 11 months; p<0.01). There was no difference among the three groups regarding symptoms of hyperandrogenism or examination findings. TT concentrations were significantly higher in the APT group (PCOS 125±35 ng/dL vs OH 183±103 ng/dL vs APT 287±135 ng/dL; p<0.001). Free testosterone concentrations were also higher in the APT group. DHEA-S was measured in 64 (74.4%) women. Significantly higher DHEA-S concentrations were found in the PCOS group (PCOS 186±15 µg/dL vs OH 77±34 µg/dL vs APT 93±31 µg/dL; p<0.01; not age adjusted). Eleven (73%) APTs localized to the ovary. A TT concentration ≥ 148ng/dL had a sensitivity of 84% and specificity of 85% for the diagnosis of APT as determined by the ROC curve. In the APT group, there was no difference between pre- and post-menopausal women in TT concentrations or tumor source.

Conclusion

A TT concentration threshold of ≥148 ng/dL identified 84% of APTs among women with TT concentrations ≥ 100ng/dL by LC-MS.

 

Nothing to Disclose: AS, EK, AYC, RJS, DE

OR34-5 31025 5.0000 A Defining a Threshold for the Identification of Androgen Producing Tumors in Women Using Serum Total Testosterone Concentrations Measured By Liquid Chromatography-Mass Spectroscopy 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 1:00:00 PM OR34 9465 11:30:00 AM Female Reproductive Endocrinology: Hyperandrogenism Oral


Adina F. Turcu*1, Juilee Rege2, Jianwei Ren2, Aya T. Nanba2, Richard J. Auchus2 and William E. Rainey1
1The University of Michigan, Ann Arbor, MI, 2University of Michigan, Ann Arbor, MI

 

Background: The menopausal transition leads to a constellation of clinical manifestations, including bone loss, increased cardiovascular risk, sexual dysfunction, sleep disturbances, skin changes, and cognitive decline. The loss of gonadal function alone does not explain the pronounced individual variability in these consequences of aging. The major 19-carbon steroids from the adrenal gland, dehydroepiandrosterone- and 5-androstenediol sulfates (DHEAS, AdiolS), also decline with age, though more gradually than estrogens. Residual sex-steroid production after menopause, however, helps to maintain bone health, muscle strength, sexuality, and well-being. The ovary and the adrenal gland are the two sources of androgens in women of reproductive age, but their contributions to healthy aging in postmenopausal women remain poorly understood. The adrenal gland is the major source of 11-oxygenated 19-Carbon derivatives of androstenedione (AD) and testosterone (T): 11b-hydroxyandrostenedione (11OHAD), 11b-hydroxytestosterone (11OHT), 11-ketoandrostenedione (11KAD) and 11-ketotestosterone (11KT). We hypothesized that, in contrast with DHEAS, these adrenal androgens do not decline with age.

Participants and methods: Morning serum was obtained from 20 pre- (YW, age 20-40 years) and 20 post-menoapausal women (OW, age 60-80 years), who were not taking any hormonal therapy. We quantified 21 steroids by liquid chromatography-tandem mass spectrometry. To understand the adrenal transformations that occur with aging and might impact its androgen synthetic potential, we performed double immunofluorescence for the key androgenic enzyme and cofactor 3b-hydroxysteroid dehydrogenase type 2 (HSD3B2) and cytochrome b5 (CYB5A) in adrenal glands from 4 YW and 4 OW. The nonparametric Mann-Whitney Utest was used for between-groups comparison.

Results: DHEA, DHEAS and AD decreased significantly with aging (1.3-2.3 fold higher in YW, p<0.001) in accordance with previously published results. In contrast, 11KT and T did not decline, and 11OHAD, 11KAD and 11OHT increasedin OW (1.4-2 fold, p<0.02). The 11KT/T ratio remained relatively constant across ages (median 2.2). As observed previously, adrenal glands from YW displayed segregation of HSD3B2 and CYB5A to the zona fasciculata and zona reticularis, respectively. In contrast, the adrenal tissue from OW displayed areas of HSD3B2 and CYB5A co-expression. These findings suggest that with aging, the adrenal gland attains a higher synthetic capacity of active androgens, at the expense of the major precursors DHEA and DHEAS, which have trivial androgenic activity.

Conclusion: These results support the hypothesis that the adrenal gland assumes a major role in the synthesis of active androgens in menopausal women.

 

Nothing to Disclose: AFT, JR, JR, ATN, RJA, WER

OR34-6 31211 6.0000 A Adrenal 11-Oxygenated 19-Carbon Steroids Are the Dominant Androgens in Postmenopausal Women 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 1:00:00 PM OR34 9465 11:30:00 AM Female Reproductive Endocrinology: Hyperandrogenism Oral


Anne H van der Spek*1, Kin Ki Jim1, Hermina C van Beeren1, Aldona Karaczyn2, Veerle M Darras3, Mariette T Ackermans1, Arturo Hernandez2, Matthijs C Brouwer1, Eric Fliers1, Diederik van de Beek1 and Anita Boelen1
1Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, 2Maine Medical Center Research Institute, Scarborough, ME, 3KU Leuven, Leuven, Belgium

 

Neutrophils are essential effector cells of the innate immune system. We have previously shown that the thyroid hormone (TH) inactivating enzyme type 3 deiodinase (D3) is present in infiltrating murine and human neutrophils [1, 2]. Furthermore, D3KO mice have impaired bacterial killing upon infection [3]. We hypothesized that D3 plays a role in neutrophil function during infection by actively regulating local TH availability.

To study whether neutrophils can alter local TH levels we measured TH concentrations in cerebral spinal fluid (CSF) from patients with bacterial meningitis versus controls using LC-MSMS. Bacterial meningitis is a severe infection characterized by high neutrophil infiltration. To determine the role of D3 in neutrophil function we analyzed neutrophils derived from D3KO mice and WT controls. Neutrophil count, survival, phagocytosis and hydrogen peroxide production in response to an activating stimulus were measured. Finally, we determined the effect of D3 knockdown (KD) on mortality and neutrophil-microbe interaction in vivousing a zebrafish embryo meningitis model [4]. Transgenic zebrafish embryos with green fluorescent neutrophils were infected with S. pneumoniae in the hindbrain ventricle. Morpholino technology was used to modulate TH availability by knocking down D3 [5]. Zebrafish survival was quantified and neutrophil recruitment over time was assessed with confocal microscopy.

Both T4 and reverse T3 (rT3) levels were strongly increased in CSF from bacterial meningitis patients compared to control CSF. Increased permeability of the blood brain barrier during meningitis could allow for leakage of T4 from the circulation to the CSF. As CSF rT3 levels are too high to be explained by leakage from the blood, this suggests that T4 is locally converted to rT3 by D3 in infiltrating neutrophils. Neutrophils from D3KO mice exhibited impaired hydrogen peroxidase production upon activation compared to WT cells indicating decreased NADPH-oxidase activity, an important component of bacterial killing. Neutrophil amount, phagocytosis and spontaneous apoptosis were not affected by D3 deficiency. Finally, the mortality rate was higher in D3KD zebrafish embryos than in controls and confocal imaging revealed reduced neutrophil recruitment over time in infected D3KD zebrafish embryos.

In summary, the altered TH profile of human CSF during bacterial meningitis is consistent with elevated D3 activity in infiltrating neutrophils. In addition, the lack of D3 in mouse and zebrafish leads in vitro to impaired neutrophil function, as evidenced by decreased NADPH oxidase activity, and in vivo to decreased neutrophil recruitment and increased mortality during bacterial meningitis. These consistent findings across experimental models suggest a critical role for intracellular TH metabolism in neutrophil function during infection, a mechanism for which D3 appears essential.

 

Nothing to Disclose: AHV, KKJ, HCV, AK, VMD, MTA, AH, MCB, EF, DV, AB

OR39-1 30590 1.0000 A The Thyroid Hormone Inactivating Type 3 Deiodinase Is Essential for Adequate Neutrophil Function In Vivo and in Vitro 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Thyroid/HPT Axis Saturday, April 1st 1:00:00 PM OR39 9471 11:30:00 AM New Insights into Thyroid Hormone Action and Thyroid Cancer Oral


Yuqian Luo*1, Takeshi Akama2, Akiko Okayama3, Yuko Ishido1, Hisashi Hirano3 and Koichi Suzuki1
1Teikyo University, Tokyo, Japan, 2Leprosy Research Center, National Institute of Infectious Diseases, Tokyo, Japan, 3Yokohama City University, Yokohama, Japan

 

We previously elucidated that thyroglobulin (Tg) stored in thyroid follicles negatively regulates follicular function by suppressing the gene expression of key molecules that are essential for thyroid hormone (TH) biosynthesis (such as Tg itself, sodium iodide symporter, thyroid peroxidase and dual oxidase 2) in a concentration-dependent manner. Thus, follicular Tg serves as an intrinsic negative-feedback regulator that keeps the thyroid stimulating hormone (TSH) effect in check in individual follicles. However, the underlying mechanisms by which follicular Tg exerts such prominent autoregulatory effect following recognition by thyrocytes remains unclear. To identify potential proteins that recognize and interact with Tg, mass spectrometry (MS) was used to analyze immunoprecipitated Tg-bound proteins derived from Tg-treated rat thyroid FRTL-5 cells. Flotillin 1 and flotillin 2, two homologs that are integral membrane proteins in lipid rafts, were identified as novel Tg-binding proteins with high confidence. In agreement with MS results, flotillin 1 and flotillin 2 were both detected in immunoprecipitated Tg-bound proteins by Western blotting using anti-flotillin1/2 antibodies, which confirmed the physical association between flotillins and internalized Tg. Flotillins have been reported to be involved in the endocytosis, intracellular traffic and signal transductions. We therefore proceeded to explore a potential role of flotillins in the endocytosis and negative-feedback effect of Tg in the thyrocytes. Double immunofluorescence staining clearly demonstrated that membrane-distributed flotillins were translocalized into endosomes after Tg internalization, in which flotillins were co-localized with the endocytosed Tg. Treatment with the lipid raft disrupter methyl-β-cyclodextrin (MβCD) abolished both the endocytosis and the negative-feedback effect of Tg on thyroid-specific gene expression. Meanwhile, siRNA-mediated knockdown of flotillin 1 or flotillin 2 also significantly inhibited Tg effects on gene expression in FRTL-5 cells. Together these results revealed a novel function of flotillins that are essential for follicular Tg to be recognized by thyrocytes and exert its negative-feedback effects in the thyrocytes.

 

Nothing to Disclose: YL, TA, AO, YI, HH, KS

OR39-2 30747 2.0000 A A Novel Role for Flotillin-Containing Lipid Rafts in Negative-Feedback Regulation of Thyroid-Specific Gene Expression By Thyroglobulin 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Thyroid/HPT Axis Saturday, April 1st 1:00:00 PM OR39 9471 11:30:00 AM New Insights into Thyroid Hormone Action and Thyroid Cancer Oral


Noelle Gillis*, Thomas Taber, Jennifer Tomczak, Jeffrey H White, Jane B Lian, Janet L. Stein, Gary Stephen Stein and Frances E Carr
University of Vermont College of Medicine, Burlington, VT

 

Transcriptional regulation in normal and malignant cells is a complex and dynamic process that is in part dependent on multisubunit chromatin remodeling complexes that modulate higher-order chromatin structure. Mutations, epigenetic silencing, and/or specific loss of the ATPase core subunits, SMARCA2 (hBRM) and SMARCA4 (BRG1) and accessory factors are often associated with tumorigenesis, including in breast, prostate, and lung, but little is known about these factors in thyroid tumor development. Our previous studies revealed a novel signaling pathway, TRβ suppression of RUNX2 and RUNX2-regulated tumorigenic genes, in thyroid cells. In the context of the onset of thyroid cancer, a compelling question is whether SMARCA2, SMARCA4, and associated subunits mediate these events. In the present study, we found differential endogenous expression of SMARCA4 protein in normal and malignant thyroid cells (high in normal and low in malignant cells) whereas SMARCA2 was not detected. Endogenous expression of BAF57 and BAF60 was unchanged. Immunofluorescence microscopy revealed that SMARCA4 and TRβ have similar nuclear distribution patterns and significant co-localization. Because TRβ and SMARCA4 are targeted to the same subnuclear domains, we considered whether these proteins cooperatively function in the regulation of tumor suppression. Since TRβ suppresses RUNX2 tumor promoter activity, we investigated the association of TRβ, SMARCA4, BAF57, and BAF60 with the RUNX2 promoter TRE by electrophoretic mobility shift assays using nuclear proteins and whole cell lysates from thyroid cells. SMARCA4 and BAF60, but not BAF57, associated with the TRE. Importantly, chromatin immunoprecipitation (ChIP)-PCR confirmed the association of SMARCA4, BAF60, TRβ, but not BAF57, on the RUNX2 promoter region encompassing the TRE. Co-immunoprecipitation assays revealed that SMARCA4 associates with TRβ. Immunocomplexes obtained with TRβ antibody contained SMARCA4, and conversely immunocomplexes with SMARCA4 antibody showed the presence of TRβ. We further evaluated whether the chromatin remodeling subunits mediated TRβ suppression of RUNX2 expression. siRNA knockdown of SMARCA4 in normal thyroid cells resulted in an increase in RUNX2 mRNA and protein levels. Because SMARCA4 and TRβ expression levels are low and RUNX2 expression is high in malignant thyroid cells and knockdown of SMARCA4 results in an increase in RUNX2 with no change in TRβ levels, SMARCA4 may be necessary to mediate TRβ suppressive effects. These results demonstrate that SMARCA4 and BAF60 subunits of the human SWI/SNF chromatin remodeling complex associate with TRβ nuclear protein complexes and may be functionally linked with TRβ genomic suppression of the tumorigenic activity of RUNX2 in thyroid cells. Thus, chromatin remodeling may be obligatory for TRβ transcriptional regulation in thyroid tumorigenesis.

 

Nothing to Disclose: NG, TT, JT, JHW, JBL, JLS, GSS, FEC

OR39-3 32043 3.0000 A Chromatin Remodeling Complexes in Thyroid Tumorigenesis: Brahma Related Gene 1 (BRG1, SMARCA4) Mediates Thyroid Hormone Receptorβ(TRβ) Transcriptional Regulation of the RUNX2 Tumor Promoter 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Thyroid/HPT Axis Saturday, April 1st 1:00:00 PM OR39 9471 11:30:00 AM New Insights into Thyroid Hormone Action and Thyroid Cancer Oral


Julie E Hallanger-Johnson*1, Cesar Abuchaibe2, Christine H Chung1, Bryan McIver1 and Pablo Valderrabano1
1H. Lee Moffitt Cancer Center, Tampa, FL, 2University of South Florida, Tampa, FL

 

Introduction:

Fine needle aspiration cytology plays a pivotal role in the evaluation of thyroid nodules. However, ~25% of the aspirates render an indeterminate diagnosis. A gene expression classifier (GEC) marketed as Afirma is utilized to select patients with Bethesda III or IV thyroid nodules appropriate for observation rather than immediate surgery. However, several reports of the assay performance results have been divergent. We sought to evaluate the GEC performance through a systematic review of the literature.

Methods:

We searched in PubMed for “gene expression classifier or Afirma or GEC” AND “thyroid”, and retrieved 87 articles that were screened by two independent reviewers. 34 articles were excluded by title; and 30 more after abstract review. After reviewing the full text of 23 articles, we excluded 5 reports with overlap of cohorts with the original validation study or other larger published series; 3 reports in which analysis was performed in a specific subset of patients, rather than in all consecutively tested nodules; and 3 reports in which the prevalence of malignancy and test metrics could not be calculated on resected nodules. Two authors independently extracted the data for each of the 12 remaining articles selected for the final analysis. Tests metrics were calculated with 95% confidence intervals. 

Results:

A total of 1502 nodules with B-III or IV cytology and informative GEC result were included. 646 (43%) were GEC-benign; and 856 (57%) were GEC-suspicious. A total of 842 nodules (56%) were resected with an overall prevalence of malignancy of 39% (36%-42%). Nodules with GEC-benign result had significantly lower rates of resection than GEC-suspicious nodules: 25 % (n=159) vs. 80 % (n=683), respectively (p<0.0001). Among nodules with histological follow-up, 312 were true positive, 369 false positive, 16 false negative and 143 true negative results. The overall performance of the test on resected nodules was: sensitivity 95% (92%-97%), specificity 28% (24%-32%), positive predictive value (PPV) 46% (42%-50%) and NPV 90% (84%-94%). Excluding the 210 nodules of the original validation study, the resection rate was 13% for GEC-benign nodules and 76% for GEC-suspicious; and the prevalence of malignancy amongst resected nodules 44%. The sensitivity, specificity PPV and NPV for the independent validation studies were 96% (93%-98%), 17% (14%-22%), 48% (43%-52%) and 85% (74%-92%), respectively.

Conclusion:

The NPV of the GEC has been poorly validated as only 13% of GEC-benign nodules had histological follow-up in independent validation series. This selection bias may be also responsible for the significantly higher prevalence of malignancy and lower specificity observed in independent studies in comparison to the original validation study. The NPV of GEC may be lower than expected and still needs independent validation.

 

Disclosure: BM: Principal Investigator, GenePro-Dx Inc. Nothing to Disclose: JEH, CA, CHC, PV

OR39-4 32270 4.0000 A Performance of a Gene Expression Classifier for Thyroid Nodules with Indeterminate Cytology: A Systematic Review 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Thyroid/HPT Axis Saturday, April 1st 1:00:00 PM OR39 9471 11:30:00 AM New Insights into Thyroid Hormone Action and Thyroid Cancer Oral


Mona M. Sabra*1, Eric J Sherman2 and R Michael Tuttle3
1Memorial Sloan Kettering Cancer Center, New York, NY, 2Memorial Sloan Kettering, New York, NY, 3Mem Sloan Kettering Cancer Ctr, New York, NY

 

Abstract: Current management guidelines provide only general guidance regarding the indications for initiation of molecular targeted therapies in RAI refractory metastatic thyroid cancer. Randomized studies of both lenvatinib and sorafenib required progression by RECIST 14 months prior to study entry; however, this was not based on any data. Thus, based on expert opinion, the current indications for these therapies include the demonstration of clinically significant tumor burden and rapid tumor progression as evaluated by RECIST criteria. While thyroglobulin doubling times less than 1 year are associated with poor survival, a rapidly rising thyroglobulin level in the absence of structural disease progression is not a sufficient criterion for initiation of molecular targeted therapies. In order to better characterize the association between survival and the rate of structural disease progression, we retrospectively measured the structural doubling time of the two dominant measurable and trackable lung metastases noted on serial CT imaging in 88 patients with metastatic thyroid cancer followed at our institution between 1992 and 2016. The average structural doubling time (midDT) of the two selected lung metastases was used to group patients into 6 clinically relevant cohorts ( < 1year, 1-2 years, 2-3 years, 3-4 years and > 4 years or negative DT). The time point when patients achieved a metastatic focus of 1 cm or greater was defined as the inflection point of the growth curve. Within each patient, the tumor growth rate was remarkably constant in lung metastasis from thyroid cancer over a median follow up period of 8.5 years (median r = 0.92, r2 = 0.85). Patients with midDT < 1 year had worse overall survival than those with higher midDT (Log rank p = 0.01). Furthermore, the 5 year overall survival from the inflection point was 20% for midDT <1 year (n = 15), 50% for midDT 1-2 years (n= 19), 53% for midDT 2-3 years (n=9), 80 % for midDT 3-4 years (n=6), and 80% for midDT > 4 years or negative (n=12). Of the 15 patients with midDT < 1 year, 8 were ultimately treated with one or more tyrosine kinase inhibitor (TKI) in the course of their follow up (median follow up from inflection point was 2.4 years). Within the midDT < 1 year group, the 2 year overall survival from the inflection point was 88% in the TKI-treated group (n=8) as opposed to 43% in the non-treated group (n=7) (p = 0.13). The TKI survival benefit was not demonstrated in other midDT groups. In conclusion, the average structural doubling time (midDT) of lung metastasis is a good prognostic indicator of overall survival in patients with metastatic differentiated thyroid cancer and may identify a cohort likely to have a survival benefit from TKI therapy.

 

Disclosure: EJS: Consultant, Bayer, Inc., Consultant, Eisai. RMT: Consultant, Bayer, Inc., Consultant, Eisai. Nothing to Disclose: MMS

OR39-5 31389 5.0000 A Structural Doubling Time Predicts Overall Survival and Can Guide Initiation of Molecular Targeted Therapy in Patients with Lung Metastases from Follicular Cell Derived Thyroid Carcinoma 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Thyroid/HPT Axis Saturday, April 1st 1:00:00 PM OR39 9471 11:30:00 AM New Insights into Thyroid Hormone Action and Thyroid Cancer Oral


Tania Jaber*1, Steven G Waguespack1, Maria E Cabanillas1, Thinh Vu2, Elmer B Santos2, Ramona Dadu1 and Naifa L Busaidy1
1The University of Texas MD Anderson Cancer Center, Houston, TX, 2The University of Texas MD Anderson Cancer Center

 

Introduction Differentiated thyroid cancer (DTC) usually carries an excellent prognosis. Many DTCs dedifferentiate and lose their ability to take up RAI, rendering it an ineffective therapy in this subgroup. Prognosis worsens in patients with metastatic RAI refractory (RAIR) DTC. Prior studies have suggested that use of serine/threonine protein kinase inhibitors (Ki) can sensitize tumors to RAI. We describe a cohort of patients treated with Ki therapy with demonstrated RAI uptake that allowed for treatment with a therapeutic dose of iodine-131 (I131).

Methods We conducted a retrospective chart review to evaluate whether, in a subset of patients with metastatic RAIR DTC, Ki therapy increased RAI uptake. Patients who were deemed to be RAIR and had diagnostic whole body scans (WBS) while on Ki therapy were included. If WBS demonstrated meaningful RAI uptake, a therapeutic dose of I131 was delivered. Post-treatment scans, thyroglobulin (TG) levels and serial CT scans were reviewed.

Results Thirteen patients with a median age of 56 (45-75) years were included. 7 (54%) were men. 10 (77%) had papillary thyroid cancer, 2 (15%) had poorly differentiated thyroid cancer, and 1 (8%) had follicular thyroid cancer. Molecular profiling of these tumors revealed 9 (70%) BRAF V600E mutations, 2 (15%) NRAS mutations, 1 (7.5%) KRAS mutation, and 1 (7.5%) with no identified mutation. Based on their mutations, they were treated with either a BRAF or a MEK inhibitor. The patient without a BRAF or RAS mutation was treated with a MEK inhibitor. Ki therapy was started for progressive disease, except in 2 patients in whom it was started for RAI resensitization. Ki therapy was continued for a median duration of 14.3 (1-76.4) months prior to diagnostic WBS.

Of the 13, 10 (77%) patients had documented RAI uptake on WBS, and 9 of these had clinically meaningful uptake to warrant therapy. The median delivered dose of I131 was 204.4 (150-253) mCi, and Ki therapy was discontinued 2 days after treatment. The median follow up was 8.3 (0-17.4) months after I131 therapy. Of those treated, 7 had sufficient follow up and restaging CT scans, and all had either an objective partial response or stable disease accompanied by decreasing TG levels, including one patient whose TG became undetectable at 9 months post-therapy.

Two of the treated patients had pneumonitis thought to be related to the I131 therapy. One patient’s symptoms are resolving and the other is undergoing evaluation.

Conclusions Use of targeted Ki therapy in BRAF- or RAS- mutated RAIR DTC can resensitize these tumors to iodine uptake and facilitate retreatment with I131 in the majority of cases. Clinically and radiographically meaningful responses are observed in appropriately selected patients. Further studies are needed to determine predictors of response and longer follow-up is required to assess the safety and long-term outcomes of this approach to treating RAIR DTC.

 

Disclosure: NLB: Investigator, GlaxoSmithKline. Nothing to Disclose: TJ, SGW, MEC, TV, EBS, RD

OR39-6 29361 6.0000 A Efficacy of Targeted Therapy in Resensitization to Radioactive Iodine (RAI) in Advanced Thyroid Cancer: The MD Anderson Experience 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Thyroid/HPT Axis Saturday, April 1st 1:00:00 PM OR39 9471 11:30:00 AM New Insights into Thyroid Hormone Action and Thyroid Cancer Oral


Walter Miller*
UCSF

 

 

Nothing to Disclose: WM

32973 1.0000 A Adrenal Steroidogenesis: Unanswered Questions 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 12:00:00 PM OR04-AL 10034 11:30:00 AM Walter L. Miller Special Lecture: Adrenal Steroidogenesis: Unanswered Questions


Elisabeth Joye Petr*, Erika Koeppe, Jenae M Osborne, Michelle Jacobs, Kristen Hanson, Monica Marvin, Jessica Everett, Elena M Stoffel and Tobias Else
University of Michigan, Ann Arbor, MI

 

Cascade genetic testing, or the genetic testing of relatives of pathogenic mutation carriers, provides an efficient mechanism to identify individuals at risk for tumor development who may benefit from screening procedures. “Uptake” or participation in cascade genetic testing varies in different inherited conditions. Prior reports suggest that 1-2 relatives of affected individuals with common inherited cancer syndromes such as Lynch syndrome or Hereditary Breast and Ovarian Cancer syndrome complete genetic testing. We investigated the uptake of genetic testing in families with Hereditary Pheochromocytoma (PCC)/Paraganglioma (PGL) syndromes.

We reviewed genetic testing records of patients evaluated at a large academic medical center from 2005-2015. We estimated the number of at-risk relatives tested per positive proband by the proxy measure of ratio of number of site-specific genetic tests ordered over the total number of positive tests resulting from comprehensive full gene analysis.

A total of 91 individuals were found to carry mutations in SDHx, VHL, RET, NF1, TMEM127 and MAX by full gene sequencing analyses and 211 additional individuals had site-specific genetic tests, resulting in 2.3 tested relatives per index patient with a Hereditary PCC/PGL syndrome. Uptake of cascade testing varied by syndrome. For SDHx, a total of 50 positive full sequence analyses and 152 total site-specific tests were performed, resulting in 3 relatives tested per index carrier. For MEN2, a total of 10 positive full sequence analyses and 23 site-specific tests were performed, resulting in 2.3 relatives tested per index carrier. For VHL, a total of 28 positive full sequence analyses and 34 total site-specific tests were performed, resulting in 1.2 relatives tested per index carrier. Overall uptake of genetic testing in families with PCC/PGL related syndromes was 2.3 relatives tested per index mutation carrier, a rate similar to that observed in families with Lynch syndrome (2.2) and Li-Fraumeni syndrome (2.1), and higher than in families with Familial Adenomatous Polyposis (1.6), Hereditary Leiomyomatosis and Renal Cell Cancer (0.6), Birt-Hogg-Dubé syndrome (1.1), and Cowden’s disease (0.7).

We found that uptake of predictive genetic testing was higher in PCC/PGL families, especially those with SDHx mutations, compared to other hereditary cancer syndromes. Patient education regarding the benefits of asymptomatic screening for PCC/PGL and prompt access to genetic testing coordinated through a specialized Endocrine Oncology Clinic likely played a role. However, despite increased availability of genetic testing, the number of tested relatives per index patient remains suboptimal. These data highlight the importance of determining factors that influence the decision of family members to undergo genetic testing in order to increase the detection of genetic mutation carriers.

 

Nothing to Disclose: EJP, EK, JMO, MJ, KH, MM, JE, EMS, TE

OR04-1 31269 1.0000 A Uptake of Cascade Genetic Testing in Hereditary Pheochromocytoma/Paraganglioma Syndromes 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 1:00:00 PM OR04 9435 12:00:00 PM Adrenal Tumors: From the Medulla to the Cortex Oral


Nana Esi Nkuma Kittah*, Irina Bancos, Oksana Hamidi, Shrikant Tamhane, Nicole Iniguez Ariza, Dusica Babovic-Vuksanovic, Cristian Bancos, William F Young Jr. and Dana Erickson
Mayo Clinic, Rochester, MN

 

Background:

Pheochromocytomas (PHEOs) are neuroendocrine tumors arising from the adrenal medulla. They are frequently unilateral and sporadic. Bilateral PHEOs are typically associated with hereditary syndromes.

Objectives:

Our aim was to describe the clinical presentation, genetics, treatment and outcomes of patients with bilateral PHEOs.

Methods:

Medical records of patients with bilateral PHEOs at Mayo Clinic, Rochester, MN from 1951to 2015 were retrospectively reviewed. Diagnosis of PHEO was based on biochemical, imaging, or histological findings.

Results:

Out of 1161 patients with PHEO, 94 (7.9%) patients (48 women, 51%) were diagnosed with bilateral PHEOs. Seventy-six (81%) patients presented with synchronous tumors, while 18 (19%) patients developed metachronous tumors. The median age at the time of surgery for the first PHEO was 31 yrs (range, 4-70). In metachronous tumors, the second PHEO was detected at a median time of 4.5 yrs after the initial surgery (range, 1-38). Median tumor size of the first PHEO was 31 mm (range, 6-120). The second PHEO measured 23 mm (range, 4-87). In 32 (34%) patients the tumors were multicentric. A genetic syndrome was documented in 75 (80%) patients and in 16 (17%) patients very limited or no genetic testing was performed. Of the patients who had a detected genetic syndrome, 41 (43.6%) had MEN 2A, 18 (19%) VHL, 8 (8.5%) MEN 2B, and 8 (8.5%) NF1.

PHEO was discovered because of symptoms of catecholamine excess in 47 (50%) patients, genetic case detection testing in 26 (28%), an incidentaloma imaging finding in 17 (18%), mass effect symptoms in 1 (1%), and in 3 (3%) patients the method of discovery was not known. Pre-operative biochemical information was available for 69 patients and showed catecholamine excess in 67 (97%) patients. Fifty (53%) patients underwent adrenalectomy by the open approach; laparoscopic in 22 (23%), and unknown type surgical approach in 21 (22%) patients who had surgery performed elsewhere. Sixteen of 72 (22%) patients had cortical sparing surgery and of these 7 (44%) required permanent glucocorticoid replacement. One patient was not operated.

Patients were followed for a median of 10 yrs (range, 0-64). Recurrent PHEO within the adrenal gland occurred in 8 (8.5%) patients. Malignant PHEO occurred in 8 (8.5%) patients. Of 20 (23%) patients who died during follow-up, 2 (10%) died from PHEO.

Conclusion:

Bilateral PHEO was diagnosed in 94 (7.9%) of 1161 patients with PHEO over 64 years. MEN 2A and VHL were the two most common syndromes associated with bilateral PHEO. At the time of diagnosis, most bilateral PHEOs are likely to be synchronous. However, in metachronous PHEOs the second tumor may be detected anywhere from 1 to 38 yrs (median, 4.5) after the initial tumor resection.

 

Nothing to Disclose: NENK, IB, OH, ST, NI, DB, CB, WFY Jr., DE

OR04-2 31603 2.0000 A Bilateral Pheochromocytomas: Clinical Presentation and Surgical Treatment of 94 Patients over 64 Years 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 1:00:00 PM OR04 9435 12:00:00 PM Adrenal Tumors: From the Medulla to the Cortex Oral


Vânia Balderrama Brondani*1, Fabio Y. Tanno2, Victor Srougi3, Madson Q. Almeida4, Carlos Buchpiegel5, Miguel Srougi6, Maria Claudia N Zerbini2, Berenice B Mendonca7, Jose Luiz Chambo8 and Maria Candida B V Fragoso9
1Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, BRAZIL, 2Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 3Sao Paulo University, Sao Paulo, Brazil, 4Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulol, 5Hospital das Clinicas da FMUSP, Sao Paulo, Brazil, 6Hospital das Clinicas, Brazil, 7Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil, 8Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 9Hospital das Clínicas & Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

 

Introduction: Partial Adrenalectomy (PA) has changed the treatment of patients affected by bilateral adrenal disorders. Currently the evidences regarding the use of PA to treat PMAH are limited 1-3.To date, outcomes of this surgical treatment on hypercortisolism control are not known. In order to overcome the hormonal replacement caveats while minimizing the risks of hypercortisolism relapse, we performed a series of simultaneous total adrenalectomy of largest adrenal gland and partial contra-lateral adrenalectomy (adrenal sparing surgery) to treat patients with PMAH. Methods: Ten patients according to hormonal workup and radiological imaging findings were diagnosed with PMAH and were treated surgically with adrenal sparing surgery. Histological analysis confirmed PMAH in all cases. Primary endpoint was hypercortisolism remission without adrenal insufficiency, considered when patients had physiologic cortisol levels (5-25 μg/L) without hormonal reposition. Adrenal insufficiency and latent adrenal insufficiency were defined when oral hydrocortisone reposition was needed, dose of > 0.2 mg/kg/day and ≤ 0.2 mg/kg/day respectively. Secondary endpoints were clinical and metabolic syndrome parameters improvement. Body mass index, blood pressure, cholesterol, lipid and glucose levels, were measured before and 12 months after the procedure. Medications to control the comorbidities were also assessed and compared previously and after surgery. Results: There were no intra-operative complications and average operation time was 189 ± 34 minutes. Median hospitalization period was 7.5 days and during post-operative recovery one patient needed surgical hematoma drainage. With a median follow-up of 34 months (range 13-73 months), 100% of the cohort had complete hypercortisolism remission, 20% persisted with latent adrenal insufficiency. Hypercortisolism recurrence was observed in one patient after one yr de follow-up and needed a new PA. Median systolic/diastolic blood pressures were 155/95 before and 123/80 after the procedure (p < 0.001). Median number of medications to control blood hypertension diminished from 3 to 1 (p < 0.001). There was no significant change in cholesterol, lipid and glucose blood levels as well as the number of diabetes and lipid lowering medications. Median BMI decreased from 31.7 ± 7.8 to 28.4 ± 4.7 after the procedure (p = 0.05). Conclusion: Adrenal sparing surgery is a feasible procedure and may provide hypercortisolism remission for patients affected by PMAH, avoiding the drawbacks of lifetime corticosteroids replacement. Furthermore, patients submitted to this surgical treatment exhibited improvement of clinical parameters. Nevertheless, further studies with higher level of evidence and comprising bigger cohorts are necessary to properly analyze the role of this therapeutic modality.

 

Nothing to Disclose: VBB, FYT, VS, MQA, CB, MS, MCNZ, BBM, JLC, MCBVF

OR04-3 30529 3.0000 A A New Insight for the Treatment of Primary Macronodular Adrenal Hyperplasia (PMAH): Adrenal Sparing Surgery 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 1:00:00 PM OR04 9435 12:00:00 PM Adrenal Tumors: From the Medulla to the Cortex Oral


Fady Hannah-Shmouni*1, Georgios Papadakis2, Amit Tirosh3, Annabel Sophie Berthon4, Fabio R Faucz3, Elena Belyavskaya5, Charalampos Lyssikatos1, Andrew Paul Demidowich1, Maya Beth Lodish3 and Constantine A Stratakis1
1Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 2National Institutes of Health, 3National Institutes of Health, Bethesda, MD, 4National Institutes of Health (NIH), Bethesda, MD, 5Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH)., Bethesda, MD

 

Background: Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) causes ACTH-independent Cushing syndrome. PBMAH typically manifests with subclinical hypercortisolemia and bilateral macronodules (≥1cm) with hyperplasia and/or internodular atrophy. Inactivating mutations in the Armadillo repeat containing 5 (ARMC5) gene, a putative tumor suppressor, causes the majority of cases. Accurate radiologic characterization of adrenal size in PBMAH and its putative correlation to disease have not been previously performed.

Methods: Forty-five patients with PBMAH were evaluated at the National Institutes of Health (NIH) under an IRB-approved protocol. Clinical, biochemical and radiographic characteristics were assessed. Biochemical diagnosis of hypercortisolemia was confirmed with loss of diurnal variation of cortisol and/or elevated 24-h urinary free cortisol (UFC) and 17-hydroxysteroids (17OHS). Criteria for radiographic diagnosis included bilateral macronodules with hyperplasia. CT scans were used to create 3-dimensional volumetric models by contouring each adrenal gland, in each slice, using Vitrea Core Fx v6.3 software (Vital Images, Minnetonka, Minnesota).

Results: Forty-five patients with PBMAH (32 females, 52.3±11.9 years) were evaluated. Their midnight cortisol concentration, UFC and 17OHS were 8.3±4.9 μg/dL, 54.6±61.9 μg/24h and 9.3±4.7 μg/24h, respectively. Their mean adrenal volumes were; right 18.5cc±10.18, left 26.6cc±19.3, and total 45.1cc±24.4. In our mixed cohort, total adrenal volume positively correlated with 17OHS (r=0.4, p=0.01, n=41). The other biochemical parameters did not significantly correlate with adrenal volume. However, in the African American cohort (n=10), total adrenal volume positively correlated with midnight cortisol concentration (r=0.8, p=0.03, n=8), UFC (r=0.8, p=0.004, n=9) and 17OHS (r=0.9, p=0.004, n=8).

Conclusion: 3-dimensional volumetric modeling, in combination with clinical and biochemical measures, may be used as a marker of severity in patients with PBMAH. This appears to be particularly useful in African American patients with PBMAH, which may reflect their previously described increased prevalence of ARMC5-variant carrier state.

 

Nothing to Disclose: FH, GP, AT, ASB, FRF, EB, CL, APD, MBL, CAS

OR04-4 30097 4.0000 A 3-Dimensional Volumetric Modeling of Adrenal Gland Size in Primary Bilateral Macronodular Adrenocortical Hyperplasia 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 1:00:00 PM OR04 9435 12:00:00 PM Adrenal Tumors: From the Medulla to the Cortex Oral


Sheng Wu*1, Yaping Ma1, Stanley Andrisse1, Zhiqiang Wang2, Ping Xue1 and Dustin Jones3
1Johns Hopkins University School of Medicine, Baltimore, MD, 2Johns Hopkins University School of Medicine, Baltimore, 3Johns Hopkins University School of Medicine

 

Androgen and Its Receptor (AR) Plays a Critical Role in Reproductive Function, Under Both Physiological and Pathophysiological Conditions. Female AR Global Knockout Mice Are Sub-Fertile Due to Both Neuroendocrine and Ovarian Defects. Female Offspring from Prenatally Androgenized Heterozygous AR Pregnant Mice Showed Rescued Estrous Cyclicity and Fertility. Ar Is Expressed in Granulosa Cells, Theca Interstitial Cells, and Oocytes in the Ovary. We Created Mice with Theca-Specific Deletion of Ar (ThARKO) By Crossing Cyp17-Icre Mice That Express Cre Recombinase Under Cyp17 Promoter with Arfl/Fl Mice. Tharko Mice Exhibited No Significant Differences in Pubertal Onset or Fertility Compared with Control Littermates, and Neither Estrogen and Testosterone Levels Were Different Between These Groups. Therefore, Ar Expression in Theca Cells Likely Does Not Influence Fertility Nor Androgen Levels in Female Mice. We then Tested the Role of AR in Theca Cells Under Hyperandrogenemic Condition. after Treatment with a Pathophysiological Level of Dihydrotestosterone (DHT), Control Mice (Con-DHT) Showed Acyclicity and Infertility. However, Estrous Cycles and Fertility Were Altered to a Significantly Less Degree in Tharko-DHT Mice Than in Con-DHT Mice. Three Months after DHT Treatment, mRNA Levels of Lhcgr (luteinizing hormone receptor) and, Timp1 (tissue inhibitor of metalloproteinase 1, and inhibitor of matrix metalloproteinase (MMP)) Were Significantly Lower in Con-DHT Ovary Compared to Con-No DHT Ovary; Whereas mRNA Levels of Fshr (follicle stimulating hormone receptor) Were Significantly Higher. Timp1 Gene Expression Was Comparable in the Tharko-DHT Ovary and the Con-No DHT Ovary. We Speculate That the Preserved Level of Timp1 in Tharko-DHT Mice Contributes to Retained Reproductive Function.

 

Nothing to Disclose: SW, YM, SA, ZW, PX, DJ

29912 1.0000 SAT 090 A Androgen Receptor in the Ovary Theca Cells Plays a Critical Role in Androgen-Induced Reproductive Dysfunction 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 3:00:00 PM SAT 090-104 9466 1:00:00 PM Female Reproductive Endocrinology: Androgenic Disorders and Beyond Poster


Ramon Bossardi Ramos*1, Fabiola Reginato2, Thaís Rasia Silva3 and Poli Mara Spritzer4
1Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil, 2UFCSPA - Universidade Federal de Ciências da Saúde de Porto Alegre, 3Gynecological Endocrinology Unit, Division of Endocrinology, Hospital de Clínicas de Porto Alegre (HCPA), BRAZIL, 4Hospital de Clínicas de Porto Alegre and Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

 

Obesity is one of the greatest global public health issues, and is associated with increased morbidity and mortality. The population aging phenomenon, together with obesity, may have an impact on metabolic comorbidities such as type 2 diabetes and cardiovascular disease. Especially, obesity negatively impacts the health of women in contraception, fertility, and metabolism. Individual susceptibility to obesity is determined by genetic and environmental factors. Among several candidate genes for obesity, the fat mass and obesity associated gene (FTO) has been identified. A single-nucleotide polymorphism (SNP) in intron 1, rs9939609 T/A, which is the most studied polymorphism in the FTO gene, has been linked to fat mass and body mass index (BMI) as well as to the risk of obesity, metabolic syndrome, and high cardiovascular risk in healthy men and women. Therefore, the aim of this study was to assess whether the FTO gene variant rs9939609 is associated with obesity and metabolic traits in a cross-sectional study of not severely obese women from Southern Brazil. In this cross sectional study carried out in a university hospital, 332 participants were enrolled. Overall participants had a mean age of 45.3 ± 13.9 years, mean BMI of 26.6 ± 4.2 kg/m² and the glucose levels 91.4 ± 9.5 mg/dL. The inclusion criteria were: BMI less than 40 kg/m2, regular cycles for women of reproductive age (10-12 cycles in the last year), and for menopausal women were last menstrual period between 6 months and 3 years before the beginning of the study plus follicle-stimulating hormone levels higher than 35 IU/L for menopausal participants. Exclusion criteria were hirsutism, diabetes, pregnancy, hepatic or renal impairment and hormonal replacement therapy. The participants were genotyped by real-time PCR for the SNP rs9939609 of the FTO gene. The genotypic distribution for rs9939609 (TT: 40.0%, TA 44.4%, AA: 15.6) was in Hardy-Weinberg equilibrium. Participant age was similar between genotypes (46.4 ± 12.9 years in TT carriers vs. 43.9 ± 14.5 years in TA/AA carriers, p=0.11). In contrast, BMI was higher in subjects with the TA/AA genotypes in comparison with the TT genotype, both on crude (27.1 ± 4.5 vs. 26.0 ± 3.7, p=0.02) and on age-adjusted analyses (p=0.04). In addition, on binary logistic regression analysis, we found a significantly higher odds ratio (OR) for BMI greater than 30 in women carrying the AA genotype compared with TT carriers on age-adjusted analyses [OR 2.60 (1.02 – 6.63); p=0.04] and the OR for BMI greater than 30 in women carrying the TA genotype compared with TT carriers on age-adjusted analyses [OR 1.51 (0.71 – 3.23); p=0.27]. In conclusion, an association between the FTO SNP rs9939609 and obesity was found in women from Southern Brazil.

 

Nothing to Disclose: RBR, FR, TRS, PMS

31754 2.0000 SAT 091 A Impact of Fat Mass and Obesity Associated Gene (FTO) Single Nucleotide Polymorphism rs9939609 on Obesity in Women throughout Adulthood: A Cross-Sectional Study 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 3:00:00 PM SAT 090-104 9466 1:00:00 PM Female Reproductive Endocrinology: Androgenic Disorders and Beyond Poster


Wassim Y Almawi*1, Rita Fayez Nemr2 and Zainab H Malalla1
1Arabian Gulf University, Manama, Bahrain, 2Risk Hospital, Achrafieh, Beyrouth, Lebanon

 

Background:

Polycystic ovary syndrome (PCOS) is a complex heterogeneous endocrine disorder in women, with poorly understood etiology. Insulin is an important regulator of glucose and lipid metabolism, and abnormal insulin signaling is a key feature of PCOS.

Hypothesis:

We investigated the gene expression profiles in unstimulated peripheral blood leucocytes of women with PCOS women vs. control women, using insulin-signaling pathway-specific PCR.

Experimental Design and Methods:

Study subjects included 12 women with PCOS, and 12 age- and BMI-matched normal ovulatory women who served as controls. Gene expression profiling was done using Qiagen RT² Profiler™ PCR Array Human Insulin Signaling Pathway. Microarray results for selected genes were confirmed by real-time quantitative PCR.

Results:

Of the 84 pathway-specific genes included in Human Insulin Signaling RT² Profiler, 13 genes were differentially expressed in women with PCOS compared to age- and BMI-matched controls. Those genes were found to be involved in lipid metabolism, insulin action, intracellular signaling, and in inflammation and immunity. Profiling results confirmed higher expression of MAP kinase 3 (5.12 fold), JAK2 (7.86-fold), UCP1 (6.82-fold), and SLC27A4 (8.73-fold). In addition, lipoprotein lipase (5.55-fold), VLDL receptor (6.54-fold), FABP4 (8.71-fold), resistin (8.34-fold), and PPARg (5.40-fold) were also differentially expressed in cases and controls. Furthermore, IGF1 receptor (4.00-fold), insulin receptor (6.48-fold), PEPCK (6.12-fold), and IL-18 receptor 1 (4.95-fold) were also differentially expressed in the two groups. The differential expression of MAP kinase 3 (P <0.001), lipoprotein lipase (P <0.001), resistin (P <0.001), SLC27A4 (P <0.001), IGF1 receptor (P <0.001), IL-18 receptor 1 (P <0.001), and PEPCK (P <0.001) were subsequently confirmed by qPCR in both PCOS and control groups.

CONCLUSION

PCR array-profiling analysis demonstrated differential expression of genes linked to insulin signaling, lipid metabolism, intracellular signaling, and inflammation in obese women with PCOS women compared to control women. It is very likely that these genes may be involved in altered metabolism associated with the different PCOS phenotypes, which in turn might provide novel drug targets and potential biological markers for PCOS.

 

Nothing to Disclose: WYA, RFN, ZHM

32191 3.0000 SAT 092 A Insulin Signaling Pathway-Specific PCR Array Profiling of Obese Women with PCOS 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 3:00:00 PM SAT 090-104 9466 1:00:00 PM Female Reproductive Endocrinology: Androgenic Disorders and Beyond Poster


Andrew James Standing1, Sia Saquee1, Gul Bano2, Helen Diane Mason3 and Suman Rice*4
1St George's University of London, London, United Kingdom, 2St George's Hosp NHS Trust, Cobham, Surrey, United Kingdom, 3Edulink Consultants, Jumeirah 3, United Arab Emirates, 4St George's University of London, Surrey, United Kingdom

 

Women with PCOS are more likely to suffer from VD deficiency, with an inverse correlation between serum VD concentrations and BMI/insulin resistance. VD supplementation improves ovulation frequency and insulin sensitivity, indicating its significant role in ovarian steroidogenesis, ovulation and fertility. The aim of our study was to investigate VD receptor (VDR) mRNA expression in human primary ovarian tissue (using qPCR), and whether VD at levels correlated with insufficiency/deficiency (serum levels <50nM equivalent to a deficient status)1 can affect reproductive parameters. We used a human granulosa cell-line (KGN) and measured insulin-stimulated aromatase expression, AMH expression and levels of insulin receptor (InsR). VDR mRNA was present in cortex and stroma from normal and polycystic ovaries (PCO), with slightly lower levels in stroma from PCO. VDR mRNA levels were significantly up-regulated in theca from follicles 7-12mm compared to 5-6mm (p=0.02); and this difference was more pronounced in PCO compared to normal ovaries. This expression pattern highlights the importance of VD in antral follicle progression. Interestingly, stroma from both normal and polycystic ovaries express CYP27B1, with higher levels found in normal compared to PCO stroma. CYP27B1 encodes for 1-α-hydroxylase, which in the kidney catalyzes the hydroxylation of 25-hydroxy VD3 to 1,25-dihydroxy VD3 (bioactive VD3). KGN cells were treated chronically (48hrs) with insulin at 10ng/ml (post-prandial levels) or 100ng/ml (hyperinsulinemia levels) ± VD at 0.02nM or 20nM. As expected chronic insulin exposure with 100ng/ml insulin significantly down-regulated basal InsR mRNA expression (p<0.05), but surprisingly addition of VD at 0.02nM further increased this down-regulation at both insulin doses (p<0.001), potentially reducing glucose uptake. The addition of 20nM VD to both insulin doses, maintained a 50% attenuation in InsR expression (p<0.05). This inhibition of InsR mRNA levels did not affect aromatase mRNA expression, indicating that forskolin-driven aromatase expression is more sensitive to a low VD environment than insulin-driven aromatase, as shown in our previous study2. We also investigated the effect of VD on AMH mRNA expression and interestingly VD at both 0.02 & 20nM significantly reduced AMH mRNA levels in the presence of forskolin (p<0.05). To conclude VD is clearly important in the ovary as shown by the presence of VDR in cortex, stroma and theca of large follicles. The ability of the ovary to make local bioactive VD could potentially reduce the effects of VD deficiency; and the attenuation of AMH mRNA expression by VD may aid antral follicle progression. However, the effect of very low VD on InsR expression and cAMP-stimulated aromatase, indicates that a severely VD deficient environment could contribute to the impaired folliculogenesis/ovulation identified in women with PCOS.

 

Nothing to Disclose: AJS, SS, GB, HDM, SR

32575 4.0000 SAT 093 A The Effect of  a Low 1,25-(OH)2D3/Vitamin D3 (VD) environment on Folliculogenesis in the Normal and Polycystic Ovary 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 3:00:00 PM SAT 090-104 9466 1:00:00 PM Female Reproductive Endocrinology: Androgenic Disorders and Beyond Poster


Mojca Jensterle*1, Vesna Salamun2, Eda Vrtacnik Bokal2 and Andrej Janez1
1University Medical Centre Ljubljana, Ljubljana, Slovenia, 2University Medical Centre Ljubljana

 

Objective: Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility, in particular when PCOS is linked to obesity. Obese PCOS has poor in vitro fertilization (IVF) outcomes associated with impaired oocyte and embryo parameters and morphology. The aim of this study was to evaluate the impact of short-term weight reduction achieved with 12-week intervention with metformin alone or in combination with liraglutide on oocyte maturity and embryo quality in infertile obese PCOS population.

Design/Participants/Main Outcome Measure: A 12-week prospective randomized open-label study was conducted with 40 infertile obese PCOS patients (aged 30,8± 3,7 years, BMI 36,7±3,5 kg/m2, mean ± SD) who had been previously poor responders to lifestyle intervention regarding weight loss. Before IVF they were assigned to metformin (MET) 1000 mg BID or combined MET 1000 mg BID and liraglutide 1.2 mg QD s.c. (COMBI) or to the control group (CON). CON directly proceeded with ovarian stimulation protocol, whereas MET and COMBI started with stimulation after 4 weeks medication free period.

Results: 11 women on MET, 13 on COMBI and 11 CON completed the study according to the protocol. Patients in MET lost on average 6,70±6,70 kg (P˂0.001) compared with 7,68± 3,74 kg loss in COMBI group (P˂0.001), with no significant between-treatment difference (P=NS). In addition, COMBI resulted in a significant reduction of visceral adipose tissue (VAT) area (-20,65± 7,40 cm2; P=0,028,). More than 5 % of weight reduction was achieved in 76,9% of patients in COMBI and 45,5% of patients in MET. In high responders who lost more than 5% of initial body weight numbers of blastocysts/patient were greater in both treatment arms than in controls (3,67±4,82 in COMBI; 3,60±6,95 in MET; vs 2,09±2,07 in CON). High responders in COMBI also had the highest number of oocytes/patient 14,67±9,59 and the highest percentage of mature oocyte 11,22±9,27 among all three groups, although the between treatment differences were not statistically significant yet. Furthermore, in COMBI one patient become spontaneously pregnant before IVF and give a birth after non-complicated pregnancy.

Conclusion: A subset of obese PCOS women who lost more than 5% of body weight reduction before IVF with short-term intervention with metformin alone or in combination with liraglutide had increased fertility potential. COMBI resulted in the highest number of women who lost more than 5% of weight and was associated with the highest number of blastocysts/patient.

 

Nothing to Disclose: MJ, VS, EV, AJ

30455 5.0000 SAT 095 A Short-Term Intervention with Liraglutide and Metformin Increased Fertility Potential in a Subset of Obese Women with PCOS Proceeding in Vitro Fertilization 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 3:00:00 PM SAT 090-104 9466 1:00:00 PM Female Reproductive Endocrinology: Androgenic Disorders and Beyond Poster


Solhild Stridsklev*1, Øyvind Salvesen2, Kjell Åsmund Salvesen3, Sven M Carlsen1, May Anita Husøy4 and Eszter Vanky1
1Norwegian University of Science and Technology, Trondheim, Norway, 2Department for Cancer Research and Molecular Medicine, Norwegian University of Science and Technology., 3Dept. of Obstetrics and Gynecology, St. Olav’s Hospital, Trondheim University Hospital, 4Department for Laboratory Medicine, Children’s and Women’s Health,

 

Polycystic ovary syndrome (PCOS) is linked to several pregnancy complications, such as GDM, preterm delivery and preeclampsia. Increased resistance in the uterine artery, measured as pulsatility index, results in decreased blood flow to the placenta and fetus and is often an early sign of placenta pathology and/or hypertensive disorder in pregnancy. Doppler ultrasound is a frequently used method for risk evaluation during pregnancy. Former studies on women with PCOS are few and report a decreased blood flow in the uterine artery in both non-pregnant and pregnant women.
In the current study we investigated: 1) whether there was a difference in uterine artery pulsatility index (UtAPI) in pregnant PCOS women versus healthy controls and 2) whether there was an immediate effect of metformin on blood flow in PCOS women. The present study was a sub-study of an RCT (The PregMet study). It was conducted at one tertiary centre, 48 pregnant women with PCOS and 119 healthy controls participated. The women with PCOS were randomly assigned to metformin (1000 mg x 2 daily) or placebo. UtAPI was measured twice in the 1st trimester and twice in the 2nd trimester.
There was no difference in UtAPI between the PCOS women and the healthy controls at any time point. P-values ranged between 0.34 and 0.77. We found no difference in UtAPI between the metformin and placebo groups two hours after intake of study medication (500 mg metformin or placebo) and a meal. Surprisingly, we found that both metformin and placebo treated PCOS women had significantly higher UtAPI two hours after intake of a meal compared to fasting state, P=0.02.
Contrary to former studies we did not find altered UtAPI (uterine blood flow) in pregnant women with PCOS compared to healthy controls. There was no immediate effect of metformin. This was the first study which showed that fasting vs. non-fasting state in the same women resulted in significant changes in blood flow of the uterine artery. Further studies are needed to clarify if standardization of food intake before Doppler examinations should be considered when interpreting the results of UtAPI measurements.

 

 

Nothing to Disclose: SS, ØS, KÅS, SMC, MAH, EV

30803 6.0000 SAT 096 A Uterine Artery Doppler in Pregnancy: Women with PCOS Compared to Healthy Controls 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 3:00:00 PM SAT 090-104 9466 1:00:00 PM Female Reproductive Endocrinology: Androgenic Disorders and Beyond Poster


George Mskhalaya*1, Elena Eltsova1, Maria Malysheva2, Timur Gusov3, Christina Nagaeva4, Victoria Zaletova1 and Svetlana Kalinchenko5
1Center for Reproductive Medicine MAMA, Moscow, Russia, 2Center for Reproductive Medicine MAMA, Moscow, Russian Federation, 3Brookdale University Hospital and Medical Center, Brooklyn, NY, 4Medical Center SlimHouse, Russian Federation, 5People's Friendship University of Russia, Moscow, Russia

 

Background: Poor response to ovarian stimulation is still considered to be one of the most challenging tasks in reproductive medicine. Many different technologies are used to improve pregnancy and live birth rates in poor responders, but none of them showed any statistically significant increase in these parameters, except for testosterone treatment. No studies considering oral form of testosterone undecanoate (Andriol, Organon) as a possible therapy were published.

The aim of the study was to evaluate the efficacy of testosterone treatment before controlled ovarian stimulation (COS) on clinical pregnancy and live birth rate in poor responders undergoing IVF. Materials and Methods: 149 women with poor ovarian response, defined according to ESHRE consensus/the Bologna criteria of low ovarian response were included. Patients were randomly divided into 2 groups: Testosterone undecanoate (TU) treatment group (98 women) or control group (51 women). For TU group Testosterone undecanoate oral form 40 mg was given daily for at least 40 days (median 54 days) preceding COS for IVF.

Primary outcome measures were clinical pregnancy (PR) and live birth (LR) rates in different age groups. Statistical research was made using a software package statistics (StatSoft Inc. U.S., version 12). Quantitative data is presented as median and quartile range. When comparing the quantitative data of two independent groups Mann Whitney U-test and Fisher exact two-tailed test were used. Values were considered statistically significant if p less than 0.05.

Results: There were no differences in patients’ characteristics between the two groups. There was no significant difference in starting FSH dose or total dose of gonadotropins administered between the groups. There was a significant increase in number of oocytes retrieved 2 [1; 3] vs 1 [1;2] in TU group (p=0.04). Сlinical pregnancy rate (per cycle) was significantly higher in TU group (24.5%) than in control group (7.8%), p=0.015. Live birth rate was higher in TU group than in control group 17.3% vs 5.9%, respectively, though the difference was not statistically significant (p=0.07).

The treatment and control groups were divided into 2 subgroups each according to age: 1 subgroup less than 40 years old and 2 subgroup – 40 years and older.

There was a significant increase in clinical pregnancy and live birth rate in TU 1 subgroup (less than 40 years old) compared to the control 1 subgroup: 38% vs 8.7% (p<0.001) and 29.3% vs 6.5% (p<0.01), respectively. There was no difference neither in clinical pregnancy nor in live birth rate between TU and control 2 subgroups.

Conclusions: Testosterone undecanoate treatment may increase pregnancy and live birth rate women with diminished ovarian response undergoing IVF. PR and LR rate are severely decreased in women 40 years and older, they may need more prolonged pretreatment with TU for better success rate.

 

Nothing to Disclose: GM, EE, MM, TG, CN, VZ, SK

32333 7.0000 SAT 097 A Testosterone Treatment in Poor Ovarian Responders Undergoing IVF: Fertility and Live Birth Rates 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 3:00:00 PM SAT 090-104 9466 1:00:00 PM Female Reproductive Endocrinology: Androgenic Disorders and Beyond Poster


Emma Nilsson*1, Anna Benrick2, Milana Kokosar3, Eva Lindgren4, Carl Johan Behre5, Antonina Sazonova6, Kurt Højlund7, Charlotte Ling8 and Elisabet Stener-Victorin9
1Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden, 2University of Gothenburg, Gothenburg, Sweden, 3Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, 4Department of Physiology and Pharmacology, Stockholm, Sweden, 5Institute of Medicine, Göteborg, Sweden, 6Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, 7Odense University, Odense, 8Lund University Diabetes Centre, Lund University, Clinical Research Centre, Malmö, Sweden, 9Karolinska Institutet, Stockholm, Sweden

 

Background and aim: Insulin resistance in skeletal muscle is a major risk factor for the development of type 2 diabetes in women with polycystic ovary syndrome (PCOS). However, the underlying molecular mechanisms are largely unknown. The aim of this study was to investigate the genome-wide gene expression and DNA methylation patterns in skeletal muscle from PCOS women and healthy controls.

Material and Methods: Skeletal muscle biopsies were obtained from 17 women with PCOS and 14 controls matched for age, weight and BMI. For analyses of gene expression and DNA methylation, Illuminas Human HT-12 Expression BeadChip and Infinium HumanMethylation450 BeadChip were used.

Results: Women with PCOS had more antral follicles, larger ovaries and higher circulating testosterone, and LH and LH/FSH ratio than controls. Fasting triglycerides, C-peptide, calculated C-peptide index, and HOMA-B were higher in women with PCOS than in controls indicating metabolic aberration and insulin resistance. Adipocyte size was enlarged and the sex steroid content were higher in women with PCOS compared with controls. After FDR-correction, 85 unique genes were found to be differentially expressed in skeletal muscle from PCOS women versus controls (q<0.05). 66% of the genes were up-regulated and 34% were down-regulated in PCOS women and the absolute expression differences were 21-186%. A large number of the identified genes are suggested to play a role in muscle function and metabolism, including DYRK1A, SYNPO2, KLF10, SCP2 and NAMPT. According to a gene set enrichment analysis, there was a significant gene expression disruption to pathways involved in the immune system in PCOS women. Also, several GWAS candidate genes for insulin resistance (e.g. APOE and PPARG) were differentially expressed in PCOS women versus controls. 21 of the significantly differentially expressed genes had one or more CpG site(s) in which the DNA methylation differed between PCOS women and controls. In addition, experiments where we quantify the expression of selected genes in isolated and cultured skeletal muscle cells derived from female donors in the presence of testosterone and insulin are ongoing.

Conclusion: We demonstrate that PCOS is associated with gene expression and DNA methylation aberrations in skeletal muscle which may explain some of the metabolic abnormalities seen in these women.

 

Nothing to Disclose: EN, AB, MK, EL, CJB, AS, KH, CL, ES

31115 8.0000 SAT 098 A Differential Expression and Methylation of Genes Influencing Skeletal Muscle Metabolism in Women with Polycystic Ovary Syndrome 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 3:00:00 PM SAT 090-104 9466 1:00:00 PM Female Reproductive Endocrinology: Androgenic Disorders and Beyond Poster


Vivian H Lin*1, Cathy Radovich2, Marianne R Plaunt1 and Pharis Mohideen1
1Millendo Therapeutics, Inc., Ann Arbor, MI, 2Millendo Therapeutics, Inc.

 

Kisspeptin/neurokinin B/dynorphin (KNDy) neurons are key regulators of the GnRH pulse generator, which is implicated in the disordered hormone signaling that is characteristic of PCOS. In a previous Phase 2a PCOS study, MLE4901, a novel neurokinin-3 (NK3) receptor antagonist, reduced LH pulse frequency and serum LH and testosterone concentrations over 28 days of treatment. Millendo Therapeutics is now conducting a Phase 2b study to evaluate the efficacy of MLE4901 in improving menstrual regularity, hirsutism, acne, and other symptoms and signs of PCOS over a longer period of treatment (NCT02865915).

At approximately 35 sites in the US and the UK, approximately 220 women with PCOS and oligo-/amenorrhea will be randomized in a double-blind fashion 1:1:1:1 to receive MLE4901 40 mg, 60 mg, or 80 mg or placebo orally twice per day for 28 weeks following a progestin challenge. The primary objective is to evaluate the efficacy of MLE4901 in improving menstrual regularity in women with oligo-/amenorrhea due to PCOS. Secondary objectives include changes in ovulation regularity, each subject’s self-identified most bothersome symptom of PCOS, hormone levels, clinical signs of hyperandrogenism, metabolic syndrome-related parameters, quality of life, and work productivity. Menstrual period frequency will be assessed using a daily menstrual diary. Hirsutism will be assessed using the modified Ferriman-Gallwey score. Quality of life, work productivity, and the bothersomeness and severity of PCOS symptoms will be assessed using validated questionnaires. Once completed, this Phase 2b study will be one of the largest, most robustly designed studies conducted to date in PCOS.

 

Disclosure: VHL: Employee, Millendo Therapeutics, Inc.. CR: Employee, Millendo Therapeutics, Inc.. MRP: Employee, Millendo Therapeutics, Inc.. PM: Employee, Millendo Therapeutics, Inc..

31857 9.0000 SAT 099 A Trial in Progress: A Double-Blind, Randomized, Parallel-Group, Placebo-Controlled Phase 2b Study of MLE4901, a Novel NK3 Receptor Antagonist, for the Treatment of PCOS 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 3:00:00 PM SAT 090-104 9466 1:00:00 PM Female Reproductive Endocrinology: Androgenic Disorders and Beyond Poster


Francis E de Zegher*1, Thomas Reinehr2, Rita Malpique3, Feyza Darendeliler4, Abel Lopez-Bermejo5 and Lourdes Ibáñez6
1Univ of Leuven, Leuven, Belgium, 2University of Witten-Herdecke, Datteln, Germany, 3Hospital Sant Joan de Déu, University of Barcelona, 4Istanbul University, Istanbul, Turkey, 5Dr. Josep Trueta Hospital, and Girona Institute for Biomedical Research, Spain, 6Univ of Barcelona, Barcelona, Spain

 

Background

Hepato-visceral fat excess is a feature of Polycystic Ovary Syndrome (PCOS). Risk factors for such excess include a reduced prenatal weight gain and an augmented postnatal weight gain. We studied whether PCOS in adolescent girls was preceded by a relatively low birth weight and/or a relatively high BMI at PCOS diagnosis.

Methods

The adolescent study population consisted of 298 non-obese and 169 obese girls with PCOS diagnosed respectively in Barcelona/Spain and Datteln/Germany; 87 healthy girls served as controls. Z-scores for weight-at-birth and for BMI-at-PCOS-diagnosis were derived from country-, age- and sex-specific references; individual changes between these Z-scores were calculated.

Results

Non-obese Spanish and obese German PCOS girls had mean birth weight Z-scores of -0.7 and 0.0, and mean BMI Z-scores of +0.4 and +2.7, so that mean Z-score increments amounted to +1.1 and +2.6 (P<0.001 versus controls).

Interpretation

PCOS in adolescent girls was found to be preceded by a marked Z-score rise between weight-at-birth and BMI-at-PCOS-diagnosis, thus corroborating the notion that prenatal and postnatal weight gain have opposing influences on PCOS development, as they have on adrenarche and on age at menarche. PCOS is not a gynecological syndrome, but an outcome of a metabolically unfavorable sequence of early weight gains.

 

Nothing to Disclose: FED, TR, RM, FD, AL, LI

30672 10.0000 SAT 100 A Reduced Prenatal Weight Gain and/or Augmented Postnatal Weight Gain Precede Polycystic Ovary Syndrome in Adolescent Girls 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 3:00:00 PM SAT 090-104 9466 1:00:00 PM Female Reproductive Endocrinology: Androgenic Disorders and Beyond Poster


Tom Hoover*1 and Matthew Voghel2
1Millendo Therapeutics, Ann Arbor, MI, 2IPSOS

 

Polycystic Ovary Syndrome, PCOS, is the most common endocrine disease in women, impacting the lives of 8-20% of reproductive aged women. PCOS manifests as a constellation of symptoms, including menstrual dysfunction, symptoms of androgen excess, emotional burden and infertility. A structured, online survey was developed and fielded in 2016. Respondents must have been formally diagnosed with PCOS, and between the ages of 18-50 to complete the survey. The respondents were asked a set of standardized questions with regard to their diagnosis, treatment, symptom burden and attitudes toward the disease. 210 respondents were included in the study.

An initial PCOS diagnosis is often the result of a purposeful interaction by the patient with her physician expressly seeking a diagnosis of her symptoms. In our survey, the most common symptom driving this interaction was menstrual dysfunction (i.e., menstrual irregularity, heavy bleeding or pelvic pain), reported by 57% of patients. Infertility was the next most common driver for women to seek a diagnosis, at approximately 15% of patients. In contrast to the most common drivers of diagnostic interactions, hyperandrogenism (e.g., facial/body hair and alopecia) and mood changes (e.g., anxiety and depression) were the two of the three most frequently reported bothersome symptoms by women with an established diagnosis of PCOS. Sixty-five percent (65%) of patients who suffer from excessive hair growth or alopecia rank these symptoms as “extremely bothersome” (≥6 on a 7-point scale) and 85% of respondents reported them as at least somewhat bothersome. However, symptoms of hyperandrogenism only drove the diagnostic interaction for 6% of patients. Mood changes such as anxiety and depression were reported in 60% of patients, and were rated as highly bothersome, to 48% of those patients. Our findings shed light on the changing burden of PCOS to patients from diagnosis through treatment. While the initial constellation of menstrual dysfunction symptoms generally respond to treatment, signs of hyperandrogenism tend to show much less patient reported improvement and remain burdensome during treatment. Our findings are consistent with the known poly-symptomatic nature of PCOS, and highlight the need for comprehensive treatment for all PCOS symptoms, beyond just menstrual dysfunction.

 

Disclosure: TH: Employee, Millendo Therapeutics. MV: Employee, IPSOS.

30077 11.0000 SAT 101 A Disconnect in PCOS: Symptoms Leading to Diagnosis Vs. Most Bothersome Symptoms 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 3:00:00 PM SAT 090-104 9466 1:00:00 PM Female Reproductive Endocrinology: Androgenic Disorders and Beyond Poster


Sylvia Asaka Yamashita Hayashida*1, Jose Maria Soares Jr2, Gustavo A R Maciel3, Daniella Di Grande Curi4, Marina Iahn Aun4, Giovana De Nardo Maffazioli5, Erika Mendonça Das Neves4, Caroline Panone Lopes4, Maria Candida Pinheiro Baracat6 and Edmund Chada Baracat4
1Faculdade de Medicina da Universidade de São Paulo, São Paulo, BRAZIL, 2Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil, 3Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil, 4Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 5Faculdade de Medicina da Universidade de São Paulol, São Paulo, MA, Brazil, 6Faculdade de Medicina da Universidade de São Paulo, São Paulo

 

Objective: We aimed at evaluating the follow up of polycystic ovary syndrome (PCOS) with metabolic syndrome. Methods: This was an observational study with 242 PCOS patients at baseline. After mean of seven years of follow-up, only 101 patients were included in this study. We evaluated the development of diabetes and metabolic syndrome after metformin (MET) treatment. These patients were divided into groups with and without metabolic syndrome (MS). The group with MS used preferably metformin and without MS made use of hormonal contraception. Metabolic changes (insulin resistance, carbohydrate intolerance, and presence of diabetes) were compared in these two groups using X2 test. Results: Metabolic changes trended to decrease using metformin and to increase when the ACO was applied, but not statistically significant. Regardless of metformin treatment and a decrease in metabolic syndrome, the number of patients with diabetes increased in both groups, but less in group with metformin treatment. However, there was a decrease of approximately 3x ODD ratio in the metabolic complications using metformin.

Conclusions: Our follow up data suggested that the metformin treatment might not reduce the risk for developing diabetes in obese Brazilian women with polycystic ovary syndrome. Also, this drug might reduce the risk of metabolic complications.

 

Nothing to Disclose: SAYH, JMS, GARM, DDGC, MIA, GDNM, EMD, CPL, MCPB, ECB

32063 12.0000 SAT 102 A The Metabolic Syndrome in Brazilian Polycystic Ovary Syndrome in Seven Years of Follow-up 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 3:00:00 PM SAT 090-104 9466 1:00:00 PM Female Reproductive Endocrinology: Androgenic Disorders and Beyond Poster


Diana Speelman*, Tiffany Dillelo and Ami Shah
Lake Erie College of Osteopathic Medicine, Erie, PA

 

Women with polycystic ovary syndrome (PCOS) exhibit elevated levels of androgens, which exacerbate clinical symptoms and contribute to the pathogenesis of the syndrome. Elevated androstenedione (A4) was recently identified as a predictor of PCOS severity, although the specific effects of this androgen have yet to be elucidated. As obesity is a common finding in women with PCOS, we hypothesized that A4 would increase adipocyte lipid storage and decrease adiponectin expression. 3T3-L1 preadipocytes were exposed to 5 ng/mL A4, an A4 concentration comparable to serum levels in women with PCOS, throughout the course of differentiation (day 0 through day 10). Cells were collected at 48-hour intervals throughout the course of differentiation and stained with Oil Red O (ORO) to visualize and indirectly quantify lipid content. Imaging and extraction and quantification of the ORO dye showed that A4 exposure resulted in greater lipid content in mature 3T3 adipocytes as compared to cells treated only with acetonitrile (vehicle). Supernatants and cells were also collected at 48-hour intervals for immunoblot analysis, which revealed decreased adiponectin exposure and secretion in the A4-exposed adipocytes. Together, these findings suggest that A4 at levels comparable to those measured in women with PCOS can promote increased lipid storage and alter adipokine expression.

 

Nothing to Disclose: DS, TD, AS

32497 13.0000 SAT 103 A Altered Lipid Storage and Adiponectin Expression in 3T3 Adipocytes Exposed to Androstenedione at Levels Comparable to Serum Levels in Women with PCOS 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 3:00:00 PM SAT 090-104 9466 1:00:00 PM Female Reproductive Endocrinology: Androgenic Disorders and Beyond Poster


Hector Francisco Escobar-Morreale*, Mora Murri, María Insenser, Elena Fernández-Durán and Jose Luis San Millan
Diabetes, Obesity and Human Reproduction Research Group. Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS, CIBER Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Spanish Ministry of Science, Madrid, Spain

 

MicroRNAs (miRNAs) are small noncoding RNA sequences that regulate negatively gene expression at the post-transcriptional level. miRNAs play important regulatory roles in a variety of biological processes, including metabolic processes. Some particular microRNAs have recently been demonstrated to abundantly and stably exist in serum and to be potentially disease-specific. The potential for detecting circulating miRNAs as biomarkers for several diseases, such as diabetes, cardiovascular disease, cancer, viral infections has been widely reported in animal models and human subjects. The aim of this profiling study was to characterize the expression of serum miRNAs in polycystic ovary syndrome (PCOS) and the influence of obesity. We included 12 control women, 12 patients with PCOS and 12 men selected as to have similar body mass index (BMI) and age. Six subjects per group had normal weight (BMI < 25 kg/m2) and 6 subjects per group were obese (BMI > 30 kg/m2). MiRNA screening was performed using miRCURY LNA™ Universal RT microRNA PCR, 4x Human panel I+II in 384well PCR plates. PCOS status altered the expression of 27 miRNAs and obesity significantly altered the expression of 47 miRNAs. Moreover, there was a significant interaction between PCOS and the group of subjects in the expression of 39 miRNAs. The serum levels of miR-378a-5p and miR-1539 shown significant differences in group, obesity, and in the interaction of both factors. Further, we found correlation between expression levels of studied microRNAs PCOS and obesity. We studied the biological function for predicted targets of miRNA with significant interaction between PCOS and the group of subjects. The present results suggest that several serum miRNAs are influenced by PCOS and obesity, which can be potential predictive tools.

 

Nothing to Disclose: HFE, MM, MI, EF, JLS

31686 14.0000 SAT 104 A Characterization of Serum microRNAs Profile of Polycystic Ovary Syndrome (PCOS), and Obesity 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Reproductive Endocrinology Saturday, April 1st 3:00:00 PM SAT 090-104 9466 1:00:00 PM Female Reproductive Endocrinology: Androgenic Disorders and Beyond Poster


Saleha Babli*1, Eyad Al-Kharashi2, Khalid Alhajri2 and Mohammed Aldawish1
1Prince Sultan Military Medical City, Riyadh, Saudi Arabia, 2Prince Sultan Military Medical City

 

Background: Leiomyoma arising from adrenals are extremely rare, with less than 20 cases reported in medical literature. Liomyomas though benign lesions, may frequently confuse with malignancy on Imaging studies. The average age of presentation of adrenal lieomyoma is (2-72 years) with female preponderance. They are usually unilateral and hormonally inactive. Human immunodeficiency virus and Ebestein –Barr virus infections have been observed in 44.4 % and 16.6% of cases respectively. However, direct link between immunodeficiency and adrenal lieomyoma has not been established. Adrenal lieomyoma can present as huge abdominal masses mimicking malignancy.

Clinical Case:  A 33 years old lady, referred to endocrinology in the context of left adrenal incidentaloma detected in CT chest performed to evaluate chronic cough. she had no history of fever, night sweat or weight loss, no history of abdominal pain, patient is not hypertensive and no symptoms to suggest Cushing's Syndrome, pheochromacytoma or hyperandrogenism. Family history was irrelevant and physical examination showed normal blood pressure, BMI of 18 and no sign suggestive of adrenal hyperfunctioning. CT scan showed, two left adrenal masses, the larger one is heterogeneous with thick peripheral calcification, mild peripheral enhancement and large central non enhancing component likely representing necrosis measured 7.7x6.2x 7.3 cm, there was no invasion to the adjacent structures. The other lesion was located inferior and medial to the former one and showed mild peripheral enhancement with central area of necrosis measured 3.5x3.3x3.3 cm. Scan through both lungs show multiple branching nodular densities representing tree in bud appearance. Laboratory investigations showed normal dexamethasone suppression test and plasma metanephrins, serologic test for Epstein- barr virus and HIV were negative. regarding her chronic cough patient was evaluated by pulmonologist and was diagnosed as hypersensitivity pneumonitis. she underwent uneventful left adrenalectomy. Gross pathologic evaluation indicated a grey lobulated mass weighed 262 grams and measured 15x9x5 cm. with pale tan whorly cut surface and focal classification. Microscopic evaluation showed a well –circumscribed and encapsulated spindle cells arranged in fascicles and whorls, no features of mitosis or pleomorphism , residual normal adrenal tissue was noted at the periphery. The immunohistochemical (IHC) studies were positive for smooth muscle actin (SMA) and desmin which support the diagnosis of lieomyoma. Additional IHC studies included Melan-A, human melanocyte black 45 ( HMB45) , and Ebestien –Barr virus latent membrane protein (EBV-LMP ) were all negative.

 

Conclusion: Adrenal liomyoma is very rare and should be considered in the differential diagnosis of huge unilateral non-functioning incidentally detected adrenal lesions.

 

Nothing to Disclose: SB, EA, KA, MA

29865 1.0000 SAT 360 A Adrenal Leiomyoma: A Rare Cause of Adrenal Incidentaloma 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Pedro Pagán Banchs*, Selma Feldman Witchel, Amr Morsi and A. Kim Ritchey
Childrens Hospital of Pittsburgh of UPMC, Pittsburgh, PA

 

Background: Co-existing congenital neuroblastoma (NB) and classical CAH are extremely rare. To our knowledge, this patient is the first to have been identified prenatally.

Case: A 7-day old baby boy (BW 3.49 kg), infant of diabetic mother treated with diet, was found to have possible cystic kidneys on prenatal ultrasound (U/S). Physical exam revealed no focal abnormalities and normal male genitalia with bilateral palpable testes. A postnatal U/S showed an enlarged left adrenal gland without focal mass, a right adrenal mass (2.9 x 3.3 x 4 cm), normal appearing kidneys, and possible UPJ obstruction. His 17-OHP newborn screen was elevated at 229 ng/mL (extracted value, 68 ng/ml). Diagnostic studies showed elevated 17-OHP, 14,800 ng/dL (80-420 ng/dl) and elevated plasma renin activity 159.59 ng/ml/h (0.25-5.82)] confirming the diagnosis of CAH due to 21-hydroxylase deficiency. Additional studies showed elevated urinary homovanillic acid (HVA) and vanillylmandelic acid (VMA) consistent with the diagnosis of congenital neuroblastoma.

After confirmation of the CAH diagnosis, hydrocortisone and fludrocortisone replacement therapies were initiated. Subsequent MRI and MIBG scans were consistent with the diagnosis of neuroblastoma. Serial adrenal imaging has shown continued decrease in the size of the adrenal mass (now 2.3 x 2.2 x 2.0 cm). HVA and VMA excretion have decreased.

Genetic analyses showed normal male 46,XY karyotype. Genetic mutation analysis of CYP21A2 revealed two mutations, an intron 2G splicing mutation (c.293-13A/C>G) and a novel mutation, T>C at nucleotide c.527 in exon 4, which is predicted to generate a missense mutation, p.L175P. Based on bioinformatics tools, p.L175P is predicted to be deleterious. Amino acid alignment with other mammalian CYP21A2 genes indicates that this is a highly conserved amino acid (1).

Conclusion: CAH was diagnosed prior to neuroblastoma among the previously reported patients with concurrent CAH and neuroblastoma (2,3). The natural history of congenital NB is typically spontaneous resolution. The NB in our patient was likely detected because of the prenatal U/S findings and diagnosis of CAH. A novel CYP21A2 mutation was identified in our patient. Although the adrenal vein provides cortisol to the adrenal medulla, likely no causal relationship exists between CAH and NB. Rather the NB represents an incidental finding in a patient with CAH.

 

Nothing to Disclose: PP, SFW, AM, AKR

29903 2.0000 SAT 361 A Congenital Neuroblastoma in the Presence of Classical Congenital Adrenal Hyperplasia (CAH) Associated with a Novel Mutation 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Anara Karaca*1, Nese Ersöz Gülçelik2, Isilay Taşkaldıran3, Hatice Incebiyik4, Tulay Omma1, Tahsin Ozenmis4, Sevde Nur Firat3, Nujen Colak Bozkurt1, Gönül Koç5 and Cavit Culha3
1Ankara Training and Research Hospital, Ankara, Turkey, 2Ankara Training and Research hospital, Ankara, Turkey, 3Ankara Training and Research Hospital, 4Ankara Training and Research hospital, 5Ankara Training and Research Hospital, Ankara, Turkey, Ankara, TURKEY

 

 

Introduction

Predominantly considered the diagnostic domain of the pediatrician, congenital adrenal hyperplasia (CAH) is most frequently associated with 21-hydroxylase deficiency. However, a less common form of CAH, 17-α-hydroxylase deficiency, can stay asymptomatic and undiagnosed until adulthood.

A case

A 32-year old female was referred to endocrinology department with complaints of mild hypertension and hypokalemia in order to investigate causes of secondary hypertension.

Her past medical history included presentation to gynecologist at 15 years of age with primary amenorrhea. A karyotype analysis revealed 46XY and after that her ovaries were surgically removed, and she was started on life time estrogen replacement therapy. Her blood pressure was normal at that time.

However, last few months before presentation, she started to have headaches every day and blood pressure was measured 150/90mmHg and above.

Height 174 cm and BMI: 25.8 kg/m2. Pubic and axillary hair were poor, and breast development was minimal (Tanner stage 3).

On given the patient’s information, an upstream block in steroid synthesis was suspected. Potassium: 2.79 mmol/L(3.5-4.5), serum cortisol: 0.89mcg/dl (6-23), estradiol <20pg/ml and testosterone <10ng/dl (14-76) and ACTH: 62.4pg/ml (0-46), FSH:80, LH:36. Aldosterone: 552pg/ml(30-300)) and renin: 2pg/ml/h (0.2-27). Synacten stimulation test showed cortisol peak 1.5 mcg/dl at 30’. These results were consistent with 17-α-hydroxylase deficiency.

An abdominal CT showed 27x32mm hypodense lesion on the right adrenal gland. 24x12mm hypodense-heterogeneous lesions on confluence point and 12x9mm on the lateral crus of the left adrenal gland. These lesions were <10 HU density.

Dynamic pituitary MRI showed no pathology of the gland.

Sequencing of CYP17A1 demonstrated heterozygosity for c.1283C>T on exon 8. Her mother, but not father, showed heterozygosity for the same genetic location.

The patient was commenced on prednisolone 10 mg/d. Hypokalemia and hypertension resolved rapidly.

Year later repeated abdominal CT demonstrated 59 % reduction of the lesion on the right and 29 % reduction on confluence point and 66 % reduction on lateral crus of the left adrenal gland.

Blood pressure is in normal range with no medications. She is on 5mg/day prednisolone.

Discussion

To date, there have been only two case reports with 17-α-hydroxylase deficiency in children from Turkey. This is the first case of the adult patient with undiagnosed 17-α-hydroxylase deficiency so far.

The condition should be considered in young women, who fail to enter puberty and have concomitant hypertension.

Although, our patient had a complete 17-α-hydroxylase enzyme deficiency, she had a mild hypertension, which may be the reason in the delay of the diagnosis. This case is a really challenge for the adult endocrinologists, as these conditions are barely seen in adults.

 

 

Nothing to Disclose: AK, NEG, IT, HI, TO, TO, SNF, NCB, GK, CC

30173 3.0000 SAT 362 A The Rare Cause of Hypertension: Undiagnosed 17-α-Hydroxylase Deficiency in an Adult Female 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Antonio Mancini*1, Sebastiano Raimondo1, Carmine Bruno2, Giulio Olivieri1, Edoardo Vergani2, Giuseppe Macis2, Laura Riccardi2, Francesca romana Ponziani2 and Maurizio Pompili2
1Catholic University of the Sacred Heart, Rome, Italy, 2Catholic University of the Sacred Heart

 

Background: Hepatocellular carcinoma (HCC) is one of the most common fatal cancers in the world. A possible role among ethiologic factors is attributed to androgens. Hepatocytes exhibit androgen receptors and a cell proliferation stimulus is exerted by testosterone (T) or dihydro-T. This association is present even after adjustment for the presence of HBV, HCV, cirrhosis, alcohol consumption and smoke.

Case report: A 35-ys man, affected by adrenal hyperplasia due to 21-hydroxylase deficiency, diagnosed at age of 10 ys for anticipated adrenarche and microorchidism, came to our observation for a clinical control. His sister was also affected by the same syndrome, diagnosed by genetic studies. He had not been previously treated with suppressive or replacement therapy, resulting a chronic exposure to high T levels.

The patient showed an elevated 17-OH-Progesterone (P): basal 9.1, after ACTH 22 ng/ml (electro-chemiluminesce method or ECLIA, nomal range 0.2-0.8); T levels were 15.9 ng/ml (ECLIA, n.r. 2.5-8.4). At abdomen Magnetic Resonance Imaging, performed for adrenal investigation, a 18 mm large nodular lesion was discovered in the liver, together with increased serum α-fetoprotein level. Computed Tomography and Contrast Enhanced Ultrasound suggested increased arterial vascularity of the lesion; on the basis of needle biopsy assessment (showing an hyperplastic-adenomatous lesion with focal inflammatory infiltration and biliary metaplasia of hepatocytes) and of the high cancerous risk, he underwent surgical removal of the lesion. Histological findings showed HCC with moderate differentiation (G1/G2). We showed an unexpected lowering of T levels. One year later recurrence of HCC, localized in a different liver segment, was diasgnosed and treated by percutaneous radiofrequency ablation. Two other HCC recurrences were detected during the subsequent follow up and were treated with the same technique. Every HCC recurrence was accompanied by elevation of T, but also SHBG; therefore we hypothesized a facilitating effect of chronic androgen elevation, but also a possible production of SHBG by tumor itself.

Conclusion: The prevalence of HCC in adrenal hyperplasia is not well described in literature; our report suggests the need for screening of liver lesions in males affected by this syndrome; the role of T in inducing or facilitating the neoplasia and the possible involvement of SHBG secretion remain to be established.

 

Nothing to Disclose: AM, SR, CB, GO, EV, GM, LR, FRP, MP

30460 4.0000 SAT 363 A Recurrent Hepatocellular Carcinoma in a Male Affected By 21-Hydroxylase Deficiency: A Role for  Hypertestosteronemia? 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Milay Luis*1 and Christine A Resta2
16155 JUNCTION BOULEVARD, REGO PARK, NY, 2Maimonides Medical Center, Brooklyn, NY

 

Background: Congenital adrenal hyperplasia refers to a group of autosomal recessive disorders characterized by a genetic defect in the protein and enzymes involved in cortisol biosynthesis creating different clinical manifestations from increased or decreased mineralocorticoids and androgens depending on the site of the block. In the case of CYP17A1 deficiency the clinical manifestations are hypertension and hypokalemia due to the accumulation of cortisol precursors with mineralocorticoid activity upstream of the block, plus sexual infantilism due to inability to synthesize androgens and estrogens. Unlike most other forms of CAH, mineralocorticoid excess and high corticosterone production mitigate the clinical consequences of cortisol deficiency, and symptomatic adrenal insufficiency is rare

Clinical Case: A 21 year old woman from Ecuador initially seen in pediatrics endocrinology at the age of 18years for primary amenorrhea. Her initial physical exam showed height of 154.5 cm, normal blood pressure of 113/74mmHg, sexual characteristics tanner 1. Initial blood work were as follows: Cortisol 19.3 nmol/L (110-606), ACTH 56.1 pmol/L (1.32-11), corticosterone >10000 nmol/dL ( 1.7-37.3) 11 Deoxycortisol 4.21nmol/L (<3.09), testosterone <0.0347nmol/L( 0.07-1.56) estradiol <7.3pmol/L (follicular phase 143-1376, luteal phase 176-1615) FSH 30.9 IU/L ( follicular phase 2.5-10.2 mid cycle peak 3.1-17.7, luteal phase 1.5-9.1) LH 24.5 IU/L (follicular phase 1.9-12.5, mid cycle peak 8.7-76.3, luteal phase 10.0-54.7) progesterone 2.0nmol/L (follicular phase<3.2, luteal phase8.3-68.3) Aldosterone <0.02nmol/L ( <0.77)

pelvic sonogram : no ovaries seen, small uterus

Karyotype 46 XX. Genetic evaluation: homozygous mRNA.C334-336:3 bp duplication of AATC. Codon 113. (This has not been previously reported as a mutation causing CAH due to CYP17A1 deficiency)

She was started on low dose estradiol with plans to titrate up. Once there is sonographic evidence of significant uterine growth, the plan is to treat the CAH with methylprednisolone as a means of reducing the high level of adrenal-derived progesterone and therefore induce menses. Current physical exam shows secondary sexual characteristics tanner 2.

Conclusion: this is the first case reported with CYP17A1 with a mutation on the codon 113 that can cause CAH due to CYP17A1 deficiency without hypertension or potassium abnormalities.

 

Nothing to Disclose: ML, CAR

30722 5.0000 SAT 364 A New Mutation in CYP17A1 Gene Causing Congenital Adrenal Hyperplasia 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Stacy Goldbaum*1, Sonali Biligiri2 and Alan Chang3
1Drexel University College of Medicine, Philadelphia, PA, 2Drexel University College of Medicine, 3Drexel University College of Medicine, PA

 

BACKGROUND:

Congenital adrenal hyperplasia (CAH) is an inherited disorder of adrenal steroid synthesis, the majority of which is caused by 21-hydroxylase deficiency. Multiple alleles could be mutated with each allele being associated with classical or nonclassical CAH. In untreated compound heterozygous patients, this can still cause complications such as testicular adrenal rest tumors (TARTs) and benign adrenal tumors such as myelolipomas. These can be easily missed or misinterpreted on routine imaging.  

CLINICAL CASE:

37 year old male presented for evaluation after incidental imaging revealed bilateral adrenal enlargement. He was told he had adrenal cancer and should see an endocrinologist. At the office visit, he stated he was diagnosed with CAH as a child (type unknown) and started on fludrocortisone by a pediatric endocrinologist, which was stopped 12 years ago. He had never been on glucocorticoids, nor was he ever hospitalized for adrenal insufficiency. Prior to the visit, a CT abdomen/pelvis with contrast was performed for abdominal pain and showed enlargement of both adrenal glands: 7.8x9.1x6.5cm on the left, 5.1x10x7.1cm on the right. Multiple masses with fat density on the right anterior limb were also noted, the largest being 3.1x3.7x3.9cm, along with small hypodense lesions posteriorly. Additionally, a testicular ultrasound was performed after he noticed his testicles felt firm, and bilateral testicular tissue replaced with solid, hypoechoic lobulated masses were noted. The right was 4.1x1.8x2.4cm and 3.8x2.5x2.5cm on the left; both were surrounded by normal testicular tissue. While his adrenal and testicular abnormalities fit classical CAH with presumed myelolipomas and TARTs, respectively, the lack of prior glucocorticoid therapy pointed towards a non-classical etiology. Further work-up to establish diagnosis was then obtained. The 17-hydroxyprogesterone level was 34526 ng/dl (ref 42-196) and the CYP21A2 gene analysis showed P453S mutation and 30kb deletion. Plasma free metanephrines were negative: metanephrines <25pg/ml (ref<57), normetanephrines 78 pg/ml (ref<148), and total metanephrines 78 pg/ml (ref <205). The DHEA-S level was not elevated at 61 mcg/dl (ref 106-464). Initially, dexamethasone 0.75mg at bedtime was started as the patient also took carbamazepine, a CYP3A4 inducer; this was eventually decreased to 0.5mg. On follow up, the patient did well without cushingoid symptoms.

CONCLUSION:

Clinicians should consider a diagnosis of compounded heterozygous CAH in patients with findings of myelolipomas and TARTs. Failure to understand this entity can result in misdiagnosis, and the patient may undergo improper treatment which can be detrimental to their health. Currently, there is a lack of literature in regards to compounded heterozygous patients and the prevalence of TARTS and myelolipomas. 

 

Nothing to Disclose: SG, SB, AC

31084 6.0000 SAT 365 A Misdiagnosed Radiological Findings in a Patient with Compound Heterozygous 21-Hydroxylase Deficiency    2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Ben Brannick*1 and Saba Khayal2
1University of Tennessee, Memphis, TN, 2University of Tennessee Health Science Center, Memphis, TN

 

Case: This is a case of a 45-year-old male who presented to the Endocrinology clinic. He has a past medical history significant for congenital adrenal hyperplasia (CAH), recurrent pancreatitis from overuse of alcohol, major depressive disorder, hypertension, and childhood genitoplasty at age 14 years. He stated that he was raised as a girl by his parents/grandparents. However, he never developed periods or menstrual cycles and was never treated medically (such as with glucocorticoids) prior to coming to Endocrinology in 2014. In addition, he never had a salt-wasting crisis and was never hospitalized for hypovolemia, shock, or hypotension. In review of his prior laboratory data he was found to have a 17-OH-Progesterone of 18,409 ng/dl (27-199). An androstenedione level was found to be 192 ng/ml (27-152). He was subsequently started on glucocorticoids which brought the 17-OH-Progesterone down to 146 ng/dl. His social history is significant for drinking four 24-ounce beers daily. He enjoys watching sports on television, particularly football.  Pertinent positives on physical exam revealed his height of 59 inches (4’11”). He also demonstrated round, cushingoid “moon facies.” On genitourinary exam, there was the presence of fused labia, clitoromegaly, and a single orifice in the perineum. In addition, there was a small, vaginal introitus. No palpable inguinal masses. He did have a pelvic ultrasound which demonstrated “No sign of testicles with the inguinal canal or into the perineum.” A prior CT of the abdomen and pelvis showed “diffuse nodular enlargement of the adrenal glands bilaterally. On the left, there are multiple rounded hypodensities with largest distinct mass measuring 2.0 x 1.8 cm in size.”

Discussion: In summary, this is a case of 45-year-old phenotypically and (likely) karyotypically female, but who identifies socially and psychologically as male. He most likely has deficiency in CYP21A2 activity due to the high levels of plasma 17-hydroxyprogesterone, physical exam findings and medical history. In spite of childhood rearing as a female, his social and psychological preference is to identify as a male. In review of the literature, between 5-15% of patients with CAH, karyotypically female, will identify as male. This is felt to be related to the concept of androgen imprinting where elevated levels of androgens on the developing brain influence gender preference over karyotype and sexual assignment(1). It is important to note that the androgen elevation is not from testicular or ovarian production but from the adrenal glands. These lifelong elevated androgen levels in this patient likely contributed to his gender identity.

Conclusion: In cases of congenital adrenal hyperplasia it is important to consider the role of androgens in gender identity which may have more influence than childhood sexual assignment.

 

Nothing to Disclose: BB, SK

31774 7.0000 SAT 366 A Gender Identity in a Case of Congenital Adrenal Hyperplasia 21-Hydroxylase Deficiency, Non-Salt Wasting Type and the Role of Androgens on Social and Gender Development 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Taiga Inoue1, Alan Scott Sacerdote*2, Mayur Neog3, Ronakkumar Patel2, Gabriel Fenteany4, Krishna Patibandla5 and Gul Bahtiyar6
1Woodhull Medical & Mental Health Center, Brooklyn, NY, 2SUNY Downstate Medical Center, Brooklyn, NY, 3NYC Helath+Hospitals/Woodhull, Brooklyn, NY, 4NYC Health+Hospitals, New York, NY, 5NYC Health+Hospitals, Brooklyn, NY, 6NYU School of Medicine, New York, NY, New York, NY

 

The differential diagnosis of adrenal incidentalomas includes primary hyperaldosteronism, Cushing’s syndrome, and pheochromocytoma, and, when the first 3 have been excluded,-non-classic adrenal hyperplasia (NCAH). We have previously shown that insulin-sensitizing interventions ameliorate the expression of both classic and non-classic CAH.

The patient is a 56 year-old African-American man who was referred to Endocrine in 2002 for hypertension with a 3.0x2.8x2.1 cm, well circumscribed, ovoid, hypodense, soft tissue mass in the medial limb of the right adrenal first noted in 2001. Endocrine evaluation was negative for primary hyperaldosteronism, Cushing’s syndrome, and pheochromocytoma, however plasma renin activity (PRA) by liquid chromatography tandem mass spectrometry (LC/MS/MS) was low at 0.52 ng/ml/hr., at least suggesting the possibility of a deoxycorticosterone-secreting adenoma (DOComa). Unstimulated serum deoxycorticosterone by LC/MS/MS on 9/20/11 was 38 ng/dl (3.5-11.5). Both hypo- and hyperkalemia were occasionally noted, but not at DOC or aldosterone sampling times. Unstimulated serum 11-deoxycortisol by LC/MS/MS on 1/31/08 was 130 ng/dl (<76). Serum 17-OH-pregnenolone was normal and serum 17-OH-progesterone by LC/MS/MS was low at 43 ng/dl (61-334). Metformin 500 mg daily after supper was started on 5/6/08, following which serum 11-deoxycortisol fell to 84 ng/dl. After this the patient was lost to follow-up for several years and ran out of metformin. On 6/13/12 his serum 25-OH-Vitamin D by immunoassay (IA) was 6 ng/ml (30-100). Between 1/8/08 and 6/8/12 the patient had lost 2.3 kg, after which he underwent right below knee amputation due to peripheral arterial disease with gangrene. On 7/15/16 serum 11-deoxycortisol fell to 53 ng/dl (<42), serum deoxycorticosterone normalized to 6ng/dl (2-19), serum 25-OH-Vitamin D was 14.4 ng/ml (30.0-100.0). On 8/5/16 serum 11-deoxycortisol fell to 47 ng/dl, DOC was 5.2 ng/dl, and 25-OH-Vitamin D was 36.3 ng/ml. The right adrenal mass has not changed in size or appearance since 2001. This case illustrates the importance of considering NCAH in the differential diagnosis of adrenal incidentaloma and again illustrates the potential benefit of improvement of insulin sensitivity by both weight loss and correction of hypovitaminosis D in NCAH.

 

Nothing to Disclose: TI, ASS, MN, RP, GF, KP, GB

29225 8.0000 SAT 367 A Non-Classic 11-Hydroxylase Deficiency Presenting As an Adrenal Incidentaloma with Biochemical Amelioration Associated with Weight Loss and Vitamin D Repletion 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Saleha Babli*
Prince Sultan Military Medical City, Riyadh, Saudi Arabia

 

Background:

Adrenal cysts are rare, around 600 cases have been reported in the Medical literature. They are usually non-functional, asymptomatic and less than 10 cm in diameter when discovered incidentally. They may occur at any age, but most of them are seen in the 3rd to 4th decades of life with a higher preponderance in females. Traditionally, adrenal cysts are divided into neoplastic and nonneoplastic groups. Non-neoplastic adrenal cysts may be further categorized as any of the 4 major types: pseudocyst(39%), epithelial (9%), parasitic (7% generally echinococcal), or endothelial cysts (45%). Symptoms occur when adrenal cysts become large enough to cause pain or as a consequence of intracystic bleeding or infection. Less frequent presentations include hypertension or spontaneous rupture of the cyst. Radiologic evaluation is helpful in identification benign versus malignant lesions (7 % of adrenal cyst are potentially malignant). Any functional lesions, potentially malignant lesions, or benign lesions more than 5 cm in diameter deserves surgical treatment. For small, benign lesions, conservative management is a viable option, although no surveillance protocols have been described.

Clinical case:

A 41 years old male referred to endocrinology in the context of left adrenal mass found in CT abdomen performed to evaluate right loin pain, patient is normotensive and no history of adrenal hyper functioning. physical examination showed normal blood pressure with no signs of adrenal hyper functioning.

CT scan showed mass originating from the lateral limb of the left adrenal gland measuring 6 X 5 cm and showing CT characteristic of clear fluid with attenuation value 13 HU consistent with adrenal cyst. No evidence of solid component or septations. No evidence of calcifications. There is no infiltration or invasion of surrounding structure.The right adrenal gland is normal.

MRI adrenals showed thin walled well defined rounded 6 x 5 cm lesion involves the lateral limb of the left adrenal gland. It depicts high T2 and low T1 signal intensity and no change of signal in the out of phase sequence. No septa or hemorrhagic component.

Laboratory investigations showed negative hydatid antibody, normal DST and normal urinary metanephrines.

Patient offered left adrenalectomy but he elects to wait with follow up images.

CT abdomen a year later showed increase in the size of the cyst to 6.7X6.8 cm, 2 years later the size increase to 8.2x7.4 cm, and 3 years later the size increase to 10x9 cm no change in the radiological characteristic. Patient remain asymptomatic. Repeated hormonal screen was again normal. Patient finally agree for adrenalectomy which will be done in 2 months.

 

Conclusion:

 With the increasing use of imaging modalities in patient evaluation, an increase in incidentally detected adrenal cysts is expected. Surgical excision of these cysts is an acceptable method of treatment where the indications are met.

 

Nothing to Disclose: SB

31097 9.0000 SAT 368 A Adrenal Cyst: An Uncommon Cause of Adrenal Incidentaloma 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Shailesh Baral*1, Wonil Tae2, Rama Poola3, Carmel Maria Fratianni1 and Michael G Jakoby IV3
1Southern Illinois University School of Medicine, Springfield, IL, 2OSF Saint Anthony's Health Center, Alton, IL, 3SIU School of Medicine, Springfield, IL

 

Background : Adrenal cysts are rare, with a prevalence no higher than 0.2% in autopsy series and accounting for approximately 1% of incidentally discovered adrenal masses. There have been only about 600 cases reported in the peer reviewed literature. We present a case of an incidental adrenal cyst found during evaluation for trauma after high elevation fall from a tree.

Case: A 34 year old male with history of hypertension diagnosed four years before presentation was brought to the emergency department after falling approximately 12 feet from his deer stand to the ground, sustaining a fracture of the left posterior acetabulum. Computed tomography (CT) of the abdomen revealed a 10 cm right adrenal cyst with peripheral calcifications but no septations, hemorrhage, or solid component. Blood pressure (BP, 197/121 mm Hg) and heart rate (HR, 110-120 bpm) were significantly elevated, and the patient reported he had stopped BP lowering medications approximately three years before admission. The magnitude of BP and HR elevations raised concern for a cystic pheochromocytoma, though plasma free metanephrines drawn while the patient was still in the emergency room were unremarkable. Morning cortisol suppressed to < 1.8 mg/dL on an overnight dexamethasone suppression test. Echinococcal serologies were obtained due to a military deployment to Iraq, with no significant titer of Echinococcus IgG antibody detected. Hypertension and tachycardia were controlled with diltiazem and prazosin, and the patient did well after open reduction and internal fixation of his fracture. Unfortunately, he did not come to endocrinology clinic after hospital discharge.

Conclusions. Historically, adrenal cysts have presented with abdominal pain and a palpable flank mass, though a large number are now discovered incidentally on abdominal imaging studies. They are generally classified into four major histopathological types: endothelial, pseudocyst, epithelial, and parasitic. Endothelial cysts and pseudocysts are most common, though the distinction may be insignificant as both appear to be variants of vascular cysts. In most series, a small number (≤ 5%) of cysts are associated with pheochromocytomas or adrenocortical carcinomas. Surgery is recommended for symptomatic patients, cysts > 5 cm, functional lesions, hemorrhagic cysts, cysts with evidence of mass effect, or suspected carcinoma. Adrenalectomy is preferred by most authors, though in some case series laparoscopic aspirations and gland sparing surgeries have been performed. Asymptomatic patients with cysts < 5 cm and no evidence of hormonal secretion or carcinoma can be followed prospectively with abdominal CT imaging, though there is no consensus on the timing and duration of surveillance due to the low incidence of cases. Surgery was indicated for our patient due to the size of his cyst, though he was unfortunately lost to follow up.

 

Nothing to Disclose: SB, WT, RP, CMF, MGJ IV

31296 10.0000 SAT 369 A Incidental Adrenal Cyst Discovered on Evaluation after High Elevation Fall from a Tree 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Mehmet Sercan Marangoz*, Stephanie Moss, Brian Boulmay, Farah Naz Mushtaq and Taniya DeSilva
LSUHSC, New Orleans, LA

 

Introduction:

Adrenocortical cancer (ACC) is a rare and aggressive malignancy with metastatic potential in 40% of patients within 2 years despite complete resection. The pathologic differentiation of ACC from benign neoplasms is challenging.

We present the case of a 49-year-old woman with recurrent masses despite complete left adrenalectomy 4 years prior for what was deemed benign adrenocortical hyperplasia.

Case report:

A 49-year-old presented in 11/2011 for evaluation of an incidental adrenal mass. She was noted to have a 6.7cm left adrenal mass with Hounsfield units<10. Hormonal evaluation was negative. She underwent left adrenalectomy in 4/2012. Pathology was notable for a modified Weiss score positive for 3/9 criteria, consistent with ACC. However, given the size of the neoplasm, mitotic activity and invasiveness, ultimately she was classified to have adrenocortical hyperplasia.

She was lost to follow up for 4 years finally returning to clinic in 6/2016. She complained of weight gain, unusual facial hair growth and constant left upper quadrant, abdominal pain. Her physical exam was negative for Cushingoid features, or hirsutism.

Her biochemical evaluation was significant for: aldosterone 8.7 (4.0-31ng/dl), renin:0.7 (0.2-1.6ng/ml/hr), DHEA-S: 94(32-240 ug/dl), 24 hr urine Cortisol: 15(0-50ug/24hr) for a creatinine of 2.2g/24h, TSH: 1.31(0.5-5 IUI/ml), 24hr urine epinephrine, norepinephrine, metanephrine were within normal limits. Repeat CT revealed new lesions in the left adrenal bed, anterior to the left kidney and adjacent to the diaphragm concerning for recurrent or metastatic disease.

CT guided FNA of the diaphragmatic lesion was performed. Cytology revealed similar features to the patient’s previously resected adrenal lesion. According to the modified Weiss score these features are consistent with a malignant lesion of uncertain potential.

Repeat CT scan in 10/2016 revealed further enlargement of patient’s left adrenalectomy bed nodule. She is awaiting surgical resection of the nodules.

Discussion:

ACC is a rare but aggressive malignancy that can lead to multiple endocrine disorders. Five-year survival is approximately 45 to 60% for early stage disease, and 10 to 25% for advanced stage disease. A modified Weiss scoring system is used for pathologic diagnosis. This case highlights the difficulties in pathologic diagnosis of ACC and the importance of strict adherence to the Weiss scoring system. Patients diagnosed with a malignant lesion or lesions with uncertain potential should be treated aggressively and followed closely.

 

Nothing to Disclose: MSM, SM, BB, FNM, TD

31495 11.0000 SAT 370 A Benign or Malignant? Challenging Case of an Adreanal Mass! 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Travis J Mason*, Joseph D Jakowski, Diane Mary Biskobing, Francesco Saverio Celi and Giao Quynhthi Phan
Virginia Commonwealth University, Richmond, VA

 

Introduction: Adrenal cysts are uncommon, making up <10% of adrenal masses, and most present as nonfunctional incidentalomas or with vague abdominal pain.

Clinical Case: A 24 years-old man presented with acute onset of right abdominal pain while lying in bed. Past medical history was significant only for hepatitis A at age 15. Physical exam showed a healthy-looking male who was afebrile, with heart rate 106, BP 115/74, and BMI 27 kg/m2. He had mild bilateral gynecomastia but no other unusual signs. Initial labs showed elevated WBC 20K and normal liver function tests. Abdominal ultrasound showed a large cystic adrenal/liver mass. CT scan showed a 15cm x 11cm x 10cm well-circumscribed hypodense cystic right adrenal mass abutting the liver and kidney. The mass was relatively homogenous except for a fluid-layering effect, with the nondependent upper half measuring 18 HU and the dependent lower half measuring 28 HU, suggesting recent bleeding settling in the dependent areas. The parenchyma of the right adrenal gland appeared to be compressed by the mass and displaced anteromedially.

The patient was admitted for pain control and workup of the adrenal mass. 24-hour urine collection (2070 mL) showed elevated free cortisol, measuring 282 mcg/24 hrs (normal 0-50). Plasma and 24-hour urine metanephrines and normetanephrines were normal. Plasma aldosterone was <1.0 ng/dL, and plasma renin activity was 1.39 ng/mL/hr, with A-R ratio <1. Random ACTH was suppressed at 3.0 pg/mL (normal 7-63). DHEA-S was low at 87 mcg/dL (normal 164-530). The remaining laboratory workup was notable for low albumin 3.6 g/dL (3.7-5.2 g/dL), low total protein 6.0 g/dL (normal 6.4-8.5), anemia with Hgb 11.8 g/dL (normal 13.3-17.2), and hypocalcemia of 8.4 mg/dL (normal 8.9-10.7). Although his WBC was elevated at presentation, it decreased to normal spontaneously.

He underwent open right adrenalectomy uneventfully with perioperative stress dose hydrocortisone. Histological examination showed a benign adrenal gland associated with a hemorrhagic pseudocyst. No adrenal cortical or medullary tumor was seen on extensive pathologic sectioning. The adrenal cyst consisted of a thick fibrous wall with organized internal contents of fibrin clot and degenerating blood. There was chronic periadrenal inflammation. The normal appearing adrenal gland was intimately associated with the fibrous wall of the pseudocyst. The patient was discharged home with hydrocortisone taper and currently doing well on low dose replacement 20mg/5 mg hydrocortisone.

Conclusion: Adrenal pseudocysts are rare and can present with nonspecific abdominal pain, but hormonal excess due to adrenal cysts is rare, with pheochromocytoma the most common. Some case reports have documented spontaneous hemorrhage or infection in adrenal cysts. Based on literature review, this may be the first case of a hemorrhagic adrenal pseudocyst causing Cushing’s syndrome.

 

Nothing to Disclose: TJM, JDJ, DMB, FSC, GQP

32111 12.0000 SAT 371 A Large Adrenal Pseudocyst Causing Subclinical Cushing's Syndrome 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Akiyo Tanabe*1, Masashi Kameyama1, Rina Owada2, Daisuke Yamada1, Haruki Kume3 and Hiroshi Kajio4
1National Center for Global Health and Medicine, Tokyo, Japan, 2Saitama Sekishinkai Hospital, 3National Center for Global Health and Medicine, 4National Center for Global Health and Medicine, Japan

 

Introduction: The Endocrine Society clinical practice guidelines recommend adrenal venous sampling (AVS) as the gold standard test to distinguish between unilateral and bilateral subtypes of primary aldosteronism (PA). Except for patients younger than 35 years of age who have marked PA and a solitary unilateral apparent adenoma on CT, all patients with PA should have AVS before surgery. However, successful cannulation of the right adrenal vein is difficult and leads to high rates of failed AVS at centers with low patient volumes. Herein we describe a patient with unilateral aldosterone-producing adenoma (APA) that was confirmed by 131-I-6-betaiodomethylnorcholesterol (NP-59) single-photon emission CT/CT (SPECT/CT).

Clinical Case: A 45-year-old Japanese woman with 2 drug hypertension was recently found to be hypokalemic (serum K = 2.0 mEq/L). Laboratory testing showed: plasma renin activity (PRA) = 0.1 ng/ml/h, plasma aldosterone concentration (PAC) = 43.9 ng/dL, and urine aldosterone excretion = 44 mcg/d (urine Na 188 mEq/d). The PAC was not suppressed with the captopril challenge test or the saline infusion test, and PA was confirmed. CT scan demonstrated a low density right adrenal nodule measuring 11 x 6 mm. The right adrenal vein was visualized with multidetector CT and AVS with cosyntropin stimulation was performed. However, the serum cortisol levels in IVC and the right and the left adrenal veins (17.1, 15.1 and 122.6 mcg/dL, respectively), showed unsuccessful cannulation of the right adrenal vein. PAC levels in IVC and the right and the left adrenal veins were 63.2, 10.9 and 313.1 ng/dL, respectively. Instead of repeating AVS, a NP-59 SPECT/CT scan with dexamethasone (DEX)-suppression was obtained. The patient took oral DEX (3 mg/day for 4 days before and 2 mg/day for 7 days after NP-59 intravenous injection) to suppress cortisol production in normal adrenal gland. The patient was also treated with iodine tablets for 9 days to block thyroidal uptake of free 131-I. SPECT/CT images were obtained at 5 and 7 days after NP-59 administration. NP-59 SPECT/CT revealed intense uptake within the right adrenal gland without significant uptake in left adrenal gland. After laparoscopic right adrenalectomy, serum K, PAC and PRA were 4.3 mEq/L, 9.2 ng/dL, and 1.0 ng/mL/hr, respectively. Her blood pressure normalized without antihypertensive medications.

Conclusion: The role of NP-59 planar scintigraphy has been thought to be limited for subtype classification of PA because tracer uptake is poor in APAs smaller than 1.5 cm in diameter (sensitivity <50%). However, with the development of SPECT technology the resolution of scintigraphy has been improved. NP-59 SPECT/CT with DEX-suppression should be reconsidered as an effective test to determine the clinical significance of CT-detected adrenal nodules in patients with PA.

 

Disclosure: AT: Protocol review committee, ONO-Pharma, Investigator, ONO-Pharma. Nothing to Disclose: MK, RO, DY, HK, HK

29698 13.0000 SAT 372 A Use of NP-59 SPECT/CT for Lateralization in Primary Aldosteronism: A Case Report 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Jamila Benmoussa*1 and James Desemone2
1Albany Medical College, Albany, NY, 2Albany Medical College, Albany

 

Introduction:

Takotsubo cardiomyopathy is believed to be induced by excess catecholamine release and is frequently associated with emotional stress. We report a case of this condition associated with an Aldosterone Producing Adenoma (APA).

Case Presentation:

A 47-year-old African American female with hypertension since age 28 presented with an acute MI. Her history was significant for right renal artery fibromuscular dysplasia which was treated with angioplasty. Her blood pressure had been controlled with calcium channel blockers until age 45 when an ARB was added. Four months prior to presentation she had chest pain and was diagnosed clinically with perimyocarditis. A cardiac catheterization showed normal coronary and a chest CT revealed a 1.6 x 1.8 cm left adrenal incidentaloma (0 Hounsfield units). Subsequent laboratory evaluation showed a serum aldosterone of 42 ng/dl (normal <3.0 – 23.2 ng/dl), and a renin <0.15 mg/ml/hr. Epleronone therapy was started, and four days later she presented with rapidly escalating chest pain associated with headache, high blood pressure, and diapherosis. The ECG showed an acute inferior wall MI and the troponin level rose to 16 ng/dl. she denied emotional stress. A cardiac catheterization showed apical hypokinesis, no evidence of ASCVD, and normal renal arteries. The ejection fraction was 55%. An adrenal MRI showed a 2.0 x 1.3 x 1.8 cm left adrenal nodule which was consistent with a lipid rich adenoma. A 24 hour urine collection for catecholamines, metanephrenes , normetanephrines, and cortisol was normal. The epleronone dose was adjusted and surgical consultation was obtained.

Discussion:

The effect of hypealdosteronism on cardiac morbidity could be from HTN alone and/or the direct effects of aldosterone on myocardial and vascular cells. It is known that high levels of aldosterone stimulate renal sodium retention by increasing expression of the thiazide-sensitive sodium-chloride cotransporter and the amiloride-sensitive epithelial sodium channel (ENaC) leading to plasma volume expansion and HTN. The role of aldosterone in eliciting acute vascular effects through nongenomic signaling pathways has been increasingly recognized. High levels of aldosterone increase markers of oxidative stress in plasma and heart tissue and alter intracellular Mg and Ca concentrations in smooth muscle cells and lead to coronary artery dysfunction. Acute aldosterone exposure causes dose-dependent myosin light-chain phosphorylation, a mechanism by which it can mediate vasoconstriction. These rapid effects of aldosterone can be inhibited by both spironolactone and eplerenone.

Conclusion:

To our knowledge, this is the first report of Takotsubo’s cardiomyopathy associated with an APA. It suggests that non-genomic effects of aldosterone may enhance the risk of acute coronary vasoconstriction and can lead to myocardial ischemia in susceptible patients.

 

Nothing to Disclose: JB, JD

31491 14.0000 SAT 373 A Aldosterone Producing Adenoma Associated with Takotsubo Cardiomyopathy 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Kei Omata*1, Yuto Yamazaki2, Yasuhiro Nakamura3, Sharath Anand4, Justine Barletta5, Scott A Tomlins1, Hironobu Sasano2, William E. Rainey1 and Anand Vaidya5
1University of Michigan, Ann Arbor, MI, 2Tohoku University Graduate School of Medicine, Sendai, Japan, 3Tohoku Medical and Pharmaceutical University, Sendai, Japan, 4University of Michigan, 5Brigham and Women's Hospital, Harvard Medical School, Boston, MA

 

Context. Whether primary aldosteronism (PA) is the consequence of a monoclonal or multiclonal neoplastic process is unclear.

Case Description. A 48-year-old man with severe bilateral PA refractory to medical therapy underwent unilateral adrenalectomy of the dominant adrenal. Although computed tomography (CT) showed three left-sided cortical adenomas, post-surgical histopathology and genetic analysis revealed five different adrenocortical adenomas. Two zona fasciculata (ZF)-like aldosterone producing adenomas (APAs) each harbored distinct known somatic KCNJ5 mutations (L168R and T158A). A zona glomerulosa (ZG)-like APA harbored a known CACNA1D G403R somatic mutation, while a zona reticularis (ZR)-like adenoma, which was a so-called black adenoma (pigmented appearance) with histologic characteristics more associated cortisol-producing adenomas, expressed CYP11B2, CYP17 and DHEA-ST by immunohistochemistry (IHC) and harbored no known somatic mutations. The fifth tumor was ZF-type, negative for CYP11B2 and CYP17 IHC, and harbored no known somatic mutations.

Conclusions. This case highlights complex intra-patient heterogeneity in histology, steroidogenesis and somatic mutations in multiple adrenocortical adenomas arising in a patient with PA. The extent of multiclonal adenoma involvement in PA, including apparent unifcoal tumors by morphology, warrants additional study.

 

Disclosure: SAT: Principal Investigator, Thermo Fisher Scientific, Speaker, Thermo Fisher Scientific. Nothing to Disclose: KO, YY, YN, SA, JB, HS, WER, AV

31628 15.0000 SAT 374 A Coexistence of Five Histopathologically and Genetically Distinct Adrenocortical Adenomas in a Patient with Primary Aldosteronism 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Min Ji Kim*, Eun Yeong Mo, Sung Dae Moon, Eun Sook Kim and Je Ho Han
Incheon St. Mary’s Hospital, The Catholic University of Korea, Incheon, Korea, Republic of (South)

 

Introduction

Primary aldosteronism is mainly caused by either unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia (BAH). Usual diagnostic approaches in patients with primary aldosteronism are focused on differentiating unilateral APA and BAH. Bilateral adrenal cortical adenomas in the setting of primary aldosteronism are very rare, but possible.

Clinical case

A 48-year-old man was referred to our hospital with hypokalemia and poorly controlled hypertension despite four antihypertensive medications. Physical examination showed blood pressure of 180/100 mmHg. The serum potassium level was 3.0 mEq/L, arterial blood gas analysis revealed metabolic alkalosis. The Plasma aldosterone concentration (PAC) was 57.62 ng/dL (normal 1.3 to 14.5), and the Plasma rennin activity (PRA) was 0.26 ng/mL/hr (normal 0.32 to 1.84) with a calculated aldosterone to renin ratio was 221.6. Intravenous saline infusion test for confirmation failed to suppress plasma aldosterone level significantly (pre-infusion PAC: 35.9 ng/dL, post-infusion PAC: 58.5 ng/dL), consistent with a primary aldosteronism. Upright posture for 240 minutes suppressed plasma aldosterone concentration. (Basal PAC: 50.1 ng/dL, after upright PAC: 38.7 ng/dL). Abdomen computed tomography (CT) demonstrated a 1.5 cm sized right adrenal mass and a 1.2 cm sized left adrenal mass both with less than 10 Hounsfield unit (HU) on pre-contrast image. The adrenal venous sampling was performed and revealed the following adrenal vein - inferior vena cava (IVC) ratio of cortisol was greater than 10, right - left adrenal vein ratio of aldosterone - cortisol ratio was 5.56, left adrenal vein - IVC ratio of aldosterone - cortisol ratio was 0.64. Although the right-sided hyper-functioning mass was suspected in the adrenal vein sampling, we planned to explore both adrenal glands due to discrete masses were existed on both adrenal glands on CT. Right total adrenalectomy and left partial adrenalectomy were performed by laparoscopic approach. The pathology confirmed the bilateral adrenal cortical adenomas with marked cytologic atypia and the sections from both sides shared a nearly identical appearance. 7 days after surgery, laboratory finding showed the normal basal PAC of 0.68 ng/dL, after intravenous saline infusion PAC was 0.23 ng/Dl and PRA was 0.2 ng/ml/hr. 14 Days after surgery, the patient was normotensive (130/80 mmHg) on a calcium channel blocker and a angiotensin ll receptor blocker (Nefidipine 90 mg, fimasartan 30 mg a day), and the serum potassium was 4.5 mEq/L without any potassium supplement.

Conclusion

In this case, unilateral hyperfunction was suspected in the adrenal vein sampling, but bilateral adrenal adenomas was presented on the CT and then confirmed by pathology. Clinicians should consider the possibility of bilateral adenomas in diagnosis and treatment with primary aldosteronism.

 

Nothing to Disclose: MJK, EYM, SDM, ESK, JHH

30864 16.0000 SAT 375 A Bilateral Adrenal Adenomas in the Presence of Primary Aldosteronism 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Tania A Bachega*1, Andresa S Rodrigues2, Rosa Paula Mello Biscolla3, Décio Mion4 and Marcello D Bronstein5
1Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 2Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil, 3Grupo Fleury, Sao Paulo, Brazil, 4Faculdade de Medicina, Universidade de São Paulo, Sao Paulo, Brazil, 5Disciplina de Endocrinologia e Metabologia, Unidade de Neuroendocrinologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil.

 

autosomal recessive disorder characterized by early-onset hypokalemic hypertension and low renin and aldosterone levels. The disease is caused by HSD11B2 gene mutations, which result in impaired peripheral metabolism of cortisol to cortisone, leading to increased urinary-free cortisol to cortisone ratio. AMES therapy is based on spironolactone and potassium supplementation; nevertheless, the use of dexamethasone remains controversial. Objective: to report a female patient with AMES responsible to dexamethasone therapy carrying a new HSD11B2 mutation. Subject: a 20 yrs old female patient born with normal weight and height and normal external genitalia. She developed hypertension during childhood and was treated with spironolactone and enalapril, remaining with inadequate blood pressure (BP) control. Menarche occurred at 13 yrs and final height was close to midparental height, 154 and 159cm, respectively. Parents were not consanguineous and presented with “mild essential” hypertension. Methods: free salivary cortisol and free-urinary cortisol and cortisone levels were measured by LC-MS/MS, serum ACTH levels by electrochemiluminometric assay, aldosterone and PRA levels by RIE assays and serum cortisol by competitive electrochemiluminescence assay. DNA samples were available from the proband and mother, HSD11B2 gene having been PCR amplified and submitted to automated sequencing.Results: clinical evaluation identified left ventricular hypertrophy and renal ultrasonography ruled out the presence of arterial stenosis. AMES was diagnosed through the following laboratorial analysis: Na 144 mEq/L, K 2.4 mEq/L, aldosterone 2.0 ng/mL and PRA 0.1 ng/mL/h (aldosterone/PRA ratio: 20). Late-night salivary cortisol and ACTH levels were 329 µg/dL (reference range: <100 µg/dL) and 5 pg/mL (reference range: 7-63 pg/mL), respectively, the 24-h urinary free cortisol to cortisone ratio was significantly increased (9.3/<4). A novel homozygous p.Y295* mutation at HSD11B2 exon 5 (c.885C>A) was identified, also found in heterozygosis in her mother’s DNA sample. The novel mutation was not identified in the 1000 Genomes and in silico three dimensional modeling showed a strongly truncated protein suggesting a severe damage on protein sequence (P=1). At adulthood, despite the use of spironolactone, enalapril and potassium supplemental, patients still remained with low serum potassium levels and inadequate BP control. The dexamethasone therapy (0.75mg) allowed adequate BP control and late-night salivary cortisol decreased to 47 ug/dL. After 6 months, dexamethasone doses decreased to 0.25 mg/day. Conclusion: A new mutation in the HSD11B2gene has been described, expanding the molecular AMES diagnosis. The achievement of clinical control after the introduction of dexamethasone therapy could be related to the patients’ genetic background as previously described in the literature.

 

Nothing to Disclose: TAB, ASR, RPMB, DM, MDB

32510 17.0000 SAT 376 A A Case of Apparent Mineralocorticoid Excess Responsible to Dexamethasone Caused By a Novel HSD11B2 Mutation 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Amanda J Brahm*1, Stan Van Uum2, Deborah Penava3 and Dongmei Sun3
1Western University, London, ON, 2Division of Endocrinology and Metabolism, Department of Medicine, Western University, London, ON, Canada, 3Western University

 

A 36-year-old woman with no personal or family history of hypertension presented at 16 weeks gestation with hypertensive urgency. Potassium was intermittently low (3.1mmol/L). Aldosterone was elevated (3000pmol/L (N <1118)), renin remained unsuppressed (40.7ng/L (N1.7-23.9)), with normal aldosterone to renin ratios. An adrenal MR detected a 1.8 x 1.4 cm left adrenal adenoma. 24-hour urine collection for metanephrines and catecholamines was normal. She was managed conservatively, with close maternal and fetal surveillance, and treatment with labetalol and nifedipine. She achieved reasonable blood pressure control, with no obstetric complications. Post-partum blood pressures remained elevated with normal aldosterone (539 pmol/L), unsuppressed renin (5.2 ng/L) and normal aldosterone-to-renin ratio (104 (N<144)). She had normal response to 1mg dexamethasone suppression test and normal suppression of aldosterone with saline infusion. These results suggest an alternative cause of her hypertesion with an incidental finding of an adrenal adenoma.

This case highlights the many difficulties associated with investigations and management of suspected primary hyperaldosteronism in pregnancy. Outside of pregnancy, the accepted screening test is the aldosterone to renin ratio, with confirmatory tests including a saline suppression test, captopril challenge or salt/fludrocortisone load. However, these tests lack validated pregnancy reference ranges or are contraindicated. Pregnancy has significant effects on the renin-angiotensin-aldosterone pathway leading to physiologic elevations in both aldosterone and renin: progesterone competitively binds to aldosterone receptors; ovaries and placental tissues secrete renin; estrogen stimulates angiotensinogen production. While primary hyperaldosteronism has been associated with poor pregnancy outcomes, optimal management in pregnancy is not clearly established. Conservative treatment with traditional antihypertensives, cautious use of mineralocorticoid receptor antagonists, or surgical adrenalectomy are all possible treatment options reported in the literature.

 

Nothing to Disclose: AJB, SV, DP, DS

32317 18.0000 SAT 377 A High Aldosterone Levels, Hypertension and Adrenal Adenoma in a 36 Year-Old Pregnant Patient: Is This Primary Hyperaldosteronism? 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Yuta Tezuka*1, Ryo Morimoto1, Yoshikiyo Ono2, Yoshitsugu Iwakura3, Masataka Kudo1, Yasuhiro Igarashi1, Mariko Miyazaki4, Hiroshi Sato4, Kazumasa Seiji1, Kei Takase1, Yoichi Arai1, Yuto Yamazaki5, Yasuhiro Nakamura6, Hironobu Sasano5, Sadayoshi Ito1 and Fumitoshi Satoh5
1Tohoku University Hospital, Sendai, Japan, 2Tohoku Uiversity Hospital, Sendai, Japan, 3Tohoku Medical and Pharmaceutical University Hospital, Sendai, Japan, 4Tohoku University Hospital, 5Tohoku University Graduate School of Medicine, Sendai, Japan, 6Tohoku Medical and Pharmaceutical University, Sendai, Japan

 

[Introduction] Primary aldosteronism (PA) is characterized by low plasma renin activity (PRA) suppressed by high plasma aldosterone concentration (PAC). However, in some cases with nephropathy developed by PA or other causes, PRA can be elevated that makes the diagnosis of PA, especially Aldosterone-Producing Adenoma (APA), more difficult. [Case report] A 59-year-old man was referred to our hospital due to a right adrenal tumor with hypokalemia. He also had difficult-to-control hypertension treated with five anti-hypertensive agents and chronic renal failure (CRF) accompanied with nephrotic-range proteinuria, 5.3 g/gCr. With the medications including β blocker, aldosterone-to-renin ratio (ARR) was 68.2 ng/dL per ng/mL/hr so that PA was suspected. Clinical parameters at the first visit were as follows; body mass index 28.8; blood pressure 135/74 mmHg; heart rate 61 bpm; serum pottasium 2.8 mM; serum albumin 2.5g/dL; estimated GFR 20.8 mL/min/1.73m2. However, PAC and PRA were decreased to 29.4 ng/dL and increased to 2.2 ng/mL/hr, respectively, that resulted in low ARR, 13.4, after discontinuing β blocker. PRA fluctuated between 1.0 and 2.8 ng/mL/hr. Although it seemed to secondary hyperaldosteronism (SHA), PAC remained around 30 ng/dL during 50 mg captopril challenge test (CCT). Above results suggested the probability of coexistence of autonomous aldosterone hypersecretion (AAH) and SHA. In order to confirm the existence and determine the laterality of AAH, we decided to perform adrenal venous sampling (AVS). Because of CRF, we used non-contrast-enhanced magnetic resonance venography to map adrenal veins prior to AVS. After mapping, cosyntropin-stimulated AVS was performed with carbon dioxide and only 8 mL of contrast material by skilled angiographers. As a result, aldosterone-to-cortisol ratio in right adrenal venous sample was 12.8 times higher than that in left adrenal venous sample. Accordingly, we diagnosed him with AAH from right adrenal gland which harbored a tumor, complicated with SHA due to CRF. In preparation for laparoscopic right adrenalectomy, angiotensin II receptor blocker and mineralocorticoid receptor antagonist were started and gradually increased to reduce proteinuria. Finally, we achieved a 90% reduction in proteinuria with 30 mg of azilsartan and 90 mg of spironolactone without exacerbation of CRF. And then, he underwent laparoscopic right adrenalectomy. The removed adrenal gland had an adrenocortical tumor which was classified into benign adenoma based on Weiss's criteria. In immunohistochemical staining, the adrenocortical adenoma showed diffuse expression of CYP11B2, indicating that the adenoma was an APA. After operation, his blood pressure and proteinuria were improved. [Conclusion] We experienced a suggestive case of APA which showed normal PRA due to CRF. In cases with decreased renal function, CCT and AVS, not ARR, may be useful to evaluate AAH.

 

Nothing to Disclose: YT, RM, YO, YI, MK, YI, MM, HS, KS, KT, YA, YY, YN, HS, SI, FS

32363 19.0000 SAT 378 A Aldosterone-Producing Adenoma Hidden behind Chronic Renal  Failure with Nephrotic Syndrome 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Aida Veronica Araya*1, Gonzalo Cardemil2, Arnaldo Marin2, Gerson Ocares2, Ivan Gallegos2 and Constantine A Stratakis3
1UNIVERSIDAD DE CHILE CLINICAL HOSPITAL, Santiago, Chile, 2UNIVERSIDAD DE CHILE CLINICAL HOSPITAL, SANTIAGO, Chile, 3NICHD/NIH, Rockville, MD

 

Background: The glucocorticoid resistance syndrome (GCRS) is a familial or sporadic condition characterized by generalized or partial tissue insensitivity to GC. A compensatory activation of the hypothalamic-pituitary-adrenal axis occurs with increased ACTH, cortisol, mineralocorticoid and androgen secretion and hypertrophy/hyperplasia adrenocortical. It is caused by a mutation/deletion in the GC receptor (GR) gene.

Clinical case: A 39 y.o. male with Congenital Adrenal Hyperplasia (CAH) (simple virilizing form, that was diagnosed as a neonate) was studied; his twin with the same diagnosis, died before 5 y.o.

He was treated with oral Hydrocortisone in different schedules. At 29 y.o., high blood pressure was detected and dose is reduced to 10 mg/day. Finally, he discontinued Hydrocortisone 6 months before admission. In the last 2 years, abdominal and left lumbar pain appeared. Abdominal ultrasound reported enlarged adrenals and the CT-scan showed bilateral adrenal masses of 16 cm at right and 24 cm at left (large diameter), with features of myelolipomas. He was admitted in our center for surgical resolution. At physical exam he was dehydrated with low blood pressure and tachycardia. Height: 147cm, pigmented skin, palpable masses in the upper abdomen. Clinically, impressed like adrenal insufficiency, serum sodium: 131 mEq/L and potassium: 4.7 mEq/L. The early morning Cortisol was 61.6 ug/dl. After that, we continued the study performing adrenal steroids determinations. Free urinary Cortisol: 924 µg/24h, plasma ACTH: 1019 pg/ml, Aldosterone: 100 ng/ml, plasma renin activity: 36 ng/ml/h, 17 OH Progesterone: >20 µg/dl, Total Testosterone: 1740 ng/dl.

These results suggested GCRS. Then, an evening dose of 1mg oral Dexamethasone was started. The morning cortisol decreased to 19.9 ug/dl and ACTH to 116 pg/ml. His general condition improved, serum sodium and potassium normalized. Sellar MRI was normal and testicular ultrasound showed bilateral adrenal rests. Bilateral adrenalectomy was performed. The histology confirmed bilateral myelolipomas. Cortisol at one week was undetectable.

Molecular analysis did not find a mutation in the GR but, a variant in theNF1 gene (NF1 (NF1) ADp.P678A c.2032_2034delCCGinsGCA). Nevertheless, there were not obvious manifestations of neurofibromatosis.

Conclusions: GCRS is very rare. It can be confused with CAH. It should be suspected in all patients with elevated cortisol and ACTH without signs of hypercortisolism. We do not know what role if any the NF1 gene mutation played in this case, but there are several non-GR-mutant cases of GCRS.

 

Nothing to Disclose: AVA, GC, AM, GO, IG, CAS

30246 20.0000 SAT 379 A Glucocorticoid Resistance Syndrome Mimicking Congenital Adrenal Hyperplasia, Detected in Adulthood By Bilateral Adrenal Masses 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Juan Diego Palacios*1, Zeina Carolina Hannoush2, Josefina Farra3 and Alejandro Ayala4
1UNIVERSITY OF MIAMI/JACKSON MEMORIAL HOSPITAL, Miami, FL, 2University of Miami and Jackson Memorial Hospital, Miami, FL, 3University OF Miami, 4University of Miami Miller School of Medicine, Miami, FL

 

Background

Bilateral adrenal macronodular hyperplasia (BAMH) is a rare form of Cushing's syndrome characterized by the presence of bilateral cortisol-secreting adrenal nodules and hypercortisolism. Familial Adenomatous polyposis(FAP) is an autosomal dominant disease resulting from an inactivating germline mutation of the tumor suppressor gene APC. The association of these two syndromes is rare and it is possible that they share common pathophysiologic pathways.

Case Presentation.

A 68 yo female presented with plethora, lower extremity edema, progressive proximal myopathy, centripetal weight gain, recent diagnosis of type 2 DM, hypertension and metabolic alkalosis with hypokalemia. She had severe osteoporosis with multiple thoracic vertebral compression fractures. Laboratory evaluation revealed elevated 24 hour urine cortisol ranging from 177 – 227(4 - 50 mcg/24h), cortisol level 20.6 mcg/dL after administration of 1 mg of dexamethasone, with ACTH level < 5 pg/ml. There was no evidence of hyperaldosteronism. Abdominal CT revealed enlarged adrenal glands with multinodular appearance with maximum diameters of 6.5 x 2.6 cm on the right side and 6.9 x 3.4 cm on the left side, pre-contrast attenuation of -3 and 10HU. The patient underwent bilateral adrenalectomy confirming a multinodular cortical hyperplasia with a left adrenal gland weighing 76 grams and right adrenal gland weighing 42 grams. Four weeks following surgery, she underwent a colonoscopy for evaluation of hematochezia, revealing 10 to 15 pediculated polyps averaging 5 to 20 mm and involving the recto-sigmoid area. A fungating, polypoid non-obstructing large mass was biopsied. Histopathology reported tubulovillous adenoma with high-grade dysplasia with immunohistochemistry positive for MLH1, MSH2, MSH6, PMS2 compatible with microsatellite stability. Discussion

BAMH is a rare cause of Cushing Syndrome(CS), accounting for less than 1% of adrenal CS.(1) Cushing syndrome in BAMH may result from intra-adrenal corticotropin signaling, from aberrant adrenal expression of ectopic receptors or increased activity of eutopic peptide hormone receptors(2). BAMH has been reported in patients with hereditary leiomyomatosis, renal cell cancer, MEN-1 and McCune–Albright syndrome (3). The medical literature reveals 3 other cases of BMAH associated with familial adenomatous polyposis. Yamakita et al reported a case of BAMH associated with multiple colon carcinomas. Gaujoux et al isolated a heterozygous germ line deletion (c.1863_1866del4/p.Thr621fsX628) in a patient with BAMH and FAP, while Hsiao et al described a heterozygous APC gene mutation(4393_4394delAG)in a patient with BAMH and colonic polyps. Our case illustrates the association between colonic polyposis and BAMH. Physicians should strongly consider systematic familial screening with genetic testing for APC in similar clinical presentations.

 

Nothing to Disclose: JDP, ZCH, JF, AA

31201 21.0000 SAT 380 A Bilateral Adrenal Macronodular Hyperplasia in a Patient with Colorectal Adenomatosis 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Britany Faith Epstein*1, Hans Kumar Ghayee2, Diana Barb1, Christiana Shaw3 and Robert W. Allan4
1University of Florida College of Medicine, Gainesville, FL, 2Malcom Randall VAMC, Gainesville, FL, 3uUniversity of Florida College of Medicine, 4University of Florida College of Medicine

 

Background: Ganglioneuromas are tumors that arise from the paravertebral sympathetic ganglia. Adrenal ganglioneuromas (AGN) are rare and comprise 0-6% of all adrenal incidentalomas and 20% of all ganglioneuromas.

Clinical Case: 51-year-old male presented to the emergency room after a motor vehicle accident with left lower quadrant abdominal pain. On computed tomography (CT) scan of abdomen and pelvis it was noted that he had a contusion of the sigmoid colon as well bilateral lobular heterogeneously enhancing right greater than left adrenal masses, with patchy and rim-like areas of calcifications in both adrenals. The size of the right measured 9.5 x 5.1

x 6.1 cm and left measured 3.2 x 2.8 x 3.2 cm.

Biochemical work up revealed normal cortisol dynamics, no evidence of hyperaldosteronism or pheochromocytoma. However he was found to have slight elevation in urine dopamine levels that were less than two times the upper limit of normal.

CT guided biopsy of the right adrenal mass showed mature neural stroma with mixed ganglion cells consistent with a ganglioneuroma. After discussion with the patient and in tumor board, conservative management was chosen. A follow up CT scan three months later showed stability of the adrenal masses.

Although rare, adrenal ganglioneuromas can be found incidentally on imaging studies. Diagnosis is proven by tissue pathology, as there is a vast differential diagnosis once an adrenal mass is found on radiographic imaging. AGN are often hormonally silent or may sometimes secrete hormones. Such hormones include testosterone or if it is a composite tumor with pheochromocytoma, it may secrete catecholamines. In such cases, the diagnosis is challenging.

Conclusion: AGN needs to be considered in the differential diagnosis of an adrenal incidentaloma. Careful history, physical exam, biochemical testing, along with pathological examination is fundamental in making a diagnosis. AGN are benign and usually asymptomatic but need to be monitored for changes in size.

 

Nothing to Disclose: BFE, HKG, DB, CS, RWA

31376 22.0000 SAT 381 A Incidental Bilateral Adrenal Ganglioneuromas 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Karen Domingo Lazaro* and Perie Adorable-Wagan
The Medical City, Pasig City, Philippines

 

Background: Adrenocortical carcinoma is a rare malignancy with an incidence of approximately one to two per million population per year. 62% of adrenocortical carcinomas present as functioning tumors with the most common presentation being Cushing’s syndrome or a combination of hypercortisolism and virilization. Aldosterone producing adrenocortical carcinoma is even more uncommon, comprising 0% to 7% of all functioning adrenocortical carcinomas. We report a rare case of adrenocortical carcinoma with a clinical picture of primary aldosteronism and subclinical Cushing’s syndrome. Clinical case: An 18-year old male presented with uncontrolled hypertension, recurrent bilateral leg weakness and hypokalemia. He had no signs of hypercortisolism. Laboratory tests showed elevated plasma aldosterone concentration (47.66 ng/dL, normal 4.20 - 20.15), suppressed plasma renin activity (0.04 ng/ml/hr, normal 0.30-1.90) and elevated aldosterone/renin ratio (1,191.5). Adrenal CT scan showed a 4.7 x 4.1 x 4.8 cm left adrenal mass with enhancement features suggestive of a lipid-poor adenoma. Complete hormonal evaluation showed elevated 24 hour urine free cortisol (131.20 ug/24 hours, normal 20.00 - 90.00), nonsupressible cortisol after 1 mg dexamethasone (2.8 ug/dL, normal < 1.8), normal basal cortisol (10.00 ug/dL), normal basal ACTH (0.25 pg/ml, normal 10 - 90), elevated estradiol (60.00 pg/ml, normal 11 - 44), normal DHEA-S (176.10 ug/dL, normal 45.10 - 385), elevated 24 hour urine metanephrine (6.8 mg/24 hours, normal < 1.0) and normal plasma free metanephrine (5.650 pg/ml, normal < 90.00). Laparoscopic adrenalectomy was done with steroid coverage. Histopathologic diagnosis was malignant adrenal neoplasm (adrenocortical carcinoma versus pheochromocytoma) based on the Weiss criteria. Immunohistomorphology supported the diagnosis of adrenocortical caricnoma. The Ki67 index, a marker of proliferative activity was 5-10%. No further treatment such as chemotherapy was done after complete surgical resection. His blood pressure decreased and aldosterone, cortisol and estradiol levels returned to normal. Conclusion: Aldosterone producing adrenocortical carcinoma is a rare malignancy. In the work up of suspected adrenal carcinoma, complete hormonal evaluation is necessary even if clinical symptoms are absent. The pattern of tumor secretion and tumor characteristics on CT scan may point to the malignant potential of the tumor. It is important to exclude hypercortisolism and pheochromocytoma as these require pre operative preparation. Complete surgical resection is the cornerstone of treatment and Ki67 index is the most powerful prognostic marker and used to guide treatment decisions. Long-term monitoring is recommended with imaging and hormonal evaluation used as tumor markers for recurrence.

 

Nothing to Disclose: KDL, PA

29982 23.0000 SAT 382 A A Rare Case of Aldosterone-Producing Adrenocortical Carcinoma with Co-Secretion of Cortisol and Estradiol 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Ameya Hodarkar*1 and Leo Tchong2
1Lahey Medical Center, Burlington, MA, 2Lahey Hospital and Medical Center, Burlington, MA

 

Background: Unilateral tumors or masses of the adrenal gland are common and categorized as either functional or silent and as either benign or malignant. The majority of adrenocortical tumors are benign, nonfunctioning adenomas. Adrenocortical carcinomas (ACCs) are rare, often aggressive tumors that may be functional and cause Cushing's syndrome or virilization. But most are nonfunctional and present as an abdominal mass or an incidental finding. The incidence is approximately 1-2 per million population per year. Here we present a case of ACC which was diagnosed due to ascites and vague abdominal discomfort.

Clinical Case: A 60 year old woman with hypothyroidism presented to her primary care provider with abdominal pain. Abdominal exam revealed distension with discomfort on palpation. No organomegaly or masses were identified. A CAT scan of the abdomen and pelvis with contrast was done which revealed ascites, peritoneal masses and a large left ovarian mass suspicious for ovarian malignancy. Incidentally, a left adrenal 4.3 cm mass was also identified. She underwent total hysterectomy and bilateral oophorectomy. An omentectomy, peritoneal mass biopsy, and lymph node sampling were also performed. The ovarian mass was diagnosed to be a fibroma. However, the peritoneal biopsies, revealed poorly differentiated carcinoma consistent with ACC.

She was found to have normal plasma metanephrines and normetanephrines at 0.15 and 0.88 nmol/L respectively. Urine metanephrines and normetanephrines were elevated mildly at 0.91 and 0.71mg/day perhaps due to the stress of the diagnosis. Morning cortisol was normal at 18 μg/dL and the ACTH was also normal at 49 pg/mL. Her electrolytes were normal except for mild hyponatremia. Sodium was 132mmol/L and potassium was 4.2 mmol/L. The patient was started on chemotherapy with etoposide, cisplatin, and doxorubicin along with mitotane. The patient was not able to tolerate the side effects of mitotane and chose to only be on platinum based chemotherapy agents.

Conclusion: This case highlights that patients with non-functioning ACC can present with clinical manifestations of tumor growth such as abdominal or flank pain or with constitutional symptoms like weight loss, anorexia. They may even be detected incidentally on imaging performed for a different reason. One needs to have a high index of suspicion to diagnose ACC given the low incidence rate. A careful history and physical examination should be performed to exclude pheochromocytoma, hyperaldosteronism, hyperandrogenism, and Cushing's syndrome. Complete surgical resection is the treatment of choice, but in cases with metastasis, chemotherapy and mitotane is needed. Five-year survival is approximately 45 to 60 percent for early stage disease, and 10 to 25 percent for advanced stage disease. As a result early diagnosis is key to better outcomes.

 

Nothing to Disclose: AH, LT

30032 24.0000 SAT 383 A Incidentally Diagnosed Adrenocrtical Carcinoma with Intraperitoneal Metastases 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Itivrita Goyal* and Chi Tang
University at Buffalo, Buffalo, NY

 

Background: Adrenocortical carcinoma (ACC) is extremely rare with an incidence of 1-2 cases per 1 million population and account for 0.05%-0.2% of all malignancies. In addition, aldosterone-producing adrenocortical carcinoma (APAC) accounts for less than 1% of cases of primary hyperaldosteronism. It is a common practice to give mitotane as adjuvant therapy for post-surgical ACC patients with high risk of recurrence1. However, there is no randomized clinical trial on the selection of patients for mitotane adjuvant therapy due to the rarity of ACC. Based on small retrospective studies, an international panel of ACC specialists proposed that mitotane therapy should not be mandatory for stage I or II disease (based on the European Network for the Study of Adrenal Tumors staging system) with negative resection margin and Ki-67<10%2. Here we report a case of aldosterone-producing ACC that fulfilled the criteria above, and therefore did not receive adjuvant mitotane therapy. Despite fitting the above criteria, he developed recurrence of the tumor in one year after left adrenalectomy.

Clinical case: A 57-year-old man was referred to our endocrinology clinic for persistent hypertension and hypokalemia. Laboratory tests showed serum sodium levels varied between high normal and high with persistently low serum potassium (in the absence of potassium depleting diuretics), plasma renin activity (PRA) of 0.28 ng/ml/hour, plasma aldosterone concentration (PAC) of 36.6 ng/dl and markedly elevated PAC/PRA ratio of 130.71 ng/dl per ng/ml/hr. CT abdomen/pelvis showed a 4.3 cm mass in the left adrenal gland. Repeated CT scans showed marked interval enlargement, suggestive of an adrenal carcinoma. The patient underwent left adrenalectomy. Pathology showed a 7 cm organ-confined, necrotic adrenocortical carcinoma with clear margin, large vessel (muscular venous) vascular invasion and Ki-67 of <10%. No evidence of regional lymph node or distant metastasis was identified. Plasma aldosterone became undetectable after the operation. Adjuvant therapy was not started as it was categorized as stage II, Ki-67 was < 10% and resection margin was negative. However, a year following surgery the patient developed a nodule in the bed of the resected left adrenal gland. Another resection was performed and pathology showed recurrent adrenocortical carcinoma partly evident within a distended muscular vein. Mitotane was started since then.

Conclusion: Therefore, we propose that vascular invasion and necrotic state of the tumor might be associated with higher risk of recurrence and should therefore be considered in determining the need for adjuvant chemotherapy, in addition to the criteria based on the international consensus. This case provides evidence to support Weiss criteria, which takes into account mitotic count, tumor necrosis and vascular invasion status in predicting recurrence.

 

Nothing to Disclose: IG, CT

30180 25.0000 SAT 384 A Rare Recurrent ‘Aldosterone Secreting Adrenocortical Carcinoma (APACs)’ Requiring Adjuvant Therapy 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Romina Lomonaco* and Antonella Bianchi
University of Florida, Gainesville, FL

 

Background: Adrenocortical carcinoma (ACC) is a rare but highly aggressive malignancy. It has an incidence of 0.5-2 cases per million per year. Many patients have no symptoms until the tumor starts causing mass effect. About 50% of these tumors are hormonally active, being hypercortisolism the most common presentation. The majority of the patients have already metastatic disease at the time of diagnosis, with a survival rate for stage 4 disease of 7-10% at 5 years.

Clinical case: A 19 year-old man presented to the ER complaining of abdominal pain and nausea. Initial CT abdomen/pelvis showed a large right adrenal mass measuring 11x10x16cm with calcifications. Initial endocrine work up was remarkable for slightly elevated plasma and urinary normetanephrines, 1.20 nmol/L (0-0.89) and 673 μg/d (95-379) respectively, with normal metanephrines. Morning baseline cortisol was 22 mcg/dL (7.0-22.0) with ACTH of 31 pg/mL (7-69). A 1mg-dexamethasone suppression test revealed a morning cortisol of 20.2 mcg/dL (dexamethasone level of 427 ng/dL). PRA and aldosterone, potassium, total testosterone and SHBG were within normal limits. DHEA-S value was highly elevated at 1168 μg/dL (88-483). Patient also had normal TSH, FT4, calcium, iPTH, and creatinine. Calcitonin and chromogranin A were negative. Repeat CT abdomen/pelvis confirmed a large right adrenal mass with invasion of the inferior vena cava, hepatic veins and right atrium. CTA chest revealed bilateral pulmonary emboli and innumerable nodules suggestive for metastasis. Echocardiogram revealed a 4.7cm non-mobile mass obstructing the right atrium. Considering the stage of the disease, no surgery was recommended by surgical oncology, cardiothoracic and vascular surgery. CT-guided biopsy of the adrenal mass was performed after alpha and beta blockade. Pathology showed poorly differentiated ACC. Immunohistochemichal profile was positive for MelanA, and focally positive for Synaptophysin and Inhibin, negative for Calretinin and S-100. Patient was initiated on adjuvant mitotane monotherapy. After 1 week of mitotane, DHEA-S level went down to 166 μg/dL. Cortisol levels also decreased due to the adrenolytic effect of mitotane. Patient was initiated on glucocorticoid replacement with 30mg daily. PRA was in the normal range and there was no need for mineralocorticoid replacement. Palliative chemotherapy with cisplatin/etoposide/doxorubincin was also offered to the patient but was decilined.

Conclusion: ACC is an aggressive, rare and heterogeneous tumor with poor prognosis, particularly if it occurs in children/young adults. It is essential to differentiate it from benign adenomas by correlating with clinical, biochemical, imaging and histological features, as the outcome can vary greatly. Also because of the increased incidence of genetic mutations in this population with ACC, genetic testing for TP53 germline mutation should be considered.

 

Nothing to Disclose: RL, AB

32671 26.0000 SAT 385 A an Aggressive Adrenocortical Ccrcinoma in a Young Man Presenting with Abdominal Pain 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Rebecca Simon, Amal Hejab and Sharon Wu Lahiri*
Henry Ford Health System, Detroit, MI

 

Pheochromocytoma (PCC) is a rare neuroendocrine tumor with a heterogeneous presentation. Headaches, palpitations and diaphoresis occur in 60-80% of cases, yet 8% are asymptomatic (1). Hypertension is found in 80-90%, although 13% are normotensive (1). The frequency of cardiovascular complications in PCC is not well studied, but reports of Takotsubo cardiomyopathy (TC) have been increasing (2). We report a case of a normotensive female presenting with TC and cardiogenic shock who was diagnosed with PCC. The diagnosis was considered only after the incidental discovery of an adrenal tumor.

A 66-year-old female presented to the emergency department with acute onset chest pain, vomiting and back pain. She was hypotensive and tachycardic. Electrocardiogram showed sinus tachycardia and new anterior ST segment elevations. Laboratory evaluation revealed markedly elevated troponin. She also had acute kidney injury, acute liver injury with elevated transaminases >1000 IU/L (reference <52 IU/L) and elevated lactate. She underwent emergent cardiac catheterization showing normal coronary arteries. Echocardiogram revealed reduced ejection fraction (EF) of 13% with severe hypokinesis of the anterior, lateral and inferior wall. Takotsubo cardiomyopathy was diagnosed although she did not report any acute physical or emotional stress. Inotropic support and afterload reduction led to clinical improvement. Cardiac imaging 6 days later demonstrated dramatic improvement of EF to 64%. An abdominal ultrasound performed on presentation to evaluate the abnormal liver function revealed a right upper quadrant mass of uncertain origin. This prompted abdominal computed tomography which showed an 8.5 x 8 x 7.5 cm heterogeneous adrenal mass. On further questioning, the patient reported a 3-year history of debilitating episodes of substernal pressure associated with belching, vomiting, and palpitations. Her symptoms had been diagnosed as gastroesophageal reflux disease. PCC had not been considered since she was always normotensive. Hormonal testing to evaluate this mass revealed elevated total plasma free metanephrines 20,878 pg/ml (<205 pg/ml) with normetanephrine 17,279 pg/ml and metanephrines 3599 pg/ml. Catecholamine excess from PCC was considered to be the cause of her TC. Doxazosin was titrated over 3 weeks for adequate alpha blockade and propranolol was added prior to surgery to control reflex tachycardia. She underwent a successful open adrenalectomy. Pathology confirmed PCC.

Pheochromocytoma is a rare disease with variable presentation. Takotsubo cardiomyopathy is an increasingly recognized, yet still uncommon, presentation of PCC. In our patient, the diagnosis of PCC was entertained only after an adrenal mass was incidentally found on imaging. We suggest evaluation for PCC in patients with TC even in the absence of hypertension, as a missed diagnosis can have fatal consequences.

 

Nothing to Disclose: RS, AH, SWL

29319 27.0000 SAT 386 A Pheochromocytoma Presenting As Takotsubo Cardiomyopathy:  a Nearly Missed Diagnosis in the Absence of Hypertension 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Franco Alejandro Vallejo*, Carolina Hurtado, Katherine Lopez and Rodrigo Garcia
Icahn School of Medicine at Mount Sinai - Mount Sinai West & Mount Sinai St Luke's, New York, NY

 

INTRODUCTION

Pheochromocytoma is a rare tumor from chromaffin cells of the adrenal medulla first described in 1884 by Felix Fränkel. This tumor has an annual incidence of 0.8 per 100,000 person year.

CASE PRESENTATION

A 56-year-old Caucasian man went to the emergency room because of sudden left lower extremity pain radiated to the chest and back. The patient’s physical examination showed blood pressure (BP) of 110/70, heart rate of 112 bpm and diaphoresis, the rest was unremarkable. The EKG did not show signs of ischemia although troponin was elevated. Patient was sent to coronary catheterization which revealed normal coronaries and severe left ventricular dysfunction and ejection fraction (EF) of 20%. Twelve hours after the procedure the patient developed hypotension and shock requiring vasopressor support. Hemoglobin dropped from 15 g/dl to 9.4 g/dl. CT abdomen was done to rule out bleed and showed a large left retroperitoneal hematoma and a retroperitoneal mass (12x10x13 cm) displacing the kidney into the pelvis. Patient's clinical course progressed to severe acute kidney injury and anuria requiring temporal hemodialysis. An embolization of the left middle adrenal artery was done to stop the bleeding. Endocrine work-up of retroperitoneal mass resulted in normal values of 7-OH progesterone, androstenedione, DHEA sulfate, testosterone and cortisol. Urine and plasma metanephrines were consistently elevated in multiple occasions and the diagnosis of pheochromocytoma was made.

For preoperative treatment patient was started on alpha blocker (doxazosin 1mg daily) but patient had multiple episodes of hypotension. Given intolerance to alpha blocker pre-operative treatment consisted mainly of metyrosine 250mg every 6 hours before surgery. After 14 days of pre-op treatment he was taken to surgery to remove the mass. The pathology showed a benign pheochromocytoma. Patient improved clinically and his EF increased to 60%.

DISCUSSION

This case highlights a unique presentation and complication of pheochromocytoma and opens the possibility of different treatment modalities when patients cannot tolerate alpha blocker. Our patient presented with lower extremity and back pain with retroperitoneal hematoma and did not have any of the classic symptoms of episodic headache, sweating, tachycardia and hypertension. About 5-15% of patients can present with normal blood pressure like is the case with our patient. He also had a rare complication of pheochromocytoma which is dilated cardiomyopathy and it is due to catecholamine production by the tumor. Lastly our patient was not able to be treated with alpha blocker given recurrent episodes of hypotension so treatment was started with metyrosine which inhibits the production of catecholamines and is an uncommon treatment modality.

 

Nothing to Disclose: FAV, CH, KL, RG

29339 28.0000 SAT 387 A An Atypical Presentation, Complication and Preoperative Management of Pheochromocytoma 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Margaret L Burks1, Shichun Bao*1 and Carmen Solorzano2
1Vanderbilt University Medical Center, Nashville, TN, 2Vanderbilt University

 

Background: Catecholamine secreting tumors in pregnancy (paragangliomas or pheochromocytomas) are rare, with an incidence of 0.007%; however, they represent one of the most life threatening medical conditions to a mother and fetus (1). Early recognition is important, as maternal and fetal mortality rates decline substantially with timely management. A high degree of suspicion is required as signs and symptoms can mimic those of more common conditions of pregnancy like pre-eclampsia. We present a case of a paraganglioma in a 33-year-old pregnant female which required robotic resection during the second trimester of pregnancy.

Clinical Case: The patient was seen in the emergency room prior to the index pregnancy for nausea, vomiting and intermittent, left lower quadrant abdominal pain. A CT scan of the abdomen and pelvis showed a 4.8 x 4.3 cm heterogeneously enhancing mass near the left adrenal gland and renal hilum. She reported episodic sweating for one year, palpitations weekly, and feeling anxious. Laboratory results were concerning for a norepinephrine secreting tumor. She had normal plasma metanephrines of 0.46 nmol/L (normal <0.49 nmol/L), but markedly elevated plasma normetanephrines of 7.12 nmol/L (normal <0.89). 24-hour urine epinephrine and dopamine were normal (<6 mcg/24 hrs and 218 mcg/24 hrs, respectively). Urine norepinephrine was elevated to 604 mcg/24 hrs (normal <90 mcg/24 hrs) and urine catecholamines were elevated to 610 mcg/24 hrs (normal <115 mcg/24 hrs). Chromogranin A level was elevated to 940 ng/mL (normal 0-95 ng/mL). Cortisol, DHEAS, renin, and aldosterone levels were normal. Soon after evaluation, the patient became pregnant. Her systolic and diastolic blood pressure were elevated during this time to 140 mmHg systolic and 100 mmHg diastolic. She was referred to endocrine surgery for resection. At 12 weeks of gestation, doxazosin was started. The mass was thought to be a paraganglioma, and removal was felt to be safest during the second trimester. Doxazosin dose was up titrated prior to surgery for blood pressure control. At 18 weeks of pregnancy, she underwent a robotic left retroperitoneal paraganglioma resection with excellent maternal and fetal outcomes.

Conclusion: Catecholamine secreting tumors in pregnancy are rare but must be recognized and treated to reduce maternal and fetal complications. Biochemical testing with 24-hour urine metanephrines and catecholamines is the same as for non-pregnant patients (1). Despite no formal guidelines for management of these patients, it is generally recommended tumors be removed either before 24 weeks of gestation or after delivery. Second trimester operative intervention is considered safest due to decreased risk of spontaneous abortion and less anatomic distortion (1). Medical management prior to surgery is approached similarly to non-pregnant patients. 

 

Nothing to Disclose: MLB, SB, CS

29883 29.0000 SAT 388 A Robotic Paraganglioma Resection in a Pregnant Patient 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Recie Davern*1 and Siobhán Estelle McQuaid2
1Mater Miscericordiae University Hospital, Dublin, IRELAND, 2Mater Miscericordiae University Hospital, Drumree, Ireland

 

Patient Characteristics: 63 year old female with ten years follow up of 18 cm malignant phaeochromocytoma with urinary catecholamine and genetic screening to date all negative. Therefore a case of a non-functioning malignant phaeochromocytoma.

History of presenting illness: At the age of 53 years old, she presented to the gynaecological outpatient clinic with two weeks of left upper abdomen fullness, fatigue and weight loss. No reported history of headache, hypertension or sweating.

Past Medical/Surgical History: Right lobe thyroidectomy in 1983 for cosmetic reasons. Dilation and curettage procedure for investigation of infertility

Social/Family History: She was a non-smoker and had minimal C2H5OH intake. There was no family history of neuroendocrine tumours.

Medications (+ allergies): Eltroxin 100mcg OD and no drug allergies

Physical Examination: She was not tachycardic or hypertensive. Only positive findings were previous partial thyroidectomy scar and splenomegaly.

Report of laboratory and imaging studies: 

Summary of Relevant investigations

  • CT TAP - 18cm adrenal mass with calcification at the centre appearing to arise from the left adrenal gland. No evidence of lymphovascular invasion or distal metastatis
  • MRI Abdomen - 18cm left adrenal mass with left kidney pushed inferiomedially by the mass. Lesion encapsulated with no local extension. Suggestive of adrenal carcinoma
  • 24 hour urinary catecholamine collection - adrenalin 24 nmol/24 hours (0-230nmol/24housr), noradrenalin 160nmol/24 hours (0-290nmol/24 hours) and VMA 9.6 umol/24 hours (2.5-40 umol/24 hours)

Interventions and outcome: Left adrenalectomy with nephrectomy 2006. No intra-operative hypertension or complications. Histology confirmed phaeochromocytoma with malignant potential. It showed tumour composed of epithelioid appearing cells with abundant pink cytoplasm. Individual cells showed severe nuclear pleomorphism including numerous giant forms with prominent nucleoli. Occasional mitotic figures are identified. In addition, there is extensive necrosis. There is evidence of definite lymphovascular space invasion and capsule invasion. A rim of normal residual adrenal gland is identified. These appearances favor a malignant pheochromocytoma.The submitted kidney unremarkable. Immunochemistry testing confirmed neuroendocrine histogenesis/pheochromocytoma. MIB 1 proliferation index of 30-40%. is extremely high and strongly supports a diagnosis of malignancy Subsequent follow up over ten years has revealed negative MIBG scans, CT TAPs, urinary and plasma catecholamines and genetic screening tests. This case raises the issues of management and radiological and biochemical follow up of non functioning and malignant phaeochromocytomas and the role of genetic screening for such tumours. It also highlights the advances in diagnostics that have occurred over the last decade.

 

Nothing to Disclose: RD, SEM

29915 30.0000 SAT 389 A An Case of Malignant Phaeochromocytoma with Negtive Urinary Catecholamines at Presentation 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Deepthi Venkat Byreddy*1, Christina M Lovato2 and Matthew Frederick Bouchonville1
1University of New Mexico School of Medicine, Albuquerque, NM, 2University of New Mexico Health Sciences Center, Albuquerque, NM

 

Introduction: Catecholamine-secreting tumors are rare neoplasms, occurring in less than 0.2 percent of patients with hypertension. Pheochromocytoma is a tumor of chromaffin cells that is considered in the evaluation of hypertension, arrhythmias, or panic disorder. Affected patients can present with a classic triad of headache, sweating, and tachycardia. There have been a few case reports of pheochromocytoma and takotsubo cardiomyopathy that have been reported in the literature. We describe a case of pheochromocytoma-associated takotsubo cardiomyopathy that was reversed with medical therapy.

Clinical Case:A 59 year old woman with a history of hypertension (controlled with a thiazide and ACE inhibitor) and prediabetes presented after a motor vehicle collision. She was incidentally found to have a 4.5 x 3.8 x 3.4 cm heterogeneous, enhancing left adrenal mass on the CT scan of the abdomen. She endorsed occasional palpitations but denied headaches, tremors, and diaphoresis.

Blood pressure (119/73 mmHg) and heart rate (76 bpm) were normal. Troponin was elevated at 1.830 ng/ml (reference range: < 0.060 ng/ml) with concern for an anterolateral infarct with ST elevations on EKG. Medical therapy was initiated to treat for possible ischemic heart disease. Transthoracic echocardiogram showed a moderately reduced EF of 31-35% and findings suggestive of takotsubo cardiomyopathy. Cardiology did not perform coronary angiography as the patient was in traction due to C6 and C7 vertebral fractures from the MVC. Additional laboratory studies included plasma fractionated normetanephrines that were elevated at 27 nmol/L (reference range: 0.00 to 0.89 nmol/L) and 24h urine normetanephrines at 7088 ug/d (reference range: 109 to 393 ug/d). Alpha and beta blockade was initiated in anticipation of laparoscopic adrenalectomy. However, the surgery was delayed as the patient required cervical fixation of the vertebral fractures. Repeat transthoracic echocardiogram after 2 weeks of medical therapy showed an improved EF of 70% with resolution of the takotsubo cardiomyopathy. The patient subsequently underwent a left laparoscopic adrenalectomy with surgical pathology confirming a 6.5 cm pheochromocytoma.

Discussion: Takotsubo cardiomyopathy was first described in 1990 in Japan and occurs in approximately 1 to 2 percent of patients presenting with troponin-positive acute coronary syndrome (ACS) or ST-elevation myocardial infarction. This syndrome is characterized by transient regional systolic dysfunction of the left ventricle (LV), mimicking myocardial infarction, but in the absence of angiographic evidence of obstructive coronary artery disease or acute plaque rupture. In this case report we will review the literature describing the occurrence of takotsubo cardiomyopathy and pheochromocytoma as well as the treatment considerations of these two clinical conditions.

 

Nothing to Disclose: DVB, CML, MFB

30516 31.0000 SAT 390 A A Case of Pheochromocytoma-Associated Takotsubo Cardiomyopathy: Case Report and Review of the Literature 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Sravanthi Sanivarapu*, Alice Kit-wah Lee and Salini Chellappan Kumar
Nassau University Medical Center, East Meadow, NY

 

Introduction:

Oncocytic Adrenocortical neoplasms(OAN) are extremely rare. Only 150 cases of OAN have been reported in the literature. It is most frequently found as an incidental finding between the ages 27–72 years. It is more common in women and in the left gland [1-3]. We report a case of OAN in a 25 year old man with a 6.7 cm right adrenal incidentaloma producing dopamine and a positive MIBG scan.

Case Report:

25 year old Hispanic male with PMH of alcoholism and polysubstance abuse was referred to Endocrinology for palpitation, sweating and elevated BP of 169/111mmHg. ROS was negative. Family history was negative for pheochromocytoma. Vital signs and physical examination was normal. In 2012, CT abdomen showed an incidental 2.1 x 1.6 cm right adrenal lesion. In 6/2015 CT showed a 5.5 x 4 cm solid heterogeneous right adrenal mass. A 24 hour urine study showed elevated dopamine levels of 1276µg/24h(52-480). MRI in 10/2015 showed a 6.7 x 4.7 x 4.5 cm well circumscribed mass of the right adrenal gland with several irregular foci with T2 hyperintense signal compatible with necrosis. MIBG scan showed a focus of increased tracer uptake in region corresponding to lesion seen on MRI. After premedication with α blocker, he underwent right adrenalectomy. The pathology report showed predominant cells with eosinophilic and granular cytoplasm, high nuclear grade and diffuse architectural pattern consistent with OAN favoring an adenoma. Immnunohistochemistry was positive for MART-1, inhibin and calretinin, negative for S-100, Chromogranin, Oct4 and SF-1 consistent with adrenocortical origin. 24 hour urine for dopamine normalized 1 month after surgery.

Discussion:

Only 17% of OAN are functional adrenal masses [1-3]. Only 3 case reports of OAN mimicking pheochromocytoma have been reported. (4-6). Our patient presentation was unique with the tumor on the right side, with an isolated elevation of dopamine and false positive MIBG scan. OAN are classified according to Weiss criteria(7) which include major criteria (mitotic rate of >5 mitoses per 50 high power fields, atypical mitoses and venous invasion), minor criteria (large size >10 cm and huge weight > 200 g, necrosis, capsular invasion, sinusoidal invasion) and definitional criteria(predominantly cells with eosinophilic and granular cytoplasm, high nuclear grade, diffuse architectural pattern). The presence of any one of the major criteria indicates malignancy, one to four minor criteria indicates uncertain potential and the absence of all major and minor criteria indicates benign behavior. Routine imaging studies cannot be used to differentiate benign versus malignant oncocytic neoplasms. Microscopic criteria are able to identify precise histology and clinical behavior, so adrenalectomy is the mainstay of therapy.

 

Nothing to Disclose: SS, AKWL, SCK

30582 32.0000 SAT 391 A A Rare Case of Oncocytic Adrenocortical Neoplasm Mimicking Pheochromocytoma 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Sanjeda Sultana*, Sonia K Hans and Steven N Levine
Louisiana State University Health Sciences Center, Shreveport, LA

 

Background:

CT imaging of pheochromocytomas almost always reveals precontrast attenuation of greater than 10 HU, are heterogeneous on venous phase imaging, and <50% washout on delayed phase. In fact, some authorities suggest that biochemical evaluation for pheochromocytomas is unnecessary when precontrast HU are <10.2 We report a patient with a pheochromocytoma with precontrast HU of 2.

Clinical Case:

A 36 year old female was referred for an incidentally discovered left adrenal mass during a workup for groin pain and an enlarged lymph node. She reported an increasing frequency of paroxysmal episodes consisting of diaphoresis, palpitations, flushing and increased systolic hypertension (up to 160 mm Hg) that lasted for 1 hour and spontaneously resolved. These episodes started 2-3 years ago and increased in frequency to 2-3 times per week over the past year. On exam her BP was 140/90 mm Hg with no orthostasis. Her past medical history included anxiety and hypertension, diagnosed at 21 years of age treated with lisinopril.

24 hour urine normetanephrines were 3412 ug/24h (82-500), metanephrines 160 ug/24h (45-290), norepinephrine 447 ug/24h (0-135). On CT imaging at our facility the left adrenal mass measured 4.8 cm x 1.8 cm x 4.2 cm with homogeneous non-contrast attenuation of 2HU, heterogeneous attenuation of 80HU in portal venous phase while 15 minute delayed attenuation of 20HU. Absolute washout was 76%.

History, and biochemical assessment confirmed a pheochromocytoma despite imaging of the left adrenal mass with HU <10. She was optimized on alpha- and beta-adrenergic blockade prior to left adrenalectomy. Pathology showed an 8 cm x 2.5 cm x 2 cm pheochromocytoma extending into the periadrenal adipose tissue with invasion into the capsule. In the immediate postoperative period the patient did not require anti-hypertensive medications.

Conclusion:

Clinical suspicion and laboratory assessment indicated our patient had a pheochromocytoma, while the diagnosis of a pheochromocytoma was less likely based on non-contrast attenuation data published in the peer reviewed medical literature. This is a reminder that while 87-100% of pheochromocytomas exhibit precontrast attenuation HU of >101, rare cases present with HU<10.

 

Nothing to Disclose: SS, SKH, SNL

30610 33.0000 SAT 392 A Atypical Imaging Features of Pheochromocytoma 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Zeina Carolina Hannoush*1, Juan Diego Palacios2, Oren Lifshitz3, John I Lew1 and Alejandro Raul Ayala4
1University of Miami Miller School of Medicine, Miami, FL, 2UNIVERSITY OF MIAMI/JACKSON MEMORIAL HOSPITAL, Miami, FL, 3Private practice, miami, 4University of Miami, Miami, FL

 

Background

 

Pemphigus vulgaris is an epidermal disease affecting the skin and mucous membranes caused by autoantibodies to the desmosomal protein desmoglein ultimately resulting in acantholysis and blistering with complement activation and release of inflammatory mediators [1]. Multiple studies suggest that non-neuronal adrenergic/cholinergic systems play a pathophysiologic role in several dermatoses, including pemphigus [2]. Pheochormocytomas are catecholamine-secreting tumors that arise from chromaffin cells of the adrenal medulla leading to a hyperadrenergic state.

Case Presentation

 

The patient is a 39 year-old female with new onset hypertension, palpitations panic attacks, anxiety and headaches. She had history of pemphigus vulgaris diagnosed by skin biopsy revealing intraepidermal acantholysis and linear/granular IgG and C3 antibody epithelial surface deposits on immunofluorescence with no IgA or IgM antibodies. She was treated with mycophenolate mofetil without adequate response. She underwent a CT of the abdomen for evaluation of nephrolithiasis  that revealed a 3.4 cm left adrenal tumor with no signal dropout on out of face imaging and high T2 weighted intensity strongly suggesting a pheochromocytoma. Hormonal evaluation revealed elevated 24 hour urine metanephrine 841 mcg/24h (normal <190 mcg/24h), normetanephrine 1192 mcg/24h (normal < 482 mcg/24h) and total metanephrines 2033 mcg/24h (normal < 695 mcg/24h). Aldosterone, renin, TSH, comprehensive metabolic profile and urine free cortisol where unrevealing. Her PTH was elevated at 81 pg/mL, calcium of 10.1 mg/dL, with normal phosphorus, albumin and vitamin D level. The diagnosis of normocalcemic hyperparathyroidism was entertained raising the question of a multi-gland neoplastic syndrome currently under investigation.

The patient underwent successful laparoscopic left adrenalectomy. Pathology revealed a left 3.8 cm pheochromocytoma. Within a week, her blood pressure normalized and surprisingly, her pemphigus spontaneously resolved.

Discussion and conclusions

 

Multiple studies suggest that the epidermal-adrenergic/cholinergic signal pathway controls calcium homeostasis, cell growth, differentiation, motility and pigmentation via B2 and a1 adrenoreceptors [2]. In addition, patients with may also have anti acetylcholine receptor antibodies [3]. Research in mice has shown that these non-desmoglein antibodies can induce pemphigus-like lesions [4].

These findings, along with the striking clinical improvement seen in our patient suggest that catecholamines may play an important role in the pathophysiology of pemphigus vulgaris. Paraneoplastic pemphigus has been described associated with multiple types of tumors [5-7]. To the best of our knowledge this is the first case report of refractory pemphigus spontaneously resolving after resection of a pheochromocytoma.

 

Disclosure: ARA: Advisory Group Member, Novartis Pharmaceuticals, Consultant, NHT theapeutics. Nothing to Disclose: ZCH, JDP, OL, JIL

31330 34.0000 SAT 393 A Prompt Resolution of Refractory Pemphigus vulgaris Following Removal of a Pheochromocytoma: Case Report and Overview of Putative Pathophysiologic Mechanisms 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Sravanthi Madala*1 and Ricardo Rafael Correa2
1Warren Alpert Medical School of Brown University, East Providence, RI, 2Brown University, Warren, RI

 

Background: While incidental pheochromocytomas (pheo) can be asymptomatic, active catecholamine-secreting pheos can be devastating when symptoms such as tachycardia, paroxysmal hypertension, sweating and headaches are present. A complete lack of symptoms in the setting of a giant pheo with extremely high catecholamine levels is unusual, especially in post-biopsy setting.

Case: A 41 year old African-American male with past history of polycythemia vera, hyperlipidemia and CAD was incidentally found to have a palpable non-tender left-sided abdominal mass in setting of normotension by his hematologist during a routine follow up visit. A CT abdomen/pelvis revealed a left retroperitoneal 14.8 x 12.0 x 17.0 cm mixed cystic and solid mass of uncertain origin with calcific focus, displacing the surrounding organs. An FNA biopsy was done without complication, which showed neuroendocrine tumor consistent with pheo/paraganglioma with atypical features. Biopsy sample stained positive for chromogranin A, synaptophysin, CD56, GATA3 and focal positivity for S100. There was no increase in mitotic activity or necrosis and Ki-67 proliferation index was <5%. At this point, the patient was referred to endocrinology and endocrine surgery services. Home medications included carvedilol 3.125mg BID and Lisinopril 2.5mg daily for cardioprotection in setting of CAD. The patient denied ever having hypertension, dizzy spells, sweating, palpitations, headaches, chest pain, fainting, or vertigo. No family history of pheo/para. Biochemical work up revealed 24-hour urine: metanephrines 2410 (52-341 mcg/24hr), normetanephrines 3670 (88-444 mcg/24hr), norepinephrine 38 (15-80 mcg/24hr), epinephrine 25 (0-20 mcg/24hr) and dopamine 7874 (65-400 mcg/24hr); plasma: metanephrine 750 (<57 pg/mL), normetanephrines 3519 (<148 pg/mL), norepinephrine 751 (0-600 pg/mL), epinephrine 86 (0-90 pg/mL), and dopamine <20 (0-35 pg/mL). He was started on phenoxybenzamine for blockage and underwent adrenalectomy without complications. Pathology revealed a 20 cm pheochromocytoma without extension into surrounding soft tissue or lymph node involvement.

Conclusion: This case illustrates the rare presentation of a giant asymptomatic hormone-secreting pheo. While large pheochromocytomas can be asymptomatic, they are usually known to have lower secretory function. There is very little literature on any pheos greater than 20 cm with elevated hormone levels that are asymptomatic. Interestingly, this patient did not go into catecholamine storm while on beta blocker therapy without simultaneous alpha blockade or while the mass was manipulated during initial biopsy, prior to its classification as a pheo. The extremely large size of the tumor, degree of metabolic activity and absence of end organ damage or metastatic disease, as seen in this patient, may be attributable to biochemically inactive hormone production.

 

Nothing to Disclose: SM, RRC

31485 35.0000 SAT 394 A A GIANT Asymptomatic Pheochromocytoma 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Amer Issa* and Wael Taha
Wayne State University, Detroit, MI

 

Background:

Pheochromocytoma can cause hypertension and other non-specific symptoms. The associated clinical picture depends on the amount and pattern of catecholamine release. Most pheochromocytomas present as adrenal incidentalomas with biochemical evidence of catecholamine excess. The typical management of these tumors has been surgical resection.

We present a case of pheochromocytoma with low secretory activity in a hypertensive elderly patient in whom surgical resection of the tumor did not have any clinical impact on patient’s symptoms or hypertension.

Clinical case:

A 73-year-old African American male was referred to the endocrinology clinic for evaluation of a 3.2 cm left adrenal incidentaloma. He did not have any complaints of episodic headaches, palpitations, sweating or chest pain. He had hypertension for 10 years, which was well controlled on Lisinopril 10 mg daily, Carvedilol 6.25 mg twice daily and Amlodipine 10 mg daily. There was no history of weight gain, excess hair growth, acne or proximal muscle weakness.

On examination, pulse was 81 beats/min and blood pressure was 109/74 mmHg. The rest of his physical examination was unremarkable.

MRI showed a 3.2 cm lipid poor, left adrenal mass.

Biochemical tests showed: plasma aldosterone (15.4 ng/dl), plasma renin (0.4 ng/ml/hr), aldosterone/renin ratio (38.5), DHEA-S (77 ug/dl, n 28-175 ug/dl), low-dose dexamethasone suppression test (cortisol after 1 mg dexamethasone 1.9 ug/dl), plasma metanephrine (0.24 nmol/l, n <0.49 nmol/l), plasma normetanephrine (5.3 nmol/l, n <0.89 nmol/l), 24-hour urinary metanephrine (218 ug/d, n 30-350 ug/d) and 24-hour urinary normetanephrine (1780 ug/d, n 50-650 ug/d).

Further testing showed: plasma aldosterone (13.4 ng/dl), plasma renin (0.4 ng/ml/hr), aldosterone/renin ratio (33.5), saline infusion test (aldosterone level after infusion of 2 liters of 0.9% saline IV over 4 hours was 5.6 ng/dl), late night salivary cortisol (0.134 ug/dl, n < 0.228 ug/dl), plasma metanephrine (0.15 nmol/l, n <0.49 nmol/l), plasma normetanephrine (3.56 nmol/l, n <0.89 nmol/l). Repeated plasma normetanephrine level at different occasions was (3.42, 3.51 nmol/l).

Although being asymptomatic, patient elected to proceed with surgery. He was prescribed doxazosin 2 mg and carvedilol 12.5 mg twice a day prior to the surgery. He underwent left adrenalectomy with no complications. Surgical pathology showed pheochromocytoma.

After surgery, he continued to require carvedilol 6.25 mg twice daily, amlodipine 10 mg and lisinopril 10 mg daily to control his blood pressure. Biochemical testing after surgery showed: plasma normetanephrine (0.99 nmol/l, nl <0.89 nmol/l).

Conclusion:

Pheochromocytoma with steady low catecholamine release may not be the cause of hypertension. Close monitoring of such cases with controlled hypertension might be an alternative option to surgery in otherwise asymptomatic patients.

 

Nothing to Disclose: AI, WT

31506 36.0000 SAT 395 A Pheochromocytoma with Steady Low Secretory Activity, Can We Observe? 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Mohamad Rachid*, Samantha Tan, Irfan Siddiqui and Tahira Yasmeen
Advocate Christ Medical Center, Oak Lawn, IL

 

Background:

Pheochromocytoma (PC) is a neuroendocrine catecholamine secreting tumor that originates from the adrenal medulla. We present a case of pheochromocytoma presenting initially with abdominal pain with extreme elevation of plasma normetanephrines. This case highlights the challenges in preoperative management of a patient with pheochromocytoma and associated with low normal blood pressure.

Case:

A 40 year old female with no medical history presented with complaints of vague right-sided abdominal pain of 2 weeks associated with hot flashes. Physical exam showed blood pressure of 115/85 mmHg and heart rate of 75 beats per minute. A Computed Tomography (CT) of abdomen without contrast showed a 6 cm soft tissue attenuation on the right adrenal. A follow up CT abdomen with contrast confirmed a 6 cm right adrenal mass with marked hypervascularity and no significant washout consistant with PC. A MIBG scan showed large solitary right adrenal lesion consistent with PC with no other abnormal MIBG activity seen. Lab evaluation revealed elevated plasma metanephrine of 0.78 nmol/L (0.00-0.49 nmol/L), plasma normetanephrine >50 nmol/L (0.00-0.89 nmol/L), urine metanephrine of 449 mcg/24hr (52-341 mcg/24h), urine normetanephrine 18233 mcg/24hr (88-444 mcg/24h), and urine epinephrine of 9 mcg/24hr (2-24 mcg/24hr). Blood pressure remained normal to low with a systolic blood pressure of 110-80 mmHg and diastolic blood pressure of 80-55 mmHg. Surgical resection of PC was contemplated with preoperative preparation with alpha blockade. As alpha blockers could further worsen the hypotension, the patient was observed in the hospital for 24-hours and therapy initiated with phenoxybenzamine 10 mg twice daily. Liberal fluid and dietary salt intake was encouraged. She was given sodium chloride tablets 1 gm three times daily. After one week of phenoxybenzamine, beta blockade was initiated with metoprolol 12.5 mg daily for tachycardia. The patient underwent laparoscopic right adrenalectomy without complications. Phenoxybenzamine and metoprolol were stopped after surgery and the patient was discharged 2 days later in stable condition. After 6 weeks, repeated work up showed low plasma metanephrine < 0.10 nmol/L (0.00-0.49 nmol/L) and plasma normetanephrine 0.30 nmol/L (0.00-0.89 nmol/L).

Conclusion:

We present a rare case of normotensive pheochromocytoma with extreme elevation of plasma normetanephrines and normal metanephrines which was managed successfully with pre-operative alpha blockade using phenoxybenzamine and beta blockers. This case highlights the challenges in the preoperative management of normotensive PC and demonstrates successful management with alpha and beta blockers without complications. In addition this case reinforces the need for prospective clinical trials to address the optimum management of normotensive pheochromocytoma.

 

Nothing to Disclose: MR, ST, IS, TY

31540 37.0000 SAT 396 A A Case of Normotensive Pheochromocytoma with Extreme Elevation of Normetanephrines 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Sushuma Kalidindi*1, Diane Barker2, Arun M A Vijay1, Feaz Babwah1, Fraz Umar2, Cherian George1, John Oxtoby1, Julian Waldron1, Anthony A Fryer3 and Fahmy WF Hanna1
1University Hospitals of North Midlands NHS Trust, United Kingdom, 2University Hospitals of North Midlands NHS Trust, 3University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, United Kingdom

 

Introduction:
Catecholamine-secreting tumours are rare neoplasms. Rarely pheochromocytoma is associated with cardiomyopathy attributed to catecholamine excess; this is similar to stress induced cardiomyopathy1. We present the case of a patient who presented with acute heart failure and was noted to have a 4.6cm adrenal lesion.

Clinical case:
A 51-year old male presented on a weekend with chest pain. He had an 18 month history of headaches and flushing episodes. He is on treatment for hypertension and had no other significant past medical or family history. On examination he was in overt heart failure.

Results:
His troponin was 23,488 ng/L (0-39ng/L). Transthoracic echocardiogram showed a global left ventricular systolic dysfunction, ejection fraction of 10%. All walls were almost akinetic. Cardiac MRI excluded a myocardial infarction. CT aortogram excluded dissection, however an incidental indeterminate, lipid poor right adrenal lesion was found.
The adrenal lesion along with the presentation gave the clinical appearance of a pheochromocytoma. Plasma and urine metanephrines were requested, although they can take up to a week to be reported. Urine metadrenaline which were reported at a later stage were markedly elevated at 89,408 nmol/24h (0-2000 nmol/24h).

Management:
Acute heart failure was treated with diuretics. His case was discussed with the cardiac transplant centre in case he failed to respond to medical treatment. As the patient was in extremis, we had to proceed with coronary angiography without metanephrines results. In this setting, as a life saving measure, we started an alpha blocker and proceeded cautiously, expecting worsening of crisis and considered other agents (eg-nitroprusside infusion if needed). The coronary angiogram was uneventful and revealed normal coronary arteries.

Discussion:
This case highlights:
1. The necessity of multidisciplinary approach when dealing with possible pheochromocytoma. This case required the direct interaction of the consultant cardiologist, endocrinologist, radiologist and clinical biochemist to discuss the findings and plan the necessary investigations.
2. The need to carefully consider the pros and cons of an intensive intervention (coronary angiogram) in a patient with possible pheochromocytoma. This can be a lifesaving measure, but needed to be done before the results of the urinary/plasma metanephrines, especially as the patient presented over a weekend.
3. Urinary metanephrines require a full 24 hour accurate collection with restrictions. The analysis is only done once per week in our centre. Plasma metanephrines are often sent to a reference lab and therefore take more than 4 weeks to come back. This adds pressure on the handling of acute presentations like our case. We needed to ensure multi-disciplinary interaction and full engagement with patient, family to appreciate the uncertainties and impact on decision making.

 

Nothing to Disclose: SK, DB, AMAV, FB, FU, CG, JO, JW, AAF, FWH

31701 38.0000 SAT 397 A Adrenal Incidentaloma with Cardiogenic Shock; How to Manage a Possible Phaechromocytoma? 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Boram Han*1, Sira Korpaisarn1, Jirat Chenbhanich1 and Samir Malkani2
1Metrowest Medical Center, Framingham, MA, 2University of Massachusetts Medical School, Worcester, MA

 

A 43-year-old Caucasian male with a past history of adrenal insufficiency and type 1 diabetes, was admitted in October 2016 with a 3 week history of left-sided pleuritic chest pain. The patient was noted to have tanned skin with diffuse hyperpigmentation. His blood pressure was 69/44 mmHg, pulse was 114/min and temperature 98.0F. Lung and heart exam were normal without friction rubs. Thyroid and neurologic exam were normal. EKG showed inferior lead ST elevation, along with elevation of troponin. Echocardiogram showed small pericardial effusion. Coronary arteries were normal on cardiac catheterization. His blood pressure responded to aggressive hydration and stress dose steroids. He had been non-compliant with adrenal replacement therapy at admission but was discharged on hydrocortisone, fludrocortisones and anti-inflammatory medications. Admission laboratory data: ESR 35mm/h (0-15), CRP 39.2 mg/L (0.0-8.0); Hgb 12.1 g/dL, WBC 10.9x109/L; sodium 149 mEq/L, potassium 4.0 mEq/L; creatinine 1.42 mg/dL; normal liver functions; HbA1c 6.7%. Anti TPO elevated, and TSH normal. Ds-DNA, c-ANCA, p-ANCA, anti-Smith antibody, TTG-IgA, and intrinsic factor antibody were all negative. Complement C3 and C4 were normal. Adrenal CT was unremarkable. The patient was diagnosed with acute pericarditis due to unknown cause.

 Prior records revealed admissions in 2008 and 2012 for left pleuritic chest pain. EKGs, cardiac enzymes and nuclear stress tests were negative. Echocardiogram revealed small pericardial effusion, and he also had a pleural effusion on chest X-ray. At that time, the patient had no signs of adrenal insufficiency with normal blood pressure and electrolytes. Adrenal insufficiency was diagnosed in 2013, when he presented with headache, hypotension, hyperpigmentation, hyponatremia and hyperkalemia. Plasma ACTH was 1250 pg/mL (9-52) and baseline cortisol <1.9 mcg/dL (normal 8am cortisol: 8-19) with no response to cosyntropin stimulation. The patient was started on hydrocortisone and fludrocortisones replacement, but he stopped these after several months.

 Autoimmune polyglandular syndrome (APS) type 2, is defined by the co-occurence of autoimmune adrenal insufficiency, thyroid disease and/or type 1 diabetes mellitus. Other manifestations include hypogonadism, vitiligo and pernicious anemia. So far, the definition does not include pericarditis. In the literature, there have been few reported cases of pericarditis associated with Addison’s disease. In APS, the occurrence of pericarditis prior to the development of adrenal insufficiency, as in this patient who only had type 1 diabetes when he presented with the initial two episodes of pericarditis, has only been reported once before. We propose that pericarditis can be the initial manifestation of APS type 2, and that the mechanism and pathophysiology of this is not currently understood.

 

Nothing to Disclose: BH, SK, JC, SM

31147 39.0000 SAT 398 A Recurrent Pericarditis As an Initial Manifestation of Autoimmune Polyglandular Syndrome Type 2 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 360-398 9475 1:00:00 PM Adrenal Case Reports Poster


Britta Winkler*1, Hendrik Lehnert2, Henrik Oster3 and Birgit Harbeck3
1University of Luebeck, Lübeck, GERMANY, 2University of Luebeck, Luebeck, Germany, 3University of Lübeck, Lübeck, Germany

 

Introduction

Currently employed hydrocortisone replacement regimens for patients with adrenal failure insufficiently mimic the circadian rhythm of cortisol secretion, resulting in temporary hypo- and hypercortisolism. Robust biomarkers measuring cortisol exposure over weeks or months are lacking.

FKBP5 is a co-chaperone of hsp90 which regulates glucocorticoid receptor sensitivity. Previous studies on mice showed that chronic exposure to glucocorticoids (GC) results in loss of DNA methylation in the introns 1 and 5 of the FKBP5 gene in blood and other tissues. Four weeks of GC exposure reduce FKBP5 methylation in a dose-dependent manner. Moreover, demethylation of the FKBP5promoter was recently shown in human trabecular cells after dexamethasone treatment.

The aim of this pilot study was to evaluate the relevance of CpG methylation within the FKBP5gene as a possible long-term biomarker of cortisol exposure.

Materials and Methods

Twenty-one healthy adults (6 females, 15 males, median age: 24 years) were recruited. A high dose (250 mcg) ACTH stimulation test was performed to evaluate adrenal function in all subjects. Serum cortisol was measured prior to and 1h following the stimulation. In addition, blood samples were taken prior and 24h following ACTH-exposure. FKBP5 methylation in leukocytes was measured using pyrosequencing. The CpG-site analysed was located in the promoter region of FKBP5(chr6: 35,729,046; hg38).

Results

Methylation values ranged from 17.72% to 29,79% (mean = 24.14%) prior to the ACTH-test and 19.30% to 31.45% (mean = 25.73%) following the ACTH-test, meaning no significant change in average methylation was found. Basal FKBP5methylation before ACTH stimulation was negatively correlated with basal serum cortisol levels (r = -0.509; p = 0.04). Furthermore, a negative correlation was found between serum cortisol 1h and methylation 24h following ACTH-exposure (r = -0.588; p = 0.005) as well as between the post ACTH-test methylation status and the delta of serum cortisol (r = -0.626; p = 0.002). In addition, delta methylation and delta serum cortisol were negatively correlated as well (r = -0.537; p = 0.012).

Discussion

The negative correlation observed between FKBP5 methylation and serum cortisol supports previous studies, showing that FKBP5 methylation is altered by GC exposure. Average FKBP5 promoter methylation remained unchanged. Considering previous studies showing demethylation of FKBP5 after 2-4 weeks of GC stimulation, our findings suggest that FKBP5 methylation could be used as a a robust biomarker that reacts stronger to long term GC exposure than to a singular ACTH stimulus as used in our study. This hypothesis will be evaluated in future studies.

 

Nothing to Disclose: BW, HL, HO, BH

29347 1.0000 SAT 399 A FKBP5 Methylation As a Long-Term Marker for Cortisol Exposure in Healthy Subjects 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Merav Serebro1, Ohad Bentur2, Yael Sofer1, Etty Osher3, Naftali Stern3 and Yona Greenman*3
1Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, 2Tel Aviv-Sourasky Medical Center, 3Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

 

Background: Titration of glucocorticoid replacement therapy in adrenal insufficiency is mostly based on clinical assessment, due to the lack of precise laboratory tools for treatment monitoring. Overdosing might lead to increased morbidity including hypertension, weight gain, diabetes and osteoporosis whereas underdosing may result in life threatening adrenal crises. We examined the efficacy of cortisol curves as an objective tool for dose titration.

Methods: Retrospective review of hydrocortisone loading curves performed in adrenal insufficient patients between 2008 and 2015 in our institute. Serum cortisol levels were measured prior and 30, 60, 120, 180, 240 and 300 minutes following administration of the patient`s regular morning hydrocortisone dose. Dose adjustments were performed by the treating physician based on cortisol profile results. Metabolic data, including weight, blood pressure and lipid profile were documented before and after performance of the curve.

Results: Sixty five hydrocortisone loading curves were performed in 51 patients during the study period. Pertinent clinical data was available for 28 patients. Mean age 44.8±13.7 years, 43% males, average weight was 82.9±21.9kg, 36% were hypertensive and 25% had diabetes. Mean daily hydrocortisone dose was 23.1±7.3 mg. Based on cortisol curve results, the dose was decreased in 54% of patients, unchanged in 36% and increased in 11%. There were no statistically significant between-group differences in age, sex, starting dose, starting weight, diabetes and hypertension prevalence. The average dose change was -8.2mg in the dose reduction group and +1.5mg in the rest of the study population (p<0.05). The average change in blood pressure was -11.38/-9.13 in the dose reduction group as compared to +0.8/+2.9 in the rest of the study population (p<0.05). A statistically non-significant reduction in weight, LDL and total cholesterol levels was also noted in the dose reduction group.

Discussion: Our findings suggest that cortisol curves are an effective tool for hydrocortisone dose titration, leading to a significant reduction in blood pressure in this cohort.

 

Nothing to Disclose: MS, OB, YS, EO, NS, YG

29590 2.0000 SAT 400 A Cortisol Curve after Hydrocortisone Loading – an Effective Tool for Optimization of Replacement Therapy in Adrenal Insufficiency 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Ferdinand Roelfsema*1, Paul Aoun2, Paul Y. Takahashi3, Rebecca Y. Yang4 and Johannes D. Veldhuis5
1Leiden University Medical Center, Leiden, Netherlands, 2Palm Beach Diabetes & Endocrine Specialists, West Palm Beach, FL, 3Mayo Clinic, Rochester, MN, 4Mayo Cinic, Rochester, MN, 5Mayo Clinic School of Medicine, Rochester, MN

 

Background: Study of the HPA-axis is hampered by unobservable hypothalamic CRH and AVP pulses acting on the corticotrope. Exogenously clamping one of the secretagogue inputs would allow quantification of the impact of the endogenous heterotypic hormone. This approach could also facilitate assessing the importance of sex and sex hormones on CRH and AVP actions.

Methods: 28 healthy adults, mean age 55 yr, 16 men, were subjected to a randomized, double blind, placebo-controlled cross-over study. They were made hypogonadal with leuprolide, and randomized to placebo or gender-specific sex steroid addback. Eucortisolemia was accomplished by ketoconazole and continuous cortisol infusion. Peptide infusion sessions and 10-min blood sampling (2200 h overnight to 1200 h the next day) comprised 4 separate randomly ordered double-blind continuous i.v. infusions of CRH, AVP, the combination or saline at maximally stimulatory doses. At the end of the 10 h infusion, a submaximal dose of the non-infused hormone was injected i.v. and blood sampling continued for 2.5 h. Data are mean ± SEM.

Results. Mean 10-h ACTH concentrations (ng/L) in the gender-combined analysis were: saline 32±4.6, AVP 29±4.6, CRH 67±6.2 and CRH-AVP 67±8.8: saline vs AVP P=NS; CRH vs CRH-AVP P=NS; CRH vsAVP P<0.0001. Secretagogues induced stable ACTH concentrations after 4-6 h. Comparable contrasts were obtained by deconvolution analysis. Secretory burst regularity and burst mode were similar among groups. Cortisol levels were higher in women than men (P<0.0001), and higher during CRH than AVP infusion (P<0.0001). ApEn was increased by AVP and CRH (P<0.0001). Pattern synchrony of ACTH and cortisol was diminished by CRH and CRH-AVP, but not by AVP. Gender and sex-hormone administration were not significant categorical variables. AVP injection after exposure to CRH yielded mean 2.5-h ACTH concentrations of 46±4.3, exceeding that after CRH or saline injection (26±3.3 and 24±3.6, respectively; P=0.002 and 0.001).

Conclusions. CRH infusion is more potent than AVP. Exogenous single and dual-peptide clamping does not interfere with pulsatile ACTH secretion, but yields higher secretory randomness putatively by deleting endogenous peptide feedforward control. Conversely, clamping with AVP, an inferably desensitizing ACTH secretagogue in this setting, resulted in endogenously alleged CRH pulses’ driving lesser ACTH secretion approaching saline infusion. As expected the increased forward drive caused increase of ApEn and cross-ApEn. Bolus AVP injection induced greater ACTH release, likely caused by the sensitization of the corticotrope by CRH infused in the preceding 10 h. Accordingly, this paradigm generates a framework for investigating AVP’s putative desensitization of CRH action, and CRH’s inferred potentiation of AVP action. These interactions may explain unexpected effects of certain neuropsychiatric stressors.

 

Nothing to Disclose: FR, PA, PYT, RYY, JDV

29608 3.0000 SAT 401 A Estimation of Endogenous Heterotypic Peptidyl Stimulation of ACTH Secretion Under an Exogenous Secretagogue Clamp 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Laura E. Dichtel*1, Melanie Schorr1, Claudia Loures de Assis2, Jessica K. Sims2, Kathleen E. Corey1, Richard E. Reitz3, Michael J. McPhaul3 and Karen K. Miller1
1Massachusetts General Hospital/Harvard Medical School, Boston, MA, 2Massachusetts General Hospital, Boston, MA, 3Quest Diagnostics Nichols Institute, San Juan Capistrano, CA

 

Accurate diagnosis of adrenal insufficiency (AI) is critical, as there are risks to both over and under diagnosis. Data using LC-MS/MS assays for total cortisol (TC) and free cortisol (FC) in states of high or low cortisol binding globulin (CBG) levels, including oral estrogen use, cirrhosis and critical illness, are needed. The goals of this study were to determine: 1) the relationship between TC and FC levels in healthy individuals and groups with abnormal CBG levels, and 2) the FC level by LC-MS/MS that best predicts a TC of 18 μg/dl (the standard AI diagnostic cut-off on ACTH-stimulation testing) in healthy individuals.

338 subjects in 4 groups were studied: healthy controls (HC)(n=243), oral contraceptive users (OCP)(n=31), patients with cirrhosis (n=38) and intensive care unit patients (ICU)(n=26). FC and TC were measured by LC-MS/MS and albumin by spectrophotometry (Quest Diagnostics Nichols Institute, San Juan Capistrano, CA), and CBG by ELISA (Biovendor, Ashville, NC).

Mean age was 48±17 y and mean BMI 28±7 kg/m2. Mean albumin (g/dL) and CBG (μg/mL) were higher in OCP and HC than in cirrhosis and ICU [(albumin: OCP 4.6±0.3, HC 4.7±0.3 versus cirrhosis 3.5±0.9 and ICU 3.1±0.7, p<0.001) and (CBG: OCP 57±18 and HC 28±7 versus ICU 22±4 and cirrhosis 21±7, p<0.0001)]. CBG correlated weakly with albumin in HC (R=0.32, p<0.0001) and cirrhosis (R=0.46, p<0.02) but not in OCP or ICU. Mean random TC (μg/dL) was 18.9±8.5 in OCP, 14.7±6.6 in ICU, 11.5±7.3 in HC and 9.9±5.7 in cirrhosis. Mean FC (μg/dL) and % FC were highest in ICU subjects (FC: ICU 1.29±1.08, cirrhosis 0.59±0.47, HC 0.58±0.67 and OCP 0.33±0.15, p<0.01 vs. ICU; % FC: ICU 7.7±4.8%, cirrhosis 5.4±2.7%, HC 4.2±2.2% and OCP 1.8±0.8%, p<0.05 vs. ICU). TC strongly correlated with FC in the ICU, HC and cirrhosis groups and more weakly in the OCP group (ICU R=0.91, HC R=0.90, cirrhosis R=0.86, OCP R=0.70, all p<0.0001). Consistent with Hamrahian et al, ICU subjects with albumin <2.5 gm/dL had higher FC despite similar TC. In receiver operator curve (ROC) analysis in the HC group, an FC cutoff of 1.0 μg/dL predicted a TC of ≥18 μg/dL with 91% sensitivity and 98% specificity (AUC 0.98, p<0.0001). No HC subject with an FC ≥ 1.6 μg/dL had a TC < 18 μg/dL (67% sensitivity; 100% specificity). An FC cutoff of ≥1.0 μg/dL predicted a TC of ≥15.1 mcg/dL in ICU and ≥13.4 mcg/dL in cirrhosis with 100% sensitivity but only 92% and 83% specificity, respectively. In a separate group of 8 HC who underwent ACTH-stimulation testing, all had stimulated TC ≥ 18 μg/dL and FC levels ≥1.0 μg/dL, except one, who had a TC of 16.7 μg/dL with an FC of 1.4 μg/dl.

In conclusion, an FC of ≥ 1.0 μg/dL in this LC-MS/MS assay predicts a TC level of ≥ 18 μg/dL with maximum sensitivity and specificity. Clinicians should use caution in interpreting TC levels in patient groups with altered CBG levels, particularly in women on OCPs, given the variable resulting increase in CBG.

 

Disclosure: RER: Employee, Quest Diagnostics, Employee, Quest Diagnostics. MJM: Employee, Quest Diagnostics, Employee, Quest Diagnostics. Nothing to Disclose: LED, MS, CL, JKS, KEC, KKM

30340 4.0000 SAT 402 A Plasma Free Cortisol Vs. Total Cortisol in Healthy Individuals and in States of High and Low Cortisol Binding Globulin, Including Oral Contraceptive Use, Cirrhosis and Critical Illness: Implications for Diagnosing Adrenal Insufficiency 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Juliana Hendrika Hey-Hadavi*1, Nina Cecilia Camacho-Hubner2, Natasa Rajicic3, Kaijie Pan1 and Jose Francisco Cara1
1Pfizer Inc, New York, NY, 2Pfizer, Dobbs Ferry, NY, 3Pfizer, Inc., New York, NY

 

Introduction:Pegvisomant (PEGV) is a competitive antagonist of Growth Hormone (GH) and its effects are the result of its reversible binding to the GH receptor. ICTD contains efficacy data from previous PEGV clinical trials. The efficacy of PEGV in subjects with acromegaly was evaluated using this integrated data.

Subjects and Methods: The pegvisomant integrated clinical trial database includes data from 550 unique (non-duplicate) subjects (56% males) who received at least one dose of PEGV and 47 unique placebo subjects (51% males), all of whom were included in the safety analysis. Because subjects may have participated in one or more studies and received more than one dosage of PEGV, a total of 827 subjects (456 (55%) males, mean age 47 yrs., range 20 – 84) enrolled in 13 phase 2b, 3 and 4 clinical trials were included in the efficacy analysis. Studies were of variable length and only the studies with daily dosing were included. IGF-I normalization rates were defined as the percent of subjects who achieved an IGF-I value < 1.2 X ULN at least once at any time during the study, at the end of study, or based on last observation carried forward.

Results:Treatment duration ranged from 6 to 84.7 weeks and average PEGV dose was 7.8 mg to 22.6 mg/day. IGF-I normalization rates ranged from 19.4 to 94.7%, with the highest rate using daily therapy, longer study drug exposure and appropriate dose titration. Over 50% of acromegaly subjects had normalization of IGF-I within 2 weeks. IGF-I normalization was achieved in >50% of subjects in 9 studies, >75% of subjects in 7 studies, and >90% of subjects in 2 studies. Normalization of IGF-I was found to persist throughout 84.7 weeks of treatment. Average duration of the treatment, average dose, and proper PEGV titration appear to be related to the proportion of subjects with IGF-I normalization; adequate titration of PEGV was key for efficacy, as ~95% of subjects had IGF-I normalization with proper PEGV dose titration. Among PEGV patients, 83.8% reported Treatment Emergent Adverse Events (TEAE), and 8.4% discontinued due to AEs. Among PEGV female patient, 89.3% reported TEAE, and 11.6% discontinued due to AEs. Among PEGV male patient, 79.3% reported TEAE, and 5.8% discontinued due to AE. Common adverse events reported by > 10% of PEGV subjects included headache, nasopharyngitis, arthralgia, diarrhea, fatigue and back pain.

Conclusions: PEGV is found to be highly effective in normalizing IGF-I levels in subjects with acromegaly. The integrated data shows that full efficacy of PEGV is contingent upon adequate duration of exposure and suitable dose titration, which ultimately results in IGF-I control in the majority of subjects without evidence of drug tolerance. Review of safety data supports the positive benefit-risk profile.

 

Disclosure: JHH: Employee, Pfizer, Inc.. NCC: Employee, Pfizer, Inc.. NR: Employee, Pfizer, Inc.. KP: Employee, Pfizer, Inc.. JFC: Employee, Pfizer, Inc..

31521 5.0000 SAT 403 A Evaluating of the Efficacy of Pegvisomant in Treatment of Acromegaly: Analysis of Integrated Clinical Trial Database (ICTD) 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Ramon Marcelino do Nascimento*1, Pedro Junqueira de Godoy Pereira2, Bruna Sabrina de Sanabria Irigoitia3, Aline Guimarães de Faria2, Valter Angelo Sperling Cescato4, Nina de Castro Musolino5, Maria Candida Barisson Villares Fragoso6, Marcello D Bronstein7, Publio Cesar Cavalcanti Viana2 and Marcio Carlos Machado8
1Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 2Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil, 3Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil, 4Hosp das Clin Faculd Med USP, Sao Paulo, Brazil, 5Hospital das Clínicas, FMUSP, São Paulo, Brazil, 6Hospital das Clinicas, University of Sao Paulo, School of Medicine, Sao Paulo, BRAZIL, 7Disciplina de Endocrinologia e Metabologia, Unidade de Neuroendocrinologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil., 8University of Sao Paulo Medical School, Sao Paulo, Brazil

 

Background: During the etiological investigation of ACTH-dependent Cushing's syndrome is not uncommon to observe hyperplasia of the adrenal glands. In addition, adrenal nodules also are eventually found making important the differential diagnosis of ACTH-producing source.

Objective: To study the prevalence of adrenal changes in patients with CD and to correlate the findings with clinical characteristics at diagnosis and impact on postoperative outcome.

Methods: From 2007 to 2016, were evaluated 163 patients with ACTH-dependent Cushing's syndrome. Of these, we selected 89 cases with confirmed diagnosis of CD, who had CT (93%) or MRI of the abdomen/adrenal with imaging available for reassessment by a single radiologist with experience in adrenal diseases. Cases were excluded when imaging was not available for the re-evaluation or in cases with exams done out of our Service.

Results: There was a prevalence of 30% (27/89) of adrenal abnormal findings: 16 cases (18%) had hyperplasia of the adrenal glands (Hyperplasia Group: HPG) and 11 cases (12%) had unilateral or bilateral nodules (Nodules Group: NDG). In NDG, seven cases were unilateral with an average diameter of 16.6 ± 5.1 mm and 12.7 ± 13.5 Hounsfield unit (HU) and four cases were bilateral with a diameter of 17.6 mm ± 4.9 and 1.3 ± 6.9 HU. All nodules had sharp edges and 85% had a homogeneous texture. In relation to the hormonal profile, higher cortisol levels were found in HPG patients. Late-night salivary cortisol (LNSC): HPG: 2270.3 ± 4818.6 ng/dL (Reference [R]: <120 ng/dL); normal group (NG): 644.6 ± 660.4 ng/dL; NDG: 574.5 ± 453.0 ng/dL. 24h urinary cortisol (UC): HPG: 2994.7 ± 8041.3 µg/24h (R: 50-310 µg/24h); NG: 876.4 ± 864.4 µg/24h; NDG: 808.6 ± 856.9 µg/24h. Overall, remission rate after transsphenoidal surgery was 68% (59/87), similar in all subgroups of adrenal imaging. Recurrence was detected in 24% of cases in a median follow-up of 36 months: 12 cases in NG, two cases in HPG and one case in NG. Adrenal imaging (CT) was reassessed in six patients of NG (55%, 3 uni- and 3 bilateral): unilateral: one nodule reduced (21 to 9 mm), one described as hyperplasia and one case did not show nodule; bilateral (six nodes in three cases): four reduced (18.0 ± 4.5 to 14.3 ± 5.9 mm) and two (one patient without remission) increased in size (15.0 to 27.5 mm). Hyperaldosteronism and pheochromocytoma were excluded in the researched cases.

Conclusion: There was a higher prevalence of adrenal abnormalities in patients with CD, greater than observed in the normal population. Concentrations of LNSC and UC denote greater severity of Cushing's syndrome in the HPG. There was no impact on remission and recurrence rates compared to adrenal findings. The partial re-evaluation of these nodules during follow-up suggests that chronic stimulation of ACTH is responsible for the appearance of these changes.

 

Nothing to Disclose: RMDN, PJDGP, BSDSI, AGD, VASC, NDCM, MCBVF, MDB, PCCV, MCM

31671 6.0000 SAT 404 A Prevalence of Adrenal Abnormalities in Patients with Cushing's Disease: Correlation with Clinical Characteristics at Diagnosis and Impact on Postoperative Outcome 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Nuria Valdés*1, Amit Tirosh2, Lyssikatos Charalampos1, Margaret Farmar Keil3, Elena Belyavskaya1, Constantine A Stratakis1 and Maya Beth Lodish1
1Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 2Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH, Bethesda, MD, 3Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH)., Bethesda, MD

 

Introduction: Due to the rarity of Cushing syndrome (CS) in pediatric patients data are scarce about body mass index (BMI) and cardiovascular risk factors during active disease and following remission and/or cure.

Objective: The purpose of our study was to study BMI and its relationship with cardiovascular risk factors before and after surgical treatment in pediatric patients with CS.

Patients and methods: We selected patients biochemically cured after surgery of CS and with at least 1 visit following cure. Data were collected from 73 patients, 40 males (58%), median age of 12 years (IQR: 9-15 years) and median follow up time of 14 months (IQR: 11-27 months). Cushing disease was diagnosed in 58 patients and primary adrenal CS in 15 patients according to pathological diagnosis.

Results: Mean BMI z-score at diagnosis was 2.0±0.7 (range: -0.4-3.1), 8 (11%) patients had a normal weight, 23 (31.5%) were overweight and 42 (57.5%) were obese. Hypertension (HTN) was diagnosed in 68.5% patients, dyslipidemia in 41.4% and DM2 in 4%. BMI z-score correlated positively with the duration of disease (r: 0.23, P=0.04), HOMA-IR (r:0.58, P<0.001), and negatively with age (r:-0.39, P=0.03). At the last follow up after cure HTN was present in 3.3%, dyslipidemia in 18.8%, whereas no patient had DM2. BMI z-score at last follow up was 1.2±1.1 (range:-1.5-2.8) and positively correlated with HOMA-IR (r: 0.54, P=0.01).Importantly, while overall the BMI z-score improved from pre-operative to post-cure values (2.0±0.7 to 1.2±1.1, P<0.001) a large percentage of patients remained overweight (24.6%) or obese (28.7%).

There were no differences in BMI, HTN, dyslipidemia and DM2 according to the etiology of CS or gender. The estimated cumulative frequency of achieving a normal weight by Kaplan-Meier curve reached 50% of patients at 16 months (95% CI: 3.93-28.06) and 62% at 25 months. Patients with normal weight at final follow up compared with those without it had shorter duration of hypercortisolism (2.1±2.2 vs 3.6±2.6 years, P=0.03), lower BMI z-score at diagnosis (2.0±0.4 vs 2.6±0.2, P<0.001), lower HOMA-IR (4.9±3.4 vs 36.6±9.7, P<0.006) and higher mean BMI z-score change at 6 months (0.8±0.7 vs 0.2±0.09, P<0.001) and at first visit after cure (1±0.6 vs 0.1±0.1, P<0.001). Cox regression analysis demonstrated that only the change of BMI z-score at 6 months was an independent predictor factor for reaching normal weight (HR: 3.73, 95% CI: 1.02- 12.85; P=0.03) with high accuracy when using a cutoff of 0.5 on ROC analysis (AUC= 0.87 (0.72-1, P<0.001).

Conclusions: Pediatric patients with CS had a great risk of remaining obese or overweight associated with an increase of insulin resistance despite improvements after cure of their CS. A decrease in BMI z-score of – 0.5 by 6 months post-operatively is highly predictive of reaching a normal BMI; thus, efforts should be focused in these early phases post surgery for healthy diet and lifestyle.

 

Nothing to Disclose: NV, AT, LC, MFK, EB, CAS, MBL

31487 7.0000 SAT 405 A Body Mass Index and Cardiovascular Risk Factors in Children with Cushing Syndrome before and after Surgical Treatment 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Raven N. McGlotten*1 and Lynnette K. Nieman2
1NIDDK, NIH, 2NIH, Bethesda, MD

 

Background: The Endocrine Society’s Guideline states that it is important to normalize co-morbidities of Cushing’s syndrome (CS) (1). Hypertension (HTN) is one of the most common comorbidities of CS, affecting about 80% of adult patients (pts) (2). While the pathophysiology of hypertension is multifactorial, its reversibility after successful surgical cure of CS is not well understood. We evaluated changes to blood pressure (BP) shortly after surgical remission and up to one year later.

Methods: We retrospectively studied all patients undergoing surgical treatment of CS under our protocols at the NIH Clinical Center from 12/2011 through 9/2016. Ectopic ACTH syndrome (EAS), Adrenal adenoma (AA) or Cushing ’s disease (CD) was diagnosed based on surgical pathology. Pts were considered to have HTN based on medical history, physical examination or if they were on oral antihypertensive agents (AHAs). After surgery pts remained inpatient for 7-15 days. Hydrocortisone (10-12mg/m2) was started when remission was confirmed, usually by post-operative day 4. Resolution of HTN was defined as systolic BP ≤120 mmHg and diastolic BP ≤80 mmHg off AHAs. BP values were compared between 1) the first morning after pre-operative inpatient admission from 0600-0800h, 2) the morning of discharge (DC), and 3) the morning of follow up (f/u) clinic visit(s).

Results: At baseline (BL) 30 (25 female) of 51 patients had a diagnosis of HTN and all received AHAs (25=CD, 4=EAS, 1-AA); each achieved remission. By DC, 12 were on no AHAs, 15 had a decrease in the number or dose of AHAs, and 2 had no change in AHAs. The median systolic value decreased from 130 to 125 mmHg with no change in diastolic values (p>0.05). Three pts had no further f/u.

Of 25 patients with 6 month f/u, 13 were taking no AHAs, 10 had a decrease in AHA number from BL, and 2 had no change to medications. Of note, one patient with no change was on an increased dose of hydrocortisone due to severe fatigue. There was a decrease in systolic (p=0.012, median 124 vs 130 mmHg) and diastolic (p=0.016, median 72 vs 75 mmHg) values from BL.

23 pts had 12 month f/u, including 2 who were not seen at 6 mo. Of these, 15 were on no AHAs; 5 had a decrease in medication number or dose. Of 3 pts with no change from BL, 2 were on a stable antihypertensive regimen from BL to 12 month f/u. One pt, who was on a decreased regimen at DC, restarted BL AHAs 3 months post-surgery due to rising BP. There was a decrease in systolic (p=0.0026, median 116 mmHg) and diastolic (p=0.0015, median 66 mmHg) values from BL. HTN fully resolved in 11 of the 23 pts.

Conclusion: While many factors affect BP, surgical remission of CS can lead to rapid improvement of HTN, requiring adjustment of antihypertensive agents as early as the first week after surgery. We recommend close monitoring of BP, especially in the first 15 days post operatively, patient education, and long term follow up for optimal treatment of hypertension in this population.

 

Nothing to Disclose: RNM, LKN

29712 8.0000 SAT 406 A Resolution of Hypertension with Surgical Remission of Cushing's Syndrome 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Yosra Moria*, Ribal Alaridi, Nadine El Asmar and Baha M Arafah
UH Cleveland Medical Center/Case Western Reserve University, Cleveland, OH

 

Introduction: DHEA and its sulfated ester DHEA-S are ACTH-dependent adrenal androgens that are increasingly utilized as markers of HPA functional integrity1. In patients with adrenal insufficiency, loss of adrenal androgens precede the decrease in glucocorticoid secretion1,2 and hence, it has been stated that a normal serum DHEA-S makes the diagnosis of adrenal insufficiency unlikely. Published data suggest that PRL modulates DHEA/DHEA-S secretion.

IN this study, we examined changes in serum DHEA-S in patients with prolactinomas who had normal HPA function and others with impaired function before and after medical therapy with dopamine agonist.

Methods: We included 30 patients (20-60 years of age; 34±10.2) with prolactinomas who had normal HPA function (23F / 7M) as well as 5 males (51 ± 15.1 years of age) with prolactinomas and impaired HPA function (Am cortisol of 2.3 ±1.9 ug/dL). Serum levels of cortisol, PRL and DHEA-S were measured repeatedly after dopamine agonist therapy. None of the 30 patients were known to have other illnesses or were taking medications known to influence PRL levels or adrenal function. Patients with impaired HPA function had other pituitary hormone deficits whereas those with normal HPA function had only gonadal dysfunction.

Results:  In all patients with normal HPA function serum PRL levels decreased gradually from a baseline of 421.8±859 to 30.8±40.3 at 3-6 months (P<0.01) and to 12.2±12.8 ug/L at 12 months (P<0.01). Concurrently, their serum DHEA-S levels decreased from 231.8±191.9 to 170.2±137 at 3-6 months (P<0.001) and to 119.1±61 ug/dL at 12 months (P<0.001). Even though the decline in mean PRL concentration between 3-6 and 12 months was modest (from 30.8 to 12. 2 ug/L) and of borderline significance (P=0.06) it was still associated with significant (P<0.04) decrease in respective DHEA-S levels. Discontinuation of therapy in some patients was associated with a rise in serum PRL and a parallel increase in DHEA-S levels. Although younger patients had higher serum DHEA-S levels, the aforementioned parallel changes in PRL and DHEA-S levels were observed in all patients irrespective of their age. However, despite marked elevation in serum PRL 374±196 ug/L in patients with impaired HPA function, the respective serum DHEA-S levels remained very low (28.4±24 ug/dL).

Conclusion: The data indicate that hyperprolactinemia results in elevation of serum DHEA-S levels that decrease with medical therapy. However, despite markedly elevated serum PRL levels, patients with impaired HPA function had low serum DHEA-S concentrations that remained as low when PRL levels were lowered with dopamine agonists. This indicates that the modulating influence of PRL on serum DHEA-S levels requires normal ACTH secretion. Thus, a normal age and gender adjusted serum DHEA-S level implies normal HPA function even in patients with hyperprolactinemia.

 

Nothing to Disclose: YM, RA, NE, BMA

31298 9.0000 SAT 407 A Hyperprolactinemia Is Associated with Reproducible Rise in Serum DHEA-S Levels: The Important Role of Intact HPA Function 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Andrea Paissan*1, Valeria de Miguel1, Mariela Glerean1, Andrea Kozak1, Maria Ines Ortiz1, Ester Gabriela Scheinfeld1, Soledad Lovazzano1, Patricia Fainstein Day1, Demetrio Cavadas2 and Patricio Garcia Marchiñena1
1Hospital Italiano de Buenos Aires, Buenos Aires, Argentina, 2Hospital Italiano de Buenos Aires, Buenos Aires

 

Severe Cushing's syndrome (SCS) is considered an acute medical emergency. It is defined by massive cortisol excess with serum levels higher than 36 mcg/dL or a 24-h urinary free cortisol (UFC) more than fourfold the upper limit of normal and/or severe hypokalemia (<3.0 mmol/L) along with the recent onset of one or more of the following: sepsis, opportunistic infection, uncontrolled hypertension, heart failure, gastrointestinal hemorrhage, glucocorticoid-induced acute psychosis, progressive debilitating myopathy, thromboembolism or uncontrolled hyperglycemia. Our aim was to review the clinical characteristics, management and outcomes of hospitalized patients with SCS. This is a retrospective case record study. Thirteen patients, 9 females and 4 males with a median age of 49 years (range 24-85), 77% had ectopic ACTH secretion, with a median time from the onset of hypercortisolism of two months (range 1-36). The median follow up was 13.5 months (range 2.5 – 55). The most prevalent clinical features were hypertension (84.6%), diabetes mellitus (84.6%), proximal weakness (69.2%) and CS classic stigmata (61.5%). The more frequents complications were hypokalemia (92%), proximal myopathy (61.5%), bacterial infection (46%), arrhythmia (31%), thromboembolism (15%) and septic shock (15%). The median of UFC was 1750 mcg range 431 – 21040 (normal < 100), serum cortisol was 106 mcg/dL range 22.6 – 482 (normal 5-25) and ACTH was 184 pg/ml range 5-1000 (normal <37). Medical treatment in order to control hypercortisolism was prescribed: ketoconazole (75%), octreotide (58%) and intravenous fluconazole (25%). Bilateral laparoscopic adrenalectomy (BLA) was performed in five patients and unilateral open adrenalectomy in one patient with adrenal carcinoma. Morbidity (66%) was related to pulmonary embolism, hematoma in surgical bed and hospital acquired infections. The overall mortality was 30.8% and it was related to progression of the underlying oncological disease in three patients and due to consequences of SCS in one. In conclusion this group of patients presented high risk of complications and mortality. Acute stabilization management of metabolic and infectious disorders and simultaneous adrenostatic therapy in order to control hypercortisolism is essential. BLA is a safe and effective treatment and has to be performed in the shortest possible time span in high risk patients.

 

Nothing to Disclose: AP, VD, MG, AK, MIO, EGS, SL, PF, DC, PG

32309 10.0000 SAT 408 A Clinical Characteristics, Management and Outcomes of Hospitalized Patients with Severe Hypercortisolism 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Bernadette Kleist1, Sonja Siegel1, Christa Gammel2, Karen Campbell3, Victoria Kuhna4, Agnieszka Grzywotz1, Ulrich Sure1, Oliver Müller1, Michael Buchfelder2 and IIonka Kreitschmann-Andermahr*1
1University of Duisburg-Essen, Essen, Germany, 2University Hospital Erlangen, Erlangen, Germany, 3Cushing's Support and Research Foundation, Plymouth, MA, 4Ev. Hospital Oldenburg, Oldenburg, Germany

 

Introduction: Long term sequelae of hypercortisolism caused by Cushing´s disease (CD) or Cushing’s syndrome (CS) lead to an overall decreased quality of life (QoL) in the long-term, oftentimes despite biochemical control of the underlying disease. For patients with other chronic diseases (e.g. diabetes, multiple sclerosis) special educational and support programs, empowering patients to cope with the long-term effects of the illness, have already been developed, but not for CD/CS. Therefore, it was the aim of the present survey to gain information about disease-specific support needs in patients with CD and CS in Germany and the U.S. and to identify approaches for patient-centered support and psychosocial care.

Methods: Patients with CD treated in 2 neurosurgical tertiary referral centers in Germany and patients with CD/CS who are members of the U.S. based Cushing’s Support and Research Foundation (CRSF) completed a self-developed survey inquiring about disease burden, coping strategies and timepoints when support was needed the most. Additionally, the degree of interest in different offers, e.g. internet-based programs and seminars, was assessed. Data were analyzed using SPSS. Answers provided in free-text fields were clustered and counted.

Results: 84 U.S. and 71 German patients answered the questionnaire. There was no difference between groups with regard to sex and age (p>0.05). Patients in both countries indicated to suffer primarily from common Cushing-related symptoms (e.g. weight gain, buffalo hump, skin problems), reduced performance and psychological problems (e.g. depression, anxiety). 48.8% of patients from the U.S. and 44.4% of the German patients stated that good medical care and skilled doctors helped them the most in coping with the illness. Support was needed to a greater extent before therapy by the U.S patients (63.1%) than by the German patients (45.1%) with p=0.035. The U.S. patients were significantly more interested in support groups (51.2% vs. 33.8%, p=0.035) and in courses on illness coping than the German patients (48.8% vs. 26.8%, p=0.008), who stated to prefer brochures (45.1% vs 20.2%, p=0.001). 89.3% of U.S. patients would attend internet-based programs compared to 75.4% of German patients (p=0.040). There were no differences between groups for the duration of and the willingness to pay for such a program, but U.S. patients would be willing to travel longer distances to attend a support meeting (p=0.027).

Conclusion: Patients in both countries need skilled physicians and long-term medical care in dealing with the effects of CD/CS, whereas the interest in specific topics addressed in support programs differs between patients of both countries. The latter implies that not only disease-specific but also culture-specific training programs would need to be considered to satisfy the needs of patients in different countries.

 

Nothing to Disclose: BK, SS, CG, KC, VK, AG, US, OM, MB, IK

30859 11.0000 SAT 409 A Support Needs of Patients with Cushing’s Disease and Cushing’s Syndrome in Germany and the U.S.: Results of a Survey Conducted Among Patients of 2 German Neurosurgical Centers and the U.S. Based Cushing’s Research and Support Foundation 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Vivian H Lin*, Marian Ijzerman, Marianne R Plaunt and Pharis Mohideen
Millendo Therapeutics, Inc., Ann Arbor, MI

 

ATR-101 (Millendo Therapeutics, Inc., Ann Arbor, MI, USA) is an orally-administered adrenal-selective inhibitor of ACAT1 (acyl coenzyme A:cholesterol acyltransferase 1) in clinical development for the treatment of classic congenital adrenal hyperplasia (CAH), Cushing’s syndrome, and adrenocortical carcinoma. ACAT1 catalyzes cholesterol ester formation and, in the adrenal glands, is particularly important for creating a reservoir of substrate for steroidogenesis. In nonclinical studies, including a Cushing’s syndrome dog study, ATR-101 was shown to inhibit adrenal steroidogenesis.

 

Cushing’s syndrome results from the chronic effects of excessive glucocorticoids. Endogenous Cushing’s syndrome is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumors (i.e., Cushing’s disease), primary adrenal gland tumors, or ectopic (non-pituitary) ACTH-secreting tumors. Medical therapies for Cushing’s are generally used immediately prior to transsphenoidal surgery (for pituitary tumors) or following surgery if there is disease recurrence. Medical therapies can be broadly categorized as steroidogenesis inhibitors, cortisol receptor blockers or centrally-acting agents. In the United States (US), only mifepristone and pasireotide are labeled for the treatment of Cushing’s syndrome and Cushing’s disease, respectively; and both of these medications are limited to specific subsets of patients. Consequently, there is a need for additional medical therapies for Cushing’s syndrome.

 

ATR-101-301 is a Phase 2 randomized, double-blind, placebo-controlled clinical study that will be conducted at approximately 10 centers in the US and the United Kingdom (UK). Subjects with endogenous Cushing’s syndrome will first enter a 6-week open-label dose-titration period. All enrolled subjects will be started on ATR-101 250 mg orally BID. Every 14 days, the ATR-101 dose will be titrated to a maximum dose of 1000 mg BID as needed based on 24-h urinary free cortisol levels. After the open-label dose-titration period, responders will be randomized in a double-blind fashion either to continue their current dose of ATR-101 or be switched to a matching placebo for up to 4 weeks. The primary objective is to evaluate the efficacy and safety of ATR-101 in subjects with Cushing’s syndrome. Secondary objectives include changes in adrenal steroids and intermediates, and changes in ACTH. The study is open to adults with endogenous Cushing’s syndrome who are not considered to be surgical candidates and do not have cyclic Cushing’s syndrome. Approximately 16 subjects will be enrolled.

 

Disclosure: VHL: Employee, Millendo Therapeutics, Inc.. MI: Employee, Millendo Therapeutics, Inc.. MRP: Employee, Millendo Therapeutics, Inc.. PM: Employee, Millendo Therapeutics, Inc..

32089 12.0000 SAT 410 A Trial in Progress: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ATR-101 for the Treatment of Cushing’s Syndrome 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Harleen Kaur Dehal*1, Asha Thomas2 and Joanne Hayes1
1Sinai Hospital of Baltimore, Baltimore, MD, 2Sinai Hospital, Baltimore, MD

 

Introduction:

Ritonavir is known to cause inhibition of cytochrome P450 CYP3A4, a fact that is exploited in the various “Ritonavir boosted” regimens in patients with HIV. Though this works to our advantage in formulation of HAART (Highly Active Antiretroviral Therapy) regimens, it also results in altered metabolism of other medications, such as glucocorticoids.

Objective:

To describe iatrogenic Cushing’s (IC) in patients with HIV (on HAART) with exposure to intraarticular steroids and a review of the literature.

Design:

We present a series of 4 patients with HIV, on various “boosted” HAART regimens, who were diagnosed with secondary adrenal insufficiency. This is followed by a review of the literature and a comparison with our patient group, of the patient characteristics and the type of steroidal preparations that have been described to be associated with Cushing's.

Results:

Our patients were diagnosed with IC, with symptom onset related temporally to various intraarticular (IA) steroidal injections. Literature search suggests that though IC in HIV has been described, most of the cases reported were secondary to inhaled glucocorticoids. Ritonavir, the most commonly used medication to “boost” the levels of other protease inhibitors (PI), was associated with all the case reports that have been previously described. Although 3/4 patients in our cohort were on Ritonavir boosted therapies, one developed Cushing's while on treatment with a cobicistat boosted regimen.

The mean age of our patient population was 50, with an average of about 22 years on antiretroviral therapy. All patients received IA triamcinolone a minimum of 2 times within a span of 2-5 months. Although the steroid dosing and frequency were similar, the time to onset of symptoms varied widely, ranging from a minimum of 4 weeks to a maximum noted duration of 5 months. Recovery of their HPA axis occured within several months (~ 5.1). 48.8% of the patients described in literature required exogenous steroids, a finding similar to our cohort. All patients on presentation had undetectable serum cortisol which increased to an average 60 minute cortisol of 18.45mcg/dL at the time of resolution with complete symptom recovery.

Conclusion:

Awareness and strict pharmacovigilance is necessary when prescribing exogenous steroids to patients on HAART. Missing HPA axis suppression could have potentially disastrous consequences. Furthermore, the overlap of symptoms with PI associated lipodystrophy may sometimes delay diagnosis. We advocate a high clinical suspicion for IC in patients on HAART who receive any formulation of exogenous steroids. In tandem with the increasing life expectancy of patients living with HIV, age related health problems are also on a rise in this subgroup of patients. Hence, presentations similar to our cohort of patients are, now, more likely to be encountered in various clinical settings with steroid exposure.

 

Nothing to Disclose: HKD, AT, JH

31385 13.0000 SAT 411 A Cushing's Syndrome in Patients with HIV and Intraarticular Steroid Expsoure 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Mariana Soledad Gonzalez Pernas1, Soledad Sosa1, Joanna Milena Márquez Fernández2, Marcos Manavela3, Graciela Cross4 and Karina Danilowicz*5
1Hospital de Clínicas "José de San Martín" Universidad de Buenos Aires, 2Universidad de Antioquia, 3Consultorios de Endocrinología Dr Manavela, Caba, Argentina, 4Hospital de Clínicas “José de San Martín” Universidad de Buenos Aires, Argentina, 5Hospital de Clínicas “José de San Martín” Universidad de Buenos Aires., Buenos Aires, Argentina

 

Prolactin-secreting adenomas (PA) are the most frequent pituitary adenoma, accounting for 40-60%. Incidence prevails in young females (F), between 25-35 years old (yo) and at an older age in men (M). The purposes of this report were to analyze the presentation of PA in a cohort of patients and the therapeutic outcomes.

Data was retrospectively collected from clinical records of patients followed up between June 1992 and May 2016. Tumor size (TS, MI < 10 mm, MA ≥ 10mm) and basal prolactin levels (bPRL, ng/ml) were registered. Biochemical and radiological responses were evaluated during the follow-up (F/U).

Response to dopaminergic agonists (DA) was defined as 50% reduction of TS and/or PRL. Resistance (R) was considered as the absence of response despite CBG dose > 3.5 mg/weekly (w). Statistical software corresponded to SPSS 20.0

Among 1040 patients with pituitary adenomas, 209 PA (19.8%) were identified: 60.2% MA (n=124) and 39.8% MI (n=82). Gender distribution according to TS was 70 F and 54 M in MA and 75 F and 7 M in MI (p<0.001). 99 patients were included for analysis of F/U: 71 F (29.4±12.3 yo) and 28 M (40.6±13.8 yo) (p<0.001 regarding gender and age); 68.7% were MA (23±12.8 mm) and 31.3% MI (5.7±1.8 mm). Mean bPRL was 2707.6±6564.4 (90-33000) in MA and 120.6±84.5 (54.4-349) in MI.

After age subgroup distinction (<25 vs ≥ 45 yo), significant differences were found regarding TS (p=0.02) and bPRL (p=0.03).

The most common initial complaints were menstrual abnormalities 50%, galactorrhea 30.4%, visual defects 27.9%, headache 19.6%, infertility 15.7% and decreased libido 8.8%.

As initial treatment (T) 81.8% received CBG and 18.2% BEC, with median dose of 1 (0.25-13) mg/w and 5 (1.25-20) mg/day, respectively. Mean duration of T was 41.9±36.4 months (6-204).

Treatment achieved PRL normalization in 87.8% (n=87) and TS reduction in 48.5% (n=48). Accordingly to age subgroups, no differences were present regarding T duration, complete tumor disappearance and PRL normalization.

R was found in 15.1% (n=15), without differences in relation to age, contrary to bPRL (5360.9±9236.5 vs 1239.1±4350; p<0.001) and TS (28.9±17 vs 15.6±11.6; p=0.002). A higher proportion corresponded to MA (p=0.002) and M (p=0.002). T withdrawal was reached in 36.4% (n=36), with MI preponderance and recurrence documentation in 33.3% (n=12).

In discrepancy with most reports, a fewer PA frequency was found in this cohort, with predominance of MA, since ours is a neurosurgical reference centre. As expected, the majority of patients achieved response with low CBG doses, regardless of TS, with PRL reduction and TS shrinkage. Younger patients presented with larger TS and higher bPRL; however no differences were established in T response. In concordance with most important series, CBG R was uncommon, prevailing in MA and M, associated with higher bPRL and larger TS. Recurrence observed in this cohort was 33.3%

 

Disclosure: MM: , Novartis Pharmaceuticals. Nothing to Disclose: MSG, SS, JMM, GC, KD

29703 14.0000 SAT 412 A Clinical and Biochemical Characteristics of a Cohort of Patients with Prolactinomas at a University's Hospital 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Alejandro L Arregger*1, Rocio Sanchez2, Estela Maria Cardoso3, Maria Laura Saglio4, Carolina Muchnik4 and Liliana N Contreras5
1University of Buenos Aires, Buenos Aires CF, Argentina, 2IDIM A Lanari. University of Buenos Aires, 3IDIM- CONICET, 4University of Buenos Aires, CABA, Argentina, 5University of Buenos Aires; IDIM-CONICET, Buenos Aires, Argentina

 

Increased susceptibility of the aging brain to psychosocial stressors has been associated with harmful effects of cortisol on learning and memory. The purpose of this study was to evaluate the relationship between lifestyle, HPA activity and memory in aging women. Fourteen women aged 70±5 yo were studied. They had no history of stroke, primary dementia, major depressive disorder, hepatic or renal failure, antipsychotic drugs, major tranquilizers, general anesthesia during the last year, or drugs that may affect the HPA axis. Once completed the Beck inventory (BDI-II), they were divided in two groups: A (mild depression symptoms, score 9.9±3.6) and B (moderate to severe depression symptoms, score 25±5). All subjects obtained whole saliva samples to assess circadian rhythm of salivary cortisol (SAF) at 8.00 H (SAF8) and 23.00 H (SAF23)( normal variation: SAF23 ≤ 3.8 nM and less than 50% of SAF8). The HPA suppressibility was evaluated by the overnight 1 mg dexamethasone suppression test (DST). Salivary cortisol after DST was determined at 8.00 H (SAF8dex) and 16.00 H (SAF16dex). (normal DST: SAF8dex and SAF16 dex ≤ 2.0 nM). Quality of life (QL) and lifestyle (LS) were investigated by self-administered questionnaires (SF36 and LS). Coding, storage and retrieval of episodic memory; logical memory, working memory, semantic memory, visuospatial perception and attention were assessed in two weekly sessions. The protocol was approved by the Ethics Committee of the IDIM A. Lanari and all subjects gave their written informed consent. Salivary cortisol was determined by RIA and expressed in nM. Statistical analysis was performed using Mann-Whitney, Spearman and Campbell tests (p<0.05 was considered significant). SF36 and LS scores ranged from 0 to 100, higher values were associated to better mental health. Results: Diurnal cortisol variation and suppressibility in A ( SAF8: 9.0±2.3; SAF23: 1.1 ± 1.0; SAF8dex: 0.83±0.3 and SAF16dex: 0.7 ± 0.2 ) were not different than B (SAF8: 6.4±1.8; SAF23: 1.0 ± 1.25; SAF8dex: 0.62± 0.2 and SAF16dex: 0.7 ± 0.2); p >0.1 in all cases. A positive and significant correlation was observed between SAF8dex and SAF16dex in A (r = 0.738) and B (r= 0.889); p<0.04 for both. Mental summary of QL and LS in A were significantly higher (49.6 ± 5.5 and 77.7±22.0) than in B (38.6±10.6 and 40.0); p<0.046. The following aspects of memory showed low performance in the fourteen women: logical in 50% of cases, episodic in 21%, semantic in 14% and working memory in 7%. Attention was reduced in 28%, while visuospatial perception was adequate in all.
Conclusion: Social isolation was associated with worsening of emotional well-being without effects on HPA axis. Short and long term memory impairment highlights the need to investigate elderly patients without dementia in order to prevent further damage.

 

Nothing to Disclose: ALA, RS, EMC, MLS, CM, LNC

30909 15.0000 SAT 413 A Lifestyle, Cortisol Dynamics and Memory in Aging Women 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Keisuke Kakizawa*, Yutaka Okawa, Miho Yamashita and Yutaka Oki
Hamamatsu University School of Medicine, Hamamatsu, Japan

 

[Background]

In patients with Cushing’s syndrome, we have to use metyrapone frequently to control severe hypercortisolemia before surgery. Theoretically, plasma ACTH increases after metyrapone treatment in patients with Cushing’s disease (CD). However, we have experienced that plasma ACTH decreased after its treatment in some patients with CD. In this study, we investigated the background of those patients retrospectively.

[Methods]

Fifteen patients with Cushing’s disease (CD) were divided into two groups. Eight patients showed that plasma ACTH increased one week after metyraponse initiation (group A). On the other hand, seven patients showed that plasma ACTH decreased after metyrapone (group B). The clinical backgrounds were compared between two groups.

[Results]

The doses of metyrapone between in group A and B were not different (3000 ± 755 vs, 2000 ± 800 mg/day), respectively. Urinary free cortisol excretions between in both groups were not different (490 ± 618 vs. 382 ± 1368 μg/day). Plasma ACTH levels were greater in group B than in group A (138 ± 49 vs. 186 ± 149 pg/mL, P<0.05). Plasma ACTH responses to CRH were greater in group A than in group B (401± 304 vs. 39 ± 2.9% of basal levels, P< 0.03). The sizes of pituitary adenomas were significantly larger in group B than group A (25 ± 9.4 vs. 6 ± 4.0 mm in diameter, P<0.005).

[Discussion and Conclusion]

ACTH secretion from pituitary is negatively regulated by glucocorticoid. Therefore, metyrapone, a 11 beta hydroxylase inhibitor, theoretically decreases plasma cortisol and subsequently plasma ACTH level increases. From our results, CD with macroadenoma and low ACTH response to CRH may show the ACTH suppression by metyrapone. These suggest that glucocorticoid unexpectedly stimulate ACTH secretion in some patients with CD.

 

Nothing to Disclose: KK, YO, MY, YO

30091 16.0000 SAT 414 A Effects of Metyrapone on ACTH Secretion in Patients with ACTH-Dependent Cushing’s Syndrome 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Nicholas Krasnow*, Owen Bersot, Winston Weiler, Bradley Pogostin, James Haigney, Marion Kessler, Michael Tenner and Richard A Noto
New York Medical College, Valhalla, NY

 

Background: The progression of PAs and the effect of GH treatment has, to our knowledge, not been investigated.

Objective: To show longitudinally the change in volume (Vol) and percentage of the gland occupied (POGO) of nonfunctioning PAs in children treated with GH.

PTS/Methods: Children identified to have a PA who underwent post-contrast MRI with 1-2mm spatial resolution at the Div. of Neuroradiology at NYMC between 2007-16 were considered for inclusion. 16 patients (PTS) were identified who met these criteria. We excluded 8 PTS without follow-up (f/u) MRIs, 3 with functioning adenomas, and 1 with hydrocephalus. The 4 included PTS had nonfunctioning incidental PAs and were treated for GHD with GH. For those included, ages ranged from 4-12 YRs at baseline (mean 9.23±3.32YRs, median (MD) 10.65 YRs). Time between scans ranged from .41-2.24 YRs (mean .98±.49 YRs, MD .96 YRs). Number of scans ranged from 2-9 (mean 5.5±2.89, MD 5.5). Pituitary (Pit) and PA Vols were calculated with the ellipsoid formula (LxWxH/2).The POGOs of the PAs were calculated as PA Vol/Pit Vol x 100. PAs with an initial width 10 mm were classified as a macroadenoma (MAAD), and those with a width <10 mm were classified as a microadenoma (MIAD).

Results: 2 PTS were found to have a MIAD, and 2 PTS were found to have a MAAD. PA Vol increased in 2 PTS and decreased in 2 PTS. One MIAD resolved. POGO decreased in 3/4 PTS. Change in PA Vol between f/u ranged from -52.0-68.4mm3 with a mean of 2.72±32.41mm3 (MD 3.69mm3). Rate of PA growth ranged from -114.05-66.74mm3/YR with a mean of 1.31±41.88mm3/YR (MD 3.46mm3/YR). Change in POGO between f/u ranged from -15.25-12.80% with a mean of -2.10±8.09% (MD -2.53%). Rate of change (RC) in POGO ranged from -27.25-14.58%/YR with a mean of -3.01±10.63%/YR (MD -2.85%/YR). For the MIADs, change in PA Vol between f/u ranged from -25.77-40.24mm3 with a mean of 5.35±28.78mm3 (MD -.26mm3), rate of PA growth ranged from -40.87-45.85mm3/YR with a mean of 2.64±35.98mm3/YR (MD 0.21mm3/YR), change in POGO between f/u ranged from -14.20-12.80% with a mean of -1.42±9.47% (MD -3.11%), and RC in POGO ranged from -17.21-14.58%/YR with a mean of -1.97±11.12%/YR (MD -3.65%/YR). For the MAADs, change in PA Vol between f/u ranged from -51.96-68.40mm3 with a mean of 1.40±35.23mm3(MD 4.48mm3), rate of PA growth ranged from -114.05-66.74mm3/YR with a mean of .64±46.06mm3/YR (MD 7.97mm3/YR), change in POGO between f/u ranged from -15.25-12.53% with a mean of -2.44±7.75% (MD -2.25%), and RC in POGO ranged from -27.25-12.22%/YR with a mean of -3.53±10.84%/YR (MD -2.85%/YR).

Conclusion: Pediatric PAs demonstrate variable changes in size. We found minimal differences between the progression of MIADs and MAADs. POGO tended to decrease, so Pit growth outpaced PA growth. The variable growth during GH therapy suggests that GH plays no role in the evolution of PAs. We ask any investigator with similar PTS to contact us to develop a comprehensive database.

 

Nothing to Disclose: NK, OB, WW, BP, JH, MK, MT, RAN

29381 17.0000 SAT 415 A The Natural History of Non-Functioning Pituitary Adenomas (PAs) in Children Treated with Growth Hormone (GH): A Case Series 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Hande Mefkure Ozkaya*1, Tugce Apaydin2, Fatma Ela Keskin3 and Pinar Kadioglu4
1Cerrahpaşa Medical School, University of İstanbul, istanbul, Turkey, 2Cerrahpasa Medical School, ISTANBUL, Turkey, 3Cerrahpasa Medical School, University of Istanbul, Istanbul, Turkey, 4Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey

 

Purpose: To report the general characteristics of patients with primary and secondary hypophysitis and to evaluate treatment and long-term follow-up results.

Methods: Medical charts of 2596 patients who were followed-up at University of Istanbul, Cerrahpasa Medical School, Endocrinology and Metabolism Outpatient Clinic between 2007-2016 with a diagnosis of pituitary adenoma, empty sella, and hypopituitarism were reviewed retrospectively. A total of 14 patients (9F/5 M) were diagnosed with hypophysitis.

Results: The mean age of patients at diagnosis was 39.14 ±17.7 years. Median follow-up time was 45 (IQR: 13.5-61.2) months. Four out 7 female patients were postmenauposal and three were nulliparous. All but one patient did not have an accompanying autoimmune disease. The most common symptoms and signs were headache (42.9%) and diabetes inspidus (42.9%), followed by hypopituitarism (35.7%). Four out of 14 patients had secondary hypophysitis (3 patients with histiocytosis X, 1 patient with neurosarcoidosis). The remaining 10 patients had primary hypophysitis (8 patients with lymphocytic hypophysitis, 2 patients with xanthomatous hypophysitis). A total of 9 patients were operated. Eight out of 9 patients had a presumptive diagnosis of pituitary macroadenoma. These patients had the histopathological evidence of hypophysitis. One patient was operated due to the mass effect of the lesion .The presumptive diagnosis for this case was lymphocytic hypophysitis which was confirmed by histopathology. Five patients were started on glucocorticoid therapy. The starting doses for metylprednisolone were 60 mg/d in three patients and 120mg/d in two patients. The glucocorticoid dose was tapered in 2 months. The clinical response was assessed in 4 patients . Half of the patients were good responders. Avascular necrosis of femoral head was the most common complication (40%) after glucocorticoid therapy. Two patients with primary hypophysitis required gama-knife or cyber-knife radiosurgery after failure of surgery and glucocorticoid therapy . Another patient with histiocytosis X received gama-knife radiosurgery after operation. The response to radiosurgery was good in all of the patients. No significant side effect was detected. Anterior and posterior pituitary hormone deficiencies were still present at the last follow-up visit in all of the patients who had one or more pituitary hormone deficiencies at the time of diagnosis.

Conclusisons: Hypophysitis, albeit rare, may cause severe pituitary dysfunction which tend to persist during the disease course. Misdiagnosis is frequent. Disease’s pathogenesis might involve mechanisms other than autoimmunity in some patients. A considerable number of patients may require combined therapies which might cause serious side effects.

 

Nothing to Disclose: HMO, TA, FEK, PK

32214 18.0000 SAT 416 A Characteristics of Patients with Primary and Secondary Hypophysitis: A Single Center Experience 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Samir Hardevsingh Saini*1, Jaya Bhanu Kanwar1, Subhash B Yadav2, Shruti Gupta1, Sanjay Behari1 and Eesh Bhatia1
1Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, 2Sanjay Gandhi Postgraduate Institute of Medical Sciences

 

Abstract: The results of trans-sphenoidal surgery (TSS) in Cushing’s disease (CD) vary widely depending upon patient characteristics as well as surgical experience. Patients in low-middle income countries such as India are often referred late for surgery which may affect outcome. We studied remission rates and endocrine deficiencies after TSS in patients with CD presenting to an academic centre in India. Sixty consecutive patients (45 females, median age 24.5 years) who underwent TSS between January 2000-2015 were studied. The median (range) duration of follow-up was 40 (3-138) months. Initial and long-term remission and relapse rates and pituitary hypofunction post-TSS were evaluated. Eighteen (30%) patients harboured macroadenomas. Twenty-eight (47%) patients achieved remission in the immediate post-operative period (8 AM serum cortisol <140 nmol/l). However, remission rate was higher at 6 months (72%). At 1 year 70% of patients and at final follow-up [median 40 (range 3–138) months], 58% of patients were in remission. No pre- or post-surgical variables were consistently associated with remission except for the immediate post-operative 8 AM serum cortisol. Seven (18%) patients relapsed during follow-up, including 5 patients who had serum cortisol <140 nmol/l immediately after surgery. Mortality occurred in 5 (8%) of patients, all with persistent disease or relapse. Twelve (25%) patients newly developed hypothyroidism and 1 (1.6%) patient developed amenorrhoea after TSS. Thus, remission rate at six months was higher than immediately after TSS. A significant proportion of patients relapsed, thus necessitating life-long follow-up. New-onset hypothyroidism was frequent after TSS.

 

Nothing to Disclose: SHS, JBK, SBY, SG, SB, EB

32546 19.0000 SAT 417 A Long-Term Outcome of Trans-Sphenoidal Surgery for Cushing’s Disease in Indian Patients 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Raquel Villavicencio*1 and Melissa Cavaghan2
1Indiana University School of Medicine, Indianapolils, IN, 2Indiana University School of Medicine, Indianapolis, IN

 

Introduction

Cyclical Cushing’s syndrome (CCS) can be an elusive diagnosis and may go unrecognized for years, even after appropriate endocrine evaluation. We illustrate a case in which serial salivary cortisol levels were used to make the diagnosis of CCS.

Clinical Case

A 36 year old woman presented with one year history of fifty pound weight gain, irregular menses, hirsuitism, irritability, fatigue and proximal muscle weakness. She had already undergone extensive testing, which collectively did not clearly establish Cushing’s. Five of twelve dexamethasone (Dex) suppression tests (DST) were abnormal, ranging from 0.6-6 µg/dL (<1.8). Fourteen of eighteen urine free cortisols (UFC) were elevated, ranging from 29-139.7 µg/24h (4-50). A Dex-CRH test showed a cortisol of 2.9 µg/dL (<1.8) after two days of Dex and 30-minute cortisol peak of 5.7 µg/dL (>20% rise is consistent with Cushing’s disease). However, 48-hr DST suppressed serum cortisol (1.1 µg/dL) and UFC (9.5 µg/24h). She was normotensive (111/55) but obese (81.6 kg, BMI 32.7), with facial plethora, rounded face, subtle cervical fat pads, proximal muscle weakness and mild hypertrichosis. There was no acanthosis nigricans, supraclavicular fat pads, edema, purple striae or hyperpigmentation.

Late night salivary cortisols over ten months were intermittently above normal, ranging from <0.04-0.97 µg/dL (0-0.1), but never long enough for localization testing. During testing, 31% of salivary cortisols were above normal. ACTH levels were never suppressed. MRI showed a 3 mm adenoma in the left inferior aspect of the pituitary gland. A 10 µg desmopressin stimulation test was also performed. ACTH increased by 131% and cortisol increased by 34%, consistent with Cushing’s disease.

At transsphenoidal exploration, intraoperative smear showed a monomorphic population of cells compatible with adenoma. However, final pathology showed adenohypophysis tissue with patchy areas of expanded acini. The cells in these areas stained with ACTH and CM5.2 with the final diagnosis of corticotroph hyperplasia. Post-op day one and two AM cortisols were 33 and 9 µg/dL respectively and she ultimately developed relative adrenal insufficiency which responded to hydrocortisone. Off hydrocortisone, salivary cortisols ranged from undetectable to occasionally elevated, in the range of 0.12-0.19 µg/dL. A repeat desmopressin stimulation test was essentially flat.

Conclusion

Here we demonstrate the effective use of serial salivary cortisols in diagnosing CCS. Second, we illustrate the utility of the desmopressin stimulation test in the work-up of ACTH-dependent Cushing’s syndrome. Although not necessary in the routine evaluation of Cushing’s syndrome, when faced with challenging diagnostic dilemmas such as that presented by CCS, it can be a valuable, additional tool to differentiate between Cushing’s disease and ectopic ACTH secretion.

 

Nothing to Disclose: RV, MC

31609 20.0000 SAT 418 A Serial Salivary Cortisol and Desmopressin Stimulation Testing in the Diagnosis of Cyclical Cushing’s 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Adrenal HPA Axis Saturday, April 1st 3:00:00 PM SAT 399-421 9477 1:00:00 PM Pituitary Disorders Poster


Elizabeth Rendina-Ruedy*1, Anyonya R Guntur2, Brenda J Smith3, Michael P Czech4 and Clifford J Rosen5
1Maine Medical Center, 2Maine Medical Center, Scarborough, ME, 3Oklahoma State University, 4University of Massachsetts Medical School, Worcester, MA, 5Maine Medical Center Research Institute, Scarborough, ME

 

Type 2 diabetes mellitus (T2DM) is a major public health problem that results in an ~2 fold increase in fracture risk independent of bone mineral density (BMD). While the paradoxical relationship between BMD and fracture has perplexed researchers and clinicians alike, one potential explanation is the apparent decrease in bone turnover. Specifically, the high energetic demand bone formation requires has led to a renewed interest in the intracellular metabolism of osteoblasts. Therefore, we hypothesized that the decrease in bone formation associated with T2DM is a function of impaired metabolic capacity of the osteoblast. To test this hypothesis we utilized an in vivo mouse model of diet-induced obesity to model the metabolic perturbations associated with T2DM, along with ex vivo and in vitroprimary bone marrow stromal cell cultures (BMSCs). Our results demonstrate that osteoblasts from mice on a high fat diet had lower extracellular acidification rates (ECAR) and oxygen consumption rates (OCR) compared to control osteoblasts, indicative of a more quiescent cell compared to the energetic profile from the control osteoblasts. Interestingly, we observed the accumulation of intracellular lipid droplets in bone-lining osteo-progenitor cells from mice on the high fat diet, which led us to further explore whether these lipid droplets served as a readily available metabolic substrate during osteoblast differentiation. Indeed blunting lysosomal function with bafilomycin A1 (BafA1) or chloroquine (CQ) resulted in increased accumulation of neutral lipid droplets in BMSCs. Accordingly, when either lysosomal lipolysis (BafA1 or CQ) or mitochondrial fatty acid transport (etomoxir or Eto) were impaired OCR was significantly reduced in early osteogenic cells, suggesting that intracellular lipids were capable of providing endogenous fatty acid substrates for ATP generation. Collectively, these data are the first to demonstrate that osteo-progenitor cells have the ability to store, degrade, and utilize lipid droplets. Furthermore, these data suggest that the ability for osteo-progenitor cells to mobilize fatty acids from lipid droplets is impaired during T2DM, contributing to decreased bone formation and the subsequent increase in fracture risk.

 

Nothing to Disclose: ER, ARG, BJS, MPC, CJR

32361 1.0000 SAT 338 A Intracellular Lipid Droplets Serve As a Source of Energy Substrates to Support Osteoblast Function 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Agnes Choppin, Daniel Bedinger, Rachel Hunt, Catarina Tran, Sujeewa Wijesuriya, Robyn Cotter, Elizabeth Pongo, Robert Shimizu, Jessica Chen, Khanh Pham, Amer Mirza, Kirk W. Johnson*, Toshihiko Takeuchi and Raphael Levy
XOMA Corporation, Berkeley, CA

 

The PTH1R receptor is one of the family B GPCRs and the primary receptor of two ligands, parathyroid hormone (PTH) and parathyroid related protein (PTHrP). Hypercalcemia can occur when elevated levels of PTH, as seen in primary hyperparathyroidism (PHPT), or elevated levels of PTHrP, as seen in humoral hypercalcemia of malignancy (HHM), leading to excessive activation of the PTH1R receptor. A potent and long acting receptor antagonist could reverse hypercalcemia in these conditions. We therefore have developed a highly potent PTH1R antagonist monoclonal antibody for the treatment of disorders related to elevated PTH or PTHrP. This antibody was discovered using fully human phage display libraries and selected for potent binding to and antagonism of the human and murine PTH1R. PTH1R antagonism by our antibody against both the PTH and PTHrP peptides was determined by cAMP accumulation in osteosarcoma cell lines Saos-2 (human) and UMR106 (rat). The antibody showed roughly equivalent inhibition of both the human and murine receptors. We also demonstrated in vitro that this antibody inhibited both PTH- and PTHrP-induced osteoclast differentiation by greater than 10-fold in a Saos-2 and human monocyte co-culture system: the PTH1R receptor is expressed on osteoblasts and osteocytes, and stimulation by PTH or PTHrP leads these cells to increase the expression of RANKL and other factors. These drive the differentiation and activation of bone resorbing osteoclast cells, which release calcium and decrease bone density. In vivo proof-of-concept was obtained in rodent models where hypercalcemia was established in rats by SC infusion of PTH or PTHrP via osmotic pumps. IV administration of 2 and 10 mg/kg antibody dose-dependently reduced serum calcium levels by a minimum of 2 mg/dL within 48 hours of dosing. Additionally, the antibody was tested in a model of HHM wherein mice developed hypercalcemia following implantation of mouse colon tumor cells C26. In this tumor model, the antibody given at 10 mg/kg IV was capable of completely reversing hypercalcemia within 24 hours. The pharmacokinetic parameters of the antibody were also defined in rats.

This highly potent PTH1R receptor antagonist antibody has the potential to become a valuable therapeutic agent in a variety of indications including hyperparathyroidism, humoral hypercalcemia of malignancy, and, potentially, the PTHrP-mediated cachexia seen in some cancers.

 

Disclosure: AC: Employee, XOMA Corporation. DB: Employee, XOMA Corporation. RH: Employee, XOMA Corporation. CT: Employee, XOMA Corporation. SW: Employee, XOMA Corporation. RC: Employee, XOMA Corporation. EP: Employee, XOMA Corporation. RS: Employee, XOMA Corporation. JC: Employee, XOMA Corporation. KP: Employee, XOMA Corporation. AM: Employee, XOMA Corporation. KWJ: Vice President, XOMA Corporation. TT: Employee, XOMA Corporation. RL: Employee, XOMA Corporation.

30409 2.0000 SAT 339 A A Novel Anti-PTH1R Receptor Antagonist Monoclonal Antibody Reverses Hypercalcemia Induced By PTH or PTHrP: A Potential Treatment of Primary Hyperparathyroidism and Humoral Hypercalcemia of Malignancy 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


James Koh*1, Thomas J Weber1, Samantha Thomas2, Joyce Hogue1 and Julie Ann Sosa3
1Duke University Medical Center, Durham, NC, 2Duke University, 3Duke University, Durham, NC

 

Bone loss and fractures are a major source of morbidity in patients with primary hyperparathyroidism (PHPT). A clinically distinct subset of PHPT patients with a more severe disease phenotype characterized by bone loss, fractures, recurrent nephrolithiasis, and other physical dysfunctions has been recognized for some time, yet the underlying reasons for this disparity in clinical presentation remain unknown. To identify new mechanistic indices that could inform personalized post-operative management of PHPT, we developed a comprehensive clinical registry of PHPT patient information and related these data to live-cell functional assessment of parathyroid tumor biochemical signaling capacity. We assembled data from 228 patients undergoing parathyroidectomy for PHPT at our institution, aligning pre-, peri-, and post-operative records of patient disease course with demographic, clinical, and pathological information. Calcium sensing capacity in parathyroid tumors was evaluated in an unselected series of 71 patients from the registry. Intracellular calcium flux was recorded ex vivo at single cell resolution in intact tumor specimens from these patients as a readout of calcium sensitivity, expressed as the concentration required for half-maximal response (EC50). Parathyroid tumors segregated into two distinct groups of calcium responsiveness. One group (n=25) demonstrated a mean calcium EC50 value of 2.48 mM [95% CI: 2.43 – 2.54], consistent with reference normal activity. In contrast, a second group (n= 46) displayed attenuated sensitivity with a mean calcium EC50 value of 3.48 mM [3.41 – 3.55]. The bimodal distribution of EC50 values in the overall patient cohort was consistent with mechanistically separable sub-populations of parathyroid tumor behaviors. Retrospective analysis of the clinical registry data using Wilcoxon Rank Sum and Fisher’s Exact tests suggested that patients whose tumors displayed reduced calcium sensitivity (high EC50) presented with significantly more pronounced radiographic evidence of pre-operative BMD deficit. BMD as measured by lowest T-score was -0.9 [-2.1 - -0.4] for patients in the low EC50 group compared to -2.7 [-3.4 - -1.9] in the high EC50 group (p < 0.001). After adjusting for gender, 25 OH vitamin D level, age, BMI, and pre-operative iPTH, lowest T-score and calcium EC50 were found to be inversely correlated, with a partial Spearman correlation coefficient of -0.351 (p=0.02). This observation challenges the predominant paradigm of PHPT as an etiologically monolithic disorder and implies that a distinction between tumor-intrinsic and tumor-extrinsic drivers of PHPT could underlie differences in PHPT disease course, provenance, and outcome. Assessment of parathyroid tumor biochemical behavior may be a useful predictor of disease severity, bone density loss, and the potential for post-parathyroidectomy BMD re-accrual.

 

Disclosure: JAS: Member, Data Monitoring Committee, Medullary Thyroid Cancer Consortium Registry, Novo Nordisk, Astra Zeneca, GlaxoSmithKline, Eli Lilly. Nothing to Disclose: JK, TJW, ST, JH

30466 3.0000 SAT 340 A Impaired Calcium Sensing in Parathyroid Tumors Is Selectively Associated with Lower Bone Mineral Density in Patients with Primary Hyperparathyroidism 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Aaliyah Riccardi*1, Justin Bellizzi2, Jessica Costa-Guda1 and Andrew Arnold1
1University of Connecticut School of Medicine, Farmington, CT, 2University of Connecticut School of Medicine

 

Benign parathyroid adenomas are the most common cause of primary hyperparathyroidism while malignant parathyroid carcinomas account for less than 1% of hyperparathyroid cases. Making the distinction between parathyroid adenomas and parathyroid carcinomas on histopathologic examination of a primary tumor can be particularly difficult, and a diagnosis of parathyroid carcinoma may only become clear at a later time, when the rigorous diagnostic criteria of local invasion of surrounding tissues and/or distant metastases are fulfilled. Thus, new insights into their respective molecular bases could result in more precise and efficient diagnostic discrimination between parathyroid adenomas and parathyroid carcinomas. Current understanding of the genetic underpinnings of parathyroid adenomas includes driver mutations in the MEN1 tumor suppressor, the oncogene CCND1 (encoding cyclin D1) and, in small percentages each, EZH2, ZFX, and several cyclin-dependent kinase inhibitor (CDKI) genes, while in parathyroid carcinoma the only established recurrent driver has been inactivating mutation of CDC73/HRPT2. Recently, a gain-of-function mutation in PIK3CA was identified by Kasaian et al. in a single parathyroid carcinoma subjected to whole genome sequencing (1), and by Pandya et al. as a recurrent finding in a subset (<20%) of locally invasive or metastatic parathyroid carcinomas (2). PIK3CA, a recognized driver oncogene in many human malignancies including breast cancer, encodes the p110-alpha subunit of PI3-Kinase, controlling cell proliferation and apoptosis via phosphorylation of AKT. Known PIK3CA mutational hotspots in codons 111, 542/545, and 1047 overlap those in the described parathyroid carcinomas. To assess these mutations’ potential specificity for malignant, as opposed to benign disease, we PCR-amplified and Sanger sequenced those regions of the PIK3CA gene in genomic DNA from 81 typical, sporadic parathyroid adenomas. In 80 of the 81 tumors, there were no known activating hotspot mutations or other mutations in the immediately flanking regions of the amplicons. One parathyroid adenoma (1.2%) had a somatic, heterozygous, activating H1047R mutation. These data suggest that PIK3CA activating mutations in the specified major hotspots are preferentially associated with malignant rather than benign parathyroid neoplasia, but larger sample sizes must be analyzed to assess their potential diagnostic utility. Furthermore, exploration of PIK3CA mutations' role in parathyroid neoplasia could result in insights into pathogenesis and improved therapy through precision targeting.

 

Nothing to Disclose: AR, JB, JC, AA

32418 4.0000 SAT 341 A PIK3CA Mutational Analysis of Parathyroid Adenomas 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Kelly Brewer*1, Isabel Nip1, Jessica Costa-Guda2 and Andrew Arnold1
1University of Connecticut School of Medicine, Farmington, CT, 2University of Connecticut School of Dental Medicine, Farmington, CT

 

The molecular mechanisms underlying the tumorigenesis of sporadic parathyroid adenomas are incompletely understood. Overexpression of the oncoprotein cyclin D1, encoded by CCND1/PRAD1, has been documented in up to 40% of sporadic parathyroid adenomas; however, known aberrations in the gene encoding cyclin D1 account for less than half of these cases, and thus far no other potential mechanisms of cyclin D1 overexpression have been identified in this tumor type. Degradation of cyclin D1 is tightly regulated and genetic alterations of FBXO4, which encodes one essential member of the cyclin D1-degrading complex, have been identified in a number of human tumors (1). Genetic aberrations in FBXO4 and CCND1 appear to be mutually exclusive, strongly suggesting a common pathway. We postulated that genetic inactivation of FBXO4 and the consequential increase in stability of cyclin D1 may contribute to the development of sporadic parathyroid adenoma. We therefore sought to identify FBXO4 coding region mutations by direct Sanger sequencing of genomic DNA samples isolated from sporadic parathyroid adenomas, as well as identify FBXO4 copy number changes by loss of heterozygosity. The entire coding region and intron-exon boundaries of FBXO4 were examined in a cohort of seventy-six typically presenting, sporadic parathyroid adenomas. In addition, allelic imbalance was assessed by analysis of two microsatellite markers flanking the FBXO4 genomic region in seventy-one of the seventy-six samples (those for which matched germline DNA was available). No clearly inactivating or cancer-associated genetic alterations (e.g. early stop codons, frameshifts, indels, etc.) were found. One known polymorphism, rs144096644, was identified in one sample; however, this SNP does not effect any changes in amino acid sequence and is not associated with cancer. A second sample exhibited loss of one copy of the proximal microsatellite yet retained two copies of the distal microsatellite, suggesting the possibility of partial or whole deletion of FBXO4, but not contradicting the possibility that the gene may have remained intact. The absence of intragenic mutations in FBXO4, as well as the absence or exceedingly low frequency of allelic loss in the surrounding genomic region, suggests that such aberrations do not commonly contribute to the development of sporadic parathyroid adenoma. However, because such intragenic mutations could be rare, a significant role for cyclin D1 accumulation due inactivation of FBXO4 in parathyroid tumor formation cannot be ruled out. Further research must be done to elucidate the mechanism(s) of cyclin D1 accumulation in parathyroid adenomas in which CCND1 aberrations are not present.

 

Nothing to Disclose: KB, IN, JC, AA

31830 5.0000 SAT 342 A Mutational and Copy Number Analysis of Candidate Tumor Suppressor Gene FBXO4 in Sporadic Parathyroid Adenoma 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Said M Shawar*, Ahmad R Ramadan and Shazia Sabir
Arabian Gulf University, Manama, Bahrain

 

Hyperphosphatemic familial tumoral calcinosis (HFTC, OMIM 211900) is a rare autosomal recessive disorder. It is characterized by hyperphosphatemia, normal or elevated serum 1,25-dihydroxyvitamin D, and ectopic calcifications. Eight loss-of-function mutations in the amino fragment (N-fragment) of fibroblast growth factor-23 (FGF23) between residues 41-129 are implicated in causing HFTC. Recently, we established that high levels of inactive FGF23/S129F are present in the circulation of HFTC patients. To test whether phenylalanine substitution of serine 129 causes a 3D structural change in the hormone, we employed computer simulation modeling based on the crystal structure of human wild-type (WT) FGF23 (2P39). Our simulation data indicated that the substitution causes a visible structural change between the WT and the mutant hormone. We confirmed our computer simulation results using antibodies that recognize linear or conformational epitopes on the hormone. WT FGF23 from healthy individuals or transfected HEK293 cells were recognized by a monoclonal antibody that recognizes a discontinuous epitope on the native hormone. In contrast, the mutant hormone from HFTC patients or transfected HEK293 cells failed to bind the same monoclonal. Alternatively, affinity purified goat polyclonal antibodies generated against human FGF23 peptide 51-69 recognized all species of WT FGF23 and mutant hormone. Our results indicate that the inactivity by FGF23/S129F is associated with a conformational change at the fibroblast growth factor receptor/α-Klotho complex.

 

Nothing to Disclose: SMS, ARR, SS

31539 8.0000 SAT 345 A Conformational Changes Induced By Phenylalanine Substitution of Serine 129 Are Associated with Loss of Function in Fibroblast Growth Factor23/S129F 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Revathy Carnagarin*1, Arun M Dharmarajan2 and Crispin Dass3
1Curtin University, Perth, AUSTRALIA, 2Curtin University, Perth, WA, Australia, 3Curtin University, Perth, Australia

 

Pigment epithelium derived factor induces osteogenic properties in skeletal myocytes: PEDF upregulates osteogenic markers and enhances mineralisation mediated by 1/2Erk MAPK signalling in skeletal myocytes.

Revathy Carnagarina,b,c, , Arun M. Dharmarajana,c, Crispin R. Dassa,b

aCurtin Health Innovation Research Institute, Bentley 6102, Australia

bSchool of Pharmacy, Curtin University, Bentley 6102, Australia

cSchool of Biomedical Sciences, Curtin University, Bentley 6102, Australia

 

Bone regeneration is a complex physiological process that is currently addressed by a plethora of different strategies and autologous bone grafting continues to remain the gold standard. However, massive defects arising from skeletal abnormalities post trauma, infection and tumour resection necessitates the identification of further strategies in the form tissue engineering, gene therapy and potent osteo-inductive agents that could enhance the bone repair process. PEDF has a signatory effect on osteogenesis. PEDF gene defect results in osteogenesis imperfecta IV characterised by bone mineralisation defects and PEDF restoration improved bone mineralisation in murine models of osteogenesis imperfecta VI and normalised mineralisation defects in pluripotent stem cells derived from PEDF null patients [Belinsky et al 2016]. PEDF regulates the expression of osteoblastic genes, enhanced mineralisation in murine and human MSCs [Elahy et al 2016] and suppressed inhibitors of bone formation [Li et al 2013, 2015]. Muscle plays a vital role in bone regeneration by contributing satellite cells, muscle stem cells and growth factors and the use of muscle flaps to cover bone defects and prevent infections could be further improvised to support bone healing directly by using a suitable osteokine such as PEDF.

To study the potency of PEDF in this perspective, we analysed PEDF-treated mice and human skeletal myoblasts for osteogenic properties. PEDF treatment of skeletal myoblasts at a physiological concentration of 100nM induced the expression of osteogenic markers such as osteocalcin and alkaline phosphatase. PEDF activated Erk1/2 MAPK signalling which governed the expression of osteogenic markers and mineralisation. Additional analysis demonstrated PEDF as a potent osteogenic signal that induced osteogenesis independent of osteogenic supplements to convert the C2C12 myogenic differentiation pathway into osteoblast lineage. PEDF also enhanced mineral deposition in human primary muscle myoblasts. These effects of PEDF were tested in vivo using Balbc mice. This study provides new insights into the signalling and molecular aspects of PEDF to modulate the differentiation commitment of skeletal myocytes, and we speculate that this could pave the way for new strategies that could overcome the limitations of existing therapies to accelerate bone regeneration, or even to address skeletal disorders.

 

Nothing to Disclose: RC, AMD, CD

29490 9.0000 SAT 346 A Pigment Epithelium Derived Factor (PEDF) Induces Osteogenic Properties in Skeletal Myocytes: PEDF Upregulates Osteogenic Markers and Enhances Mineralisation Mediated By 1/2Erk MAPK Signalling in Skeletal Myocytes 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Manish Raisingani*1, Zhongbo Liu2, Tianzhen Han2, Emi Shimizu2 and Shoshana Yakar2
1New York University School of Medicine, New York, NY, 2New York University College of Dentistry, New York, NY

 

Eph receptors belong to a subfamily of receptor tyrosine kinases activated by membrane bound ligands called ephrins. Recent studies have shown that osteoblasts express the EphB4 receptor and it’s ligand ephrinB2 and B1, while osteoclasts express a few members of the ephrinBs, suggesting that these proteins are involved in bone modeling during growth.

Past studies have shown that parathyroid hormone (PTH) stimulates bone modeling via enhanced expression of the insulin-like growth factor-1 (IGF‐I) and the ephrinB2 and EphB4 in osteoblasts.

To define the interactions between PTH/IGF-1/Eph signaling pathways in bone, male mice at 4 weeks of age were injected 80 mcg/kg/day for 5 days. To our surprise we found 3 fold increase in the expression of Ephrin B1 in the femoral cortical shells from male mice, while the expression of ephrinB2 or EphB4 did not differ significantly between PTH treated and untreated groups. Thus, we used the osteoblast- and osteocyte-specific ephrinB1 knockout (KO) mice (using the osteocalcin-cre and the dentin matrix protein (DMP)-1-cre, respectively) to investigate their bone response to intermittent PTH treatment.

We used micro Computer Tomography (CT) to characterize the basal morphology of femurs dissected from male mice. We found decreases in tissue mineral density in cortical bone of the mid-shaft femur in both Osteocalcin-ephrinB1 (1.45 ± 0.05 g/cm3, p=0.01) and DMP-1-ephrinB1 KO mice (1.465 ± 0.05 mg/cm3, p=0.02) as compared to controls (1.64 ± 0.02 mg/cm3). Similarly, we found decreased bone mineral density in the trabecular bone assessed at the distal femur (Osteocalcin-eprinB1 0.147±0.005 p=0.004, DMP-1-ephrinB1 0.175 ± 0.02 p=0.06, and controls 0.248 ± 0.02 mg/cm3). However, cortical and trabecular bone morphology of males did not differ between the groups. Female DMP-ephrinB1 KO mice showed decreased total cross-sectional area (1.14 ± 0.09 vs 1.27±0.06 mm2, p = 0.02), polar moment of inertia (0.12 ± 0.03 vs 0.14± 0.01 mm4, p= 0.03), and marrow area (0.76 ± 0.03 vs 0.86 ± 0.06 mm2, p = 0.03) as compared to control mice with no significant difference in tissue mineral density. Female DMP-ephrinB1 KO mice did not show any trabecular bone phenotype.

Bone anabolic response to intermittent PTH treatment in Osteocalcin-eprinB1 and DMP-1-ephrinB1 KO mice is under investigation.

 

Nothing to Disclose: MR, ZL, TH, ES, SY

29832 10.0000 SAT 347 A Effects of ephrin B1 Gene Ablation in Osteoblasts or Osteocytes on Cortical and Trabecular Bone Morphology 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Kosuke Kimura, Nahoko Iwata and Fumio Otsuka*
Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

 

Osteoblasts undergo differentiation in response to various factors including growth factors and steroids. Bone mass is diminished in androgen- and/or growth hormone (GH)-deficient patients. Replacement of testosterone for male patients with androgen deficiency improves their bone density and architecture. These changes are mediated, at least in part, by conversion of testosterone to estradiol. GH replacement for male cases with GH deficiency also improves bone mineral density. Although it was shown that testosterone and GH act synergistically to induce protein synthesis and elicit anabolic effects, it has been recently reported that combined treatment for males with hypopituitarism did not improve bone parameters more than did treatment with testosterone alone. Hence, the functional relationship between androgen and GH and their combined and/or mutual effects on bone metabolism remain unclear. Here we investigated the mutual effects of androgen and GH on osteoblastic marker expression using mouse myoblastic C2C12 and osteoblast-like MC3T3-E1 cells. Combined treatment with dihydrotestosterone (DHT) and GH enhanced BMP-2-induced expression of Runx2, ALP and osteocalcin mRNA compared with the individual treatments in C2C12 cells. Co-treatment with DHT and GH activated BMP-2-induced Smad phosphorylation and Id-1 transcription in C2C12 cells but not in MC3T3-E1 cells. Insulin-like growth factor (IGF-I) mRNA level was amplified by GH and BMP-2 treatment and was restored by co-treatment with DHT in C2C12 cells. The mRNA level of the IGF-I receptor was not significantly altered by GH or DHT, while it was increased by IGF-I treatment. In addition, IGF-I treatment increased collagen-1 mRNA expression, whereas blockage of endogenous IGF-I activity using an anti-IGF-I antibody failed to suppress the effect of GH and DHT on BMP-2-induced Runx2 expression in C2C12 cells, suggesting that endogenous IGF-I was not substantially involved in the underlying GH actions. On the other hand, androgen receptor and GH receptor mRNA expression was suppressed by BMP-2 treatment in both cell lines, implying the existence of a feedback action. Collectively, the results showed that combined effects of androgen and GH facilitated BMP-2-induced osteoblast differentiation at the early stage by upregulating BMP receptor signaling.

 

Nothing to Disclose: KK, NI, FO

30154 11.0000 SAT 348 A Combined Effects of Androgen and GH on BMP-Induced Expression of Osteoblast Markers in C2C12 and MC3T3-E1 Cells 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Dalia Somjen*1, Sara Katzburg2, Orli Sharon1, David Hendel3, Gary H Posner4 and Naftali Stern5
1Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel, 2Tel aviv med ctr, Tel-aviv, Israel, 3Sharei Zedek medical center, 4The John Hopkins Univ, Baltimore, MD, 5Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel

 

Femarelle (F), a chemical derivative of the phytoestrogen daidzein (D), has an estrogen-like activity and activates human derived cultured female bone cells (hObs) which express receptors for estradiol-17β (E2; ERα and ERβ) and vitamin D (VDR). Estrogens and Vitamin D metabolites and analogs regulate cell proliferation (DNA) and energy metabolism through modulation of the specific activity of creatine kinase (CK). Pre- treatment with vitamin D less-calcemic analog: JKF 1624F2-2 (JKF) up-regulated responsiveness to E2 and to different estrogens via modulation of ERs mRNA expression. Estrogens, in turn, induce VDR and 25- hydroxy vitamin D3 1- α hydroxylase (1OHase) expression and 1,25(OH)2D3 (1,25D) synthesis. Here we compare the effects of F to those of D and E2 on DNA and CK, and examine whether or not these effects can be modulated by pre-treatment with the vitamin D analog JKF. We found: 1. F, D and E2 stimulated DNA [170% and 160% in pre and in post hObs respectively by F; 175% and160% respectively by D and 156% and150% respectively by E2] and CK [160 and 150% by F; 160 and 150% by D and 160 and 140% by E2 respectively]. The effect of F was not related to the age of patients from whom the cells were harvested. 2. JKF increased ERα (120 and 170% respectively) and decreased ERβ (45 and 40% respectively) mRNA expression, up-regulated DNA and CK response to E2 and D but not to F. 3. JKF increased only E2 but not D or F intracellular competitive binding in pre-menopausal, but not in post-menopausal hObs. 4. F, D and E2 increased VDR (145 and 130% by F; 130 and 125% by D and 150 and 140% by E2 respectively) and 1OHase mRNA expression (300 and 180% by F; 250 and 160% by D and 220 and 150% by E2 respectively) and its activity measured by 1,25D production (210 and 170% by F; 270 and 220% by D and 170 and 150% by E2 respectively), with slightly bigger effect in pre- compared to post- menopausal cells. In conclusion, F, D and E2 increase DNA and CK, 1,25D production as well as the mRNA expression of ERs, VDR and 1OHase. Pre- treatment with JKF modulates the effect of E2 and D but not of F. On the other hand all estrogens modulate VDR expression and both mRNA expression and activity of 1OHase in the cells which, in turn, up-regulate ERs expression and activity in hObs. The observation that the effects of F are independent of pre-treatment with vitamin D analog in women-derived hObs may offer an advantage in its use in post-menopausal women, since it appears to operated well even in the absence of vitamin D analog.

 

Nothing to Disclose: DS, SK, OS, DH, GHP, NS

30845 12.0000 SAT 349 A Mutual Modulation of Femarelle and Vitamin D Analog Activities in Human Derived Female Cultured Osteoblasts 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Anyonya R Guntur*1 and Clifford J Rosen2
1Maine Medical Center, Scarborough, ME, 2Maine Medical Center Research Institute, Scarborough, ME

 

MitoNEET is an outer mitochondrial membrane protein that regulates mitochondrial metabolism. Overexpression of MitoNEET in adipocytes specifically leads to inhibition of β-oxidation and decreased oxidative phosphorylation. To study the role of oxidative phosphorylation in osteoblasts we utilized a Doxycycline (Dox) inducible (Tet-ON) mouse model to overexpress MitoNEET in vivo. In this overexpression model, mice containing the tetracycline responsive element (TRE) fused to the MitoNEET open reading frame were crossed to Runx2 reverse-tetracycline trans-activator (rtTA) to generate osteoblast specific overexpression. Two groups of 4 week old male mice were generated and Dox+Saccharin, and Saccharin were introduced through drinking water for 12 weeks. To confirm overexpression, tibiae from mice positive and negative for TRE MitoNEET on Dox+Saccharin were isolated and rtQPCR analysis performed showing a significant increase in MitoNEET expression in bone. Skeletal phenotyping using DEXA at 8 and 12 weeks of age revealed that osteoblast specific MitoNEET overexpression led to a significant decrease in femoral BMD (n=6). Next, we performed indirect calorimetry to obtain energy expenditure (EE) and respiratory quotient (RQ) data. We found no significant difference in 24 hour energy expenditure even though body weight in the Dox+Saccharin group animals was significantly higher compared to Saccharin controls. Interestingly, 24 hour RQ was significantly lower in the MitoNEET overexpressing animals suggesting oxidation of fat (n=8-10, p=0.03). There was no difference in food consumption, but the group on Dox+Saccharindrank significantly less amount of water (n=8-10, p=0.009). Furthermore, MitoNEET overexpressing mice also had significantly lower sleep hours (n=8, p=0.017). In sum, manipulating MitoNEET expression specifically in the osteoblast impairs bone mass and leads to decreased respiratory quotient, further studies are underway to analyze potential mechanisms.

 

Nothing to Disclose: ARG, CJR

32129 13.0000 SAT 350 A Osteoblast Specific Overexpression of Mitoneet Leads to Decreased Bone Mass 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Victoria DeMambro*1, Lindsey Gower1, Carolina Figueroa1, Susan D'Costa2, David Clemmons2 and Clifford Rosen1
1Maine Medical Center Research Institute, Scarborough, ME, 2University of North Carolina, Chapel Hill, NC

 

We previously reported a sexual dimorphism in the Igfbp2-/- mice in regards to bone, where males have reduced bone mass while females have normal bone relative to controls. Ovariectomized Igfbp2-/- female mice exhibited greater bone loss than controls, becoming a skeletal phenocopy of the Igfbp2-/- males. IGFBP-2 has been shown to bind to the PTPRZ1 receptor, which also binds pleotrophin (PTN), a molecule produced by bone cells and stimulated by estrogen. We hypothesized that PTN/PTPRZ1 signaling could be an alternative pathway for female Igfbp2-/- mice to maintain bone mass in the absence of IGFBP-2 and that the gender differences in bone in the absence of IGFBP-2 are related to the estrogen stimulation of PTN expression. To test this hypothesis in vitro we silenced IGFBP-2 in a MC3T3L1 cell line and treated with estrogen (200pg/ml) in the presence and absence of an anti-fibronectin3 antibody (α-FN3), which disrupts ligand binding to the PTPRZ1 receptor. In vivo we implanted either 17B estradiol (0.18mg) or control pellets in 8 week old +/+ and Igfbp2-/- male mice for 8 weeks to determine if estrogen stimulation of PTN/PTPRZ1 signaling was sufficient to rescue the bone phenotype in the male null mice or if the presence of IGFBP-2 was also required for full rescue. Mice were assessed for body composition and aBMD by DEXA at 8 and 16 weeks of age. At harvest bones were isolated for gene expression and MicroCT. In vitro, in the absence of IGFBP-2 estrogen stimulated PTN secretion, which increased differentiation, while an inhibitor of ligand binding to the PTPRZ1 receptor repressed the effect of PTN. Likewise PTN knockdown in the absence of IGFBP-2 inhibited differentiation. In vivo at 8 weeks of age Igfbp2-/- mice had significant decreases in whole body aBMD (p=0.01) and aBMC (p=0.003) as expected. At 16 weeks of age estrogen treatment increased aBMD and aBMC compared to controls in both genotypes (P<0.0001). Strikingly Igfbp2-/- mice had a 26% increase in aBMD vs. 21% increase in +/+ mice (p=0.04), eliminating the low aBMD present in the 16 week Igfbp2-/- controls. MicroCT analysis of the femur confirmed that the Igfbp2-/- mice were more responsive to estrogen treatment with greater increases in trabecular BV/TV (+/+ = 129% vs. -/- 221%; p= 0.007), due to increased number and thickness of the trabeculae. Igfbp2-/- cortical bone was also more sensitive to estrogen stimulation with a 30% increase in Ct. A/TA vs. a 22% increase in the +/+ mice (p= 0.007). Gene expression analysis of the femur revealed a two-fold increase in Ptn and Ptprz1 in the mice treated with estrogen confirming the upregulation of this pathway observed in vitro. In summary, an estrogen stimulated alternate signaling pathway through PTN/PTPRZ1 in the absence of IGFBP-2 can completely rescue the low bone mass observed in males and appears to be responsible for the gender differences observed in the bones of the Igfbp2-/- mice.

 

Nothing to Disclose: VD, LG, CF, SD, DC, CR

SH01-7 32370 14.0000 SAT 351 A An Estrogen Stimulated Alternative Signaling Pathway Responsible for the Sexual Dimorphisms Observed in Igfbp2-/- Mice 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Sanjay Bhadada*
Postgraduate institute of medical education & research, Chandigarh, INDIA

 

 

Background: FIO is a rare metabolic bone disease clinically characterized by generalized bone pain andfragility fractures in both the axial and appendicular skeleton.Bone biopsy shows extensive mineralization defect (hyperosteoidosis)and loss of collagen birefringence under polarized microscopy.Etiology of the diseaseis unknown and noeffective therapycurrently exists.

Methods: We performed global gene expression profiling in mRNA isolated from bone biopsy specimen from a 48yold man with FIO, which suggested a possible molecular basis for thepathogenesis of FIO. Based on this information he was treated with human growth hormone for one year with frequent biochemical monitoring and a repeat bone biopsy.

Result: The global gene expression profile revealed 8,916 differentially expressed genes (out of total 35,307). The genetic and functional analyses suggestedthat FIO is associated with defects in osteoblast maturation, collagen fibril arrangement, matrix organization and bone mineralization with a possible defect in paracrine action of IGF1. Following therapy with human growth hormone there was a marked clinical, radiological and histological improvement.

Conclusion: Gene profile analysis of the bone biopsy specimen from a patient with FIO provided crucial information underlying the bone abnormality and a therapeutic basis for clinical management. We suggest that growth hormone may be a potential novel therapy for FIO. 

 

Nothing to Disclose: SB

31772 15.0000 SAT 352 A Title: Differential Gene Expression Profiling in Fibrogenesisimperfectaossium (FIO) and Effects of Human Growth Hormone Treatment 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Vandana Dhiman*
Panjab University, Chandigarh, India

 

Introduction: OI is a heritable disorder of abnormal collagen and predisposes to increased bone deformity and fragility. The underlying molecular mechanism of abnormal collagen is poorly understood. The Hsp47 is involved in control­ling the quality of procollagen folding in the endoplasmic reticulum(ER) and attenuates misfolding of triple helix collagen, suggesting that Hsp47 might be involved inthe pathogenesis of OI. However, Hsp47 cannot prevent the export of incom­pletely folded chains from the ER by preferentially bind­ing and tagging them. Instead, Hsp47 preferentially binds to, and is co-transported with, natively folded procollagen from the ER to Golgi.

Objective: In the present study, we investigated the mechanisms underlying the apoptosis of Hsp47-/- cells and involvement of autophagy and unfolded protein response (UPR) in the clearance of misfolded type I procollagen in the absence of Hsp47. We hypothesized that misfolded type I procollagen in the ER might cause ER stress, resulting in apoptosis of Hsp47-disrupted triple helix of collagens when autophagy isinhibited.

Methodology: Peripheral blood mononuclear cell (PBMC) derived osteoblasts were cultured. RNA and proteins were isolated from bone. Mutation analysis of Hsp47 gene was done through sequencing followed by restriction digestion. Hsp47 control- and mutant-gene were cloned in expression vector pEGFP-C1.Further,in-vitro analysis was performed to study the interaction between triple helix and mutant Hsp47 under confocal microscope. Immunoblot for mutant protein analysis was done, RT-PCR and quantitative RT-PCR were performed for expression and functional analyses.

Results and Conclusion: ER stress-induced apoptosis may underlie the clearance of collagen-producing osteoblast cells. Experimental findings suggest that Hsp47 plays a pivotal role in ER/cis-Golgi transport. The changes in triple helical structure could affect fibril assembly in extra cellular matrix and lead to irregular mineralization and an OI phenotype.

 

Disclosure: VD: , AMBRX.

32324 16.0000 SAT 353 A Mutation in the Collagen-Specific Molecular Chaperone Heat-Shock Protein-47 (Hsp47) Causes Endoplasmic Reticulum Stress in Osteoblast Cells of Osteogenesis Imperfecta (OI) Patients 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Sylvester Jusu*1, John Presley2 and Richard Kremer3
1McGill University Health Centre, Montreal, QC, Canada, 2McGill University, Montreal, Canada, 3McGill University Health Center, Montreal, QC, Canada

 

1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the biologically active metabolite of vitamin D, is a pleiotropic fat-soluble hormone that regulates calcium homeostasis via the transcriptional activation of target genes through the nuclear vitamin D receptor (nVDR). This hormonally active form is synthesized from its precursor 25 hydroxyvitamin D [25(OH)D] via the catalytic action of the mitochondria cytochrome P450 enzyme 25(OH)D-1a-hydroxylase (CYP27B1). We used fixed and live cell fluorescence imaging techniques to examine the effects of CYP27B1 knockout on subcellular localization, nucleocytoplasmic trafficking of the vitamin D receptor (VDR) and VDR/RXR interaction in normal mouse MT1107 and CYP27B1 knockout AOH931 cell lines. A GFP tagged human VDR or hRXRα expression plasmid was transfected in both cell lines followed by treatment with either 1,25(OH)2D3 or 25(OH)D3.

We show, through transfection of hVDR and hRXRα GFP-tagged constructs, that both hVDR and hVDR/ hRXRα complex are localized in the nucleus of MT1107 cells treated with either 1α,25(OH)2D3 or 25-hydroxyvitamin D3 [25(OH)D3]. In contrast, in CYP27B1 knockout AOH932 cells impaired nuclear localization of hVDR and hVDR/hRXRα is observed. Furthermore, we demonstrate using Fluorescence Resonance Energy Transfer (FRET) that hVDR/hRXRα interaction is also impaired in AOH931 cells. Lastly, we demonstrate using Fluorescence Recovery After Photobleaching (FRAP) and Fluorescence Loss in Photobleaching (FLIP) that the nucleocytoplasmic trafficking of VDR within the nucleus of CYP27B1 knockout AOH931 cells is reduced consistent with its binding to chromatin.

Our results show that CYP27B1 knockout disrupts VDR function by significantly impairing its nuclear localization, nucleocytoplasmic trafficking and hVDR/hRXR interaction consistent with the complex binding to DNA.

 

Nothing to Disclose: SJ, JP, RK

32643 17.0000 SAT 354 A Targeted Ablation of 25-Hydroxyvitamin D-1a-Hydroxylase (CYP27B1) Impairs VDR Subcellular Localization, Nucleocytoplasmic Trafficking and VDR/RXR Interaction in AOH931 Cells 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Kennett Sprogoe*1, Susanne Pihl2, Caroline Elisabeth Rasmussen3, Lars Holten-Andersen3, Felix Cleeman3 and Vibeke Miller Breinholt3
1Ascendis Pharma A/S, Hellerup, Denmark, 2Ascendis Pharma, Hellerup, Denmark, 3Ascendis Pharma

 

Background

Natpara (PTH1-84) is approved for subcutaneous injection as an adjunct to vitamin D and calcium in patients with hypoparathyroidism but has not demonstrated the ability to reduce the incidence of hypercalcemia, hypocalcemia, or hypercalciuria relative to conventional therapy. Continuous infusion of teriparatide (PTH1-34) has been shown to be superior to twice daily injections in clinical studies. Thus, a PTH product that provides continuous exposure with daily dosing could represent a major step forward in addressing a large unmet medical need. TransCon PTH is a prodrug releasing unmodified teriparatide via non-enzymatic hydrolysis of the proprietary TransCon Linker for the treatment of hypoparathyroidism.

Objective

TransCon PTH has been designed to maintain a normal range, steady concentration of PTH in the blood stream. It is intended to address the fundamental limitation of short-acting PTH molecules by providing infusion-like PTH blood levels.

Design and methods

TransCon PTH was administered to rat and cynomolgus monkeys in single dose studies and in 28-day toxicology studies with daily dosing. The systemic concentrations of TransCon PTH and calcium were assessed at multiple time point following dosing.

Results

TransCon PTH exhibited in both rat and monkey long half-lives providing infusion-like pharmacokinetics. In both species, exposure to TransCon PTH increased in a dose proportional manner. Sex differences in systemic exposure of TransCon PTH and serum calcium were observed in rats, with females exhibiting increased exposures compared to males. No differences between sexes were observed for TransCon PTH or serum calcium in cynomolgus monkeys.

Conclusion

Nonclinical experiments in rats and cynomolgus monkeys demonstrated that TransCon PTH may provide full therapeutic coverage in contrast to available therapies; PTH(1-34) and PTH(1-84) both have half-lives on the order of minutes. The PK characteristics of TransCon PTH after steady state resemble an infusion like profile, suggesting that TransCon PTH can support continuous PTH exposure in hypoparathyroid patients. The substantial extension of PTH half-life may more closely mimic physiological levels of PTH observed in healthy individuals and therefore maintain blood calcium and phosphorous levels while normalizing urinary calcium excretion.

 

Disclosure: KS: Employee, Ascendis Pharma. SP: Employee, Ascendis Pharma. CER: Employee, Ascendis Pharma. LH: Employee, Ascendis Pharma. FC: Employee, Ascendis Pharma. VMB: Employee, Ascendis Pharma.

30298 18.0000 SAT 355 A Pharmacokinetics of Transcon PTH, a Sustained-Release PTH Prodrug for Hypoparathyroidism, in Rat and Cynomolgus Monkey 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Kelly Lauter Roszko*1, Ruiye Bi1, Caroline M Gorvin2, Hans brauner-Osborne3, Xiao-Feng Xiong4, Asuka Inoue5, Rajesh V Thakker2, Kristian Strømgaard4, Thomas J Gardella1 and Michael Mannstadt1
1Massachusetts General Hospital and Harvard Medical School, Boston, MA, 2University of Oxford, Oxford, United Kingdom, 3University of Copenhagen, Copenhagan, Denmark, 4University of Copenhagen, Copenhagen, Denmark, 5Tohoku University, Japan

 

Parathyroid hormone (PTH) acts to maintain extracellular calcium in a tight range. Low PTH levels result in hypocalcemia and hyperphosphatemia. Autosomal dominant hypocalcemia type 2 (ADH2) is caused by activating mutations in GNA11, encoding Gα11, which activate the CASR pathway. One such mutation, found in a family with ADH2, is the heterozygous missense mutation c.178C->T leading to the replacement of arginine 60 with cysteine in helix α1 of the GTPase domain.

We expressed wildtype (WT) Arg60 and mutant Cys60 Gα11 in HEK293 cells stably expressing the CASR and measured the intracellular calcium response to changes in extracellular calcium concentrations. The leftward shift of the concentration-response curve in the cells expressing mutant Gα11 illustrated an increased sensitivity to calcium. We treated these cells with the calcilytic NPS 2143 and the EC50of the mutant cells returned to that of WT cells.

With CRISPR/Cas9 technology, we created a mouse model harboring the Arg60Cys mutation. Compared to WT littermates, nine-week-old mice heterozygous and homozygous for Gα11 R60C were hypocalcemic. Compared to WT animals, PTH was inappropriate in heterozygous and homozygous animals. Serum phosphate was higher in homozygous mice. We also noted increased pigmentation of the tails and ears of mutant mice, implicating the activation of other GPCRs by the mutant Gα11. μCT analysis of 12-week old mice revealed lower bone mineral density (BMD) and bone volume/total volume (BV/TV) of female heterozygous/homozygous and male heterozygous mice. This finding was surprising given that humans with hypoparathyroidism typically have increased BMD. The urinary fractional excretion index of calcium (FECa) was not different in mutant mice, raising the possibility that Gα11 does not have a dominant effect on CASR function in the distal tubule cells.

We injected 30 mg/kg of NPS 2143 i.p.; 4 hours after injection, serum calcium was increased in mice WT, heterozygous and homozygous for R60C. Serum PTH increased in all animal groups, and serum phosphate increased in WT mice. The urinary FECa decreased in heterozygous and homozygous animals. We tested the effects of the specific Gα11/Gαq inhibitor YM-254890. A single dose of 0.15mg/kg YM-254890 i.p. increased the calcium in WT and heterozygous R60C mice. Published crystallography studies predict that YM-254890 inhibits WT Gα11, but not Gα11 R60C, consistent with our findings of no change in serum calcium in response to treatment of R60C homozygous animals.

We have used CRISPR/Cas9 to create a mouse with the p.Arg60Cys mutation found in humans with ADH2. Our mouse model mimics the biochemical findings of the human disease, i.e. hypocalcemia and inadequate PTH. Mutant mice also have decreased BMD, increased pigmentation, and unchanged urinary FECa. This mouse model has identified phenotypes, in addition to hypocalcemia, associated with Gα11 mutations.

 

Disclosure: KS: Founder, Avilex Pharma. MM: Advisory Group Member, NPS-Shire. Nothing to Disclose: KL, RB, CMG, HB, XFX, AI, RVT, TJG

32706 19.0000 SAT 356 A Knock-in Mouse with Mutant Gα11: Characterization of Phenotype and Pharmacological Rescue of Hypocalcemia By Inhibitors 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Caroline M Gorvin*1, Raghu Metpally2, John D Overton3, Jeffrey G Reid3, Gerda E Breitwieser4 and Rajesh V Thakker1
1University of Oxford, Oxford, United Kingdom, 2Geisinger Clinic, Weis Center for Research, Danville, PA, 3Regeneron Genetics Center, Tarrytown, NY, 4Weis Center for Research, Danville, PA

 

Mutations of the sigma subunit of the clathrin-mediated endocytic adaptor protein-2 (AP2σ), encoded by the AP2S1 gene, impair internalisation of the calcium-sensing receptor (CaSR), a G-protein coupled receptor (GPCR), and cause familial hypocalciuric hypercalcemia type-3 (FHH3). To date, AP2σ mutations have only been identified at one residue, Arg15 (R15). We hypothesized that additional rare AP2σ variants, identified in large-scale sequencing projects may be associated with altered in vitro activity, and associated with hypercalcemia in humans. Using the Geisinger Health System-Regeneron DiscovEHR exome sequencing dataset on 51,289 individuals, we identified four patients with heterozygous AP2S1 variants and hypercalcaemia (i.e. plasma calcium concentrations (p[Ca] of >10.0mg/dL). Two patients had the previously reported Arg15His (R15H) mutation, with p[Ca] of 11.4 and 10.5 mg/dL, and two other patients, each of whom had a p[Ca] of 10.1 mg/dL, had novel heterozygous AP2σ variants, Phe52Tyr (F52Y) and Met117Ile (M117I). F52 and M117 are conserved residues in >175,000 human sequences from the NHLBI exome sequencing project and the Exome Aggregation Consortium, and in vertebrate AP2σ subunit orthologues, thereby indicating that the substitutions Y52 and I117 likely represent AP2σ mutations rather than polymorphic variants. Three-dimensional modelling predicted that F52Y, which is located within AP2σ β3, would likely have no effect on the structure of AP2σ, but that the M117I, which is within a helix-loop-helix structure that provides structural stability to the AP2 complex, would reduce the flexibility of AP2σ and hinder AP2 complex movement that is required for its activation. To further assess the functional consequences of these variants we expressed AP2σ wild-type and mutant proteins in HEK293 cells stably expressing CaSR, and measured intracellular calcium responses to elevations in extracellular calcium using flow cytometry and the calcium binding dye Indo-1. F52Y had a mean half-maximal concentration (EC50) value that was not significantly different to the wild-type AP2σ, whereas M117I led to a rightward shift of the dose-response curve with a significantly increased EC50, consistent with a loss-of-function (Wild-type EC50 = 3.47mM (95% confidence interval (CI) = 3.32-3.62mM), F52Y EC50 = 2.70mM (95%CI = 2.70-2.95mM), and M117I EC50 = 2.89mM (95%CI = 2.76-3.00mM)). Furthermore, treatment of cells expressing AP2σ-M117I with the CaSR positive allosteric modulator cinacalcet reduced the EC50 to 2.59mM (95%CI = 2.40-2.80mM), such that it was not significantly different to wild-type. Thus, our studies have identified that mutations in residues other than R15 can lead to AP2σ loss-of-function, and indicate an important role for the AP2σ helix-loop-helix structure.

 

Disclosure: JDO: Management Position, Regeneron Pharmaceuticals, Inc.. JGR: Management Position, Regeneron Pharmaceuticals, Inc.. Nothing to Disclose: CMG, RM, GEB, RVT

30365 20.0000 SAT 357 A An Adaptor Protein 2 Sigma Subunit (AP2σ) Met117Ile Mutation within a Helix-Loop-Helix Structure Causes Familial Hypocalciuric Hypercalcaemia Type-3 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Frederic Jean-Alphonse* and Jean-Pierre Vilardaga
University of Pittsburgh, Pittsburgh, PA

 

Cells express several G protein-coupled receptors (GPCRs) at their surfaces transmitting simultaneous extracellular hormonal and chemical signals into cells. A comprehensive understanding of mechanisms underlying the integrated signaling response induced by distinct GPCRs is thus required. Here we found that the b2-adrenergic receptor, which induces short cAMP response, prolongs nuclear cAMP and PKA activation by promoting endosomal cAMP production in PTH receptor signaling through the stimulatory action of Gbg subunits on adenylate cyclase type 2

 

Nothing to Disclose: FJ, JPV

31342 21.0000 SAT 358 A β2-Adrenergic Receptor Control of Endosomal PTH Receptor Signaling Via Gβγ 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Patrick Hanna*1, Anne Rochtus2, Deborah Mackay3, Bruno Francou4, Jérôme Bouligant4, Anne Mantel4, Elli Anagnostou5, Elpis Vlachopapadopoulou5, Dominique Gaillard6 and Agnes Linglart7
1INSERM U1169, LE KREMLIN BICETRE, France, 2Department of Pediatrics, University Hospitals, Leuven, Belgium, 3Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, United Kingdom, 4Laboratory of Molecular Genetics, Pharmacogenetics and Hormonology, University Hospital of Bicetre, LE KREMLIN BICETRE, France, 5Endocrinology Department-Department of growth and development, Children's Hospital “P. & A. Kyriakou”, ATHENS, Greece, 6service de Génétique et Biologie de la Reproduction, Hôpital Maison Blanche, Centre Hospitalier Universitaire, REMIS, France, 7, INSERM and APHP, CMR Calcium-Phosphore, LE KREMLIN BICETRE, France

 

Pseudohypoparathyroidism type 1B (PHP1B) (iPPSD3 according to the novel classification) is a rare disorder characterized in most patients mainly by a proximal tubule resistance to the parathyroid hormone (PTH) that manifests as hypocalcemia, hyperphosphatemia and elevated PTH. PHP1B is caused by epigenetic changes at one or several Differentially Methylated Regions (DMRs) within the GNAS locus, including loss of methylation (LOM) at the GNAS-A/B DMR. The autosomal dominant PHP1B (AD-PHP1B) patients present with a loss of imprinting (LOI) restricted to the GNAS-A/B DMR, and most of them carry a recurrent maternal deletion comprising the STX16 exons 3-9 while the sporadic patients (sporPHP1B) present with broad methylation defects. Recently, Rochtus et al identified a novel DMR within the GNAS locus (GNAS-AS2).

Objectives and patients: Characterize the methylation pattern of the GNAS-AS2-DMR in patients with AD-PHP1B and LOM at the GNAS-A/B-DMR (AD+: n=10) and in patients without (AD-: n=4) STX16 deletion, sporPHP1B (n=10) and controls (n=10). STX16 and GNAS deletion were excluded in the AD- patients by MLPA and genomic multiplex and quantitative PCR of the GNAS and the STX16 regions.

Results:

1- AD- patients showed significantly higher methylation compared to controls (respectively 38% and 22,7%; P<0.05). GNAS-AS2 was unmethylated in AD+ and sporPHP1B patients (respectively 4.0% and 2.9%).

2- Subsequently, we performed bisulfite sequencing of the GNAS-AS2-DMR. First, we identified 2 CG-rich subdomains separated by 184 bp. Second, the AD- patients displayed a unique pattern of methylation (methylated on the 1st subdomain, unmethylated on the 2nd subdomain) that was absent in controls, AD+ and sporPHP1B patients.

Conclusion: We have better refined the DMR GNAS-AS2. We have identified a subgroup of PHP1B patients who have a specific pattern of methylation/signature at the GNAS-AS2 DMR.

 

Nothing to Disclose: PH, AR, DM, BF, JB, AM, EA, EV, DG, AL

31706 22.0000 SAT 359 A Methylation Patterns of the Novel DΜR of GNAS (GNAS-AS2) in the Pseudohypoparathyroidism 1B (iPPSD3) Subtypes 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 338-359 9479 1:00:00 PM Innovations in Bone Biology Poster


Nurgun Kandemir*1, Meghan Slattery2, Kathryn E Ackerman3, Shreya Tulsiani2, Vibha Singhal1, Anne Klibanski4 and Madhusmita Misra1
1Massachusetts General Hospital/Harvard Medical School, Boston, MA, 2Massachusetts General Hospital, Boston, MA, 3Boston Children's Hospital/ Massachusetts General Hospital and Harvard Medical School, 4Massachusetts General Hospital and Harvard Medical School, Boston, MA

 

Background: Whereas low body weight and hypogonadism are deleterious to bone, mechanical loading has positive effects. We have reported low bone mineral density (BMD), impaired bone structure, and increased fracture risk in low-weight, amenorrheic girls with anorexia nervosa (AN) and normal-weight, oligo-amenorrheic athletes (OA) engaged in weight-bearing sports. However, effects of body weight vs. gonadal status vs. mechanical loading on site and compartment specific bone parameters remain to be clarified.

Objective:To evaluate effects of body weight, gonadal status and repetitive weight-bearing exercise on bone parameters, and describe high risk groups for fracture.

Methods: 391 females 14-21.9 years old were included, 215 with AN, 85 OA and 91 normal-weight eumenorrheic controls (C). The AN group was further classified according to duration of amenorrhea (< 1 year or ≥ 1 year). Areal BMD of the whole body less head (WBLH), lumbar spine and total hip was determined using DXA. BMD Z-scores were calculated for sex, age and race using reference curves from the BMD in Childhood Study, and adjusted for height Z-scores. Fracture history (stress and non-stress) was obtained. Volumetric BMD (vBMD), bone geometry and structure were assessed at the distal radius and tibia using high resolution peripheral quantitative CT (HR-pQCT).

Results: Groups did not differ for age and height Z-scores; BMI was lower in AN than OA and C (p<0.0001). AN had lower WBLH and hip BMD Z-scores than OA and C regardless of amenorrhea duration (p<0.0001 for all). AN (both groups) and OA had lower spine BMD Z-scores than C (p<0.0001, p<0.01). However, AN with ≥ 1 y of amenorrhea had lower spine BMD Z-scores than OA (p=0.02), whereas AN with <1 y of amenorrhea did not differ from OA. OA did not differ from C for WBLH and hip BMD Z-scores. AN and OA had higher fracture rates than C (p=0.03, p=0.009). Prevalence of stress fracture was higher in OA than AN and C (p<0.0001 for both); AN had more non-stress fractures than OA (p=0.02). HR-pQCT of the non-weight-bearing radius showed lower cortical area and thickness and lower total vBMD in AN and OA vs. C (p≤ 0.02 for all); cortical vBMD was lower in OA than C (p=0.02). At the weight-bearing tibia, AN had lower measures for most tibial parameters than OA and C; OA did not differ from C, except for lower cortical vBMD (p=0.0005).

Conclusion: Low weight and amenorrhea (in AN) are deleterious to bone at all sites and both bone compartments. Normal-weight OA have lower spine BMD and lower cortical vBMD at weight-bearing and non-weight-bearing sites compared to C (indicative of effects of oligo-amenorrhea), while most other bone parameters do not differ (indicative of the compensating effect of normal-weight and/or mechanical loading). Yet, the stress fracture rate is higher in OA than AN and C, indicating that bone measures in OA need to be stronger than in C to avoid fractures from weight-bearing activity.

 

Nothing to Disclose: NK, MS, KEA, ST, VS, AK, MM

32504 1.0000 SAT 298 A Differential Effects of Low-Weight, Amenorrhea and Exercise on Bone in Adolescent Girls 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Shatha Murad*1 and Yuval Eisenberg2
1University of Illinois, Chicago, Chicago, IL, 2University of Illinois at Chicago, Chicago, IL

 

Background: Primary hyperoxaluria I is a rare disorder of oxalate overproduction caused by enzyme deficiencies in metabolism of glyoxylate. It presents with urolithiasis, nephrocalcinosis, CKD and progresses to systemic oxalosis. We present a case of systemic oxalosis leading to nonPTH mediated hypercalcemia, primary hypothyroidism, and primary hypogonadism.

Clinical Case: A 35 year old male with primary hyperoxaluria type I complicated by ESRD, resistant anemia, and skeletal oxalosis is evaluated for weakness, fatigue, low energy, constipation, erectile dysfunction, and testicular sensitivity.

Initial laboratory workup revealed a peak calcium of 13.5 mg/dL (8.6-10.6mg/dL), phosphorous 7 mg/dL (3-4.5mg/dL), 25 (OH) vitamin D 30 ng/mL (20-80 ng/mL) and iPTH of 11 pg/mL (12-88pg/ml), suggesting nonPTH mediated hypercalcemia. 1,25 vitamin D and PTHrP were elevated at 93pg/ml (19.9-79.3pg/ml) and 11 pmol/L(0-2.3 pmol/L), respectively. This was thought to be secondary to excess 1, alpha hydroxylase from bone granulomas or secondary to malignancy. He underwent bone marrow biopsy to evaluate for granulomas, which revealed extensive bone marrow replacement by large crystalline deposits and fibrosis, consistent with history of oxaluria, but did not show evidence of granulomas.

Labs suggested primary hypothyroidism with TSH 8.33 mcIU/mL (0.35-4mcIU/mL), Free T4 0.8 ng/dL (0.6-1.7ng/dL) and thyroid ultrasound showed probable multiple punctate microcalcifications diffusely throughout the thyroid gland, suggestive of infiltration as a cause.

AM Total Testosterones on 2 occasions were 142 and 235 ng/dl (300-1086 ng/dL), FSH 10.8 ng/ml (1.5-14 mIU/ml), LH 9.8 mIU/ml (1.4-7.7mIU/ml). Testicular ultrasound showed bilateral testicles and epididymides with multiple punctate echogenic foci, suggestive of deposition as cause of primary hypogonadism.

Hypogonadism was treated with testosterone 1% gel and hyperthyroidism treated with levothyroxine 175mcg daily. Hypercalcemia improved with daily hemodialysis The patient was listed for sequential kidney and liver transplant.

Conclusion: There are rare reports of hypercalcemia in association with PH, thought to be due to osteoclast-stimulating activity of macrophages in granulomas in bone marrow. Here we describe a case of hypercalcemia without evidence of granuloma in the bone marrow, thought to be due to excess 1, alpha hydroxylase activity in bone granulomas. Primary hypothyroidism and primary hypogonadism are thought to be due to calcium oxalate deposition and this is one of the first reported cases of primary hypogonadism with evidence of deposition in testes. It is important to consider the possibility of and monitor for various endocrinopathies in the setting of primary hyperoxaluria with systemic oxalosis as there are good treatment options that improve quality of life.


 

Nothing to Disclose: SM, YE

32669 2.0000 SAT 299 A Primary Hyperoxaluria in an Adult Complicated By ESRD, Resistant Anemia, Skeletal Oxalosis, and Multiple Endocrinopathies: Hypercalcemia, Hypothyroidism, and Hypogonadism 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Sowjanya Naha*1, Pratyusha Bollimunta2, Kushal Naha2 and Farah Faridi2
1Presence Saint Francis Hospital, 2Presence Saint Francis Hospital, Evanston, IL

 

Introduction: Calcific uremic arteriolopathy also known as calciphylaxis is a rare and serious disorder characterized by painful ischemic skin necrosis and calcification of dermal arterioles on histological examination. It is typically seen in patients with end-stage renal disease (ESRD) on dialysis.

Case report: We report a 67 year old Caucasian female who presented with features of sepsis. The putative source was cellulitis of her lower extremities at the site of multiple painful non-healing skin ulcerations that had gradually developed in the past two months. Past medical history was notable for ESRD on hemodialysis for about six months, as well as chronic atrial fibrillation on therapeutic anticoagulation with warfarin. Review of previous blood work showed elevated parathyroid hormone (PTH) of over 1000 pg/mL. Biopsy of the skin lesions demonstrated arteriolar wall calcification consistent with calciphylaxis. Sodium thiosulfate was initiated with every hemodialysis session in addition to the broad spectrum antibiotics that she was already receiving. Warfarin therapy was discontinued. The patient reported symptomatic improvement with these measures. She continues to receive treatment with sodium thiosulfate as of this day.

Conclusion: Calciphylaxis carries a grave prognosis with a one-year survival rate of less than 50%. It is frequently complicated by infection as was seen in this instance. The incidence of calciphylaxis is expected to rise in the immediate future paralleling the rapid growth of the ESRD population in the US. Physicians should therefore be aware of this unusual but deadly etiology for painful non-healing wounds.

 

Nothing to Disclose: SN, PB, KN, FF

32222 3.0000 SAT 300 A Calcific Uremic Arteriolopathy: All Skin and Bones 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Tanvi Parikh*1, Joseph G. Verbalis2, Fady Hannah-Shmouni3, Sharleen Sidhu4 and Shirisha Avadhanula5
1MedStar Georgetown University/MedStar Washington Hospital Center, Silver Spring, MD, 2Georgetown University Medical Center, Washington, DC, 3Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 4MedStar Georgetown University Hospital/MedStar Washington Hospital Center, Arlington, VA, 5Medstar Georgetown University/Washington Hospital Center, Washington, DC

 

Introduction:

Calciphylaxis is a rare disorder of calcium (Ca) homeostasis associated with significant morbidity and mortality. Calciphylaxis due to end stage renal disease or medications (e.g., warfarin) has been previously described. We report a case of normocalcemic primary hyperparathyroidism (PHPT) with non-uremic calciphylaxis (NUC).

Case Description:

A 60-year-old African American female was evaluated for long standing (3 years), painful and non-healing right leg ulcers. Past medical history was significant for presumed normocalcemic PHPT, morbid obesity and pre-diabetes. She had failed previous wound debridement and grafting procedures. Medications included Vitamin D3 2,000 IU daily. She denied symptoms of hypercalcemia or history of fractures. Physical examination showed several indurated and darkened plaques, with non-healing, tender ulcers on the right lower leg. Biochemical evaluation revealed: corrected Ca=9.8 mg/dl (8.7-10.2), Phosphorus (P)=4.2 mg/dl (2.5-4.5), Ca X P product=41.6 mg/dl (goal < 55), PTH=92.1 pg/ml (12-65), 25-OHD=43 ng/ml (30-100), 1,25-OHD=62 pg/ml (21-65), Cr=0.9 mg/dl (0.5-1.04), GFR >60 ml/min, ALP=99 U/L (45-117), Ca/Cr=0.03, calcitonin=2 pg/ml (0-5). Right tibia/fibula X-ray showed extensive soft tissue calcifications and subchondral sclerosis. Sestamibi scan revealed mediastinal focus of early uptake with washout on delayed (6h) imaging, concerning for a parathyroid lesion. Excisional biopsy of the ulcer showed arteriolar thrombi and Ca deposits in the subcutaneous fat, confirming the diagnosis of calciphylaxis. She was treated with phosphate binders (PB, sevelamer 800 mg 3X daily), and received hyperbaric oxygen therapy and allografts to the leg ulcers. Parathyroid surgery was considered but deferred.

Discussion:

  1. The reported disorders associated with NUC include: PHPT, malignancies (lymphomas), autoimmune diseases (SLE, rheumatoid arthritis), alcoholic liver disease, DM, chemotherapy-induced Protein C and Protein S deficiency, obesity, warfarin and glucocorticoid exposure. (1,2)
  2. A high index of clinical suspicion for NUC should be maintained if a patient with any of the aforementioned diagnoses presents with unexplained skin lesions. 
  3. Data on the treatment of NUC is very limited; strategies such as local wound care and hyperbaric oxygen therapy are commonly employed; the roles of PB, cinacalcet or parathyroidectomy in PHPT-induced NUC remains unclear.
  4. In this case, we hypothesized that her Ca X P was normal due to rapid Ca deposition in soft tissues; we therefore chose to use PB, which lowered post-treatment (i.e., 4d) P=3.4 mg/dl, PTH=42 ng/dl and increased Ca=10.1 mg/dl.
  5. We postulate that PB might retard progression of calciphylaxis by further lowering the Ca X P product. If PB therapy is unsuccessful, we will consider parathyroid surgery, cinacalcet and genetic testing as possible next steps.

 

Disclosure: JGV: , Ferring Pharmaceuticals, , Otsuka. Nothing to Disclose: TP, FH, SS, SA

30629 4.0000 SAT 301 A Normocalcemic Primary Hyperparathyroidism and Non-Uremic Calciphylaxis 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Tasma Harindhanavudhi*1, Richard Jones2, Sara Van Nortwick2, Kyriakie Sarafoglou3, Bradley Scott Miller4, Tara Holm2 and Anna Petryk2
1Univ of Minnesota, Minneapolis, MN, 2University of Minnesota, Minneapolis, MN, 3Leo Fung Center for CAH and DSD, Minneapolis, MN, 4University of Minnesota Masonic Children's Hospital, Minneapolis, MN

 

Background: Dual-energy X-ray absorptiometry (DXA) remains the most common mode of bone mineral density (BMD) evaluation in adults and children. In adults, the presence of a disproportionately higher BMD Z-score (>1 SD difference) between the individual lumbar vertebrae could be an indicator of a vertebral fracture and, therefore, warrant further evaluation of the lateral vertebral morphology. However, in children, the skeleton is still growing and undergoing changes in geometry (modeling), introducing developmental aspects as a confounding variable.

Objective: The goal of the study was to correlate the results of a lumbar spine DXA with lateral lumbar spine morphology to elucidate the clinical significance of discrepancies between individual vertebral BMD Z-scores.

Methods: A retrospective chart review identified 360 DXA scans performed between 9/01/2014 and 5/01/2016 in patients <18 years of age. DXA scans were cross-referenced against all lumbar spine x-ray and DX vertebral fracture analysis (DX VFA) database within the 6 months preceding or following the date of a DXA scan. Vertebral fractures were assessed using a semiquantitative method of Genant et al. and defined as a ≥15% loss in the anterior, middle, or posterior height ratio.

Results: Out of 360 DXA scans, 52 (14.4%) had both a vertebral BMD L1-L4 Z-score ≥1 SD difference, and either lumbar spine x-ray or DX VFA. Only two patients (3.8%) with vertebral BMD Z-score ≥1 SD difference had a vertebral fracture at the same site. The most common vertebra with the highest BMD Z-score was L1 (67%), followed by L3 (23%), L2 (8%) and L4 (2%) vertebrae. The vertebrae with the highest BMD Z-score had a normal anatomy. Although helpful as an imaging modality, DX VFA provided images of an inferior quality compared to the radiographs, particularly in younger children.

Conclusions: We conclude that the correlation between the finding of ≥1 SD difference between vertebral BMD Z-scores and vertebral fracture is low. We postulate that variations in BMD Z-scores of otherwise anatomically normal vertebrae reflect differences in the timing of the vertebral growth. Therefore, it does not appear justified to recommend further imaging based solely on the results of a DXA scan without clinically meaningful indications. Moreover, since L1 was the most frequent vertebra with a disproportionately higher BMD Z-score, it may be more appropriate to use L2-L4 average rather than L1-L4 average for reporting BMD Z-scores in children.

 

Disclosure: BSM: Advisory Group Member, Abbvie, Coinvestigator, BioMarin, Coinvestigator, Armagen, Principal Investigator, Alexion, Principal Investigator, Endo Pharmaceuticals, Ad Hoc Consultant, Ferring Pharmaceuticals, Principal Investigator, Genentech, Inc., Principal Investigator, Novo Nordisk, Ad Hoc Consultant, Novo Nordisk, Ad Hoc Consultant, Pfizer, Inc., Ad Hoc Consultant, Sandoz, Principal Investigator, Sandoz, Scientific Content Contributor, Up To Date, Principal Investigator, Versartis, Ad Hoc Consultant, Versartis, Coinvestigator, Shire, Principal Investigator, Tolmar, Coinvestigator, Eli Lilly & Company. Nothing to Disclose: TH, RJ, SV, KS, TH, AP

29650 5.0000 SAT 302 A Poor Correlation Between Disproportionately Higher BMD Z-Scores of the Individual Lumbar Vertebrae By DXA and Vertebral Fractures in Children 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Asma Al-Zougbi*1, Swarna Rai2 and Joseph Stephen Dillon2
1University of Iowa Hospitals and Clinics, Iowa City, IA, 2University of Iowa Hospital and Clinics, Iowa City, IA

 

Background: Tracheopathia osteochondroplastica (TO) is a rare non-neoplastic disorder characterized by the development of osseous and/or cartilaginous nodules in the trachea or bronchial walls. Often, the condition is silent, however, it can occasionally cause obstruction of the tracheal passage leading to life-threatening respiratory compromise. Severe TO is traditionally treated surgically. In this report, we report a unique case of severe TO that is being treated conservatively with bisphosphonate therapy

Clinical case: A 47 year old woman with significant history of Crohn’s disease presented to our clinic for the evaluation of TO. In the past, she presented with respiratory distress, stridor and hoarseness. Her imaging at that time demonstrated laryngeal calcification and right vocal cord fixation secondary to heterotopic growth of cartilage and bone. Nuclear bone scan showed uptake at the mid cervical spine, confirming active heterotopic ossification. Her severe condition at the time required surgical intervention via tracheostomy. Her postoperative course was complicated by delayed subglottic involvement in soft tissues immediately cranial to tracheostomy site a few months later. Work up for an autoimmune etiology was negative and she had no improvement of activity on nuclear bone scan after a one year trial of adalimumab (Humira).

TO does not usually require treatment, however may occasionally require tracheostomy or surgical resection of the affected tracheal segment or outgrowths. Owing to the patient’s multifocal disease and the expectation of recurrence, surgical resection was not a good option in our patient. TO is a corollary of calcium deposition, as is heterotopic ossification (HO). Bisphosphonates have been shown to halt primary and secondary progression of HO. In effect, we initiated the treatment of our patient on Zoledronic Acid since bisphosphonates have been shown to halt the progression of HO.

Clinical lessons: While bisphosphonate therapy has been used successfully to treat HO, to our knowledge, this is the first report demonstrating the possible benefit of bisphosphonates in the rare setting of TO.

 

Nothing to Disclose: AA, SR, JSD

29682 6.0000 SAT 303 A Bisphosphonate Therapy for Tracheopathia Osteochondroplastica 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Spandana Brown* and Laila Tabatabai
Houston Methodist Hospital, Houston, TX

 

Background:Calcinosis cutis (CC) is commonly seen in juvenile dermatomyositis (JDM) and typically presents 1-3 years from diagnosis. However, late presentation of CC in adulthood is rare and portends more difficulty with management.

Case: A 28-year female with a past medical history of JDM diagnosed at the age of 18 was referred to endocrinology clinic for progressive CC and low bone density. She noticed subcutaneous nodules 2 years prior to presentation along her medial thighs, ankles and right upper calf. Despite control of her JDM with cyclosporine and IVIG, she continued to have progressive calcinosis in her lower extremities without skin ulcerations or joint involvement. Her initial lab values showed a calcium 10.2 mg/dL (8.6-10.5 mg/dL), phosphate 4.2 mg/dL (2.4-4.2 mg/dL) , PTH 20 pg/mL (12-65 pg/mL) and 25-OH vitamin D 69 ng/mL (>30 ng/mL). At 3-months she was unable to tolerate higher doses of diltiazem due to side effects and stopped this medication 1 month later. Additionally, she developed new nodules on her left calf. At this time, she was started on IV pamidronate daily for 3 days every 3 months for 1 year. As it was difficult to assess the patient’s CC progression based on her subjective reports, we proceeded to obtain CT imaging to objectively quantify her calcium burden, including smaller nodules which were not yet causing symptoms. Baseline CT imaging of her lower extremities confirmed lower-extremity subcutaneous calcium deposition and quantified total soft-tissue calcium volume at 4.28 cm3 (N 0.0 cm3). At 11 months, IV pamidronate was discontinued because her lesions continued to progress. She was restarted on a lower dose of diltiazem and colchicine which she tolerated well. Lab studies at this time showed slightly elevated phosphorus level of 4.3 mg/dL and 25-OH vitamin D of 70 ng/mL. She was advised to limit dairy product intake to 2 servings daily and consume non-vitamin D fortified foods. However, despite these interventions, she developed rapidly-progressing pain behind her left knee and ultrasound imaging revealed calcification of the semimembranosus and semitendinosus tendons. Repeat CT showed 126.7% increase in lower-extremity calcium volume. Referral was made to orthopedic surgery for intervention.

Conclusion: The management of CC is extremely challenging, especially when it develops later in the course of JDM. There are currently no uniformly effective regimens to treat this debilitating condition. Medications including bisphosphonates, calcium-channel blockers, sodium thiosulfate and others may be effective, but results vary widely. Surgical intervention is necessary when calcifications cause severe pain or limit mobility. Additionally, to our knowledge, ours is the first case in which radiologic quantification of calcium volume was performed in a patient with CC secondary to JDM; this may serve as an effective method to monitor response to treatment.

 

Nothing to Disclose: SB, LT

30959 7.0000 SAT 304 A Late-Onset Calcinosis Cutis in a Patient with Juvenile Dermatomyositis: An Uncommon Treatment Challenge 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Semira Vasanti Gopie*, Reshma Ramakrishnan, Sudhaker D. Rao and Vaishali Thudi
Henry Ford Hospital, Detroit, MI

 

Introduction: PHP is a group of heterogeneous disorders defined by targeted end-organ (kidney and bone) unresponsiveness to PTH action and associated with hypocalcemia, hyperphosphatemia and elevated PTH levels. PHP-1 is a rare autosomal dominant disorder that appears to be caused by hypermethylation or mutations of the genes affecting the regulatory elements of GNAS1 (a gene encoding the alpha subunit of the coupled G protein receptor). Although PHP-1A has characteristic phenotypic features, PHP-1B usually presents with symptoms of hypocalcemia, low bone mineral density and sometimes osteitis fibrosa. We present an unusual patient with PHP-1B, with prolonged relatively asymptomatic hypocalcemia, and intra-cranial and extensive subcutaneous calcifications of the scalp resulting in alopecia.

Clinical Case:A 37 year old woman presented to our clinic for management of chronic hypocalcemia and hyperphosphatemia. She gave history of progressive alopecia of the scalp for 5 years, seizures, and hypothyroidism and had a low IQ, and has been in a group home for a number of years. She reported no symptoms of hypocalcemia, had not had seizures recently, and was not taking vitamin D, calcitriol or calcium supplements.

She weighed 67.1 kg and stood at 150cm tall with a BMI of 28.9 kg/m2and had none of the phenotypic features of PHPH-1A. Trousseau and negative Chvostek's signs were absent and there were no soft tissue calcifications. However, palpation of the skull revealed a granular/pebble-like feeling.

When seen in April 2016 showed her albumin adjusted serum calcium was 5.9 mg/dL (RR: 8.2 - 10.2 mg/dL), ionized calcium 0.80 mmol/L (RR: 1.00 - 1.35 mmol/L), phosphorus 5.3 mg/dL (RR: 2.5 - 4.5 mg/dL), PTH 650 pg/mL (RR: 15 - 65 pg/mL), 25-hydroxyvitamin D of 45 ng/mL (RR: >20 ng/mL), alkaline phosphatase of 167 IU/L, and a creatinine of 0.61 mg/dL (RR: <1.03 mg/dL). Previous labs from EMR from February 2013 showed a serum calcium of 7.9 mg/dL (range: 6.5 – 7.9 mg/dL) and phosphate of 5.7 and 5.3 mg/dl.

X-rays of the hands showed osteopenia and normal metacarpals, and CT scan of the head showed diffuse intracranial calcifications (basal ganglia and cerebellum), and diffuse subcutaneous punctate calcifications of the entire scalp.

She was started on calcitriol 0.25 mcg twice a day, and calcium carbonate 1000 mg with lunch and 500 mg with dinner. The daily dose of calcitriol was increased to 0.75 mcg, and then to 1.0 mcg. After 2 months, serum calcium had improved to 7.6 mg/dL, ionized calcium 0.99 mmol/L (1.00 - 1.35 mmol/L), phosphorus 4.5 mg/dL (2.5 - 4.5 mg/dL).

Conclusion: Although intracranial calcification is a well-known complication of all varieties of hypoparathyroid states, it is less common in pseudo and post-surgical hypoparathyroidism. We believe that extensive sub-cutaneous scalp calcifications caused her progressive scarring alopecia, a finding that has not been reported previously.

 

Nothing to Disclose: SVG, RR, SDR, VT

32445 8.0000 SAT 305 A Progressive Scarring Alopecia Due to Extensive Subcutaneous Scalp Calcifications in a Patient with Pseudohypoparathyroidism (PHP) 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Trisha Cubb*1, Sapna Patel2, Nadeem Tajuddin1, Travis Goodale3, Theresa Rodgers2, Van Anh Trinh2, Hussein Tawbi2 and Ramona Dadu4
1Baylor College of Medicine, 2University of Texas MD Anderson, 3Houston Methodist Hospital, Houston, TX, 4The University of Texas MD Anderson Cancer Center, Houston, TX

 

Context: The advent of checkpoint inhibitors has dramatically impacted the clinical course of multiple malignancies, but these drugs can also result in aberrant immune activation leading to undesirable off-target inflammation and autoimmunity. Although several endocrine irAEs following administration of anti PD-1 and CTLA-4 agents have been observed, parathyroid involvement has not yet been reported.

Case Description: A 73yo male was diagnosed with melanoma for which he underwent surgical excision but a year later developed diffuse metastatic disease involving soft tissue sites, bone, and liver. Combination immunotherapy with Nivolumab (anti PD-1 antibody) and Ipilimumab (anti CTLA-4 antibody) was initiated. Patient underwent two cycles of therapy, but shortly thereafter developed fatigue and bilateral extremity paresthesia. He reported to ED due to progressive symptoms including ataxia requiring use of wheelchair, slow speech, and perioral tingling. On exam, he displayed normal orientation, ataxia, and negative Chvostek/Trousseau sign. Laboratories revealed: total calcium markedly low (5mg/dl, 8.4-10.2mg/dl), albumin normal (4.1g/dL, 3.5-4.7g/dL), ionized calcium decreased (0.67mMol/L, 1.13-1.32mMol/L), magnesium low (1.5mg/dL, 1.8-2.9mg/dL), high phosphorous (6.6mg/dL, 2.5-4.5mg/dL), undetectable iPTH (<1.0pg/mL, 9-80pg/mL), decreased 25-hydroxyvitamin D (18ng/mL, 30-100ng/mL), normal 1,25-dihydroxyvitamin D (29pg/mL, 18-64pg/mL), FeCa 0.017, and negative PTH antibody. Evaluation of calcium sensing receptor antibodies was unavailable clinically, but pursued in research setting (pending). Laboratories a week prior to presentation were normal. He had no history of neck radiation and imaging showed no parathyroid infiltrative process. He was admitted with diagnosis of autoimmune primary hypoparathyroidism and started on calcium gluconate drip in addition to oral calcium carbonate, calcitriol, ergocalciferol, and magnesium supplementation. Close laboratory monitoring and aggressive repletion were pursued. He experienced significant improvement in symptoms that correlated with calcium correction. His parathyroid function has not recovered since diagnosis. Other irAEs have included: thyroiditis, hepatitis, dermatitis, and possible neuropathy. IrAEs have been medically managed, and he has shown great response to ongoing therapy.

Conclusion: Temporal proximity of hypoparathyroidism to initiation of Ipilimumab and Nivolumab without other mechanism for acute injury points towards immunotherapy as the most likely cause of primary hypoparathyroidism. The underlying etiology is likely nonspecific immune activation, but presence of CaSR antibodies is being evaluated. This case highlights the need to further understand the mechanism of irAEs and increase clinical vigilance to detect early signs and symptoms of endocrine irAEs.


 

Disclosure: RD: Advisory Group Member, Bristol-Myers Squibb. Nothing to Disclose: TC, SP, NT, TG, TR, VAT, HT

31423 9.0000 SAT 306 A Primary Hypoparathyroidism: A New Endocrine Immune Related Adverse Event (irAEs) Secondary to Combination Treatment with PD-1 and CTLA-4 Checkpoint Inhibitors 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Iana Mizumukai de Araujo1, Carlos Ernesto Garrido Salmon2, Marcello Henrique Nogueira-Barbosa3 and Francisco J A de Paula*4
1Ribeirao Preto Medical School, USP, Ribeirao Preto, Brazil, 2Ribeirão Preto Medical School, USP, Ribeirao Preto, Brazil, 3Ribeirão Preto Medical School, USP, Ribeirao Preto, Brazil, 4Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil

 

Introduction: The interaction between bone and adipose tissue is complex and it is still to be delineated. Recent studies call attention that not only marrow adipose tissue quantity but also lipids composition impacts bone health. Paradoxically, bone fragility in type 2 diabetes mellitus (T2DM) emerges in individuals showing high bone mass combined with low bone turnover, namely decreased serum levels of biochemical bone markers. The interplay between lipids composition and osteocalcin still is to be studied.

Objective:To investigate the relationship between bone marrow lipid fractions with bone mass and bone turnover markers in T2DM and obesity.

Material and Methods: The study group comprised 19 controls (6M and 13F), 21 (7M and 14F) obese and 22 T2DM subjects (11M and 11F). Magnetic resonance 1H spectroscopy (MRS) was used to assess BMAT and lipid fractions [saturated (SL) and unsaturated lipids (UL)] in the third lumbar vertebra (L3). DXA was used to measure bone mass in lumbar spine (L1-L4 BMD). Osteocalcin (OC) and CTX were assessed by ELISA immunoassay.

Results:The 3 groups were well matched by age (C: 54.8±7.2; O: 52.5±11.8; T2DM: 54.2±9.6 years) and height (C: 1.67±0.1; O: 1.62±0.1; T2DM: 1.63±0.1m). Weight was lower in C than in O and T2DM (C: 67.9±8.2; O: 83.1±18.7; T2DM: 87.1±16.9 Kg), as well as BMI (C: 24.1±1.6; O: 31.3±3; T2DM: 33±7 Kg/m²) (p<0.05). The mean values of L1-L4 BMD in T2DM was higher than in C (C: 0.952±0.109; O: 0.971±0.166; T2DM: 1.061±0.140g/cm²; p<0.05). BMAT (C: 35.2±9.5; O:32.3±6.1; T2DM: 36.4±8.5%); SL (C: 29.3±7%; O: 27.2±5; T2DM: 28.3±6.87) and UL (C: 3±1.2; O: 2.8±1.5; T2DM: 2.7±0.8%) values were similar in the 3 groups. The serum levels of OC were slightly lower in T2DM (C: 9.6±4; O: 9.5±7; T2DM: 6.8±2.8ng/mL), while CTX was lower in T2DM than in C group (CTX= C: 0.36±0.15; O: 0.35±0.14; T2DM: 0.25±0.1 ng/mL, p<0.05). As expected there was a negative correlation between BMAT and L1-L4 BMD (r=-0.25;p<0.05). Also, there was a positive correlation between OC and CTX (r=0.65;p<0.05). The circulatory levels of OC and was negatively correlated with L1-L4 BMD (r=-0.38; p<0.05). There was a positive correlation between OC and SL (r=0.29;p<0.05).

Conclusion:This study highlights interesting aspects concerning the osteometabolic profile in T2DM, which potentially can contribute to fracture susceptibility in this condition. Bone markers are not only low in T2DM, OC is both negatively correlated with bone mass as well as positively correlated with the bone marrow saturated lipids. These results indicate that high bone mass in T2DM is closely linked to decreased rate of bone remodeling and this process can be influenced by the lipid profile in bone marrow microenvironment.

 

Nothing to Disclose: IMD, CEGS, MHN, FJAD

31846 10.0000 SAT 307 A The Relationship Between Bone Mass with Osteocalcin and Bone Marrow Lipids in Type 2 Diabetes Mellitus 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Stefano Frara*, Teresa Porcelli, Filippo Maffezzoni, Anna Maria Formenti, Maura Saullo, Andrea Giustina and Gherardo Mazziotti
University of Brescia, Italy

 

Differently from what has been observed in the general population, HIV+ patients treated with HAART have increased risk of fragility fractures without significant differences between males and females. Moreover, HIV infection is frequently associated with hypogonadism the diagnosis of which is often challenging, due to variable values of gonadotropins and elevated circulating levels of sex-steroid biding globulin (SHBG). Whether hypogonadism may influence skeletal fragility in HIV patients is still largely unknown. In this cross-sectional study, we aimed at evaluating the association between bone mineral density (BMD, Hologic DEXA), radiological vertebral fractures (VFs) and serum gonadotropins (LH and FSH), total testosterone (TT), SHBG and calculated free (fT) testosterone in 103 subjects affected by HIV. VFs were found in 34 patients (33%); 15 had multiple fractures and 7 had at least one moderate-to-severe VF. Only 26% showed osteoporosis, whilst 13% had normal BMD and 61% had osteopenia. 26% had an increase in FSH and/or LH, but only 4 patients showed contextually a reduction in TT. We observed increased SHBG values with reduced fT in 29% of subjects. In univariate analysis, VFs were significantly associated with high levels of FSH (OR 4.2; p=0.02), high SHBG (OR 3.6; p=0,02), patients’ age (OR 1.1; p=0,01) and pathological T-scores (OR 4.0; p=0,001), whereas no association was observed between VFs and TT (p=0.47), fT (p=0.5) or LH (p=0.59). Elevated SHBG, but not FSH, also correlated with pathological T-score values (OR 2.7; p=0,03).
In conclusion, our study suggested an influence of gonadal status on VFs risk in males affected by HIV, consistently with the concept that increased levels of SHBG and FSH might be markers of hypogonadism. However, we cannot exclude that high circulating SHBG may have a direct and independent effect on skeletal health in HIV patients, such as already demonstrated in male patients with primary osteoporosis.

 

Disclosure: AG: Ad Hoc Consultant, Abiogen. GM: Chairman, Abiogen. Nothing to Disclose: SF, TP, FM, AMF, MS

30581 11.0000 SAT 308 A  Sex-Hormone Binding Globulin As Determinant of Radiological Vertebral Fractures in Male HIV Patients Under Antiretroviral Therapy 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Ayesha Farooq Malik* and Robert C. Smallridge
Mayo Clinic, Jacksonville, FL

 

Introduction:There is evidence that tenofovir can cause hypophosphatemia and Fanconi syndrome. Tenofovir induced hypophosphatemia has been reported with a normal fibroblast growth factor 23 (FGF-23) in a few case reports and elevated in one case. We present a patient with tenofovir induced hypophosphatemia and proteinuria with an elevated FGF-23 level.

Case:A 69-year-old male with HIV for 13 years was seen for weight loss (not suspected to be from HIV) and thyroid nodules. At our facility calcium = 8.9 mg/dL (8.9 -10.1 mg/dL), phosphorus = 2.1 mg/dL (2.5-4.5mg/dL) and alkaline phosphatase (ALP) = 315 U/L (45-115 U/L). 10 days later, calcium = 8.3 mg/dL (8.6 -10.3 mg/dL), 25-hydroxyvitamin D = 32 (30-100ng/mL), parathyroid hormone = 105 (10-65 pg/mL) and alkaline phosphatase = 293 U/L. He was started on ibandronate for a T score of -5.2 (distal forearm) and -2.8 (lumbar spine).

At his local lab, a parathyroid hormone = 29, calcium =9.1mg/dL, phosphorus = 1.6mg/dL (2.1-4.3mg/dL), and alkaline phosphatase = 282 with 75% bone iso-enzyme (28-66%). He had been taking tenofovir for 3 years but this was recently changed to Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate).

A 24-hour urine phosphorus was 711mg (0-1099mg), urine protein = 1.1gm and percent tubular reabsorption of phosphorus = 45.5%. An FGF-23 was elevated at 1740 (<=180 RU/mL), with serum calcium = 8.7mg/dL, phosphorus = 1.3mg/dL, and 1,25 hydroxyvitamin D= 44 (18- 64pg/mL). He was advised to stop Atripla and two weeks later his phosphorus level normalized to 2.7mg/dL. Two months later the phosphorus was 2.3mg/dL and ALP remained elevated at 328.

Four months after stopping Atripla, a calcium was 8.6mg/dL, phosphorus was at 2.1mg/dL, and ALP= 275. FGF-23 remained elevated at 1740 RU/mL. Two months later, phosphorus was 2.3mg/dL with an improved ALP of 141 U/L. The patient also had resolution of muscle weakness and 20 pound weight gain.

Nine months after stopping tenofovir, phosphorus=2.7mg/dL and at one year a repeat 24 hour urine phosphorus = 284 mg and urine protein =207mg. Attempts to repeat an FGF 23 level were unsuccessful.

Discussion:A case series found that those on tenofovir who had hypophosphatemia had normal FGF 23 levels. Suggested mechanism of hypophosphatemia was possibly due to a parathyroid hormone-like factor. One patient had an elevated FGF-23 level that returned to normal six months after discontinuing tenofovir. This case is the second described in which FGF-23 may be implicated as a cause for hypophosphatemia in an HIV patient on tenofovir. Fibroblast Growth Factor 23 (FGF-23) is involved in regulation of calcium and phosphorus homeostasis. When elevated, it inhibits 1,25 hydroxyvitamin D thus decreasing phosphorus absorption. It also decreases expression of 1 alpha hydroxylase, decreasing renal absorption of phosphorus. It also may decrease parathyroid hormone.

 

Nothing to Disclose: AFM, RCS

31823 12.0000 SAT 309 A Tenofovir Associated Hypophosphatemia with Elevated Fibroblast Growth Factor 23 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Namki Hong*1, Da Hea Seo1, Hokyou Lee2, Chang Oh Kim3, Yoosik Youm4, Hyeon Chang Kim5 and Yumie Rhee1
1Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea, Republic of (South), 2Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, 3Yonsei University College of Medicine, Seoul, Korea, Republic of (South), 4Yonsei University, Seoul, Korea, Republic of (South), 5Yonsei University College of Medicine

 

Red blood cell distribution width (RDW), a conventional marker for ineffective erythropoiesis, has been found to be associated with mortality in many diseases including coronary heart disease, heart failure, and in community-dwelling elderly population (1). A recent study demonstrated that elevated RDW also predicted mortality in a hip fracture cohort (2). Furthermore, rapid hip bone loss in elderly men was associated with increased odds of anemia and low lymphocytes, suggesting the possible interdependency between hematopoiesis and bone health (3). However, whether RDW is associated with vertebral fracture (VF), the most common fracture in elderly, has not been investigated yet. Data of 576 elderly women were collected between 2012 and 2015 in a community-based cohort study (4). Primary outcome was presence of morphometric VF assessed by lateral thoracolumbar radiograph. Information regarding fracture history, comorbidities, and medication use was collected by interviewer-assisted questionnaire. Physical performance was measured by timed up-and-go test. After excluding those with estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2, history of malignancy, or without available VF assessment or RDW measurements, a total of 559 subjects were analyzed. Mean age and body mass index of study population was 71.1 ± 4.3 years and 24.5 ± 3.1 kg/m2, respectively. Morphomectric VF was detected in 127 subjects (22.7 %). Mean RDW was higher in subjects with VF compared to those without (13.1 ± 0.5 % vs. 12.9 ± 0.5 %, P = 0.005). Prevalence of VF increased in stepwise fashion from 16.9 % in lowest RDW tertile (RDW < 12.7 %) to 27.5 % in highest tertile (RDW ≥ 13.0 %, P for trend = 0.014). RDW was positively correlated with age, serum osteocalcin, and alkaline phosphatase level, whereas hemoglobin, ferritin, albumin, and eGFR showed negative correlation with RDW. However, serum 25-hydroxyvitamin D, C-reactive protein (CRP) level, and lumbar spine areal bone mineral density (LSBMD) did not correlate with RDW. In logistic regression analysis, higher RDW value was independently associated with greater odds of morphomectric VF (odds ratio 1.49, 95% CI 1.01-2.20, P = 0.043) after adjustment for hemoglobin and conventional risk factors including age, history of fracture, smoking status, physical performance, previous steroid use and hormone replacement therapy, LSBMD, and 25-hydroxyvitamin D level. Further adjustment for serum ferritin as an indicator of iron status, osteocalcin, CRP, albumin, and eGFR did not attenuate the association of RDW with prevalent VF (odds ratio 1.55, 95% CI 1.04-2.31, P = 0.029). Our findings suggest that elevated RDW level, a readily available marker in most clinical settings, may be an independent risk factor for prevalent VF, which merits further investigation in line with crosstalk between hematopoietic system and bone metabolism.

 

Nothing to Disclose: NH, DHS, HL, COK, YY, HCK, YR

30844 13.0000 SAT 310 A Elevated Red Blood Cell Distribution Width Is Associated with Greater Risk of Morphometric Vertebral Fracture in Elderly Women Independent of Anemia, Inflammation, and Nutritional Status 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Amena Iqbal*1, Boby G Theckedath2, Janice L Gilden3 and Alvia Moid4
1Rosalind Franklin University of Medicine /Chicago Medical School and Captain James A. Lovell Federal Health Care Center, North Chicago, IL, Lincolnwood, IL, 2Rosalind Franklin University of Medicine and Science/ Chicago Medical School, and Captain James A. Lovell Federal Health Care Center, North Chicago, IL, 3Rosalind Franklin University of Medicine and Science/Chicago Medical School and Captain James A Lovell Federal Health Care Center, North Chicago, IL, 4Captain James A. Lovell Federal Health Care Center and Rosalind Franklin University of Medicine and Science Chicago Medical School, North Chicago, IL

 

Background:Most metabolic bone disease is assumed to be osteoporosis and evaluation for other causes is not common. Although celiac disease with malabsorption occurs in both pediatric and adult patients, it can present with minor and subclinical manifestations of the disease. Furthermore, osteomalacia may be the sole manifestation of celiac disease. We present an interesting case of a young male patient who was referred to Endocrinology for treatment of “osteoporosis” after L4 compression fracture of the spine and discovered to have ostemalacia from this malabsorptive disease.

Clinical case: A 32 year old young male with no significant past medical history was referred for evaluation of osteopenia on Bone density (DXA), ordered due to a traumatic L4 lumbar spine compression fracture suffered while playing dodgeball. He denies steroid use, personal or family history of bone disorders. He did admit to having loose stools intermittently for the past few years.

Physical Examination: Normal except for BMI of 22.83 kg/m2. No signs of tetany. Laboratory Tests : Hgb 14g/dL (13-17) , Calcium 7.5 mg/dL(8.5-10.1) , Phosphate 3.3 mg/dL (2.5-4.9) , Magnesium 2 mg/dL (1.8-2.4) ,Vitamin D 25ng/mL (30-100), PTH 29 pg/ mL (12.4-76.8), Iron 45 ug/dL(65-175) , TIBC 334 ug/dL (250-450), Iron saturation 13% (10-50), folate 16.1 ng/mL(8.7-55.4), Cr 0.99 mg/dL(0.67-1.17), (eGFR = 109.8 ml/min).

Alkaline phosphatase 134 U/L (45-117), TSH 2.30 uIU/mL ( 0.358-3.74) , ESR 16 mm/HR (0-15), CRP 1 mg/dL(0.0-0.9) , SPEP/UPEP normal , Calcium 24 hr urine <5mg/24hr (42 - 353) . Dual-energy x-ray absorptiometry (DXA) : Anterior lumbar spine BMD 0.828, T- score -2.4, Femoral neck BMD 0.695, T- score -1.7 and total hip BMD 0.764, T- score -1.8 .

Due to iron deficiency anemia and Vitamin D deficiency, the differential diagnosis included syndromes of malabsorption. Upper gastrointestinal endoscopy showed Duodenitis, followed by a biopsy of duodenum which showed severe villous blunting, consistent with celiac disease. Celiac titers: Anti-tissue transglutaminase IgA antibodies TTG IgA >100 U/mL (<5) and Gliadin IgA 97 Units (<20 Antibody not detected), Gliadin IgG 84 Units (>or=20 Antibody detected), and suggested celiac disease. Oral Vitamin D calcium and iron supplements, and gluten free diet were advised.

Conclusion:  The diagnosis of celiac disease was made in an asymptomatic patient for hypocalcemia and osteomalacia, due to evaluation for the etiology of metabolic bone disease, following a traumatic fracture, which prompted a DEXA scan. Celiac disease, an uncommon autoimmune disease characterized by small intestinal damage typically associated with loss of absorptive villi causing malabsorption, osteomalacia and fracture as the first presenting findings is rare. Therefore, malabsorptive causes of metabolic bone disease should be considered in these cases so that proper treatment is administered. 

 

Nothing to Disclose: AI, BGT, JLG, AM

30050 14.0000 SAT 311 A Low Bone Density Is Not Always Osteoporosis! 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Preethi Kadambi* and Nisha Nathan
GWU, Washington, DC

 

Introduction:

The use of proton pump inhibitors (PPI) has been associated with hypomagnesemia especially in older individuals. Incidence is more common with concurrent use of diuretics or impaired kidney function.

Clinical Case:

A 68 year old woman presented to the Emergency Department when labs checked by her primary care physician revealed a critically low magnesium of 0.3 mg/dL (normal 1.6-2.3 mg/dL) and corrected calcium of 6.2 mg/dL (normal 8.7-10.3 mg/dL). Medical history was significant for recent occipital stroke and diabetes mellitus (DM). She had noticed perioral numbness, tingling, weakness and fatigue over a few weeks. She reported decreased appetite and a 20 lb weight loss over several months. Ionized calcium was 3.1 mg/dL (normal 4.5–5.6 mg/dL). PTH was 23 pg/mL (normal 15-65 pg/mL) and increased to 62 pg/mL after magnesium replacement. Her 25-hydroxy Vitamin D was 39.0 ng/mL (normal 30.0-100.0 ng/mL) with 1,25-hydroxy Vitamin D of 50.1 pg/mL (normal 19.9-79.3 pg/mL). Her creatinine was 0.8 mg/dL (0.5-1.0 mg/dL) with a GFR of 88 mL/min (normal > 59 mL/min).

She was on many medications including omeprazole, metformin, dulaglutide, levetiracetam, Vitamin D, amlodipine and atorvastatin. None of the other medications she was on were known to cause hypomagnesemia. She was not on diuretics. Her DM was well controlled with A1C of 6.4% (normal 4.8-5.6%) and could not have caused her profound hypomagnesemia. Omeprazole was considered to be the cause and was stopped. She had aggressive IV magnesium and calcium replacement - eventually transitioned to oral supplements. Her calcium improved to 10.3 mg/dL and has remained above 9.0 mg/dL since, without supplements. Her magnesium has been in the range of 1.7-2.0 mg/dL without supplements.

Conclusion:

PPI use is associated with 43% increased incidence of hypomagnesemia in patients older than 65, predominantly with concurrent use of diuretics. Our patient was unique with respect to the degree of hypomagnesemia and lack of concurrent diuretic use. Severely low magnesium and subsequent profound hypocalcemia was completely reversed, and did not recur after cessation of PPI. It is important to recognize and treat PPI associated hypomagnesemia to prevent cardiac complications especially in the elderly.

 

Nothing to Disclose: PK, NN

31623 15.0000 SAT 312 A The Calcium-Magnesium Byplay with Proton Pump Inhibitors 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Grace Y Kim*, Joanna Khatib, Jamila Benmoussa and Hassan Shawa
Albany Medical College, Albany, NY

 

Introduction: CYP24A1 homozygous gene mutation is a well known cause of infantile hypercalcemia and adult onset nephrocalcinosis. A mutation in this gene causes the loss of function of 24 hydroxylase enzyme that is essential for the excretion of vitamin D metabolites. We describe a rare case of an adult patient with recurrent nephrolithiasis carrying a heterozygous mutation of the CYP24A1 gene.

Case presentation: A 35 year old man presented with recurrent nephrolithiasis that began in his adulthood. Biochemical work up was remarkable for hypercalcemia (10.6 mg/dl, nl. 8-6-10.3), hypercalciuria (24-hr urine calcium 421 mg/24hr, nl < 300), high 1,25-dihydroxyvitamin D (160 pg/mL, nl. 10.0 – 75.0) and low parathyroid hormone level (12.4 pg/mL, nl. 14 –72). 25-hydroxyvitamin D was 20.4 pg/ml (nl. 21–50). He had no known history of hypercalcemia during childhood. Patient denies the use of vitamin D supplement. Extensive workup for granulomatous, infectious, autoimmune diseases and malignancies were negative. Genetic testing revealed a double heterozygous mutation in the CYP24A1 gene.

Conclusion: This case illustrates that heterozygous mutation of CYP24A1 gene can precipitate adult onset recurrent nephrolithiasis. Performing the genetic testing for CYP24A1 gene mutations in adults with recurrent nephrolithiasis should be considered especially if it is associated with non PTH-mediated hypercalcemia and/or hypercalciuria even without history of hypercalcemia during childhood.

 

Nothing to Disclose: GYK, JK, JB, HS

30523 16.0000 SAT 313 A A Novel Variant Heterozygote CYP24A1 Gene Mutation: A Rare Cause of Adult Onset Recurrent Nephrolithiasis 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Dinesh Edem, Helena Levitt and Sue Marion Challinor*
UPMC, Pittsburgh, PA

 

Introduction: Diagnosis of hypophosphatemia is often missed due to non specific symptoms, but it can cause considerable morbidity. Causes of hypophosphatemia include decreased intestinal absorption, internal redistribution, or increased renal excretion. FGF-23 is an osteocyte - derived hormone that maintains normal phosphate levels by decreasing both phosphate reabsorption and plasma calcitriol levels. We present a case of FGF-23 mediated hypophosphatemia caused by treatment with IV Ferric Carboxymaltose (FCM), resulting in severe muscle weakness.

Case: An 81 yr old male with a history of gastric bypass surgery 32 yrs previously, was admitted for evaluation after a 14- month history of progressive back pain, muscle weakness, frequent falls and inability to ambulate coinciding with onset of monthly IV FCM for Iron deficiency anemia. FCM was last given 1 week before admission. Physical exam revealed a wheelchair-bound obese male, L3-L5 point tenderness, decreased motor strength of 4/5 in lower extremities, and difficulty ambulating. CT revealed diffuse osteopenia and compression deformities of L1, L2 and L3. He was found to have a low phosphorus (Phos) level of 1.4 mg/dl (2.5-4.5). Phos was normal at 2.9, 3 yrs before. Further workup revealed elevated urine fractional excretion of phosphate (UFE Phos) of 49% (5-20%), inappropriately normal (nl) 24 hr urine Phos of 540 mg/D (400-1300), nl corrected Ca of 10.0, nl Mg of 1.7, elevated PTH of 194 pg/ml(15-65), nl 25- OH Vitamin (Vit.) D level of 33 ng/ml, and a low 1, 25 OH Vit. D level of 11 pg/ml (18-72). His FGF-23 level was elevated at 269 RU/ml (n<180). Markers of bone resorption were elevated: Alk Phos at 276 IU/L (38-126), Urine NTX at 118 nmol BCG/mmol Cr (9-60), and CTX at 1711 pg/ml (87-345). He was treated with oral Calcitriol 0.25mcg BID, oral 25-OH Vit. D 2000 IU QD, and oral K-Phos 1500 mg TID. IV FCM injections were changed to iron Dextran( DXN). Improvement in muscle weakness correlated with normalization of his Phos levels. Calcitriol and oral Phos supplementation were stopped after discharge at 4 weeks and 10 weeks, respectively. At 2 months after discharge, his FGF-23 level and 1,25 OH Vit. D normalized at 110 and 30, respectively. At 5 months follow-up, he was able to ambulate with use of a cane.

Discussion: Our case is similar to prior reports, indicating that IV iron preparations with carbohydrate moieties like FCM, lead to increased FGF-23 levels and cause hypophosphatemia, low 1,25 OH Vit-D and increased UFE Phos 1-4 . In contrast to FCM, IV iron DXN was not associated with elevated FGF-23 or low Phos in a prospective study which compared the two forms of iron 2. Similarly, our patient maintained a normal Phos after switching to iron DXN treatment. Parenteral iron formulations are increasingly prescribed, hence clinicians should be aware of the risk of significant, symptomatic hypophosphatemia that is a consequence of FCM infusions.

 

Nothing to Disclose: DE, HL, SMC

31602 17.0000 SAT 314 A A Case Report of Symptomatic Hypophosphatemia Secondary to Elevated FGF-23 from Parenteral Ferric Carboxymaltose Treatment for Iron Deficiency Anemia 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Anne Trinh1, Phillip Wong1, Anuradha Sakthivel2, Michael Fahey3, Sabine Hennel4, Justin Brown3, Boyd J Strauss3, Peter R Ebeling3, Peter J Fuller1 and Frances Milat*1
1Hudson Institute of Medical Research, Clayton, Australia, 2Eastern Health, Australia, 3Monash University, Australia, 4Monash Health

 

Context: Spina bifida (SB) can lead to marked changes in body composition and bone mineral density (BMD) through diminished ambulation, renal impairment and anticonvulsant medication use. With increased life expectancy, diseases of adulthood such as obesity and osteoporosis are emerging co-morbidities in SB, but there is limited literature to guide clinical management.

Objective: To examine the relationship between body composition, BMD, and fractures in adults with SB.

Design: Retrospective cross-sectional study.

Setting and Participants: 49 adults with SB (median age 32.7 years, interquartile range 22.6-39.0) who had dual-energy x-ray absorptiometry (DXA) imaging at a single tertiary hospital between 2004-2015.

Results: Despite the young age of the cohort, there was a high prevalence of metabolic comorbidities: obesity (79.6%), obstructive sleep apnoea (20.4%), hypertension (8.2%), deep vein thrombosis/pulmonary embolism (8.2%) and type 2 diabetes requiring medication (4.1%). The mean BMI was 31.7 ± 7.5 kg/m2, and BMI incorrectly classified 7 of 8 patients as normal who had an increased percentage total body fat on DXA. BMI was not statistically different between ambulatory and non-ambulatory patients (30.3 ± 6.8 kg/m2 vs 32.0 ± 8.7 kg/m2 respectively; p= 0.58). Using age and sex-matched fat centiles from NHANES III, 25 of 40 (62.5%) had total body percentage fat over the 95th centile as measured by DXA. Fat distribution was altered with leg and trunk fat increased to the 95th centile compared to the NHANES III population.

Low bone mass (defined as a Z score of ≤-2.0) was present in 21.9% of subjects at the L1 vertebra and in 35.1 % at the femoral neck (FN). Ten patients (20.4%) had a history of fragility fracture, all were of the femur and tibia apart from two fractures involving the shoulder. Fat mass accounted for 18.6% of the variance in BMD (p=0.005), which remained significant and positively associated with BMD after adjustment for age, gender and height. BMD or Z-score at L1, FN or total body site did not correlate with fracture.

Conclusions: Obesity and low BMD are common in young adults with SB. Changes in body composition seen in this cohort do not appear to be satisfactorily explained by ambulatory status. Strategies to improve BMI and body composition parameters are necessary to minimise comorbidities in this group.

 

Nothing to Disclose: AT, PW, AS, MF, SH, JB, BJS, PRE, PJF, FM

32582 18.0000 SAT 315 A Characterisation of Bone and Body Composition Parameters in Young Adults with Spina Bifida 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Hye-Sun Park*1 and Sung-Kil Lim2
1Yonsei University College of Medicine, Korea, Republic of (South), 2Yonsei University College of Medicine, Seoul, Korea, Republic of (South)

 

To evaluate whether muscle area and lipid accumulation in muscle/liver are related with insulin resistance and bone mineral density (BMD), we performed quantitative computed tomography (QCT). 149 postmenopausal women > 60 years old were enrolled. Serum fasting glucose and insulin were measured and QCT was performed. The cross sectional areas (CSA) of the muscle were obtained using free-hand drawn regions of interests (ROI). Areas of gluteus and quadriceps were measured at the level of symphysis pubis and at the level of 7cm from the lesser trochanter, respectively. Hounsfield units (HUs) of quadriceps and gluteus were measured at ROIs and those of liver were measured at the liver segment VII. Hand grip test (HGT) and short physical performance battery (SPPB) were performed to estimate muscle strength. The mean age of enrolled subjects was 72.37 years, and BMI was 23.64 kg/m2. Smaller muscle area and lower HU of muscle/liver were related with higher insulin resistance. Both gluteus and quadriceps area were inversely related with HOMA-IR (r=-0.499 and -0.247, respectively) and fasting glucose level (r=-0.409 and -0.271, respectively). HU of gluteus, quadriceps and liver were also inversely related with HOMA-IR (r=-0.265, -0.289 and -0.506, respectively), not with HOMA-β. They were all statistically significant (p < 0.05). In contrast, HGT and SPPB were not associated with insulin resistance (p = 0.562 and 0.801, respectively). Furthermore, we compared the parameters between osteoporosis group and non-osteoporosis group. The mean value of muscle area was significantly lower in osteoporosis group. The mean value of gluteus area of osteoporosis group was 3125.20 ± 609.35 mm2, whereas 3421.46 ± 534.38 mm2 in non-osteoporosis group (p=0.004). The same trend was found in quadriceps. The mean value of quadriceps area in osteoporosis group was 3301.87 ± 506.31 mm2 and in non-osteoporosis group, it was 3514.98 ± 607.69 mm2 (p=0.032). In addition, HU of liver was also statistically different between the two groups. In osteoporosis group, liver HU was 55.90 ± 8.89, whereas in non-osteoporosis group, it was 59.87 ± 6.17 (p=0.002), which means higher fat content of liver in osteoporosis group. In osteoporosis group, hand grip strength was lower than in non-osteoporosis group (p = 0.011), however, no statistical significance was found on SPPB. In conclusion, parameters from QCT, such as muscle area and HU of muscle/liver, are clearly associated with high insulin resistance and low bone mineral density. There is lack of study regarding interrelation between muscle, liver, and bone altogether. This study shows that QCT is a simple and easy tool in evaluating interaction between insulin target organs. However, further investigations are needed to elucidate their causal relationship.

 

Nothing to Disclose: HSP, SKL

31395 19.0000 SAT 316 A Muscle Area and Hounsfield Unit of Muscle/Liver Measured By Quantitative Computed Tomography Are Significantly Associated with Insulin Resistance and Low Bone Mass in Postmenopausal Women 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Ieva Ruza*1, Zane Lucane1, Alvils Krams1 and Aivars Lejnieks2
1Riga Eastern Clinical University Hospital, Riga, Latvia, 2Riga Stradins University, Riga, Latvia

 

Background. Sarcoidosis is a granulomatous disease that most commonly affects lungs, but it may also affect any other organ. There is an increased synthesis of calcitriol in sarcoid granulomas. Elevated blood levels of the active form of vitamin D can cause hypercalcemia, hypercalciuria, and it can affect bone metabolism. Many factors, like use of glucocorticoids, abnormal metabolism of calcium and vitamin D, decreased intake of calcium, and decreased level of physical activity, can cause bone loss and increase the risk of fractures in patients with sarcoidosis.

Aim.To evaluate 10-year osteoporotic fracture and hip fracture risk and to analyze factors affecting fracture risk for newly diagnosed patients with sarcoidosis.

Materials and methods. The cross-sectional study included 171 patients (68 men and 103 women) with histologically newly confirmed diagnosis of sarcoidosis who were hospitalized due to suspected disease during the time period from the 1st of January 2013 until the 31st of December 2014 and agreed to participate in the telephone interview in December 2015. QFracture®-2012 1.0 algorithm questions were asked to patients. All data were analyzed using Microsoft Office Excel and IBM SPSS® 22.0.

Results. The age of patients ranged from 30 to 80 years with mean age of 44±12 years. The mean 10-year risk of any osteoporotic fracture in patients was 1.7% (from 0.3% to 20.7%), the mean 10-year risk of hip fracture – 0.4% (from 0% to 13.6%). 10-year risk of any osteoporotic fracture above 11.1% was found in 5.9% of postmenopausal women, and in none of premenopausal women. 10-year risk of any osteoporotic fracture above 2.6% was found in 4.4% of men.

In 7.6% of cases one of the patient’s parents had had an osteoporotic fracture, and in 2.3% of cases there was an osteoporotic fracture in the personal history. 3.3% of patients had had a symptomatic fracture after being diagnosed with sarcoidosis. 26.3% of patients had used medication for the treatment of sarcoidosis, and 21.6% of these patients had used short-term glucocorticoids after diagosis. 33.9% of patients had used vitamin D supplements in the six months preceding the study. 24.0% of patients had a comorbidity that could affect the risk of osteoporotic fracture. Most common comorbidities were asthma and angina pectoris.

Conclusions. An increased 10-year risk of osteoporotic fracture (above 11.1% in women and above 2.6% in men) was found in 5.9% of postmenopausal women, none of premenopausal women, and 4.4% of men. Multiple factors can affect bone metabolism and risk of osteoporotic fracture in patients with sarcoidosis. Osteoporotic fracture risk assessment should include all possible risk factors, and preventive measures should be taken.

 

Nothing to Disclose: IR, ZL, AK, AL

30644 20.0000 SAT 317 A Osteoporotic Bone Fracture Risk Assessment in Latvian Patients with Newly Diagnosed Sarcoidosis 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Hyun-Ae Seo*1 and Eui-Hyun Kim2
1Deagu Fatima Hospital, Daegu, Korea, Republic of (South), 2Daegu Fatima Hospital, Daegu, Korea, Republic of (South)

 

Objective : Due to its high prevalence, osteoporosis is considered as a serious public health concern. Overweight is known to have a beneficial effect on bone mass density (BMD). But, there are not many studies about the independent effect of fat mass and lean mass on BMD. In this study, we investigated the association between the body composition and bone mass density.

Material and Methods : A total of 760 Korean (446 male, 314 female), who had undergone comprehensive routine health examinations at the Daegu Fatima Hospital, were included in this study. The bone mineral density of lumbar spines (L1 to L4) was measured by dual-energy X-ray absorptiometry. Bioelectrical impedance analysis was used to measure the body composition by composition analyzer (Inbody 3.0, Biospace, Seoul, Korea).

Results : The mean age of total subjects was 47.29 ± 11.60. There was significantly positive association between muscle mass and BMD of lumbar spines in both males and females. Fat mass was significantly related with BMD of lumbar spines in male subjects, but this association was not shown in females. After adjustments for age and height, the significant positive correlation between muscle mass and BMD of lumbar spines was retained in both males and females. In males, the positive association between fat mass and BMD of lumbar spines was only shown in L1 and L2. In females, all sites of lumbar spine were related with fat mass. 

Conclusion : In this study, muscle mass was highly related with BMD of lumbar spines in males and females. Association between fat mass and BMD was inconsistent. Muscle mass is more important that fat mass for BMD. 

 

Nothing to Disclose: HAS, EHK

30104 21.0000 SAT 318 A Association Between Body Composition and Bone Mass Density 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Almoutaz Shakally*1 and Ameer Khowaja2
1University of Minnesota, Minneapolis, MN, 2Hennepin County Medical Center, Minneapolis, MN

 

Introduction:

Fahr's syndrome is a rare, neurological disorder characterized by abnormal calcified deposits in basal ganglia and cerebral cortex. The etiology of this syndrome is not fully understood. However, associations with a number of conditions have been noted; most common of which are endocrine disorders including hypoparathyroidism, pseudohypoparathyroidism and hyperparathyroidism. Clinically, it may present with an array of movement disorders, cognitive impairment, dementia and seizure.

Clinical Case:

We present a case of a 53-year-old female who was admitted for evaluation of seizures. She had 3 episodes of tonic-clonic seizures within a period of 48 hours. The patient was found to have extremely low calcium upon admission with an ionized calcium of 2.24 mg/dl and a total calcium of 4.6 mg/dl. Phosphorus was elevated to 8.3 mg/dl. Further investigation revealed undetectable iPTH level and a 25-OH Vitamin D level of 15 pg/ml

Head CT scan showed Diffuse and prominent calcifications of the subcortical white matter, basal ganglia, and choroid plexus in a bilateral symmetric distribution throughout the cerebral and cerebellar hemispheres. A Follow up brain MRI revealed Diffuse T2 hypointensity involving the basal ganglia, dentate nuclei and linear/curvilinear T2 hypo intensities within cerebral hemispheres and cerebellum. The diagnosis of Fahr's disease was made based on the clinical presentation and the radiographic findings.

The patient was started on calcium gluconate 1 amp intravenously twice daily, IV calcitriol 1 mcg IV daily, and PhosLo (calcium acetate) one tablet three times daily with meals. The patient's calcium level was monitored throughout her hospital course. Upon discharge, her calcium level was 6.8 mg/dl. The patient was sent home on a prescription of calcium carbonate with vitamin D supplement 500/200, 1 tablet orally three times daily, calcitriol 0.5 mcg 2 capsules orally twice daily. The pt was also recommended to be placed on a divalproex 1 gram ER daily permanently due to the extensive brain calcifications.

Conclusion:

Fahr’s syndrome is a rare disease. However, the association with endocrine disorders especially hypoparathyroidism is common. Since correcting the impaired calcium and phosphorus metabolism often leads to considerable improvement, it is essential to evaluate and treat patients with this syndrome for parathyroid disorders.

 

Nothing to Disclose: AS, AK

30527 22.0000 SAT 319 A A Rare Case of Fahr's Syndrome and Associated Hypoparathyroidism 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Swathi Sista* and Seth Mathew Arum
University of Massachusetts, Worcester, MA

 

Background:Teriparatide (PTH 1-34) is a PTH analog that is FDA approved to treat post-menopausal osteoporosis. The use of teriparatide in managing adynamic bone disease, which is a multi-factorial process characterized by low-bone turnover, PTH resistance, and relative PTH deficiency may prove promising in improving bone-related outcomes.

Clinical Case: A 67 year-old woman with a history of long-standing, severe osteoporosis in the setting of CKD stage 5 from lupus nephritis presented to the Endocrinology Clinic due to multiple compression fractures. She was initially treated by her Rheumatologist with alendronate and low-dose calcitriol soon after her first fracture, though given her underlying history of renal dysfunction her dose of alendronate was briefly reduced by 50%. Due to ongoing fractures, her alendronate was eventually increased to the full dose and she was referred to Endocrinology for further evaluation. At her first clinic visit, she was noted to have relatively low intact parathyroid hormone (iPTH) (46 pg/mL, n 12-65 pg/mL) and bone-specific alkaline phosphatase (BSAP) (8.0 mcg/L, n 5.6-29.0), thus raising concerns for adynamic bone disease (ABD). She was advised to discontinue both alendronate and calcitriol and to undergo repeat iPTH (85 pg/mL) and BSAP (15.9 mcg/L) in 4 weeks. Seeing that both studies remained relatively unchanged, a bone biopsy was performed revealing low-bone turnover, thus confirming a diagnosis of ABD. Soon after her diagnosis, she began treatment with teriparatide and has yet to sustain another compression fracture as confirmed on plain films of the thoracic and lumbar spine nearly 18 months since initiating this therapy. Furthermore, her iPTH subsequently increased (119 pg/mL) and her BSAP remains stable (10.8 mcg/L). An English-language literature search reveals 4 individual studies describing 17 patients with biopsy-proven ABD who were treated with teriparatide. They achieved similar increases to their iPTH soon after initiating treatment, and had improvements to their bone mineral density as measured on dual-energy x-ray absorptiometry (DXA).

Conclusion: This case demonstrates the potential benefit of using teriparatide as a treatment strategy in patients with adynamic bone disease so as to improve their bone-related outcomes.

 

Nothing to Disclose: SS, SMA

32612 23.0000 SAT 320 A The Management of Adynamic Bone Disease with Teriparatide 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Dorothea Barbara Szczawinska*1, Reinhard Santen1, Martin Engelbach2, H. Skladny3, Peter Herbert Kann4 and Christof Schoefl5
1Endocrine Clinic, Frankfurt am Main, GERMANY, 2Endocrine Clinic, Frankfurt am Main, Germany, 3Synlab Humangenetik Mannheim, 4University Hospital Marburg, Marburg, Germany, 5Endocrine Clinic, Bamberg, Germany

 

Background

Osteogenesis imperfecta is a clinically and genetically heterogenous connective tissue disorder characterized by bone fragility, deformity and growth deficiency. With its estimated incidence of 1:20000 it’s a differential diagnosis to consider while evaluating for secondary causes of osteoporosis.

Most cases are caused by mutations in the type 1 collagen genes. Elucidating new mutations and correlating them with the clinical phenotype may provide new insights about new possible therapeutic approaches.

Clinical Case

A 36-year old man with a history of multiple (15) non-traumatic fractures during childhood and a recent non-traumatic thoracic spine fracture presented for further evaluation in our endocrine clinic. Physical examination revealed short stature (168cm) and bilateral pendular nystagmus (congenital). There was no evidence of bone deformities or blue sclerae. On further questioning, he was diagnosed with otosclerosis and underwent corrective operations in year 2009 and 2013. There was also a history of primary hyperparathyreoidism with a subsequent parathyroidectomy performed in 1997. Of note, there was no family history of fractures, osteoporosis, bone deformities or primary hyperparathyreoidism. Subsequently performed DXA (04/16) scan confirmed the diagnosis of osteoporosis (Lumbar spine 4 T-score: -4,5 SD, Z-score: -4,5 SD, Hip T- score: -2,4 SD, Z-score: -1.8 SD). Comprehensive biochemical evaluation showed no evidence for possible secondary causes of osteoporosis. Next, genetic testing was done and revealed a new, previously not reported (reference HGMD Professional 2016.1) heterozygous nonsense variant c. 2677G>T in the COL1A1 gene, that most probably arised de novo- This alteration leads to an exchange of a glycin residue for a stopcodon in the protein synthesis, most probably leading to a quantitative defect of type 1 collagen. This may lead to degradation of transcripts from the mutant COL1A1 allele (nonsense-mediated RNA-decay), so that only about half of the amount of the matrix will be deposited. The relatively mild phenotype is most likely due to the presence of almost entirely normal collagen from the normal COL1A1 allele. The bone biopsy showed nonspecific changed and no obvious mineralization defects. Based on clinical findings and the genetic tests the patient was diagnosed with an autosomal dominant classical 'Sillence' type I Osteogenesis imperfecta. On the background of previous diagnosis of primary hyperparathyreoidism additional genetic tests were performed and the presence of RET-oncogene and MEN-1-gene mutation was ruled out.

The patient received genetic counselling and was started on oral bisphosphonates. He has been tolerating the therapy well and has so far not had any further fractures.

Conclusion

This case demonstrates a previously not described mutation in the COL1A1 gene and its phenotypical correlations.

 

Nothing to Disclose: DBS, RS, ME, HS, PHK, CS

32181 24.0000 SAT 321 A Type I Osteogenesis Imperfecta Caused By a New Mutation 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Tarunya Reddy Vedere*1 and Faryal Sardar Mirza2
1University of Connecticut, Farmington, CT, 2University of Connecticut Health Center, Farmington, CT

 

Introduction:

The incidence of osteoporosis (OP) in primary biliary cirrhosis (PBC) ranges from 20 to 44% and increases with disease progression(1). An increase in bone resorption and slowed remodeling are thought to contribute to the low bone mineral density (BMD). There is no reported data on the use of denosumab for OP in patients with PBC.

Clinical case:

A 68-year-old female with a history of PBC, scleroderma, Raynaud’s disease, hypothyroidism and OP was referred for declining bone density while on a drug holiday for 2 years, after completing 5 years of treatment with alendronate. History was significant for 3 inches of height loss and a moderate wedge compression fracture in the thoracic spine noted on vertebral morphometric analysis at presentation. Risk factors for OP included being postmenopausal with history of early menopause (42 years), Caucasian race, chronic liver disease, prior cigarette smoking and family history of OP. She was never on long-term steroids. BMD by DEXA showed OP in the spine (L1-L2 T-score of -2.7; BMD 0.937 g/cm2) and forearm (33% radius T score of -2.8) and osteopenia at the hips. Bone turnover markers were elevated with Bone Specific Alkaline Phosphatase (BSAP) of 50.8 IU/L (7-22 IU/L) and urine N-terminal telopeptide (NTX) of 98 NTX units (26-124 BCE/mm creatinine), with normal calcium and Vitamin D levels. It was decided to start her on denosumab. Due to high bone turnover at baseline, markers were repeated at 6 and 12 months. Her urine NTX was only 17% and 22% suppressed at 6 and 12 months respectively after starting denosumab. BSAP remained above the upper limits of reference range. BMD was stable with non-significant increase at 1 year. A nuclear bone scan done to rule out metastatic disease did not show any focal uptake. Hence denosumab was continued every 6 months and her treatment period was uneventful except for a wrist fracture sustained in the 3rdyear of treatment.

To investigate if denosumab was indeed suppressing bone resorption, urine NTX levels were checked 1, 3 and 6 months after the 5thinjection. Urine NTX was 72% suppressed at 1 month and only 22% suppressed at 3 months. DEXA scan after 3 years of treatment with denosumab did show a significant increase in BMD at lumbar spine of 9.1% (T-score of -2 at L1-L2) and stable BMD at the hips.

Conclusion:

Our patient demonstrated escape from suppression of bone resorption effects of denosumab. Prior studies have shown that denosumab given every 6 months causes sustained suppression of bone resorption with a nadir at 1 month and sustained suppression at 3 and 6 months(2). Escape from suppression of bone resorption with denosumab has been reported in patients with advanced cancer and bone metastases but not in OP(3). The effect of denosumab was much more short lived in our patient despite a positive effect on bone density. This case highlights the need to be vigilant in monitoring the effect of treatment with denosumab in patients with PBC.

 

Nothing to Disclose: TRV, FSM

31172 25.0000 SAT 322 A Escape from Denosumab Mediated Suppression of Bone Resorption in Primary Biliary Cirrhosis 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Sridevi Challa1, Richa Sharma2, Ali Ghazanfari3, Kanaan Abow Alkhier4 and Mohamad Hosam Horani*5
1Banner Baaywood hospital, 2American University of Integrative Sciences School of Medicine, 3Banner Baywood Hospital, 4Arizona Oncology, 5Alsham Endocrinology, Chandler, AZ

 

Renal cell carcinoma (RCC) is the third most common neoplasm to metastasize to the head and neckregion, where 85% of the reported cases do not constitute of head and neck findings. Parathyroid

involvement is a rare occurrence and hypercalcemia may occur in certain patients with advanced cases of

RCC.
 We present a case of a 50 year old female who complained of menorrhagia following hysterectomy
due to uterine fibroids and a past medical history of anxiety. Consequently, there was an incidental finding
of hypertension and hypercalcemia with an initial serum calcium level of 11.6 mg/dl and albumin of
3.7g/dl. The physical exam findings were negative. Patient reported a previously elevated calcium level
above 11 mg/dl two years ago, that was left untreated. She denied use of calcium or vitamin D
supplements.
Further lab evaluation displayed elevated PTH of 192 pg/ml, decreased 25-OH vitamin D of
below 4ng/ml, decreased TSH of 0.37 mu/ml, and normal Free T4 1.23 ng/dl. Tc-99m Sestamibi
parathyroid scan showed parathyroid adenoma in the region of left lower parathyroid gland. Computed
tomography of abdomen/pelvis revealed a large left adrenal mass measuring 3.7 cm x 2.5 cm.
Subsequently, the patient had left parathyroidectomy performed, where the histopathology displayed
hypercellular parathyroid tissue consistent with parathyroid adenoma, along with an incidental finding of
high nuclear grade malignant nodule with features of clear cell carcinoma, suggestive of primary renal
origin. The nuclear stain results were positive for GATA3 and negative for TTF-1 and GCDFP, where
GATA3 links the tumor to RCC variants. Post-parathyroidectomy, calcium normalized to 8.8 mg/dl.
Discussion : Metastatic spread to the parathyroid gland from other cancers may occur in approximately 10% of
reported cases. This spread may be explained by the rich blood supply present specifically in endocrine
tumors. Following the finding of parathyroid adenoma, further workup revealed no renal mass on imaging,
instead, a left-sided adrenal mass was found. The adrenal mass biopsy displayed benign findings. Some
probable theories, for the absence of a renal neoplasm, may include the presence of an autoimmune
phenomenon behind RCC or even spontaneous regression of RCC after metastasis. However
 spontaneous regression of RCC is a rare (1%), but known phenomenon, with several theoretical
models described in the past. Our patient shows us the value of following up on incidental lab findings,
with a specific focus on rare causes of such irregularities.
Conclusion: Although unusual, metastasis to the parathyroidgland from RCC is a possibility, thus patients with presenting features of hypercalcemia should be
evaluated further for primary hyperparathyroidism. Appropriate workup and management of
hypercalcemia can potentially lead to early detection of underlying neoplasms and improvement of
survival as well as patient quality of life

 

Nothing to Disclose: SC, RS, AG, KA, MHH

29598 26.0000 SAT 324 A Rhypercalcemia: Rare Finding of Renal Cell Carcinoma Metastasis to Parathyroid Adenoma 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Jenna L. Sarvaideo*1, Jasmin Kristianto2, Jennifer M Connelly3 and Robert Daniel Blank1
1Medical College of Wisconsin, Milwaukee, WI, 2University of Wisconsin-Madison, Madison, WI, 3Medical College of Wisconsin

 

Introduction

Endothelin-1 (ET-1) has been identified as a mediator of osteoblastic bone metastases by stimulating osteoblast proliferation and new bone formation (1). Expression of ET-1 has been found in human meningiomas and thought to play a role in tumoral growth (2). Osteosclerosis in the presence of meningiomas is occasionally seen, but it is unknown how often. It has not previously been associated with ET-1. It is here we illustrate the potential role of ET-1 in both osteosclerosis and meningiomatosis.

Clinical case

A 48-year-old woman with past medical history of meningioma diagnosed in 2001 s/p bifrontal meningioma resection was referred for hyperostosis seen on imaging. She was doing well until early 2016 when she noted a painful bump on right temple that did not resolve. Imaging revealed multiple, sclerotic, expansile osseous lesions. Appearance on CT head most suggestive of multiple intraosseous meningiomas or meningiomatosis.

She had a history of obesity, hypertension, hyperlipidemia and depression. Medications included atorvastatin, bupropion, citalopram, black cohosh, ferrous sulfate, losartan/hydrochlorothiazide, nebivolol, potassium chloride, probiotic and vitamin D3. She was a non-smoker and drank alcohol occasionally. She was employed. Her family history was notable for hypertension and arthritis. There was no family history of endocrine diseases, fractures, bone disorders or cancer. On exam, she was alert and oriented to time, place and person. Her memory, behavior, speech and language were normal. There was a bony protuberance of the right temple that was non-tender to palpation. There were postsurgical changes from prior craniotomy. She did not have torus palatinus. The remainder of her exam was unremarkable.

The head CT was reviewed. The most important lesion was adjacent to the left cavernous sinus, which had led to left optic atrophy. There was also a lesion present in the right temporal region corresponding to the palpable mass appreciated on exam. A DXA scan was ordered to evaluate skeletal mass, which did not show evidence of generalized osteosclerosis. Her highest Z-score was 1.4.

A tissue block from patient’s prior neurosurgery was obtained and stained for RUNX2 and ET-1. Her tumor was found to produce ET-1. She was referred for radiation, but pharmacologic blockage of ET signaling might be considered if standard treatments fail.

Conclusion

Tumor production of ET-1 may promote osteoblastogenesis by downregulating dickkopf homolog 1 (DKK1), which allows Wnt signaling pathway activation and osteoblast differentiation (1). Furthermore, ET-1 along with other growth factors and cytokines contributes to angiogenesis and tumor growth (2). In this case we identified ET-1 produced by our patient’s meningioma as a probable contributor to both osteosclerosis and meningiomatosis.

 

Disclosure: RDB: Investigator, Novo Nordisk, Contributor, Up To Date, N/A, Abbvie. Nothing to Disclose: JLS, JK, JMC

31542 27.0000 SAT 325 A Endothelin-1 Driving Osteosclerosis and Meningiomatosis in Intraosseous Meningioma 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Rowella Licup Sirbiladze*, Denise Uyar, Jennifer Geurts and Joseph L Shaker
Medical College of Wisconsin, Milwaukee, WI

 

Hyperparathyroidism-Jaw Tumor Syndrome (HPT-JT) is a rare autosomal dominant disorder characterized by primary hyperparathyroidism (PHPT), ossifying fibromas of the mandible or maxilla, kidney lesions and uterine tumors. This is caused by a heterozygous germline pathogenic mutation in CDC73. To our knowledge, this is the first reported case of an ovarian granulosa cell tumor (GCT) associated with HPT-JT.

A 31 year old woman with persistent abdominal pain was found to have a heterogenous 3cm right (R) ovarian cyst on pelvic ultrasound and MRI. A laparoscopic R ovarian cystectomy was performed which revealed an adult GCT. She was referred to gynecology oncology. Surgical staging with possible bilateral salpingo-oophorectomy was planned. She was also referred to endocrinology for low bone density although values were within the expected range for age.

Her history was significant for PHPT at age 23 with calcium (Ca) 10.8 mg/dL (8.6-10.2 mg/dL), ionized Ca 1.48 mmol/L (1.18-1.33 mmol/L), PTH 107 pg/mL (15-72 pg/mL), and 24 hour (24h) urinary Ca 275 mg (100-321 mg/24h). She underwent 1-gland parathyroidectomy. Of note, her mother also had PHPT with 1-gland removal as well as history of renal cysts. Her brother and 2 maternal aunts have reportedly normal Ca levels.

There was no history of fractures. Her examination was normal. Ca, creatinine, phosphorus, PTH, 25-OH vitamin D, and 24h urinary Ca were also normal. Due to personal and familial history of PHPT, she underwent germline gene sequencing and deletion/duplication analysis of genes associated with PHPT including CASR, CDC73, CDKN1B, MEN1 and RET. Result showed a CDC73 gene pathogenic mutation (c.687_688dupAG) which creates a premature translational stop signal causing loss-of-function. Due to the history of GCT, 52 other tumor predisposition genes, including STK11, were analyzed which did not show pathogenic mutations.

She underwent a R salpingo-oophorectomy with fertility sparing staging surgery. No residual disease was noted on final pathology (Stage IC). The uterus and left ovary were preserved.

CDC73 is a tumor suppressor gene that encodes the protein parafibromin. HPT-JT is a CDC73-related disorder associated with PHPT (~15% malignant), benign fibro-osseous jaw tumors, benign or malignant renal tumors and cysts and benign or malignant uterine tumors. We found no reports of ovarian tumors with HPT-JT. However, there is a report of bilateral ovarian GCT in a patient with MEN-1.

GCTs are rare, accounting for less than 5% of all ovarian tumors. They usually occur in a younger age group who present with nonspecific symptoms such as abdominal pain or distention. Genetic syndromes associated with GCT include Peutz Jeghers (STK11) and Ollier Disease/Maffucci syndrome (IDH1 or IDH2).

In summary, we reported a patient with CDC73 mutation causing PHPT who also has a rare adult GCT. We believe that ovarian GCT may be another tumor associated with HPT-JT.

 

Disclosure: JLS: Consultant, Shire, Consultant, Alexion. Nothing to Disclose: RLS, DU, JG

30750 28.0000 SAT 326 A Ovarian Granulosa Cell Tumor Associated with Hyperparathyroidism-Jaw Tumor Syndrome 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


James Castillo Paningbatan*
Makati Medical Center, Philippines

 

Background: The diagnosis of hypercalcemic crisis can be difficult to make clinically when associated with malignancy. Hypercalcemia of malignancy may be explained by four mechanisms: tumor secretion of Parathyroid Hormone-related Peptide, local release of osteolytic cytokines, ectopic Parathyroid Hormone (PTH) and increased Vitamin D production. Very few cases have been reported in which the production and secretion of intact PTH by a non-parathyroid tumor has been authenticated. A high index of suspicion for a hypercalcemic state should be considered in a patient with a big tumor or cancer in a confusional state.

Clinical Case: A 45 year old woman, was transferred to our institution due to five days history of increasing weakness, lethargy, fever, disorientation and incoherence after falling out of bed. She was initially seen in another institution where a CT scan done showed no signs of acute infarct or bleeding.

Patient was seen weak, delirious and febrile. There was note of a palpable, firm, nontender hypogastric mass. A lumbar tap was done and showed a non xanthochromic, clear CSF. CSF gram stain, fungal smear, india ink, KOH, CALAS, MTB gene expert, Listeria, enteroviral PCR, Herpes simplex, all of which turned out to be negative. CSF sample was examined for anti-NMDA encephalitis and turned out to be negative. Chemistry showed severe hypercalcemia (17.24 mmol/L), hypokalemia (3.3mg/dl), low Mg (1.22 mg/dl), and elevated Creatinine (1.52 mg/dl). Repeat calcium showed hypercalcemia (16.6 mmol/L). Measurement of the PTH revealed a markedly elevated intact PTH (306.7 pg/ml). Patient was hydrated adequately, was given Calcitonin, Cinacalcet and underwent hemodialysis. Ultrasound of the neck and thyroid was negative. Sestamibi scan was negative for a parathyroid adenoma. CT scan of the whole abdomen showed a heterogeneously enhancing foci within the uterine wall 2.8 x 5.2 cm in the posterior wall and 1.8 x 2.5 cm in the anterior wall; a 2.9 x 2.4 cm hypoenhancing focus in the cervical region. There were heterogeneously enhancing masses noted in the bilateral hemipelvis measuring 8.4 x 5.0 x 6.4 cm in the right and 3.4 x 2.5 x 4.1 cm in the left. The patient underwent extrafascial hysterectomy, bilateral salpingooophorectomy, bilateral lymphadenectomy, omentectomy, peritoneal fluid cytology. PTH level was monitored preoperatively (326.89 pg/ml), 6 hours post op (78.375 pg/ml) and 24 hours post op (77.0 pg/ml). Histopathologic diagnosis was a large cell neuroendocrine carcinoma involving the right and left ovary with metastasis to the myometrium; well differentiated endometrial adenocarcinoma. Post operatively, patient started chemotherapy with Carboplatin and Paclitaxel.

Conclusion: These results support the ectopic production of intact PTH by a neuroendocrine tumor and indicate a rare neoplastic cause of hyperparathyroidism.

 

Nothing to Disclose: JCP

32634 29.0000 SAT 327 A Hypercalcemic Crisis Secondary to a Parathyroid Hormone Secreting Neuroendocrine Ovarian Tumor 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Heba Albasha1, Waseem Albasha2, Basel Imam3, Kanaan Abow Alkhier4 and Mohamad Hosam Horani*5
1Midwestern AZCOM, CHANDLER, 2University of Arizona college of Medicine, 3Saint Joseph Hospital, 4Arizona Oncology, 5Alsham Endocrinology, Chandler, AZ

 

Humoral hypercalcemia of malignancy is a well-described paraneoplastic syndrome most often associated with breast, renal, and squamous cell lung cancers. It is typically caused by ectopic production of parathyroid hormone-related protein (PTHrP). A handful of case reports, however, have described patients with humoral hypercalcemia of malignancy without elevated PTHrP, but rather with elevated intact parathyroid hormone (PTH) levels. This case report describes a patient with a history of endometrial cancer status post resection via total abdominal hysterectomy and bilateral salpingo-oophorectomy and radiation therapy who presented with abdominal pain. Computed tomorgraphy (CT) of the abdomen revealed a new left adnexal mass, with repeat CT imaging revealing lung and liver lesions consistent with possible metastases. She was found to have hypercalcemia and elevated intact PTH, but undetectable PTHrP. Labs showed no kidney disease or vitamin D deficien cy. Neck exploration was done, with excision of two parathyroid glands; pathology showed normal parathyroid tissue. Biopsies were taken of the adnexal mass and liver lesions. Pathology suggested the adnexal mass was a poorly differentiated neuroendocrine carcinoma of probable gastrointestinal origin, mixed with recurrent endometrial carcinoma. The liver lesions were metastases consistent with the same neuroendocrine carcinoma found in the adnexal mass, with the report noting the appendix as a possible origin given the CDX-2 staining pattern of the mass. This case would represent one of only a few reports in the literature of a gastrointestinal neuroendocrine carcinoma associated with hypercalcemia of malignancy that demonstrated increased intact PTH as the cause of hypercalcemia rather than PTHrP. This case is also unique in that it describes such a neoplasm mixed with a separate carcinoma. Literature review did not reveal a similar case for comparison. This case provides an importa nt lesson to the medical literature: intact PTH is perhaps a more common cause of hypercalcemia of malignancy than once thought. Patients presenting with a new mass and with that appears to be new onset primary hyperparathyroidism may in fact have this atypical cause of humoral hypercalcemia of malignancy

 

Nothing to Disclose: HA, WA, BI, KA, MHH

29552 30.0000 SAT 328 A Ectopic Production of Intact Parathyroid Hormone By Poorly Differentiated Neuroendocrine Carcinoma 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Ji Wei Yang*1, Zu-hua Gao2 and Richard Kremer1
1McGill University Health Center, Montreal, QC, Canada, 2McGill University Health Centre, Montreal, QC, Canada

 

Background: PTHrP secretion by gastroenteropancreatic neuroendocrine tumors (NET) is extremely rare. The treatment of hypercalcemia in this context can be challenging. Clinical case: A 53-year-old man was referred for the evaluation of a pancreatic NET with concomitant severe hypercalcemia. The patient’s past medical history was significant for type 2 diabetes. His family history was positive for breast and ovarian cancers in his mother and 2 sisters. The patient was started on lanreotide 120 mcg SC every 4 weeks shortly after the diagnosis of pancreatic NET. He initially presented to the hospital with abdominal pain, night sweats and a 20-lbs weight loss over 3 months. He was found to have severe hypercalcemia refractory to multiple treatment modalities, including aggressive hydration, zoledronic acid 4 mg IV, pamidronate 180 mg IV and denosumab 60 mg SC every 4 weeks. Early laboratory investigations showed total calcium 3.51 mmol/L (2.12-2.62 mmol/L), ionized calcium 1.89 mmol/L (1.15-1.32 mmol/L), albumin 42 g/L (38-52 g/L), magnesium 0.49 mmol/L (0.75-1.05 mmol/L), phosphate 0.54 mmol/L (0.80-1.45 mmol/L), PTH < 0.80 mmol/L (1.50-9.30 pmol/L), 25-(OH)D 50 nmol/L (50-125 nmol/L), 1,25-(OH)2D3 158 pmol/L (90-174 pmol/L), and 24-hour urinary calcium 1.0 mmol/day (2.5-7.5 mmol/day). Imaging done before treatment with lanreotide showed a 12.4 cm lesion occupying the body and tail of the pancreas, with metastases to the liver. Biopsy of the liver metastases confirmed neuroendocrine carcinoma. The specimen stained positive for CK19, synaptophysin and chromogranin, and exhibited cytoplasmic and membranous positivity for PTHrP. PTHrP staining was done using a monoclocal antibody directed against the PTHrP N-terminal (PTHrP 1-34). Interestingly, circulating levels of PTHrP measured by an immunoradiometric assay (PTHrP IRMA, Beckman Coulter) yielded normal levels despite on-going hypercalcemia. Nephrogenous cycle AMP, a surrogate marker of PTHrP activity, was elevated at 5.0 nmol/dL (1.3-3.7 nmol/dL). This indicates that the circulating PTHrP moieties in our patient were likely not recognized by the 2-site assay specific for PTHrP 1-86. We therefore hypothesize that the NET secreted a shorter form of PTHrP with an intact N-terminus. The patient underwent extensive debulking surgery. Post-op course was complicated by severe hypocalcemia likely induced by the removal of the PTHrP-secreting NET (similar to hungry bone syndrome following parathyroid surgery) with total calcium reaching a nadir of 1.36 mmol/L (2.12-2.62 mmol/L), requiring oral calcium and calcitriol supplementation. Conclusion: We report a case of refractory PTHrP-mediated hypercalcemia in the context of metastatic pancreatic NET. The normal PTHrP levels add to the interest of this case as we hypothesize that the NET likely secreted a shorter form of PTHrP not recognized by a commonly used commercial assay.

 

Nothing to Disclose: JWY, ZHG, RK

31334 31.0000 SAT 329 A Refractory Hypercalcemia Caused By PTHrP Secretion from Metastatic Pancreatic Neuroendocrine Tumor 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Kidmealem Zekarias*1, Amir Moheet2 and Almoutaz Shakally3
1Univeristy of Minnesota, Minneapolis, MN, 2University of Minnesota Medical Center, minneapolis, MN, 3University of Minnesota, Minneapolis, MN

 

Introduction/Background: Hypocalcemia is a rare complication of malignant diseases.

A 58-yr-old woman with stage IVB Clear cell carcinoma of the ovary with extensive sclerotic bony metastasis is described here. She had a generalized multiple osteoblastic bone metastases.

Clinical case: Patient presented with bilateral upper and lower extremity weakness. She had prolonged QT interval on EKG; QTc was 508ms. Laboratory examination on admission showed that the ionized whole blood calcium level was 2.2 mg/dl (4.4-5.2 mg/dl), serum phosphorus was 3.6mg/dl (2.5 -4.5 mg/dl) Magnesium was 1.1 mg /dl (1.7-2.2 mg/dl), serum alkaline phosphatase was 402 U/L (40-150 U/L), 25 OH Vit D total was <12 ug/L (20-75 ug/L), normal 24 hour urine calcium, Parathyroid Hormone Intact was 134pg/ml (12-72 pg/ml) and GFR was within the normal limits. CT scan showed sclerotic lesions in the spine and pelvic with the appearance of metastatic disease and possible right sacral fracture. Bone scan showed multiple radiotracer uptake in the calvarium, proximal left humerus, right rib, cervical, thoracolumbar spine, sacrum, bilateral iliac bones, left proximal femur and bilateral proximal tibia.

After the initial correction of hypocalcemia and hypomagnesaemia with IV calcium gluconate and IV magnesium sulfate respectively; patient was treated with oral high dose calcitriol 0.5 mcg TID and liquid calcium 2500 mg TID. Acute symptoms of weakness and EKG changes resolved after IV replacement. Patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectimy, lymph node dissection and was started on carboplatin and Paclitaxel. Hypocalcemia improved once treatment for the underlying issue is started however, patient needed ongoing intermittent magnesium infusion and oral supplementation due to chemotherapy induced magnesium wasting. Patient was continued on oral calcitriol, vitamin D supplement, oral calcium and magnesium supplementation.

Conclusion: Bone metastasis related hypocalcemia secondary to osteoblast activity is not a well-described cause of hypocalcemia. The likely main mechanism of hypocalcemia in a patient with extensive osteoblastic bone metastasis is increased deposition of calcium in the bones as a result of accelerated osteogenesis secondary to the extensive blastic metastases. Increased osteoblast activity leads to new bone formation without removal of the old one; a condition known as sclerosis. Early recognition, correction of vitamin D deficiency and treatment of hypocalcemia is essential in patients with metastatic cancer with osteoblastic bone metastasis.

 

Nothing to Disclose: KZ, AM, AS

29588 32.0000 SAT 330 A A Case of Advanced Ovarian Cancer Associated with Hypocalcaemia 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Melissa Orlandin Premaor*, Juliana Ebling Brondani, Liziane Maahs Flores and Fabio Vasconcellos Comim
Federal University of Santa Maria, Santa Maria, Brazil

 

Although fruits and vegetables appear to have a positive effect on bone markers and bone mineral density, its effect on fractures is yet to be established. This study aims to assess whether the intake of fruits and vegetables were associated with a decreased risk of bone fractures. We performed a systematic review of randomized controlled trials (RCTs) and cohort studies, whose protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the number 2016: CRD42016041462. Studies that have evaluated the intake of fruit and vegetables, in women and men aged over 50 years and that reported the incidence of bone fractures as the outcome were included. The search strategy included the following descriptors: fruit; vegetables; vegetable products; bone and bones; bone fractures, postmenopausal osteoporosis e osteoporosis in the databases PubMed, BIREME, EMBASE and the Cochrane Library. Also, some studies were of selected based on the reference lists of the included articles. It was considered studies written in any language and with no publication date limits. The analysis of the studies was performed by two research members independently, discussed and agreed between both. In total 442 studies were found, of which 33 were duplicates. After the screening for the inclusion and exclusion criteria, seven studies remained. Of these, one was excluded due to no control group with usual diet, and the other was excluded due to redundant publication. Three cohort studies (Benetou et al., 2011; Langsetmo et al., 2011; Samieri et al., 2013) and one ECR (McTiernan et al., 2009) were included in the analysis. The meta-analysis was performed only in the cohort studies and HR (95% IC) of fracture was 0.9 (0,86 to 1,00), I² 21,6%. The HR and 95%IC of fracture in the ECR was 0,97 (0,92 to 1,02). In conclusion, a small number of studies were found, and there might be a trend in the reduction of the fracture risk with the intake of fruits and vegetables. More studies evaluating the impact of fruits and vegetable intake on fractures are needed.

 

Nothing to Disclose: MOP, JEB, LMF, FVC

31394 33.0000 SAT 331 A Effects of Fruit and Vegetable Intake on Bones: Systematic Review and Meta-Analysis 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Ruchita Patel*, Vinita Singh and Sarah Nadeem
Loyola University Medical Center, Maywood, IL

 

Introduction:

Osteonecrosis of the jaw (ONJ) is defined as the presence of exposed bone in the maxilla-facial region that does not heal within 8 weeks after identification by a health care provider (1). ONJ is a rare but important side effect of antiresorptives like bisphosphonates and Denosumab, occurring in the mandible in about two-thirds of reported cases (1). We present an interesting case of Denosumab associated osteonecrosis of the maxilla.

Case:

A 72-year-old female with PMH of long-term glucocorticoid use for giant cell arteritis and polymyalgia rheumatica, presented to our clinic for osteoporosis management, for which she had been receiving treatment for ten years now. She initially received alendronate for five years, then yearly intravenous zoledronic acid for three years, and most recently, subcutaneous injections Denosumab every six months for the last two years. She tolerated these medications well without any side effects. She denied any history of fractures. Risk factors of osteoporosis included vitamin D deficiency, cigarette smoking, long-term steroid use and her postmenopausal status. Since patient had been on treatment for over ten years, drug holiday was considered, but due to recent breast cancer diagnosis and aromatase inhibitor initiation, denosumab was continued. Patient followed up with her dentist and diagnosed with a palatal ulcer. Six months prior, she underwent palatal gingival graft harvesting for a periodontal procedure. She had received Denosumab shortly after this procedure. Now, in her return visit, her dentist discovered a palatal ulcer at a different location than the previous harvesting site. She was referred to oral maxillofacial surgery. Their exam showed a 5 x 3 mm area of exposed bone at the level of palatal mucosa adjacent to tooth #3 in the right maxilla. Biopsy of the exposed bone revealed necrotic bone sequestrum. Since her clinical presentation was highly concerning for medication related ONJ, Denosumab has been held.

Discussion:

Our case demonstrates osteonecrosis of the maxilla associated with Denosumab use in the setting of recent periodontal procedure. Our patient was previously on bisphosphonate therapy for eight years but temporal association with dental procedure and denosumab administration points to it as the likely culprit. Per ASBMR report, the risk of osteonecrosis of jaw associated with oral bisphosphonate therapy for osteoporosis is low, ranging between 1/10,000 and <1/100,000 patient-treatment years (1). The risk of Denosumab related ONJ in osteoporosis has been reported to be very low at 0.04% (4 cases per 10,000 patients) and majority of case reports involved the mandible. Our case is unique as the patient developed osteonecrosis of the maxilla (2). The exact mechanism is not fully understood but Denosumab induced decreased osteoclastic activity and bone turnover might play a role in development of ONJ.

 

Nothing to Disclose: RP, VS, SN

32517 34.0000 SAT 332 A An Interesting and Rare Case of Denosumab Associated Osteonecrosis of the Maxilla 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Anna Kornete1, Ingvars Rasa*2, Maija Mukane3 and Elizabete Kadakovska4
1Riga Stradins University, Riga, Latvia, 2Riga East Clinical University Hospital; Riga Stradins University; Latvian Diabetes Association, Riga, Latvia, 3Riga East Clinical University Hospital; Riga Stradins University; Latvian Osteoporosis and Bone Metabolism Diseases Association, Riga, Latvia, 4MFD; Latvian Osteoporosis and Bone Metabolism Diseases Association, Riga, Latvia

 

Background: Pregnancy- and lactation-associated osteoporosis (PLO) is a rare form of osteoporosis characterized by significant changes in calcium and bone metabolism, resulting in musculoskeletal pain syndrome, fragile bones and increased risk of fractures during late pregnancy and early postpartum period. The etiology and pathogenesis remain incomprehensible, hence there is no mutually agreed opinion on the management of this condition. Three clinical cases of PLO present patients with multiple severe osteoporotic fractures during peri-pregnancy period and different treatment strategies.

Clinical cases: We came across a case of a 34-year-old primiparous woman who had severe lower back pain that worsened two months after a Cesarean delivery. Computed tomography revealed multiple vertebral osteoporotic fractures of the thoracic (Th11, Th12) and lumbar (L1, L2) spine. The lumbar spine bone mineral density (BMD) was below the expected range of age (–2.7 SD). The patient had serum 25-hydroxyvitamin D (25(OH)D) deficiency (11.5 ng/mL). Biochemical markers of bone turnover were increased (serum osteocalcin level – 52.8 ng/ml and serum C-terminal cross-linking telopeptide of type I collagen (𝛽 CTX) level – 0.766 ng/mL). We also encountered a 29-year-old patient with musculoskeletal pain syndrome began in the third trimester of pregnancy and deteriorated immediately postpartum. Magnetic resonance imaging (MRI) showed vertebral compressions of the thoracic (Th11, Th12) and lumbar (L1) spine, osteoporotic fracture of the L2 vertebra. The lumbar spine BMD was below the expected range of age (–4.5 SD). 25(OH)D vitamin level was slightly decreased (21.6 ng/mL), while osteocalcin level and 𝛽 CTX level was increased 56.6 ng/ml and 0.759 ng/ml, respectively. Finally, we report a case of a 35-years-old patient with complaints of progressive unilateral pain in the back, hip and lower extremity, accompanied by reduced general mobility. MRI revealed multiple sacral and femoral osteoporotic fractures. The lumbar spine and femoral BMD was below the expected range of age (–3.9 SD, –3.6 SD, –2.8 SD, respectively). The laboratory assessments (including the 25(OH)D vitamin, osteocalcin, 𝛽 CTX) showed no abnormality. Peripheral blood examination unveiled normal calcium and parathormone level in all the cases. In case 1 daily injection of teriparatide for 10 months was used. In case 2 once-yearly infusion of zoledronic acid and L2 vertebroplasty was performed. In case 3 ibandronic acid injection every three months for two times was conducted.

Conclusion: PLO must be kept in mind in the differential diagnosis in patients presenting with musculoskeletal pain syndrome during peri-pregnancy period. Different treatment strategies may help to reach targets of the therapy in cases of PLO: increase BMD, prevent chronic pain and new fractures and improve the quality of life.

 

Nothing to Disclose: AK, IR, MM, EK

29785 35.0000 SAT 333 A Different Treatment Strategies in Pregnancy- and Lactation-Associated Osteoporosis: Three Cases Reports 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Matthew Nicholson* and Rene J Harper
Augusta University, Augusta, GA

 

Objective:

To discuss the use of bisphosphonate use during pregnancy and review the effects on neonatal outcomes

Case presentation:

A 30 year old female at 26 weeks gestation presented to a community hospital with hypercalcemia, altered mental status, and preterm labor. She had been diagnosed with invasive ductal breast carcinoma four months earlier. Hypercalcemia did not respond to IV fluids and nasal calcitonin and she was transferred to our institution. Evaluation showed serum calcium 20.1 mg/dL (8.7 - 10.4), ionized calcium 11.1 mg/dL (4.5 - 5.3), albumin 3.3 g/dL (3.2-4.0), magnesium 2.2 mg/dL (1.3 - 2.7), intact PTH undetectable, total 25-(OH) vitamin D 10.6 ng/mL (30 – 100), 1,25-(OH)2 vitamin D 72 pg/mL (18 – 78), and PTHrP 9.5 pmol/L (< 2.0). She was continued on IV fluids and started on calcitonin 4 units/kg SC every 12 hours. Due to continued severe hypercalcemia pamidronate 90 mg was given intravenously. She required hemodialysis for 3 days while waiting for bisphosphonate therapy to work, after which her serum calcium declined to 8.3 mg/dL. At this time her uterine contractions improved and preterm labor ceased. Labor was induced due to concern for further deterioration in her clinical condition and prolonged fetal risk. Her newborn had transient hypocalcemia but an otherwise uneventful stay in the NICU.

Discussion:

This is one of a limited number of reported cases of IV pamidronate given for hypercalcemia during pregnancy. Bisphosphonates are considered to be contraindicated in pregnancy, as animal studies have shown bisphosphonates cross the placenta and may lead to preterm labor and harm to the mother and fetus. Studies of bisphosphate administration in rodents have reported dystocia and abnormal tooth growth, tremors and hypocalcemia-associated death in the pups. In human newborns whose mother received IV pamidronate, transient, mild hypocalcemia has been reported, which resolved after 5-10 days as in our patient’s newborn. Neonatal hypocalcemia may be secondary to fetal parathyroid hormone suppression from maternal hypercalcemia and/or from the direct effects of bisphosphonates. In previous cases, growth and development of the newborn have been reported normal at 8 weeks and at 10 months. Despite the risks to the fetus, IV bisphosphonates produce a reduction of the serum calcium that reduces uterine contractions, thus leading to more stable fetal monitoring until delivery. Aggressive hydration and calcitonin are only temporary measures in hypercalcemia during pregnancy, and the risks versus benefits of IV bisphosphonates need to be considered. Hemodialysis may be required when medical therapy fails to resolve the hypercalcemia in a timely manner. This case demonstrates the short-term safety and efficacy of IV pamidronate for humoral hypercalcemia of malignancy during pregnancy. The long-term effects on growth and skeletal development of the infant are not known.

 

Nothing to Disclose: MN, RJH

30185 36.0000 SAT 334 A Bisphosphonate Therapy in Pregnancy 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Joyce George* and Leila Zeinab Khan
Cleveland Clinic Foundation, Cleveland, OH

 

Background: Osteogenesis imperfecta (OI) is an inherited connective tissue disorder characterized by significant osseous fragility due to mutations in type 1 collagen. This condition paired with intestinal transplantation is a recipe for poor bone health and fractures. Visceral transplant recipients are at an extremely high risk for early and late deterioration of bone health after transplantation due to deleterious effects of chronic parenteral nutrition, gut failure, steroid use and high allointestine immunogenicity. This case highlights how fractures were kept to a minimum in a very high-risk patient after intestinal transplant using bisphosphonates.

Clinical Case: CN, a 26 year (yr) old female with OI Type 4 presented to our Endocrinology clinic at age 23 yrs for the management of metabolic bone disease. She was diagnosed with OI at age 12 yrs due to history of 40+ fractures (clavicular fracture at birth, tibial fracture at 8 months (mo) of age, fractures of hands/feet/ long bones and multiple vertebral compression fractures). Her last fracture occurred 9 mo prior to presentation to us. There was family history of OI only in a maternal second cousin. She underwent an isolated small bowel transplant in 2014 for chronic gastroparesis and diffuse intestinal dysmotility.

CN received IV pamidronate since age 12 yrs every 3-4 mo for bone pain with long off cycles. Bone pain used to resolve with pamidronate and fracture frequency also decreased. BMD in 2013 showed: Lumbar spine: 0.955 g/cm2, Z-score -1.3; Femoral Neck: 0.842 g/cm2, Z-score -1.1; Total Hip: 0.813 g/cm2, Z-score -1.1 (Lunar Prodigy). Pamidronate 60 mg Q3 mo was continued until her intestinal transplant, a year later.

Patient had been on total parenteral nutrition (TPN) for 4 yrs prior to the transplant and was receiving vitamin D and calcium supplementation through TPN. Patient was on high doses of steroids in the immediate post-transplant period, including steroids for possible acute rejection. Steroids were tapered down eventually to hydrocortisone 15 mg tid. Patient developed a compression fracture of T6, 5 mo after surgery during a seizure. BMD scan a month later (6 mo after transplant) showed a statistically significant decrease in BMD at all three sites: Lumbar spine: 0.874 ( Z-score -2.5); Femoral Neck: 0.660 (Z-score -2.7); Total Hip: 0.628 (Z-score -3.0). IV Pamidronate was restarted at 60 mg Q3 mo at this time.

Patient continued to receive pamidronate along with Vitamin D and calcium supplementation for the next 2 yrs with no new fractures and with improvement seen in the BMD at the spine, no change at the hip and decrease at the femoral neck: Lumbar spine: 0.919 (Z-score -2.2); Femoral Neck: 0.595 ( Z-score -3.2); Left Total Hip: 0.612 (Z-score -3.1). [All DXAs performed on same scanner]

Conclusion: This case draws attention to the remarkable ability of bisphosphonates to keep OI quiescent in a patient who underwent intestinal transplant.

 

Nothing to Disclose: JG, LZK

30404 37.0000 SAT 335 A Bisphosphonate Therapy in a Patient with Osteogenesis Imperfecta Type 4 and Intestinal Transplant 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Rachel Coleman-Pierron* and Kathryn McCrystal Dahir
Vanderbilt University Medical Center, Nashville, TN

 

Hypophosphatasia (HPP) is a rare inherited disorder caused by the loss of function mutation in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP), resulting in low alkaline phosphatase (AP) activity and elevated extracellular inorganic pyrophosphate and pyridoxal 5’-phosphate. Presentation of HPP is variable, ranging from no deformity to lethal during the perinatal period.

39 year old woman presented for evaluation of osteoporosis. Medical history included traumatic bimalleolar fracture at age 17 and loss of deciduous teeth prior to age 5. She reported migraines, menorrhagia, balance difficulty and arthralgia of bilateral ankles and left hip. When pregnant with her first child 7 years prior, routine prenatal ultrasonography detected extreme skeletal hypomineralization. After birth, genetic testing revealed C119C>T and C1231A>G. Newborn was diagnosed with HPP and started on asfotase alfa, recombinant bone targeted TNSALP. Bone mineralization substantially improved, but death occurred from infectious cause at 8 months of life. Her sister was diagnosed with osteoporosis at age 49. Patient and two other sisters, age 59 and 45, were then diagnosed with osteoporosis. Their father had cracked teeth, collar bone fracture and feet deformities. Suspicion that the family’s bone mineralization disorders could be related to her late child’s diagnosis prompted genetic testing. The patient did not undergo mutational analysis, but screening of 4 siblings revealed C1231A>G. Musculoskeletal examination demonstrated mild thoracolumbar scoliosis and left hand grip weaker than right. AP was 38 (40-15) units/L with bone specific AP 5.2 (4.5-16.9)mcg/L and vitamin B6 92.4 (20-125) nmol/L. Bilateral lower extremity, spine and skull radiographs showed normal mineralization. Diagnosis of HPP was made. Screening for disease complications included renal ultrasound, dental films, ophthalmology examination and physical therapy evaluation.

Prevalence of severe forms of HPP is estimated at 1 in 100,000. At least 300 TNSALP mutations have been detected. Autosomal dominant and autosomal recessive transmission typically leads to mild versus severe HPP. The natural history of adults with likely dominant negative mutations is largely unknown given that it is under or misdiagnosed. Adult symptoms are premature loss of deciduous teeth, arthropathy without bone disease, femoral pseudofractures and failure to heal metatarsal stress fractures. Extracellular accumulation of inorganic pyrophosphate can lead to pseudogout, calcific periarthritis and ossification of ligaments causing debilitating pain and muscle weakness. Laboratory testing typically reveals low AP and elevated vitamin B6 levels. Diagnosis does not require mutation analysis and can be made clinically with medical history, physical examination, routine laboratory studies and radiographic findings.

 

Disclosure: KMD: Clinical Trial Investigator, Alexion. Nothing to Disclose: RC

29215 38.0000 SAT 336 A Dissecting a Family History 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Ayesha Jameel*, Ahmad A Chaudhary, Umair Iqbal and Madiha M Alvi
Bassett Medical Center, Cooperstown, NY

 

Introduction:
Use of osteoclast inhibitor denosumab (high dose 120 mg) significantly reduces risk of skeletal-related events (SREs) including fractures secondary to metastatic bone disease. Denosumab is a monoclonal antibody that inhibits the RANK ligand, a powerful bone-resorbing cytokine. The RANK pathway is critical in progression of bone metastasis. Severe hypocalcemia is a rare but potentially life-threatening outcome of this medication. It can be difficult to treat, especially with coexisting occult vitamin D deficiency as seen in patients with chronic kidney disease. Incidence of hypocalcemia is reported to be around 3 - 18%, and according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), only 3% are grade 3, grade 5 being death. We present a patient with metastatic prostate cancer who received denusomab with normal kidney functions and developed grade 4 hypocalcemia (serum calcium <6.0 mg/dL).
Clinical Case:
An 89-year-old male with recent diagnosis of prostate cancer with bone metastasis was given high-dose denusomab, after pre-treatment with vitamin D3 and calcium supplementation. Twelve days later he presented with generalized tremors, muscle cramps and myoclonic jerks. He had stable vital signs, normal mental status, but positive Chvostek’s and Trousseau’s signs. EKG showed normal sinus rhythm with prolonged QTc - 488 ms (n ≤ 440 ms). Laboratory analysis showed corrected serum calcium (SCa) 5.64 (pre-denosumab SCa 8.3; n 8.4–10.2 mg/dl); albumin 3.2 (n 3.5–5.0 g/dl); iCal 2.7 (n 4.2-5.4 mg/dL); Phos 2.0 (n 2.5-4.9 mg/dL), Magnesium 2.0 (n 1.5-2.5 mg/dL); Alkaline Phosphatase (ALP) 2470 (pre-denosumab ALP 3870; n 38-125 U/L); Intact PTH 487 (n 14-72 pg/mL). His electrolytes and kidney function were normal. He was started on calcium infusion and simultaneous high-dose oral supplements of calcium, calcitriol and cholecalciferol. Over the next 5 days the calcium levels stabilized to low normal range with improvement in his clinical symptoms. Calcium infusion was successfully weaned off and he was later discharged on oral therapy with a close outpatient follow up. 
Conclusion:
Denusomab-induced hypocalcemia is usually prolonged and resistant to treatment potentially due to its long half-life (25 – 28 days) and elimination via the reticuloendothelial system. Predisposing risk factors include Vitamin D deficiency, inadequate oral calcium intake and high pre-treatment ALP levels as seen in this patient. Prior to initiation of osteoclast inhibitor therapy, serum calcium and vitamin D levels should be corrected. It is strongly recommended to closely monitor corrected serum calcium especially after first treatment in such patients.

 

Nothing to Disclose: AJ, AAC, UI, MMA

31443 39.0000 SAT 337 A Iatrogenic Severe Hypocalcemia with the Use of High Dose Denusomab for Metastatic Bone Disease 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Bone, Calciotropic Hormones & Vitamin D Saturday, April 1st 3:00:00 PM SAT 298-337 9484 1:00:00 PM Bone and Mineral Disorders Poster


Annabel JOSON Mata*1 and Gabriel Villaflor Jasul2
1St Luke's Medical Center, Quezon City, Philippines, 2St Luke's Medical Center Quezon City, Quezon City, Philippines

 

Metabolic Syndrome is a common condition worldwide. Diagnosis includes 5 main criteria: abdominal obesity, elevated triglycerides, low High density lipoprotein (HDL), elevated fasting blood sugar (FBS) and hypertension. This has been predominantly associated with obesity but recent evidences have shown otherwise especially in Asian. There have been local prevalence studies of metabolic syndrome among Filipinos, but no studies done yet to determine prevalence of metabolic syndrome among the different BMI categories and specifically those with lower BMI.

Objective: To determine the prevalence of metabolic syndrome and its individual components across different BMI categories (normal-weight, overweight, pre obese, obese individuals) among patients seen at Wellness Center and Obesity and Weight Management Center, St. Luke’s Medical Center Quezon City (SLMC-QC).

Methods: This is a cross sectional study which utilized records review of patients seen at the Wellness and Weight Management center at SLMC QC from January 2013 to October 2016. All adult patients’ included with age ≥18 years, BMI of ≥ 18.5 kg/m2 with complete data of Waist circumference and metabolic variables (FBS, HDL, Triglycerides, Systolic and diastolic blood pressure). Classification of patient having metabolic syndrome was based on the NCEP/ATP III-AHA/NHLBI (2005) criteria fulfilling any 3 of the 5 features of the syndrome namely Waist circumference using the Southeast Asians cut off: Male ≥ 90 cm and Female ≥80 cm, Raised Triglycerides of ≥ 150 mg/dL or specific treatment for this lipid abnormality, Reduced HDL cholesterol of <40 mg/dL in males or 50 mg/dL in females or specific treatment for this lipid abnormality, Raised BP with an SBP ≥ 130 mmHg or DBP ≥85 mmHg or treatment of previously diagnosed hypertension and Raised Fasting plasma glucose of FPG ≥100 mg/dL or previously diagnosed Type 2 Diabetes Mellitus.

Results: A total of 379 adults were included in the analysis. 92 with normal BMI, mean of 21.09kg/m2, 97 were overweight (mean BMI 24.04 kg/m2), 116 pre obese (mean BMI 27.45 kg/m2 and 74 obese (mean BMI of 38.42 kg/m2) . The prevalence of metabolic syndrome across the BMI categories is 48.3% with highest prevalence in the pre obese group at 16.35% (62) followed by 12.92% (49) in obese, 12.66%(48) in overweight and 6.33%(24) in normal BMI. Among the different components, central obesity with the highest prevalence of 77.89 % and with 12% of which has normal BMI, followed by elevated FBS and elevated BP.

Conclusion: Metabolic syndrome has been commonly linked with obesity and these individuals are at high risk for CVD events. Our data has shown that metabolic syndrome is present even in patients with lower BMI of 18-24.9 kg/m2 hence screening for other components of metabolic syndrome should be done even in normal weight individuals in the presence of even 1 individual component of the syndrome.

 

Nothing to Disclose: AJM, GVJ

32205 1.0000 SAT 504 A Prevalence of Metabolic Syndrome and Its Individual Features Across Different (Normal, Overweight, Pre-Obese and Obese) Body Mass Index (BMI) Categories in a Tertiary Hospital: A Cross-Sectional Study 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Melanie Schorr*1, Aaron Leong1, Bianca Porneala2, Laura E. Dichtel1, Miriam A. Bredella1 and Karen K. Miller1
1Massachusetts General Hospital/Harvard Medical School, Boston, MA, 2Massachusetts General Hospital, Boston, MA

 

Sarcopenic obesity, reduced skeletal muscle mass in the setting of obesity, is an important cardiometabolic risk factor in the elderly. Skeletal muscle mass is generally greater in young overweight/obese than lean adults, in part due to higher load (weight). It is unknown whether relatively lower skeletal muscle mass for BMI in young adults, i.e. relative sarcopenia, contributes to cardiometabolic risk. We hypothesized that relative sarcopenia is associated with insulin resistance (IR) and the presence of metabolic syndrome (MetS) and type 2 diabetes mellitus (DM) in young overweight/obese adults.

We studied 1507 US adults (BMI ≥ 25kg/m2, 20-49 y) in NHANES 2005-2006. Exclusion criteria included pregnancy, menopause and glucocorticoid use. Skeletal muscle mass of both arms and legs [appendicular lean mass (ALM)] and total body fat mass (FM) were measured by DXA. Relative sarcopenia was defined as low ALM/BMI. MetS was defined per NCEP ATPIII criteria. IR was assessed by HOMA-IR. Using sex-stratified regression models adjusted for age, race and physical activity (PA), we tested whether relative sarcopenia was associated with IR or the presence of MetS or DM. Effect estimates were reported per standard deviation (SD) change in ALM or ALM/BMI.

Non-Hispanic Blacks had higher, and Hispanics lower, ALM and ALM/BMI than non-Hispanic Whites. Age was a negative, and PA a positive, determinant of ALM and ALM/BMI. Oral contraceptive use was not associated with ALM or ALM/BMI. MetS was present in 21% of participants, and DM in 7%. Higher ALM was associated with MetS (in both sexes) (men: OR 2.33 (1.73-3.14), p<0.0001; women: OR 1.83 (1.34-2.50), p=0.0001). In contrast, relative sarcopenia (lower ALM/BMI) was associated with MetS (in men only) (men: OR 0.60 (0.44-0.83), p=0.002; women: OR 0.87 (0.64-1.19), p=0.38). When relative sarcopenia was defined as lower ALM/FM, it was associated with MetS (in both sexes) (men: OR 0.36 (0.28-0.48), p<0.0001; women: OR 0.71 (0.50-1.0), p=0.05). In participants without DM, higher ALM was associated with higher IR (in both sexes) (men: β=1.19, p<0.0001; women: β=0.72, p<0.0001), whereas lower ALM/BMI was associated with higher IR (in men only) (men: β=-1.04, p<0.0001; women: β=-0.25, p=0.09). Similarly, higher ALM was associated with DM (in both sexes) (men: OR 1.71 (1.16-2.51), p=0.006; women: OR 1.96 (1.39-2.75), p=0.0001), whereas lower ALM/BMI was associated with DM (in men only) (men: OR 0.36 (0.20-0.67), p=0.001; women: OR 0.90 (0.57-1.43), p=0.66). 

In conclusion, relative sarcopenia is a risk factor for MetS, IR and DM in young overweight/obese adults. Examining skeletal muscle mass without accounting for BMI obscures the relationship between reduced muscle mass and cardiometabolic risk factors because higher BMI is associated with greater muscle mass. Determining whether sex differences exist and if so, why, merits further study.

 

Nothing to Disclose: MS, AL, BP, LED, MAB, KKM

30345 2.0000 SAT 505 A Sarcopenic Obesity Is a Risk Factor for Metabolic Syndrome in Young Adult Men, but Not Women 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Christian Alvarado Araiza*1, Lluvia Vianey Fajardo2, Paulina Correa3, Estela Blanco4, Sheila Gahagan4 and Raquel Burrows5
1Instituto Nacional de Pediatría, Mexico DF, Mexico, 2Instituto Nacional de Pediatría, Mexico City, Mexico, 3Institute of Nutrition and Food Technology, University of Chile, Santiago Chile, 4Division of Child Development and Community Health, University of California San Diego, CA, 5Instituto Nacional de Tecnología en Alimentos, Chile

 

Insulin resistance (IR) is the main metabolic disturbance associated with obesity, and it is related with the development of Diabetes Mellitus type 2 and Metabolic Syndrome (MetS). The final stage of IR is beta cell dysfunction, however the lipid metabolism disruption which develops first is strongly related with cardiovascular risk. Different insulin sensitivity markers (ISM) have been proposed for the diagnosis of IR, but there is limited evidence regarding the sensitivity of these indicators to diagnose biological risk. The aim of this study was to establish the validity of different ISM to identify adolescents with MetS. In 667 adolescents (16.8 ± 0.3 y), BMI, waist circumference, blood arterial pressure, glucose, insulin, cholesterol profile, adiponectin and leptin were measured after a 12-hour overnight fast. The optimal cut-off of the Homeostatic Model (HOMA), the Quantitative Insulin Sensitivity Check Index (QUICKI), the Single Point Insulin Sensitivity Estimator (SPISE) and the Leptin/Adiponectin ratio (LAR) for MetS diagnosis were determined by ROC analysis and the best combination for specificity and sensibility was stablished using Youden’s index. MetS was diagnosed according to the AHA/IDF/ATP 2009. SPICE showed the best sensitivity and specificity for diagnosing MetS with a cut-off point of 5.89 in males (aROC: 0.95, Sens: 96% and Spec: 84%)and 6.27 in females (aROC: 0.89, Sens: 89% and Spec: 77%). LAR was the second best index with an optimal cut-off point of 0.88 in males (aROC: 0.88, Sens: 88% and Spec: 80%) and 2.0 in females (aROC: 0.79, Sens: 79% and Spec: 70%). We observed a strong correlation between the ISM and MetS, even in lower cut-off levels as the ones proposed to diagnose insulin resistance in the general population. This suggests that the lipid disorders appear even before the biochemical insulin resistance is observed.

 

Nothing to Disclose: CA, LVF, PC, EB, SG, RB

30738 3.0000 SAT 506 A Insulin Sensitivity Indexes Cutoff Points As Surrogates for Metabolic Syndrome Diagnosis in Chilean Adolescents 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Kyung Ah Han*1, JaeMyung Yu2, Sang Hak Lee3, Hui Kyung Jeon4, Sang Hyun Kim5, Seok Yeon Kim6, Ki Hoon Han7, Kyungheon Won6, Dong-Bin Kim8, Kwang-Jae Lee9, Kyungwan Min10, Dong Won Byun11, Sang-Wook Lim12, Chul Woo Ahn13, SeongHwan Kim14, Young Joon Hong15, Jidong Sung16, Seung-Ho Hur17, Soon Jun Hong18, Hong-Seok Lim19, Ie Byung Park20, In Joo Kim21, Hyoungwoo Lee22 and Hyo-Soo Kim23
1Eulji University, Seoul Eulji hospital, Seoul, Korea, Republic of (South), 2Kangnam Sacred Heart Hospital, Seoul, Korea, Republic of (South), 3Severance Cardiovascular Hospital,, Seoul,, Korea, Republic of (South), 4Division of Cardiology, Seoul, Korea, Republic of (South), 5Seoul National University College of Medicine, Seoul, Korea, Republic of (South), 6Seoul Medical Center, Seoul, Korea, Republic of (South), 7Asan Medical Center Heart Institute, Seoul, Korea, Republic of (South), 8The Catholic University of Korea College of Medicine, Seoul, Korea, Republic of (South), 9Daedong Hospital, Seoul, Korea, Republic of (South), 10Eulji University Medical Center, Seoul, Korea, Republic of (South), 11Soonchunhyang University Hospital, Seoul, Korea, Republic of (South), 12Bundang Cha General Hospital, Seoul, Korea, Republic of (South), 13Gangnam Severance Hospital, Seoul, Korea, Republic of (South), 14Korea University Ansan Hospital, Seoul, Korea, Republic of (South), 15Chonnam National University, Seoul, Korea, Republic of (South), 16Samsung Medical Center, Seoul, Korea, Republic of (South), 17Department of Internal Medicine, Daegu, Korea, Republic of (South), 18Korea University, Seoul, Korea, Republic of (South), 19Ajou University School of Medicine, Suwon, Korea, Republic of (South), 20Gachon University Gil Medical Center, Incheon, Korea, Republic of (South), 21Pusan National University College of Medicine, Busan, Korea, Republic of (South), 22Yeungnam University College of Medicine, Daegu, Korea, Republic of (South), 23Cardiovascular Centre, Seoul, Korea, Republic of (South)

 

Ratio of apolipoprotein B/A1 (ApoB/A1) was known to be a stronger predictor of cardiovascular events than cholesterol. Lowering triglyceride with omega-3 free fatty acid (OM3-FA) may give further reduction in ApoB/A1 as a marker of CVD risk. This study was designed to evaluate the efficacy of adding OM3-FFA on statin therapy in lowering non-HDL-C, TG levels, and ApoB/A1 in subjects with persistent hypertriglyceridemia.

In this double-blind, parallel-group controlled trial, we enrolled patients with residual hypertriglyceridemia under treatment with rosuvastatin for more than 4 weeks (fasting TG levels between 200 and 500 mg/dL and LDL<110mg/dL) and randomized them into two groups: rosuvastatin (20 mg daily) with omega 3 fatty acid (4 g/d) (OM3-R, n=97) or rosuvastatin (20 mg daily) alone (R, n=104). Assessments included fasting serum levels of lipids and ApoB/A1, and 10-year risk for coronary heart disease Framingham point scores (CHD10)

Participants’ BMI was 27.5 kg/M2.. Male was 61.8 %, CHD10 was 9.5% without significant differences between two groups, The age was higher in OM3-R group than in R (59.7±10.8 and 56.6±10.4 years , respectively, P =0.0397). After 8 weeks, non-HDL-C levels were reduced from baseline more in OM3-R than in R (-13.1±2.6% vs -2.63±2.4%; P < 0.001), as were TG levels (78.1±9.5% vs -37.8±10.1%; P < 0.001). There were no differences between groups in HDL-C, Apo B, Apo A1, and ApoB/A1.

Within group analysis using paired T test showed that HDL-C levels significantly increased for 8 weeks interval both in OM3-R and R groups (40.9 to 42.3 mg/dl, p=0.035, 40.3 to 42.9 mg/dl, p<0.001, respectively). ApoB levels was decreased (87.0 to 72.5 mg/dl, p<0.001: 83.6 to 74.5 mg/dl, p<0.001, respectively). Apo-A1 levels insignificantly decreased in in OM3-R and increased in R.

Thus, ratio of Apo B/A1 significantly decreased in OM3-R (0.65 to 0.56 mg/dl, p<0.001), and also in R (0.63 to 0.55, p<0.001).

CHD10 was inversely correlated with percent change of the Apo B/A1 only in R (r= -0.369 p<0.001) and not in OM3-R after adjusting age, gender, and BMI. Presence of diabetes was still important determinant for percent change of nonHDL cholesterol and Apo B/A1 after controlling the effects of treatment groups (p=0.01, p=0.003, respectively) using ANCOVA (analysis of covariance).

These findings suggested that omega 3 fatty acid was well tolerated and effectively lowered non-HDL-C and TG levels, but no further decrease in Apo B/A1, in patients with persistent hypertriglyceridemia taking a statin. And it might be more effective in person with higher CHD10 or diabetes.

 

Nothing to Disclose: KAH, JY, SHL, HKJ, SHK, SYK, KHH, KW, DBK, KJL, KM, DWB, SWL, CWA, SK, YJH, JS, SHH, SJH, HSL, IBP, IJK, HL, HSK

31753 4.0000 SAT 507 A Effects of Omega-3 Free Fatty Acid on Nonhdl Cholesterol and Apolipoprotein B/A1 Ratio in Statin-Treated Patients with Residual Hypertriglyceridemia. Romantic (Rosuvastatin-OMAcor iN residual hyperTrIglyCeridemia) Randomized Controlled Trial 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Nivedita Patni*1 and Abhimanyu Garg2
1UT Southwestern Medical Center, Dallas, TX, 2University of Texas Southwestern Medical Center, Dallas, TX

 

Abstract: Very severe or extreme hypertriglyceridemia (HTG; serum TG ≥ 2000 mg/dL)(1), poses a significant risk for acute pancreatitis. There is paucity of data regarding the prevalence and etiology of extreme HTG in children. Therefore, we determined demographics, clinical features and etiologies of patients with extreme HTG at a tertiary children’s hospital with 418-beds and >28,000 admissions and >173,000 emergency room visits per year. A retrospective cross sectional chart review of electronic medical records was performed for all patients admitted with any serum TG value ≥ 2000 mg/dL from January 2000 till December 2015. Forty-two patients had extreme HTG, of which 6 patients had a single anomalous laboratory value while on parenteral nutrition; these patients were excluded from further analysis. Of the remaining 36 patients (14 males and 22 females), 58% of the patients were Caucasians, 17% African-Americans, 11% Asians and 8% Hispanics. Median age of presentation in males was 15.5 years compared to 12.8 years in females. Median body mass index was 25 kg/m2 in males and 19.4 kg/m2 in females. Nine females and 3 males had also had acute pancreatitis. Five patients (14%) had type 1 hyperlipoproteinemia (2 with lipoprotein lipase deficiency, one with GPIHBP1 deficiency, and the other two so far have not had comprehensive genetic testing). Others had secondary causes including type 2 diabetes mellitus in 7 (19%), type 1 diabetes mellitus in 4 (11%), and hypothyroidism in 3 (8%) patients. Interestingly, 10 (28%) patients had acute lymphoid leukemia (ALL) and had received L-asparaginase and high dose steroids therapy. Five (14%) patients were post solid organ transplant, and 4 of them were on sirolimus or tacrolimus. End stage renal disease (ESRD), acute myeloid leukemia (AML), neonatal HIV on antiretroviral therapy including protease inhibitor, and propofol therapy was observed in one patient each. Interestingly, no patient was receiving estrogen or retinoid therapy. Seven patients died during the study period, four with ALL, one with AML, one with ESRD and one post heart transplant; and only the patient with ESRD had acute pancreatitis at the time of death. Conclusions: Extreme HTG is rare in pediatric population. Uncontrolled diabetes mellitus, L-asparaginase therapy for ALL and genetic disorders are the most common underlying etiologies of extreme HTG in children. In contrast to adults with extreme HTG, ethanol use, estrogen therapy and obesity do not contribute to extreme HTG in children.

 

Disclosure: AG: Consultant, Aegerion Pharmaceuticals, Inc., Study Investigator, Aegerion, Principal Investigator, Pfizer, Inc., Consultant, Ionis Pharmaceuticals, Inc., Principal Investigator, Ionis Pharmaceuticals, Inc., Principal Investigator, Intercept Pharmaceuticals, Inc., Principal Investigator, Kadmon Pharmaceuticals, Inc., Consultant, Akcea Pharmaceuticals, Inc.. Nothing to Disclose: NP

31058 5.0000 SAT 508 A Etiology of Extreme Hypertriglyceridemia in Children: Data from a Tertiary Children’s Hospital 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Francisco Cordero*1, Alejandra Lanas2 and Jorge Alfaro3
1Clínica Davila, 2Hospital Clínico Universidad de Chile, Santiago, Chile, 3Clinica Davila

 

Background: During pregnancy serum triglyceride (TG) increase, however levels usually remain <300 mg/dl. In women with genetic forms of hypertriglyceridemia, pregnancy may cause extremely elevated TG levels leading to potentially life-threatening pancreatitis. The only safe medical treatment during pregnancy is omega 3 fatty acids, which have a moderate effect. Therapeutic apheresis could be used in particular cases during pregnancy.

Clinical case: A 30 years old female diagnosed in childhood with primary hypertriglyceridemia. No family history of dyslipidemia. Clinical history of acute pancreatitis associated to hypertriglyceridemia in 2008. At clinical examination BMI 19 kg/m2, without skin xantomas, no signs of insulin resistance, normal ocular fundus.

After pancreatitis treatment with fibrates was initiated. On clinical course the treatment was adjusted several times and Omega-3 were added with partial response. At June 2012, patient suspended treatment because of pregnancy. She was evaluated at week 12. Laboratory tests demonstrated: TG 3010mg/dl and glycemia 74 mg/dl.

A 1600 kcal diet with 150g fractionated carbon hydrates without sucrose and medium chain fatty acids 15-20% was initiated. She started omega 3 (EPA 300mg DHA 300mg) 2 tablets every 8 hours and topical sunflower oil. At week 13 fenofibrate 200mg was added. Treatment response was poor and TG reached 9186 mg/dL. She started orlistat 120mg with each meal and metformin was added to reduce any influence of physiological insulin resistance of pregnancy on triglycerides.

At week 24 she presented with abdominal pain and was admitted to hospital. Laboratory test demonstrate lipase 1176 IU/L (<160) and TG 4293 mg/dl. Abdominal ecography showed signs of pancreatitis. The clinical course was complicated with severe abdominal pain, persistent tachycardia and inflammatory parameters increased. Given the severity of the case plasmapheresis was programmed. Two plasmapheresis were made lowering TG to 245 mg/dl, with marked clinical improvement.

A week later TG raised and serial plasmapheresis were programmed. Medical therapy was restarted. Patient is discharged after the third plasmapheresis. Weekly control of TG and plasmaréresis scheduled approximately every 2 weeks to keep triglycerides under 3000 mg/dl. A total of 9 plasmapheresis were performed. At week 37 she was hospitalized for elective caesarean section after the last plasmaferesis. Newborn was healthy without complications.

Clinical conclusions: In pregnancy severe hypertrigliceridemia therapy should include a multidisciplinary team, dietary fat restriction, appropriate supplements and pharmacological therapy. Plasmapheresis is an alternative for cases resistant to medical treatment and severe cases associated to pancreatitis. We successfully used plasmapheresis to manage hypertriglyceridemia-induced pancreatitis during pregnancy.

 

Nothing to Disclose: FC, AL, JA

30940 6.0000 SAT 509 A Pancreatits Associated with Severe Hypertriglyceridemia in Pregnancy Treated with Plasmapheresis 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Christopher Bowman*1, Joesph Wiencek1, Craig Richard Sussman1, Brad Adams2, Gregory Sephel2, Jennifer Colby2, James Nichols2 and Alison Woodworth2
1Vanderbilt University Medical Center, Nashville, TN, 2Vanderbilt University Medical Center

 

Background: Lipemia is a common interference in clinical laboratory testing.

Clinical case: A 62-year male with past medical history of type 2 diabetes mellitus, CAD, and hypertriglyceridemia presented to pre-op clinic for routine evaluation prior to carpal tunnel surgery. A basic metabolic panel (reference interval in parentheses) showed a sodium 124 mmol/L (136-144), potassium 4.3 mmol/L (3.3-4.8), Chloride 92 mmol/L (98-107), CO2 6 mmol/L (23-31), and glucose 392 mg/dl (70-99). Patient was admitted for DKA and treated with an insulin infusion and IV fluids. Urinalysis was negative for ketones, lactic acid was mildly elevated at 2.6 mEq/L, and urine drug screen was negative. The lipid panel (mg/dL) showed triglycerides >5680 (<149), HDL 17 (>40), LDL 47 (1-129), and cholesterol 814 (0-199). Lipase was within the reference interval. Patient denied any nausea, vomiting, or shortness of breath. He was treated with insulin infusion, fenofibrate, fish oil, and rosuvastatin. Review of previous discharge summary showed a routine office visit with asymptomatic serum CO2 <5 mmol/L leading to a hospital admission. He was treated for DKA over 4 days and metformin was discontinued. Of note, during both admissions, his venous blood gases showed pH 7.39-7.43 (7.35-7.45) with serum HCO3 24-26 mmol/L (21-28). The discordant results between serum basic metabolic panel and blood gas analysis were further investigated in our laboratory. To determine the amount of lipemia needed to interfere with the CO2 assay, hyperlipidemic specimens from a patient with severe hypertriglyceridemia (triglycerides >3,500 mg/dL) were titrated into normolipidemic plasma pool at various percent concentrations. Samples with increasing lipid concentrations of 0, 5, 15, 25, 35, 50, and 100% were analyzed by either the Abbott Architect or Ortho Vitros enzymatic CO2 assays. Differences were noted between expected (calculated via linear regression analysis) and observed CO2 concentrations with both assays, with the highest difference present on the current assay (Abbott) used at Vanderbilt University hospital. At triglyceride concentrations of 1000 mg/dL, 2000 mg/dL and 3500 mg/dL the negative bias was 23%, 42% and 65%, respectively. This pseudometabolic acidosis is due to severe hypertriglyceridemia interference within the spectrophotometric method leading to falsely low CO2 concentrations.

Conclusion: Pseudometabolic acidosis from hypertriglyceridemia can lead to unintended clinical management decisions and possibly unnecessary hospital admissions. It is important to interpret CO2 results in the context of clinical symptoms and other laboratory results in patients with hypertriglyceridemia.

 

Nothing to Disclose: CB, JW, CRS, BA, GS, JC, JN, AW

31396 7.0000 SAT 510 A Pseudometabolic Acidosis in Patient with Severe Hypertriglyceridemia 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


K.M Mohamed Shakir*1, Terry Shin1, Sam Yoon Williams2, Thanh Duc Hoang1 and Vinh Quang Mai1
1Walter Reed National Military Medical Center, Bethesda, MD, 2Walter Reed National Military Center, Bethesda, MD

 

Introduction: Statin myopathy has increasingly been described in subclinical neuromuscular disorders. There are limited treatment options for these patients who also have hyperlipidemia. Herein we describe a patient with myotonic dystrophy type 2 (DM2) with statin-induced myopathy who was treated successfully with alirocumab.

Case: A 74 year old male presented in 2004 with insulin dependent type 2 diabetes mellitus and hypogonadism on testosterone replacement therapy. Patient also had hypercholesterolemia (LDL cholesterol (LDL-C) 188 mg/dL), non-HDL cholesterol (non-HDL-C) 210 mg/dL, HDL cholesterol (HDL-C) 72 mg/dL and was treated with simvastatin. Patient developed severe pain and cramps in the proximal lower and upper extremities. The serum creatine kinase (CK) increased from a baseline of 184 to 317 U/L (ref range 38-174). Serum CK-MB was 7.5 ng/mL (ref range 0 to 5.0). No specific etiology for muscle symptoms other than statin therapy was found. Despite the simvastatin dose reduction, the myalgias persisted over the next several years. Other statin brands (atorvastatin, pravastatin) along with Coenzyme Q10 were also tried with poor outcome. The patient was also treated with bile acid binding resins and ezetimibe without improvement. In 2012, the patient was diagnosed with coronary heart disease and had underwent angioplasty. Following angioplasty, rosuvastatin 5 mg was prescribed three times per week and 6 months later rosuvastatin was discontinued due to persistent myalgias. The patient underwent surgery for posterior subcapsular cataracts in 2013. In 2014, patient noted marked weakness of the proximal thigh and shoulder muscles and at this time he was not taking any statins. Physical examination was notable for frontal baldness and muscle strength was 4/5 in both proximal thigh and shoulder muscles. A cardiac evaluation showed no conduction abnormalities. EMG showed widespread myotonia and genetic testing confirmed repeat expansion mutation >15,420 binding-proteins, confirming DM2. In 2016, his serum LDL-C was 205 mg/dL, HDL-C 73 mg/dL, and non-HDL–C 216 mg/dL. Patient was started on alirocumab 75 mg s.c every two weeks. Six weeks later his serum LDL-C was 90 mg/dL with non-HDL-C 94 mg/dl and the serum lipids remained stable. The patient did not have recurrence of myalgias with alirocumab, but his muscle weakness persisted and serum CK levels remained minimally elevated.

Conclusion: Latent neuromuscular disorders such as DM2 may be revealed or aggravated by statin therapy. Alirocumab prevents the LDL receptor from degradation mainly in the hepatic tissues. It is possible that this mode of action has very little adverse effect on muscle tissues. Thus alirocumab may be an alternate lipid lowering agent in patients with neuromuscular disorders and statin intolerance

 

Nothing to Disclose: KMMS, TS, SYW, TDH, VQM

30408 8.0000 SAT 511 A Successful Treatment of a Patient with Statin-Induced Myopathy and Myotonic Dystrophy Type 2  with PCSK9 Inhibitor, Alirocumab (PraluentTM) 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Kamonkiat Wirunsawanya*1 and David Spinks2
1University of Hawaii John A Burns School of Medicine, Honolulu, HI, 2University of Hawaii John A Burns School of Medicine, Honolulu

 

Atorvastatin-induced acute severe neutropenia is an exceedingly rare adverse drug event. We discuss a 70-year-old male presenting in the emergency department with progressive generalized weakness and bilateral lower extremity pain. Laboratory evaluation revealed severe neutropenia, elevated serum creatinine kinase, and elevated transaminases. He had recently been prescribed atorvastatin, 80 mg daily, for coronary artery disease and hyperlipidemia. Other causes of acute severe neutropenia were excluded, including parvovirus infection, Epstein-Barr Virus, cytomegalovirus, human immunodeficiency virus infection, cobalamin deficiency, and thyroid disorder. The patient was taking aspirin, clopidrogel, atorvastatin, felodipine, furosemide, and metoprolol. During the hospitalization, his home medication was continued, except for atorvastatin. Within 3 days of atorvastatin withdrawal his symptoms, elevated transaminases and neutropenia had improved. Upon literature review, there are currently no reported cases of atorvastatin-induced acute severe neutropenia. Given the rarity of this particular adverse drug event with atorvastatin, the mechanism of acute severe neutropenia secondary to atorvastatin is not well understood. The objective of this case report is to increase awareness of this infrequent adverse effect of atorvastatin in order to ensure timely diagnosis and appropriate management in the future.

 

Nothing to Disclose: KW, DS

29548 9.0000 SAT 512 A Atorvastatin-Induced Acute Agranulocytosis 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Kaitlin Ditch*1, Satbir Kaur Singh1, Adam D McIntyre2, Amnon Schlegel1, Robert Alexander Hegele2 and Deepika Santosh Reddy1
1University of Utah, Salt Lake City, UT, 2Robarts Research Institute, London, ON, Canada

 

BACKGROUND: Hypobetalipoproteinemia (HBL) is a rare autosomal recessive or co-dominant disorder, with an incidence of less than 1 in 1,000,000, characterized by hypocholesterolemia with total cholesterol, LDL cholesterol (LDL-C), and total Apolipoprotein B (APOB) levels less than the 5th percentile. Affected individuals may be asymptomatic or can develop fatty liver, transaminitis, oral fat intolerance, intestinal fat malabsorption, and complications related to fat soluble vitamin deficiencies. HBL is caused by mutations in the APOB gene leading to inappropriate packaging and secretion of apo B-containing lipoprotein particles. APOB is expressed in enterocytes and hepatocytes; its encoded protein is the signature coat molecule of chylomicrons and Very Low Density Lipoprotein (VLDL) particles, which deliver intestine- and liver-derived neutral lipids to the periphery. We present a case of hypobetalipoproteinemia involving a novel mutation of APOB, p.E137X.

CLINICAL CASE: A 26-year-old Caucasian male presented with hypocholesterolemia. Medical history included obesity, hypogonadism, impaired glucose tolerance, nonalcoholic fatty liver disease, and obstructive sleep apnea. He noted diarrhea induced by fatty food intake since childhood. Family history included hypocholesterolemia in his mother and brother. Mild dysmetria and unsteady gait assessed by tandem walking were noted on examination. Laboratory revealed serum total cholesterol 58 mg/dL (<200 mg/dL), HDL-C of 26 mg/dL (40-59 mg/dL), triglyceride 53 mg/dL (30-149 mg/dL), and LDL-C of 22 mg/dL (0-129 mg/dL). Transaminases were: ALT 91 U/L (5-50 U/L) and AST 94 U/L (9-50 U/L). Deficiencies in Vitamins A, D, and E were observed. Vitamin K stores appeared normal, with INR of 1.0. APOB levels were undetectable <25 mg/dL (55-140 mg/dL) and APOA1 was normal 108 mg/dL (94-178 mg/dL). Vitamin B12 level was normal. Genetic testing revealed a heterozygous nonsense mutation, p.E137X, in the APOB gene, which was absent from all public databases. The patient was diagnosed with HBL due to a truncation in APOB.

We recommended annual lipid profile with APOA1 and APOB, hepatic and coagulation function tests, thyroid function tests, B12 and fat-soluble vitamins levels. Neurological examination should be repeated in 6 to 12 months, and abdominal ultrasound in 3 years. Baseline DXA, ophthalmological examination, and echocardiogram were recommended. He was treated with high doses vitamins A and E, and a low fat diet supplemented with 1-2 teaspoons olive oil daily for adequate consumption of essential fatty acids. We recommended genetic testing of the patient’s mother and brother.

CONCLUSION: Up to one-quarter of patients with clinically diagnosed HBL do not have detectable mutations on sequencing of APOB. This is the first case describing a heterozygous nonsense mutation in APOB (p.E137X) causing hypobetalipoproteinemia.

 

Nothing to Disclose: KD, SKS, ADM, AS, RAH, DSR

31225 10.0000 SAT 513 A Novel Heterozygous Mutation in Apob (p.E137X) Causing Hypobetalipoproteinemia 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Fatimah Zaherah Mohamed Shah*1, Nurazam Omar2, Faradila Hatta3, Marymol Koshy2, Sazzli Sahlan Kasim2 and Rohana Abdul Ghani2
1Universiti Teknologi MARA, Kuala Lumpur, Malaysia, 2Universiti Teknologi MARA, Selangor, Malaysia, 3Universiti Teknologi MARA, Shah Alam, MALAYSIA

 

Background and Aims: NAFLD and metabolic syndrome have been shown to have a synergistic impact on atherosclerosis. Carotid intima-media thickness (CIMT) is a reliable index of subclinical atherosclerosis. The relationships between glycaemic control and degree of steatosis with CIMT in patients with NAFLD remain vague. Thus, this study aimed to determine the effects of varying degrees of steatosis and glycated haemoglobin (HbA1c) on atherosclerotic risk factors including CIMT among a high risk population of type 2 diabetes mellitus (T2DM) with established coronary artery disease (CAD) and newly identified NAFLD. Materials and Methods. This is a cross-sectional study involving T2DM patients between 18 to 65 years old with established CAD based on coronary angiogram, dobutamine stress echocardiogram or treadmill stress test (n=150). Patients with seropositive Hepatitis B or Hepatitis C, and alcohol intake more than 21 units per week for males and more than 14 units per week for females were excluded. Baseline blood investigations were performed. Participants underwent ultrasonography of the abdomen by 2 independent radiologists for diagnosis of fatty liver, and further grouped into mild, moderate, severe and no steatosis. B-mode ultrasonography of both common carotid arteries was also performed, with calculation of the average posterior wall intima media thickness of the right and left common carotid arteries to determine CIMT. Results. There were 114 (76 %) males and 36 (24 %) females, with median age 57 years (IQR 13) and mean body mass index (BMI) 29.6 ± 15.3 kg/m2. The prevalence of NAFLD was 71.3 % (n=107), with higher BMI and waist circumference in the NAFLD vs non-NAFLD group. Systolic blood pressure was significantly higher in patients with NAFLD 135 ± 16.6 mmHg vs 127 ± 15.7 mmHg (p<0.001). Median HbA1c was significantly highest within the moderate steatosis group, followed by mild steatosis group and the no NAFLD group (9.3% (IQR 2.4) vs 8.2% (IQR 5.8) vs 8.0% (IQR 2.2) p <0.001). Similarly, patients with moderate NAFLD had significantly higher mean CIMT value, followed by mild steatosis group and the no NAFLD group (0.77 mm ± 0.19 vs 0.69 mm± 0.14 vs 0.68 mm± 0.32, p value 0.01). HbA1c was significantly correlated with CIMT in the NAFLD group, r=0.324 (p=0.002) but not in the non-NAFLD group r=0.095 (p=0.606). Conclusion. In this cohort of T2DM patients with established CAD, patients with NAFLD had higher obesity parameters, blood pressure and HbA1c compared to those without NAFLD. Patients with moderate steatosis had higher HbA1c and CIMT values compared to the mild and no steatosis groups. Our findings suggested additional atherosclerotic risks within the NAFLD group with significantly higher CIMT associated with higher HbA1c, which was not seen within the non-NAFLD group.

 

Nothing to Disclose: FZM, NO, FH, MK, SSK, RA

30717 11.0000 SAT 514 A Impact of Steatosis on Atherosclerotic Risk Factors in Diabetic Patients with Non-Alcoholic Fatty Liver Disease 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Seok Jin Kang*1, Mo Kyung Jung1, Ah Reum Kwon1, Duk Hee Kim2, Ho-Seong Kim3, Hong Koh1, Seung Kim4 and Hyun-wook Chae1
1Yonsei University College of Medicine, Seoul, Korea, Republic of (South), 2Sowha Children's Hospital, Seoul, Korea, Republic of (South), 3College of Medicine Yonsei University, Seoul, Korea, Republic of (South), 4Yonsei University College of Medicine, Seoul

 

Purpose

Recently, case reports and several studies suggest that panhypopituitarism is associated with increased prevalence of nonalcoholic fatty liver disease(NAFLD). NAFLD represents a spectrum of disease from simple steatosis to nonalcoholic steatohepatitis(NASH) and it may progress to liver cirrhosis We investigated the prevalence of NAFLD in adolescents and young adults with childhood-onset panhypopituitarism. We also analysed growth hormone replacement effect on the development of NAFLD

Patients and Methods :

A total of 36 patients[M/F 23/13, age 18.6± 5.7 years, range (10-29)] were included. Thirty five had growth hormone deficiency. To exam the prevalence of NAFLD, patients underwent transient elastography and hepatic fat quantification magnetic resonance imaging. We compared these patients with healthy age- and BMI-matched controls. Clinical and laboratory parameters were reviewed.

Results

The prevalence of NAFLD in patients with panhypopituitarism was significantly higher than in controls(69.4% vs 27.3%, P<0.01) on transient elastography. Patient’s mean BMI SDS was 0.75 ± 1.37. NAFLD was diagnosed 9.9 ± 6.6 years (1-23 years) after the diagnosis of panhypopituitarism. Mean gain of BMI SDS was 0.53 ± 1.38 during that period. Eleven patients (35%) showed liver fibrosis. One of with severe fibrosis underwent liver biopsy and the result was consistent with liver cirrhosis. We also performed MRI on 35 of 36 patients. The prevalence of NAFLD was higher than in controls.(62.9% vs 27.3%, p<0.01) The prevalence of those was lower in patients who had received growth hormone more than 1 year at the time of MRI evaluation.(27 % vs 72.7%, p<0.05). Triglyceride, ALT, and BMI were significantly elevated in hypopituitary patients with fatty liver compared to patients without fatty liver

Conclusions

Patients with panhypopituitarism are at a risk of development of NAFLD. It can progress to NASH and cirrhosis like a our patient. Growth hormone replacement in GHD patients may have preventive effect to the development of NAFLD

 

Nothing to Disclose: SJK, MKJ, ARK, DHK, HSK, HK, SK, HWC

31066 12.0000 SAT 515 A Prevalence of Non-Alcoholic Fatty Liver Disease in Patients with Childhood Onset Panhypopituitarism 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Reyna Rodríguez Mortera*1, Claudia Luevano1, Sergio Solorio2, Russell Caccavello3, Alejandro Gugliucci3 and Ma Eugenia Garay-Sevilla1
1University of Guanajuato, Leon GTO, Mexico, 2Mexican Institute of Social Security, León, Mexico, 3Touro University, Vallejo, CA

 

Obesity, dyslipidemia, hypertension and hyperglycemia are all well documented risk factors for cardiovascular disease. In adult populations some studies have also demonstrated that levels of plasma sRAGE are inversely correlated with the components of the metabolic syndrome (MetS), systemic arterial pressure, body mass index (BMI), waist-to-hip ratio, serum triglycerides (TG), and insulin resistance indexes. Endothelial function measured by FMD and arterial lesion by CIMT can serve as independent predictors of cardiovascular events. However, few studies have explored the relationship between sRAGE, and other cardiometabolic risk factors with obesity.

Objective: Study the association of sRAGE and cardiometabolic risk markers in lean adolescents vs adolescents with obesity

Material and Methods: We conducted a cross-sectional study in adolescents between 15-18 years old, 30 lean and 30 with obesity. Anthropometric measurements were evaluated using standard methods, flow-mediated vasodilation (FMD) and carotid intima media thickness (CIMT) were measured by ultrasound. We collected blood samples after a 12-hour fast to determinate lipid profile, ICAM, VCAM, and serum. We also calculated the atherogenic and TG/HDL index. The Ethical Committee of the Institution approved this study and informed consent was obtained from the participant adolescents and their parents.

Results: In the study group age was 16.8±1.4 y. In the group with obesity we found higher levels of VLDL-C (p<0.005), triglycerides (p<0.0001), atherogenic (p<0.0001), and TG/HDL index (p<0.0001), VCAM (p<0.01), sRAGE (p<0.002) and CIMT (p<0.019). No significant difference was found for FMD. CIMT correlated with BMI (p<0.02) and waist circumference (p<0.018); sRAGE correlated with BMI (p<0.001), waist circumference (p<0.002), hip circumference (p<0.003) and VCAM (p<0.001).

Conclusions: Serum sRAGE are lower in adolescents with obesity as compared to lean controls and they are associated not only with surrogate cardiometabolic risk factors but with early evidence of arterial lesion, as CIMT was significantly higher in this population. Our data show that obese adolescents without the metabolic syndrome already display metabolic and vascular alterations found in adults and support the contention that earlier dietary and lifestyle interventions are warranted.

 

Nothing to Disclose: RR, CL, SS, RC, AG, MEG

32273 13.0000 SAT 516 A Cardiometabolic Risk Markers Are Associated with Soluble Receptor for Advanced Glycation End-Products in Adolescents with Obesity 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Irina Khripun1, Sergey Vorobyev2, Elena Bova*3, Michael Kogan2 and Michael Zitzmann4
1Rostov State Medical University, Rostov-on- Don, Russia, 2Rostov State Medical University, Rostov-on-Don, Russia, 3Rostov State Medical University, 4University Clinics Muenster, Muenster, Germany

 

Diabetes mellitus type 2 (T2DM) leads to the progression of endothelial dysfunction (ED), which increases the risks of cardiovascular disease. Recently, the diagnosis of cardiovascular disease is established according to the presence of clinical symptoms. The criteria for the early diagnosis of ED are not well established.

Aim To find the early signs of ED in men with T2DM without clinical symptoms of cardiovascular disease.

Materials and methods. We were examined 250 men with T2DM (mean age 54.6±5.1 years) from which 110 patients were selected with no clinical symptoms of cardiovascular diseases. These patients were divided into 2 groups: the1st one consisted of 62 patients with diabetes duration of up to 5 years, the 2nd one of 48 men with a diabetes history of 5-10 years. Endothelial function was assessed by assessment of plasma levels of nitric oxide (NO), endothelial NO synthase type 3 (eNOS3), ICAM-1, VCAM-1, E-, P-selectin, resistin, C-reactive protein and ultrasonographic determination of arterial vasoreactivity of the brachial artery (BA). The data were analyzed using the Mann Whitney U - test for two independent groups.

Results. The levels of eNOS3 (192,3 [95,1; 645,2] vs 178,6 [118,2; 341,1], p = 0.0005) and NO (103,5 [67,8; 292,6] vs 69,8 [51,2; 119], p = 0.043) were higher in the 1st group compared to the 2nd one. In the 2nd group the levels of VCAM-1were higher by 12.1% (p = 0.048), resistin by 62% (p = 0.01), C-reactive protein by 45.6%, compared to the 1st group. This indicates the raise of cardiovascular risk with increasing the duration of diabetes more that 5 years, even in the absence of clinical signs of cardiovascular disease.

There was a decrease in the arterial vasoreactivity in the 2nd (10,2 [6,4; 16,4]%) as compared to the 1st group (13,0 [10; 17]%), which remained in the normal range. Therefore, the time until the maximum vasodilatation of the BA was higher in the 2nd group (105 [90; 180] seconds) compared to the 1st one (90 [60; 120] seconds).

Biochemical and instrumental signs of ED in men with T2DM appear long before the clinical manifestation of cardiovascular diseases. The earliest markers of ED are the reduction of eNOS3 and NO levels, the increase of VCAM-1 and resistin concentrations, and the increase in the time until the maximum vasodilatation of BA – a new ultrasound index of ED.

 

Nothing to Disclose: IK, SV, EB, MK, MZ

32430 14.0000 SAT 517 A The Earliest Signs of Endothelial Dysfunction in Men with Type 2 Diabetes, without Clinical Symptoms of Cardiovascular Disease 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Su Kyoung Kwon1, Seokhyeun Kim*2, Young Chan Park3, Jeonghyun Lee4 and Young-Sik Choi5
1Kosin University College of Medicine, Busan, Korea, Republic of (South), 2Kosin University Gospel Hospital, Korea, Republic of (South), 3Kosin Gospel Hospital, busan, 4Kosin University Gospel Hospital, 5Kosin Univ Sch of Med, Busan, Korea, Republic of (South)

 

Background and Objective: Pulse wave velocity (PWV) and Ankle-brachial index (ABI) are well known non-invasive methods that measure arterial stiffness and atherosclerosis. Increased arterial stiffness measured by PWV and decreased ABI have been suggested as risk factors for increased cardiovascular risk in patient with diabetes. Framingham Risk Score (FRS) in general population and United Kingdom Prospective diabetes Study (UKPDS) risk score in type 2 diabetes and atherosclerotic cariovascular disease risk were well known clinical cardiovascular disease (CVD) Risk prediction methods. This study was performed to elucidate the correlation between PWV and VBI with widely accepted CVD risk scoring systems such as FRS and UKPDS CHD and ASCVD risk simultaneously.

Method:

From April 2010 to April 2015, total 324 (170=men and 154=women) numbers of Type 2 diabetes subjects who visited outpatients clinics or admitted in Kosin University Gospel Hospital were included. Brachial-ankle Pulse Wave Velocity (BaPWV, m/sec), Mean ankle brachial index (ABI), Age (years), DM duration (months), Systolic Blood pressure (BP, mmHg), Body mass index (BMI, m/Kg2), Albumin Creatinine Ratio (ACR), Fasting Blood Sugar (FBS, mg/dL), HbA1C(%), 25(OH)Vitamin D(IU), Total cholesterol(mg/dL), HDL (mg/dL), Triglyceride (mg/dL), Framingham risk score (FRS), United Kingdom Prospective Diabetes Study (UKPDS) CHD score, ASCVD risk, Homeostatic model assessment of insulin restance (HOMA)-IR, Homeostatic model assessment (HOMA)-β were measured. Data was analyzed by using Statistical Package for Social Science (IBM SPSS Statistics 18 Standard for Medical Science).

Result

The BaPWV was correlated with FRS (γ= 0.326 P < 0.01), UKPDS CHD (γ= 0.388 P<0.01) and ASCVD Risk (γ= 0.362 P <0.01). The BaPWV was correlated with FRS (γ= 0.423 P < 0.01), UKPDS CHD (γ=0.369 P <0.01) and ASCVD Risk (γ= 0.352 P<0.01) in men with diabetes. The BaPWV was correlated with FRS (γ=0.448 p<0.01), UKPDS CHD (γ=0.512 p < 0.01) and ASCVD Riskk (γ= 0.424 P < 0.01) in women with diabetes. ABI was not significantly correlated with FRS, UKPDS CHD risk and ASCVD Risk. BaPWV was not correlated with ABI (γ= 0.058 P <0.287).

Conclusion

BaPWV is well correlated with FRS, UKPDS CHD Risk scores and ASCVD risk but not with ABI. Increased BaPWV can be a useful marker to predict cardiovascular event in advanced Korean type 2 diabetes patient.

 

Nothing to Disclose: SKK, SK, YCP, JL, YSC

32668 15.0000 SAT 518 A Frs, Ukpds and Ascvd Risk Score Are Positively Correlated with Pulse Wave Velocity but Not with Ankle-Brachial Index in Advanced Korean Adult T2DM Subjects 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Vakkat Muraleedharan*1, Dheeraj Kapoor2 and Thomas Hugh Jones3
1University of Sheffield, Sheffield, United Kingdom, 2Barnsley Hospital NHSFT, Barnsley, United Kingdom, 3Barnsley Hospital NHSFT, Barnsley S Yorkshire, United Kingdom

 

Sex Hormone Binding Globulin (SHBG) is specific binding protein which binds to sex hormones regulating their availability in the circulation. Studies have shown that a lower SHBG strongly predict insulin resistance and diabetes and higher SHBG is favourably linked with a wide range of cardiovascular (CV) risk factors. There is no long term study looking into the effect of SHBG levels on the CV risk profile in men with type 2 diabetes.

We have investigated if the SHBG is associated with adverse CV risk profile in men with type 2 diabetes on long-term follow up. This is a 7-year follow up of 203 patients with type 2 diabetes from our research cohort. Baseline data for co morbidities, concomitant medication, anthropometric measurements and biochemical results were obtained from the research database and hospital records. Correlation analysis was performed with baseline SHBG and follow up HbA1c. Further baseline SHBG values were divided into quartiles and analysed for associations with the different cardiovascular risk profiles. Statistical analysis was done using SPSS software, general linear model and repeated measures.

Mean age at baseline 56.6+8.7 years (range 34-75). At baseline testosterone was significantly correlated with the HbA1c (r=-0.16; p=0.04. Mean baseline testosterone 12.4 +5.1nmol/l; follow up 12. ±6nmol (NS) SHBG increased from baseline 30.9nmol/l +17.8 to 34.7nmol/l+17.1 (p=.001) at follow up, probably an effect of ageing. During the follow up HbA1c deteriorated from 7.3 ±1.2% to 7.7±1.5% (p= <0.001). There was a significant improvement in diastolic blood pressure (82.9 +11 mmHg to 77.2 +11.7 mmHg p<0.00). Lipid profile, weight, body mass index, waist circumference, waist-hip ratio and diastolic blood pressure did not differ significantly when adjusted for age and medications.

There was significant negative correlation between SHBG and the follow up HbA1c (correlation coefficient = -0.194, p=0.007). When analysed in SHBG quartiles (quartile ranges: up to 18.9, 19 to 26.5, 26.6 to40.1, 40.2 and above) the HbA1c deterioration was significantly worse in the lower SHBG quartile (Q1=7.6(±1.2) to 8.6(±19); Q2 =7.1(±1.1) to 7(±0.9); Q3=7.2(±1.4) to 7.6(±1.3); Q4=7.3(±1.2) to 7.5(±1.4) p=0.042) as compared to the other 3 quartiles. Systolic blood pressure reduction was also significantly lower (Q1= 145.4(±17.6) to 136.7(±13.9); Q2=141.2(±18) to 139.6(±16); Q3=141.3(±18) to 136.8(±17.3); Q4= 145.9(±21.9) to 134.6(±20.3 p= 0.04) in the highest quartile as compared to the lowest quartile. The significance persisted after adjusting for age, testosterone levels and concomitant medications. There were no significant changes in body composition, lipid profile and diastolic blood pressure in the different quartiles.

In conclusion this study suggests baseline SHBG is an independent risk factor for cardio-metabolic risk profile in Men with type 2 diabetes on the long term follow up.

 

Disclosure: THJ: Clinical Researcher, educational lectures, advisory board member, Clinical Researcher, Pro Strakan, Consultant, Clarus, Clinical Researcher, advisory board member, Clinical Researcher, advisory board memeber. Nothing to Disclose: VM, DK

32417 16.0000 SAT 519 A SHBG Is an Independent Predictor of Cardio-Metabolic Risk Profile on Long Term Follow up in Men with Type 2 Diabetes 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Vakkat Muraleedharan*1, Dheeraj Kapoor2 and Thomas Hugh Jones3
1Kings Mill Hospital, United Kingdom, 2Barnsley Hospital NHSFT, Barnsley, United Kingdom, 3Barnsley Hospital NHSFT, Barnsley S Yorkshire, United Kingdom

 

Testosterone levels and SHBG levels have been negatively correlated with adverse cardiovascular risk (CV) profiles. Studies suggest testosterone replacement therapy (TRT) has a beneficial effect on CV profile. We have evaluated whether or not testosterone and SHBG levels negatively correlate with CV risk profile in men and physiological TRT has a beneficial effect on the CV risk profile in those with low testosterone.
This is a cross sectional study results of a cohort of 203 type 2 diabetic men from our research database. The cohort was divided into three groups, 1- Total testosterone (TT) <10.4nmol/l, no TRT (n=77); 2 – TT¬> 10.4nmol/l ( n=81); 3 – TRT >3 months (n=45). The effect of SHBG was analysed by correlation coefficients and ANOVA in the quartiles of SHBG.
Effect of TT- there was an inverse relationship between the TT and HbA1c (R2 linear =0.065). In the multivariate adjusted model (adjusted for medications, smoking and co morbidities) HbA1c (Group-1 =7.9±1.7%; Group-2 =7.3±1.2%; Group-3 =7.5±1.2% p=0.001) was significantly higher in low testosterone group compared to the high T group and no significant differences between TRT and normal TT groups. Hip circumference (Group-1=114.1±14; Group-2=107±9cm; Group-3=112.8±10.3cm p=0.033), waist Circumference (Group-1=114.1±15.9cm; Group-2=108.3±12.6cm; Group-3 119.1±13.6cm p=0.002), ), waist hip ratio (Group-1=1.03±0.08; Group-2=1±0.06; Group-3=1.06±0.08 p=0.019)weight (Group-1=98.2±20; Group-2=30.1±4.7kg; Group-3=103.9±16.5p=0.006 and BMI (Group1=32.5±6; Group2=30.2±4.8; Group3=34.4±5.6 p=0.001) were significantly higher in the low T group.

The SHBG-after adjusting for age and testosterone, HbA1c (Q1=8.4±1.5%; Q2=7.4±1.5 Q3=7.7±1.5%; Q4=7.2±1.4% p=0.037), percentage body fat (35.8±8.7%; Q4 =29.7±8.4% p=0.009), weight (Q1=108.4±17.9kg and Q4=92.7±23.5kg, p=0.002), BMI ( Q1=35.8±6.2 and Q4=30.6±6.4,p=0.001), waist circumference (Q1=119.5±14.9cm and Q4=109.7±17.4cm, p=0.013) and triglycerides (Q1=3.7±4mmol/l and Q4=1.3±0.7mmol/l, p=0.02) showed inverse relation with SHBG levels. HDL was higher in the lowest quartile (Q1=0.96±0.2mmol/l and Q4=1.2±0.3, p=<0.00).There was no significant effect of SHBG on LDL, total cholesterol, hip circumference, systolic and diastolic blood pressure.
This study reports that low TT and low SHBG levels are independently associated with worsening of cardiovascular risk profile in men. TRT group had similar glycaemic control as normal T group suggesting a beneficial effect.
Testosterone deficiency should be evaluated and treated, if appropriate, in men with metabolic syndrome and diabetes. TRT has been shown to reduce mortality (1). SHBG is a surrogate marker of insulin resistance so this may be the reason for the CV risk profile results in the study. This may be mediated through a beneficial effect of testosterone itself (2).

 

Disclosure: THJ: Clinical Researcher, educational lectures, advisory board member, Clinical Researcher, Pro Strakan, Consultant, Clarus, Clinical Researcher, advisory board member, Clinical Researcher, advisory board memeber. Nothing to Disclose: VM, DK

32771 17.0000 SAT 520 A Testosterone and SHBG Show Independent Negative Correlation with Cardiovascular Risk Profile in Men Which Improves with Testosterone Replacement in Men with Type 2 Diabetes 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Hyeong Kyu Park*, Mi Kyung Kwak, Hyun Suk Kim, Hye Jeong Kim, Dong Won Byun and Kyo-Il Suh
Soonchunhyang University Hospital, Seoul, Korea, Republic of (South)

 

Several capillary changes detected by finger nailfold capillaroscopy have been shown to correlate with microvascular complications in type 1 diabetes. However, there are few reports on the relationship between nailfold capillary abnormalities and microvascular complications in type 2 diabetes (T2DM). Herein, we investigated whether nailfold capillary microscopic changes are associated with diabetic nephropathy in patients with T2DM.

We conducted a cross-sectional study in patients with T2DM diagnosed within 20 years (duration of diabetes: 6.4 ± 6.0 years). The nailfold capillaroscopy test is non-invasive and able to visualize the capillary network in fingers. The presence of morphological abnormalities, including avascular areas, giant capillaries, dilated, tortuous, or ramified capillaries, hemorrhages and capillary architectural derangements, in finger nailfold capillaroscopy image was assessed by a single rheumatology specialist. The severity of nailfold capillary changes was scored. Statistical analyses were performed using Pearson correlation or Spearman rank correlation as appropriate.

A total of 63 patients with T2DM were enrolled. Both capillary architectural derangements and avascular areas in nailfold capillaroscopy showed significant correlations with albuminuria measured by spot urine or 24-hour urine collection after adjusting for sex, age, body mass index, duration of diabetes, hemoglobin, and HbA1C. Moreover, architectural derangements and avascular areas in nailfold capillaries were significantly associated with urinary albumin excretion rate in T2DM patients diagnosed within 10 years.

Taken together, nailfold capillary abnormalities are independently associated with albuminuria in patients with T2DM. These findings suggest a potential role of capillary changes in the pathogenesis of diabetic nephropathy.

 

Nothing to Disclose: HKP, MKK, HSK, HJK, DWB, KIS

30438 18.0000 SAT 521 A Association Between Nailfold Capillary Abnormalities and Diabetic Nephropathy in Type 2 Diabetes 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Lía Nattero Chávez1, Alonso Sara1, Sandra Redondo López1, Marta Garnica Ureña1, Elena Fernández-Durán2, María Cortes Peiró3, Hector Francisco Escobar-Morreale*4 and Manuel Luque-Ramírez4
1Hospital Universitario Ramón y Cajal, Madrid, Spain, 2Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM, Madrid, Spain, 3Diabetes, Obesity and Human Reproduction Research Group. Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS, CIBER Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Spanish Ministry of Science, Spain, 4Diabetes, Obesity and Human Reproduction Research Group. Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS, CIBER Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Spanish Ministry of Science, Madrid, Spain

 

INTRODUCTION Even though a reduced ankle-brachial pressure index (ABPI) translates the presence of peripheral arterial stenosis, the relationship between medial artery calcification (MAC), as defined by an increased ABPI, and arteriosclerosis is unclear. Considering that cardiovascular autonomic neuropathy (CAN) is associated with arteriosclerotic disease in patients with type 1 diabetes mellitus (T1DM), this study aimed to explore the risk factors related to increased ABPI and its putative association with CAN in that population.

MATERIAL AND METHODS Observational cross-sectional study in a consecutive cohort of patients with T1DM from our Outpatient Clinic (n = 143). Clinical and biochemical variables were collected from their medical records. Systolic blood pressure (SBP) measurements were obtained using a Doppler ultrasound unit (8 MHz probe). ABPI was calculated by dividing ankle BP by brachial BP readings to provide a normalized ratio. MAC was defined by an ABPI > 1·2. CAN was assessed by the BP and heart rate (HR) responses to active standing (adrenergic innervation), and HR (RR interval) variability (parasympathetic innervarion): HR response to deep breathing (DB), to Valsalva’s maneuver (VAL), and to orthostatism [(ORT) 30:15 ratio].

RESULTS Mean age of patients was 37±12 yrs (range 18-79) and 61% were men. Mean body mass index (BMI) was 25 kg/m2. Age at T1DM diagnosis was 16±8 yr and average duration of disease was 21±11 yr. 16%, 32% and 28% of patients presented with concomitant hypertension, dyslipidemia, or were current smokers, respectively. Mean HbA1c was 7·6±1·3%. Eleven patients (8%) had an ABPI < 0·9 whereas 44 (31%) showed an ABPI > 1·2 suggestive of MAC. Patients with MAC were more likely male and were older that those with normal ABPI. They also had longer duration of disease, higher BMI, waist circumference and office SBP values compared with patients without MAC. A binary logistic regression model (Nagelkerke’s R2: 0·25, χ2: 27·15, P < 0.001) identified, as main determinants of MAC, male sex [Exp (B): 2·8 (1·2 - 6·8)], BMI [Exp (B): 1·2 (1·0 - 1·3], and duration of T1DM [Exp (B): 1·1 (1·0 - 1·1)]. Twenty-two (16%) patients presented with abnormal HR variability (64% and 59% of them had abnormal DB and ORT ratios, respectively). Patients with MAC showed significant lower SBP (P = 0·03) and diastolic BP (P = 0·02) responses to active standing (sympathetic dysautonomy), and a lower HRV response to DB (P = 0·06) (parasympathetic dysautonomy).

CONCLUSIONS Male sex, adiposity and duration of disease are related to MAC in our population with T1DM. The presence of parsympathetic and sympathetic dysautonomy in these patients with MAC also suggest a link between subclinical CAN and arterial calcification.

 

Nothing to Disclose: LN, AS, SR, MG, EF, MC, HFE, ML

30635 19.0000 SAT 522 A The Association Between Vascular Calcification and Subclinical Cardiac Autonomic Neuropathy in Type 1 Diabetes Mellitus Patients 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Chinenye Usoh*1, Saadia Sherazi2, Barbara Szepietowska2, Valentina Kutyifa2, Scott Mcnitt2, Anna Papernov2, Meng Wang2, Stephen R Hammes3 and Jeffrey Alexis2
1University of Rochester School of Medicine and Dentistry, Rochester, NY, 2University of Rochester Medical Center, 3University of Rochester Medical Center, Rochester, NY

 

Prior studies have shown that patients with diabetes have worse surgical outcomes when compared to non-diabetics. Despite previous studies, the mortality risk of diabetic patients post left ventricular assist device (LVAD) implant, remains unclear. In addition, the relationship between the degree of glycemic control and long-term mortality risk in LVAD patients with diabetes has not been established.

We hypothesized that diabetic LVAD patients would have a higher mortality rate than non-diabetic LVAD patients; and amongst LVAD diabetic patients, mortality would increase with worse diabetes control (defined as higher hemoglobin A1c).

Ninety-five non-diabetic and ninety-six diabetic patients from the University of Rochester Medical Center, who received a HeartMate II continuous-flow LVAD between August 26th, 2007 and June 30th, 2014 were included in this study. Diabetics were defined as having a diagnosis of diabetes in medical records, or hemoglobin A1c greater than or equal to 6.5%, or random glucose greater than 200 mg/dL on more than one occasion prior to LVAD implantation. The primary outcome was all-cause mortality. Secondary outcomes included rates of infection, neurological dysfunction, renal dysfunction, and re-hospitalization. Kaplan-Meier cumulative probabilities of long-term all-cause mortality were assessed by diabetes and by the degree of glycemic control.

During follow-up, 32 (33%) diabetics and 15 (16%) non-diabetics died following LVAD implantation (p=0.005). Cumulative probability of death was higher in diabetics when compared to non-diabetics (42% vs. 21% at 3 years, p=0.008). There was no difference in overall rates of infection, neurological dysfunction, re-hospitalization, or renal dysfunction between the two groups. However, after initial outcome event, diabetics had a higher mortality rate when compared to non-diabetics. There was no statistically significant difference in cumulative probability of death between diabetics with pre-LVAD hemoglobin A1c < 7.5% and diabetics with pre-LVAD hemoglobin A1c ≥ 7.5% (p=0.198).

Diabetics who undergo LVAD implantation have a higher probability of death compared to non-diabetic patients. Overall rates of selected outcomes did not differ, but diabetics had increased mortality after initial event which could be contributing to the higher total mortality. Finally, the degree of glycemic control in diabetics prior to LVAD did not influence mortality.

 

Nothing to Disclose: CU, SS, BS, VK, SM, AP, MW, SRH, JA

29638 20.0000 SAT 523 A Diabetes Increases Risk of Mortality in Heart Failure Patients Who Undergo Left Ventricular Assist Device Implantation 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Antonio Mancini*1, Chantal Di Segni1, Carmine Bruno2, Giulio Olivieri1, Nunzia Ciferri2, Edoardo Vergani2, Alfredo Pontecorvi1, Andrea Silvestrini1, Elisabetta Meucci1, Angela Venuti2, Maria Anna Nicolazzi2, Raffaele Landolfi2 and Angela Maria Rita Favuzzi2
1Catholic University of the Sacred Heart, Rome, Italy, 2Catholic University of the Sacred Heart

 

It is well known that heart failure (HF) is associated with oxidative stress (OS). Reactive oxygen species in fact influence sarcolemmal and mitochondrial ione channels, which are responsible for cardiomyocyte excitability and are important in myocardial remodeling after a myocardial infarction. On the other hand, several deficiencies of anabolic hormones (including GH, DHEAS, Testosterone), are reported to be correlated with the severity and prognosis of HF; a low-T3 syndrome is also present. OS could represent an underlying mechanism causing worsening of myocardial function. 

 In order to evaluate the relationships between anabolic hormones and indexes of OS and the impact on HF, we have studied a group of 21 patients (18 males  3 females, age 49-73 ys) affected by HF (NYHA II-III; EF<40%),  evaluating metabolic parameters (glycemia, total and fractioned cholesterol, uric acid, triglycerides, proteins), hormonal parameters (IGF-1, DHEAS, Testosterone, freeT3, freeT4, TSH, NT-proBNPand total plasma antioxidant capacity (TAC). TAC was evaluated by a spectrophotometric method, using H2O2–metmyoglobin system, which, interacting with the chromogen ABTS induces the appearance of its radical forms with a latency phase (LAG) proportional to antioxidant content of the sample. Hormone were measured by electrochemiluminesce method. 

 The most prevalent hormonal deficiencies were those of IGF-1 (83%) and DHEAS (82%). The association of multiple hormonal deficiencies correlated with levels of NT-proBNP (no deficit, n=5, 882±483.1; one deficit, n=5, 787±307,4, two deficit, n=4, 4199.3±2167.7; three or four deficit, n=7, 7968,8±5123,9 pg/ml) LAG values were significantly elevated in patients with one or more deficit versus patients with normal hormone pattern (106±11,3 vs 66,7±6.7 sec), but while patients with single hormonal deficiency showed the greatest levels (123,3±6,7), suggesting a compensatory increase in antioxidant systems, no further increase was observed with the worsening of hormonal picture (two deficit, 106,7±31; three or four deficit 92,5±20,1). 

These preliminary data, while confirming that multiple hormonal deficiencies are associated with the severity of HF(1,2), suggest that an increased antioxidant defence can be observed in patients with only one anabolic hormone deficiency, but this system could not be effective in contrasting the ingravescence of the hormonal picture, perhaps contributing, in a reciprocal way, to influence hormone levels themselves

 

Nothing to Disclose: AM, CD, CB, GO, NC, EV, AP, AS, EM, AV, MAN, RL, AMRF

30555 21.0000 SAT 524 A INDEX of Oxidative Stress in Heart Failure: Reciprocal Influence on Multihormonal Deficiencies  2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Gustavo Demasi Quadros de Macedo*1, Jean Jorge Silva de Souza1, Mario Jorge Quadros de Macedo1 and Maria Luiza Gazzana2
1Federal University of Amazon, Manaus, Brazil, 2Universidade do Estado do Amazonas, Manaus, Brazil

 

Background: Thyroid hormones deficiency compromises cardiac muscle contraction, slowing myocardial relaxation, thus impairing left ventricular filling. In patients with hypothyroidism, short-term occurs a cardiac output decrease, associated to a reduction of left ventricle (LV) ejection volume and lower heart rate. After a lot of studies about the left ventricle, little is known about the effect of thyroid hormones deprivation at the right ventricle (RV). This study was aimed to evaluate the right ventricular function in patients who had hypothyroidism in different degrees of disease severity.Methods: Eighteen patients were submitted to two-dimensional echocardiography evaluation, of which 10 (55,6%) had TSH <12 mIU/L (highest TSH group) and 8 (44,4%) had TSH >12 mIU/L (less high TSH group). Global RV systolic function was evaluated by myocardial performance index (Tei index) and by percentage of systolic change in the area in the apical four-chamber view. Regional RV systolic function was evaluated by tricuspid annular plane systolic excursion (TAPSE) and by peak systolic velocity. Diastolic RV function was evaluated by transtricuspid peak early diastolic velocity/transtricuspid peak late diastolic velocity ratio (E/A tricuspid ratio) and by transtricuspid peak early diastolic velocity/early diastolic tricuspid annular velocity ratio (E/E’ tricuspid ratio).Results: Sixteen (88,9%) patients had at least one cardiovascular symptom (dyspnea, chest pain or palpitations). Patients in the highest TSH group had lower body mass index (BMI) than those in the less high TSH group (23.9 ± 3.5 vs. 27.8 ± 3.7 kg/m2; p<0.05). By comparing the two groups, there were no differences in respect of LV global systolic function, represented by ejection fraction (LVEF), or diastolic function. There was neither difference related to right atrium area and volume, nor RV diastolic and systolic areas, nor right ventricular diameter. About the right ventricular function, it was shown a difference in the myocardial performance index (Tei index), which was higher in patients who had TSH>12 compared with patients who had TSH<12 (0.52 ± 0.13 vs. 0.39 ±0.08; p<0.05), indicating worse right ventricular global function in those patients with the highest TSH levels. No differences were observed between these groups related to other variables, which are: percentage of systolic change in the VD area, TAPSE and peak systolic velocity. Variables of RV diastolic function (E/A tricuspid ratio and E/E’ tricuspid ratio), as well as pulmonary vascular resistance and pulmonary artery systolic pressure were not different between groups.Conclusion: Patients with hypothyroidism who had the highest TSH levels, as compared to those with less high TSH, presented with a reduction at the overall right ventricular function, evaluated by myocardial performance index, not observed in other parameters of RV function evaluation

 

Nothing to Disclose: GDQDM, JJSDS, MJQDM, MLG

30643 22.0000 SAT 525 A Analysis of Right Ventricular Function in Patients with Hypothyroidism 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Di Wu*1, Yintao Chen2, Haixia Guan2 and Yingxian Sun2
1Medstar Health Research Institute, Washington, DC, 2The First Affiliated Hospital of China Medical University, Shenyang, China

 

Background

The relationship between serum electrolyte levels and blood pressure is inconsistent in healthy populations and in certain subgroup populations. It is unclear whether this association exists in high salt diet populations, and whether there is an association with the odds of hypertension.

Objective

The objective of this study is to determine the prevalence of hypertension in sodium, potassium, chloride, calcium, phosphate and magnesium electrolyte disturbances (ED), and to evaluate the odds of hypertension across serum electrolyte levels in a high salt diet population.

Methods

A total of 11,956 out of 14,016 residents aged ≥ 35 years from Liaoning, China participated in the Northeast China Rural Cardiovascular Health Study between January 2012 and August 2013. Population selection and data collection methods were previously reported (1). Participants who had recent history of medication interfering with serum electrolyte levels and/or eGFR < 60 mL/min/1.73m2 were excluded from the analysis. Hypertension was classified into newly-diagnosed (NDH) and pre-existing hypertension (PDH). The prevalence and odds of hypertension in each ED, and odds of hypertension across electrolyte levels were calculated.

Results

The overall prevalence of hypertension was 46.82% in the 10,555 participants (5000 men, 5555 women) included in this study. Hypertension was most frequent in hypercalcemia (63.07%), hypokalemia (62.63%) and hyponatremia (59.65%). Hypercalcemia was the only ED significantly associated with both NDH (OR, 1.51) and PDH (OR, 2.04). In multivariate analysis, serum sodium levels had no significant correlation with hypertension, while serum potassium levels had a U-shaped trend with PDH. The highest chloride quartile had 35.5% lower odds of PDH than the lowest quartile (OR, 0.645). The highest serum calcium quartile had higher odds of NDH (OR, 0.577) and PDH (OR, 1.635) than the lowest quartile, however, highest serum phosphate quartile was only associated with lower odds of NDH (OR, 0.748). The odds of NDH (OR, 0.864) and PDH (OR, 0.768) is lower in the serum magnesium levels above the median.

Conclusion

This is the largest report in the literature evaluating the association of serum electrolyte levels with the odds of hypertension in a high salt diet population. In this population, serum sodium levels were not associated with odds of hypertension; serum calcium levels and its imbalances were significantly associated with odds of hypertension in all analysis. Further prospective studies are needed to evaluate the relationship of chronic serum electrolyte imbalances with the development of hypertension.

 

Nothing to Disclose: DW, YC, HG, YS

29639 23.0000 SAT 526 A Association of Serum Electrolyte Levels with the Prevalence of Hypertension in a High Salt Diet Population 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Nicholas Nasser*1, Geraldine Skurnik2, Jennifer Stuart3, Joeli Katz2, Grace Chen2, Andrea T Roche2, Janet Rich-Edwards2, Eleni Tsigas4, Laney Poye4 and Ellen Wells Seely5
1Tufts University, Medford, MA, 2Brigham and Women's Hospital, Boston, MA, 3Harvard T.H. Chan School of Public Health, Boston, MA, 4Preeclampsia Foundation, Melbourne, FL, 5Brigham and Women’s Hospital, Boston, MA

 

Women with prior preeclampsia (PE) are at increased risk of cardiovascular disease (CVD); the postpartum period presents an opportunity to introduce lifestyle modification to decrease risk. However, recruitment of women with infants and young children into research studies is difficult with traditional methods.

Heart Health 4 Moms (HH4M) is an ongoing nationwide study led by researchers at Brigham & Women’s Hospital (Boston, MA) in partnership with the Preeclampsia Foundation (PF), the largest patient advocacy organization for PE survivors. HH4M investigates whether a web-based lifestyle intervention for women with a recent history of PE can increase CVD risk knowledge and self-efficacy in relation to nutrition and physical activity. We aimed to recruit 150 women from across the US in one year. With input from patient focus groups and an advisory council lead by the PF, we devised a patient centered social media and web-based recruitment approach.

We recruited through social media and website postings from the PF, March of Dimes, Craigslist, and BabyCenter. The National Association of County and City Health Officials disseminated recruitment materials to providers for patient referrals. Flyers were provided to networks providers to be posted in their offices and also placed in Women Infants & Children (WIC) Program offices. Recruitment materials directed women to an online questionnaire to determine initial eligibility. Eligibility required women to be healthy, within 5 years of a live birth complicated by PE, resident of a US state/territory, 18-44 years, able to communicate in English or Spanish, and have internet access. The questionnaire also captured how women heard about the study; possible responses included Craigslist, PF (Website, Facebook, Twitter page), BabyCenter, Facebook, Twitter, doctor referral, family/friend, email, Google, flyer, and other. We asked for zip code of residence for geographic distribution and obtained medical records to validate PE.

We achieved our recruitment goal of 150 women in one year and participants represented 41 states. The majority (90%) was recruited via social media and web-based sources; 9% were recruited through flyer, email, or referral, and 1% did not specify. The plurality of participants (69/150) was directly attributable to the PF, while 41% came from Facebook. Due to the viral nature of social media sharing, it was not possible to discern the exact pathways in which all women came in contact with the web-based recruitment materials. Although Craigslist and BabyCenter generated many responses, the highest yield of medically-validated PE cases came from the PF’s online channels.

Social media and web-based recruitment tools, as well as partnering with the PF, were key to reaching our nationwide recruitment goal of 150 women within one year. These may be important tools for successful recruitment of postpartum women in future studies.

 

Nothing to Disclose: NN, GS, JS, JK, GC, ATR, JR, ET, LP, EWS

31800 24.0000 SAT 527 A Social Media and Web-Based Recruitment Strategies for a Preeclampsia Postpartum Lifestyle Intervention Trial 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Cardiovascular Endocrinology Saturday, April 1st 3:00:00 PM SAT 504-539 9485 1:00:00 PM Diabetes, Lipids and Vascular Biology II Poster


Marina Epelman*1, Lily Mohtadi2, Julianne Pereira3 and Siham D Accacha1
1Winthrop University Hospital, Mineola, NY, 2Cornell University, 3Northwell Health Hospital

 

Background: Incidence of type 1 diabetes mellitus (T1DM) in children has been increasing worldwide by 3% to 5% per year. Approximately 29.4% of newly diagnosed patients present with ketoacidosis. Good glycemic control in first years after diagnosis has been proven to preserve the residual secretion of insulin and associated with lower risk of hypoglycemia. Previous studies have suggested that poor glycemic control is associated with older age, female sex, disease duration, poor patient provider relationship. Predictor of good control are: basal bolus regimen, young age at onset, higher socioeconomic status, family support. However, little is known about association of DKA at diagnosis and future diabetes control.

Objectives/Hypothesis: We hypothesize that patient who had DKA at diagnosis have better glycemic control compared to patients with incidentally diagnosed T1DM due to better adherence to treatment.

Methods: We reviewed 134 charts of patients 0-18 years old who were diagnosed with T1DM between July 1st, 2009 and June 30th, 2012 at Winthrop University Hospital. Levels of HbA1, average blood glucose monitoring (BGM), lipid panel results were collected from diagnosis to a time 2 years following diagnosis of T1DM. Statistical analyses were done in SAS 9.4®.

Results: From 134 patients, enrolled in the study, 37 (27.6%) patients had DKA at diagnosis.

There was no significant difference in age, gender, and ethnicity among the two groups. Baseline HbA1c was significantly higher in DKA group compared to non-DKA (12.0 ± 2.5 and 11.0 ± 2.1 respectively, p=0.04). In mixed effect model there was no significant difference in improvement of HbA1C over time among the two groups. Furthermore, there was no difference in HbA1C between two groups at the end of 24 month follow up period in unadjusted and adjusted ANCOVA analysis.

Conclusions: DKA at diagnosis of T1DM was not predictive of glycemic control at 2 year follow up.

 

Nothing to Disclose: ME, LM, JP, SDA

30642 1.0000 SAT 586 A Does DKA at Diagnosis Predict Better Glycemic Control in Patients with Type I Diabetes Mellitus? 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Somlak Chuengsamarn*
Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University,, Nakornnayok, Thailand

 

Apolipoprotein C3 (APOC3) has been relevant to type 2 diabetes (DM) with abnormal lipid profiles and non alcoholic steatohepatitis (NASH). The correlation between APOC3 promoter genotypes and type 2 DM with abnormal lipid profiles and NASH is still controversial, because discrepancies among different studies exist. Ethnic differences play certain roles in these conflicting results, because the distribution of APOC3 promoter polymorphisms is different among study subjects with different racial origins. Therefore, we aim to clarify the association of two SNPs (rs2854116 T>C and rs2854117 C>T) located on the promoter of APOC3 gene in Thai patients with DM together with abnormal lipid profiles and NASH. During 2013-2014, Thai adults aged ≥ 20 years were recruited from Out Patient Department (OPD) of HRN Princess Maha Chakri Sirindhorn Medical Center, and separated into type 2 diabetes (DM) (n=474) and non-diabetes individuals (n=376) in a case-control study. Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) used for detection of two SNPs in APOC3 gene (rs2854116 T>C and rs2854117 C>T). The result showed that there were no significant associations between these two SNPS and abnormal lipid profiles together with diagnosis NASH by the Liver stiffness (FibroScan) and NAFLD fibrosis score (p>0.05). The APOC3 variant carriers did not increased risk of DM (increased HOMA-IR and higher fasting blood glucose or HbA1c level) (p>0.05). Our study is the first study in Thai population shown the non-relevance between APOC3 gene and DM together with dyslipidemia and NASH. 

 

Nothing to Disclose: SC

32554 2.0000 SAT 587 A No Association Between the Promoter APOC3 Gene rs2854116 and rs2854117 and Risk of Type 2 Diabetes Mellitus, Dyslipidemia, and Non Alcoholic Steatohepatitis (NASH) 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Amnon Zung*1, Wasef Na'amnih2 and Orit Blumenfeld2
1Kaplan Medical Center, Rehovot, Israel, 2Israel Centers for Disease Control, Ministry of Health, Tel Hashomer, Israel

 

Objective

The global rise in the incidence of type 1 diabetes (T1D) is too rapid to be attributed to susceptible genetic background, and hence it emphasizes the main role of environmental factors. Unlike the rising theory that the need for genetic susceptibility (mainly HLA class II genes) has lessened over time, we hypothesized that the incidence rise of T1D is faster in genetically susceptible population.

Research design and methods

The study population comprised of 5080 T1D patients aged 0-17 years who were reported to the Israel Diabetes Registry over 18 years (1997-2014). The patients were divided into familial cases where at least another member of the core family has T1D, and sporadic cases. Hospital outpatient records of familial cases were reviewed for unreported familial cases. Data on gender, ethnicity (Jews vs. non-Jews), age at diagnosis, seasonality and ketoacidosis (DKA) at diagnosis were retrieved from the registry. Data on age at diagnosis were divided into four age-groups: 0-4, 5-9, 10-14 and 15-17 years. Annual incidence rates (per 100,000/year) and 95% CIs for the time periods were computed separately for the sporadic and familial cohorts.

Results

The familial cases (n=583; 11.5%) and the sporadic cases (n=4497; 88.5%) were comparable for gender and seasonality, but DKA at diagnosis was twice as common in the sporadic vs. familial cases (40.62% vs. 20.74%; p<0.001), which may reflect high parental awareness to initial symptoms of diabetes. The proportion of non-Jewish cases in the familial group was higher than in the sporadic group: 26.07% vs. 22.73%; p=0.01. This ethnic distribution probably reflects a relatively high prevalence of consanguinity in the non-Jewish population, which leads to the expression of recessive T1D-related genes. The proportion of patients in the youngest age-group (0 to 4 years) tended to be higher in the familial cases: 18.35% vs. 15.45%; p=0.07. Overall, the annual increase in T1D incidence was significantly higher in the familial than the sporadic cases: 4.24% vs. 2.56%; p<0.001.

Conclusions

The fast increase of T1D incidence among familial compared with sporadic cases underscores the key role of genetic susceptibility in the rise of T1D incidence over the last decades. We suggest that the genetically susceptible population is responding vigorously to environmental factors, probably through non-HLA susceptible genes.

 

Nothing to Disclose: AZ, WN, OB

31196 3.0000 SAT 588 A The Incidence of Type 1 Diabetes Is Increasing Faster in Familial Than in Sporadic Cases. Eighteen Years of the Israeli Pediatric Diabetes Registry 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Erica B Mahany*, Nicole H Bellefontaine, Xingfa Han and Carol F Elias
University of Michigan, Ann Arbor, MI

 

The prevalence of diabetes in the reproductive-aged population is increasing, with an estimated 10-25% of pregnant women classified as having hyperglycemia in pregnancy. These women are at increased risk for pregnancy complications, including miscarriage, congenital anomalies, preeclampsia, macrosomia, and perinatal mortality. To gain insight into the underlying mechanisms, we utilized a mouse model of obesity- and diabetes-induced miscarriage to evaluate for alterations in blood glucose in obese and diabetic mice. We selectively restored the leptin receptor in the ventral premammillary nucleus (PMV) of the hypothalamus in mice otherwise null for the leptin receptor with targeted injections of a viral vector, allowing for the improvement of fertility without altering the obese and diabetic phenotype. Of 19 “PMV hit” mice, vaginal openings were followed, and all underwent puberty. They were mated with wild type (WT) males with proven fertility. Tissue and trunk blood were harvested when the dam was noted to be pregnant, based on thrice weekly body weight measurements, and embryos corresponded to mid-gestation (E9.5-15.5). Blood samples were obtained before perfusion. Only 10 of the 19 PMV hit females became pregnant; however, 80% of pregnant mice showed embryo resorptions. When compared with pregnancies of WT control mice, the mean number of implantations was similar (7.6±0.8 vs. 6.6±0.6, p=NS), although the percentage of resorptions in the obese mice was significantly higher (32.6±10.5% vs. 6.0±2.7%, p=.008). Interestingly, serum glucose was significantly lower in the PMV hit mice that became pregnant compared with the PMV hit mice that did not become pregnant (224±20 vs. 343 ± 31 mg/dL, p=.009), which was also significantly different from the WT mice, all of which got pregnant (159±10 mg/dL, p<.05 for each). Histologically, the embryos did not have malformations, although the placentas did have increased necrosis and inflammation. RT-qPCR was performed and several genes associated with angiogenesis and cellular growth were differentially expressed in the pathologic mouse placentas (e.g., Mdk, Figf, Tlr3, Crh, Timp2, Inha, Qpct, Bhlhe40, and Hif1α). The higher glucose levels in the non-pregnant obese mice compared with the pregnant obese mice suggest that hyperglycemia may have contributed to infertility. Comparing the glucose levels of the pregnant obese mice to the pregnant WT mice, hyperglycemia may have contributed to problems with pregnancy maintenance. These data show that obesity and hyperglycemia have deleterious effects on placental function and embryo development and set the stage for poor pregnancy outcome.

 

Nothing to Disclose: EBM, NHB, XH, CFE

30757 4.0000 SAT 589 A Hyperglycemia Is Associated with Infertility and Placental Dysfunction in Obese Mice 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism, Miscellaneous/Other Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Jae Han Jeon*1, In-kyu Lee2, Keun-Gyu Park2 and Sung Woo Kim3
1Kyungpook National University School of Medicine, Daegu, Korea, Republic of (South), 2Kyungpook National University School of Medicine, 3GUMI CHA Medical Center

 

It is hardly known whether use of oral contraceptives at child-bearing age may affect the onset of diabetes after menopause. Thus, we aimed to evaluate the association of past use of OCs with the development of diabetes and insulin resistance in post-menopausal women. This study was a cross-sectional study based on data from the Korea National Health and Nutrition Examination Survey carried out from 2007 to 2012. 6554 post-menopausal women were included in the analysis. The associations of OC use with the prevalence of diabetes in post-menopausal women were examined using multivariate logistic analysis. In addition, fasting glucose and insulin levels were measured in 3338
nondiabetic post-menopausal women, and the association between IR and OCs was examined by the analysis of covariance. The prevalence of diabetes was significantly
higher in post-menopausal participants who had taken OCs for more than 6 months than in those who had never taken OCs. In addition, the association remained significant after adjusting for multiple confounding factors (odd ratio 1.379; 95 % CI 1.115–1.707; P = 0.003). The duration of OC use was also positively associated with the prevalence of diabetes. Furthermore, taking OCs for more than 6 months led to a significant increase in fasting insulin levels and HOMA-IR in nondiabetic participants. Past use of OCs for more than 6 months led to a significant increase in the prevalence of diabetes in post-menopausal women, as well as an increase of IR in nondiabetic participants. These results suggest that the prolonged use of OCs at reproductive age might be an important risk factor for developing diabetes in postmenopausal women.

 

Nothing to Disclose: JHJ, IKL, KGP, SWK

31616 5.0000 SAT 590 A The Prevalence of Diabetes in Women with Menopause Is Correlated with Previous Use of Oral Contraceptives at Child-Bearing Age 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Chi Chen, Xiaomin Nie, Hualing Zhai, Yi Chen, Yingli Lu and Ningjian Wang*
Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine

 

Background: It has been hypothesized that additional pregnancies may impair the ability of beta cell function to maintain normal glucose tolerance after pregnancy. However, previous studies had contradictory results. We aimed to measure whether pregnant times in child-bearing age were associated with diabetes in postmenopausal women with no history of GDM.

Methods: Our data source was the continuous National Health and Nutrition Examination Surveys 1999-2014. Eight thousand eight hundred and nine postmenopausal women over 40 years old who did not have a history of GDM were selected. Diabetes was defined according to American Diabetes Association 2014 criteria. Logistic regression analyses were used for the association of pregnant times with diabetes.

Results: Women with ≥4 pregnancies had significantly greater FPG (6.4±2.5 vs 6.0±1.7mmol/L), HbA1c (6.0±1.2 vs 5.8±1.0%), 2hPPG (7.8±3.3 vs 7.4±2.9) and HOMA-IR [2.72 (1.67-4.86) vs 2.52 (1.43-4.63)] than those with 2-3 pregnancies (all p <0.01). These women also had significantly higher prevalence of diabetes (27.9% vs 20.1%, p<0.001). Compared to women with 2-3 pregnancies, the adjusted ORs for diabetes were 1.108 (95%CI 0.893-1.374) for women who never got pregnant, 0.934 (0.752-1.161) for those with only one pregnancy, 1.157 (1.021-1.312) for those with more than or equal to 4 pregnancies after adjustment for age, race, educational level, annual household income, current drinking, smoking, BMI and physical activity.

Conclusion: ≥4 pregnancies in child-bearing age may be a potential risk factor for diabetes in postmenopausal women without history of GDM. Future longitudinal studies are warranted to confirm our finding.

 

Nothing to Disclose: CC, XN, HZ, YC, YL, NW

30720 6.0000 SAT 591 A Pregnant Times and Diabetes in Postmenopausal Women without History of GDM 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Huguette Stephanie Brink*1, Marije Alkemade2, Aart J. van der Lely3 and Joke Van der Linden4
1Maasstad hospital, Rotterdam, Netherlands, 2Maasstad hospital, 3079 DZ, Netherlands, 3Erasmus University Medical Center, Rotterdam, Netherlands, 4Maasstad hospital, Rotterdam, NETHERLANDS

 

Aims: To analyse maternal and neonatal outcomes of gestational diabetes (GD) and identify factors associated with neonatal complications.

Methods: A retrospective analysis of singleton GD pregnancies between 2010-2015 in a large cohort in Rotterdam, the Netherlands. Outcomes were compared to a control group (CG; no GD, type 1 or 2 diabetes mellitus) from the Netherlands Perinatal Registry.

Results: 1008 consecutive singleton pregnancies with GD were analysed, N=389 (38.7%) of women required additional insulin therapy. Compared to CG (N= 574.823), the rates of pre-eclampsia (3.8% vs. 5.1%), large for gestational age (>P90) (8.5% vs. 10.7%) and pre-term birth (6.6% vs.8.1%) were not significantly different. The rate of labour induction was higher compared to the CG (56% vs. 29.2%). Neonatal complications defined as a composite neonatal outcome including: death (perinatal/neonatal), large for gestational age (>P90), APGAR < 7 at 5 minutes, pre-term birth (< 37 weeks), neonatal hypoglycaemia (< 2.6 mmol/L), admission to neonatology department, hyperbilirubinemia requiring phototherapy or birth trauma (shoulder dystocia, brachial plexus injury, bone fracture (humerus/clavicle) occurred in N= 348 (34,5%). Independent risk factors predicting the composite neonatal outcome were body mass index (kg/m²) > 30 (OR 1.5 [1.00-2.1] p=0.046) and insulin therapy (OR 1.5 [1.0-2.2] p=0.026).

Conclusions: Adverse maternal and neonatal outcomes in GD, are comparable to normoglycaemic pregnancies. However, obesity and insulin therapy are predictive of an increased risk of neonatal complications. This study underlines the importance of weight control before pregnancy. Health care professionals should play an important role in prevention of obesity in young women.

 

Nothing to Disclose: HSB, MA, AJV, JV

29383 7.0000 SAT 592 A Maternal and Neonatal Outcomes of Gestational Diabetes 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Vikash Dadlani1, Georgia Kulina2, Donna M Desjardins1, Shelly McCrady-Spitzer1, Prabin Thapa1, Eyal Dassau3, Carol J Levy2 and Yogish C Kudva*1
1Mayo Clinic, Rochester, MN, 2Icahn School of Medicine at Mount Sinai, New York, NY, 3Harvard John A. Paulson School of Engineering and Applied Sciences

 

Pregnancy is associated with fetal and maternal morbidity in patients with type 1 diabetes (T1D). Tight blood glucose (BG) control during pregnancy has been shown to decrease in congenital malformation, stillbirth and neonatal death. Continuous glucose monitors (CGM), insulin pumps or continuous subcutaneous insulin infusion (CSII) and combination of CGM and CSII especially closed loop control are achieving tight and safer glucose control in non-pregnant T1D populations but have not been tested enough in pregnant T1D patients. We evaluated glucose variability (GV) in T1D on CSII to facilitate design of future studies. Data was collected from seventeen pregnant women with T1D (9 from Mayo Clinic and 8 from Mount Sinai), age 29.1 ± 4.23 years, HbA1c 6.3 ± 0.71% on CSII during pregnancy. GV was measured with multiple measures including mean plasma glucose, standard deviation, high blood glucose index (HBGI), low blood glucose index (LBGI) and average daily risk range (ADRR). The mean BG was 128.4 ± 50.3 mg/dl. The mean number of BG readings was 1338 ± 822 during this period with average number of readings 9 ± 3 per day. 72% of the readings were in range between 70 to 180mg/dl with 11.9 % below 70mg/dl and 16.2 % above 180mg/dl. ADRR was 24 ± 7.1 with LBGI 2.8 ± 1.4 and HBGI 3.7 ± 2.7. We also analyzed CGM data in 12 subjects during this same period. Mean number of reading per day during the time subjects were on CGM was 238 and mean CGM glucose was 121.5 ± 41.4 mg/dl with 82 % of the readings in range between 70 to 180mg/dl and 9.1% and 9.3 %of CGM readings below <70mg/dl and above 180mg/dl, respectively. ADRR was 31 ± 10 with LBGI of 2.3 ± 1.2 and HBGI of 2.32 ± 1.21. Pregnant women with T1D work hard to maintain tight glucose control. In spite of this, the burden of hypoglycemia during pregnancy is high with current technologies. Therefore, new therapies such as closed-loop control in this context need to be developed and tested.

 

Nothing to Disclose: VD, GK, DMD, SM, PT, ED, CJL, YCK

32278 8.0000 SAT 593 A Glucose Variability during Pregnancy in Women with Type 1 Diabetes on Pumps     2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Ekasitt Wanitcharoenkul*1, Boonsong Ongphiphadhanakul2, Naricha Chirakalwasan3, Somvang Amnakkittikul4, Suranut Charoensri5, Sunee Saetung6, Punyu Panburana4, Sommart Bumrungphuet5 and Sirimon Reutrakul4
1Faculty of Medicine Ramathibodi hospital, Bangkok, Thailand, 2Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 3Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, 4Faculty of Medicine Ramahibodi Hospital, Bangkok, Thailand, 5Faculty of Medicine Ramathibodi Hospital, Bangkok, Thailand, 6Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

 

Obstructive sleep apnea (OSA) has emerged as a risk factor for gestational diabetes (GDM). The exact prevalence of OSA in pregnancy is unknown. In addition, studies revealed that questionnaires typically used to screen for OSA in non-pregnant population were not accurate in predicting OSA in pregnancy. Factors predicting OSA in GDM women have not been studied to date. The objectives of this study were to investigate the characteristics of GDM women with OSA, and to develop a simple and practical screening tool for OSA in GDM using classification tree analysis.

Methods: Diet-controlled, obese GDM women were enrolled at gestational age (GA) 24-36 weeks. Baseline characteristics, glycemic parameters and neck circumference were obtained. The participants completed the Berlin questionnaire which assessed three categories (snoring, daytime fatigue and hypertension/BMI). High risk for OSA was considered when two of three categories were positive. The participants underwent a diagnostic test for OSA using an overnight home monitoring device (WatchPAT200). OSA was diagnosed when an apnea hypopnea index (AHI) ≥5. Parameters were compared between OSA and non-OSA groups. A classification tree method was applied to develop an algorithm to predict OSA.

Results: Of the 82 women who completed the study, 43 (52.4%) had OSA. The prevalence of OSA was 52.4%. There were no significant differences in age, pre-pregnancy BMI, current BMI, GA at sleep assessment, fasting glucose or HbA1c at sleep assessment between OSA and non-OSA women. Neck circumference was significantly larger in the OSA than in the non-OSA group (median 35.0 vs. 34.5 cm, p = 0.018). High risk for OSA as assessed by Berlin questionnaire (2 of 3 positive categories) did not differ between OSA and non-OSA groups (16% vs. 10%, p=0.424). However, significantly more women with OSA scored positive in at least 1 category of Berlin questionnaire than the non-OSA women (74%. vs. 49%, p=0.017).

We developed a screening tool using a decision tree by including the two variables, neck circumference and Berlin questionnaire. The result was validated using statistical bootstrap. Using this model, the number of positive categories from Berlin should be considered first. Those with ≥1 positive category were considered high risk for OSA (63% by WatchPAT200 testing). For those with negative results in all categories of Berlin, neck circumference should be considered next. Those with neck circumference >35.5 cm were considered as high risk for OSA (100% by WatchPAT200). Those with neck circumference ≤35.5 cm were considered as low risk for OSA (23% by WatchPAT200). The sensitivity and specificity using this classification tree were 86% and 51% respectively. The overall accuracy was 70%.

Conclusion: OSA is highly prevalent in diet-controlled obese GDM women. An algorithm using a neck circumference and Berlin questionnaire could help in the screening for OSA in GDM.

 

Nothing to Disclose: EW, BO, NC, SA, SC, SS, PP, SB, SR

29525 9.0000 SAT 594 A Obstructive Sleep Apnea in Gestational Diabetes: Prevalence, Predictive Factors and the Development of a Screening Tool 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Sally K. Abell*1, Soulmaz Shorakae1, Cheryce L Harrison1, Danielle Hiam2, Alba Moreno-Asso2, Nigel K. Stepto2, Barbora de Courten1 and Helena J. Teede1
1Monash University, Melbourne, Australia, 2Victoria University, Melbourne, Australia

 

Background
Early prediction of Gestational Diabetes Mellitus (GDM) enables risk stratification of women, opportunities for prevention, and may improve pregnancy outcomes. Screening methods using clinical risk factors have reasonable predictive ability, but may be improved by combining biomarkers that precede the onset of hyperglycaemia.
Objective
We aimed to investigate the association of adipocytokines and other inflammatory markers in early pregnancy with development of GDM.
Methods
Adipocytokines and inflammatory markers were studied at 12-15 weeks gestation using biobanked serum control samples from a randomised trial of healthy lifestyle in pregnancy conducted in Melbourne, Australia. Study participants were identified as high risk for GDM based on an established validated clinical risk prediction tool (recruitment 2008-2010). Markers were tested using commercial ELISA kits for high molecular weight (HMW) adiponectin, interleukin-6 (IL-6), plasminogen activator inhibitor-1, visfatin, omentin-1, sex-hormone binding globulin (SHBG), monocyte chemoattractant protein and asymmetrical dimethylarginine. The association between each biomarker and development of GDM at 24-28weeks was evaluated using multivariable logistic regression analysis adjusted for maternal factors.
Results
The prevalence of GDM at our service during the study period was 8% (ADIPS 1998 criteria). There were 78 women with normal glucose tolerance and 25 women who developed GDM in the control group with serum for analysis. HMW adiponectin (adjusted odds ratio OR 0.37 [95% confidence interval 0.19-0.74]), omentin-1 (0.97[0.94-0.99]) and IL-6 (1.87[1.03-3.37]) were associated with development of GDM after adjustment for maternal factors age, body mass index and past history of GDM. Odds were also calculated for GDM using IADPSG criteria. Optimal levels were calculated to maximise odds of GDM in our study population. SHBG was negatively correlated with glucose measures on oral glucose tolerance test, however SHBG and other biomarkers were not associated with GDM development in multivariable regression analysis.
Conclusion
HMW adiponectin, omentin-1 and IL-6 may enhance sensitivity of early risk prediction tools for women at high risk of GDM. This may allow early identification and opportunities for prevention of GDM and adverse outcomes. Further research is required in large diagnostic validation studies to confirm these results.

Abbreviations: ADIPS – Australasian Diabetes in Pregnancy Society
IADPSG – International Association of Diabetes and Pregnancy Study Group

 

Nothing to Disclose: SKA, SS, CLH, DH, AM, NKS, BD, HJT

30652 10.0000 SAT 595 A High Molecular Weight Adiponectin, Omentin-1 and Interleukin-6 in Early Pregnancy Are Associated with Later Development of Gestational Diabetes 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Sujeet Jha*1, Samreen Siddiqui1, Swati W Pandit1, Amit Bhargava1, Manju Panda1 and Shweta Dubey2
1Max Healthcare Inst Ltd, New Delhi, India, 2Amity University, Noida, India

 

Objective:

Maturity onset diabetes of the young (MODY) is an autosomal inherited form of diabetes where gene mutations lead to pancreatic β cell dysfunction. At least 13 different subtypes are known to cause MODY. Individuals with mutations in MODY genes can also present with gestational diabetes mellitus (GDM). Precise molecular analysis of MODY gene variants in GDM cases is essential because it can have implications in management of diabetes in pregnancy and is crucial to the health of both mother and the fetus. However, the exact association between MODY gene variants and GDM is not established. We undertook this study to determine whether MODY gene polymorphisms induce susceptibility to GDM in pregnant Indian females.

Research Design & Methods

Of the 68 pregnant females screened, 25 were randomly selected, based on new screening criteria of BMI<25Kg/m2 and fasting blood glucose ≥5.5 mmol/L (99 mg/dL). Saliva from this GDM subset was analyzed for mutations in 3 common MODY genes (HNF1a, HNF4a and GCK). Bioinformatics tools were used to predict the outcome of identified gene mutations.

Results

4 novel mutations including 2 missense and 2 splice-site mutations were identified on the GCK (c.1030G>T (p.Asp344Tyr)), HNF1a (c.1501+1G>A, c.224G>A (p.Arg75Lys)) and HNF4a (p.Gln294Arg) genes, respectively. Further analysis revealed that 72% of the total cohort had HNF4a gene mutations, 56% had HNF1a gene mutations and 36% had GCK mutations.

Conclusions

We report 4 novel variations of MODY genes in Indian GDM population subset. Our results suggest that there might be a high prevalence of MODY amongst Indian females presenting with GDM, than previously predicted. Females with clinical features of MODY should be screened for the aforementioned genetic mutations during pregnancy.

 

Nothing to Disclose: SJ, SS, SWP, AB, MP, SD

31695 11.0000 SAT 596 A Identification of Mody Gene Polymorphisms in Asian Indians Affected with Gestational Diabetes-First Report from India 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Jens Øllgaard*1, Peter Gæde1, Peter Rossing2, Henrik Lund-Andersen3, Hans Henrik Parving3 and Oluf Pedersen4
1Slagelse Hospital, Denmark, 2Steno Diabetes Center, Denmark, 3Rigshospitalet, Denmark, 4University of Copenhagen, Copenhagen, Denmark

 

Introduction:

Intensified multifactorial intervention for 7.8 years in patients with type 2 diabetes mellitus and microalbuminuria reduced risk of macro- and microvascular complications after 13.3 years follow-up.

Complications to diabetes mellitus in other organs the heart and brain are often overlooked, but are significantly reducing patient quality of life, and end stage renal disease, amputations and blindness are the most feared late complications among patients.

Methods: 160 patients with type 2 diabetes and microalbuminuria were assigned to conventional or intensified, multi-factorial therapy targeting multiple risk factors. Mean treatment duration was 7.8 years. After 7.8 years the study continued as an observational follow-up with all patients treated as the original intensive-therapy group.

For this sub-study, the primary end-point was time to end-stage renal disease, major amputations (defined as leg-length shortening operation) or blindness in one eye.

Secondary end-point was glomerular filtration rate < 45ml/min, minor amputations or vitrectomy, photocoagulation or intravitreous injection treatment of retinopathy.

Time to event analyses were modelled using a Cox-regression adjusted for age and sex.

Results: The relative risk of the primary outcome was reduced by 64 % in the original intensive-therapy group; HR 0.36 [95% CI 0.20 – 0.67; p=0.001].

The secondary outcome was reduced by 49 % in the intensive-therapy group; HR 0.51 [0.33 – 0.80; p=0.004]. Estimates were stable, when all-cause mortality was included in analyses.

Lower baseline GFR was associated with increased risk of the primary and secondary outcome. Further, baseline HbA1c and systolic BP was associated with the secondary outcome.

Conclusions: After 21.2 years of follow up of 7.8 years of intensified, multifactorial, target driven treatment of type 2 diabetes mellitus with microalbuminuria, we demonstrate significantly reduced risk of severe microvascular complications with expectedly improved long-term quality of life as a consequence.

(ClinicalTrials.gov number, NCT00320008.)

 

Nothing to Disclose: JØ, PG, PR, HL, HHP, OP

32564 12.0000 SAT 597 A Reductions in Diabetic Renal-, Peripheral Vascular- and Eye Disease with 7.8 Years of Intensified, Multifactorial Intervention in Patients with Type 2 Diabetes and Microalbuminuria in the Steno-2 Study 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Karen SL Lam*1, Chloe YY Cheung2, Paul CH Lee1, Clara S Tang1, Aimin Xu3, Ka-Wing Au1, Lin Xu1, Carol HY Fong3, Kelvin HM Kwok1, Wing-Sun Chow4, Yu Cho Woo4, Michele MA Yuen3, Stacey S Cherny1, Jojo SH Hai1, Bernard MY Cheung5, Kathryn CB Tan1, Tai-Hing Lam1, Hung-Fat Tse3 and Pak-Chung Sham6
1The University of Hong Kong, Hong Kong, 2The University of Hong Kong, Hong Kong, China, 3University of Hong Kong, Hong Kong, Hong Kong, 4The University of Hong Kong, Hong Kong, Hong Kong, 5The Univeristy of Hong Kong, Hong Kong, 6The University of Hong, Hong Kong

 

Fibroblast growth factor 21 (FGF21) is increasingly recognized as an important metabolic hormone with beneficial effects on glucose and lipid metabolism. Here, we conducted an exome-chip association analysis by genotyping 5169 Chinese individuals, using a custom Illumina HumanExome BeadChip, to detect genetic determinants influencing circulating FGF21 levels. Single-variant association analysis interrogating 73,648 single nucleotide polymorphisms with minor allele frequencies ≥0.1% identified a novel locus, GCKR, significantly associated with circulating FGF21 levels. A common missense variant of GCKR, rs1260326 (p.Pro446Leu), showed an association with FGF21 levels at genome-wide significance with adjustment for age and sex (P =7.42x10-15; β[SE]: 0.15[0.02]). This association remained significant after adjustment for body mass index (P =1.05x10-15; β[SE]: 0.16[0.02]), indicating an adiposity-independent effect of this variant. The GCKR Leu446 variant may influence FGF21 expression via its ability to increase glucokinase (GCK) activity. This can lead to enhanced FGF21 expression via elevated fatty acid synthesis, consequent to the inhibition of carnitine/palmitoyl-transferase by malonyl-CoA; and via increased glucose-6-phosphate mediated activation of the carbohydrate response element binding protein, known to regulate FGF21 gene expression. Our findings have shed new light on the genetic regulation of FGF21 levels. Further investigations to dissect the relationship between GCKR and FGF21, with respect to the risk of metabolic diseases, are warranted.

 

Nothing to Disclose: CYYC, CHL, CST, AX, KWA, LX, CHYF, KHMK, WSC, YCW, MMAY, SSC, JSHH, BMYC, KCBT, THL, HFT, PCS, KSLL

 

Nothing to Disclose: KSL, CYC, PCL, CST, AX, KWA, LX, CHF, KHK, WSC, YCW, MMY, SSC, JSH, BMC, KCT, THL, HFT, PCS

29960 13.0000 SAT 598 A A Functional Missense Variant of the Glucokinase Regulator Gene (GCKR) Is Associated with Raised FGF21 Levels in an Exome-Chip Association Study Amongst Chinese Individuals 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Irit Hochberg*1, Chen Shapira2, Mordechai Alperin2 and Uzi Milman2
1Rambam Health Care Campus, Haifa, Israel, 2Clalit Health Services, Haifa, Israel

 

The optimal target of glucose and HbA1c for reducing cardiovascular events and mortality in patients with long standing diabetes is not clear. The ACCORD study found higher mortality in the tight control arm in diabetes patients with high cardiovascular risk, and several large retrospective studies have found a J shape of hazard-ratio curve of HbA1c and mortality, with the lowest mortality risk in patients with HbA1c 7.5%, and with increased hazard ratio for mortality in patients with lower or higher HbA1c values(1). Haptoglobin (Hp) type 2-2 is a strong cardiovascular risk factor in diabetes(2), and we hypothesized that Hp type may modify the effect of HbA1c on mortality and cardiovascular events. We followed the ADHOC study cohort, consisting of 3034 type 2 diabetes patients (285 with Hp 1-1, 1248 with Hp 2-1 and 1511 with Hp 2-2), from 2002 to 2014 for cardiovascular events and total mortality. HbA1c distribution was similar between the Hp groups. We found a J shaped curve in patients with Hp 2-2, with the highest rates of mortality and composite outcome of mortality and myocardial infarction in Hp 2-2 patients with HbA1c<6.6% (P<0.0002 for mortality and P<0.015 for the composite outcome). The J shaped curve was not found in patients with Hp 2-1 and 1-1, where HbA1c values of less than 6.6% were associated with lower occurrence of the composite outcome of mortality and myocardial infarction (P<0.033 for Hp 1-1 and P<0.036 for Hp 2-1). Our results shift current clinical paradigms in treating diabetes, utilizing a novel approach to optimize “personalised medicine” based on a genetic characteristic. Determining Hp type for each diabetes patient may be useful for making decisions on the intensity of glycemic treatment.

 

Nothing to Disclose: IH, CS, MA, UM

30888 14.0000 SAT 599 A Increased Mortality in Diabetes Patients with Low HbA1c Values Is Found Only in Patients with Haptoglobin Type 2-2  – Paradigm Shift Towards Genetically-Determined Personalized Glycemic Targets 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Sivaporn Wannaiampikul*1 and Somlak Chuengsamarn2
1Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand, 2Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University,, Nakornnayok, Thailand

 

Genetic Variations of TNF-α Gene and their Associations with Type 2 Diabetes Mellitus and Serum TNF-α Level in Thai

Sivaporn Wannaimpikul1, Siwanon Jirawatnotai2, Vipavee Anupunpisit3, Somlak Chuengsamarn4

1Department of Biochemistry, Faculty of Medicine, Srinakharinwirot University, Bangkok Thailand;

2Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand;

3Department of Anatomy, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand;

4Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University, Nakornnayok, Thailand .

Tumor Necrosis Factor-alpha (TNF-α) has been implicated in the pathogenesis of type 2 diabetes (DM) with metabolic syndrome related to insulin resistance. The correlation between TNF promoter genotypes and type 2 DM related to metabolic components is still controversial, because discrepancies among different studies exist. Ethnic differences play certain roles in these conflicting results, because the distribution of TNF tumor necrosis factor alpha promoter polymorphisms is different among study subjects with different racial origins. Therefore, we aim to clarify the association of two SNPs (rs1800629 and rs361525) located on the promoter of TNF-α gene with DM related to metabolic components in Thai patients. These two SNPs (rs1800629G>A and rs361525G>A) were detected in the case-control study, which composed of diabetes patients (n=433) and non-diabetes patients (n=348) by Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP). We found that only rs1800629 variants associated with increasing risk of being DM(adjusted OR=2.11, 95% CI=1.18-3.77, p=0.01). The rs1800629 variants carriers had higher values of fasting plasma glucose (FPG). In addition to the analysis of TNF-α level revealed that the presence of the rs1800629 variants was associated with decreased serum TNF-α level comparing to wild type carriers (p=0.035). There were no significant associations between rs361525 variations. Moreover, the haplotype analysis showed that the GA haplotype pattern (rs1800629 and rs361525) was significantly associated with increased risk to develop DM related to metabolic components (OR=1.84, 95% CI=1.06-3.18, p=0.03). Our study confirmed that rs1800629 variant was associated with DM related to metabolic components and might contribute to repress circulating TNF-α level in serum but not rs361525 in Thai population.

Nothing to Disclose: SW, SJ, VA, SC

 

Sources of Research Support: The National Research of Council Thailand (NRCT) grant to

SC (principal investigator)

Nothing to Disclose:S. Wannaiampikul, S. Jirawatnotai, V. Anupunpisit, and

S. Chuengsamarn, MD.

 

Nothing to Disclose: SW, SC

32021 15.0000 SAT 600 A Genetic Variations of TNF-α Gene and Their Associations with Type 2 Diabetes Mellitus and Serum Tnf-α Level in Thai 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Mario Clerici*
University of Milan, Milano, Italy

 

The endoplasmic reticulum enzyme glucose-6-phosphatase catalyzes the common terminal reaction in the gluconeogenic and glycogenolytic pathways and plays a central role in glucose homeostasis. In most mammals, different G6PC subunits are encoded by three paralogous genes (G6PC, G6PC2, and G6PC3). Mutations in G6PC and G6PC3 are responsible for human mendelian diseases, whereas variants in G6PC2 are associated with fasting glucose (FG) levels. We analyzed the evolutionary history of G6Pase genes in mammals. Results indicated that negative selection was the major force shaping diversity at these genes. Nonetheless, site-wise estimation of evolutionary rates at corresponding sites revealed weak correlations, suggesting that G6Pases have evolved different structural features over time. We also detected pervasive positive selection at mammalian G6PC2 genes. Most selected residues are located in the C-terminal protein region, where several human variants associated with FG levels also map. This region was thus re-sequenced in a cohort of ~560 subjects from Saudi Arabia, 185 of whom suffering from type 2 diabetes (T2D). The frequency of rare missense and nonsense variants was not significantly different in T2D and controls. Association analysis with two common missense variants (V219L and S342C) revealed a weak but significant association for both SNPs when analyses where conditioned on rs560887, previously identified in a GWAS for FG. Two haplotypes were significantly associated with T2D with an opposite effect direction. These results, although preliminary, suggest that distinct haplotypes at the G6PC2 locus modulate susceptibility to T2D.

 

Nothing to Disclose: MC

30808 16.0000 SAT 601 A Susceptibility to Type 2 Diabetes May be Modulated By Haplotypes in G6PC2, a Target of Positive Selection 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of the Endocrine Society Diabetes & Glucose Metabolism Saturday, April 1st 3:00:00 PM SAT 586-601 9487 1:00:00 PM Clinical Care and Genetic Associations in Diverse forms of Diabetes Poster


Alyson K. Myers*1, Aditya A. Bissoonauth1, Timothy Tong2 and Renee Pekmezaris3
1Northwell Health, Manhasset, NY, 2Hofstra Northwell School of Medicine, Hempstead, NY, 3Northwell Health, Great Neck, NY

 

Background: B and H/L patients have disproportionately higher rates of T2DM when compared to whites1. In addition, these disparity populations have a greater number of diabetic complications including cardiovascular disease and renal failure2. The Institute of Medicine’s (IOM) report “Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care” indicates that B and H/L’s experience a 50–100% higher burden of illness and mortality from diabetes than non-H/L white Americans, and that their disease remains poorly managed3. Although previous research suggests that patients receiving telemonitoring in the general population have improved glucose control, we do not know whether this effect generalizes to B and H/L patients with diabetes4. This 3-month study will provide further insight regarding telemonitoring feasibility as compared to follow-up phone calls in adult B and H/L patients with T2DM.

Clinical Case: Both patients were randomized to the intervention arm (telemonitoring group). They were instructed to record blood glucose (BG), physical activity, and medication adherence daily. In addition, they measured their weight, blood pressure, pulse, and pulse oxygenation. Both patients also engaged in video teleconference calls from the study investigator weekly for the first month and biweekly for the remaining months. These calls assessed vital signs, glycemic control, medication side effects, diet, sleep, and physical activity.

Case 1: 66 y/o B female with history of T2DM uncontrolled (HbA1C 9.7%), hyperlipidemia (HL), and hypertension (HTN) managed with Glipizide XL 2.5mg po qdaily and Metformin 1000mg po bid. Within a 1-month period, the patient showed a significant decrease in average weekly BG levels from 203 mg/dl lowered to 111 mg/dl, weight loss from 174.6lbs to 170.2lbs, and consistent self-report of adherence to medication regimen. Additionally, this patient made adjustments to her diet, including no meals after 8pm.

Case 2: 50 y/o B male with T2DM uncontrolled (HbA1C 12.4%), HL, and HTN managed with Glimepiride 4mg po qdaily and Metformin 1000mg po bid. Within a 1-month period the patient has shown no improvement in clinical outcomes, as the patient has not adhered to submitting his self-reported data. The patient has also not had any testing strips during the first 1.5 months of the study and missed his appointment with his primary care provider. The patient also has missed two weekly calls as he has shown difficulty in scheduling calls and having his tablet with him when he travels on business.

Conclusion: Although both patients were randomized to the telemonitoring group, issues of nonadherence were still relevant, including difficulty scheduling times with patients and a lack of self-reporting. Telemonitoring within this population can improve health outcomes with T2DM patients who are motivated to make changes and improve their glycemic control.

 

Nothing to Disclose: AKM, AAB, TT, RP

32082 1.0000 SAT 602 A Assessing the Feasibility of Using an in-Home, Tablet-Based Telemonitoring Care Management Program in Black (B) and Hispanic/Latino (H/L) Disparity Patients with Type 2 Diabetes Mellitus (T2DM) 2017-04-04 Orlando 2017-03-28 99th Annual Meeting of