Estimation of Endogenous Heterotypic Peptidyl Stimulation of ACTH Secretion Under an Exogenous Secretagogue Clamp

Presentation Number: SAT 401
Date of Presentation: April 1st, 2017

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

Abstract

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