Full Guideline: Functional Hypothalamic Amenorrhea JCEM | March 2017
Catherine M. Gordon (chair), Kathryn E. Ackerman, Sarah L. Berga, Jay R. Kaplan, George Mastorakos, Madhusmita Misra, M. Hassan Murad, Nanette F. Santoro, and Michelle P. Warren
Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline
To diagnose hypothalamic amenorrhea, healthcare providers must rule out other conditions that can halt menstruation, including benign tumors in the pituitary gland and adrenal gland disorders. The guideline recommends that providers first exclude pregnancy as a cause and then perform a full physical exam to evaluate for other potential causes. General laboratory tests, including a complete blood count and electrolytes, also are part of the recommended screening process.
Recommendations from the guideline include:
Hypothalamic amenorrhea is a “diagnosis of exclusion,” which requires healthcare providers to rule out other conditions that could be interrupting the menstrual cycle.
As part of their initial evaluation, women diagnosed with hypothalamic amenorrhea should have a series of laboratory tests to check levels of hormones including estrogen, thyroid hormones and prolactin. The workup can help identify factors preventing menstruation.
Hypothalamic amenorrhea patients should be evaluated for inpatient treatment if they have an abnormally slow heart rate, low blood pressure, or an electrolyte imbalance. Careful monitoring is needed in these cases because there is a high mortality rate associated with hypothalamic amenorrhea in the setting of eating disorders, particularly anorexia nervosa.
Select patients presumed to have hypothalamic amenorrhea should undergo a brain MRI to check for damage to or abnormalities of the pituitary gland or pituitary hormone deficiencies, if they exhibit select signs or symptoms, including a history of severe or persistent headaches; persistent vomiting that is not self-induced; changes in vision, thirst or urination not attributable to other causes; neurological signs suggesting a central nervous system abnormality; or other clinical signs or test results that suggest pituitary hormone deficiency or excess.
1.1 We suggest that clinicians only make the diagnosis of functional hypothalamic amenorrhea (FHA) after excluding the anatomic or organic pathology of amenorrhea. (Ungraded Good Practice Statement)
1.2 We suggest diagnostic evaluation for FHA in adolescents and women whose menstrual cycle interval persistently exceeds 45 days and/or those who present with amenorrhea for 3 months or more. (2|⊕⊕⚪⚪)
1.3 We suggest screening patients with FHA for psychological stressors (patients with FHA may be coping with stressors, and stress sensitivity has multiple determinants). (2|⊕⊕⊕⚪)
1.4 Once clinicians establish the diagnosis of FHA, we suggest they provide patient education about various menstrual patterns occurring during the recovery phase. We suggest clinicians inform patients that irregular menses do not require immediate evaluation and that menstrual irregularity does not preclude conception. (Ungraded Good Practice Statement)
2.1 In patients with suspected FHA, we recommend obtaining a detailed personal history with a focus on diet; eating disorders; exercise and athletic training; attitudes, such as perfectionism and high need for social approval; ambitions and expectations for self and others; weight fluctuations; sleep patterns; stressors; mood; menstrual pattern; fractures; and substance abuse. Clinicians should also obtain a thorough family history with attention to eating and reproductive disorders. (Ungraded Good Practice Statement)
2.2 In a patient with suspected FHA, we recommend excluding pregnancy and performing a full physical examination, including a gynecological examination (external, and in selected cases, bimanual), to evaluate the possibility of organic etiologies of amenorrhea. (1|⊕⊕⊕⚪)
2.3 In adolescents and women with suspected FHA, we recommend obtaining the following screening laboratory tests: β-human chorionic gonadotropin, complete blood count, electrolytes, glucose, bicarbonate, blood urea nitrogen, creatinine, liver panel, and (when appropriate) sedimentation rate and/or C-reactive protein levels. (1|⊕⊕⊕⊕)
2.4 As part of an initial endocrine evaluation for patients with FHA, we recommend obtaining the following laboratory tests: serum thyroid-stimulating hormone (TSH), free thyroxine (T4), prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and anti-Müllerian hormone (AMH). Clinicians should obtain total testosterone and dehydroepiandrosterone sulfate (DHEA-S) levels in patients with clinical hyperandrogenism and 8 AM 17-hydroxyprogesterone levels if clinicians suspect late-onset congenital adrenal hyperplasia (CAH). (1|⊕⊕⊕⊕)
2.5 After excluding pregnancy, we suggest administering a progestin challenge in patients with FHA to induce withdrawal bleeding (as an indication of chronic estrogen exposure) and ensure the integrity of the outflow tract. (2|⊕⊕⊕⚪)
2.6 We recommend a brain magnetic resonance imaging (MRI) (with pituitary cuts and contrast) in adolescents or women with presumed FHA and a history of severe or persistent headaches; persistent vomiting that is not self-induced; change in vision, thirst, or urination not attributable to other causes; lateralizing neurologic signs; and clinical signs and/or laboratory results that suggest pituitary hormone deficiency or excess. (1|⊕⊕⊕⚪)
2.7 We suggest that clinicians obtain a baseline bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry (DXA) from any adolescent or woman with 6 or more months of amenorrhea, and that clinicians obtain it earlier in those patients with a history or suspicion of severe nutritional deficiency, other energy deficit states, and/or skeletal fragility. (2|⊕⊕⊕⚪)
2.8 In cases of primary amenorrhea, we suggest evaluating Müllerian tract anomalies (congenital or acquired). Diagnostic options include physical examination, progestin challenge test, abdominal or transvaginal ultrasound, and/or MRI, depending on the context and patient preferences. (2|⊕⊕⊕⚪)
2.9 In patients with FHA and underlying polycystic ovary syndrome (PCOS), we suggest:
a baseline BMD measurement by DXA in those with 6 or more months of amenorrhea and earlier in those with history or suspicion of severe nutritional deficiency, other energy deficit states, and/or skeletal fragility (2/⊕⊕⚪⚪); and
clinical monitoring for hyperresponse in those treated with exogenous gonadotropins for infertility. (2|⊕⊕⚪⚪)
3.1 We recommend that clinicians evaluate patients for inpatient treatment who have FHA and severe bradycardia, hypotension, orthostasis, and/or electrolyte imbalance. (1|⊕⊕⊕⚪)
3.2 In adolescents and women with FHA, we recommend correcting the energy imbalance to improve hypothalamic–pituitary–ovarian (HPO) axis function; this often requires behavioral change. Options for improving energy balance include increased caloric consumption, and/or improved nutrition, and/or decreased exercise activity. This often requires weight gain. (1|⊕⊕⊕⚪)
3.3 In adolescents and women with FHA, we suggest psychological support, such as cognitive behavior therapy (CBT). (2|⊕⊕⚪⚪)
3.4 We suggest against patients with FHA using oral contraceptive pills (OCPs) for the sole purpose of regaining menses or improving BMD. (2|⊕⊕⚪⚪)
3.5 In patients with FHA using OCPs for contraception, we suggest educating patients regarding the fact that OCPs may mask the return of spontaneous menses and that bone loss may continue, particularly if patients maintain an energy deficit. (2|⊕⊕⚪⚪)
3.6 We suggest short-term use of transdermal E2 therapy with cyclic oral progestin (not oral contraceptives or ethinyl E2) in adolescents and women who have not had return of menses after a reasonable trial of nutritional, psychological, and/or modified exercise intervention. (2|⊕⚪⚪)
3.7 We suggest against using bisphosphonates, denosumab, testosterone, and leptin to improve BMD in adolescents and women with FHA. (2|⊕⊕⚪⚪)
3.8 In rare adult FHA cases, we suggest that short-term use of recombinant parathyroid hormone 1-34 (rPTH) is an option in the setting of delayed fracture healing and very low BMD. (2|⊕⚪⚪⚪)
3.9 In patients with FHA wishing to conceive, after a complete fertility workup, we suggest:
treatment with pulsatile gonadotropin-releasing hormone (GnRH) as a first line, followed by gonadatropin therapy and induction of ovulation when GnRH is not available (2|⊕⚪⚪⚪);
cautious use of gonadotropin therapy (2|⊕⚪⚪⚪);
a trial of treatment with clomiphene citrate for ovulation induction if a woman has a sufficient endogenous estrogen level (2|⊕⚪⚪⚪);
against the use of kisspeptin and leptin for treating infertility (2|⊕⚪⚪⚪); and
given that there is only a single, small study suggesting efficacy, but minimal potential for harm, clinicians can consider a trial of CBT in women with FHA who wish to conceive, as this treatment has the potential to restore ovulatory cycles and fertility without the need for medical intervention. (2|⊕⊕⚪⚪)
3.10 We suggest that clinicians should only induce ovulation in women with FHA that have a body mass index (BMI) of at least 18.5 kg/m2 and only after attempts to normalize energy balance, due to the increased risk for fetal loss, small-for-gestational-age babies, preterm labor, and delivery by Cesarean section for extreme low weight. (2|⊕⊕⚪⚪)