Functional Hypothalamic Amenorrhea

Publication Date: March 22, 2017

Diagnosis

Endocrine Society (ES) suggests that clinicians make the diagnosis of functional hypothalamic amenorrhea (FHA) only after excluding the anatomic or organic pathology of amenorrhea. ( UGPS )
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ES suggests 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. ( 2-L )
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ES suggests screening patients with FHA for psychological stressors (patients with FHA may be coping with stressors, and stress sensitivity has multiple determinants). ( 2-M )
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Once clinicians establish the diagnosis of FHA, the ES suggests they provide patient education about various menstrual patterns occurring during the recovery phase. ES suggests clinicians inform patients that irregular menses do not require immediate evaluation and that menstrual irregularity does not preclude conception. ( UGPS )
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Evaluation

In patients with suspected FHA, ES recommends 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. ( UGPS )
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In a patient with suspected FHA, ES recommends 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-M )
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In adolescents and women with suspected FHA, ES recommends 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-H )
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As part of an initial endocrine evaluation for patients with FHA, ES recommends 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-H )
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After excluding pregnancy, ES suggests 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-M )
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ES recommends 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-M )
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ES suggests that clinicians obtain a baseline bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry (DXA) from any adolescent or woman with ≥6 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-M )
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In cases of primary amenorrhea, ES suggests 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-M )
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In patients with FHA and underlying polycystic ovary syndrome (PCOS), ES suggests:
a baseline BMD measurement by DXA in those with ≥6 months of amenorrhea and earlier in those with history or suspicion of severe nutritional deficiency, other energy deficit states, and/or skeletal fragility; and (2-L)
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clinical monitoring for hyperresponse in those treated with exogenous gonadotropins for infertility. (2-L)
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Treatment

ES recommends that clinicians evaluate patients for inpatient treatment who have FHA and severe bradycardia, hypotension, orthostasis, and/or electrolyte imbalance. ( 1-M )
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In adolescents and women with FHA, ES recommends correcting the energy imbalance to improve hypothalamic–pituitary–ovarian (HPO) axis function. This often requires behavioral change. Options for improving energy balance include increased consumption and/or improved nutrition and/or decreased exercise activity. This often requires weight gain. ( 1-M )
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In adolescents and women with FHA, ES suggests psychological support, such as cognitive behavior therapy (CBT). ( 2-L )
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ES suggests against patients with FHA using oral contraceptive pills (OCPs) for the sole purpose of regaining menses or improving BMD. ( 2-L )
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In patients with FHA using OCPs for contraception, ES suggests 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-L )
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ES suggests 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-VL )
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ES suggests against using bisphosphonates, denosumab, testosterone, and leptin to improve BMD in adolescents and women with FHA. ( 2-L )
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In rare adult FHA cases, ES suggests 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-VL )
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In patients with FHA wishing to conceive, after a complete fertility workup ES suggests:
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-VL)
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cautious use of gonadotropin therapy. (2-VL)
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a trial of treatment with clomiphene citrate for ovulation induction if a woman has a sufficient endogenous estrogen level. (2-VL)
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against the use of kisspeptin and leptin for treating infertility. (2-VL)
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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, since this treatment has the potential to restore ovulatory cycles and fertility without the need for medical intervention. ( 2-L )
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ES suggests that clinicians should induce ovulation only 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-L )
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Recommendation Grading

Disclaimer

Overview

Title

Functional Hypothalamic Amenorrhea

Authoring Organization

Endorsing Organizations

Publication Month/Year

March 22, 2017

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Document Objectives

To formulate clinical practice guidelines for the diagnosis and treatment of functional hypothalamic amenorrhea (FHA).

Inclusion Criteria

Female, Male, Adolescent, Adult, Child, Infant, Older adult

Health Care Settings

Ambulatory

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Assessment and screening, Diagnosis, Management, Treatment

Diseases/Conditions (MeSH)

D000568 - Amenorrhea, D007028 - Hypothalamic Hormones

Keywords

functional hypothalamic amenorrhea (FHA), Functional Hypothalamic Amenorrhea, FHA

Source Citation

Catherine M. Gordon, Kathryn E. Ackerman, Sarah L. Berga, Jay R. Kaplan, George Mastorakos, Madhusmita Misra, M. Hassan Murad, Nanette F. Santoro, Michelle P. Warren, Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 102, Issue 5, 1 May 2017, Pages 1413–1439, https://doi.org/10.1210/jc.2017-00131