Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline

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

Disclosures

J Clin Endocrinol Metab. 2017;102(5):1413-1439.

Abstract and Introduction

Abstract

Cosponsoring Associations: The American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society.

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

Participants: The participants include an Endocrine Society–appointed task force of eight experts, a methodologist, and a medical writer.

Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies.

Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and cosponsoring organizations reviewed and commented on preliminary drafts of this guideline.

Conclusions: FHA is a form of chronic anovulation, not due to identifiable organic causes, but often associated with stress, weight loss, excessive exercise, or a combination thereof. Investigations should include assessment of systemic and endocrinologic etiologies, as FHA is a diagnosis of exclusion. A multidisciplinary treatment approach is necessary, including medical, dietary, and mental health support. Medical complications include, among others, bone loss and infertility, and appropriate therapies are under debate and investigation.

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Next Section

Abstract and Introduction
Summary of Recommendations
Method of Development of Evidence-based Clinical Practice Guidelines
Commissioned Systematic Reviews
Background
Future Directions
References

Table 1. Potential Etiologies of Amenorrhea
Congenital malformation
Septo-optic dysplasia
Holoprosencephaly
Encephalocele
Constitutional delay
Genetic conditions
Congenital deficiency of hypothalamic or pituitary transcription factors (gonadotropin deficiency)
Single-gene mutations (hypogonadotropic hypogonadism)
Hyperprolactinemia
Pituitary gland or stalk damage
Tumors and cysts [hypothalamic or pituitary tumor (hormone-secreting), craniopharyngioma, Rathke cleft cyst, other cysts, and tumors]
Infiltrative disorders (germinoma, autoimmune hypophysitis, arcoidosis, hemochromatosis, tuberculosis, Langerhans cell histiocytosis, IgG4-related hypophysitis)
Irradiation
Infarction [apoplexy in pre-existing pituitary tumors, or ollowing postpartum hemorrhage (Sheehan syndrome)]
Surgery
Trauma
Others
Eating disorders
Competitive athletics
Chronic disease
Mood disorders
Stress or psychiatric illness
Drugs
Thyroid
Hypothyroidism or hyperthyroidism
Adrenals
Congenital adrenal hyperplasia (select types)
Cushing syndrome
Addison disease (adrenal insufficiency)
Tumor (androgen-secreting)
Ovaries
Associated with high levels of gonadotropins Gonadal agenesis or dysgenesis (in the setting of Turner syndrome/other)
Ovarian insufficiency
Autoimmune oophoritis
Irradiation or surgery
Not associated with high levels of gonadotropins
Polycystic ovary syndrome
Tumor (estrogen- or androgen-secreting)
Uterus (eugonadism)
Müllerian anomalies (obstructive outflow anomalies)
Asherman syndrome
Synechiae (integral to Asherman syndrome)
Pregnancy
Infectious (e.g., tuberculous endometritis)
Agenesis (uterine or cervical)
Vagina (eugonadism)
Agenesis
Transverse septum
Hymen (eugonadism)
Imperforate

Table 2. Common Causes of Anovulation and Accompanying Laboratory Patterns
	LH (IU/L)	FSH (IU/L)	LH/FSH	E2 (pg/mL)	P4 (ng/mL)	AMH (ng/mL)	PRL (ng/mL)	TSH (μU/mL)	T4 (μg/dL)	DHEA-S (μg/dL)	17OHP (ng/dL)	T (ng/dL)
Functional hypothalamic anovulation	<10	<10	~1	<50	<1	>1	Low nl	Low nl	Low nl	nl	nl	Low nl
Ovarian insufficiency menopause	>15	>15	FSH > LH	<50	<1	<0.5	nl	nl or ↑	nl or ↓	nl	nl	Low nl
PCOS	<15	<10	LH > FSH	<50	<1	nlor↑	High nl	nl	nl	High nl	nl	High nl or slight↑
Nonclassical CAH	<15	<10	LH > FSH	<50	≤1	nl	nl	nl	nl	High nl	↑	↑
Hyperprolactinemia	<10	<10	LH < FSH	<50	<1	nl	↑	nl or ↑	nl	nl or slight ↑	nl	nl

Abbreviations: 17OHP, 17-hydroxyprogesterone; nl, normal; P4, progesterone; PRL, prolactin; T, testosterone.

Authors and Disclosures

Catherine M. Gordon¹, Kathryn E. Ackerman^2,5, Sarah L. Berga³, Jay R. Kaplan³, George Mastorakos⁴, Madhusmita Misra⁵, M. Hassan Murad⁶, Nanette F. Santoro⁷ and Michelle P. Warren⁸

¹Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229; ²Boston Children's Hospital, Boston, Massachusetts 02115; ³Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; ⁴Areteio Hospital, Medical School, National and Capodistrian University of Athens, Athens, Greece 10674; ⁵Massachusetts General Hospital, Boston, Massachusetts 02114; ⁶Division of Preventive Medicine, Mayo Clinic, Rochester, Minnesota 55905; ⁷University of Colorado School of Medicine, Aurora, Colorado 80045; and ⁸Center for Menopause, Hormonal Disorders, and Women's Health, Columbia University Medical Center, New York, New York 10021

Address all correspondence and requests for reprints to
The Endocrine Society, 2055 L Street NW, Suite 600, Washington, DC 20036. E-mail: publications@endocrine.org; Phone: 202-971-3636.

Financial Disclosures of the Task Force*
Catherine M. Gordon (chair)—Financial or Business/Organizational Interests: Janssen Pharmaceuticals (member, data safety monitor board): Department of Justice, Health Resources and Services Administration (consultant), National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development (council member), Significant Financial Interest or Leadership Position: none declared. Kathryn E. Ackerman—Financial or Business/Organizational Interests: Walden Behavioral Care Eating Disorder Treatment Center (clinical advisory board), Significant Financial Interest or Leadership Position: Walden Behavioral Care Eating Disorder Treatment Center (clinical advisory board). Sarah L. Berga—Financial or Business/Organizational Interests: Ferring Pharmaceuticals Inc. (consultant), Vermillion Pelvic Mass Registry (advisory panel), What's My Fertility (advisory board), American College of Obstetrics and Gynecology (editorial board), American Journal of Obstetrics and Gynecology (editorial board), International Society for Gynecological Endocrinology (editorial board), Menopause (editorial board), Society for Women's Health Research (editorial board), Ferring Pharmaceuticals Inc. (principal investigator), National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant/consultant), National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant), National Institutes of Health/National Cancer Institute (grant/principal investigator), National Institutes of Health/Office of the Director (grant), Significant Financial Interest or Leadership Position: none declared. Jay R. Kaplan—Financial or Business/Organizational Interests: none declared, Significant Financial Interest or Leadership Position: none declared. George Mastorakos—Financial or Business/Organizational Interests: European Society of Endocrinology (ex official member of executive committee), Hellenic Endocrine Society (president), Significant Financial Interest or Leadership Position: European Society of Endocrinology (ex official member of executive committee), Hellenic Endocrine Society (president). Madhusmita Misra—Financial or Business/Organizational Interests: none declared, Significant Financial Interest or Leadership Position: none declared. M. Hassan Murad**—Financial or Business/Organizational Interests: The Mayo Clinic, Division of Preventive Medicine, Significant Financial Interest or Leadership Position: none declared. Nanette F. Santoro—Financial or Business/Organizational Interests: Bayer, Inc. (grant investigator, initiated grant support), Menogenix (ownership interest), Significant Financial Interest or Leadership Position: none declared. Michelle P. Warren—Financial or Business/Organizational Interests: Pfizer (grantee), Significant Financial Interest or Leadership Position: none declared.
*Financial, business, and organizational disclosures of the task force cover the year prior to publication. Disclosures prior to this time period are archived.
**Evidence-based reviews for this guideline were prepared by the Mayo Clinic, Division of Preventive Medicine, under contract with the Endocrine Society.