Functional hypothalamic amenorrhea: Evaluation and management
- Kathryn E Ackerman, MD, MPH
Kathryn E Ackerman, MD, MPH
- Assistant Professor of Medicine
- Harvard Medical School
- Madhusmita Misra, MD, MPH
Madhusmita Misra, MD, MPH
- Fritz Bradley Talbot and Nathan Bill Talbot Professor of Pediatrics
- Harvard Medical School
- Section Editors
- Robert L Barbieri, MD
Robert L Barbieri, MD
- Editor-in-Chief — Obstetrics, Gynecology and Women's Health
- Section Editor — General Gynecology and Female Reproductive Endocrinology
- Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology
- Harvard Medical School
- William F Crowley, Jr, MD
William F Crowley, Jr, MD
- Section Editor — Female Reproductive Endocrinology
- Daniel K Podolsky Professor of Medicine
- Harvard Medical School
Low energy availability (from decreased caloric intake, excessive energy expenditure, or both) and stress are common causes of hypogonadotropic hypogonadism in women. Functional hypothalamic amenorrhea (FHA) is the term used to describe amenorrhea that results from such causes and is diagnosed after excluding other etiologies of amenorrhea. The terms functional hypothalamic amenorrhea and hypothalamic amenorrhea (HA) are often used interchangeably.
FHA is presumed to be a functional disruption of pulsatile, hypothalamic gonadotropin-releasing hormone (GnRH) secretion. The abnormal GnRH secretion characteristic of FHA leads to decreased pulses of gonadotropins, absent midcycle surges in luteinizing hormone (LH) secretion, absence of normal follicular development, anovulation, and low serum estradiol (E2) concentrations. Variable neuroendocrine patterns of LH secretion can be seen. Serum concentrations of follicle-stimulating hormone (FSH) are low or normal and often exceed those of LH, similar to the pattern in prepubertal girls.
This topic will review the evaluation and management of FHA. The pathophysiology and clinical manifestations of FHA, as well as the approach to women with primary and secondary amenorrhea, are presented separately. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Evaluation and management of primary amenorrhea" and "Evaluation and management of secondary amenorrhea".)
Diagnosis — FHA is a disorder that, by definition, excludes organic disease. The diagnosis of FHA is based upon the findings of amenorrhea, low serum gonadotropins and estradiol (E2), and, usually, evidence of a precipitating factor (exercise, low weight, stress). As in every woman with new-onset amenorrhea, other causes should first be excluded before diagnosing this condition. Our approach is consistent with the Endocrine Society's 2017 Clinical Practice Guideline for the diagnosis and treatment of FHA . (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Evaluation and management of primary amenorrhea" and "Evaluation and management of secondary amenorrhea".)
Exclude other disorders — Women with FHA usually present with secondary amenorrhea, although some present with primary amenorrhea. The evaluation of both types of amenorrhea includes a thorough history and physical examination, biochemical testing, assessment of estrogen status, and, in some cases, imaging. These are reviewed in detail separately (algorithm 1 and algorithm 2). (See "Evaluation and management of primary amenorrhea" and "Evaluation and management of secondary amenorrhea".)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Gordon CM, Ackerman KE, Berga SL, et al. Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2017; 102:1413.
- Hagmar M, Berglund B, Brismar K, Hirschberg AL. Hyperandrogenism may explain reproductive dysfunction in olympic athletes. Med Sci Sports Exerc 2009; 41:1241.
- De Souza MJ, Nattiv A, Joy E, et al. 2014 Female Athlete Triad Coalition Consensus Statement on Treatment and Return to Play of the Female Athlete Triad: 1st International Conference held in San Francisco, California, May 2012 and 2nd International Conference held in Indianapolis, Indiana, May 2013. Br J Sports Med 2014; 48:289.
- Crabtree NJ, Arabi A, Bachrach LK, et al. Dual-energy X-ray absorptiometry interpretation and reporting in children and adolescents: the revised 2013 ISCD Pediatric Official Positions. J Clin Densitom 2014; 17:225.
- Falsetti L, Gambera A, Barbetti L, Specchia C. Long-term follow-up of functional hypothalamic amenorrhea and prognostic factors. J Clin Endocrinol Metab 2002; 87:500.
- Warren MP, Perlroth NE. The effects of intense exercise on the female reproductive system. J Endocrinol 2001; 170:3.
- Perkins RB, Hall JE, Martin KA. Aetiology, previous menstrual function and patterns of neuro-endocrine disturbance as prognostic indicators in hypothalamic amenorrhoea. Hum Reprod 2001; 16:2198.
- Golden NH, Jacobson MS, Schebendach J, et al. Resumption of menses in anorexia nervosa. Arch Pediatr Adolesc Med 1997; 151:16.
- Misra M, Tsai P, Anderson EJ, et al. Nutrient intake in community-dwelling adolescent girls with anorexia nervosa and in healthy adolescents. Am J Clin Nutr 2006; 84:698.
- Barron E, Cano Sokoloff N, Maffazioli GD, et al. Diets High in Fiber and Vegetable Protein Are Associated with Low Lumbar Bone Mineral Density in Young Athletes with Oligoamenorrhea. J Acad Nutr Diet 2016; 116:481.
- Hadigan CM, Anderson EJ, Miller KK, et al. Assessment of macronutrient and micronutrient intake in women with anorexia nervosa. Int J Eat Disord 2000; 28:284.
- Berga SL, Marcus MD, Loucks TL, et al. Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavior therapy. Fertil Steril 2003; 80:976.
- Michopoulos V, Mancini F, Loucks TL, Berga SL. Neuroendocrine recovery initiated by cognitive behavioral therapy in women with functional hypothalamic amenorrhea: a randomized, controlled trial. Fertil Steril 2013; 99:2084.
- Blais MA, Becker AE, Burwell RA, et al. Pregnancy: outcome and impact on symptomatology in a cohort of eating-disordered women. Int J Eat Disord 2000; 27:140.
- Meczekalski B, Katulski K, Czyzyk A, et al. Functional hypothalamic amenorrhea and its influence on women's health. J Endocrinol Invest 2014; 37:1049.
- Martin KA, Hall JE, Adams JM, Crowley WF Jr. Comparison of exogenous gonadotropins and pulsatile gonadotropin-releasing hormone for induction of ovulation in hypogonadotropic amenorrhea. J Clin Endocrinol Metab 1993; 77:125.
- Guzick DS, Carson SA, Coutifaris C, et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network. N Engl J Med 1999; 340:177.
- Borges LE, Morgante G, Musacchio MC, et al. New protocol of clomiphene citrate treatment in women with hypothalamic amenorrhea. Gynecol Endocrinol 2007; 23:343.
- Djurovic M, Pekic S, Petakov M, et al. Gonadotropin response to clomiphene and plasma leptin levels in weight recovered but amenorrhoeic patients with anorexia nervosa. J Endocrinol Invest 2004; 27:523.
- Misra M, Katzman DK, Estella NM, et al. Impact of physiologic estrogen replacement on anxiety symptoms, body shape perception, and eating attitudes in adolescent girls with anorexia nervosa: data from a randomized controlled trial. J Clin Psychiatry 2013; 74:e765.
- Baskaran C, Cunningham B, Plessow F, et al. Estrogen Replacement Improves Verbal Memory and Executive Control in Oligomenorrheic/Amenorrheic Athletes in a Randomized Controlled Trial. J Clin Psychiatry 2017.
- Dominguez J, Goodman L, Sen Gupta S, et al. Treatment of anorexia nervosa is associated with increases in bone mineral density, and recovery is a biphasic process involving both nutrition and return of menses. Am J Clin Nutr 2007; 86:92.
- Miller KK, Lee EE, Lawson EA, et al. Determinants of skeletal loss and recovery in anorexia nervosa. J Clin Endocrinol Metab 2006; 91:2931.
- Warren MP, Brooks-Gunn J, Fox RP, et al. Persistent osteopenia in ballet dancers with amenorrhea and delayed menarche despite hormone therapy: a longitudinal study. Fertil Steril 2003; 80:398.
- Warren MP, Miller KK, Olson WH, et al. Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in women with hypothalamic amenorrhea and osteopenia: an open-label extension of a double-blind, placebo-controlled study. Contraception 2005; 72:206.
- Misra M, Prabhakaran R, Miller KK, et al. Weight gain and restoration of menses as predictors of bone mineral density change in adolescent girls with anorexia nervosa-1. J Clin Endocrinol Metab 2008; 93:1231.
- Misra M, Katzman D, Miller KK, et al. Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa. J Bone Miner Res 2011; 26:2430.
- Klibanski A, Biller BM, Schoenfeld DA, et al. The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa. J Clin Endocrinol Metab 1995; 80:898.
- Strokosch GR, Friedman AJ, Wu SC, Kamin M. Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in adolescent females with anorexia nervosa: a double-blind, placebo-controlled study. J Adolesc Health 2006; 39:819.
- Rickenlund A, Carlström K, Ekblom B, et al. Effects of oral contraceptives on body composition and physical performance in female athletes. J Clin Endocrinol Metab 2004; 89:4364.
- Cobb KL, Bachrach LK, Sowers M, et al. The effect of oral contraceptives on bone mass and stress fractures in female runners. Med Sci Sports Exerc 2007; 39:1464.
- Castelo-Branco C, Vicente JJ, Pons F, et al. Bone mineral density in young, hypothalamic oligoamenorrheic women treated with oral contraceptives. J Reprod Med 2001; 46:875.
- Cumming DC. Exercise-associated amenorrhea, low bone density, and estrogen replacement therapy. Arch Intern Med 1996; 156:2193.
- Gibson JH, Mitchell A, Reeve J, Harries MG. Treatment of reduced bone mineral density in athletic amenorrhea: a pilot study. Osteoporos Int 1999; 10:284.
- Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004; 351:987.
- Chou SH, Chamberland JP, Liu X, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A 2011; 108:6585.
- Golden NH, Iglesias EA, Jacobson MS, et al. Alendronate for the treatment of osteopenia in anorexia nervosa: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2005; 90:3179.
- Miller KK, Meenaghan E, Lawson EA, et al. Effects of risedronate and low-dose transdermal testosterone on bone mineral density in women with anorexia nervosa: a randomized, placebo-controlled study. J Clin Endocrinol Metab 2011; 96:2081.
- Fazeli PK, Wang IS, Miller KK, et al. Teriparatide increases bone formation and bone mineral density in adult women with anorexia nervosa. J Clin Endocrinol Metab 2014; 99:1322.
- Zhang D, Potty A, Vyas P, Lane J. The role of recombinant PTH in human fracture healing: a systematic review. J Orthop Trauma 2014; 28:57.
- Exclude other disorders
- - History and physical examination
- - Biochemical testing
- - Evaluation of estrogen status
- - Imaging
- Bone density testing
- Screening for anxiety and mood disorders
- Reproductive issues
- - Amenorrhea
- Weight gain/lifestyle changes
- - Anovulatory infertility
- - Sexual function
- Cognition and anxiety
- Low bone density
- - Initial nonpharmacologic therapy
- - Calcium and vitamin D supplementation
- - Pharmacologic therapy
- Expert guidelines
- Estrogen replacement
- - Experimental
- Addition of androgens
- Other therapies
- - Other therapies to optimize bone density
- Antiresorptive therapies
- - Bisphosphonates
- Bone-anabolic therapies
- - Teriparatide
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS