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Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations

Kathryn E Ackerman, MD, MPH
Madhusmita Misra, MD, MPH
Section Editors
Robert L Barbieri, MD
William F Crowley, Jr, MD
Deputy Editor
Kathryn A Martin, MD


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 ruling out other etiologies of amenorrhea. The terms functional hypothalamic amenorrhea and hypothalamic amenorrhea (HA) are often used interchangeably.

This topic will review the pathophysiology and clinical manifestations of FHA. The diagnosis and management of FHA, as well as the overall approach to the woman with primary and secondary amenorrhea, is presented separately. (See "Functional hypothalamic amenorrhea: Evaluation and management" and "Evaluation and management of primary amenorrhea" and "Evaluation and management of secondary amenorrhea".)


One of the most common types of secondary amenorrhea is FHA, which by definition excludes organic disease. Risk factors for FHA include eating disorders (in particular anorexia nervosa [AN]), excessive exercise, and stress. FHA is responsible for approximately 25 to 35 percent and 3 percent of secondary and primary amenorrhea cases, respectively. (See "Epidemiology and causes of secondary amenorrhea" and "Causes of primary amenorrhea".)

Low-weight eating disorders are reported in 0.2 to 4 percent of adolescents and young adult women [1]. Although amenorrhea is no longer a diagnostic criterion for AN per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [2], FHA is commonly seen in this condition. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis".).

Many, if not most, women of reproductive age engage in some form of exercise. Most obtain health benefits, but some can also develop menstrual dysfunction [3]. In addition, excessive exercise and/or inadequate caloric intake leading to relative energy deficiency at a critical time in development may delay puberty [4].

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Literature review current through: Dec 2017. | This topic last updated: Apr 21, 2017.
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  1. Keski-Rahkonen A, Mustelin L. Epidemiology of eating disorders in Europe: prevalence, incidence, comorbidity, course, consequences, and risk factors. Curr Opin Psychiatry 2016; 29:340.
  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th, American Psychiatric Association, Arlington 2013.
  3. Shangold MM. Athletic amenorrhea. Clin Obstet Gynecol 1985; 28:664.
  4. Frisch RE, Wyshak G, Vincent L. Delayed menarche and amenorrhea in ballet dancers. N Engl J Med 1980; 303:17.
  5. Giles DE, Berga SL. Cognitive and psychiatric correlates of functional hypothalamic amenorrhea: a controlled comparison. Fertil Steril 1993; 60:486.
  6. Williams NI, Berga SL, Cameron JL. Synergism between psychosocial and metabolic stressors: impact on reproductive function in cynomolgus monkeys. Am J Physiol Endocrinol Metab 2007; 293:E270.
  7. Otis CL, Drinkwater B, Johnson M, et al. American College of Sports Medicine position stand. The Female Athlete Triad. Med Sci Sports Exerc 1997; 29:i.
  8. Nattiv A, Loucks AB, Manore MM, et al. American College of Sports Medicine position stand. The female athlete triad. Med Sci Sports Exerc 2007; 39:1867.
  9. Gordon CM. Clinical practice. Functional hypothalamic amenorrhea. N Engl J Med 2010; 363:365.
  10. Santoro N, Filicori M, Crowley WF Jr. Hypogonadotropic disorders in men and women: diagnosis and therapy with pulsatile gonadotropin-releasing hormone. Endocr Rev 1986; 7:11.
  11. Gordon CM, Ackerman KE, Berga SL, et al. Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2017; 102:1413.
  12. Berga SL, Mortola JF, Girton L, et al. Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 1989; 68:301.
  13. Perkins RB, Hall JE, Martin KA. Neuroendocrine abnormalities in hypothalamic amenorrhea: spectrum, stability, and response to neurotransmitter modulation. J Clin Endocrinol Metab 1999; 84:1905.
  14. Constantini NW, Warren MP. Menstrual dysfunction in swimmers: a distinct entity. J Clin Endocrinol Metab 1995; 80:2740.
  15. Misra M, Miller KK, Bjornson J, et al. Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab 2003; 88:5615.
  16. Misra M, Miller KK, Almazan C, et al. Alterations in cortisol secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab 2004; 89:4972.
  17. Ackerman KE, Patel KT, Guereca G, et al. Cortisol secretory parameters in young exercisers in relation to LH secretion and bone parameters. Clin Endocrinol (Oxf) 2013; 78:114.
  18. Lawson EA, Donoho D, Miller KK, et al. Hypercortisolemia is associated with severity of bone loss and depression in hypothalamic amenorrhea and anorexia nervosa. J Clin Endocrinol Metab 2009; 94:4710.
  19. Boyar RM, Hellman LD, Roffwarg H, et al. Cortisol secretion and metabolism in anorexia nervosa. N Engl J Med 1977; 296:190.
  20. Pinilla L, Aguilar E, Dieguez C, et al. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev 2012; 92:1235.
  21. Crabtree DR, Chambers ES, Hardwick RM, Blannin AK. The effects of high-intensity exercise on neural responses to images of food. Am J Clin Nutr 2014; 99:258.
  22. Misra M, Miller KK, Kuo K, et al. Secretory dynamics of ghrelin in adolescent girls with anorexia nervosa and healthy adolescents. Am J Physiol Endocrinol Metab 2005; 289:E347.
  23. Ackerman KE, Slusarz K, Guereca G, et al. Higher ghrelin and lower leptin secretion are associated with lower LH secretion in young amenorrheic athletes compared with eumenorrheic athletes and controls. Am J Physiol Endocrinol Metab 2012; 302:E800.
  24. Schneider LF, Warren MP. Functional hypothalamic amenorrhea is associated with elevated ghrelin and disordered eating. Fertil Steril 2006; 86:1744.
  25. Christo K, Cord J, Mendes N, et al. Acylated ghrelin and leptin in adolescent athletes with amenorrhea, eumenorrheic athletes and controls: a cross-sectional study. Clin Endocrinol (Oxf) 2008; 69:628.
  26. Schneider LF, Monaco SE, Warren MP. Elevated ghrelin level in women of normal weight with amenorrhea is related to disordered eating. Fertil Steril 2008; 90:121.
  27. Scheid JL, De Souza MJ, Hill BR, et al. Decreased luteinizing hormone pulse frequency is associated with elevated 24-hour ghrelin after calorie restriction and exercise in premenopausal women. Am J Physiol Endocrinol Metab 2013; 304:E109.
  28. Misra M, Miller KK, Kuo K, et al. Secretory dynamics of leptin in adolescent girls with anorexia nervosa and healthy adolescents. Am J Physiol Endocrinol Metab 2005; 289:E373.
  29. Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004; 351:987.
  30. Misra M, Prabhakaran R, Miller KK, et al. Role of cortisol in menstrual recovery in adolescent girls with anorexia nervosa. Pediatr Res 2006; 59:598.
  31. Misra M, Miller KK, Tsai P, et al. Elevated peptide YY levels in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab 2006; 91:1027.
  32. Russell M, Stark J, Nayak S, et al. Peptide YY in adolescent athletes with amenorrhea, eumenorrheic athletes and non-athletic controls. Bone 2009; 45:104.
  33. Scheid JL, De Souza MJ. Menstrual irregularities and energy deficiency in physically active women: the role of ghrelin, PYY and adipocytokines. Med Sport Sci 2010; 55:82.
  34. Pfluger PT, Kampe J, Castaneda TR, et al. Effect of human body weight changes on circulating levels of peptide YY and peptide YY3-36. J Clin Endocrinol Metab 2007; 92:583.
  35. Germain N, Galusca B, Le Roux CW, et al. Constitutional thinness and lean anorexia nervosa display opposite concentrations of peptide YY, glucagon-like peptide 1, ghrelin, and leptin. Am J Clin Nutr 2007; 85:967.
  36. Bredella MA, Fazeli PK, Freedman LM, et al. Young women with cold-activated brown adipose tissue have higher bone mineral density and lower Pref-1 than women without brown adipose tissue: a study in women with anorexia nervosa, women recovered from anorexia nervosa, and normal-weight women. J Clin Endocrinol Metab 2012; 97:E584.
  37. Singhal V, Maffazioli GD, Ackerman KE, et al. Effect of Chronic Athletic Activity on Brown Fat in Young Women. PLoS One 2016; 11:e0156353.
  38. Loucks AB, Thuma JR. Luteinizing hormone pulsatility is disrupted at a threshold of energy availability in regularly menstruating women. J Clin Endocrinol Metab 2003; 88:297.
  39. Laughlin GA, Dominguez CE, Yen SS. Nutritional and endocrine-metabolic aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 1998; 83:25.
  40. Loucks AB, Verdun M, Heath EM. Low energy availability, not stress of exercise, alters LH pulsatility in exercising women. J Appl Physiol (1985) 1998; 84:37.
  41. Mountjoy M, Sundgot-Borgen J, Burke L, et al. The IOC consensus statement: beyond the Female Athlete Triad--Relative Energy Deficiency in Sport (RED-S). Br J Sports Med 2014; 48:491.
  42. Boyar RM, Katz J, Finkelstein JW, et al. Anorexia nervosa. Immaturity of the 24-hour luteinizing hormone secretory pattern. N Engl J Med 1974; 291:861.
  43. 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.
  44. Warren MP, Holderness CC, Lesobre V, et al. Hypothalamic amenorrhea and hidden nutritional insults. J Soc Gynecol Investig 1994; 1:84.
  45. Bomba M, Gambera A, Bonini L, et al. Endocrine profiles and neuropsychologic correlates of functional hypothalamic amenorrhea in adolescents. Fertil Steril 2007; 87:876.
  46. Cano Sokoloff N, Eguiguren ML, Wargo K, et al. Bone parameters in relation to attitudes and feelings associated with disordered eating in oligo-amenorrheic athletes, eumenorrheic athletes, and nonathletes. Int J Eat Disord 2015; 48:522.
  47. Couzinet B, Young J, Brailly S, et al. Functional hypothalamic amenorrhoea: a partial and reversible gonadotrophin deficiency of nutritional origin. Clin Endocrinol (Oxf) 1999; 50:229.
  48. 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.
  49. Williams NI, Leidy HJ, Hill BR, et al. Magnitude of daily energy deficit predicts frequency but not severity of menstrual disturbances associated with exercise and caloric restriction. Am J Physiol Endocrinol Metab 2015; 308:E29.
  50. Van Gend MA, Noakes TD. Menstrual patterns in ultramarathon runners. S Afr Med J 1987; 72:788.
  51. Bullen BA, Skrinar GS, Beitins IZ, et al. Induction of menstrual disorders by strenuous exercise in untrained women. N Engl J Med 1985; 312:1349.
  52. 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.
  53. Thralls KJ, Nichols JF, Barrack MT, et al. Body Mass-Related Predictors of the Female Athlete Triad Among Adolescent Athletes. Int J Sport Nutr Exerc Metab 2016; 26:17.
  54. Melin A, Tornberg ÅB, Skouby S, et al. Low-energy density and high fiber intake are dietary concerns in female endurance athletes. Scand J Med Sci Sports 2016; 26:1060.
  55. Ranganathan P, Kumar RG, Davis K, et al. Longitudinal sex and stress hormone profiles among reproductive age and post-menopausal women after severe TBI: A case series analysis. Brain Inj 2016; 30:452.
  56. Kaminski P, Bobrowska K, Pietrzak B, et al. Gynecological issues after organ transplantation. Neuro Endocrinol Lett 2008; 29:852.
  57. Ajayi AF, Akhigbe RE, Ajayi LO. Hypothalamic-pituitary-ovarian Axis in Thyroid Dysfunction. West Indian Med J 2013; 62:835.
  58. Gambacciani M, Yen SS, Rasmussen DD. GnRH release from the mediobasal hypothalamus: in vitro inhibition by corticotropin-releasing factor. Neuroendocrinology 1986; 43:533.
  59. Barbarino A, De Marinis L, Tofani A, et al. Corticotropin-releasing hormone inhibition of gonadotropin release and the effect of opioid blockade. J Clin Endocrinol Metab 1989; 68:523.
  60. Fourman LT, Fazeli PK. Neuroendocrine causes of amenorrhea--an update. J Clin Endocrinol Metab 2015; 100:812.
  61. Kondoh Y, Uemura T, Murase M, et al. A longitudinal study of disturbances of the hypothalamic-pituitary-adrenal axis in women with progestin-negative functional hypothalamic amenorrhea. Fertil Steril 2001; 76:748.
  62. Marcus MD, Loucks TL, Berga SL. Psychological correlates of functional hypothalamic amenorrhea. Fertil Steril 2001; 76:310.
  63. Edozien LC. Mind over matter: psychological factors and the menstrual cycle. Curr Opin Obstet Gynecol 2006; 18:452.
  64. Caronia LM, Martin C, Welt CK, et al. A genetic basis for functional hypothalamic amenorrhea. N Engl J Med 2011; 364:215.
  65. Robinson TL, Snow-Harter C, Taaffe DR, et al. Gymnasts exhibit higher bone mass than runners despite similar prevalence of amenorrhea and oligomenorrhea. J Bone Miner Res 1995; 10:26.
  66. Young N, Formica C, Szmukler G, Seeman E. Bone density at weight-bearing and nonweight-bearing sites in ballet dancers: the effects of exercise, hypogonadism, and body weight. J Clin Endocrinol Metab 1994; 78:449.
  67. Ackerman KE, Nazem T, Chapko D, et al. Bone microarchitecture is impaired in adolescent amenorrheic athletes compared with eumenorrheic athletes and nonathletic controls. J Clin Endocrinol Metab 2011; 96:3123.
  68. Ackerman KE, Cano Sokoloff N, DE Nardo Maffazioli G, et al. Fractures in Relation to Menstrual Status and Bone Parameters in Young Athletes. Med Sci Sports Exerc 2015; 47:1577.
  69. Ackerman KE, Putman M, Guereca G, et al. Cortical microstructure and estimated bone strength in young amenorrheic athletes, eumenorrheic athletes and non-athletes. Bone 2012; 51:680.
  70. Mitchell DM, Tuck P, Ackerman KE, et al. Altered trabecular bone morphology in adolescent and young adult athletes with menstrual dysfunction. Bone 2015; 81:24.
  71. Warren MP, Perlroth NE. The effects of intense exercise on the female reproductive system. J Endocrinol 2001; 170:3.
  72. Warren MP, Brooks-Gunn J, Fox RP, et al. Osteopenia in exercise-associated amenorrhea using ballet dancers as a model: a longitudinal study. J Clin Endocrinol Metab 2002; 87:3162.
  73. Barrack MT, Gibbs JC, De Souza MJ, et al. Higher incidence of bone stress injuries with increasing female athlete triad-related risk factors: a prospective multisite study of exercising girls and women. Am J Sports Med 2014; 42:949.
  74. 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.
  75. Christo K, Prabhakaran R, Lamparello B, et al. Bone metabolism in adolescent athletes with amenorrhea, athletes with eumenorrhea, and control subjects. Pediatrics 2008; 121:1127.
  76. Loucks AB, Mortola JF, Girton L, Yen SS. Alterations in the hypothalamic-pituitary-ovarian and the hypothalamic-pituitary-adrenal axes in athletic women. J Clin Endocrinol Metab 1989; 68:402.
  77. De Souza MJ, Toombs RJ, Scheid JL, et al. High prevalence of subtle and severe menstrual disturbances in exercising women: confirmation using daily hormone measures. Hum Reprod 2010; 25:491.
  78. Morris SN, Missmer SA, Cramer DW, et al. Effects of lifetime exercise on the outcome of in vitro fertilization. Obstet Gynecol 2006; 108:938.
  79. 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.
  80. Friday KE, Drinkwater BL, Bruemmer B, et al. Elevated plasma low-density lipoprotein and high-density lipoprotein cholesterol levels in amenorrheic athletes: effects of endogenous hormone status and nutrient intake. J Clin Endocrinol Metab 1993; 77:1605.
  81. Bairey Merz CN, Johnson BD, Sharaf BL, et al. Hypoestrogenemia of hypothalamic origin and coronary artery disease in premenopausal women: a report from the NHLBI-sponsored WISE study. J Am Coll Cardiol 2003; 41:413.
  82. O'Donnell E, Goodman JM, Harvey PJ. Clinical review: Cardiovascular consequences of ovarian disruption: a focus on functional hypothalamic amenorrhea in physically active women. J Clin Endocrinol Metab 2011; 96:3638.
  83. Anderson TJ, Gerhard MD, Meredith IT, et al. Systemic nature of endothelial dysfunction in atherosclerosis. Am J Cardiol 1995; 75:71B.
  84. Zeni Hoch A, Dempsey RL, Carrera GF, et al. Is there an association between athletic amenorrhea and endothelial cell dysfunction? Med Sci Sports Exerc 2003; 35:377.
  85. Rickenlund A, Eriksson MJ, Schenck-Gustafsson K, Hirschberg AL. Amenorrhea in female athletes is associated with endothelial dysfunction and unfavorable lipid profile. J Clin Endocrinol Metab 2005; 90:1354.
  86. Yoshida N, Ikeda H, Sugi K, Imaizumi T. Impaired endothelium-dependent and -independent vasodilation in young female athletes with exercise-associated amenorrhea. Arterioscler Thromb Vasc Biol 2006; 26:231.
  87. Hoch AZ, Papanek P, Szabo A, et al. Association between the female athlete triad and endothelial dysfunction in dancers. Clin J Sport Med 2011; 21:119.
  88. Facchinetti F, Fava M, Fioroni L, et al. Stressful life events and affective disorders inhibit pulsatile LH secretion in hypothalamic amenorrhea. Psychoneuroendocrinology 1993; 18:397.
  89. Flegal KM, Graubard BI, Williamson DF, Gail MH. Excess deaths associated with underweight, overweight, and obesity. JAMA 2005; 293:1861.