Semin Reprod Med 2017; 35(03): 256-262
DOI: 10.1055/s-0037-1603581
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Hypothalamic Amenorrhea and the Long-Term Health Consequences

Chrisandra L. Shufelt
1   Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, California
,
Tina Torbati
1   Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, California
,
Erika Dutra
1   Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, California
› Author Affiliations
Further Information

Publication History

Publication Date:
28 June 2017 (online)

Abstract

The menstrual cycle is a reproductive vital sign and provides insight into hormonal imbalance as well as pregnancy. The significance of estrogen, however, extends beyond fertility and plays a role on tissues and organs throughout the body. Functional hypothalamic amenorrhea is a common form of secondary amenorrhea resulting in estrogen deficiency in young premenopausal women. While reversible, the cause of this disorder is related to psychological stress, excessive exercise, disordered eating, or a combination of these factors resulting in suppression of the hypothalamic–pituitary–ovarian axis. The resulting loss of estrogen has profound effects on many systems throughout the body, including cardiac, skeletal, psychological, and reproductive. Often, these young women are “walking well,” as they do not have bothersome symptoms of low estrogen and are unaware of the consequences of estrogen deficiency. This review focuses on the health consequences of hypothalamic amenorrhea, current research, and available treatment options.

 
  • References

  • 1 Stevenson JC, Crook D, Godsland IF. Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atherosclerosis 1993; 98 (01) 83-90
  • 2 Riggs BL, Khosla S, Melton III LJ. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 1998; 13 (05) 763-773
  • 3 Elavsky S, McAuley E. Physical activity and mental health outcomes during menopause: a randomized controlled trial. Ann Behav Med 2007; 33 (02) 132-142
  • 4 Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril 2008; 90 (5 suppl): S219-25
  • 5 Pettersson F, Fries H, Nillius SJ. Epidemiology of secondary amenorrhea. I. Incidence and prevalence rates. Am J Obstet Gynecol 1973; 117 (01) 80-86
  • 6 U.S. Census Bureau. Statistical Abstract of the United States, 2010. Government Printing Office; 2009
  • 7 McDevitt TM. World Population Profile. US Government Printing Office; 1996
  • 8 Vadakkadath Meethal S, Atwood CS. The role of hypothalamic-pituitary-gonadal hormones in the normal structure and functioning of the brain. Cell Mol Life Sci 2005; 62 (03) 257-270
  • 9 Bairey Merz CN, Johnson BD, Sharaf BL. , et al; WISE Study Group. 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 (03) 413-419
  • 10 Mozaffarian D, Benjamin EJ, Go AS. , et al; Writing Group Members; American Heart Association Statistics Committee; Stroke Statistics Subcommittee. Heart disease and stroke statistics-2016 update: A report from the American Heart Association. Circulation 2016; 133 (04) e38-e360
  • 11 Kaplan JR, Manuck SB. Ovarian dysfunction and the premenopausal origins of coronary heart disease. Menopause 2008; 15 (4, Pt 1): 768-776
  • 12 Adams MR, Kaplan JR, Koritnik DR. Psychosocial influences on ovarian endocrine and ovulatory function in Macaca fascicularis. Physiol Behav 1985; 35 (06) 935-940
  • 13 Kaplan JR, Manuck SB, Anthony MS, Clarkson TB. Premenopausal social status and hormone exposure predict postmenopausal atherosclerosis in female monkeys. Obstet Gynecol 2002; 99 (03) 381-388
  • 14 Solomon CG, Hu FB, Dunaif A. , et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab 2002; 87 (05) 2013-2017
  • 15 Punnonen R, Jokela H, Aine R, Teisala K, Salomäki A, Uppa H. Impaired ovarian function and risk factors for atherosclerosis in premenopausal women. Maturitas 1997; 27 (03) 231-238
  • 16 Joakimsen O, Bønaa KH, Stensland-Bugge E, Jacobsen BK. Population-based study of age at menopause and ultrasound assessed carotid atherosclerosis: The Tromsø Study. J Clin Epidemiol 2000; 53 (05) 525-530
  • 17 Mack WJ, Slater CC, Xiang M, Shoupe D, Lobo RA, Hodis HN. Elevated subclinical atherosclerosis associated with oophorectomy is related to time since menopause rather than type of menopause. Fertil Steril 2004; 82 (02) 391-397
  • 18 Dwyer KM, Nordstrom CK, Bairey Merz CN, Dwyer JH. Carotid wall thickness and years since bilateral oophorectomy: the Los Angeles Atherosclerosis Study. Am J Epidemiol 2002; 156 (05) 438-444
  • 19 Parker WH, Broder MS, Chang E. , et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses' health study. Obstet Gynecol 2009; 113 (05) 1027-1037
  • 20 Martin BJ, Anderson TJ. Risk prediction in cardiovascular disease: the prognostic significance of endothelial dysfunction. Can J Cardiol 2009; 25 (Suppl A): 15A-20A
  • 21 Swerdlow AJ, Hermon C, Jacobs PA. , et al. Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet 2001; 65 (Pt 2): 177-188
  • 22 Ostberg JE, Donald AE, Halcox JP, Storry C, McCarthy C, Conway GS. Vasculopathy in Turner syndrome: arterial dilatation and intimal thickening without endothelial dysfunction. J Clin Endocrinol Metab 2005; 90 (09) 5161-5166
  • 23 Meczekalski B, Podfigurna-Stopa A, Genazzani AR. Hypoestrogenism in young women and its influence on bone mass density. Gynecol Endocrinol 2010; 26 (09) 652-657
  • 24 Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest 2006; 116 (05) 1186-1194
  • 25 Postnov AA, Vinogradov AV, Van Dyck D, Saveliev SV, De Clerck NM. Quantitative analysis of bone mineral content by x-ray microtomography. Physiol Meas 2003; 24 (01) 165-178
  • 26 Nelson ME, Fisher EC, Catsos PD, Meredith CN, Turksoy RN, Evans WJ. Diet and bone status in amenorrheic runners. Am J Clin Nutr 1986; 43 (06) 910-916
  • 27 Drinkwater BL, Nilson K, Chesnut III CH, Bremner WJ, Shainholtz S, Southworth MB. Bone mineral content of amenorrheic and eumenorrheic athletes. N Engl J Med 1984; 311 (05) 277-281
  • 28 Biller BM, Coughlin JF, Saxe V, Schoenfeld D, Spratt DI, Klibanski A. Osteopenia in women with hypothalamic amenorrhea: a prospective study. Obstet Gynecol 1991; 78 (06) 996-1001
  • 29 Podfigurna-Stopa A, Pludowski P, Jaworski M, Lorenc R, Genazzani AR, Meczekalski B. Skeletal status and body composition in young women with functional hypothalamic amenorrhea. Gynecol Endocrinol 2012; 28 (04) 299-304
  • 30 Pauli SA, Berga SL. Athletic amenorrhea: energy deficit or psychogenic challenge?. Ann N Y Acad Sci 2010; 1205: 33-38
  • 31 Brundu B, Loucks TL, Adler LJ, Cameron JL, Berga SL. Increased cortisol in the cerebrospinal fluid of women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 2006; 91 (04) 1561-1565
  • 32 Suh BY, Liu JH, Berga SL, Quigley ME, Laughlin GA, Yen SS. Hypercortisolism in patients with functional hypothalamic-amenorrhea. J Clin Endocrinol Metab 1988; 66 (04) 733-739
  • 33 Grinspoon S, Miller K, Coyle C. , et al. Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea. J Clin Endocrinol Metab 1999; 84 (06) 2049-2055
  • 34 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 (12) 4710-4716
  • 35 Hahn TJ, Halstead LR, Teitelbaum SL, Hahn BH. Altered mineral metabolism in glucocorticoid-induced osteopenia. Effect of 25-hydroxyvitamin D administration. J Clin Invest 1979; 64 (02) 655-665
  • 36 Galliford TM, Murphy E, Williams AJ, Bassett JH, Williams GR. Effects of thyroid status on bone metabolism: a primary role for thyroid stimulating hormone or thyroid hormone?. Minerva Endocrinol 2005; 30 (04) 237-246
  • 37 Tuchendler D, Bolanowski M. The influence of thyroid dysfunction on bone metabolism. Thyroid Res 2014; 7 (01) 12
  • 38 Torstveit MK, Sundgot-Borgen J. The female athlete triad: are elite athletes at increased risk?. Med Sci Sports Exerc 2005; 37 (02) 184-193
  • 39 Marcus MD, Loucks TL, Berga SL. Psychological correlates of functional hypothalamic amenorrhea. Fertil Steril 2001; 76 (02) 310-316
  • 40 Giles DE, Berga SL. Cognitive and psychiatric correlates of functional hypothalamic amenorrhea: a controlled comparison. Fertil Steril 1993; 60 (03) 486-492
  • 41 Laughlin GA, Dominguez CE, Yen SS. Nutritional and endocrine-metabolic aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 1998; 83 (01) 25-32
  • 42 Verri A, Nappi RE, Cecchini AP, Vallero E, Luzi S, Zara C. Eating disorders and Axis I psychiatric comorbidity in amenorrheic women. Int J Eat Disord 1998; 24 (02) 137-146
  • 43 Ahmed B, Bairey Merz CN, Johnson BD. , et al; WISE Study Group. Diabetes mellitus, hypothalamic hypoestrogenemia, and coronary artery disease in premenopausal women (from the National Heart, Lung, and Blood Institute sponsored WISE study). Am J Cardiol 2008; 102 (02) 150-154
  • 44 McEwen BS, Akama KT, Spencer-Segal JL, Milner TA, Waters EM. Estrogen effects on the brain: actions beyond the hypothalamus via novel mechanisms. Behav Neurosci 2012; 126 (01) 4-16
  • 45 Ruhé HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry 2007; 12 (04) 331-359
  • 46 Amin Z, Canli T, Epperson CN. Effect of estrogen-serotonin interactions on mood and cognition. Behav Cogn Neurosci Rev 2005; 4 (01) 43-58
  • 47 Groothuis PG, Dassen HH, Romano A, Punyadeera C. Estrogen and the endometrium: lessons learned from gene expression profiling in rodents and human. Hum Reprod Update 2007; 13 (04) 405-417
  • 48 Samsioe G. Urogenital aging--a hidden problem. Am J Obstet Gynecol 1998; 178 (05) S245-S249
  • 49 Bachmann GA, Nevadunsky NS. Diagnosis and treatment of atrophic vaginitis. Am Fam Physician 2000; 61 (10) 3090-3096
  • 50 Veleva Z, Tiitinen A, Vilska S. , et al. High and low BMI increase the risk of miscarriage after IVF/ICSI and FET. Hum Reprod 2008; 23 (04) 878-884
  • 51 Schleußner E. The prevention, diagnosis and treatment of premature labor. Dtsch Arztebl Int 2013; 110 (13) 227-235 , quiz 236
  • 52 Maconochie N, Doyle P, Prior S, Simmons R. Risk factors for first trimester miscarriage--results from a UK-population-based case-control study. BJOG 2007; 114 (02) 170-186
  • 53 Rondó PH, Ferreira RF, Nogueira F, Ribeiro MC, Lobert H, Artes R. Maternal psychological stress and distress as predictors of low birth weight, prematurity and intrauterine growth retardation. Eur J Clin Nutr 2003; 57 (02) 266-272
  • 54 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 (09) 1464-1473
  • 55 Berga SL, Marcus MD, Loucks TL, Hlastala S, Ringham R, Krohn MA. Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavior therapy. Fertil Steril 2003; 80 (04) 976-981
  • 56 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 (07) 2084-91.e1
  • 57 Bagnasco M, Dube MG, Kalra PS, Kalra SP. Evidence for the existence of distinct central appetite, energy expenditure, and ghrelin stimulation pathways as revealed by hypothalamic site-specific leptin gene therapy. Endocrinology 2002; 143 (11) 4409-4421
  • 58 Warren MP, Voussoughian F, Geer EB, Hyle EP, Adberg CL, Ramos RH. Functional hypothalamic amenorrhea: hypoleptinemia and disordered eating. J Clin Endocrinol Metab 1999; 84 (03) 873-877
  • 59 Welt CK, Chan JL, Bullen J. , et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004; 351 (10) 987-997
  • 60 Schenker JG, Yarkoni S, Granat M. Multiple pregnancies following induction of ovulation. Fertil Steril 1981; 35 (02) 105-123
  • 61 Hurley DM, Brian RJ, Burger HG. Ovulation induction with subcutaneous pulsatile gonadotropin-releasing hormone: singleton pregnancies in patients with previous multiple pregnancies after gonadotropin therapy. Fertil Steril 1983; 40 (05) 575-579
  • 62 Jayasena CN, Nijher GM, Chaudhri OB. , et al. Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis. J Clin Endocrinol Metab 2009; 94 (11) 4315-4323
  • 63 Ruman J, Luna M, Messenger C, Copperman A. Women with hypothalamic amenorrhea undergoing in vitro fertilization have a favorable prognosis despite higher stimulation requirements. Fertil Steril 2008; 90: S236-S237