Where Have the Periods Gone? The Evaluation and Management of Functional Hypothalamic Amenorrhea
PDF

Review

Where Have the Periods Gone? The Evaluation and Management of Functional Hypothalamic Amenorrhea

J Clin Res Pediatr Endocrinol 2020;12(1):18-27 DOI: 10.4274/jcrpe.galenos.2019.2019.S0178
, , ,
PDF
Permissions

Abstract

Functional hypothalamic amenorrhea (FHA) is a common cause of amenorrhea in adolescent girls. It is often seen in the setting of stress, weight loss, or excessive exercise. FHA is a diagnosis of exclusion. Patients with primary or secondary amenorrhea should be evaluated for other causes of amenorrhea before a diagnosis of FHA can be made. The evaluation typically consists of a thorough history and physical examination as well as endocrinological and radiological investigations. FHA, if prolonged, can have significant impacts on metabolic, bone, cardiovascular, mental, and reproductive health. Management often involves a multidisciplinary approach, with a focus on lifestyle modification. Depending on the severity, pharmacologic therapy may also be considered. The aim of this paper is to present a review on the pathophysiology, clinical findings, diagnosis, and management approaches of FHA in adolescent girls.

Keywords: Adolescent, diagnosis, functional, hypothalamic amenorrhea, treatment

Read the full text

2 sections · 2 figures · PDF

Create your free account to read the full text.

  • Full text with figures and tables
  • PDF and supplementary files
  • Access on every Galenos journal
Get free access

Already have an account?

Sign in
or
Continue with Google

One Galenos account works on every Galenos journal site.

References

1

Gordon CM. Clinical practice. Functional hypothalamic amenorrhea. N Engl J Med 2010;363:365-371.

2

Meczekalski B, Podfigurna-Stopa A, Warenik-Szymankiewicz A, Genazzani AR. Functional hypothalamic amenorrhea: Current view on neuroendocrine aberrations. Gynecol Endocrinol 2008;24:4-11.

3

Klein DA, Poth MA. Amenorrhea: An approach to diagnosis and management. Am Fam Physician 2013;87:781-788.

4

Emans SJ, Laufer MR. Pediatric & Adolescent Gynecology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2012.

5

Rosenfield RL. Clinical review: Adolescent anovulation: Maturational mechanisms and implications. J Clin Endocrinol Metab 2013;98:3572-3583. Epub 2013 Aug 2

6

Speroff L, Fritz M. Clinical Gynecologic Endocrinology and Infertility. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005;401-464.

7

Golden NH, Carlson JL. The pathophysiology of amenorrhea in the adolescent. Ann N Y Acad Sci 2008;1135:163-178.

8

Couzinet B, Young J, Brailly S, Le Bouc Y, Chanson P, Schaison G. Functional hypothalamic amenorrhoea: a partial and reversible gonadotrophin deficiency of nutritional origin. Clin Endocrinol (Oxf) 1999;50:229-235.

9

Perkins RB, Hall JE, Martin KA. Neuroendocrine abnormalities in hypothalamic amenorrhea: spectrum, stability, and response to neurotransmitter modulation. J Clin Endocrinol Metab 1999;84:1905-1911.

10

Suh BY, Liu JH, Berga SL, Quiqley ME, Laughlin GA, Yen SS. Hypercortisolism in patients with functional hypothalamic-amenorrhea. J Clin Endocrinol Metab 1988;66:733-739.

11

Berga SL, Mortola JF, Girton L, Suh B, Laughlin G, Pham P, Yen SS. Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 1989;68:301-308.

12

Bomba M, Gambera A, Bonini L, Peroni M, Neri F, Scagliola P, Nacinovich R. Endocrine profiles and neuropsychologic correlates of functional hypothalamic amenorrhea in adolescents. Fertil Steril 2007;87:876-885. Epub 2007 Jan 31

13

Meczekalski B, Tonetti A, Monteleone P, Bernardi F, Luisi S, Stomati M, Luisi M, Petraglia F, Genazzani AR. Hypothalamic amenorrhea with normal body weight: ACTH, allopregnanolone and cortisol responses to corticotropin-releasing hormone test. Eur J Endocrinol 2000;142:280-285.

14

Andrico S, Gambera A, Specchia C, Pellegrini C, Falsetti L, Sartori E. Leptin in functional hypothalamic amenorrhoea. Hum Reprod 2002;17:2043-2048.

15

Grinspoon S, Miller K, Coyle C, Krempin J, Armstrong C, Pitts S, Herzog D, Klibanski A. Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea. J Clin Endocrinol Metab 1999;84:2049-2055.

16

Devine B. Gentamicin therapy. Drug Intell Clin Pharm 1974;8:650-655.

17

No authors listed. 1983 metropolitan height and weight tables. Stat Bull Metrop Life Found 1983;64:3-9.

18

Selzer R, Caust J, Hibbert M, Bowes G, Patton G. The association between secondary amenorrhea and common eating disordered weight control practices in an adolescent population. J Adolesc Health 1996;19:56-61.

19

Scheid JL, Williams NI, West SL, VanHeest JL, De Souza MJ. Elevated PYY is associated with energy deficiency and indices of subclinical disordered eating in exercising women with hypothalamic amenorrhea. Appetite 2009;52:184-192. Epub 2008 Sep 25

20

Laughlin GA, Dominguez CE, Yen SS. Nutritional and endocrine-metabolic aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 1998;83:25-32.

21

Marcus MD, Loucks TL, Berga SL. Psychological correlates of functional hypothalamic amenorrhea. Fertil Steril 2001;76:310-316.

22

Schneider LF, Warren MP. Functional hypothalamic amenorrhea is associated with elevated ghrelin and disordered eating. Fertil Steril 2006;86:1744-1749. Epub 2006 Oct 30

23

Ackerman KE, Misra M. Bone health and the Female Athlete Triad in adolescent athletes. Phys Sportsmed 2011;39:131-141.

24

Warren MP, Chua AT. Exercise-induced amenorrhea and bone health in the adolescent athlete. Ann N Y Acad Sci 2008;1135:244-252.

25

Dusek T. Influence of high intensity training on menstrual cycle disorders in athletes. Croat Med J 2001;42:79-82.

26

Yeager KK, Agostini R, Nattiv A, Drinkwater B. The female athlete triad: Disordered eating, amenorrhea, osteoporosis. Med Sci Sports Exerc 1993;25:775-777.

27

Committee on Adolescent Health Care. Committee Opinion No.702: Female Athlete Triad. Obstet Gynecol 2017;129:160-167.

28

Brown E, Bain J, Lerner P, Shaul D. Psychological, hormonal, and weight disturbances in functional amenorrhea. Can J Psychiatry 1983;28:624-628.

29

Kondoh Y, Uemura T, Murase M, Yokoi N, Ishikawa M, Hirahara F. A longitudinal study of disturbances of the hypothalamic-pituitary-adrenal axis in women with progestin-negative functional hypothalamic amenorrhea. Fertil Steril 2001;76:748-752.

30

Facchinetti F, Fava M, Fioroni L, Genazzani AD, Genazzani AR. Stressful life events and affective disorders inhibit pulsatile LH secretion in hypothalamic amenorrhea. Psychoneuroendocrinology 1993;18:397-404.

31

Gallinelli A, Matteo ML, Volpe A, Facchinetti F. Autonomic and neuroendocrine responses to stress in patients with functional hypothalamic secondary amenorrhea. Fertil Steril 2000;73:812-816.

32

Caronia LM, Martin C, Welt CK, Sykiotis GP, Quinton R, Thambundit A, Avbelj M, Dhruvakumar S, Plummer L, Hughes VA, Seminara SB, Boepple PA, Sidis Y, Crowley WF Jr, Martin KA, Hall JE, Pitteloud N. A genetic basis for functional hypothalamic amenorrhea. N Engl J Med 2011;364:215-225.

33

Nappi RE, Petraglia F, Genazzani AD, D’Ambrogio G, Zara C, Genazzani AR. Hypothalamic amenorrhea: evidence for a central derangement of hypothalamic-pituitary-adrenal cortex axis activity. Fertil Steril 1993;59:571-576.

34

Dominguez CE, Laughlin GA, Nelson JC, Yen SS. Altered binding of serum thyroid hormone to thyroxine-binding globulin in women with functional hypothalamic amenorrhea. Fertil Steril 1997;68:992-996.

35

Miller KK, Parulekar MS, Schoenfeld E, Anderson E, Hubbard J, Klibanski A, Garinspoon SK. Decreased leptin levels in normal weight women with hypothalamic amenorrhea: The effects of body composition and nutritional intake. J Clin Endocrinol Metab 1998;83:2309-2312.

36

Warren MP, Voussoughian F, Geer EB, Hyle EP, Adberg CL, Ramos RH. Functional hypothalamic amenorrhea: Hypoleptinemia and disordered eating. J Clin Endocrinol Metab 1999;84:873-877.

37

Chumlea WC, Schubert CM, Roche AF, Kulin HE, Lee PA, Himes JH, Sun SS. Age at menarche and racial comparisons in US girls. Pediatrics 2003;111:110-113.

38

No authors listed. World Health Organization multicenter study on menstrual and ovulatory patterns in adolescent girls. II. Longitudinal study of menstrual patterns in the early postmenarcheal period, duration of bleeding episodes and menstrual cycles. World Health Organization Task Force on Adolescent Reproductive Health. J Adolesc Health Care 1986;7:236-244.

39

Goldering JM, Rosen DS. Getting into adolescent heads: an essential update. Contemp Pediatr 2004;21:64.

40

Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969;44:291-303.

41

Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, Murad MH, Santoro NF, Warren MP. Functional hypothalamic amenorrhea: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2017;102:1413-1439.

42

La Marca A, Pati M, Orvieto R, Stabile G, Carducci Artenisio A, Volpe A. Serum anti-müllerian hormone levels in women with secondary amenorrhea. Fertil Steril 2006;85:1547-1549. Epub 2006 Apr 17

43

Nakamura S, Douchi T, Oki T, Ijuin H, Yamamoto S, Nagata Y. Relationship between sonographic endometrial thickness and progestin-induced withdrawal bleeding. Obstet Gynecol 1996;87:722-725.

44

Rarick LD, Shangold MM, Ahmed SW. Cervical mucus and serum estradiol as predictors of response to progestin challenge. Fertil Steril 1990;54:353-355.

45

Olpin JD, Heilbrun M. Imaging of müllerian duct anomalies. Clin Obstet Gynecol 2009;52:40-56.

46

Berger A, Batzer F, Lev-Toaff A, Berry-Roberts C. Diagnostic imaging modalities for müllerian anomalies: The case for a new gold standard. J Minim Invasive Gynecol 2014;21:335-345. Epub 2013 Nov 15

47

Bermejo C, Martínez Ten P, Cantarero R, Diaz D, Pérez Pedregosa J, Barrón E, Labrador E, Ruiz López L. Three-dimensional ultrasound in the diagnosis of Müllerian duct anomalies and concordance with magnetic resonance imaging. Ultrasound Obstet Gynecol 2010;35:593-601.

48

Acharya SV, Gopal RA, Bandgar TR, Joshi SR, Menon PS, Shah NS. Clinical profile and long term follow up of children and adolescents with prolactinomas. Pituitary 2008;12:186-189.

49

Miller KK, Klibanski A. Clinical review 106: Amenorrheic bone loss. J Clin Endocrinol Metab 1999;84:1775-1783.

50

Lawson EA, Donoho D, Miller KK, Misra M, Meenaghan E, Lydecker J, Wexler T, Herzog DB, Klibanski A. Hypercortisolemia Is associated with severity of bone loss and depression in hypothalamic amenorrhea and anorexia nervosa. J Clin Endocrinol Metab 2009;94:4710-4716. Epub 2009 Oct 16

51

Warren MP, Brooks-Gunn J, Fox RP, Holderness CC, Hyle EP, Hamilton WG. Osteopenia in exercise-associated amenorrhea using ballet dancers as a model: A longitudinal study. J Clin Endocrinol Metab 2002;87:3162-3168.

52

Lloyd T, Myers C, Buchanan JR, Demers LM. Collegiate women athletes with irregular menses during adolescence have decreased bone density. Obstet Gynecol 1988;72:639-642.

53

Ward LM, Konji VN, Ma J. The management of osteoporosis in children. Osteoporos Int 2016;27:2147-2179. Epub 2016 Apr 28

54

Bishop N, Arundel P, Clark E, Dimitri P, Farr J, Jones G, Makitie O, Munns CF, Shaw N; International Society of Clinical Densitometry. Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2013 Pediatric Official Positions. J Clin Densitom 2014;17:275-280. Epub 2014 Mar 14

55

No authors listed. ACOG Committee Opinion No. 651: Menstruation in Girls and Adolescents: Using the Menstrual Cycle as a Vital Sign. Obstet Gynecol 2015;126:143-146.

56

Popat VB, Prodanov T, Calis KA, Nelson LM. The menstrual cycle: a biological marker of general health in adolescents. Ann N Y Acad Sci 2008;1135:43-51.

57

Kopp-Woodroffe SA, Manore MM, Dueck CA, Skinner JS, Matt KS. Energy and nutrient status of amenorrheic athletes participating in a diet and exercise training intervention program. Int J Sport Nutr 1999;9:70-88.

58

Lindberg JS, Powell MR, Hunt MM, Ducey DE, Wade CE. Increased vertebral bone mineral in response to reduced exercise in amenorrheic runners. West J Med 1987;146:39-42.

59

Javed A, Tebben PJ, Fischer PR, Lteif AN. Female Athlete Triad and its components: Toward improved screening and management. Mayo Clin Proc 2013;88:996-1009.

60

Chen EC, Brzyski RG. Exercise and reproductive dysfunction. Fertil Steril 1999;71:1-6.

61

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;80:976-981.

62

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;99:2084-2091. Epub 2013 Mar 16

63

Tschugguel W, Berga SL. Treatment of functional hypothalamic amenorrhea with hypnotherapy. Fertil Steril 2003;80:982-985.

64

Cann CE, Genant HK, Ettinger B, Gordan GS. Spinal mineral loss in oophorectomized women: determination by quantitative computed tomography. JAMA 1980;244:2056-2059.

65

Johansson BW, Kaij L, Kullander S, Lennér HC, Svanberg L, Åstedt B. On some late effects of bilateral oophorectomy in the age range 15-30 years. Acta Obstet Gynecol Scand 1975;54:449-461.

66

Liu SL, Lebrun CM. Effect of oral contraceptives and hormone replacement therapy on bone mineral density in premenopausal and perimenopausal women: a systematic review. Br J Sports Med 2006;40:11-24.

67

Hergenroeder AC, Smith EO, Shypailo R, Jones LA, Klish WJ, Ellis K. Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone, or placebo over 12 months. Am J Obstet Gynecol 1997;176:1017- 1025.

68

Castelo-Branco C, Vicente JJ, Pons F, Martínez de Osaba MJ, Casals E, Vanrell JA. Bone mineral density in young, hypothalamic oligoamenorrheic women treated with oral contraceptives. J Reprod Med 2001;46:875-879.

69

De Crée C, Lewin R, Ostyn M. Suitability of cyproterone acetate in the treatment of osteoporosis associated with athletic amenorrhea. Int J Sports Med 1988;9:187-192

70

Gulekli B, Davies MC, Jacobs HS. Effect of treatment on established osteoporosis in young women with amenorrhoea. Clin Endocrinol (Oxf) 1994;41:275-281.

71

Haenggi W, Casez JP, Birkhaeuser MH, Lippuner K, Jaeger P. Bone mineral density in young women with long-standing amenorrhea: limited effect of hormone replacement therapy with ethinylestradiol and desogestrel. Osteoporos Int 1994;4:99-103.

72

Cumming DC. Exercise-associated amenorrhea, low bone density, and estrogen replacement therapy. Arch Intern Med 1996;156:2193- 2195.

73

Rickenlund A, Carlström K, Ekblom B, Brismar TB, Von Schoultz B, Hirschberg AL. Effects of oral contraceptives on body composition and physical performance in female athletes. J Clin Endocrinol Metab 2004;89:4364-4370. Epub 2004 Aug 24

74

Gibson JH, Mitchell A, Reeve J, Harries MG. Treatment of reduced bone mineral density in athletic amenorrhea: a pilot study. Osteoporos Int 1999;10:284-289.

75

Gremion G, Rizzoli R, Slosman D, Theintz G, Bonjour JP. Oligo-amenorrheic long-distance runners may lose more bone in spine than in femur. Med Sci Sports Exerc 2001;33:15-21.

76

Zanker CL, Cooke CB, Truscott JG, Oldroyd B, Jacobs HS. Annual changes of bone density over 12 years in an amenorrheic athlete. Med Sci Sports Exerc 2004;36:137-142.

77

Misra M, Katzman D, Miller KK, Mendes N, Snelgrove D, Russell M, Goldstein MA, Ebrahimi S, Clauss L, Weigel T, Mickley D, Schoenfeld DA, Herzog DB, Klibanski A. Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa. J Bone Miner Res 2011;26:2430-2438.

78

Harel Z, Riggs S. Transdermal versus oral administration of estrogen in the management of lumbar spine osteopenia in an adolescent with anorexia nervosa. J Adolesc Health 1997;10:179-182.

79

Ackerman KE, Singhal V, Baskaran C, Slattery M, Campoverde Reyes KJ, Toth A, Eddy KT, Bouxsein ML, Lee H, Klibanski A, Misra M. Oestrogen replacement improves bone mineral density in oligo-amenorrhoeic athletes: a randomised clinical trial. Br J Sports Med 2019;53:229-236. Epub 2018 Oct 9

80

Hergenroeder AC. Bone mineralization, hypothalamic amenorrhea, and sex steroid therapy in female adolescents and young adults. J Pediatr 1995;126:683-689.

81

Vescovi JD, Jamal SA, De Souza MJ. Strategies to reverse bone loss in women with functional hypothalamic amenorrhea: a systematic review of the literature. Osteoporos Int 2008;19:465-478. Epub 2008 Jan 8

82

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;77:125-129.

83

Christou F, Pitteloud N, Gomez F. The induction of ovulation by pulsatile administration of GnRH: an appropriate method in hypothalamic amenorrhea. Gynecol Endocrinol 2017;33:598-601. Epub 2017 Mar 6

84

Dumont A, Dewailly D, Plouvier P, Catteau-Jonard S, Robin G. Comparison between pulsatile GnRH therapy and gonadotropins for ovulation induction in women with both functional hypothalamic amenorrhea and polycystic ovarian morphology. Gynecol Endocrinol 2016;32:999-1004. Epub 2016 Jun 3

85

Gompel A, Mauvais-Jarvis P. Induction of ovulation with pulsatile GnRH in hypothalamic amenorrhoea. Hum Reprod 1988;3:473-477.

86

Wildt L, Leyendecker G, Sir-Petermann T, Waibel-Treber S. Treatment with naltrexone in hypothalamic ovarian failure: induction of ovulation and pregnancy. Hum Reprod 1993;8:350-358.

87

Remorgida V, Venturini PL, Anserini P, Salerno E, De Cecco L. Naltrexone in functional hypothalamic amenorrhea and in the normal luteal phase. Obstet Gynecol 1990;76:1115-1120.

88

Wildt L, Leyendecker G. Induction of ovulation by the chronic administration of naltrexone in hypothalamic amenorrhea. J Clin Endocrinol Metab 1987;64:1334-1335.

89

Leyendecker G, Waibel-Treber S, Wildt L. Pulsatile administration of gonadotrophin releasing hormone and oral administration of naltrexone in hypothalamic amenorrhoea. Hum Reprod 1993;8(Suppl 2):184-188.

90

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;96:3638-3648. Epub 2011 Sep 28

91

Bairey Merz CN, Johnson BD, Sharaf BL, Bittner V, Berga SL, Braunstein GD, Hodgson TK, Matthews KA, Pepine CJ, Reis SE, Reichek N, Rogers WJ, Pohost GM, Kelsey SF, Sopko G; 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;41:413-419.

92

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;90:1354-1359.

93

Rickenlund A, Eriksson MJ, Schenck-Gustafsson K, Hirschberg AL. Oral contraceptives improve endothelial function in amenorrheic athletes. J Clin Endocrinol Metab 2005;90:3162-3167.

94

Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004;351:987-997.

95

Chou SH, Chamberland JP, Liu X, Matarese G, Gao C, Stefanakis R, Brinkoetter MT, Gong H, Arampatzi K, Mantzoros CS. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A 2011;108:6585-6590. Epub 2011 Apr 4

96

Jayasena CN, Nijher GM, Chaudhri OB, Murphy KG, Ranger A, Lim A, Patel D, Mehta A, Todd C, Ramachandran R, Salem V, Stamp GW, Donaldson M, Ghatei MA, Bloom SR, Dhillo WS. Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis. J Clin Endocrinol Metab 2009;94:4315-4323. Epub 2009 Oct 9