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Clinical manifestations and evaluation of spontaneous primary ovarian insufficiency (premature ovarian failure)

Robert L Barbieri, MD
Section Editor
William F Crowley, Jr, MD
Deputy Editor
Kathryn A Martin, MD


Primary ovarian insufficiency (POI) is defined as the development of hypergonadotropic hypogonadism before the age of 40 years [1]. The presenting symptoms are similar to those of menopause. The condition was previously referred to as "premature menopause" and "premature ovarian failure." The age-specific incidence of spontaneous POI is approximately 1 in 250 by age 35 years and 1 in 100 by age 40 years [2]. In its fully developed form, it is associated with oligomenorrhea or amenorrhea, symptoms of estrogen deficiency, and gonadotropin levels in the menopausal range before age 40 years.

The clinical manifestations and evaluation of women with spontaneous POI (focusing on women with a normal karyotype) will be reviewed here. The pathogenesis, causes, and management of spontaneous POI and an overview of autoimmune ovarian insufficiency are discussed separately. Turner syndrome is also reviewed separately. (See "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Management of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure)" and "Clinical manifestations and diagnosis of Turner syndrome".)


Natural menopause is defined as the permanent cessation of menstrual periods, determined retrospectively after a woman has experienced 12 months of amenorrhea without any other obvious pathological or physiological cause. It occurs at a median age of 51.4 years in normal women. Menopause is a reflection of complete, or near complete, ovarian follicular depletion, with resulting hypoestrogenemia and high follicle-stimulating hormone (FSH) concentrations. Menopause before age 40 years is considered to be abnormal and is referred to as primary ovarian insufficiency (POI). (See "Clinical manifestations and diagnosis of menopause".)

The terms "premature menopause" and "premature ovarian failure" were used in the past for POI, but both are inaccurate because many patients with spontaneous POI intermittently produce estrogen and ovulate, a few experience intermittent return of regular menses, and in 5 to 10 percent of cases, women conceive and have a normal pregnancy [3]. This can occur many years after the diagnosis [4].

POI is a spectrum disorder and is a continuum of impaired ovarian function. We define occult POI as impaired ovarian responsiveness to exogenous or endogenous gonadotropin stimulation despite the presence of regular and predictable ovulatory menstrual cycles. Overt POI refers to the presence of irregular menses, elevated serum gonadotropins, and reduced fertility.

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Literature review current through: Nov 2017. | This topic last updated: Oct 02, 2017.
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  1. Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med 2009; 360:606.
  2. Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol 1986; 67:604.
  3. van Kasteren YM, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update 1999; 5:483.
  4. Cowchock FS, McCabe JL, Montgomery BB. Pregnancy after corticosteroid administration in premature ovarian failure (polyglandular endocrinopathy syndrome). Am J Obstet Gynecol 1988; 158:118.
  5. Nelson LM, Anasti JN, Kimzey LM, et al. Development of luteinized graafian follicles in patients with karyotypically normal spontaneous premature ovarian failure. J Clin Endocrinol Metab 1994; 79:1470.
  6. Taylor AE, Adams JM, Mulder JE, et al. A randomized, controlled trial of estradiol replacement therapy in women with hypergonadotropic amenorrhea. J Clin Endocrinol Metab 1996; 81:3615.
  7. Hubayter ZR, Popat V, Vanderhoof VH, et al. A prospective evaluation of antral follicle function in women with 46,XX spontaneous primary ovarian insufficiency. Fertil Steril 2010; 94:1769.
  8. Rebar RW, Connolly HV. Clinical features of young women with hypergonadotropic amenorrhea. Fertil Steril 1990; 53:804.
  9. Alzubaidi NH, Chapin HL, Vanderhoof VH, et al. Meeting the needs of young women with secondary amenorrhea and spontaneous premature ovarian failure. Obstet Gynecol 2002; 99:720.
  10. Benetti-Pinto CL, de Almeida DM, Makuch MY. Quality of life in women with premature ovarian failure. Gynecol Endocrinol 2011; 27:645.
  11. Biscotti CV, Hart WR, Lucas JG. Cystic ovarian enlargement resulting from autoimmune oophoritis. Obstet Gynecol 1989; 74:492.
  12. Larrea F, Lisker R, Bañuelos R, et al. Hypergonadotrophic hypogonadism in an XX female subject due to 17,20 steroid desmolase deficiency. Acta Endocrinol (Copenh) 1983; 103:400.
  13. Crisponi L, Deiana M, Loi A, et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 2001; 27:159.
  14. Bannatyne P, Russell P, Shearman RP. Autoimmune oophoritis: a clinicopathologic assessment of 12 cases. Int J Gynecol Pathol 1990; 9:191.
  15. Burrell LM, Murdoch A, Angus B, White MC. Autoimmune ovarian failure with elevated serum levels of luteinizing hormone and enlarged ovaries. Case report. Br J Obstet Gynaecol 1990; 97:362.
  16. Lonsdale RN, Roberts PF, Trowell JE. Autoimmune oophoritis associated with polycystic ovaries. Histopathology 1991; 19:77.
  17. Welt CK, Hall JE, Adams JM, Taylor AE. Relationship of estradiol and inhibin to the follicle-stimulating hormone variability in hypergonadotropic hypogonadism or premature ovarian failure. J Clin Endocrinol Metab 2005; 90:826.
  18. Welt CK, Falorni A, Taylor AE, et al. Selective theca cell dysfunction in autoimmune oophoritis results in multifollicular development, decreased estradiol, and elevated inhibin B levels. J Clin Endocrinol Metab 2005; 90:3069.
  19. Mishell DRJ, Stenchever MA, Droegemueller W, Herbst AL. Primary and Secondary Amenorrhea. In: Comprehensive Gynecology, 3rd ed, Mosby, St. Louis 1997. p.1043.
  20. Bakalov VK, Vanderhoof VH, Bondy CA, Nelson LM. Adrenal antibodies detect asymptomatic auto-immune adrenal insufficiency in young women with spontaneous premature ovarian failure. Hum Reprod 2002; 17:2096.
  21. Bakalov VK, Gutin L, Cheng CM, et al. Autoimmune disorders in women with turner syndrome and women with karyotypically normal primary ovarian insufficiency. J Autoimmun 2012; 38:315.
  22. van Kasteren YM, Hundscheid RD, Smits AP, et al. Familial idiopathic premature ovarian failure: an overrated and underestimated genetic disease? Hum Reprod 1999; 14:2455.
  23. Marozzi A, Vegetti W, Manfredini E, et al. Association between idiopathic premature ovarian failure and fragile X premutation. Hum Reprod 2000; 15:197.
  24. Hagerman RJ, Leavitt BR, Farzin F, et al. Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 2004; 74:1051.
  25. Nishi Y, Hamamoto K, Kajiyama M, Kawamura I. The Perrault syndrome: clinical report and review. Am J Med Genet 1988; 31:623.
  26. Meyers CM, Boughman JA, Rivas M, et al. Gonadal (ovarian) dysgenesis in 46,XX individuals: frequency of the autosomal recessive form. Am J Med Genet 1996; 63:518.
  27. Bakalov VK, Anasti JN, Calis KA, et al. Autoimmune oophoritis as a mechanism of follicular dysfunction in women with 46,XX spontaneous premature ovarian failure. Fertil Steril 2005; 84:958.
  28. Betterle C, Volpato M, Rees Smith B, et al. I. Adrenal cortex and steroid 21-hydroxylase autoantibodies in adult patients with organ-specific autoimmune diseases: markers of low progression to clinical Addison's disease. J Clin Endocrinol Metab 1997; 82:932.
  29. Kim TJ, Anasti JN, Flack MR, et al. Routine endocrine screening for patients with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol 1997; 89:777.
  30. Khastgir G, Abdalla H, Studd JW. The case against ovarian biopsy for the diagnosis of premature menopause. Br J Obstet Gynaecol 1994; 101:96.
  31. Krauss CM, Turksoy RN, Atkins L, et al. Familial premature ovarian failure due to an interstitial deletion of the long arm of the X chromosome. N Engl J Med 1987; 317:125.
  32. Gemmill RM, Pearce-Birge L, Bixenman H, et al. Y chromosome--specific DNA sequences in Turner-syndrome mosaicism. Am J Hum Genet 1987; 41:157.
  33. Tho SP, McDonough PG. Use of Y DNA probes to identify children at risk for dysgenetic gonadal tumors. Clin Obstet Gynecol 1987; 30:671.
  34. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG committee opinion. No. 338: Screening for fragile X syndrome. Obstet Gynecol 2006; 107:1483.
  35. Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med 2005; 7:584.
  36. McConkie-Rosell A, Finucane B, Cronister A, et al. Genetic counseling for fragile x syndrome: updated recommendations of the national society of genetic counselors. J Genet Couns 2005; 14:249.
  37. Wittenberger MD, Hagerman RJ, Sherman SL, et al. The FMR1 premutation and reproduction. Fertil Steril 2007; 87:456.
  38. Sherman SL. Premature ovarian failure in the fragile X syndrome. Am J Med Genet 2000; 97:189.
  39. Conway GS, Hettiarachchi S, Murray A, Jacobs PA. Fragile X premutations in familial premature ovarian failure. Lancet 1995; 346:309.
  40. Welt CK, Smith PC, Taylor AE. Evidence of early ovarian aging in fragile X premutation carriers. J Clin Endocrinol Metab 2004; 89:4569.
  41. De Caro JJ, Dominguez C, Sherman SL. Reproductive health of adolescent girls who carry the FMR1 premutation: expected phenotype based on current knowledge of fragile x-associated primary ovarian insufficiency. Ann N Y Acad Sci 2008; 1135:99.
  42. Pouillès JM, Trémollières F, Bonneu M, Ribot C. Influence of early age at menopause on vertebral bone mass. J Bone Miner Res 1994; 9:311.
  43. Leite-Silva P, Bedone A, Pinto-Neto AM, et al. Factors associated with bone density in young women with karyotypically normal spontaneous premature ovarian failure. Arch Gynecol Obstet 2009; 280:177.
  44. De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet 2010; 376:911.
  45. Gallagher JC. Effect of early menopause on bone mineral density and fractures. Menopause 2007; 14:567.