Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)

Corrine K Welt, MD
Section Editors
Robert L Barbieri, MD
William F Crowley, Jr, MD
Deputy Editor
Kathryn A Martin, MD


Primary hypogonadism in women is defined as ovarian failure accompanied by high serum follicle-stimulating hormone (FSH) concentrations. Premature ovarian failure (POF), now referred to as primary ovarian insufficiency (POI), is defined as primary hypogonadism in a woman under the age of 40 years.

POI is characterized by loss of oocytes, lack of folliculogenesis and ovarian estrogen production, and infertility. Transient or partial resumption of ovarian activity has been documented in over 50 percent of women based upon hormonal measurements, pelvic ultrasonography, or conception [1,2].

There are several known causes of ovarian failure, including chromosomal defects like Turner syndrome and fragile X syndrome premutation carriers, exposure to radiation and certain drugs, and autoimmune disease. The list of mutations that can cause ovarian failure has increased rapidly, as discoveries from the human genome project and next generation sequencing increase our understanding of the factors involved in ovarian development. Unfortunately, the etiology remains unknown in approximately 75 to 90 percent of cases [3].

The pathogenesis and causes of POI will be reviewed here (table 1); its evaluation and treatment are discussed separately. (See "Clinical manifestations and evaluation of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Management of spontaneous primary ovarian insufficiency (premature ovarian failure)".)


Normal ovarian development is dependent on a carefully timed cascade of events; as a result, there are multiple potential etiologies for ovarian dysfunction. Pathophysiologically, these defects can be divided into two major categories:

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:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jul 01, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. 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.
  2. 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.
  3. Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med 2009; 360:606.
  4. Jacobs PA. The incidence and etiology of sex chromosome abnormalities in man. Birth Defects Orig Artic Ser 1979; 15:3.
  5. Hook EB, Warburton D. The distribution of chromosomal genotypes associated with Turner's syndrome: livebirth prevalence rates and evidence for diminished fetal mortality and severity in genotypes associated with structural X abnormalities or mosaicism. Hum Genet 1983; 64:24.
  6. Albright F, Smith PH, Fraser R. A syndrome characterized by primary ovarian insufficiency and decreased stature: Report of 11 cases with a digression on hormonal control of axillary and pubic hair. Am J Med Sci 1942; 204:625.
  7. Singh RP, Carr DH. The anatomy and histology of XO human embryos and fetuses. Anat Rec 1966; 155:369.
  8. Schlessinger D, Herrera L, Crisponi L, et al. Genes and translocations involved in POF. Am J Med Genet 2002; 111:328.
  9. Bione S, Sala C, Manzini C, et al. A human homologue of the Drosophila melanogaster diaphanous gene is disrupted in a patient with premature ovarian failure: evidence for conserved function in oogenesis and implications for human sterility. Am J Hum Genet 1998; 62:533.
  10. Fryns JP. The female and the fragile X. A study of 144 obligate female carriers. Am J Med Genet 1986; 23:157.
  11. Allingham-Hawkins DJ, Babul-Hirji R, Chitayat D, et al. Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in Fragile X study--preliminary data. Am J Med Genet 1999; 83:322.
  12. de Vries BB, Halley DJ, Oostra BA, Niermeijer MF. The fragile X syndrome. J Med Genet 1998; 35:579.
  13. Bodega B, Bione S, Dalprà L, et al. Influence of intermediate and uninterrupted FMR1 CGG expansions in premature ovarian failure manifestation. Hum Reprod 2006; 21:952.
  14. Bretherick KL, Fluker MR, Robinson WP. FMR1 repeat sizes in the gray zone and high end of the normal range are associated with premature ovarian failure. Hum Genet 2005; 117:376.
  15. 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.
  16. Greco CM, Hagerman RJ, Tassone F, et al. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 2002; 125:1760.
  17. Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 2003; 72:869.
  18. Sullivan AK, Marcus M, Epstein MP, et al. Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod 2005; 20:402.
  19. Kenneson A, Zhang F, Hagedorn CH, Warren ST. Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers. Hum Mol Genet 2001; 10:1449.
  20. Tassone F, Hagerman RJ, Taylor AK, et al. Clinical involvement and protein expression in individuals with the FMR1 premutation. Am J Med Genet 2000; 91:144.
  21. Tassone F, Hagerman RJ, Taylor AK, et al. Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome. Am J Hum Genet 2000; 66:6.
  22. Mailick MR, Hong J, Greenberg J, et al. Curvilinear association of CGG repeats and age at menopause in women with FMR1 premutation expansions. Am J Med Genet B Neuropsychiatr Genet 2014; 165B:705.
  23. Welt CK, Smith PC, Taylor AE. Evidence of early ovarian aging in fragile X premutation carriers. J Clin Endocrinol Metab 2004; 89:4569.
  24. Gersak K, Meden-Vrtovec H, Peterlin B. Fragile X premutation in women with sporadic premature ovarian failure in Slovenia. Hum Reprod 2003; 18:1637.
  25. Marozzi A, Vegetti W, Manfredini E, et al. Association between idiopathic premature ovarian failure and fragile X premutation. Hum Reprod 2000; 15:197.
  26. Uzielli ML, Guarducci S, Lapi E, et al. Premature ovarian failure (POF) and fragile X premutation females: from POF to to fragile X carrier identification, from fragile X carrier diagnosis to POF association data. Am J Med Genet 1999; 84:300.
  27. Sherman SL. Premature ovarian failure in the fragile X syndrome. Am J Med Genet 2000; 97:189.
  28. Rousseau F, Rouillard P, Morel ML, et al. Prevalence of carriers of premutation-size alleles of the FMRI gene--and implications for the population genetics of the fragile X syndrome. Am J Hum Genet 1995; 57:1006.
  29. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG committee opinion. No. 338: Screening for fragile X syndrome. Obstet Gynecol 2006; 107:1483.
  30. Chen YT, Mattison DR, Feigenbaum L, et al. Reduction in oocyte number following prenatal exposure to a diet high in galactose. Science 1981; 214:1145.
  31. Kaufman FR, Kogut MD, Donnell GN, et al. Hypergonadotropic hypogonadism in female patients with galactosemia. N Engl J Med 1981; 304:994.
  32. Cramer DW, Harlow BL, Barbieri RL, Ng WG. Galactose-1-phosphate uridyl transferase activity associated with age at menopause and reproductive history. Fertil Steril 1989; 51:609.
  33. Knauff EA, Richardus R, Eijkemans MJ, et al. Heterozygosity for the classical galactosemia mutation does not affect ovarian reserve and menopausal age. Reprod Sci 2007; 14:780.
  34. Caburet S, Arboleda VA, Llano E, et al. Mutant cohesin in premature ovarian failure. N Engl J Med 2014; 370:943.
  35. Zhao H, Chen ZJ, Qin Y, et al. Transcription factor FIGLA is mutated in patients with premature ovarian failure. Am J Hum Genet 2008; 82:1342.
  36. Qin Y, Choi Y, Zhao H, et al. NOBOX homeobox mutation causes premature ovarian failure. Am J Hum Genet 2007; 81:576.
  37. AlAsiri S, Basit S, Wood-Trageser MA, et al. Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. J Clin Invest 2015; 125:258.
  38. Day FR, Ruth KS, Thompson DJ, et al. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat Genet 2015; 47:1294.
  39. Kasippillai T, MacArthur DG, Kirby A, et al. Mutations in eIF4ENIF1 are associated with primary ovarian insufficiency. J Clin Endocrinol Metab 2013; 98:E1534.
  40. Pfender S, Kuznetsov V, Pasternak M, et al. Live imaging RNAi screen reveals genes essential for meiosis in mammalian oocytes. Nature 2015; 524:239.
  41. Di Pasquale E, Beck-Peccoz P, Persani L. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am J Hum Genet 2004; 75:106.
  42. Di Pasquale E, Rossetti R, Marozzi A, et al. Identification of new variants of human BMP15 gene in a large cohort of women with premature ovarian failure. J Clin Endocrinol Metab 2006; 91:1976.
  43. 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.
  44. Raile K, Stobbe H, Tröbs RB, et al. A new heterozygous mutation of the FOXL2 gene is associated with a large ovarian cyst and ovarian dysfunction in an adolescent girl with blepharophimosis/ptosis/epicanthus inversus syndrome. Eur J Endocrinol 2005; 153:353.
  45. Settas N, Anapliotou M, Kanavakis E, et al. A novel FOXL2 gene mutation and BMP15 variants in a woman with primary ovarian insufficiency and blepharophimosis-ptosis-epicanthus inversus syndrome. Menopause 2015; 22:1264.
  46. Beysen D, De Paepe A, De Baere E. FOXL2 mutations and genomic rearrangements in BPES. Hum Mutat 2009; 30:158.
  47. Barlow C, Liyanage M, Moens PB, et al. Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I. Development 1998; 125:4007.
  48. Ellis NA, German J. Molecular genetics of Bloom's syndrome. Hum Mol Genet 1996; 5 Spec No:1457.
  49. Fogli A, Rodriguez D, Eymard-Pierre E, et al. Ovarian failure related to eukaryotic initiation factor 2B mutations. Am J Hum Genet 2003; 72:1544.
  50. Pagnamenta AT, Taanman JW, Wilson CJ, et al. Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma. Hum Reprod 2006; 21:2467.
  51. Li Y, Xiao B, Xiao L, et al. Myasthenia gravis accompanied by premature ovarian failure and aggravation by estrogen. Intern Med 2010; 49:611.
  52. Ryan MM, Jones HR Jr. Myasthenia gravis and premature ovarian failure. Muscle Nerve 2004; 30:231.
  53. Hoek A, Schoemaker J, Drexhage HA. Premature ovarian failure and ovarian autoimmunity. Endocr Rev 1997; 18:107.
  54. Morrison JC, Givens JR, Wiser WL, Fish SA. Mumps oophoritis: a cause of premature menopause. Fertil Steril 1975; 26:655.
  55. Smith PC, Nusbaum KE, Kwapien RP, et al. Necrotic oophoritis in heifers vaccinated intravenously with infectious bovine rhinotracheitis virus vaccine during estrus. Am J Vet Res 1990; 51:969.
  56. Williams DJ, Connor P, Ironside JW. Pre-menopausal cytomegalovirus oophoritis. Histopathology 1990; 16:405.
  57. Subietas A, Deppisch LM, Astarloa J. Cytomegalovirus oophoritis: ovarian cortical necrosis. Hum Pathol 1977; 8:285.
  58. Willett W, Stampfer MJ, Bain C, et al. Cigarette smoking, relative weight, and menopause. Am J Epidemiol 1983; 117:651.
  59. McKinlay SM, Bifano NL, McKinlay JB. Smoking and age at menopause in women. Ann Intern Med 1985; 103:350.
  60. Stanford JL, Hartge P, Brinton LA, et al. Factors influencing the age at natural menopause. J Chronic Dis 1987; 40:995.
  61. Shelling AN, Burton KA, Chand AL, et al. Inhibin: a candidate gene for premature ovarian failure. Hum Reprod 2000; 15:2644.
  62. Lin D, Sugawara T, Strauss JF 3rd, et al. Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 1995; 267:1828.
  63. Mallin SR. Congenital adrenal hyperplasia secondary to 17-hydroxylase deficiency. Two sisters with amenorrhea, hypokalemia, hypertension, and cystic ovaries. Ann Intern Med 1969; 70:69.
  64. Ito Y, Fisher CR, Conte FA, et al. Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries. Proc Natl Acad Sci U S A 1993; 90:11673.
  65. Lourenço D, Brauner R, Lin L, et al. Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med 2009; 360:1200.
  66. Janse F, de With LM, Duran KJ, et al. Limited contribution of NR5A1 (SF-1) mutations in women with primary ovarian insufficiency (POI). Fertil Steril 2012; 97:141.
  67. Voican A, Bachelot A, Bouligand J, et al. NR5A1 (SF-1) mutations are not a major cause of primary ovarian insufficiency. J Clin Endocrinol Metab 2013; 98:E1017.
  68. Aittomäki K. The genetics of XX gonadal dysgenesis. Am J Hum Genet 1994; 54:844.
  69. Aittomäki K, Lucena JL, Pakarinen P, et al. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 1995; 82:959.
  70. Nakamura Y, Maekawa R, Yamagata Y, et al. A novel mutation in exon8 of the follicle-stimulating hormone receptor in a woman with primary amenorrhea. Gynecol Endocrinol 2008; 24:708.
  71. Latronico AC, Anasti J, Arnhold IJ, et al. Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene. N Engl J Med 1996; 334:507.
  72. Levine MA, Downs RW Jr, Moses AM, et al. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein. Am J Med 1983; 74:545.
  73. Shapiro MS, Bernheim J, Gutman A, et al. Multiple abnormalities of anterior pituitary hormone secretion in association with pseudohypoparathyroidism. J Clin Endocrinol Metab 1980; 51:483.
  74. Faull CM, Welbury RR, Paul B, Kendall-Taylor P. Pseudohypoparathyroidism: its phenotypic variability and associated disorders in a large family. Q J Med 1991; 78:251.