Skip to main content
SpringerLink
Log in

Genetic aspects of premature ovarian failure: a literature review

  • Reproductive Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Background

The diagnosis of premature ovarian failure (POF) is based on the finding of amenorrhea before the age of 40 years associated with follicle-stimulating hormone levels in the menopausal range. It is a heterogeneous disorder affecting approximately 1% of women <40 years, 1:10,000 women by age 20 years and 1:1,000 women by age 30 years. POF is generally characterized by low levels of gonadal hormones (estrogens and inhibins) and high levels of gonadotropins (LH and FSH) (hypergonadotropic amenorrhea).

Methods

Review of significant articles regarding genetic causes that are associated with POF.

Results

Heterogeneity of POF is reflected by a variety of possible causes, including autoimmunity, toxics, drugs, as well as genetic defects. Changes at a single autosomal locus and many X-linked loci have been implicated in women with POF. X chromosome abnormalities (e.g., Turner syndrome) represent the major cause of primary amenorrhea associated with ovarian dysgenesis. Many genes have been involved in POF development, among them BMP15, FMR1, FMR2, LHR, FSHR, INHA, FOXL2, FOXO3, ERα, SF1, ERβ and CYP19A1 genes.

Conclusion

Despite the description of several candidate genes, the cause of POF remains undetermined in the vast majority of cases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Santoro N (2003) Mechanisms of premature ovarian failure. Ann Endocrinol 64:87–92

    CAS  Google Scholar 

  2. Goswami D, Conway GS (2005) Premature ovarian failure. Hum Reprod Update 11(4):391–410

    Article  CAS  PubMed  Google Scholar 

  3. Vilodre LC, Moretto M, Kohek MB, Spritzer PM (2007) Premature ovarian failure: present aspects. Arq Bras Endocrinol Metabol 51(6):920–929

    PubMed  Google Scholar 

  4. Welt CK (2008) Primary ovarian insufficiency: a more accurate term for premature ovarian failure. Clin Endocrinol (Oxf) 68(4):499–509

    Article  Google Scholar 

  5. Timmreck LS, Reindollar RH (2003) Contemporary issues in primary amenorrhea. Obstet Gynecol Clin North Am 30(2):287–302

    Article  PubMed  Google Scholar 

  6. Van Kasteren YM, Schoemaker J (1999) Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update 5:483–492

    Article  PubMed  Google Scholar 

  7. Beck-Peccoz P, Persani L (2006) Premature ovarian failure. Orphanet J Rare Dis 1:9

    Article  PubMed  Google Scholar 

  8. Fassnacht W, Mempel A, Strowitzki T, Vogt PH (2006) Premature ovarian failure (POF) syndrome: towards the molecular clinical analysis of its genetic complexity. Curr Med Chem 13(12):1397–1410

    Article  CAS  PubMed  Google Scholar 

  9. Bretherick KL, Hanna CW, Currie LM, Fluker MR, Hammond GL, Robinson WP (2008) Estrogen receptor alpha gene polymorphisms are associated with idiopathic premature ovarian failure. Fertil Steril 89(2):318–324

    Article  CAS  PubMed  Google Scholar 

  10. Goswami D, Conway GS (2007) Premature ovarian failure. Horm Res 68(4):196–202

    Article  CAS  PubMed  Google Scholar 

  11. Conway GS, Hettiarachchi S, Murray A, Jacobs PA (1995) Fragile X premutations in familial premature ovarian failure. Lancet 346(8970):309–310

    Article  CAS  PubMed  Google Scholar 

  12. Sherman SL (2000) Premature ovarian failure in the fragile X syndrome. Am J Med Genet 97:189–194

    Article  CAS  PubMed  Google Scholar 

  13. Bianco B, Oliveira KC, Guedes AD, Barbosa CP, Lipay MV, Verreschi IT (2010) OCT4 gonadal gene expression related to the presence of Y-chromosome sequences in Turner syndrome. Fertil Steril 94(6):2347–2349

    Article  CAS  PubMed  Google Scholar 

  14. Bianco B, Nunes Lipay MV, Guedes AD, Verreschi IT (2008) Clinical implications of the detection of Y-chromosome mosaicism in Turner’s syndrome: report of 3 cases. Fertil Steril 90(4):1197.e17–1197.e20

    Google Scholar 

  15. Simpson JL, Rajkovic A (1999) Ovarian differentiation and gonadal failure. Am J Med Genet 89:186

    Article  CAS  PubMed  Google Scholar 

  16. Ogata T, Matsuo N (1995) Turner syndrome and female sex chromosome aberrations: deduction of the principal factors involved in the development of clinical features. Hum Genet 95:607–629

    Article  CAS  PubMed  Google Scholar 

  17. Tartaglia NR, Howell S, Sutherland A, Wilson R, Wilson L (2010) A review of trisomy X (47, XXX). Orphanet J Rare Dis 5:8

    Article  PubMed  Google Scholar 

  18. Linden MG, Bender BG, Harmon RJ, Mrazek DA, Robinson A (1988) 47, XXX: what is the prognosis? Pediatrics 82(4):619–630

    CAS  PubMed  Google Scholar 

  19. Lin HJ, Ndiforchu F, Patell S (1993) Exstrophy of the cloaca in a 47, XXX child: review of genitourinary malformations in triple-X patients. Am J Med Genet 45(6):761–763

    Article  CAS  PubMed  Google Scholar 

  20. Villanueva AL, Rebar RW (1983) Triple-X syndrome and premature ovarian failure. Obstet Gynecol 62(3 Suppl):70s–73s

    CAS  PubMed  Google Scholar 

  21. Goswami R, Goswami D, Kabra M, Gupta N, Dubey S, Dadhwal V (2003) Prevalence of the triple X syndrome in phenotypically normal women with premature ovarian failure and its association with autoimmune thyroid disorders. Fertil Steril 80(4):1052–1054

    Article  PubMed  Google Scholar 

  22. Persani L, Rossetti R, Cacciatore C, Bonomi M (2009) Primary ovarian insufficiency: X chromosome defects and autoimmunity. J Autoimmun 33(1):35–41

    Article  CAS  PubMed  Google Scholar 

  23. Sybert VP, McCauley E (2004) Turner’s syndrome. N Engl J Med 351(12):1227–1238

    Article  CAS  PubMed  Google Scholar 

  24. Hogan BL (1996) Bmps: multifunctional regulators of mammalian embryonic development. Harvey Lect 92:83–98

    PubMed  Google Scholar 

  25. McNatty KP, Juengel JL, Reader KL, Lun S, Myllymaa S, Lawrence SB et al (2005) Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function in ruminants. Reproduction 129:481–487

    Article  CAS  PubMed  Google Scholar 

  26. Galloway SM, McNatty KP, Cambridge LM, Laitinen MP, Juengel JL, Jokiranta TS et al (2000) Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner. Nat Genet 25:279–283

    Article  CAS  PubMed  Google Scholar 

  27. Di Pasquale E, Beck-Peccoz P, Persani L (2004) Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am J Hum Genet 75:106–111

    Article  CAS  PubMed  Google Scholar 

  28. Zinn AR, Tonk VS, Chen Z, Flejter WL, Gardner HA, Guerra R et al (1998) Evidence for a Turner syndrome locus or loci at Xp11.2–p22.1. Am J Hum Genet 63:1757–1766

    Article  CAS  PubMed  Google Scholar 

  29. McNatty KP, Smith P, Moore LG, Reader K, Lun S, Hanrahan JP et al. (2005) Oocyte-expressed genes affecting ovulation rate. Mol Cell Endocrinol 29:234(1–2):57–66

    Google Scholar 

  30. Tiotiu D, Alvaro Mercadal B, Imbert R, Verbist J, Demeestere I, De Leener A et al (2010) Variants of the BMP15 gene in a cohort of patients with premature ovarian failure. Hum Reprod 25(6):1581–1587

    Article  CAS  PubMed  Google Scholar 

  31. Zhang P, Shi YH, Wang LC, Chen ZJ (2007) Sequence variants in exons of the BMP-15 gene in Chinese patients with premature ovarian failure. Acta Obstet Gynecol Scand 86(5):585–589

    Article  CAS  PubMed  Google Scholar 

  32. Ledig S, Röpke A, Haeusler G, Hinney B, Wieacker P (2008) BMP15 mutations in XX gonadal dysgenesis and premature ovarian failure. Am J Obstet Gynecol 98(1):84.e1–84.e5

    Google Scholar 

  33. Amiri K, Hagerman RJ, Hagerman PJ (2008) Fragile X-associated tremor/ataxia syndrome: an aging face of the fragile X gene. Arch Neurol 65:19–25

    Article  PubMed  Google Scholar 

  34. Martin JR, Arici A (2008) Fragile X and reproduction. Curr Opin Obstet Gynecol 20(3):216–220

    Article  PubMed  Google Scholar 

  35. Greco CM, Berman RF, Martin RM, Tassone F, Schwartz PH, Chang A et al (2006) Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 129(Pt 1):243–255

    CAS  PubMed  Google Scholar 

  36. Allen EG, Sullivan AK, Marcus M, Small C, Dominguez C, Epstein MP et al (2007) Examination of reproductive aging milestones among women who carry the FMR1 premutation. Hum Reprod 22:2142–2152

    Article  CAS  PubMed  Google Scholar 

  37. Christofolini DM, Pinheiro FS, Bianco B, Melaragno MI, Ramos AP, Brunoni D et al (2009) Síndrome de tremos e ataxia associada ao X frágil: rastreamento por PCR em amostras de idosos. Arq Bras Ciências Saúde 34:1–5

    Google Scholar 

  38. Hagerman RJ, Leavitt BR, Farzin F, Jacquemont S, Greco CM, Brunberg JA et al (2004) Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 74:1051–1056

    Article  CAS  PubMed  Google Scholar 

  39. Corrigan EC, Raygada MJ, Vanderhoof VH, Nelson LM (2005) A woman with spontaneous premature ovarian failure gives birth to a child with fragile X syndrome. Fertil Steril 84(5):1508

    Article  PubMed  Google Scholar 

  40. Lin YS, Yang ML (2006) Familial premature ovarian failure in female premutated carriers of fragile X syndrome: a case report and literature review. Taiwan J Obstet Gynecol 45(1):60–63

    Article  PubMed  Google Scholar 

  41. Sullivan AK, Marcus M, Epstein MP, Allen EG, Anido AE, He W et al (2005) Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod 20:402–412

    Article  CAS  PubMed  Google Scholar 

  42. Murray A, Webb J, Dennis N, Conway G, Morton N (1999) Microdeletions in FMR2 may be a significant cause of premature ovarian failure. J Med Genet 36(10):767–770

    CAS  PubMed  Google Scholar 

  43. Risma KA, Clay CM, Nett TM, Wagner T, Yun J, Nilson JH (1995) Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors. Proc Natl Acad Sci USA 92:1322–1326

    Article  CAS  PubMed  Google Scholar 

  44. Liao WX, Roy AC, Chan C, Arulkumaran S, Ratnam SS (1998) A new molecular variant of luteinizing hormone associated with female infertility. Fertil Steril 69(1):102–106

    Article  CAS  PubMed  Google Scholar 

  45. Piersma D, Verhoef-Post M, Berns EM, Themmen AP (2007) LH receptor gene mutations and polymorphisms: an overview. Mol Cell Endocrinol 282(6):260–262

    Google Scholar 

  46. Sundblad V, Chiauzzi VA, Escobar ME, Dain L, Charreau EH (2004) Screening of FSH receptor gene in Argentine women with premature ovarian failure (POF). Mol Cell Endocrinol 222(1–2):53–59

    Article  CAS  PubMed  Google Scholar 

  47. Aittomaki K, Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J et al. (1995) Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 82:959–968

    Google Scholar 

  48. Vilodre LC, Kohek MB, Spritzer PM (2008) Screening of follicle-stimulating hormone receptor gene in women with premature ovarian failure in southern Brazil and associations with phenotype. J Endocrinol Invest 31(6):552–557

    CAS  PubMed  Google Scholar 

  49. Ghadami M, El-Demerdash E, Salama SA, Binhazim AA, Archibong AE, Chen X et al (2010) Toward gene therapy of premature ovarian failure: intraovarian injection of adenovirus expressing human FSH receptor restores folliculogenesis in FSHR(−/−) FORKO mice. Mol Hum Reprod 16(4):241–250

    Article  CAS  PubMed  Google Scholar 

  50. Burger HG (1992) Inhibin. Reprod Med Rev 1:1–20

    Article  Google Scholar 

  51. Groome NP, Illingworth PJ, O’Brien M, Cooke I, Ganesan TS, Baird DT et al (1994) Detection of dimeric inhibin throughout the human menstrual cycle by two-site enzyme immunoassay. Clin Endocrinol (Oxf) 40(6):717–723

    Article  CAS  Google Scholar 

  52. Groome NP, Illingworth PJ, O’Brien M, Pai R, Rodger FE, Mather JP et al (1996) Measurement of dimeric inhibin B throughout the human menstrual cycle. J Clin Endocrinol Metab 81(4):1401–1405

    Article  CAS  PubMed  Google Scholar 

  53. Ying SY (1988) Inhibins, activins, and follistatins: gonadal proteins modulating the secretion of follicle-stimulating hormone. Endocr Rev 9:267–293

    Article  CAS  PubMed  Google Scholar 

  54. Shelling AN, Burton KA, Chand AL, van Ee CC, France JT, Farquhar CM et al (2000) Inhibin: a candidate gene for premature ovarian failure. Hum Reprod 15(12):2644–2649

    Article  CAS  PubMed  Google Scholar 

  55. Marozzi A, Vegetti W, Manfredini E, Tibiletti MG, Testa G, Crosignani PG et al (2000) Association between idiopathic premature ovarian failure and fragile X premutation. Hum Reprod 15(8):1874–1875

    Article  Google Scholar 

  56. Harris SE, Chand AL, Winship IM, Gersak K, Nishi Y, Yanase T et al. (2005) INHA promoter polymorphisms are associated with premature ovarian failure. Mol Hum Reprod 11:779–84.40

    Google Scholar 

  57. Dixit H, Rao KL, Padmalatha V, Kanakavalli M, Deenadayal M, Gupta N et al (2006) Expansion of the germline analysis for the INHA gene in Indian women with ovarian failure. Hum Reprod 21(6):1643–1644

    Article  CAS  PubMed  Google Scholar 

  58. Woad KJ, Watkins WJ, Prendergast D, Shelling AN (2006) The genetic basis of premature ovarian failure. Aust NZ J Obstet Gynaecol 46:242–244

    Article  Google Scholar 

  59. Sundblad V, Chiauzzi VA, Andreone L, Campo S, Charreau EH, Dain L (2006) Controversial role of inhibin alpha-subunit gene in the aetiology of premature ovarian failure. Hum Repro 21(5):1154–1160

    Article  CAS  Google Scholar 

  60. Santoro N, Adel T, Skurnick JH (1999) Decreased inhibin tone and increased activin A secretion characterize reproductive aging in women. Fertil Steril 71:658–662

    Article  CAS  PubMed  Google Scholar 

  61. Pisarska MD, Bae J, Klein C, Hsueh AJ (2004) Forkhead l2 is expressed in the ovary and represses the promoter activity of the steroidogenic acute regulatory gene. Endocrinology 145:3424–3433

    Article  CAS  PubMed  Google Scholar 

  62. Schmidt D, Ovitt CE, Anlag K, Fehsenfeld S, Gredsted L, Treier AC et al (2004) The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development 131:933–942

    Article  CAS  PubMed  Google Scholar 

  63. Uda M, Ottolenghi C, Crisponi L, Garcia JE, Deiana M, Kimber W et al (2004) Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development. Hum Mol Genet 13:1171–1181

    Article  CAS  PubMed  Google Scholar 

  64. Jeyasuria P, Ikeda Y, Jamin SP, Zhao L, De Rooij DG, Themmen AP et al (2004) Cell-specific knockout of steroidogenic factor 1 reveals its essential roles in gonadal function. Mol Endocrinol 18:1610–1619

    Article  CAS  PubMed  Google Scholar 

  65. Park M, Shin E, Won M, Kim JH, Go H, Kim HL et al (2010) FOXL2 interacts with steroidogenic factor-1 (SF-1) and represses SF-1-induced CYP17 transcription in granulosa cells. Mol Endocrinol 24(5):1024–1036

    Article  CAS  PubMed  Google Scholar 

  66. Watkins WJ, Umbers AJ, Woad KJ, Harris SE, Winship IM, Gersak K et al (2006) Mutational screening of FOXO3A and FOXO1A in women with premature ovarian failure. Fertil Steril 86(5):1518–1521

    Article  CAS  PubMed  Google Scholar 

  67. Castrillon DH, Miao L, Kollipara R, Horner JW, DePinho RA (2003) Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science 301(5630):215–218

    Article  CAS  PubMed  Google Scholar 

  68. Yoon SH, Choi YM, Hong MA, Lee GH, Kim JJ, Im HJ et al (2010) Estrogen receptor alpha gene polymorphisms in patients with idiopathic premature ovarian failure. Hum Reprod 25(1):283–287

    Article  CAS  PubMed  Google Scholar 

  69. Lindzey J, Jayes FL, Yates MM, Couse JF, Korach KS (2006) The bi-modal effects of estradiol on gonadotropin synthesis and secretion in female mice are dependent on estrogen receptor-alpha. J Endocrinol 191(1):309–317

    Article  CAS  PubMed  Google Scholar 

  70. Walter P, Green S, Greene G, Krust A, Bornert JM, Jeltsch JM et al (1985) Cloning of the human estrogen receptor cDNA. Proc Natl Acad Sci USA 82(23):7889–7893

    Article  CAS  PubMed  Google Scholar 

  71. Mosselman S, Polman J, Dijkema R (1996) ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett 392(1):49–53

    Article  CAS  PubMed  Google Scholar 

  72. Kolibianakis EM, Papanikolaou EG, Fatemi HM, Devroey P (2005) Estrogen and folliculogenesis: is one necessary for the other? Curr Opin Obstet Gynecol 17(3):249–253

    Article  PubMed  Google Scholar 

  73. Weel AE, Uitterlinden AG, Westendorp IC, Burger H, Schuit SC, Hofman A et al (1999) Estrogen receptor polymorphism predicts the onset of natural and surgical menopause. J Clin Endocrinol Metab 84(9):3146–3150

    Article  CAS  PubMed  Google Scholar 

  74. Stavrou I, Zois C, Ioannidis JP, Tsatsoulis A (2002) Association of polymorphisms of the oestrogen receptor alpha gene with the age of menarche. Hum Reprod 17(4):1101–1105

    Article  CAS  PubMed  Google Scholar 

  75. Syrrou M, Georgiou I, Patsalis PC, Bouba I, Adonakis G, Pagoulatos GN (1999) Fragile X premutations and (TA)n estrogen receptor polymorphism in women with ovarian dysfunction. Am J Med Genet 84(3):306–308

    Article  CAS  PubMed  Google Scholar 

  76. Kim S, Pyun JA, Kang H, Kim J, Cha DH, Kwack K (2010) Epistasis between CYP19A1 and ESR1 polymorphisms is associated with premature ovarian failure. Fertil Steril [Epub ahead of print]

  77. Shelling AN (2010) Premature ovarian failure. Reproduction 140(5):633–641

    Article  CAS  PubMed  Google Scholar 

  78. Bidet M, Bachelot A, Touraine P (2008) Premature ovarian failure: predictability of intermittent ovarian function and response to ovulation induction agents. Current Opin Obstet Gynaecol 20:416–420

    Article  Google Scholar 

  79. Picton HM, Harris SE, Muruvoi W, Chambers EL (2008) The in vitro growth and maturation of follicles. Reproduction 136:703–715

    Article  CAS  PubMed  Google Scholar 

  80. van Kasteren Y, Schoemaker J (1999) Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update 5:483–492

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Human Reproduction, Department of Gynecology and Obstetrics, Faculdade de Medicina do ABC, Avenida Príncipe de Gales, 821, Santo André, SP, CEP 09060-650, Brazil

    Emerson Barchi Cordts, Denise Maria Christofolini, Aline Amaro dos Santos, Bianca Bianco & Caio Parente Barbosa

Authors
  1. Emerson Barchi Cordts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Denise Maria Christofolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aline Amaro dos Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bianca Bianco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Caio Parente Barbosa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Caio Parente Barbosa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cordts, E.B., Christofolini, D.M., dos Santos, A.A. et al. Genetic aspects of premature ovarian failure: a literature review. Arch Gynecol Obstet 283, 635–643 (2011). https://doi.org/10.1007/s00404-010-1815-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-010-1815-4

Keywords

Search

Navigation