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

Ovarian development and failure (menopause) in normal women

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


This topic will review the basic aspects of ovarian development and the pathogenesis and epidemiology of menopause. The clinical manifestations, diagnosis, and management of menopause are reviewed separately. (See "Clinical manifestations and diagnosis of menopause" and "Treatment of menopausal symptoms with hormone therapy".)


There are three main steps in ovarian development: germ cell differentiation, continuous follicular growth, and continuous follicular atresia.

Germ cell differentiation — One of the first events of sexual differentiation, occurring as early as the two-cell stage of the zygote, is the random, nearly complete inactivation of one X chromosome in all female somatic cells [1] but not germ cells [2]. Thus, somatic cells have only a few active X chromosome genes, whereas germ cells have two complete X chromosomes [2].

The primordial undifferentiated germ cells then migrate during the fourth to eighth weeks of gestation from the yolk sac to the gonadal ridge, where they are required for development of the ovaries [3]. In the absence of a testicular differentiation factor from the Y chromosome, which directs the production of müllerian-inhibiting substance (MIS) by four to six weeks gestation in males [4], the germ cells differentiate into primitive oogonia, which begin mitosis at approximately six weeks. (See "Normal sexual development".)

A quantitative morphologic study of germ cells in 17 normal human fetuses revealed a maximum of seven million germ cells five months after conception [3]; this small study remains the basis of most of our current understanding of oogenesis in humans. The first meiotic division is initiated at approximately 15 weeks, signaling the transformation of oogonia to oocytes. This meiotic division is then arrested at the first prophase until primordial follicles are formed. Medullary structures infiltrate the ovarian cortex and surround the oocytes to invest each one with a single layer of primordial granulosa cells at approximately 20 weeks of gestation, thereby beginning the formation of primordial follicles.

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: Oct 2017. | This topic last updated: Sep 11, 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. Huynh KD, Lee JT. Inheritance of a pre-inactivated paternal X chromosome in early mouse embryos. Nature 2003; 426:857.
  2. Gartler SM, Liskay RM, Campbell BK, et al. Evidence for two functional X chromosomes in human oocytes. Cell Differ 1972; 1:215.
  4. Jost A, Vigier B, Prépin J, Perchellet JP. Studies on sex differentiation in mammals. Recent Prog Horm Res 1973; 29:1.
  5. Gustafson ML, Lee MM, Scully RE, et al. Müllerian inhibiting substance as a marker for ovarian sex-cord tumor. N Engl J Med 1992; 326:466.
  6. Orsini LF, Salardi S, Pilu G, et al. Pelvic organs in premenarcheal girls: real-time ultrasonography. Radiology 1984; 153:113.
  7. diZerega GS, Hodgen GD. Folliculogenesis in the primate ovarian cycle. Endocr Rev 1981; 2:27.
  8. Peters H, Byskov AG, Himelstein-Braw R, Faber M. Follicular growth: the basic event in the mouse and human ovary. J Reprod Fertil 1975; 45:559.
  9. Goldenberg RL, Powell RD, Rosen SW, et al. Ovarian morphology in women with anosmia and hypogonadotropic hypogonadism. Am J Obstet Gynecol 1976; 126:91.
  10. Baker TG, Scrimgeour JB. Development of the gonad in normal and anencephalic human fetuses. J Reprod Fertil 1980; 60:193.
  11. May JV, McCarty K Jr, Reichert LE Jr, Schomberg DW. Follicle-stimulating hormone-mediated induction of functional luteinizing hormone/human chorionic gonadotropin receptors during monolayer culture of porcine granulosa cells. Endocrinology 1980; 107:1041.
  12. Peters H, Byskov AG, Grinsted J. Follicular growth in fetal and prepubertal ovaries of humans and other primates. Clin Endocrinol Metab 1978; 7:469.
  13. Lintern-Moore S, Peters H, Moore GP, Faber M. Follicular development in the infant human ovary. J Reprod Fertil 1974; 39:53.
  14. Himelstein-Braw R, Byskov AG, Peters H, Faber M. Follicular atresia in the infant human ovary. J Reprod Fertil 1976; 46:55.
  15. Apter D, Cacciatore B, Alfthan H, Stenman UH. Serum luteinizing hormone concentrations increase 100-fold in females from 7 years to adulthood, as measured by time-resolved immunofluorometric assay. J Clin Endocrinol Metab 1989; 68:53.
  16. Jakacki RI, Kelch RP, Sauder SE, et al. Pulsatile secretion of luteinizing hormone in children. J Clin Endocrinol Metab 1982; 55:453.
  17. Morita Y, Tilly JL. Oocyte apoptosis: like sand through an hourglass. Dev Biol 1999; 213:1.
  18. Hirshfield AN. Effect of a low dose of pregnant mare's serum gonadotropin on follicular recruitment and atresia in cycling rats. Biol Reprod 1986; 35:113.
  19. Richards JS. Molecular loci for potential drug toxicity in ovaries. Environ Health Perspect 1986; 70:159.
  20. Tsafriri A, Channing CP. An inhibitory influence of granulosa cells and follicular fluid upon porcine oocyte meiosis in vitro. Endocrinology 1975; 96:922.
  21. Hillensjö T, Batta SK, Schwartz-Kripner A, et al. Inhibitory effect of human follicular fluid upon the maturation of porcine oocytes in culture. J Clin Endocrinol Metab 1978; 47:1332.
  22. Ueno S, Manganaro TF, Donahoe PK. Human recombinant mullerian inhibiting substance inhibition of rat oocyte meiosis is reversed by epidermal growth factor in vitro. Endocrinology 1988; 123:1652.
  23. Tsafriri A, Picard JY, Josso N. Immunopurified anti-müllerian hormone does not inhibit spontaneous resumption of meiosis in vitro of rat oocytes. Biol Reprod 1988; 38:481.
  24. Ueno S, Kuroda T, Maclaughlin DT, et al. Mullerian inhibiting substance in the adult rat ovary during various stages of the estrous cycle. Endocrinology 1989; 125:1060.
  25. Perez GI, Robles R, Knudson CM, et al. Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency. Nat Genet 1999; 21:200.
  26. Ratts VS, Flaws JA, Kolp R, et al. Ablation of bcl-2 gene expression decreases the numbers of oocytes and primordial follicles established in the post-natal female mouse gonad. Endocrinology 1995; 136:3665.
  27. Vaskivuo TE, Anttonen M, Herva R, et al. Survival of human ovarian follicles from fetal to adult life: apoptosis, apoptosis-related proteins, and transcription factor GATA-4. J Clin Endocrinol Metab 2001; 86:3421.
  28. Johnson J, Canning J, Kaneko T, et al. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 2004; 428:145.
  29. Johnson J, Bagley J, Skaznik-Wikiel M, et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell 2005; 122:303.
  30. Eggan K, Jurga S, Gosden R, et al. Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature 2006; 441:1109.
  31. Zou K, Yuan Z, Yang Z, et al. Production of offspring from a germline stem cell line derived from neonatal ovaries. Nat Cell Biol 2009; 11:631.
  32. BLOCK E. Quantitative morphological investigations of the follicular system in women; variations at different ages. Acta Anat (Basel) 1952; 14:108.
  33. Baker TG. Radiosensitivity of mammalian oocytes with particular reference to the human female. Am J Obstet Gynecol 1971; 110:746.
  34. Costoff A, Mahesh VB. Primordial follicles with normal oocytes in the ovaries of postmenopausal women. J Am Geriatr Soc 1975; 23:193.
  35. Richardson SJ, Senikas V, Nelson JF. Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987; 65:1231.
  36. Klein NA, Battaglia DE, Miller PB, et al. Ovarian follicular development and the follicular fluid hormones and growth factors in normal women of advanced reproductive age. J Clin Endocrinol Metab 1996; 81:1946.
  37. Maroulis GB. Effect of aging on fertility and pregnancy. Semin Reprod Endocrinol 1991; 9:165.
  38. Santoro N, Schneyer AL, Ibrahim J, Schmidt CL. Gonadotropin and inhibin concentrations in early pregnancy in women with and without corpora lutea. Obstet Gynecol 1992; 79:579.
  39. McKinlay SM, Bifano NL, McKinlay JB. Smoking and age at menopause in women. Ann Intern Med 1985; 103:350.
  40. Freeman EW, Sammel MD, Gracia CR, et al. Follicular phase hormone levels and menstrual bleeding status in the approach to menopause. Fertil Steril 2005; 83:383.
  41. Burger HG, Cahir N, Robertson DM, et al. Serum inhibins A and B fall differentially as FSH rises in perimenopausal women. Clin Endocrinol (Oxf) 1998; 48:809.
  42. Welt CK, McNicholl DJ, Taylor AE, Hall JE. Female reproductive aging is marked by decreased secretion of dimeric inhibin. J Clin Endocrinol Metab 1999; 84:105.
  43. van Rooij IA, Broekmans FJ, Scheffer GJ, et al. Serum antimullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study. Fertil Steril 2005; 83:979.
  44. Méduri G, Massin N, Guibourdenche J, et al. Serum anti-Müllerian hormone expression in women with premature ovarian failure. Hum Reprod 2007; 22:117.
  45. van Disseldorp J, Faddy MJ, Themmen AP, et al. Relationship of serum antimüllerian hormone concentration to age at menopause. J Clin Endocrinol Metab 2008; 93:2129.
  46. La Marca A, Giulini S, Tirelli A, et al. Anti-Müllerian hormone measurement on any day of the menstrual cycle strongly predicts ovarian response in assisted reproductive technology. Hum Reprod 2007; 22:766.
  47. Sowers MR, Eyvazzadeh AD, McConnell D, et al. Anti-mullerian hormone and inhibin B in the definition of ovarian aging and the menopause transition. J Clin Endocrinol Metab 2008; 93:3478.
  48. Santoro N, Brown JR, Adel T, Skurnick JH. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab 1996; 81:1495.
  49. Taffe JR, Dennerstein L. Menstrual patterns leading to the final menstrual period. Menopause 2002; 9:32.
  50. Hee J, MacNaughton J, Bangah M, Burger HG. Perimenopausal patterns of gonadotrophins, immunoreactive inhibin, oestradiol and progesterone. Maturitas 1993; 18:9.
  51. Weiss G, Skurnick JH, Goldsmith LT, et al. Menopause and hypothalamic-pituitary sensitivity to estrogen. JAMA 2004; 292:2991.
  52. McKinlay SM. The normal menopause transition: an overview. Maturitas 1996; 23:137.
  53. Cramer DW, Barbieri RL, Xu H, Reichardt JK. Determinants of basal follicle-stimulating hormone levels in premenopausal women. J Clin Endocrinol Metab 1994; 79:1105.
  54. McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992; 14:103.
  55. de Bruin JP, Bovenhuis H, van Noord PA, et al. The role of genetic factors in age at natural menopause. Hum Reprod 2001; 16:2014.
  56. He C, Kraft P, Chen C, et al. Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat Genet 2009; 41:724.
  57. Stolk L, Zhai G, van Meurs JB, et al. Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nat Genet 2009; 41:645.
  58. Stolk L, Perry JR, Chasman DI, et al. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. Nat Genet 2012; 44:260.
  59. Ma X, Chen Y, Zhao X, et al. Association study of TGFBR2 and miR-518 gene polymorphisms with age at natural menopause, premature ovarian failure, and early menopause among Chinese Han women. Medicine (Baltimore) 2014; 93:e93.
  60. Chen CT, Liu CT, Chen GK, et al. Meta-analysis of loci associated with age at natural menopause in African-American women. Hum Mol Genet 2014; 23:3327.
  61. Weel AE, Uitterlinden AG, Westendorp IC, et al. Estrogen receptor polymorphism predicts the onset of natural and surgical menopause. J Clin Endocrinol Metab 1999; 84:3146.
  62. Sullivan AK, Marcus M, Epstein MP, et al. Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod 2005; 20:402.
  63. Allen EG, Sullivan AK, Marcus M, et al. Examination of reproductive aging milestones among women who carry the FMR1 premutation. Hum Reprod 2007; 22:2142.
  64. Henderson KD, Bernstein L, Henderson B, et al. Predictors of the timing of natural menopause in the Multiethnic Cohort Study. Am J Epidemiol 2008; 167:1287.
  65. Gold EB, Bromberger J, Crawford S, et al. Factors associated with age at natural menopause in a multiethnic sample of midlife women. Am J Epidemiol 2001; 153:865.
  66. Kaufman DW, Slone D, Rosenberg L, et al. Cigarette smoking and age at natural menopause. Am J Public Health 1980; 70:420.
  67. Willett W, Stampfer MJ, Bain C, et al. Cigarette smoking, relative weight, and menopause. Am J Epidemiol 1983; 117:651.
  68. Cramer DW, Barbieri RL, Fraer AR, Harlow BL. Determinants of early follicular phase gonadotrophin and estradiol concentrations in women of late reproductive age. Hum Reprod 2002; 17:221.
  69. Fleming LE, Levis S, LeBlanc WG, et al. Earlier age at menopause, work, and tobacco smoke exposure. Menopause 2008; 15:1103.
  70. Ertunc D, Tok EC, Aytan H, Gozukara YM. Passive smoking is associated with lower age at menopause. Climacteric 2015; 18:47.
  71. Cooper GS, Hulka BS, Baird DD, et al. Galactose consumption, metabolism, and follicle-stimulating hormone concentrations in women of late reproductive age. Fertil Steril 1994; 62:1168.
  72. 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.
  73. Dorman JS, Steenkiste AR, Foley TP, et al. Menopause in type 1 diabetic women: is it premature? Diabetes 2001; 50:1857.
  74. Hatch EE, Troisi R, Wise LA, et al. Age at natural menopause in women exposed to diethylstilbestrol in utero. Am J Epidemiol 2006; 164:682.
  75. Wide L, Hobson BM. Qualitative difference in follicle-stimulating hormone activity in the pituitaries of young women compared to that of men and elderly women. J Clin Endocrinol Metab 1983; 56:371.
  76. Chappel SC, Ulloa-Aguirre A, Coutifaris C. Biosynthesis and secretion of follicle-stimulating hormone. Endocr Rev 1983; 4:179.
  77. Wise PM, Krajnak KM, Kashon ML. Menopause: the aging of multiple pacemakers. Science 1996; 273:67.
  78. Soules MR, Sherman S, Parrott E, et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Fertil Steril 2001; 76:874.