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Polycystic ovary syndrome: etiology, pathogenesis and diagnosis

This article has been updated

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age, with a prevalence of up to 10%. Various diagnostic criteria have been proposed, generally centered around the features of hyperandrogenism and/or hyperandrogenemia, oligo-ovulation and polycystic ovarian morphology. Insulin resistance is present in a majority of cases, with compensatory hyperinsulinemia contributing to hyperandrogenism via stimulation of ovarian androgen secretion and inhibition of hepatic sex hormone-binding globulin production. Adipose tissue dysfunction has been implicated as a contributor to the insulin resistance observed in PCOS. Environmental and genetic factors also have a role in the development of PCOS. The syndrome is associated with numerous morbidities, including infertility, obstetrical complications, type 2 diabetes mellitus, cardiovascular disease, and mood and eating disorders. Despite these morbidities, PCOS may be common in our society owing to evolutionary advantages of the syndrome in ancient times, including smaller family sizes, reduced exposure to childbirth-related mortality, increased muscle mass and greater capacity to store energy. The diagnosis of PCOS hinges on establishing key features while ruling out other hyperandrogenic or oligo-ovulatory disorders. Treatment is focused on the goals of ameliorating hyperandrogenic symptoms, inducing ovulation and preventing cardiometabolic complications.

Key Points

  • The central diagnostic features of polycystic ovary syndrome (PCOS) are hyperandrogenemia, hyperandrogenism (hirsutism), oligoanovulation and polycystic ovaries; the three main diagnostic schemes utilize different combinations of these criteria

  • The prevalence of PCOS in women of reproductive age is 6–10%; prevalence is remarkably similar across different populations across the globe

  • Insulin resistance, a common feature of PCOS that arises in part from adipose tissue dysfunction, results in compensatory hyperinsulinemia, which maintains normal glucose levels but adversely effects ovarian androgen production

  • Abnormal folliculogenesis and gonadotropin production, particularly luteinizing hormone hypersecretion, also contribute to the development of PCOS; these abnormalities may arise from environmental insults as well as genetic predisposition

  • Long-term complications of PCOS include infertility, obstetrical complications, type 2 diabetes mellitus, cardiovascular disease, and mood and eating disorders

  • Treatment of PCOS must be tailored to the specific needs of each patient; goals of therapy may include ameliorating hyperandrogenic symptoms, inducing ovulation, regulating menstruation and preventing cardiometabolic complications

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Change history

  • 10 February 2011

    In the version of this article initially published online, there was a mistake in the Hirsutism section on page 7. In the first paragraph of this section, the phrase "flutamide 2.5–5 mg per day" should have read "flutamide 62.5–250 mg per day". The error has been corrected in all electronic versions of the text.

References

  1. 1

    Azziz, R. in Androgen Excess Disorders in Women 2nd edn (eds Azziz, R., Nestler, J. E. & Dewailly, D.) 1–16 (Humana Press, Totowa, 2006).

    Google Scholar 

  2. 2

    Stein, I. F. & Leventhal, M. L. Amenorrhea associated with bilateral polycystic ovaries. Am. J. Obstet. Gynecol. 29, 181–191 (1935).

    Article  Google Scholar 

  3. 3

    Zawadzki, J. K. & Dunaif, A. in Polycystic Ovary Syndrome (eds Dunaif, A., Givens, J. R., Haseltine, F. P. & Merriam G. R.) 377–384 (Blackwell Scientific, Boston, 1992).

    Google Scholar 

  4. 4

    [No authors listed] Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil. Steril. 81, 19–25 (2004).

  5. 5

    [No authors listed] Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum. Reprod. 19, 41–47 (2004).

  6. 6

    Azziz, R. et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J. Clin. Endocrinol. Metab. 91, 4237–4245 (2006).

    Article  CAS  Google Scholar 

  7. 7

    Asunción, M. et al. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J. Clin. Endocrinol. Metab. 85, 2434–2438 (2000).

    PubMed  Google Scholar 

  8. 8

    Azziz, R. et al. The prevalence and features of the polycystic ovary syndrome in an unselected population. J. Clin. Endocrinol. Metab. 89, 2745–2749 (2004).

    Article  CAS  Google Scholar 

  9. 9

    Diamanti-Kandarakis, E. et al. A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J. Clin. Endocrinol. Metab. 84, 4006–4011 (1999).

    Article  CAS  Google Scholar 

  10. 10

    Knochenhauer, E. S. et al. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J. Clin. Endocrinol. Metab. 83, 3078–3082 (1998).

    CAS  PubMed  Google Scholar 

  11. 11

    Michelmore, K. F., Balen, A. H., Dunger, D. B. & Vessey, M. P. Polycystic ovaries and associated clinical and biochemical features in young women. Clin. Endocrinol. (Oxf.) 51, 779–786 (1999).

    Article  CAS  Google Scholar 

  12. 12

    Broekmans, F. J. et al. PCOS according to the Rotterdam consensus criteria: change in prevalence among WHO-II anovulation and association with metabolic factors. BJOG 113, 1210–1217 (2006).

    Article  CAS  Google Scholar 

  13. 13

    Azziz, R. et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil. Steril. 91, 456–488 (2009).

    Article  Google Scholar 

  14. 14

    Azziz, R. et al. Androgen excess in women: experience with over 1000 consecutive patients. J. Clin. Endocrinol. Metab. 89, 453–462 (2004).

    Article  CAS  Google Scholar 

  15. 15

    Clayton, R. N. et al. How common are polycystic ovaries in normal women and what is their significance for the fertility of the population? Clin. Endocrinol. (Oxf.) 37, 127–134 (1992).

    Article  CAS  Google Scholar 

  16. 16

    Hassan, M. A. & Killick, S. R. Ultrasound diagnosis of polycystic ovaries in women who have no symptoms of polycystic ovary syndrome is not associated with subfecundity or subfertility. Fertil. Steril. 80, 966–975 (2003).

    Article  Google Scholar 

  17. 17

    Wong, I. L., Morris, R. S., Lobo, R. A., Paulson, R. J. & Sauer, M. V. Isolated polycystic morphology in ovum donors predicts response to ovarian stimulation. Hum. Reprod. 10, 524–528 (1995).

    Article  CAS  Google Scholar 

  18. 18

    Yildiz, B. O., Bolour, S., Woods, K., Moore, A. & Azziz, R. Visually scoring hirsutism. Hum. Reprod. Update 16, 51–64 (2010).

    Article  Google Scholar 

  19. 19

    Rosner, W., Auchus, R. J., Azziz, R., Sluss, P. M. & Raff, H. Position statement: Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J. Clin. Endocrinol. Metab. 92, 405–413 (2007).

    Article  CAS  Google Scholar 

  20. 20

    Huang, A., Brennan, K. & Azziz, R. Prevalence of hyperandrogenemia in the polycystic ovary syndrome diagnosed by the National Institutes of Health 1990 criteria. Fertil. Steril. 93, 1938–1941 (2010).

    Article  Google Scholar 

  21. 21

    Hull, M. G. Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies. Gynecol. Endocrinol. 1, 235–245 (1987).

    Article  CAS  Google Scholar 

  22. 22

    Jonard, S. et al. Ultrasound examination of polycystic ovaries: is it worth counting the follicles? Hum. Reprod. 18, 598–603 (2003).

    Article  CAS  Google Scholar 

  23. 23

    Gougeon, A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr. Rev. 17, 121–155 (1996).

    Article  CAS  Google Scholar 

  24. 24

    Jakimiuk, A. J., Weitsman, S. R., Brzechffa, P. R. & Magoffin, D. A. Aromatase mRNA expression in individual follicles from polycystic ovaries. Mol. Hum. Reprod. 4, 1–8 (1998).

    Article  CAS  Google Scholar 

  25. 25

    Agarwal, S. K., Judd, H. L. & Magoffin, D. A. A mechanism for the suppression of estrogen production in polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 81, 3686–3691 (1996).

    CAS  PubMed  Google Scholar 

  26. 26

    Jakimiuk, A. J., Weitsman, S. R. & Magoffin, D. A. 5alpha-reductase activity in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 84, 2414–2418 (1999).

    CAS  PubMed  Google Scholar 

  27. 27

    Moghetti, P. et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J. Clin. Endocrinol. Metab. 85, 139–146 (2000).

    CAS  PubMed  Google Scholar 

  28. 28

    Bergh, C., Carlsson, B., Olsson, J. H., Selleskog, U. & Hillensjö, T. Regulation of androgen production in cultured human thecal cells by insulin-like growth factor I and insulin. Fertil. Steril. 59, 323–331 (1993).

    Article  CAS  Google Scholar 

  29. 29

    Balen, A. H., Conway, G. S., Homburg, R. & Legro, R. S. Polycystic Ovary Syndrome. A Guide to Clinical Management (Taylor & Francis, London, 2005).

    Google Scholar 

  30. 30

    Franks, S., Gilling-Smith, C., Watson, H. & Willis, D. Insulin action in the normal and polycystic ovary. Endocrinol. Metab. Clin. North Am. 28, 361–378 (1999).

    Article  CAS  Google Scholar 

  31. 31

    Willis, D., Mason, H., Gilling-Smith, C. & Franks, S. Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J. Clin. Endocrinol. Metab. 81, 302–309 (1996).

    CAS  PubMed  Google Scholar 

  32. 32

    Knight, P. G. & Glister, C. Local roles of TGF-beta superfamily members in the control of ovarian follicle development. Anim. Reprod. Sci. 78, 165–183 (2003).

    Article  CAS  Google Scholar 

  33. 33

    Seifer, D. B. & Maclaughlin, D. T. Mullerian Inhibiting Substance is an ovarian growth factor of emerging clinical significance. Fertil. Steril. 88, 539–546 (2007).

    Article  CAS  Google Scholar 

  34. 34

    Visser, J. A., de Jong, F. H., Laven, J. S. & Themmen, A. P. Anti-Müllerian hormone: a new marker for ovarian function. Reproduction 131, 1–9 (2006).

    Article  CAS  Google Scholar 

  35. 35

    Pellatt, L. et al. Granulosa cell production of anti-Müllerian hormone is increased in polycystic ovaries. J. Clin. Endocrinol. Metab. 92, 240–245 (2007).

    Article  CAS  Google Scholar 

  36. 36

    Erickson, G. F., Magoffin, D. A., Garzo, V. G., Cheung, A. P. & Chang, R. J. Granulosa cells of polycystic ovaries: are they normal or abnormal? Hum. Reprod. 7, 293–299 (1992).

    Article  CAS  Google Scholar 

  37. 37

    Mason, H. D. et al. Estradiol production by granulosa cells of normal and polycystic ovaries: relationship to menstrual cycle history and concentrations of gonadotropins and sex steroids in follicular fluid. J. Clin. Endocrinol. Metab. 79, 1355–1360 (1994).

    CAS  PubMed  Google Scholar 

  38. 38

    DeUgarte, C. M., Bartolucci, A. A. & Azziz, R. Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment. Fertil. Steril. 83, 1454–1460 (2005).

    Article  CAS  Google Scholar 

  39. 39

    Legro, R. S., Kunselman, A. R., Dodson, W. C. & Dunaif, A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J. Clin. Endocrinol. Metab. 84, 165–169 (1999).

    CAS  PubMed  Google Scholar 

  40. 40

    Ehrmann, D. A., Kasza, K., Azziz, R., Legro, R. S. & Ghazzi, M. N. Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 90, 66–71 (2005).

    Article  CAS  Google Scholar 

  41. 41

    Ehrmann, D. A. et al. Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J. Clin. Invest. 96, 520–527 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Diamanti-Kandarakis, E., Kouli, C., Alexandraki, K. & Spina, G. Failure of mathematical indices to accurately assess insulin resistance in lean, overweight, or obese women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 89, 1273–1276 (2004).

    Article  CAS  Google Scholar 

  43. 43

    Yildiz, B. O., Knochenhauer, E. S. & Azziz, R. Impact of obesity on the risk for polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 93, 162–168 (2008).

    Article  CAS  Google Scholar 

  44. 44

    Carmina, E. et al. Abdominal fat quantity and distribution in women with polycystic ovary syndrome and extent of its relation to insulin resistance. J. Clin. Endocrinol. Metab. 92, 2500–2505 (2007).

    Article  CAS  Google Scholar 

  45. 45

    Ciaraldi, T. P. et al. Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. J. Clin. Endocrinol. Metab. 75, 577–583 (1992).

    CAS  PubMed  Google Scholar 

  46. 46

    Dunaif, A., Wu, X., Lee, A. & Diamanti-Kandarakis, E. Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). Am. J. Physiol. Endocrinol. Metab. 281, E392–E399 (2001).

    Article  CAS  Google Scholar 

  47. 47

    Ciaraldi, T. P., Aroda, V., Mudaliar, S., Chang, R. J. & Henry, R. R. Polycystic ovary syndrome is associated with tissue-specific differences in insulin resistance. J. Clin. Endocrinol. Metab. 94, 157–163 (2009).

    Article  CAS  Google Scholar 

  48. 48

    Rosenbaum, D., Haber, R. S. & Dunaif, A. Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes. Am. J. Physiol. 264, E197–E202 (1993).

    CAS  PubMed  Google Scholar 

  49. 49

    Ciaraldi, T. P. Molecular defects of insulin action in the polycystic ovary syndrome: possible tissue specificity. J. Pediatr. Endocrinol. Metab. 13 (Suppl. 5), 1291–1293 (2000).

    PubMed  Google Scholar 

  50. 50

    Ciaraldi, T. P. et al. Cellular insulin resistance in adipocytes from obese polycystic ovary syndrome subjects involves adenosine modulation of insulin sensitivity. J. Clin. Endocrinol. Metab. 82, 1421–1425 (1997).

    CAS  PubMed  Google Scholar 

  51. 51

    Glintborg, D. et al. Impaired insulin activation and dephosphorylation of glycogen synthase in skeletal muscle of women with polycystic ovary syndrome is reversed by pioglitazone treatment. J. Clin. Endocrinol. Metab. 93, 3618–3626 (2008).

    Article  CAS  Google Scholar 

  52. 52

    Højlund, K. et al. Impaired insulin-stimulated phosphorylation of Akt and AS160 in skeletal muscle of women with polycystic ovary syndrome is reversed by pioglitazone treatment. Diabetes 57, 357–366 (2008).

    Article  CAS  Google Scholar 

  53. 53

    Ibáñez, L. et al. Low body adiposity and high leptinemia in breast-fed infants born small-for-gestational-age. J. Pediatr. 156, 145–147 (2010).

    Article  Google Scholar 

  54. 54

    Virtue, S. & Vidal-Puig, A. It's not how fat you are, it's what you do with it that counts. PLoS Biol. 6, e237 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Virtue, S. & Vidal-Puig, A. Adipose tissue expandability, lipotoxicity and the metabolic syndrome—an allostatic perspective. Biochim. Biophys. Acta 1801, 338–349 (2010).

    Article  CAS  Google Scholar 

  56. 56

    Chazenbalk, G. et al. Regulation of adiponectin secretion by adipocytes in the polycystic ovary syndrome: role of tumor necrosis factor-{alpha}. J. Clin. Endocrinol. Metab. 95, 935–942 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Lobo, R. A. in Infertility, Contraception, and Reproductive Endocrinology 3rd edn (eds Mishell, D. R. Jr, Davajan, V. & Lobo, R. A.) 447–487 (Blackwell Scientific Publications, Cambridge, 1991).

    Google Scholar 

  58. 58

    Blank, S. K., McCartney, C. R. & Marshall, J. C. The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome. Hum. Reprod. Update 12, 351–361 (2006).

    Article  CAS  Google Scholar 

  59. 59

    McCartney, C. R., Eagleson, C. A. & Marshall, J. C. Regulation of gonadotropin secretion: implications for polycystic ovary syndrome. Semin. Reprod. Med. 20, 317–326 (2002).

    Article  CAS  Google Scholar 

  60. 60

    Waldstreicher, J., Santoro, N. F., Hall, J. E., Filicori, M. & Crowley, W. F. Jr. Hyperfunction of the hypothalamic–pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J. Clin. Endocrinol. Metab. 66, 165–172 (1988).

    Article  CAS  Google Scholar 

  61. 61

    Chhabra, S. et al. Progesterone inhibition of the hypothalamic gonadotropin-releasing hormone pulse generator: evidence for varied effects in hyperandrogenemic adolescent girls. J. Clin. Endocrinol. Metab. 90, 2810–2815 (2005).

    Article  CAS  Google Scholar 

  62. 62

    Marshall, J. C. & Eagleson, C. A. Neuroendocrine aspects of polycystic ovary syndrome. Endocrinol. Metab. Clin. North Am. 28, 295–324 (1999).

    Article  CAS  Google Scholar 

  63. 63

    Eagleson, C. A. et al. Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J. Clin. Endocrinol. Metab. 85, 4047–4052 (2000).

    CAS  PubMed  Google Scholar 

  64. 64

    Barnes, R. B. et al. Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women. J. Clin. Endocrinol. Metab. 79, 1328–1333 (1994).

    CAS  PubMed  Google Scholar 

  65. 65

    Rosenfield, R. L., Barnes, R. B., Cara, J. F. & Lucky, A. W. Dysregulation of cytochrome P450c 17 alpha as the cause of polycystic ovarian syndrome. Fertil. Steril. 53, 785–791 (1990).

    Article  CAS  Google Scholar 

  66. 66

    Pagán, Y. L. et al. Inverse relationship between luteinizing hormone and body mass index in polycystic ovarian syndrome: investigation of hypothalamic and pituitary contributions. J. Clin. Endocrinol. Metab. 91, 1309–1316 (2006).

    Article  CAS  Google Scholar 

  67. 67

    Srouji, S. S. et al. Pharmacokinetic factors contribute to the inverse relationship between luteinizing hormone and body mass index in polycystic ovarian syndrome. J. Clin. Endocrinol. Metab. 92, 1347–1352 (2007).

    Article  CAS  Google Scholar 

  68. 68

    Hall, J. E., Taylor, A. E., Hayes, F. J. & Crowley, W. F. Jr. Insights into hypothalamic–pituitary dysfunction in polycystic ovary syndrome. J. Endocrinol. Invest. 21, 602–611 (1998).

    Article  CAS  Google Scholar 

  69. 69

    Taylor, A. E. et al. Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 82, 2248–2256 (1997).

    CAS  PubMed  Google Scholar 

  70. 70

    Abbott, D. H., Barnett, D. K., Bruns, C. M. & Dumesic, D. A. Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? Hum. Reprod. Update 11, 357–374 (2005).

    Article  CAS  Google Scholar 

  71. 71

    Dumesic, D. A., Abbott, D. H. & Padmanabhan, V. Polycystic ovary syndrome and its developmental origins. Rev. Endocr. Metab. Disord. 8, 127–141 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Abbott, D. H. et al. Endocrine antecedents of polycystic ovary syndrome in fetal and infant prenatally androgenized female rhesus monkeys. Biol. Reprod. 79, 154–163 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Abbott, D. H., Tarantal, A. F. & Dumesic, D. A. Fetal, infant, adolescent and adult phenotypes of polycystic ovary syndrome in prenatally androgenized female rhesus monkeys. Am. J. Primatol. 71, 776–784 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Padmanabhan, V., Manikkam, M., Recabarren, S. & Foster, D. Prenatal testosterone excess programs reproductive and metabolic dysfunction in the female. Mol. Cell. Endocrinol. 246, 165–174 (2006).

    Article  CAS  Google Scholar 

  75. 75

    Padmanabhan, V., Veiga-Lopez, A., Abbott, D. & Dumesic, D. in Novel Concepts in Ovarian Endocrinology (ed. Gonzalez-Bulnez, A.) 329–352 (Transworld Research Network, Kerala, 2007).

    Google Scholar 

  76. 76

    Dumesic, D. A., Schramm, R. D. & Abbott, D. H. Early origins of polycystic ovary syndrome. Reprod. Fertil. Dev. 17, 349–360 (2005).

    Article  CAS  Google Scholar 

  77. 77

    Hickey, M. et al. The relationship between maternal and umbilical cord androgen levels and polycystic ovary syndrome in adolescence: a prospective cohort study. J. Clin. Endocrinol. Metab. 94, 3714–3720 (2009).

    Article  CAS  Google Scholar 

  78. 78

    de Zegher, F. & Ibáñez, L. Early origins of polycystic ovary syndrome: hypotheses may change without notice. J. Clin. Endocrinol. Metab. 94, 3682–3685 (2009).

    Article  CAS  Google Scholar 

  79. 79

    Anderson, H. et al. Infants of women with polycystic ovary syndrome have lower cord blood androstenedione and estradiol levels. J. Clin. Endocrinol. Metab. 95, 2180–2186 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Barry, J. A. et al. Umbilical vein testosterone in female infants born to mothers with polycystic ovary syndrome is elevated to male levels. J. Obstet. Gynaecol. 30, 444–446 (2010).

    Article  CAS  Google Scholar 

  81. 81

    Crisosto, N. et al. Anti-Müllerian hormone levels in peripubertal daughters of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 92, 2739–2743 (2007).

    Article  CAS  Google Scholar 

  82. 82

    Sir-Petermann, T. et al. Increased anti-Müllerian hormone serum concentrations in prepubertal daughters of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 91, 3105–3109 (2006).

    Article  CAS  Google Scholar 

  83. 83

    Sir-Petermann, T. et al. Metabolic and reproductive features before and during puberty in daughters of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 94, 1923–1930 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Hart, R. et al. Circulating maternal testosterone concentrations at 18 weeks of gestation predict circulating levels of antimüllerian hormone in adolescence: a prospective cohort study. Fertil. Steril. 94, 1544–1547 (2010).

    Article  CAS  Google Scholar 

  85. 85

    Maliqueo, M. et al. Metabolic parameters in cord blood of newborns of women with polycystic ovary syndrome. Fertil. Steril. 92, 277–282 (2009).

    Article  CAS  Google Scholar 

  86. 86

    Ibáñez, L., Potau, N., Francois, I. & de Zegher, F. Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J. Clin. Endocrinol. Metab. 83, 3558–3562 (1998).

    Article  Google Scholar 

  87. 87

    Rosenfield, R. L. Clinical review: Identifying children at risk for polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 92, 787–796 (2007).

    Article  CAS  Google Scholar 

  88. 88

    Maliqueo, M. et al. Adrenal function during childhood and puberty in daughters of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 94, 3282–3288 (2009).

    Article  CAS  Google Scholar 

  89. 89

    Franks, S. Polycystic ovary syndrome in adolescents. Int. J. Obes. (Lond.) 32, 1035–1041 (2008).

    Article  CAS  Google Scholar 

  90. 90

    McCartney, C. R. et al. Obesity and sex steroid changes across puberty: evidence for marked hyperandrogenemia in pre- and early pubertal obese girls. J. Clin. Endocrinol. Metab. 92, 430–436 (2007).

    Article  CAS  Google Scholar 

  91. 91

    Ferriman, D. & Purdie, A. W. The inheritance of polycystic ovarian disease and a possible relationship to premature balding. Clin. Endocrinol. (Oxf.) 11, 291–300 (1979).

    Article  CAS  Google Scholar 

  92. 92

    Hague, W. M., Adams, J., Reeders, S. T., Peto, T. E. & Jacobs, H. S. Familial polycystic ovaries: a genetic disease? Clin. Endocrinol. (Oxf.) 29, 593–605 (1988).

    Article  CAS  Google Scholar 

  93. 93

    Kahsar-Miller, M. D., Nixon, C., Boots, L. R., Go, R. C. & Azziz, R. Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS. Fertil. Steril. 75, 53–58 (2001).

    Article  CAS  Google Scholar 

  94. 94

    Legro, R. S., Driscoll, D., Strauss, J. F. 3rd, Fox, J. & Dunaif, A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc. Natl Acad. Sci. USA 95, 14956–14960 (1998).

    Article  CAS  Google Scholar 

  95. 95

    Lunde, O., Magnus, P., Sandvik, L. & Høglo, S. Familial clustering in the polycystic ovarian syndrome. Gynecol. Obstet. Invest. 28, 23–30 (1989).

    Article  CAS  Google Scholar 

  96. 96

    Wilroy, R. S. Jr et al. Hyperthecosis: an inheritable form of polycystic ovarian disease. Birth Defects Orig. Artic. Ser. 11, 81–85 (1975).

    CAS  PubMed  Google Scholar 

  97. 97

    Vink, J. M., Sadrzadeh, S., Lambalk, C. B. & Boomsma, D. I. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J. Clin. Endocrinol. Metab. 91, 2100–2104 (2006).

    Article  CAS  Google Scholar 

  98. 98

    Colilla, S., Cox, N. J. & Ehrmann, D. A. Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their first degree relatives. J. Clin. Endocrinol. Metab. 86, 2027–2031 (2001).

    CAS  PubMed  Google Scholar 

  99. 99

    Legro, R. S. et al. Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 87, 2134–2138 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Kaushal, R., Parchure, N., Bano, G., Kaski, J. C. & Nussey, S. S. Insulin resistance and endothelial dysfunction in the brothers of Indian subcontinent Asian women with polycystic ovaries. Clin. Endocrinol. (Oxf.) 60, 322–328 (2004).

    Article  CAS  Google Scholar 

  101. 101

    Coviello, A. D., Sam, S., Legro, R. S. & Dunaif, A. High prevalence of metabolic syndrome in first-degree male relatives of women with polycystic ovary syndrome is related to high rates of obesity. J. Clin. Endocrinol. Metab. 94, 4361–4366 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Goodarzi, M. O. Looking for polycystic ovary syndrome genes: rational and best strategy. Semin. Reprod. Med. 26, 5–13 (2008).

    Article  CAS  Google Scholar 

  103. 103

    Gaasenbeek, M. et al. Large-scale analysis of the relationship between CYP11A promoter variation, polycystic ovarian syndrome, and serum testosterone. J. Clin. Endocrinol. Metab. 89, 2408–2413 (2004).

    Article  CAS  Google Scholar 

  104. 104

    Goodarzi, M. O. et al. Nonreplication of the type 5 17beta-hydroxysteroid dehydrogenase gene association with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 93, 300–303 (2008).

    Article  CAS  Google Scholar 

  105. 105

    Powell, B. L. et al. Analysis of multiple data sets reveals no association between the insulin gene variable number tandem repeat element and polycystic ovary syndrome or related traits. J. Clin. Endocrinol. Metab. 90, 2988–2993 (2005).

    Article  CAS  Google Scholar 

  106. 106

    Urbanek, M. et al. Candidate gene region for polycystic ovary syndrome on chromosome 19p13.2. J. Clin. Endocrinol. Metab. 90, 6623–6629 (2005).

    Article  CAS  Google Scholar 

  107. 107

    Jones, M. R. et al. Independent confirmation of association between metabolic phenotypes of polycystic ovary syndrome and variation in the type 6 17beta-hydroxysteroid dehydrogenase gene. J. Clin. Endocrinol. Metab. 94, 5034–5038 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Ewens, K. G. et al. Family-based analysis of candidate genes for polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 95, 2306–2315 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Lindgren, C. M. & McCarthy, M. I. Mechanisms of disease: genetic insights into the etiology of type 2 diabetes and obesity. Nat. Clin. Pract. Endocrinol. Metab. 4, 156–163 (2008).

    Article  CAS  Google Scholar 

  110. 110

    Carmina, E. et al. Circulating levels of adipose products and differences in fat distribution in the ovulatory and anovulatory phenotypes of polycystic ovary syndrome. Fertil. Steril. 91 (Suppl.), 1332–1335 (2009).

    Article  Google Scholar 

  111. 111

    Carmina, E., Chu, M. C., Longo, R. A., Rini, G. B. & Lobo, R. A. Phenotypic variation in hyperandrogenic women influences the findings of abnormal metabolic and cardiovascular risk parameters. J. Clin. Endocrinol. Metab. 90, 2545–2549 (2005).

    Article  CAS  Google Scholar 

  112. 112

    Dewailly, D., Catteau-Jonard, S., Reyss, A. C., Leroy, M. & Pigny, P. Oligoanovulation with polycystic ovaries but not overt hyperandrogenism. J. Clin. Endocrinol. Metab. 91, 3922–3927 (2006).

    Article  CAS  Google Scholar 

  113. 113

    Moran, L. & Teede, H. Metabolic features of the reproductive phenotypes of polycystic ovary syndrome. Hum. Reprod. Update 15, 477–488 (2009).

    Article  CAS  Google Scholar 

  114. 114

    Rizzo, M. et al. Milder forms of atherogenic dyslipidemia in ovulatory versus anovulatory polycystic ovary syndrome phenotype. Hum. Reprod. 24, 2286–2292 (2009).

    Article  CAS  Google Scholar 

  115. 115

    Welt, C. K. et al. Characterizing discrete subsets of polycystic ovary syndrome as defined by the Rotterdam criteria: the impact of weight on phenotype and metabolic features. J. Clin. Endocrinol. Metab. 91, 4842–4848 (2006).

    Article  CAS  Google Scholar 

  116. 116

    Carmina, E., Legro, R. S., Stamets, K., Lowell, J. & Lobo, R. A. Difference in body weight between American and Italian women with polycystic ovary syndrome: influence of the diet. Hum. Reprod. 18, 2289–2293 (2003).

    Article  Google Scholar 

  117. 117

    Clark, A. M., Thornley, B., Tomlinson, L., Galletley, C. & Norman, R. J. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum. Reprod. 13, 1502–1505 (1998).

    Article  CAS  Google Scholar 

  118. 118

    Guzick, D. S., Wing, R., Smith, D., Berga, S. L. & Winters, S. J. Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil. Steril. 61, 598–604 (1994).

    Article  CAS  Google Scholar 

  119. 119

    Huber-Buchholz, M. M., Carey, D. G. & Norman, R. J. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J. Clin. Endocrinol. Metab. 84, 1470–1474 (1999).

    CAS  PubMed  Google Scholar 

  120. 120

    Pasquali, R. et al. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J. Clin. Endocrinol. Metab. 68, 173–179 (1989).

    Article  CAS  Google Scholar 

  121. 121

    Moran, L. J., Pasquali, R., Teede, H. J., Hoeger, K. M. & Norman, R. J. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil. Steril. 92, 1966–1982 (2009).

    Article  Google Scholar 

  122. 122

    Bruner, B., Chad, K. & Chizen, D. Effects of exercise and nutritional counseling in women with polycystic ovary syndrome. Appl. Physiol. Nutr. Metab. 31, 384–391 (2006).

    Article  CAS  Google Scholar 

  123. 123

    Vandenberg, L. N., Maffini, M. V., Sonnenschein, C., Rubin, B. S. & Soto, A. M. Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption. Endocr. Rev. 30, 75–95 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Zhou, W., Liu, J., Liao, L., Han, S. & Liu, J. Effect of bisphenol A on steroid hormone production in rat ovarian theca-interstitial and granulosa cells. Mol. Cell. Endocrinol. 283, 12–18 (2008).

    Article  CAS  Google Scholar 

  125. 125

    Alonso-Magdalena, P., Morimoto, S., Ripoll, C., Fuentes, E. & Nadal, A. The estrogenic effect of bisphenol A disrupts pancreatic beta-cell function in vivo and induces insulin resistance. Environ. Health Perspect. 114, 106–112 (2006).

    Article  CAS  Google Scholar 

  126. 126

    Takeuchi, T., Tsutsumi, O., Ikezuki, Y., Takai, Y. & Taketani, Y. Positive relationship between androgen and the endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction. Endocr. J. 51, 165–169 (2004).

    Article  CAS  Google Scholar 

  127. 127

    Takeuchi, T. et al. Gender difference in serum bisphenol A levels may be caused by liver UDP-glucuronosyltransferase activity in rats. Biochem. Biophys. Res. Commun. 325, 549–554 (2004).

    Article  CAS  Google Scholar 

  128. 128

    Diamanti-Kandarakis, E. et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr. Rev. 30, 293–342 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    [No authors listed] Consensus on infertility treatment related to polycystic ovary syndrome. Fertil. Steril. 89, 505–522 (2008).

  130. 130

    Schramm, R. D. & Bavister, B. D. A macaque model for studying mechanisms controlling oocyte development and maturation in human and non-human primates. Hum. Reprod. 14, 2544–2555 (1999).

    Article  CAS  Google Scholar 

  131. 131

    Hardy, K. et al. Normal development and metabolic activity of preimplantation embryos in vitro from patients with polycystic ovaries. Hum. Reprod. 10, 2125–2135 (1995).

    Article  CAS  Google Scholar 

  132. 132

    Heijnen, E. M. et al. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum. Reprod. Update 12, 13–21 (2006).

    Article  CAS  Google Scholar 

  133. 133

    Urman, B. et al. The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins. Fertil. Steril. 57, 1269–1273 (1992).

    Article  CAS  Google Scholar 

  134. 134

    Hwang, J. L. et al. IVF versus ICSI in sibling oocytes from patients with polycystic ovarian syndrome: a randomized controlled trial. Hum. Reprod. 20, 1261–1265 (2005).

    Article  Google Scholar 

  135. 135

    Ludwig, M., Finas, D. F., al-Hasani, S., Diedrich, K. & Ortmann, O. Oocyte quality and treatment outcome in intracytoplasmic sperm injection cycles of polycystic ovarian syndrome patients. Hum. Reprod. 14, 354–358 (1999).

    Article  CAS  Google Scholar 

  136. 136

    Sengoku, K. et al. The chromosomal normality of unfertilized oocytes from patients with polycystic ovarian syndrome. Hum. Reprod. 12, 474–477 (1997).

    Article  CAS  Google Scholar 

  137. 137

    Chang, P. L. et al. Normal ovulatory women with polycystic ovaries have hyperandrogenic pituitary-ovarian responses to gonadotropin-releasing hormone-agonist testing. J. Clin. Endocrinol. Metab. 85, 995–1000 (2000).

    CAS  PubMed  Google Scholar 

  138. 138

    Cano, F. et al. Oocyte quality in polycystic ovaries revisited: identification of a particular subgroup of women. J. Assist. Reprod. Genet. 14, 254–261 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Tian, L., Shen, H., Lu, Q., Norman, R. J. & Wang, J. Insulin resistance increases the risk of spontaneous abortion after assisted reproduction technology treatment. J. Clin. Endocrinol. Metab. 92, 1430–1433 (2007).

    Article  CAS  Google Scholar 

  140. 140

    Foong, S. C. et al. Follicle luteinization in hyperandrogenic follicles of polycystic ovary syndrome patients undergoing gonadotropin therapy for in vitro fertilization. J. Clin. Endocrinol. Metab. 91, 2327–2333 (2006).

    Article  CAS  Google Scholar 

  141. 141

    Phy, J. L. et al. Insulin and messenger ribonucleic acid expression of insulin receptor isoforms in ovarian follicles from nonhirsute ovulatory women and polycystic ovary syndrome patients. J. Clin. Endocrinol. Metab. 89, 3561–3566 (2004).

    Article  CAS  Google Scholar 

  142. 142

    Wood, J. R., Dumesic, D. A., Abbott, D. H. & Strauss, J. F. 3rd Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis. J. Clin. Endocrinol. Metab. 92, 705–713 (2007).

    Article  CAS  Google Scholar 

  143. 143

    Wijeyaratne, C. N., Balen, A. H., Barth, J. H. & Belchetz, P. E. Clinical manifestations and insulin resistance (IR) in polycystic ovary syndrome (PCOS) among South Asians and Caucasians: is there a difference? Clin. Endocrinol. (Oxf.) 57, 343–350 (2002).

    Article  CAS  Google Scholar 

  144. 144

    Palep-Singh, M., Picton, H. M., Vrotsou, K., Maruthini, D. & Balen, A. H. South Asian women with polycystic ovary syndrome exhibit greater sensitivity to gonadotropin stimulation with reduced fertilization and ongoing pregnancy rates than their Caucasian counterparts. Eur. J. Obstet. Gynecol. Reprod. Biol. 134, 202–207 (2007).

    Article  CAS  Google Scholar 

  145. 145

    Dumesic, D. A., Padmanabhan, V. & Abbott, D. H. Polycystic ovary syndrome and oocyte developmental competence. Obstet. Gynecol. Surv. 63, 39–48 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  146. 146

    Sir-Petermann, T. et al. Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum. Reprod. 17, 2573–2579 (2002).

    Article  CAS  Google Scholar 

  147. 147

    Boomsma, C. M. et al. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum. Reprod. Update 12, 673–683 (2006).

    Article  CAS  Google Scholar 

  148. 148

    Mikola, M., Hiilesmaa, V., Halttunen, M., Suhonen, L. & Tiitinen, A. Obstetric outcome in women with polycystic ovarian syndrome. Hum. Reprod. 16, 226–229 (2001).

    Article  CAS  Google Scholar 

  149. 149

    Sir-Petermann, T. et al. Birth weight in offspring of mothers with polycystic ovarian syndrome. Hum. Reprod. 20, 2122–2126 (2005).

    Article  Google Scholar 

  150. 150

    Urman, B., Sarac, E., Dogan, L. & Gurgan, T. Pregnancy in infertile PCOD patients. Complications and outcome. J. Reprod. Med. 42, 501–505 (1997).

    CAS  PubMed  Google Scholar 

  151. 151

    Weerakiet, S. et al. Prevalence of gestational diabetes mellitus and pregnancy outcomes in Asian women with polycystic ovary syndrome. Gynecol. Endocrinol. 19, 134–140 (2004).

    Article  CAS  Google Scholar 

  152. 152

    Pandolfi, C. et al. Low birth weight and later development of insulin resistance and biochemical/clinical features of polycystic ovary syndrome. Metabolism 57, 999–1004 (2008).

    Article  CAS  Google Scholar 

  153. 153

    Laitinen, J. et al. Body size from birth to adulthood as a predictor of self-reported polycystic ovary syndrome symptoms. Int. J. Obes. Relat. Metab. Disord. 27, 710–715 (2003).

    Article  CAS  Google Scholar 

  154. 154

    Legro, R. S. et al. Associations of birthweight and gestational age with reproductive and metabolic phenotypes in women with polycystic ovarian syndrome and their first-degree relatives. J. Clin. Endocrinol. Metab. 95, 789–799 (2010).

    Article  CAS  Google Scholar 

  155. 155

    Sadrzadeh, S. et al. Birth weight and age at menarche in patients with polycystic ovary syndrome or diminished ovarian reserve, in a retrospective cohort. Hum. Reprod. 18, 2225–2230 (2003).

    Article  CAS  Google Scholar 

  156. 156

    Melo, A. S. et al. High prevalence of polycystic ovary syndrome in women born small for gestational age. Hum. Reprod. 25, 2124–2131 (2010).

    Article  CAS  Google Scholar 

  157. 157

    Corbould, A. Insulin resistance in skeletal muscle and adipose tissue in polycystic ovary syndrome: are the molecular mechanisms distinct from type 2 diabetes? Panminerva Med. 50, 279–294 (2008).

    CAS  PubMed  Google Scholar 

  158. 158

    Dunaif, A., Segal, K. R., Futterweit, W. & Dobrjansky, A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38, 1165–1174 (1989).

    Article  CAS  Google Scholar 

  159. 159

    Carmina, E. & Lobo, R. A. Use of fasting blood to assess the prevalence of insulin resistance in women with polycystic ovary syndrome. Fertil. Steril. 82, 661–665 (2004).

    Article  Google Scholar 

  160. 160

    Ehrmann, D. A., Barnes, R. B., Rosenfield, R. L., Cavaghan, M. K. & Imperial, J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 22, 141–146 (1999).

    Article  CAS  Google Scholar 

  161. 161

    Tominaga, M. et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care 22, 920–924 (1999).

    Article  CAS  Google Scholar 

  162. 162

    Palmert, M. R. et al. Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 87, 1017–1023 (2002).

    Article  CAS  Google Scholar 

  163. 163

    Boudreaux, M. Y., Talbott, E. O., Kip, K. E., Brooks, M. M. & Witchel, S. F. Risk of T2DM and impaired fasting glucose among PCOS subjects: results of an 8-year follow-up. Curr. Diab. Rep. 6, 77–83 (2006).

    Article  CAS  Google Scholar 

  164. 164

    Legro, R. S., Gnatuk, C. L., Kunselman, A. R. & Dunaif, A. Changes in glucose tolerance over time in women with polycystic ovary syndrome: a controlled study. J. Clin. Endocrinol. Metab. 90, 3236–3242 (2005).

    Article  CAS  Google Scholar 

  165. 165

    Norman, R. J., Masters, L., Milner, C. R., Wang, J. X. & Davies, M. J. Relative risk of conversion from normoglycaemia to impaired glucose tolerance or non-insulin dependent diabetes mellitus in polycystic ovarian syndrome. Hum. Reprod. 16, 1995–1998 (2001).

    Article  CAS  Google Scholar 

  166. 166

    Moran, L. J., Misso, M. L., Wild, R. A. & Norman, R. J. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum. Reprod. Update 16, 347–363 (2010).

    Article  CAS  Google Scholar 

  167. 167

    Cibula, D. et al. Increased risk of non-insulin dependent diabetes mellitus, arterial hypertension and coronary artery disease in perimenopausal women with a history of the polycystic ovary syndrome. Hum. Reprod. 15, 785–789 (2000).

    Article  CAS  Google Scholar 

  168. 168

    Legro, R. S., Kunselman, A. R. & Dunaif, A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am. J. Med. 111, 607–613 (2001).

    Article  CAS  Google Scholar 

  169. 169

    Macut, D. et al. Oxidised low-density lipoprotein concentration—early marker of an altered lipid metabolism in young women with PCOS. Eur. J. Endocrinol. 155, 131–136 (2006).

    Article  CAS  Google Scholar 

  170. 170

    Shaw, L. J. et al. Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health--National Heart, Lung, and Blood Institute sponsored Women's Ischemia Syndrome Evaluation. J. Clin. Endocrinol. Metab. 93, 1276–1284 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Talbott, E. O. et al. Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 89, 5454–5461 (2004).

    Article  CAS  Google Scholar 

  172. 172

    Essah, P. A., Nestler, J. E. & Carmina, E. Differences in dyslipidemia between American and Italian women with polycystic ovary syndrome. J. Endocrinol. Invest. 31, 35–41 (2008).

    Article  CAS  Google Scholar 

  173. 173

    Rizzo, M. & Berneis, K. Lipid triad or atherogenic lipoprotein phenotype: a role in cardiovascular prevention? J. Atheroscler. Thromb. 12, 237–239 (2005).

    Article  CAS  Google Scholar 

  174. 174

    Wild, R. A. Long-term health consequences of PCOS. Hum. Reprod. Update 8, 231–241 (2002).

    Article  Google Scholar 

  175. 175

    Rizzo, M., Longo, R. A., Guastella, E. & Carmina, E. Assessing cardiovascular risk in Mediterranean women with polycystic ovary syndrome. J. Endocrinol. Invest. doi:10.3275/7294.

  176. 176

    Valkenburg, O. et al. A more atherogenic serum lipoprotein profile is present in women with polycystic ovary syndrome: a case–control study. J. Clin. Endocrinol. Metab. 93, 470–476 (2008).

    Article  CAS  Google Scholar 

  177. 177

    Holte, J., Bergh, T., Berne, C., Berglund, L. & Lithell, H. Enhanced early insulin response to glucose in relation to insulin resistance in women with polycystic ovary syndrome and normal glucose tolerance. J. Clin. Endocrinol. Metab. 78, 1052–1058 (1994).

    CAS  PubMed  Google Scholar 

  178. 178

    Apridonidze, T., Essah, P. A., Iuorno, M. J. & Nestler, J. E. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 90, 1929–1935 (2005).

    Article  CAS  Google Scholar 

  179. 179

    Dokras, A. et al. Screening women with polycystic ovary syndrome for metabolic syndrome. Obstet. Gynecol. 106, 131–137 (2005).

    Article  Google Scholar 

  180. 180

    Ehrmann, D. A. et al. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 91, 48–53 (2006).

    Article  CAS  Google Scholar 

  181. 181

    Cascella, T. et al. Visceral fat is associated with cardiovascular risk in women with polycystic ovary syndrome. Hum. Reprod. 23, 153–159 (2008).

    Article  CAS  Google Scholar 

  182. 182

    Diamanti-Kandarakis, E., Spina, G., Kouli, C. & Migdalis, I. Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy. J. Clin. Endocrinol. Metab. 86, 4666–4673 (2001).

    Article  CAS  Google Scholar 

  183. 183

    Carmina, E. et al. Endothelial dysfunction in PCOS: role of obesity and adipose hormones. Am. J. Med. 119, 356.e1–356.e6 (2006).

    Article  CAS  Google Scholar 

  184. 184

    Guzick, D. S. et al. Carotid atherosclerosis in women with polycystic ovary syndrome: initial results from a case-control study. Am. J. Obstet. Gynecol. 174, 1224–1229 (1996).

    Article  CAS  Google Scholar 

  185. 185

    Luque-Ramírez, M., Mendieta-Azcona, C., Alvarez-Blasco, F. & Escobar-Morreale, H. F. Androgen excess is associated with the increased carotid intima-media thickness observed in young women with polycystic ovary syndrome. Hum. Reprod. 22, 3197–3203 (2007).

    Article  CAS  Google Scholar 

  186. 186

    Talbott, E. O. et al. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arterioscler. Thromb. Vasc. Biol. 20, 2414–2421 (2000).

    Article  CAS  Google Scholar 

  187. 187

    Christian, R. C. et al. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 88, 2562–2568 (2003).

    Article  CAS  Google Scholar 

  188. 188

    Birdsall, M. A., Farquhar, C. M. & White, H. D. Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catheterization. Ann. Intern. Med. 126, 32–35 (1997).

    Article  CAS  Google Scholar 

  189. 189

    Wild, R. A. et al. Clinical signs of androgen excess as risk factors for coronary artery disease. Fertil. Steril. 54, 255–259 (1990).

    Article  CAS  Google Scholar 

  190. 190

    Azevedo, G. D. et al. Menstrual cycle irregularity as a marker of cardiovascular risk factors at postmenopausal years. Arq. Bras. Endocrinol. Metabol. 50, 876–883 (2006).

    Article  Google Scholar 

  191. 191

    Krentz, A. J., von Mühlen, D. & Barrett-Connor, E. Searching for polycystic ovary syndrome in postmenopausal women: evidence of a dose-effect association with prevalent cardiovascular disease. Menopause 14, 284–292 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  192. 192

    Hollinrake, E., Abreu, A., Maifeld, M., Van Voorhis, B. J. & Dokras, A. Increased risk of depressive disorders in women with polycystic ovary syndrome. Fertil. Steril. 87, 1369–1376 (2007).

    Article  Google Scholar 

  193. 193

    Kerchner, A., Lester, W., Stuart, S. P. & Dokras, A. Risk of depression and other mental health disorders in women with polycystic ovary syndrome: a longitudinal study. Fertil. Steril. 91, 207–212 (2009).

    Article  Google Scholar 

  194. 194

    Pasch, L. A. et al. Factors associated with risk for depression among women with polycystic ovarian syndrome. Fertil. Steril. 90 (Suppl.), S178 (2008).

    Article  Google Scholar 

  195. 195

    Guyatt, G., Weaver, B., Cronin, L., Dooley, J. A. & Azziz, R. Health-related quality of life in women with polycystic ovary syndrome, a self-administered questionnaire, was validated. J. Clin. Epidemiol. 57, 1279–1287 (2004).

    Article  Google Scholar 

  196. 196

    Okamura, F. et al. Insulin resistance in patients with depression and its changes during the clinical course of depression: minimal model analysis. Metabolism 49, 1255–1260 (2000).

    Article  CAS  Google Scholar 

  197. 197

    Rasgon, N. L. et al. Depression in women with polycystic ovary syndrome: clinical and biochemical correlates. J. Affect. Disord. 74, 299–304 (2003).

    Article  Google Scholar 

  198. 198

    Timonen, M. et al. Insulin resistance and depressive symptoms in young adult males: findings from Finnish military conscripts. Psychosom. Med. 69, 723–728 (2007).

    Article  Google Scholar 

  199. 199

    Benson, S. et al. Obesity, depression, and chronic low-grade inflammation in women with polycystic ovary syndrome. Brain Behav. Immun. 22, 177–184 (2008).

    Article  CAS  Google Scholar 

  200. 200

    Howren, M. B., Lamkin, D. M. & Suls, J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom. Med. 71, 171–186 (2009).

    Article  CAS  Google Scholar 

  201. 201

    Weiner, C. L., Primeau, M. & Ehrmann, D. A. Androgens and mood dysfunction in women: comparison of women with polycystic ovarian syndrome to healthy controls. Psychosom. Med. 66, 356–362 (2004).

    CAS  PubMed  Google Scholar 

  202. 202

    Isojärvi, J. I., Laatikainen, T. J., Pakarinen, A. J., Juntunen, K. T. & Myllylä, V. V. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N. Engl. J. Med. 329, 1383–1388 (1993).

    Article  Google Scholar 

  203. 203

    Klipstein, K. G. & Goldberg, J. F. Screening for bipolar disorder in women with polycystic ovary syndrome: a pilot study. J. Affect. Disord. 91, 205–209 (2006).

    Article  Google Scholar 

  204. 204

    Joffe, H. et al. Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism in women with bipolar disorder. Biol. Psychiatry 59, 1078–1086 (2006).

    Article  CAS  Google Scholar 

  205. 205

    Rasgon, N. L. et al. Reproductive function and risk for PCOS in women treated for bipolar disorder. Bipolar Disord. 7, 246–259 (2005).

    Article  Google Scholar 

  206. 206

    Rasgon, N. L. et al. Longitudinal evaluation of reproductive function in women treated for bipolar disorder. J. Affect. Disord. 89, 217–225 (2005).

    Article  Google Scholar 

  207. 207

    Chittenden, B. G., Fullerton, G., Maheshwari, A. & Bhattacharya, S. Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review. Reprod. Biomed. Online 19, 398–405 (2009).

    Article  CAS  Google Scholar 

  208. 208

    Gadducci, A., Gargini, A., Palla, E., Fanucchi, A. & Genazzani, A. R. Polycystic ovary syndrome and gynecological cancers: is there a link? Gynecol. Endocrinol. 20, 200–208 (2005).

    Article  Google Scholar 

  209. 209

    Navaratnarajah, R., Pillay, O. C. & Hardiman, P. Polycystic ovary syndrome and endometrial cancer. Semin. Reprod. Med. 26, 62–71 (2008).

    Article  Google Scholar 

  210. 210

    March, W. A. et al. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum. Reprod. 25, 544–551 (2010).

    Article  Google Scholar 

  211. 211

    Moran, C. et al. Prevalence of polycystic ovary syndrome and related disorders in Mexican women. Gynecol. Obstet. Invest. 69, 274–280 (2010).

    Article  Google Scholar 

  212. 212

    Azziz, R., Dumesic, D. A. & Goodarzi, M. O. Polycystic ovary syndrome: an ancient disorder? Fertil. Steril. doi:10.1016/j.fertnstert.2010.09.032.

  213. 213

    Carmina, E., Guastella, E., Longo, R. A., Rini, G. B. & Lobo, R. A. Correlates of increased lean muscle mass in women with polycystic ovary syndrome. Eur. J. Endocrinol. 161, 583–589 (2009).

    Article  CAS  Google Scholar 

  214. 214

    Good, C., Tulchinsky, M., Mauger, D., Demers, L. M. & Legro, R. S. Bone mineral density and body composition in lean women with polycystic ovary syndrome. Fertil. Steril. 72, 21–25 (1999).

    Article  CAS  Google Scholar 

  215. 215

    Chakravarthy, M. V. & Booth, F. W. Eating, exercise, and “thrifty” genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases. J. Appl. Physiol. 96, 3–10 (2004).

    Article  Google Scholar 

  216. 216

    Corbett, S. J., McMichael, A. J. & Prentice, A. M. Type 2 diabetes, cardiovascular disease, and the evolutionary paradox of the polycystic ovary syndrome: a fertility first hypothesis. Am. J. Hum. Biol. 21, 587–598 (2009).

    Article  Google Scholar 

  217. 217

    Azziz, R. The evaluation and management of hirsutism. Obstet. Gynecol. 101, 995–1007 (2003).

    PubMed  Google Scholar 

  218. 218

    Azziz, R., Waggoner, W. T., Ochoa, T., Knochenhauer, E. S. & Boots, L. R. Idiopathic hirsutism: an uncommon cause of hirsutism in Alabama. Fertil. Steril. 70, 274–278 (1998).

    Article  CAS  Google Scholar 

  219. 219

    Azziz, R. et al. Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study. Fertil. Steril. 72, 915–925 (1999).

    Article  CAS  Google Scholar 

  220. 220

    Martin, K. A. et al. Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 93, 1105–1120 (2008).

    Article  CAS  Google Scholar 

  221. 221

    Diamanti-Kandarakis, E., Christakou, C. D., Kandaraki, E. & Economou, F. N. Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur. J. Endocrinol. 162, 193–212 (2010).

    Article  CAS  Google Scholar 

  222. 222

    Graham, D. J. et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 304, 411–418 (2010).

    Article  CAS  Google Scholar 

  223. 223

    Salley, K. E. et al. Glucose intolerance in polycystic ovary syndrome--a position statement of the Androgen Excess Society. J. Clin. Endocrinol. Metab. 92, 4546–4556 (2007).

    Article  CAS  Google Scholar 

  224. 224

    Wild, R. A. et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J. Clin. Endocrinol. Metab. 95, 2038–2049 (2010).

    Article  CAS  Google Scholar 

  225. 225

    Nestler, J. E. Metformin in the treatment of infertility in polycystic ovarian syndrome: an alternative perspective. Fertil. Steril. 90, 14–16 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. 226

    Casper, R. F. & Mitwally, M. F. Review: aromatase inhibitors for ovulation induction. J. Clin. Endocrinol. Metab. 91, 760–771 (2006).

    Article  CAS  Google Scholar 

  227. 227

    Palomba, S., Falbo, A., Zullo, F. & Orio, F. Jr. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr. Rev. 30, 1–50 (2009).

    Article  CAS  Google Scholar 

  228. 228

    Badawy, A., Abdel Aal, I. & Abulatta, M. Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial. Fertil. Steril. 92, 849–852 (2009).

    Article  CAS  Google Scholar 

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All authors contributed to researching data for the article, a substantial contribution to the discussion of content, writing, and reviewing/editing the manuscript before submission.

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Correspondence to Ricardo Azziz.

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Evaluation of patients with potential hyperandrogenism (PPT 73 kb)

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Goodarzi, M., Dumesic, D., Chazenbalk, G. et al. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 7, 219–231 (2011). https://doi.org/10.1038/nrendo.2010.217

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