Endocrinol Metab.  2012 Sep;27(3):180-190. 10.3803/EnM.2012.27.3.180.

Reproduction and Metabolism: Insights from Polycystic Ovary Syndrome

• Jasti P
• Dunaif A

• KMID: 2282400
• DOI: http://doi.org/10.3803/EnM.2012.27.3.180

Abstract

Until the 1980s, polycystic ovary syndrome (PCOS) was considered to be a poorly defined reproductive disorder. During that decade, it was recognized that PCOS was associated with profound insulin resistance and a substantially increased risk for type 2 diabetes mellitus in young women. Accordingly, the mechanisms linking the reproductive and metabolic features of the syndrome became the subject of intense investigation. Insulin is now recognized as a reproductive as well as a metabolic hormone and insulin signaling in the central nervous system participates in normal reproductive function. These insights have been directly translated into a novel therapy for PCOS with insulin sensitizing drugs. Androgens also have reversible metabolic actions to decrease insulin sensitivity and increase visceral fat. Prenatal androgen administration to non-human primates, sheep and rodents produces reproductive and metabolic features of PCOS suggesting that the disorder also has developmental origins. PCOS is highly heritable and male as well as female relatives have reproductive and metabolic phenotypes. A number of confirmed genetic susceptibility loci have now been mapped for PCOS and genes in well-known as well as novel biologic pathways have been implicated in disease pathogenesis.

Keyword

Androgens; Fetal origins; Genetics; Insulin; Insulin resistance; Polycystic ovary syndrome; Signal transduction

MeSH Terms

Androgens
Central Nervous System
Diabetes Mellitus, Type 2
Female
Genetic Predisposition to Disease
Humans
Insulin
Insulin Resistance
Intra-Abdominal Fat
Male
Phenotype
Polycystic Ovary Syndrome
Primates
Reproduction
Rodentia
Sheep
Signal Transduction
Androgens
Insulin

Figure

• 

  Fig. 1 Pathophysiology of the polycystic ovary syndrome (PCOS). The frequency of pulsatile gonadotropin-releasing hormone (GnRH) release is increased, which selectively increases LH secretion, while simultaneously suppressing follicle-stimulating hormone (FSH) release. Luteinizing hormone (LH) stimulates ovarian theca cell testosterone (T) production. There are also constitutive increases in the activity of multiple steroidogenic enzymes in polycystic ovaries contributing to increased androgen production. A similar defect is postulated to be present in the adrenal gland, which shares these steroidogenic enzymes, contributing to adrenal androgen excess that often occurs in PCOS (not shown). T is incompletely aromatized into estradiol by the adjacent granulosa cells because of relative FSH deficiency. Accordingly, increased circulating T levels are the result of increased LH-mediated T production, intrinsic increases in thecal T biosynthesis and decreased conversion of T into estradiol. T acts in the periphery to produce signs of androgen excess, such as hirsutism, acne and alopecia. T and androstenedione can also be aromatized extragonadally to estradiol and estrone, respectively, resulting in unopposed estrogen action on the endometrium (not shown). T feeds back on the hypothalamus to decrease the sensitivity to the normal feedback effects of estradiol and progesterone to slow GnRH pulse frequency. Insulin resistance is commonly associated with PCOS. Used with permission Andrea Dunaif.

• 

  Fig. 2 Molecular mechanisms of insulin resistance in polycystic ovary syndrome (PCOS). The number and binding affinity of the insulin receptor is unchanged in PCOS, but there is a post-binding defect in insulin signaling resulting in marked decreases in insulin sensitivity in classic target tissues, such as muscle and adipocytes. There is a more modest defect in the maximal responsiveness to insulin of glucose uptake. The signaling defect appears to be due to increased inhibitory serine phosphorylation of the insulin receptor and IRS-1 secondary to intracellular serine kinases. This abnormality results in a selective decrease in insulin-mediated IRS-1-associated PI3K activation and resistance to insulin's metabolic action to stimulate glucose uptake. However, mitogenic signaling is preserved and there is constitutive activation of kinases in this MAPK-ERK mitogenic pathway in PCOS. Furthermore, it appears that kinases in this pathway feedback to decrease metabolic signaling by causing inhibitory serine phosphorylation of IRS-1. This feedback is increased in PCOS because this mitogenic serine pathway is constitutively activated. Serine phosphorylation of P450c17 increases its activity and it has been postulated that the same kinase may inhibit insulin signaling and increase androgen production in PCOS. P, phosphate; S, serine; S-S, disulfide bond; Y, tyrosine. Used with permission Andrea Dunaif.

• 

  Fig. 3 Hypothesis for the Association of Reproduction and Metabolism in polycystic ovary syndrome (PCOS). Hyperinsulinemia resulting from insulin resistance can amplify the reproductive abnormalities of PCOS. Insulin signaling in the central nervous system is important for normal fertility. Androgens can produce insulin resistance and increase visceral fat. Susceptibility genes for PCOS may lead to increased androgen production and defects in insulin signaling. LH, luteinizing hormone. Used with permission Andrea Dunaif.

Reference

1. Morgani GB. De Sedibus et Causis Morborum per Anatomen Indagata [The seats and causes of diseases investigated by anatomy]. 1765. Padua: Remondini.

2. Achard C, Theirs J. Le Virilisme pilaire et son association a l'insuffisance glycolytique (diabete des femme a barbe). Bull Acad Natl Med. 1921. 86:51–83.

3. Vague J. La différentiation sexuelle. Facteur determinant des formes de l'obesité. Presse Med. 1947. 55:339–340.

4. Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM, Roth J. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976. 294:739–745.

5. Taylor SI, Cama A, Accili D, Barbetti F, Quon MJ, de la Luz Sierra M, Suzuki Y, Koller E, Levy-Toledano R, Wertheimer E, Moncadaj VY, Kadowaki H, Kadowaki T. Mutations in the insulin receptor gene. Endocr Rev. 1992. 13:566–595.

6. Semple RK, Savage DB, Cochran EK, Gorden P, O'Rahilly S. Genetic syndromes of severe insulin resistance. Endocr Rev. 2011. 32:498–514.

7. Garg A. Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab. 2011. 96:3313–3325.

8. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012. In press.

9. Burghen GA, Givens JR, Kitabchi AE. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab. 1980. 50:113–116.

10. Flier JS, Eastman RC, Minaker KL, Matteson D, Rowe JW. Acanthosis nigricans in obese women with hyperandrogenism. Characterization of an insulin-resistant state distinct from the type A and B syndromes. Diabetes. 1985. 34:101–107.

11. Dunaif A, Hoffman AR, Scully RE, Flier JS, Longcope C, Levy LJ, Crowley WF Jr. Clinical, biochemical, and ovarian morphologic features in women with acanthosis nigricans and masculinization. Obstet Gynecol. 1985. 66:545–552.

12. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998. 83:3078–3082.

13. Diamanti-Kandarakis E, Kouli CR, Bergiele AT, Filandra FA, Tsianateli TC, Spina GG, Zapanti ED, Bartzis MI. A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab. 1999. 84:4006–4011.

14. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004. 89:2745–2749.

15. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989. 38:1165–1174.

16. O'Meara NM, Blackman JD, Ehrmann DA, Barnes RB, Jaspan JB, Rosenfield RL, Polonsky KS. Defects in beta-cell function in functional ovarian hyperandrogenism. J Clin Endocrinol Metab. 1993. 76:1241–1247.

17. Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005. 90:1929–1935.

18. Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. J Clin Endocrinol Metab. 2006. 91:492–497.

19. Sam S, Legro RS, Bentley-Lewis R, Dunaif A. Dyslipidemia and metabolic syndrome in the sisters of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005. 90:4797–4802.

20. Ehrmann DA, Kasza K, Azziz R, Legro RS. PCOS/Troglitazone Study Group. Troglitazone Study Group: Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005. 90:66–71.

21. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F. National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005. 112:2735–2752.

22. Palmert MR, Gordon CM, Kartashov AI, Legro RS, Emans SJ, Dunaif A. Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002. 87:1017–1023.

23. Legro RS, Kunselman AR, Dodson WC, 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. 1999. 84:165–169.

24. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999. 22:141–146.

25. Gambineri A, Patton L, Altieri P, Pagotto U, Pizzi C, Manzoli L, Pasquali R. Polycystic ovary syndrome is a risk factor for type 2 diabetes: results from a long-term prospective study. Diabetes. 2012. 61:2369–2374.

26. Randeva HS, Tan BK, Weickert MO, Lois K, Nestler JE, Sattar N, Lehnert H. Cardiometabolic aspects of the polycystic ovary syndrome. Endocr Rev. 2012. In press.

27. Herzog AG. Polycystic ovarian syndrome in women with epilepsy: epileptic or iatrogenic? Ann Neurol. 1996. 39:559–560.

28. Teede H, Deeks A, Moran L. Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med. 2010. 8:41.

29. Pierpoint T, McKeigue PM, Isaacs AJ, Wild SH, Jacobs HS. Mortality of women with polycystic ovary syndrome at long-term follow-up. J Clin Epidemiol. 1998. 51:581–586.

30. Puurunen J, Piltonen T, Morin-Papunen L, Perheentupa A, Järvelä I, Ruokonen A, Tapanainen JS. Unfavorable hormonal, metabolic, and inflammatory alterations persist after menopause in women with PCOS. J Clin Endocrinol Metab. 2011. 96:1827–1834.

31. Schmidt J, Landin-Wilhelmsen K, Brännström M, Dahlgren E. Cardiovascular disease and risk factors in PCOS women of postmenopausal age: a 21-year controlled follow-up study. J Clin Endocrinol Metab. 2011. 96:3794–3803.

32. Solomon CG, Hu FB, Dunaif A, Rich-Edwards JE, Stampfer MJ, Willett WC, Speizer FE, Manson JE. Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab. 2002. 87:2013–2017.

33. Shaw LJ, Bairey Merz CN, Azziz R, Stanczyk FZ, Sopko G, Braunstein GD, Kelsey SF, Kip KE, Cooper-Dehoff RM, Johnson BD, Vaccarino V, Reis SE, Bittner V, Hodgson TK, Rogers W, Pepine CJ. 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. 2008. 93:1276–1284.

34. Wild RA, Carmina E, Diamanti-Kandarakis E, Dokras A, Escobar-Morreale HF, Futterweit W, Lobo R, Norman RJ, Talbott E, Dumesic DA. 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. 2010. 95:2038–2049.

35. Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A. 1998. 95:14956–14960.

36. Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab. 2006. 91:2100–2104.

37. Urbanek M. The genetics of the polycystic ovary syndrome. Nat Clin Pract Endocrinol Metab. 2007. 3:103–111.

38. Maliqueo M, Echiburú B, Crisosto N, Amigo P, Aranda P, Sánchez F, Sir-Petermann T. Metabolic parameters in cord blood of newborns of women with polycystic ovary syndrome. Fertil Steril. 2009. 92:277–282.

39. Anderson H, Fogel N, Grebe SK, Singh RJ, Taylor RL, Dunaif A. Infants of women with polycystic ovary syndrome have lower cord blood androstenedione and estradiol levels. J Clin Endocrinol Metab. 2010. 95:2180–2186.

40. Sir-Petermann T, Codner E, Pérez V, Echiburú B, Maliqueo M, Ladrón de Guevara A, Preisler J, Crisosto N, Sánchez F, Cassorla F, Bhasin S. Metabolic and reproductive features before and during puberty in daughters of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2009. 94:1923–1930.

41. Dumesic DA, Abbott DH, Padmanabhan V. Polycystic ovary syndrome and its developmental origins. Rev Endocr Metab Disord. 2007. 8:127–141.

42. Marshall JC, Eagleson CA. Neuroendocrine aspects of polycystic ovary syndrome. Endocrinol Metab Clin North Am. 1999. 28:295–324.

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

44. Nelson VL, Legro RS, Strauss JF 3rd, McAllister JM. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. Mol Endocrinol. 1999. 13:946–957.

45. Ehrmann DA, Barnes RB, Rosenfield RL. Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev. 1995. 16:322–353.

46. Eagleson CA, Gingrich MB, Pastor CL, Arora TK, Burt CM, Evans WS, Marshall JC. 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. 2000. 85:4047–4052.

47. Franks S, Stark J, Hardy K. Follicle dynamics and anovulation in polycystic ovary syndrome. Hum Reprod Update. 2008. 14:367–378.

48. Ehrmann DA, Sturis J, Byrne MM, Karrison T, Rosenfield RL, Polonsky KS. Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J Clin Invest. 1995. 96:520–527.

49. Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes. 1992. 41:1257–1266.

50. Holte J, Bergh T, Berne C, Wide L, Lithell H. Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1995. 80:2586–2593.

51. Ovesen P, Moller J, Ingerslev HJ, Jorgensen JO, Mengel A, Schmitz O, Alberti KG, Moller N. Normal basal and insulin-stimulated fuel metabolism in lean women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1993. 77:1636–1640.

52. Ciaraldi TP, el-Roeiy A, Madar Z, Reichart D, Olefsky JM, Yen SS. Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. J Clin Endocrinol Metab. 1992. 75:577–583.

53. Rosenbaum D, Haber RS, Dunaif A. Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes. Am J Physiol. 1993. 264(2 Pt 1):E197–E202.

54. Ciaraldi TP, Aroda V, Mudaliar S, Chang RJ, Henry RR. Polycystic ovary syndrome is associated with tissue-specific differences in insulin resistance. J Clin Endocrinol Metab. 2009. 94:157–163.

55. Ek I, Arner P, Rydén M, Holm C, Thörne A, Hoffstedt J, Wahrenberg H. A unique defect in the regulation of visceral fat cell lipolysis in the polycystic ovary syndrome as an early link to insulin resistance. Diabetes. 2002. 51:484–492.

56. Ek I, Arner P, Bergqvist A, Carlström K, Wahrenberg H. Impaired adipocyte lipolysis in nonobese women with the polycystic ovary syndrome: a possible link to insulin resistance? J Clin Endocrinol Metab. 1997. 82:1147–1153.

57. Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest. 1995. 96:801–810.

58. Li M, Youngren JF, Dunaif A, Goldfine ID, Maddux BA, Zhang BB, Evans JL. Decreased insulin receptor (IR) autophosphorylation in fibroblasts from patients with PCOS: effects of serine kinase inhibitors and IR activators. J Clin Endocrinol Metab. 2002. 87:4088–4093.

59. 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. 2001. 281:E392–E399.

60. DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988. 37:667–687.

61. Corbould A, Kim YB, Youngren JF, Pender C, Kahn BB, Lee A, Dunaif A. Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling. Am J Physiol Endocrinol Metab. 2005. 288:E1047–E1054.

62. Eriksen M, Pørneki AD, Skov V, Burns JS, Beck-Nielsen H, Glintborg D, Gaster M. Insulin resistance is not conserved in myotubes established from women with PCOS. PLoS One. 2010. 5:e14469.

63. Book CB, Dunaif A. Selective insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1999. 84:3110–3116.

64. Corbould A, Zhao H, Mirzoeva S, Aird F, Dunaif A. Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome. Diabetes. 2006. 55:751–759.

65. Rice S, Christoforidis N, Gadd C, Nikolaou D, Seyani L, Donaldson A, Margara R, Hardy K, Franks S. Impaired insulin-dependent glucose metabolism in granulosa-lutein cells from anovulatory women with polycystic ovaries. Hum Reprod. 2005. 20:373–381.

66. Rajkhowa M, Brett S, Cuthbertson DJ, Lipina C, Ruiz-Alcaraz AJ, Thomas GE, Logie L, Petrie JR, Sutherland C. Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo. Biochem J. 2009. 418:665–671.

67. Zhang LH, Rodriguez H, Ohno S, Miller WL. Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci U S A. 1995. 92:10619–10623.

68. Bremer AA, Miller WL. The serine phosphorylation hypothesis of polycystic ovary syndrome: a unifying mechanism for hyperandrogenemia and insulin resistance. Fertil Steril. 2008. 89:1039–1048.

69. Martens JW, Geller DH, Arlt W, Auchus RJ, Ossovskaya VS, Rodriguez H, Dunaif A, Miller WL. Enzymatic activities of P450c17 stably expressed in fibroblasts from patients with the polycystic ovary syndrome. J Clin Endocrinol Metab. 2000. 85:4338–4346.

70. Tee MK, Dong Q, Miller WL. Pathways leading to phosphorylation of p450c17 and to the posttranslational regulation of androgen biosynthesis. Endocrinology. 2008. 149:2667–2677.

71. Nestler JE, Barlascini CO, Matt DW, Steingold KA, Plymate SR, Clore JN, Blackard WG. Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1989. 68:1027–1032.

72. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism. 1994. 43:647–654.

73. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1996. 81:3299–3306.

74. Willis D, Franks S. Insulin action in human granulosa cells from normal and polycystic ovaries is mediated by the insulin receptor and not the type-I insulin-like growth factor receptor. J Clin Endocrinol Metab. 1995. 80:3788–3790.

75. Moghetti P, Castello R, Negri C, Tosi F, Spiazzi GG, Brun E, Balducci R, Toscano V, Muggeo M. Insulin infusion amplifies 17 alpha-hydroxycorticosteroid intermediates response to adrenocorticotropin in hyperandrogenic women: apparent relative impairment of 17,20-lyase activity. J Clin Endocrinol Metab. 1996. 81:881–886.

76. Nestler JE, Singh R, Matt DW, Clore JN, Blackard WG. Suppression of serum insulin level by diazoxide does not alter serum testosterone or sex hormone-binding globulin levels in healthy, nonobese women. Am J Obstet Gynecol. 1990. 163(4 Pt 1):1243–1246.

77. Burks DJ, Font de Mora J, Schubert M, Withers DJ, Myers MG, Towery HH, Altamuro SL, Flint CL, White MF. IRS-2 pathways integrate female reproduction and energy homeostasis. Nature. 2000. 407:377–382.

78. Hill JW, Elias CF, Fukuda M, Williams KW, Berglund ED, Holland WL, Cho YR, Chuang JC, Xu Y, Choi M, Lauzon D, Lee CE, Coppari R, Richardson JA, Zigman JM, Chua S, Scherer PE, Lowell BB, Brüning JC, Elmquist JK. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab. 2010. 11:286–297.

79. Brothers KJ, Wu S, DiVall SA, Messmer MR, Kahn CR, Miller RS, Radovick S, Wondisford FE, Wolfe A. Rescue of obesity-induced infertility in female mice due to a pituitary-specific knockout of the insulin receptor. Cell Metab. 2010. 12:295–305.

80. Wu S, Divall S, Wondisford F, Wolfe A. Reproductive tissues maintain insulin sensitivity in diet-induced obesity. Diabetes. 2012. 61:114–123.

81. Dunaif A. Drug insight: insulin-sensitizing drugs in the treatment of polycystic ovary syndrome: a reappraisal. Nat Clin Pract Endocrinol Metab. 2008. 4:272–283.

82. Evans DJ, Hoffmann RG, Kalkhoff RK, Kissebah AH. Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. J Clin Endocrinol Metab. 1983. 57:304–310.

83. Kirschner MA, Samojlik E, Drejka M, Szmal E, Schneider G, Ertel N. Androgen-estrogen metabolism in women with upper body versus lower body obesity. J Clin Endocrinol Metab. 1990. 70:473–479.

84. Patel SM, Ratcliffe SJ, Reilly MP, Weinstein R, Bhasin S, Blackman MR, Cauley JA, Sutton-Tyrrell K, Robbins J, Fried LP, Cappola AR. Higher serum testosterone concentration in older women is associated with insulin resistance, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab. 2009. 94:4776–4784.

85. Kissebah AH, Peiris AN. Biology of regional body fat distribution: relationship to non-insulin-dependent diabetes mellitus. Diabetes Metab Rev. 1989. 5:83–109.

86. Polderman KH, Gooren LJ, Asscheman H, Bakker A, Heine RJ. Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab. 1994. 79:265–271.

87. Elbers JM, Asscheman H, Seidell JC, Megens JA, Gooren LJ. Long-term testosterone administration increases visceral fat in female to male transsexuals. J Clin Endocrinol Metab. 1997. 82:2044–2047.

88. Lovejoy JC, Bray GA, Bourgeois MO, Macchiavelli R, Rood JC, Greeson C, Partington C. Exogenous androgens influence body composition and regional body fat distribution in obese postmenopausal women: a clinical research center study. J Clin Endocrinol Metab. 1996. 81:2198–2203.

89. Diamanti-Kandarakis E, Mitrakou A, Raptis S, Tolis G, Duleba AJ. The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1998. 83:2699–2705.

90. Gambineri A, Patton L, Vaccina A, Cacciari M, Morselli-Labate AM, Cavazza C, Pagotto U, Pasquali R. Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: a randomized, 12-month, placebo-controlled study. J Clin Endocrinol Metab. 2006. 91:3970–3980.

91. Dunaif A, Green G, Futterweit W, Dobrjansky A. Suppression of hyperandrogenism does not improve peripheral or hepatic insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1990. 70:699–704.

92. Moghetti P, Tosi F, Castello R, Magnani CM, Negri C, Brun E, Furlani L, Caputo M, Muggeo M. The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J Clin Endocrinol Metab. 1996. 81:952–960.

93. Hickey M, Sloboda DM, Atkinson HC, Doherty DA, Franks S, Norman RJ, Newnham JP, Hart R. The relationship between maternal and umbilical cord androgen levels and polycystic ovary syndrome in adolescence: a prospective cohort study. J Clin Endocrinol Metab. 2009. 94:3714–3720.

94. Barry JA, Kay AR, Navaratnarajah R, Iqbal S, Bamfo JE, David AL, Hines M, Hardiman PJ. Umbilical vein testosterone in female infants born to mothers with polycystic ovary syndrome is elevated to male levels. J Obstet Gynaecol. 2010. 30:444–446.

95. Cole B, Hensinger K, Maciel GA, Chang RJ, Erickson GF. Human fetal ovary development involves the spatiotemporal expression of p450c17 protein. J Clin Endocrinol Metab. 2006. 91:3654–3661.

96. Urbanek M, Sam S, Legro RS, Dunaif A. Identification of a polycystic ovary syndrome susceptibility variant in fibrillin-3 and association with a metabolic phenotype. J Clin Endocrinol Metab. 2007. 92:4191–4198.

97. Kashar-Miller M, Azziz R. Heritability and the risk of developing androgen excess. J Steroid Biochem Mol Biol. 1999. 69:261–268.

98. Yildiz BO, Yarali H, Oguz H, Bayraktar M. Glucose intolerance, insulin resistance, and hyperandrogenemia in first degree relatives of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003. 88:2031–2036.

99. Legro RS, Kunselman AR, Demers L, Wang SC, Bentley-Lewis R, Dunaif A. Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002. 87:2134–2138.

100. Veldhuis JD, Rogol AD, Samojlik E, Ertel NH. Role of endogenous opiates in the expression of negative feedback actions of androgen and estrogen on pulsatile properties of luteinizing hormone secretion in man. J Clin Invest. 1984. 74:47–55.

101. Legro RS, Bentley-Lewis R, Driscoll D, Wang SC, Dunaif A. Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity. J Clin Endocrinol Metab. 2002. 87:2128–2133.

102. Sam S, Legro RS, Essah PA, Apridonidze T, Dunaif A. Evidence for metabolic and reproductive phenotypes in mothers of women with polycystic ovary syndrome. Proc Natl Acad Sci U S A. 2006. 103:7030–7035.

103. Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat Rev Genet. 2005. 6:95–108.

104. Urbanek M, Legro RS, Driscoll DA, Azziz R, Ehrmann DA, Norman RJ, Strauss JF 3rd, Spielman RS, Dunaif A. Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Proc Natl Acad Sci U S A. 1999. 96:8573–8578.

105. Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993. 52:506–516.

106. Jordan CD, Bohling SD, Charbonneau NL, Sakai LY. Fibrillins in adult human ovary and polycystic ovary syndrome: is fibrillin-3 affected in PCOS? J Histochem Cytochem. 2010. 58:903–915.

107. International HapMap Consortium. A haplotype map of the human genome. Nature. 2005. 437:1299–1320.

108. Chen ZJ, Zhao H, He L, Shi Y, Qin Y, Li Z, You L, Zhao J, Liu J, Liang X, Zhao X, Sun Y, Zhang B, Jiang H, Zhao D, Bian Y, Gao X, Geng L, Li Y, Zhu D, Sun X, Xu JE, Hao C, Ren CE, Zhang Y, Chen S, Zhang W, Yang A, Yan J, Ma J, Zhao Y. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet. 2011. 43:55–59.

109. Shi Y, Zhao H, Cao Y, Yang D, Li Z, Zhang B, Liang X, Li T, Chen J, Shen J, Zhao J, You L, Gao X, Zhu D, Zhao X, Yan Y, Qin Y, Li W, Yan J, Wang Q, Geng L, Ma J, Zhao Y, He G, Zhang A, Zou S, Yang A, Liu J, Li B, Wan C, Shi J, Yang J, Jiang H, Xu JE, Qi X, Sun Y, Zhang Y, Hao C, Ju X, Zhao D, Ren CE, Li X, Zhang W, Zhang J, Wu D, Zhang C, He L, Chen ZJ. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet. 2012. 44:1020–1025.

110. Goodarzi MO, Jones MR, Li X, Chua AK, Garcia OA, Chen YD, Krauss RM, Rotter JI, Ankener W, Legro RS, Azziz R, Strauss JF 3rd, Dunaif A, Urbanek M. Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J Med Genet. 2012. 49:90–95.

111. Welt CK, Styrkarsdottir U, Ehrmann DA, Thorleifsson G, Arason G, Gudmundsson JA, Ober C, Rosenfield RL, Saxena R, Thorsteinsdottir U, Crowley WF, Stefansson K. Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry. J Clin Endocrinol Metab. 2012. 97:E1342–E1347.