Abstract

Polycystic ovary syndrome (PCOS) affects 5–20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) — with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder.

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References

  1. 1.

    et al. Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic–hyperinsulaemic clamp. Hum. Reprod. 28, 777–784 (2013).

  2. 2.

    , , & Heritability of polycystic ovary syndrome in a Dutch twin-family study. J. Clin. Endocrinol. Metab. 91, 2100–2104 (2006). This study clearly demonstrates the very high heritability of PCOS through twin studies.

  3. 3.

    , , , & Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span. J. Clin. Endocrinol. Metab. 90, 4650–4658 (2005).

  4. 4.

    , , & Insulin resistance and polycystic ovary syndrome through life. Curr. Pharm. Des. 18, 5569–5576 (2012).

  5. 5.

    et al. The criteria, prevalence and phenotypes of PCOS. Fertil. Steril. 106, 6–15 (2016).

  6. 6.

    & in Polycystic Ovary Syndrome (eds Dunaif, A., , & ) 377–384 (Blackwell Scientific Publications, 1992).

  7. 7.

    Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum. Reprod. 19, 41–47 (2004).

  8. 8.

    Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil. Steril. 81, 19–25 (2004).

  9. 9.

    , & Referral bias in defining the phenotype and prevalence of obesity in polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 98, E1088–E1096 (2013). This is the first study to clearly demonstrate that the phenotype of PCOS observed in clinical studies may be very different from that observed in medically unbiased populations, indicating the need to better understand the true phenotype of PCOS.

  10. 10.

    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).

  11. 11.

    , , & Degree of facial and body terminal hair growth in unselected black and white women: toward a populational definition of hirsutism. J. Clin. Endocrinol. Metab. 91, 1345–1350 (2006).

  12. 12.

    , , , & The prevalence of androgen excess among patients with minimal unwanted hair growth. Am. J. Obstet. Gynecol. 191, 1914–1920 (2004).

  13. 13.

    , , & Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38, 1165–1174 (1989). This is one of the first studies to conclusively demonstrate that women with PCOS have significant insulin resistance that is independent of obesity, changes in body composition and impairment of glucose tolerance, and that hyperinsulinaemia in PCOS is not the result of decreased insulin clearance.

  14. 14.

    , , & 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).

  15. 15.

    , , & Changes in glucose tolerance over time in women with polycystic ovary syndrome: a controlled study. J. Clin. Endocrinol. Metab. 90, 3236–3242 (2005).

  16. 16.

    , , , & 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).

  17. 17.

    et al. Diabetes and impaired glucose tolerance in patients with polycystic ovary syndrome — a long term follow-up. Hum. Reprod. 26, 1462–1468 (2011).

  18. 18.

    et al. Polycystic ovary syndrome is a risk factor for type 2 diabetes: results from a long-term prospective study. Diabetes 61, 2369–2374 (2012).

  19. 19.

    , , & Cardiovascular disease and risk factors in PCOS women of postmenopausal age: a 21-year controlled follow-up study. J. Clin. Endocrinol. Metab. 96, 3794–3803 (2011).

  20. 20.

    , , & Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum. Reprod. Update 18, 618–637 (2012).

  21. 21.

    et al. Referral bias in female functional hyperandrogenism and polycystic ovary syndrome. Eur. J. Endocrinol. 173, 603–610 (2015).

  22. 22.

    , , , & Health-related quality of life in women with polycystic ovary syndrome, a self-administered questionnaire, was validated. J. Clin. Epidemiol. 57, 1279–1287 (2004).

  23. 23.

    , , , & Of PCOS symptoms, hirsutism has the most significant impact on the quality of life of Iranian women. PLoS ONE 10, e0123608 (2015).

  24. 24.

    , , , & Health related quality of life among different PCOS phenotypes of infertile women. J. Turk. Ger. Gynecol. Assoc. 13, 247–252 (2012).

  25. 25.

    et al. Reproductive health of women electing bariatric surgery. Fertil. Steril. 94, 1426–1431 (2010).

  26. 26.

    , , & Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Arch. Intern. Med. 166, 2081–2086 (2006).

  27. 27.

    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).

  28. 28.

    et al. Longitudinal weight gain in women identified with polycystic ovary syndrome: results of an observational study in young women. Obesity (Silver Spring) 21, 1526–1532 (2013).

  29. 29.

    , & Impact of obesity on the risk for polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 93, 162–168 (2008).

  30. 30.

    , , , & Prevalence, phenotype and cardiometabolic risk of polycystic ovary syndrome under different diagnostic criteria. Hum. Reprod. 27, 3067–3073 (2012).

  31. 31.

    et al. FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome. PLoS ONE 6, e16390 (2011).

  32. 32.

    , & Association between fat mass- and obesity-associated (FTO) gene polymorphism and polycystic ovary syndrome: a meta-analysis. PLoS ONE 9, e86972 (2014).

  33. 33.

    et al. BMI-associated alleles do not constitute risk alleles for polycystic ovary syndrome independently of BMI: a case–control study. PLoS ONE 9, e87335 (2014).

  34. 34.

    , , , & Prevalence of infertility and use of fertility treatment in women with polycystic ovary syndrome: data from a large community-based cohort study. J. Womens Health (Larchmt) 24, 299–307 (2015).

  35. 35.

    , , & Long-term consequences of polycystic ovary syndrome: results of a 31 year follow-up study. Hum. Fertil. (Camb.) 3, 101–105 (2000).

  36. 36.

    et al. Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline. Med. J. Aust. 195, S65–112 (2011).

  37. 37.

    , , & Increased risk for abnormal depression scores in women with polycystic ovary syndrome: a systematic review and meta-analysis. Obstetr. Gynecol. 117, 145–152 (2011).

  38. 38.

    , , & Emotional distress is a common risk in women with polycystic ovary syndrome: a systematic review and meta-analysis of 28 studies. Hum. Reprod. Update 18, 638–651 (2012).

  39. 39.

    , , & Psychological parameters in the reproductive phenotypes of polycystic ovary syndrome. Hum. Reprod. 27, 2082–2088 (2012).

  40. 40.

    et al. Depression, anxiety and cardiometabolic risk in polycystic ovary syndrome. Hum. Reprod. 26, 3339–3345 (2011).

  41. 41.

    et al. Risk of adverse pregnancy outcomes in women with polycystic ovary syndrome: population based cohort study. BMJ 343, d6309 (2011).

  42. 42.

    et al. Pregnancy outcomes in women with polycystic ovary syndrome undergoing in vitro fertilization. Fertil. Steril. 105, 791–797.e2 (2016).

  43. 43.

    , , & Relationship between polycystic ovarian syndrome and subsequent gestational diabetes mellitus: a nationwide population-based study. PLoS ONE 10, e0140544 (2015).

  44. 44.

    et al. Pregnancy complications in women with polycystic ovary syndrome. Hum. Reprod. Update 21, 575–592 (2015).

  45. 45.

    et al. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J. Clin. Endocrinol. Metab. 95, E448–E455 (2010). This is the first study to clearly demonstrate that metformin treatment from the first trimester to delivery did not reduce pregnancy complications in women with PCOS.

  46. 46.

    Polycystic ovary syndrome: metabolic consequences and long-term management. Scand. J. Clin. Lab. Invest. Suppl. 244, 23–26; discussion 26 (2014).

  47. 47.

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

  48. 48.

    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).

  49. 49.

    , , & 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).

  50. 50.

    , , , & Effect of lifestyle intervention on features of polycystic ovarian syndrome, metabolic syndrome, and intima–media thickness in obese adolescent girls. J. Clin. Endocrinol. Metab. 96, 3533–3540 (2011).

  51. 51.

    et al. Polycystic ovarian syndrome and subclinical atherosclerosis among women of reproductive age in the Dallas heart study. Clin. Endocrinol. (Oxf.) 74, 89–96 (2011).

  52. 52.

    , , , & Polycystic ovary syndrome and risk for myocardial infarction. Evaluated from a risk factor model based on a prospective population study of women. Acta Obstet. Gynecol. Scand. 71, 599–604 (1992).

  53. 53.

    , & Emergence of ovulatory cycles with aging in women with polycystic ovary syndrome (PCOS) alters the trajectory of cardiovascular and metabolic risk factors. Hum. Reprod. 28, 2245–2252 (2013).

  54. 54.

    et al. Trend of cardio-metabolic risk factors in polycystic ovary syndrome: a population-based prospective cohort study. PLoS ONE 10, e0137609 (2015).

  55. 55.

    et al. Cardiovascular disease and 10-year mortality in postmenopausal women with clinical features of PCOS. J. Womens Health (Larchmt) 6 June 2016 [epub ahead of print].

  56. 56.

    & The potential implications of a PCOS diagnosis on a woman's long-term health using data linkage. J. Clin. Endocrinol. Metab. 100, 911–919 (2015).

  57. 57.

    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).

  58. 58.

    et al. Diabetes and cardiovascular events in women with polycystic ovary syndrome: a 20-year retrospective cohort study. Clin. Endocrinol. (Oxf.) 78, 926–934 (2013).

  59. 59.

    , & Searching for polycystic ovary syndrome in postmenopausal women: evidence of a dose–effect association with prevalent cardiovascular disease. Menopause 14, 284–292 (2007).

  60. 60.

    , , & Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study. Clin. Endocrinol. (Oxf.) 52, 595–600 (2000).

  61. 61.

    et al. Risk of cardiovascular events in patients with polycystic ovary syndrome. Neth. J. Med. 70, 74–80 (2012).

  62. 62.

    Oral contraceptives and cardiovascular risk in women with polycystic ovary syndrome. J. Endocrinol. Invest. 36, 358–363 (2013).

  63. 63.

    , , , & Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis. CMAJ 185, E115–E120 (2013).

  64. 64.

    , & Risk of coronary heart disease and risk of stroke in women with polycystic ovary syndrome: a systematic review and meta-analysis. Int. J. Cardiol. 176, 486–487 (2014).

  65. 65.

    , & A 20-year follow-up of young women with polycystic ovary syndrome. Obstet. Gynecol. 119, 263–269 (2012).

  66. 66.

    & Cancer risk and PCOS. Steroids 78, 782–785 (2013).

  67. 67.

    & The development of the polycystic ovary syndrome: family history as a risk factor. Trends Endocrinol. Metab. 9, 55–58 (1998).

  68. 68.

    , , , & Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc. Natl Acad. Sci. USA 95, 14956–14960 (1998).

  69. 69.

    , , & Influence of a positive family history of both type 2 diabetes and PCOS on metabolic and endocrine parameters in a large cohort of PCOS women. Eur. J. Endocrinol. 170, 727–739 (2014).

  70. 70.

    & Genetics of the polycystic ovary syndrome. Mol. Cell. Endocrinol. 373, 29–38 (2013).

  71. 71.

    et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat. Genet. 44, 1020–1025 (2012).

  72. 72.

    et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat. Genet. 43, 55–59 (2011). This is the first genome-wide association study of PCOS.

  73. 73.

    et al. Family-based analysis of INSR polymorphisms in Chinese PCOS. Reprod. Biomed. Online 29, 239–244 (2014).

  74. 74.

    et al. Family-based analysis of eight susceptibility loci in polycystic ovary syndrome. Sci. Rep. 5, 12619 (2015).

  75. 75.

    et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat. Commun. 6, 7502 (2015).

  76. 76.

    et al. Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat. Commun. 6, 8464 (2015).

  77. 77.

    PCOS in 2015: new insights into the genetics of polycystic ovary syndrome. Nat. Rev. Endocrinol. 12, 74–75 (2016).

  78. 78.

    et al. Genotype–phenotype correlations of PCOS susceptibility SNPs identified by GWAS in a large cohort of Han Chinese women. Hum. Reprod. 28, 538–544 (2013).

  79. 79.

    et al. Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry. J. Clin. Endocrinol. Metab. 97, E1342–E1347 (2012).

  80. 80.

    et al. Han Chinese polycystic ovary syndrome risk variants in women of European ancestry: relationship to FSH levels and glucose tolerance. Hum. Reprod. 30, 1454–1459 (2015).

  81. 81.

    et al. Polycystic ovary syndrome susceptibility single nucleotide polymorphisms in women with a single PCOS clinical feature. Hum. Reprod. 30, 732–736 (2015).

  82. 82.

    et al. Pathway analysis based on a genome-wide association study of polycystic ovary syndrome. PLoS ONE 10, e0136609 (2015).

  83. 83.

    et al. Systems genetics reveals the functional context of PCOS loci and identifies genetic and molecular mechanisms of disease heterogeneity. PLoS Genet. 11, e1005455 (2015).

  84. 84.

    , , & Incidence of elevated LH/FSH ratio in polycystic ovary syndrome women with normo- and hyperinsulinemia. Rocz. Akad. Med. Bialymst. 48, 131–134 (2003).

  85. 85.

    , , & Body weight, hyperinsulinemia, and gonadotropin levels in the polycystic ovarian syndrome: evidence of two distinct populations. Fertil. Steril. 58, 487–491 (1992).

  86. 86.

    , , , & Hyperandrogenaemia in adolescent girls: origins of abnormal gonadotropin-releasing hormone secretion. BJOG 117, 143–149 (2010).

  87. 87.

    et al. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr. Rev. 36, 487–525 (2015). This paper provides a comprehensive overview of the complexity of PCOS and also provides some useful practical guidelines on how to take care of these patients in daily practice.

  88. 88.

    & Manipulation of human ovarian function: physiological concepts and clinical consequences. Endocr. Rev. 18, 71–106 (1997).

  89. 89.

    et al. Anti-Müllerian hormone and ovarian dysfunction. Trends Endocrinol. Metab. 19, 340–347 (2008).

  90. 90.

    et al. Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome. Hum. Reprod. 24, 2014–2022 (2009).

  91. 91.

    et al. Anti-Müllerian hormone serum concentrations in normoovulatory and anovulatory women of reproductive age. J. Clin. Endocrinol. Metab. 89, 318–323 (2004).

  92. 92.

    et al. Anti-Müllerian hormone protein expression is reduced during the initial stages of follicle development in human polycystic ovaries. J. Clin. Endocrinol. Metab. 90, 5536–5543 (2005).

  93. 93.

    et al. Increased oocyte degeneration and follicular atresia during the estrous cycle in anti-Müllerian hormone null mice. Endocrinology 148, 2301–2308 (2007).

  94. 94.

    & Pathophysiology of polycystic ovary syndrome: the role of hyperandrogenism. Front. Horm. Res. 40, 22–27 (2013).

  95. 95.

    et al. Dynamics of bioactive follicle-stimulating hormone secretion in women with polycystic ovary syndrome: effects of estradiol and progesterone. Fertil. Steril. 75, 881–888 (2001).

  96. 96.

    et al. Formation and early development of follicles in the polycystic ovary. Lancet 362, 1017–1021 (2003).

  97. 97.

    et al. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J. Clin. Endocrinol. Metab. 83, 2001–2005 (1998).

  98. 98.

    , , & Anti-Müllerian hormone: an ovarian reserve marker in primary ovarian insufficiency. Nat. Rev. Endocrinol. 8, 331–341 (2012).

  99. 99.

    et al. Aberrant expression of growth differentiation factor-9 in oocytes of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 87, 1337–1344 (2002).

  100. 100.

    , , & Quantitative estimation of insulin sensitivity. Am. J. Physiol. 236, E667–E677 (1979).

  101. 101.

    et al. Defects in beta-cell function in functional ovarian hyperandrogenism. J. Clin. Endocrinol. Metab. 76, 1241–1247 (1993).

  102. 102.

    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).

  103. 103.

    & Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 81, 942–947 (1996).

  104. 104.

    & Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr. Rev. 33, 981–1030 (2012).

  105. 105.

    et al. Insulin and C-peptide levels in obese patients with polycystic ovaries. Horm. Metab. Res. 14, 284–287 (1982).

  106. 106.

    et al. Insulin and C-peptide secretion in non-obese patients with polycystic ovarian disease. Horm. Metab. Res. 21, 502–506 (1989).

  107. 107.

    , , , & 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. 96, 801–810 (1995).

  108. 108.

    et al. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 41, 1257–1266 (1992).

  109. 109.

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

  110. 110.

    , , , & Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome. Diabetes 55, 751–759 (2006).

  111. 111.

    et al. Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo. Biochem. J. 418, 665–671 (2009).

  112. 112.

    & Selective insulin resistance in the polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 84, 3110–3116 (1999).

  113. 113.

    et al. Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling. Am. J. Physiol. Endocrinol. Metab. 288, E1047–E1054 (2005).

  114. 114.

    et al. Insulin resistance is not conserved in myotubes established from women with PCOS. PLoS ONE 5, e14469 (2010).

  115. 115.

    , , , & Polycystic ovary syndrome is associated with tissue-specific differences in insulin resistance. J. Clin. Endocrinol. Metab. 94, 157–163 (2009).

  116. 116.

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

  117. 117.

    et al. Adipose tissue has aberrant morphology and function in PCOS: enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance. J. Clin. Endocrinol. Metab. 96, E304–E311 (2011).

  118. 118.

    , , , & Impaired adipocyte lipolysis in nonobese women with the polycystic ovary syndrome: a possible link to insulin resistance? J. Clin. Endocrinol. Metab. 82, 1147–1153 (1997).

  119. 119.

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

  120. 120.

    et al. Pretranslational suppression of a glucose transporter protein causes insulin resistance in adipocytes from patients with non-insulin-dependent diabetes mellitus and obesity. J. Clin. Invest. 87, 1072–1081 (1991).

  121. 121.

    , , , & Insulin resistance with low cellular IRS-1 expression is also associated with low GLUT4 expression and impaired insulin-stimulated glucose transport. FASEB J. 15, 1101–1103 (2001).

  122. 122.

    , , , & Enhanced basal activation of mitogen-activated protein kinases in adipocytes from type 2 diabetes: potential role of p38 in the downregulation of GLUT4 expression. Diabetes 52, 634–641 (2003).

  123. 123.

    et al. miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance. Diabetes 62, 2278–2286 (2013).

  124. 124.

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

  125. 125.

    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).

  126. 126.

    et al. MicroRNA-223 expression is upregulated in insulin resistant human adipose tissue. J. Diabetes Res. 2015, 943659 (2015).

  127. 127.

    , , & 3rd. Functional genomics of PCOS: from GWAS to molecular mechanisms. Trends Endocrinol. Metab. 26, 118–124 (2015).

  128. 128.

    & The adrenal and polycystic ovary syndrome. Rev. Endocr. Metab. Disord. 8, 331–342 (2007).

  129. 129.

    , & Anxiety and depression in polycystic ovary syndrome: a comprehensive investigation. Fertil. Steril. 93, 2421–2423 (2010).

  130. 130.

    , , & Polycystic ovary syndrome: a biopsychosocial understanding in young women to improve knowledge and treatment options. J. Psychosomat. Obstetr. Gynaecol. 31, 24–31 (2010).

  131. 131.

    , , & Women's experiences of polycystic ovary syndrome diagnosis. Fam. Pract. 31, 545–549 (2014).

  132. 132.

    & ‘The thief of womanhood’: women's experience of polycystic ovarian syndrome. Soc. Sci. Med. 54, 349–361 (2002).

  133. 133.

    , , , & Risk of metabolic complications in the new PCOS phenotypes based on the Rotterdam criteria. Fertil. Steril. 88, 1389–1395 (2007).

  134. 134.

    et al. Cardiovascular and metabolic profiles amongst different polycystic ovary syndrome phenotypes: who is really at risk? Fertil. Steril. 102, 1444–1451.e3 (2014).

  135. 135.

    et al. Excess metabolic and cardiovascular risk is not manifested in all phenotypes of polycystic ovary syndrome: implications for diagnosis and treatment. Curr. Vasc. Pharmacol. 13, 788–800 (2015).

  136. 136.

    , , , & The prevalence of metabolic disorders in various phenotypes of polycystic ovary syndrome: a community based study in Southwest of Iran. Reprod. Biol. Endocrinol. 12, 89 (2014).

  137. 137.

    , , , & Early metformin therapy (age 8–12 years) in girls with precocious pubarche to reduce hirsutism, androgen excess, and oligomenorrhea in adolescence. J. Clin. Endocrinol. Metab. 96, E1262–E1267 (2011).

  138. 138.

    et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 98, 4565–4592 (2013).

  139. 139.

    et al. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil. Steril. 97, 28–38.e25 (2012).

  140. 140.

    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).

  141. 141.

    et al. Sleep disturbances in a community-based sample of women with polycystic ovary syndrome. Hum. Reprod. 30, 466–472 (2015).

  142. 142.

    et al. Lifestyle management improves quality of life and depression in overweight and obese women with polycystic ovary syndrome. Fertil. Steril. 94, 1812–1816 (2010).

  143. 143.

    , , & Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst. Rev. 7, CD007506 (2011). A meta-analysis of the data reported on lifestyle changes, and summarizes results that may be obtained and problems that arise with this treatment.

  144. 144.

    PCOS: metabolic impact and long-term management. Minerva Ginecol. 64, 501–505 (2012).

  145. 145.

    et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin. Endocrinol. (Oxf.) 36, 105–111 (1992).

  146. 146.

    et al. Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 88, 812–819 (2003).

  147. 147.

    et al. Dietary composition in the treatment of polycystic ovary syndrome: a systematic review to inform evidence-based guidelines. J. Acad. Nutr. Diet. 113, 520–545 (2013).

  148. 148.

    et al. Effects of a eucaloric reduced-carbohydrate diet on body composition and fat distribution in women with PCOS. Metabolism 63, 1257–1264 (2014).

  149. 149.

    et al. Favourable metabolic effects of a eucaloric lower-carbohydrate diet in women with PCOS. Clin. Endocrinol. (Oxf.) 79, 550–557 (2013).

  150. 150.

    , , , & Effects of exercise and group counselling on body composition and VO2max in overweight women with polycystic ovary syndrome. Acta Obstetricia Gynecol. Scand. 92, 272–277 (2013).

  151. 151.

    , , & Exercise therapy in polycystic ovary syndrome: a systematic review. Hum. Reprod. Update 17, 171–183 (2011).

  152. 152.

    , , & The impact of intensified exercise training on insulin resistance and fitness in overweight and obese women with and without polycystic ovary syndrome. Clin. Endocrinol. (Oxf.) 76, 351–357 (2012).

  153. 153.

    et al. The impact of bariatric surgery on polycystic ovary syndrome: a systematic review and meta-analysis. Obes. Surg. 26, 169–176 (2016).

  154. 154.

    , , , & Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, d-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst. Rev. 5, CD003053 (2012).

  155. 155.

    et al. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis. Hum. Reprod. Update 21, 560–574 (2015).

  156. 156.

    et al. A systematic review and meta-analysis of randomized controlled trials comparing pioglitazone versus metformin in the treatment of polycystic ovary syndrome. Curr. Med. Res. Opin. 28, 723–730 (2012).

  157. 157.

    et al. Metformin versus thiazolidinediones for treatment of clinical, hormonal and metabolic characteristics of polycystic ovary syndrome: a meta-analysis. Clin. Endocrinol. (Oxf.) 74, 332–339 (2011).

  158. 158.

    et al. American Association Of Clinical Endocrinologists, American College Of Endocrinology, And Androgen Excess And PCOS Society Disease State clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome — part 2. Endocr. Pract. 21, 1415–1426 (2015).

  159. 159.

    , & Myo-inositol versus d-chiro inositol in PCOS treatment. Minerva Ginecol. 67, 321–325 (2015).

  160. 160.

    & Reflections on inositol(s) for PCOS therapy: steps toward success. Gynecol. Endocrinol. 31, 501–505 (2015).

  161. 161.

    , & Effects of acarbose on polycystic ovary syndrome: a meta-analysis. Exp. Clin. Endocrinol. Diabetes 122, 373–378 (2014).

  162. 162.

    , & Statin is a reasonable treatment option for patients with polycystic ovary syndrome: a meta-analysis of randomized controlled trials. Exp. Clin. Endocrinol. Diabetes 120, 367–375 (2012).

  163. 163.

    et al. An investigation into the therapeutic effects of statins with metformin on polycystic ovary syndrome: a meta-analysis of randomised controlled trials. BMJ Open 5, e007280 (2015).

  164. 164.

    et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA 315, 2424–2434 (2016).

  165. 165.

    , , , & Effect of long-term orlistat treatment on serum levels of advanced glycation end-products in women with polycystic ovary syndrome. Clin. Endocrinol. (Oxf.) 66, 103–109 (2007).

  166. 166.

    et al. Effect of vitamin D on clinical and biochemical parameters in polycystic ovary syndrome women: a meta-analysis. J. Obstetr. Gynaecol. Res. 41, 1791–1802 (2015).

  167. 167.

    , & Use of ethinylestradiol/drospirenone combination in patients with the polycystic ovary syndrome. Ther. Clin. Risk Manag. 4, 487–492 (2008).

  168. 168.

    et al. The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur. J. Endocrinol. 171, 1–29 (2014).

  169. 169.

    Approach to the patient: contraception in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 100, 794–802 (2015).

  170. 170.

    Centers for Disease Control and Prevention (CDC). U. S. medical eligibility criteria for contraceptive use, 2010. MMWR Recomm. Rep. 59, 1–86 (2010).

  171. 171.

    et al. Leuprolide and estrogen versus oral contraceptive pills for the treatment of hirsutism: a prospective randomized study. J. Clin. Endocrinol. Metab. 80, 3406–3411 (1995).

  172. 172.

    et al. Effect of the insulin sensitizers metformin and pioglitazone on endothelial function in young women with polycystic ovary syndrome: a prospective randomized study. Fertil. Steril. 95, 203–209 (2011).

  173. 173.

    & Surgically induced ovulation in the polycystic ovary syndrome: wedge resection revisited in the age of laparoscopy. Fertil. Steril. 63, 439–463 (1995).

  174. 174.

    , & Laparoscopic drilling by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst. Rev. 6, CD001122 (2012).

  175. 175.

    , , & Three decades after Gjonnaess's laparoscopic ovarian drilling for treatment of PCOS; what do we know? An evidence-based approach. Arch. Gynecol. Obstetr. 288, 409–422 (2013).

  176. 176.

    & A systematic review of commonly used medical treatments for hirsutism in women. Clin. Endocrinol. (Oxf.) 68, 800–805 (2008).

  177. 177.

    Assessment, diagnosis and treatment of a patient with hirsutism. Nat. Clin. Prac. Endocrinol. Metab. 4, 294–300 (2008).

  178. 178.

    et al. Clinical review: antiandrogens for the treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials. J. Clin. Endocrinol. Metab. 93, 1153–1160 (2008).

  179. 179.

    , , & Interventions for hirsutism (excluding laser and photoepilation therapy alone). Cochrane Database Syst. Rev. 4, CD010334 (2015).

  180. 180.

    et al. A prospective randomized trial comparing low dose flutamide, finasteride, ketoconazole, and cyproterone acetate-estrogen regimens in the treatment of hirsutism. J. Clin. Endocrinol. Metab. 84, 1304–1310 (1999).

  181. 181.

    et al. Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society. Hum. Reprod. Update 18, 146–170 (2012).

  182. 182.

    & Relative safety and efficacy of finasteride for treatment of hirsutism. Ann. Pharmacother. 38, 1070–1073 (2004).

  183. 183.

    et al. Comparison of spironolactone, flutamide, and finasteride efficacy in the treatment of hirsutism: a randomized, double blind, placebo-controlled trial. J. Clin. Endocrinol. Metab. 85, 89–94 (2000). This randomized controlled trial clearly demonstrates the positive effect and comparability of androgen blockade on hirsutism in PCOS.

  184. 184.

    & Topical eflornithine. Am. J. Clin. Dermatol. 2, 197–201; discussion 202 (2001).

  185. 185.

    , , & Androgen excess: investigations and management. Best Pract. Res. Clin. Obstet. Gynaecol. (2016).

  186. 186.

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

  187. 187.

    et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N. Engl. J. Med. 356, 551–566 (2007). This is the first large randomized controlled trial to demonstrate the relative inferiority of metformin as a primary ovulatory agent in PCOS.

  188. 188.

    et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N. Engl. J. Med. 371, 119–129 (2014).

  189. 189.

    , , & Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction, achievement of pregnancy, and live birth in Asian women with polycystic ovary syndrome: a randomized controlled trial. Fertil. Steril. 91, 514–521 (2009).

  190. 190.

    , , & A comparative, randomized study of low-dose human menopausal gonadotropin and follicle-stimulating hormone in women with polycystic ovarian syndrome. Fertil. Steril. 55, 56–60 (1991).

  191. 191.

    , , & Ovulation of a single dominant follicle during treatment with low-dose pulsatile follicle stimulating hormone in women with polycystic ovary syndrome. Clin. Endocrinol. (Oxf.) 26, 205–212 (1987).

  192. 192.

    et al. Clomifene citrate or low-dose FSH for the first-line treatment of infertile women with anovulation associated with polycystic ovary syndrome: a prospective randomized multinational study. Hum. Reprod. 27, 468–473 (2012).

  193. 193.

    in Te Linde's Atlas of Gynecologic Surgery (eds Cundiff, G. W., Azziz, R. & Bristow, R. E.) 217–222 (Lippincott Williams & Wilkins, 2013).

  194. 194.

    Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil. Steril. 89, 505–522 (2008).

  195. 195.

    Is ovarian reserve diminished after laparoscopic ovarian drilling? Gynecol. Endocrinol. 25, 159–165 (2009).

  196. 196.

    et al. Long-term outcomes in women with polycystic ovary syndrome initially randomized to receive laparoscopic electrocautery of the ovaries or ovulation induction with gonadotrophins. Hum. Reprod. 26, 1899–1904 (2011).

  197. 197.

    et al. Obstetric outcome of patients with polycystic ovary syndrome treated by in vitro maturation and in vitro fertilization–embryo transfer. Fertil. Steril. 83, 1461–1465 (2005).

  198. 198.

    et al. In vitro maturation in women with versus without polycystic ovarian syndrome: a systematic review and meta-analysis. PLoS ONE 10, e0134696 (2015).

  199. 199.

    et al. In vitro maturation as an alternative to standard in vitro fertilization for patients diagnosed with polycystic ovaries: a comparative analysis of fresh, frozen and cumulative cycle outcomes. Hum. Reprod. 30, 88–96 (2015).

  200. 200.

    et al. Live birth after fresh embryo transfer versus elective embryo cryopreservation/frozen embryo transfer in women with polycystic ovary syndrome undergoing IVF (FreFro-PCOS): study protocol for a multicenter, prospective, randomized controlled clinical trial. Trials 15, 154 (2014).

  201. 201.

    , , , & The use of metformin for women with PCOS undergoing IVF treatment. Hum. Reprod. 21, 1416–1425 (2006).

  202. 202.

    , , , & Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst. Rev. 2, CD006105 (2009).

  203. 203.

    Health status assessment methods for adults: past accomplishments and future challenges. Annu. Rev. Public Health 20, 309–335 (1999).

  204. 204.

    et al. Polycystic ovary syndrome is associated with negatively variable impacts on domains of health-related quality of life: evidence from a meta-analysis. Fertil. Steril. 96, 452–458 (2011).

  205. 205.

    et al. Development of a health-related quality-of-life questionnaire (PCOSQ) for women with polycystic ovary syndrome (PCOS). J. Clin. Endocrinol. Metab. 83, 1976–1987 (1998). The authors of this article developed the first PCOS-dedicated health-related QOL questionnaire for PCOS.

  206. 206.

    et al. Quality of life and psychological well being in polycystic ovary syndrome. Hum. Reprod. 22, 2279–2286 (2007).

  207. 207.

    et al. Metformin treatment of polycystic ovary syndrome improves health-related quality-of-life, emotional distress and sexuality. Hum. Reprod. 21, 1925–1934 (2006).

  208. 208.

    et al. The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study. Fertil. Steril. 95, 1059–1066.e7 (2011).

  209. 209.

    , , , & Improvement in quality-of-life questionnaire measures in obese adolescent females with polycystic ovary syndrome treated with lifestyle changes and oral contraceptives, with or without metformin. Fertil. Steril. 93, 1016–1019 (2010).

  210. 210.

    , , & Effect of an oral contraceptive on emotional distress, anxiety and depression of women with polycystic ovary syndrome: a prospective study. Hum. Reprod. 27, 1840–1845 (2012).

  211. 211.

    , , & Is having polycystic ovary syndrome a predictor of poor psychological function including anxiety and depression? Hum. Reprod. 26, 1399–1407 (2011).

  212. 212.

    et al. Determinants of emotional distress in women with polycystic ovary syndrome. Hum. Reprod. 21, 1092–1099 (2006).

  213. 213.

    et al. Evidence for gonadotrophin secretory and steroidogenic abnormalities in brothers of women with polycystic ovary syndrome. Hum. Reprod. 29, 2764–2772 (2014).

  214. 214.

    , , & 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).

  215. 215.

    et al. Metabolic profile in sons of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 93, 1820–1826 (2008).

  216. 216.

    & Brothers of women with polycystic ovary syndrome are characterised by impaired glucose tolerance, reduced insulin sensitivity and related metabolic defects. Diabetologia 50, 2424–2432 (2007).

  217. 217.

    , , , & The NK3 receptor antagonist ESN364 suppresses sex hormones in men and women. J. Clin. Endocrinol. Metab. 101, 417–426 (2016).

  218. 218.

    , & Polycystic ovary syndrome: an ancient disorder? Fertil. Steril. 95, 1544–1548 (2011).

  219. 219.

    et al. Early metabolic derangements in daughters of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 92, 4637–4642 (2007).

  220. 220.

    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).

  221. 221.

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

  222. 222.

    et al. Polycystic ovaries in childhood: a common finding in daughters of PCOS patients. A pilot study. Hum. Reprod. 17, 771–776 (2002).

  223. 223.

    et al. Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism. J. Clin. Endocrinol. Metab. 76, 1599–1603 (1993).

  224. 224.

    et al. Endocrine consequences of premature pubarche in post-pubertal Caucasian girls. Clin. Endocrinol. (Oxf.) 57, 101–106 (2002).

  225. 225.

    et al. The association of obesity and hyperandrogenemia during the pubertal transition in girls: obesity as a potential factor in the genesis of postpubertal hyperandrogenism. J. Clin. Endocrinol. Metab. 91, 1714–1722 (2006).

  226. 226.

    et al. Predictive value of menstrual cycle pattern, body mass index, hormone levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum. Reprod. 19, 383–392 (2004). This study demonstrates the predictive nature of the degree of menstrual dysfunction, particularly for persistent menstrual dysfunction in adolescents.

  227. 227.

    , & Prospective follow-up of menstrual disorders in adolescence and prognostic factors. Acta Obstetricia Gynecol. Scand. 87, 1162–1168 (2008).

  228. 228.

    et al. Androgen profiling by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in healthy normal-weight ovulatory and anovulatory late adolescent and young women. J. Clin. Endocrinol. Metab. 98, 3058–3067 (2013).

  229. 229.

    et al. Hirsutism and oligomenorrhea are appropriate screening criteria for polycystic ovary syndrome in adolescents. Gynecol. Endocrinol. 31, 625–629 (2015).

  230. 230.

    et al. Polycystic ovaries in nonobese adolescents and young women with ovarian androgen excess: relation to prenatal growth. J. Clin. Endocrinol. Metab. 93, 196–199 (2008).

  231. 231.

    et al. Fetal growth, length of gestation, and polycystic ovaries in adult life. Lancet 350, 1131–1135 (1997).

  232. 232.

    , & Pathogenesis of NIDDM. A balanced overview. Diabetes Care 15, 318–368 (1992).

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Acknowledgements

The authors thank Y.-H. Chen, Augusta University, Georgia, USA.

Author information

Affiliations

  1. Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, 1120 15th Street, CB-2209, Augusta, Georgia 30912, USA.

    • Ricardo Azziz
    •  & Daria Lizneva
  2. Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.

    • Ricardo Azziz
  3. Department of Health Sciences and Mother and Child Care, University of Palermo, Palermo, Italy.

    • Enrico Carmina
  4. Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.

    • ZiJiang Chen
  5. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China.

    • ZiJiang Chen
  6. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

    • Andrea Dunaif
  7. Division of Reproductive Medicine, Department of OBGYN, Erasmus Medical Centre, Rotterdam, The Netherlands.

    • Joop S. E. Laven
  8. Department of Obstetrics and Gynecology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, USA.

    • Richard S. Legro
  9. Department of Reproductive Health Protection, Scientific Center of Family Health and Human Reproduction, Irkutsk, Russian Federation.

    • Daria Lizneva
  10. Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

    • Barbara Natterson-Horowtiz
  11. Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University in partnership with Monash Health, Clayton, Victoria, Australia.

    • Helena J. Teede
  12. Division of Endocrinology and Metabolism, Department of Internal Medicine, Hacettepe University School of Medicine, Hacettepe, Ankara, Turkey.

    • Bulent O. Yildiz

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Contributions

Introduction (R.A.); Epidemiology (R.A.); Mechanisms/pathophysiology (R.A., E.C., Z.-J.C., A.D., J.S.E.L., H.J.T. and B.O.Y.); Diagnosis, screening and prevention (R.A. and H.J.T.); Management (R.A., E.C., Z.-J.C., R.S.L., D.L. and B.O.Y.); Quality of life (E.C. and B.O.Y.); Outlook (R.A., B.N.-H., D.L. and R.S.L.); Overview of Primer (R.A.).

Competing interests

R.A. has a consulting agreement with KinDex Pharmaceutical Inc., is on the advisory board of Global PET Imaging, and has a consulting appointment with Selge Holdings and Ventures. J.S.E.L. has received unrestricted research grants from Ferring, Merck-Serono, MSD, Schering Plough, Serono and Okganon. R.S.L. is a consultant for Takeda, KinDex, Euroscreen and Ferring, and has received research funding from and is a consultant for Ferring. All other authors declare no competing interests.

Corresponding author

Correspondence to Ricardo Azziz.

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DOI

https://doi.org/10.1038/nrdp.2016.57

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