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Polycystic ovary syndrome

Nature Reviews Disease Primers volume 10, Article number: 27 (2024) Cite this article

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Abstract

Despite affecting ~11–13% of women globally, polycystic ovary syndrome (PCOS) is a substantially understudied condition. PCOS, possibly extending to men’s health, imposes a considerable health and economic burden worldwide. Diagnosis in adults follows the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome, requiring two out of three criteria — clinical or biochemical hyperandrogenism, ovulatory dysfunction, and/or specific ovarian morphological characteristics or elevated anti-Müllerian hormone. However, diagnosing adolescents omits ovarian morphology and anti-Müllerian hormone considerations. PCOS, marked by insulin resistance and hyperandrogenism, strongly contributes to early-onset type 2 diabetes, with increased odds for cardiovascular diseases. Reproduction-related implications include irregular menstrual cycles, anovulatory infertility, heightened risks of pregnancy complications and endometrial cancer. Beyond physiological manifestations, PCOS is associated with anxiety, depression, eating disorders, psychosexual dysfunction and negative body image, collectively contributing to diminished health-related quality of life in patients. Despite its high prevalence persisting into menopause, diagnosing PCOS often involves extended timelines and multiple health-care visits. Treatment remains ad hoc owing to limited understanding of underlying mechanisms, highlighting the need for research delineating the aetiology and pathophysiology of the syndrome. Identifying factors contributing to PCOS will pave the way for personalized medicine approaches. Additionally, exploring novel biomarkers, refining diagnostic criteria and advancing treatment modalities will be crucial in enhancing the precision and efficacy of interventions that will positively impact the lives of patients.

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Fig. 1: Life course in women with PCOS.
Fig. 2: Genetic and epigenetic inheritance of PCOS.
Fig. 3: Alterations in the hypothalamic–pituitary–gonadal axis in women with PCOS.
Fig. 4: The normal endometrium and the anovulatory endometrium.
Fig. 5: Proposed vicious circuit triggered by hyperandrogenism contributing to insulin resistance in PCOS.
Fig. 6: Proposed mechanisms of adipose tissue dysfunction in PCOS.
Fig. 7: Diagnosis of PCOS.

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References

  1. Teede, H. J. et al. Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. Fertil. Steril. https://doi.org/10.1016/j.fertnstert.2023.07.025 (2023).

    Article  PubMed  Google Scholar 

  2. Azziz, R., Marin, C., Hoq, L., Badamgarav, E. & Song, P. Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span. J. Clin. Endocrinol. Metab. 90, 4650–4658 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Riestenberg, C., Jagasia, A., Markovic, D., Buyalos, R. P. & Azziz, R. Health care-related economic burden of polycystic ovary syndrome in the United States: pregnancy-related and long-term health consequences. J. Clin. Endocrinol. Metab. 107, 575–585 (2022). This paper highlights that early diagnosis and interventions could possibly reduce the risk of developing comorbidities and the health-care-related economic burden of PCOS.

    Article  PubMed  Google Scholar 

  4. Yadav, S. et al. Direct economic burden of mental health disorders associated with Polycystic ovary syndrome: systematic review and meta-analysis. eLife 12, e85338 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Liu, Q. et al. A genome-wide cross-trait analysis identifies shared loci and causal relationships of type 2 diabetes and glycaemic traits with polycystic ovary syndrome. Diabetologia 65, 1483–1494 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ruth, K. S. et al. Using human genetics to understand the disease impacts of testosterone in men and women. Nat. Med. 26, 252–258 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Long, C. et al. Prevalence of polycystic ovary syndrome in patients with type 2 diabetes: a systematic review and meta-analysis. Front. Endocrinol. 13, 980405 (2022).

    Article  Google Scholar 

  8. Cooney, L. G. & Dokras, A. Cardiometabolic risk in polycystic ovary syndrome: current guidelines. Endocrinol. Metab. Clin. North Am. 50, 83–95 (2021).

    Article  PubMed  Google Scholar 

  9. Hoeger, K. M., Dokras, A. & Piltonen, T. Update on PCOS: consequences, challenges, and guiding treatment. J. Clin. Endocrinol. Metab. 106, e1071–e1083 (2021).

    Article  PubMed  Google Scholar 

  10. Zhuang, C. et al. Cardiovascular risk according to body mass index in women of reproductive age with polycystic ovary syndrome: a systematic review and meta-analysis. Front. Cardiovasc. Med. 9, 822079 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ollila, M. M., Hoek, A. & Piltonen, T. T. The association between polycystic ovary syndrome and early cardiovascular disease morbidity strengthens. Eur. J. Endocrinol. 189, R4–R5 (2023).

    Article  PubMed  Google Scholar 

  12. Berni, T. R., Morgan, C. L. & Rees, D. A. Women with polycystic ovary syndrome have an increased risk of major cardiovascular events: a population study. J. Clin. Endocrinol. Metab. 106, e3369–e3380 (2021). This study shows that women with PCOS have a higher incidence of myocardial infarction, angina pectoris and revascularization.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Millan-de-Meer, M., Luque-Ramirez, M., Nattero-Chavez, L. & Escobar-Morreale, H. F. PCOS during the menopausal transition and after menopause: a systematic review and meta-analysis. Hum. Reprod. Update 29, 741–772 (2023).

    Article  PubMed  Google Scholar 

  14. van der Ham, K. et al. Change in androgenic status and cardiometabolic profile of middle-aged women with polycystic ovary syndrome. J. Clin. Med. 12, 5226 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Johnson, J. E., Daley, D., Tarta, C. & Stanciu, P. I. Risk of endometrial cancer in patients with polycystic ovarian syndrome: a meta-analysis. Oncol. Lett. 25, 168 (2023). This study shows that women with PCOS have a fivefold increased risk of developing endometrial cancer.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Hanna, F., Wu, P., Heald, A. & Fryer, A. Diabetes detection in women with gestational diabetes and polycystic ovarian syndrome. BMJ 382, e071675 (2023).

    Article  PubMed  Google Scholar 

  17. Mills, G., Badeghiesh, A., Suarthana, E., Baghlaf, H. & Dahan, M. H. Polycystic ovary syndrome as an independent risk factor for gestational diabetes and hypertensive disorders of pregnancy: a population-based study on 9.1 million pregnancies. Hum. Reprod. 35, 1666–1674 (2020). This study shows that women with PCOS have an increased risk for pregnancy complications, including gestational diabetes and hypertension, independent of coexisting metabolic conditions.

    Article  PubMed  Google Scholar 

  18. Gibson-Helm, M., Teede, H., Dunaif, A. & Dokras, A. Delayed diagnosis and a lack of information associated with dissatisfaction in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 102, 604–612 (2017).

    PubMed  Google Scholar 

  19. Dapas, M. & Dunaif, A. Deconstructing a syndrome: genomic insights into PCOS causal mechanisms and classification. Endocr. Rev. 43, 927–965 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Leinonen, J. T. et al. Genetic analyses implicate complex links between adult testosterone levels and health and disease. Commun. Med. 3, 4 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Xue, A. et al. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat. Commun. 9, 2941 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Davitadze, M. et al. Body image concerns in women with polycystic ovary syndrome: a systematic review and meta-analysis. Eur. J. Endocrinol. 189, R1–R9 (2023).

    Article  PubMed  Google Scholar 

  23. Nasiri-Amiri, F., Faramarzi, M., Omidvar, S. & Alizadeh-Navaei, R. Depression and anxiety in adolescents and young women with polycystic ovary syndrome: a systematic review and meta-analysis. Int. J. Adolesc. Med. Health 35, 233–242 (2023).

    Article  PubMed  Google Scholar 

  24. Mousa, A., Thien Tay, C. & Teede, H. Technical Report for the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome https://doi.org/10.26180/23625288.v1 (Monash University, 2023).

  25. 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).

    Article  Google Scholar 

  26. Lizneva, D. et al. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil. Steril. 106, 6–15 (2016).

    Article  PubMed  Google Scholar 

  27. 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  PubMed  Google Scholar 

  28. Piltonen, T. T. et al. AMH as part of the diagnostic PCOS workup in large epidemiological studies. Eur. J. Endocrinol. 188, 547–554 (2023).

    Article  PubMed  Google Scholar 

  29. Wu, Q., Gao, J., Bai, D., Yang, Z. & Liao, Q. The prevalence of polycystic ovarian syndrome in Chinese women: a meta-analysis. Ann. Palliat. Med. 10, 74–87 (2021).

    Article  PubMed  Google Scholar 

  30. Moran, C., Arriaga, M., Rodriguez, G. & Moran, S. Obesity differentially affects phenotypes of polycystic ovary syndrome. Int. J. Endocrinol. 2012, 317241 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  32. Kataoka, J. et al. Prevalence of polycystic ovary syndrome in women with severe obesity — effects of a structured weight loss programme. Clin. Endocrinol. 91, 750–758 (2019). This study demonstrates that the prevalence of PCOS increases up to 25% with severe obesity.

    Article  CAS  Google Scholar 

  33. van Keizerswaard, J., Dietz de Loos, A. L. P., Louwers, Y. V. & Laven, J. S. E. Changes in individual polycystic ovary syndrome phenotypical characteristics over time: a long-term follow-up study. Fertil. Steril. 117, 1059–1066 (2022).

    Article  PubMed  Google Scholar 

  34. Kujanpaa, L. et al. Women with polycystic ovary syndrome are burdened with multimorbidity and medication use independent of body mass index at late fertile age: a population-based cohort study. Acta Obstet. Gynecol. Scand. 101, 728–736 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ollila, M. M. et al. Women with PCOS have an increased risk for cardiovascular disease regardless of diagnostic criteria-a prospective population-based cohort study. Eur. J. Endocrinol. 189, 96–105 (2023).

    Article  PubMed  Google Scholar 

  36. Ollila, M. M. et al. Weight gain and dyslipidemia in early adulthood associate with polycystic ovary syndrome: prospective cohort study. J. Clin. Endocrinol. Metab. 101, 739–747 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Hagberg, C. E. & Spalding, K. L. White adipocyte dysfunction and obesity-associated pathologies in humans. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-023-00680-1 (2023).

    Article  PubMed  Google Scholar 

  38. Lim, S. S., Davies, M. J., Norman, R. J. & Moran, L. J. Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum. Reprod. Update 18, 618–637 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Koivuaho, E. et al. Age at adiposity rebound in childhood is associated with PCOS diagnosis and obesity in adulthood-longitudinal analysis of BMI data from birth to age 46 in cases of PCOS. Int. J. Obes. 43, 1370–1379 (2019). This study demonstrates that early weight gain in childhood plays a crucial role in the emerging PCOS, highlighting the importance of early preventive interventions against metabolic disorders.

    Article  CAS  Google Scholar 

  40. Kakoly, N. S., Earnest, A., Moran, L. J., Teede, H. J. & Joham, A. E. Group-based developmental BMI trajectories, polycystic ovary syndrome, and gestational diabetes: a community-based longitudinal study. BMC Med. 15, 195 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Sendur, S. N. & Yildiz, B. O. Influence of ethnicity on different aspects of polycystic ovary syndrome: a systematic review. Reprod. Biomed. Online 42, 799–818 (2021).

    Article  CAS  PubMed  Google Scholar 

  42. Kim, J. J. & Choi, Y. M. Phenotype and genotype of polycystic ovary syndrome in Asia: ethnic differences. J. Obstet. Gynaecol. Res. 45, 2330–2337 (2019).

    Article  PubMed  Google Scholar 

  43. Ramezani Tehrani, F., Behboudi-Gandevani, S., Bidhendi Yarandi, R., Saei Ghare Naz, M. & Carmina, E. Prevalence of acne vulgaris among women with polycystic ovary syndrome: a systemic review and meta-analysis. Gynecol. Endocrinol. 37, 392–405 (2021).

    Article  CAS  PubMed  Google Scholar 

  44. Carmina, E. et al. Female pattern hair loss and androgen excess: a report from the multidisciplinary androgen excess and PCOS committee. J. Clin. Endocrinol. Metab. 104, 2875–2891 (2019).

    Article  PubMed  Google Scholar 

  45. Karjula, S. et al. Psychological distress is more prevalent in fertile age and premenopausal women with PCOS symptoms: 15-year follow-up. J. Clin. Endocrinol. Metab. 102, 1861–1869 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Cassar, S. et al. Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies. Hum. Reprod. 31, 2619–2631 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. Stepto, N. K. et al. Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic-hyperinsulaemic clamp. Hum. Reprod. 28, 777–784 (2013). Although insulin resistance is present independently of BMI, this study highlights that insulin resistance worsens by increased BMI irrespective of visceral fat accumulation, supporting inherent insulin resistance.

    Article  CAS  PubMed  Google Scholar 

  48. Pelanis, R. et al. The prevalence of type 2 diabetes is not increased in normal-weight women with PCOS. Hum. Reprod. 32, 2279–2286 (2017).

    Article  CAS  PubMed  Google Scholar 

  49. Wekker, V. et al. Long-term cardiometabolic disease risk in women with PCOS: a systematic review and meta-analysis. Hum. Reprod. Update 26, 942–960 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ollila, M. M. et al. OR35-06 polycystic ovary syndrome is associated with an increased mortality risk. J. Endocr. Soc. 7, bvad114.1712 (2023).

    Article  PubMed Central  Google Scholar 

  51. Kasarinaite, A., Sinton, M., Saunders, P. T. K. & Hay, D. C. The influence of sex hormones in liver function and disease. Cells 12, 1604 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rinella, M. E. et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J. Hepatol. 79, 1542–1556 (2023).

    Article  CAS  PubMed  Google Scholar 

  53. Manzano-Nunez, R. et al. Non-alcoholic fatty liver disease in patients with polycystic ovary syndrome: a systematic review, meta-analysis, and meta-regression. J. Clin. Med. 12, 856 (2023). This study shows that women with PCOS already at a young age have an increased prevalence of MASLD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Joham, A. E., Teede, H. J., Ranasinha, S., Zoungas, S. & Boyle, J. 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 24, 299–307 (2015).

    Article  Google Scholar 

  55. West, S. et al. The impact of self-reported oligo-amenorrhea and hirsutism on fertility and lifetime reproductive success: results from the Northern Finland Birth Cohort 1966. Hum. Reprod. 29, 628–633 (2014).

    Article  CAS  PubMed  Google Scholar 

  56. Persson, S. et al. Fecundity among women with polycystic ovary syndrome (PCOS) — a population-based study. Hum. Reprod. 34, 2052–2060 (2019).

    Article  CAS  PubMed  Google Scholar 

  57. Haase, C. L., Varbo, A., Laursen, P. N., Schnecke, V. & Balen, A. H. Association between body mass index, weight loss and the chance of pregnancy in women with polycystic ovary syndrome and overweight or obesity: a retrospective cohort study in the UK. Hum. Reprod. 38, 471–481 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Bahri Khomami, M. et al. Increased maternal pregnancy complications in polycystic ovary syndrome appear to be independent of obesity-a systematic review, meta-analysis, and meta-regression. Obes. Rev. 20, 659–674 (2019).

    Article  PubMed  Google Scholar 

  59. Ahmed, M., Shellenberger, J. & Velez, M. P. Polycystic ovary syndrome, gestational diabetes mellitus, and the mediating role of obesity: a population-based cohort study. J. Obstet. Gynaecol. Can. 46, 102238 (2023).

    Article  PubMed  Google Scholar 

  60. Chen, X., Gissler, M. & Lavebratt, C. Association of maternal polycystic ovary syndrome and diabetes with preterm birth and offspring birth size: a population-based cohort study. Hum. Reprod. 37, 1311–1323 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Alur-Gupta, S., Boland, M. R., Barnhart, K. T., Sammel, M. D. & Dokras, A. Postpartum complications increased in women with polycystic ovary syndrome. Am. J. Obstet. Gynecol. 224, 280.e1–280.e13 (2021).

    Article  PubMed  Google Scholar 

  62. Pastoor, H., Both, S., Laan, E. T. M. & Laven, J. S. E. Sexual dysfunction in women with PCOS: a case control study. Hum. Reprod. 38, 2230–2238 (2023). This study shows that women with the syndrome suffer from impaired sexual function with minimal impact of endocrine dysfunction, highlighting the importance of psychosexual counselling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Glintborg, D., Hass Rubin, K., Nybo, M., Abrahamsen, B. & Andersen, M. Morbidity and medicine prescriptions in a nationwide Danish population of patients diagnosed with polycystic ovary syndrome. Eur. J. Endocrinol. 172, 627–638 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Beavis, A. L. et al. Identifying women 45 years and younger at elevated risk for endometrial hyperplasia or cancer. Gynecol. Oncol. 174, 98–105 (2023).

    Article  PubMed  Google Scholar 

  65. Lu, L., Luo, J., Deng, J., Huang, C. & Li, C. Polycystic ovary syndrome is associated with a higher risk of premalignant and malignant endometrial polyps in premenopausal women: a retrospective study in a tertiary teaching hospital. BMC Womens Health 23, 127 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Zhu, T., Cui, J. & Goodarzi, M. O. Polycystic ovary syndrome and breast cancer subtypes: a Mendelian randomization study. Am. J. Obstet. Gynecol. 225, 99–101 (2021).

    Article  PubMed  Google Scholar 

  67. Wu, P. F. et al. Polycystic ovary syndrome is causally associated with estrogen receptor-positive instead of estrogen receptor-negative breast cancer: a Mendelian randomization study. Am. J. Obstet. Gynecol. 223, 583–585 (2020).

    Article  CAS  PubMed  Google Scholar 

  68. Amiri, M., Bidhendi-Yarandi, R., Fallahzadeh, A., Marzban, Z. & Ramezani Tehrani, F. Risk of endometrial, ovarian, and breast cancers in women with polycystic ovary syndrome: a systematic review and meta-analysis. Int. J. Reprod. Biomed. 20, 893–914 (2022).

    PubMed  PubMed Central  Google Scholar 

  69. Barry, J. A., Azizia, M. M. & Hardiman, P. J. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum. Reprod. Update 20, 748–758 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Greenwood, E. A., Yaffe, K., Wellons, M. F., Cedars, M. I. & Huddleston, H. G. Depression over the lifespan in a population-based cohort of women with polycystic ovary syndrome: longitudinal analysis. J. Clin. Endocrinol. Metab. 104, 2809–2819 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Dwivedi, A. K., Vishwakarma, D., Dubey, P. & Reddy, S. Association of polycystic ovary syndrome with cardiovascular disease among female hospitalizations in the United States. Eur. J. Endocrinol. 188, 555–563 (2023).

    Article  PubMed  Google Scholar 

  72. Zhang, J., Xu, J. H., Qu, Q. Q. & Zhong, G. Q. Risk of cardiovascular and cerebrovascular events in polycystic ovarian syndrome women: a meta-analysis of cohort studies. Front. Cardiovasc. Med. 7, 552421 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Forslund, M., Schmidt, J., Brannstrom, M., Landin-Wilhelmsen, K. & Dahlgren, E. Morbidity and mortality in PCOS: a prospective follow-up up to a mean age above 80 years. Eur. J. Obstet. Gynecol. Reprod. Biol. 271, 195–203 (2022).

    Article  PubMed  Google Scholar 

  74. Merz, C. N. et al. Cardiovascular disease and 10-year mortality in postmenopausal women with clinical features of polycystic ovary syndrome. J. Womens Health 25, 875–881 (2016).

    Article  Google Scholar 

  75. Legro, R. S. et al. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc. Natl Acad. Sci. USA 95, 14956–14960 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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). This study demonstrates a strong contribution of familial factors to PCOS by using data from monozygotic twins.

    Article  CAS  PubMed  Google Scholar 

  77. Laven, J. S. E. Follicle stimulating hormone receptor (FSHR) polymorphisms and polycystic ovary syndrome (PCOS). Front. Endocrinol. 10, 23 (2019).

    Article  Google Scholar 

  78. Chen, Z. J. 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).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  82. Day, F. et al. Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLoS Genet. 14, e1007813 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Zhang, Y. et al. A genome-wide association study of polycystic ovary syndrome identified from electronic health records. Am. J. Obstet. Gynecol. 223, 559.e1–559.e21 (2020).

    Article  CAS  PubMed  Google Scholar 

  84. Tyrmi, J. S. et al. Leveraging Northern European population history: novel low-frequency variants for polycystic ovary syndrome. Hum. Reprod. 37, 352–365 (2022).

    Article  PubMed  Google Scholar 

  85. Alan Harris, R. et al. Loci on chromosome 12q13.2 encompassing ERBB3, PA2G4 and RAB5B are associated with polycystic ovary syndrome. Gene 852, 147062 (2023).

    Article  CAS  PubMed  Google Scholar 

  86. Waterbury, J. S. et al. The PCOS GWAS candidate gene ZNF217 influences theca cell expression of DENND1A.V2, CYP17A1, and androgen production. J. Endocr. Soc. 6, bvac078 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Zhu, T. & Goodarzi, M. O. Causes and consequences of polycystic ovary syndrome: insights from mendelian randomization. J. Clin. Endocrinol. Metab. 107, e899–e911 (2022).

    Article  PubMed  Google Scholar 

  88. Brower, M. A. et al. Bidirectional Mendelian randomization to explore the causal relationships between body mass index and polycystic ovary syndrome. Hum. Reprod. 34, 127–136 (2019).

    Article  CAS  PubMed  Google Scholar 

  89. Zhao, Y. et al. Body mass index and polycystic ovary syndrome: a 2-sample bidirectional mendelian randomization study. J. Clin. Endocrinol. Metab. 105, dgaa125 (2020).

    Article  PubMed  Google Scholar 

  90. Liu, Q. et al. Genomic correlation, shared loci, and causal relationship between obesity and polycystic ovary syndrome: a large-scale genome-wide cross-trait analysis. BMC Med. 20, 66 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhu, T., Cui, J. & Goodarzi, M. O. Polycystic ovary syndrome and risk of type 2 diabetes, coronary heart disease, and stroke. Diabetes 70, 627–637 (2021).

    Article  CAS  PubMed  Google Scholar 

  92. Harris, H. R. et al. Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study. Int. J. Epidemiol. 48, 822–830 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Goodarzi, M. O. Genetics of common endocrine disease: the present and the future. J. Clin. Endocrinol. Metab. 101, 787–794 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Dapas, M. et al. Distinct subtypes of polycystic ovary syndrome with novel genetic associations: an unsupervised, phenotypic clustering analysis. PLoS Med. 17, e1003132 (2020). Using unsupervised cluster analyses, two distinct subtypes, one reproductive and one metabolic, were identified and they were associated with novel susceptible loci.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Burns, K. et al. Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry. BMC Genomics 25, 208 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhu, J. et al. Evidence from men for ovary-independent effects of genetic risk factors for polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 107, e1577–e1587 (2022). This study showed that applying a polygenic risk score for PCOS has distinct phenotypic consequences in men.

    Article  PubMed  Google Scholar 

  97. Cesta, C. E. et al. Maternal polycystic ovary syndrome and risk of neuropsychiatric disorders in offspring: prenatal androgen exposure or genetic confounding? Psychol. Med. 50, 616–624 (2020).

    Article  PubMed  Google Scholar 

  98. Stener-Victorin, E. & Deng, Q. Epigenetic inheritance of polycystic ovary syndrome — challenges and opportunities for treatment. Nat. Rev. Endocrinol. 17, 521–533 (2021).

    Article  PubMed  Google Scholar 

  99. Kent, J. et al. Gestational weight gain in women with polycystic ovary syndrome: a controlled study. J. Clin. Endocrinol. Metab. 103, 4315–4323 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Tata, B. et al. Elevated prenatal anti-Mullerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood. Nat. Med. 24, 834–846 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Maliqueo, M. et al. Placental steroidogenesis in pregnant women with polycystic ovary syndrome. Eur. J. Obstet. Gynecol. Reprod. Biol. 166, 151–155 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Maliqueo, M. et al. Placental STAT3 signaling is activated in women with polycystic ovary syndrome. Hum. Reprod. 30, 692–700 (2015).

    Article  CAS  PubMed  Google Scholar 

  103. Gautam, R., Prambil, A. M., Patel, A. K. & Arora, T. Emerging pollutants in etiology and pathophysiology of polycystic ovary syndrome. Reprod. Toxicol. 123, 108515 (2024).

    Article  CAS  PubMed  Google Scholar 

  104. Barker, D. J., Osmond, C. & Law, C. M. The intrauterine and early postnatal origins of cardiovascular disease and chronic bronchitis. J. Epidemiol. Commun. Health 43, 237–240 (1989).

    Article  CAS  Google Scholar 

  105. Barrett, E. S. et al. Anogenital distance in newborn daughters of women with polycystic ovary syndrome indicates fetal testosterone exposure. J. Dev. Orig. Health Dis. 9, 307–314 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Risal, S. et al. Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome. Nat. Med. 25, 1894–1904 (2019).

    Article  CAS  PubMed  Google Scholar 

  107. Mimouni, N. E. H. et al. Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process. Cell Metab. 33, 513–530.e8 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chen, X., Koivuaho, E., Piltonen, T. T., Gissler, M. & Lavebratt, C. Association of maternal polycystic ovary syndrome or anovulatory infertility with obesity and diabetes in offspring: a population-based cohort study. Hum. Reprod. 36, 2345–2357 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Risal, S. et al. Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome. Cell Rep. Med. 4, 101035 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Lambertini, L. et al. Intrauterine reprogramming of the polycystic ovary syndrome: evidence from a pilot study of cord blood global methylation analysis. Front. Endocrinol. 8, 352 (2017).

    Article  Google Scholar 

  111. Risal, S. et al. Prenatal androgen exposure causes a sexually dimorphic transgenerational increase in offspring susceptibility to anxiety disorders. Transl. Psychiatry 11, 45 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Dubey, P. et al. A systematic review and meta-analysis of the association between maternal polycystic ovary syndrome and neuropsychiatric disorders in children. Transl. Psychiatry 11, 569 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Stener-Victorin, E. et al. Are there any sensitive and specific sex steroid markers for polycystic ovary syndrome? J. Clin. Endocrinol. Metab. 95, 810–819 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Chappell, N. R., Gibbons, W. E. & Blesson, C. S. Pathology of hyperandrogenemia in the oocyte of polycystic ovary syndrome. Steroids 180, 108989 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Gilling-Smith, C., Willis, D. S., Beard, R. W. & Franks, S. Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries. J. Clin. Endocrinol. Metab. 79, 1158–1165 (1994).

    CAS  PubMed  Google Scholar 

  116. Comim, F. V., Teerds, K., Hardy, K. & Franks, S. Increased protein expression of LHCG receptor and 17α-hydroxylase/17-20-lyase in human polycystic ovaries. Hum. Reprod. 28, 3086–3092 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. McAllister, J. M. et al. Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype. Proc. Natl Acad. Sci. USA 111, E1519–E1527 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Nisenblat, V. & Norman, R. J. Androgens and polycystic ovary syndrome. Curr. Opin. Endocrinol. Diabetes Obes. 16, 224–231 (2009).

    Article  CAS  PubMed  Google Scholar 

  119. Baillargeon, J. P. & Carpentier, A. Role of insulin in the hyperandrogenemia of lean women with polycystic ovary syndrome and normal insulin sensitivity. Fertil. Steril. 88, 886–893 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. di Clemente, N., Racine, C., Pierre, A. & Taieb, J. Anti-mullerian hormone in female reproduction. Endocr. Rev. 42, 753–782 (2021).

    Article  PubMed  Google Scholar 

  121. Norman, R. J., Milner, C. R., Groome, N. P. & Robertson, D. M. Circulating follistatin concentrations are higher and activin concentrations are lower in polycystic ovarian syndrome. Hum. Reprod. 16, 668–672 (2001).

    Article  CAS  PubMed  Google Scholar 

  122. Walters, K. A., Allan, C. M. & Handelsman, D. J. Androgen actions and the ovary. Biol. Reprod. 78, 380–389 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Tropea, A. et al. Estrogens and androgens affect human luteal cell function. Fertil. Steril. 94, 2257–2263 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Pea, J. et al. Ultrasonographic criteria in the diagnosis of polycystic ovary syndrome: a systematic review and diagnostic meta-analysis. Hum. Reprod. Update 30, 109–130 (2023).

    Article  Google Scholar 

  125. Wildt, L. et al. Frequency and amplitude of gonadotropin-releasing hormone stimulation and gonadotropin secretion in the rhesus monkey. Endocrinology 109, 376–385 (1981).

    Article  CAS  PubMed  Google Scholar 

  126. Patel, B. et al. The emerging therapeutic potential of kisspeptin and neurokinin B. Endocr. Rev. 45, 30–68 (2023).

    Article  PubMed Central  Google Scholar 

  127. Koysombat, K., Dhillo, W. S. & Abbara, A. Assessing hypothalamic pituitary gonadal function in reproductive disorders. Clin. Sci. 137, 863–879 (2023).

    Article  CAS  Google Scholar 

  128. Burt Solorzano, C. M. et al. Neuroendocrine dysfunction in polycystic ovary syndrome. Steroids 77, 332–337 (2012).

    Article  CAS  PubMed  Google Scholar 

  129. Barbotin, A. L. et al. Hypothalamic neuroglial plasticity is regulated by anti-Mullerian hormone and disrupted in polycystic ovary syndrome. EBioMedicine 90, 104535 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Blank, S. K. et al. Modulation of gonadotropin-releasing hormone pulse generator sensitivity to progesterone inhibition in hyperandrogenic adolescent girls–implications for regulation of pubertal maturation. J. Clin. Endocrinol. Metab. 94, 2360–2366 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Palomba, S., Piltonen, T. T. & Giudice, L. C. Endometrial function in women with polycystic ovary syndrome: a comprehensive review. Hum. Reprod. Update 27, 584–618 (2021). This comprehensive review highlights that endometrial dysfunction in PCOS can predispose to miscarriage and pregnancy complications.

    Article  CAS  PubMed  Google Scholar 

  132. Wang, A. et al. Expression of GPR30, ERα and ERβ in endometrium during window of implantation in patients with polycystic ovary syndrome: a pilot study. Gynecol. Endocrinol. 27, 251–255 (2011).

    Article  CAS  PubMed  Google Scholar 

  133. Apparao, K. B., Lovely, L. P., Gui, Y., Lininger, R. A. & Lessey, B. A. Elevated endometrial androgen receptor expression in women with polycystic ovarian syndrome. Biol. Reprod. 66, 297–304 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. Orostica, L., Poblete, C., Romero, C. & Vega, M. Pro-Inflammatory markers negatively regulate IRS1 in endometrial cells and endometrium from women with obesity and PCOS. Reprod. Sci. 27, 290–300 (2020).

    Article  CAS  PubMed  Google Scholar 

  135. Gibson, D. A., Simitsidellis, I., Collins, F. & Saunders, P. T. K. Androgens, oestrogens and endometrium: a fine balance between perfection and pathology. J. Endocrinol. 246, R75–R93 (2020).

    Article  CAS  PubMed  Google Scholar 

  136. Piltonen, T. T. et al. Mesenchymal stem/progenitors and other endometrial cell types from women with polycystic ovary syndrome (PCOS) display inflammatory and oncogenic potential. J. Clin. Endocrinol. Metab. 98, 3765–3775 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Piltonen, T. T. et al. Endometrial stromal fibroblasts from women with polycystic ovary syndrome have impaired progesterone-mediated decidualization, aberrant cytokine profiles and promote enhanced immune cell migration in vitro. Hum. Reprod. 30, 1203–1215 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Meltsov, A. et al. Targeted gene expression profiling for accurate endometrial receptivity testing. Sci. Rep. 13, 13959 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Khatun, M. et al. Decidualized endometrial stromal cells present with altered androgen response in PCOS. Sci. Rep. 11, 16287 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Zhou, M. et al. Decreased PIBF1/IL6/p-STAT3 during the mid-secretory phase inhibits human endometrial stromal cell proliferation and decidualization. J. Adv. Res. 30, 15–25 (2021).

    Article  CAS  PubMed  Google Scholar 

  141. Kangasniemi, M. H. et al. Artificial intelligence deep learning model assessment of leukocyte counts and proliferation in endometrium from women with and without polycystic ovary syndrome. F S Sci. 3, 174–186 (2022).

    PubMed  Google Scholar 

  142. Liu, S. et al. Evaluation of endometrial immune status of polycystic ovary syndrome. J. Reprod. Immunol. 144, 103282 (2021).

    Article  CAS  PubMed  Google Scholar 

  143. Ge, X., Zhang, J., Shi, H. & Bu, Z. Polycystic ovary syndrome increases the rate of early spontaneous miscarriage in women who have undergone single vitrified euploid blastocyst transfer. Reprod. Biomed. Online 47, 103223 (2023).

    Article  PubMed  Google Scholar 

  144. Joshi, A. et al. PCOS and the risk of pre-eclampsia. Reprod. Biomed. Online 45, 961–969 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Shetty, C. et al. Risk of gynecological cancers in women with polycystic ovary syndrome and the pathophysiology of association. Cureus 15, e37266 (2023).

    PubMed  PubMed Central  Google Scholar 

  146. Zhang, Y. et al. Landscape of PCOS co-expression gene and its role in predicting prognosis and assisting immunotherapy in endometrial cancer. J. Ovarian Res. 16, 129 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  147. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  149. Manneras-Holm, L. 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). This study demonstrates that enlarged adipocytes together with low adiponectin and increased waist circumference are strong drivers of insulin resistance in women with PCOS.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  151. Dunaif, A., Xia, J., Book, C. B., 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. 96, 801–810 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Caro, J. F., Dohm, L. G., Pories, W. J. & Sinha, M. K. Cellular alterations in liver, skeletal muscle, and adipose tissue responsible for insulin resistance in obesity and type II diabetes. Diabetes Metab. Rev. 5, 665–689 (1989).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  154. Skov, V. et al. Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome. Diabetes 56, 2349–2355 (2007).

    Article  CAS  PubMed  Google Scholar 

  155. Nilsson, E. et al. Transcriptional and epigenetic changes influencing skeletal muscle metabolism in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 103, 4465–4477 (2018).

    Article  PubMed  Google Scholar 

  156. Stepto, N. K. et al. Exercise and insulin resistance in PCOS: muscle insulin signalling and fibrosis. Endocr. Connect. 9, 346–359 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Manti, M., Stener-Victorin, E. & Benrick, A. Skeletal muscle immunometabolism in women with polycystic ovary syndrome: a meta-analysis. Front. Physiol. 11, 573505 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Stener-Victorin, E. et al. Proteomic analysis shows decreased type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS. eLife 12, e87592 (2024). This study showed that PCOS leads to a shift in muscle fibre type resulting in fewer insulin-sensitive type 1 muscle fibres and an increased accumulation of fat in skeletal muscles.

    Article  Google Scholar 

  159. Barber, T. M. et al. Global adiposity rather than abnormal regional fat distribution characterizes women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 93, 999–1004 (2008).

    Article  CAS  PubMed  Google Scholar 

  160. Tchernof, A. et al. Androgens and the regulation of adiposity and body fat distribution in humans. Compr. Physiol. 8, 1253–1290 (2018).

    Article  PubMed  Google Scholar 

  161. Raeisi, T. et al. Circulating resistin and follistatin levels in obese and non-obese women with polycystic ovary syndrome: a systematic review and meta-analysis. PLoS ONE 16, e0246200 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Schuler-Toprak, S., Ortmann, O., Buechler, C. & Treeck, O. The complex roles of adipokines in polycystic ovary syndrome and endometriosis. Biomedicines 10, 2503 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Echiburu, B. et al. Enlarged adipocytes in subcutaneous adipose tissue associated to hyperandrogenism and visceral adipose tissue volume in women with polycystic ovary syndrome. Steroids 130, 15–21 (2018).

    Article  CAS  PubMed  Google Scholar 

  164. Chazenbalk, G. et al. Androgens inhibit adipogenesis during human adipose stem cell commitment to preadipocyte formation. Steroids 78, 920–926 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Blouin, K. et al. Effects of androgens on adipocyte differentiation and adipose tissue explant metabolism in men and women. Clin. Endocrinol. 72, 176–188 (2010).

    Article  CAS  Google Scholar 

  166. Fisch, S. C. et al. Precocious subcutaneous abdominal stem cell development to adipocytes in normal-weight women with polycystic ovary syndrome. Fertil. Steril. 110, 1367–1376 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Dumesic, D. A. et al. Accelerated subcutaneous abdominal stem cell adipogenesis predicts insulin sensitivity in normal-weight women with polycystic ovary syndrome. Fertil. Steril. 116, 232–242 (2021).

    Article  CAS  PubMed  Google Scholar 

  168. Ezeh, U., Chen, I. Y., Chen, Y. H. & Azziz, R. Adipocyte expression of glucose transporter 1 and 4 in PCOS: relationship to insulin-mediated and non-insulin-mediated whole-body glucose uptake. Clin. Endocrinol. 90, 542–552 (2019).

    Article  CAS  Google Scholar 

  169. Ezeh, U., Chen, I. Y., Chen, Y. H. & Azziz, R. Adipocyte insulin resistance in PCOS: relationship with GLUT-4 expression and whole-body glucose disposal and β-cell function. J. Clin. Endocrinol. Metab. 105, e2408-20 (2020).

    Article  Google Scholar 

  170. Faulds, G., Ryden, M., Ek, I., Wahrenberg, H. & Arner, P. Mechanisms behind lipolytic catecholamine resistance of subcutaneous fat cells in the polycystic ovarian syndrome. J. Clin. Endocrinol. Metab. 88, 2269–2273 (2003).

    Article  CAS  PubMed  Google Scholar 

  171. Arner, P. Effects of testosterone on fat cell lipolysis. Species differences and possible role in polycystic ovarian syndrome. Biochimie 87, 39–43 (2005).

    Article  CAS  PubMed  Google Scholar 

  172. Ek, I. et al. A unique defect in the regulation of visceral fat cell lipolysis in the polycystic ovary syndrome as an early link to insulin resistance. Diabetes 51, 484–492 (2002).

    Article  CAS  PubMed  Google Scholar 

  173. Morigny, P., Boucher, J., Arner, P. & Langin, D. Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics. Nat. Rev. Endocrinol. 17, 276–295 (2021).

    Article  CAS  PubMed  Google Scholar 

  174. Ek, I., Arner, P., Bergqvist, A., Carlstrom, K. & Wahrenberg, H. 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).

    CAS  PubMed  Google Scholar 

  175. Bril, F. et al. Adipose tissue dysfunction in polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 109, 10–24 (2023).

    Article  PubMed  Google Scholar 

  176. Chazenbalk, G. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. O’Reilly, M. W. et al. AKR1C3-mediated adipose androgen generation drives lipotoxicity in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 102, 3327–3339 (2017). This study demonstrates that adipose tissue in PCOS has intra-adipose androgen activation contributing to adipose tissue remodelling with lipid accumulation and insulin resistance.

    Article  PubMed  PubMed Central  Google Scholar 

  178. Huang, Z. H. et al. PCOS is associated with increased CD11c expression and crown-like structures in adipose tissue and increased central abdominal fat depots independent of obesity. J. Clin. Endocrinol. Metab. 98, E17–24 (2013).

    Article  CAS  PubMed  Google Scholar 

  179. Chazenbalk, G. et al. Abnormal expression of genes involved in inflammation, lipid metabolism, and Wnt signaling in the adipose tissue of polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 97, E765–E770 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Jones, M. R. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Kokosar, M. et al. Epigenetic and transcriptional alterations in human adipose tissue of polycystic ovary syndrome. Sci. Rep. 6, e1022883 (2016).

    Google Scholar 

  182. Velez, L. M., Seldin, M. & Motta, A. B. Inflammation and reproductive function in women with polycystic ovary syndrome. Biol. Reprod. 104, 1205–1217 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Wu, Z. et al. Association of circulating monocyte chemoattractant protein-1 levels with polycystic ovary syndrome: a meta-analysis. Am. J. Reprod. Immunol. 86, e13407 (2021).

    Article  CAS  PubMed  Google Scholar 

  184. Vasyukova, E. et al. Inflammatory and anti-inflammatory parameters in PCOS patients depending on body mass index: a case-control study. Biomedicines 11, 2791 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Aboeldalyl, S. et al. The role of chronic inflammation in polycystic ovarian syndrome-a systematic review and meta-analysis. Int. J. Mol. Sci. 22, 2734 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. He, S. et al. Peripheral blood inflammatory-immune cells as a predictor of infertility in women with polycystic ovary syndrome. J. Inflamm. Res. 13, 441–450 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Juan, C. C. et al. Increased regulated on activation, normal T-cell expressed and secreted levels and cysteine-cysteine chemokine receptor 5 upregulation in omental adipose tissue and peripheral blood mononuclear cells are associated with testosterone level and insulin resistance in polycystic ovary syndrome. Fertil. Steril. 116, 1139–1146 (2021).

    Article  CAS  PubMed  Google Scholar 

  188. Kem, D. C. et al. The role of GnRH receptor autoantibodies in polycystic ovary syndrome. J. Endocr. Soc. 4, bvaa078 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Xiao, N. et al. Altered subsets and activities of B lymphocytes in polycystic ovary syndrome. J. Allergy Clin. Immunol. 143, 1943–1945.e4 (2019).

    Article  PubMed  Google Scholar 

  190. Ascani, A. et al. The role of B cells in immune cell activation in polycystic ovary syndrome. eLife 12, e86454 (2023). Although this study highlights that B cells are affected in PCOS, potentially contributing to an increased susceptibility to certain comorbidities, the findings suggest that B cells do not themselves cause PCOS.

    Article  PubMed  PubMed Central  Google Scholar 

  191. Yildirim, E. et al. Echocardiographic evaluation of diastolic functions in patients with polycystic ovary syndrome: a comperative study of diastolic functions in sub-phenotypes of polycystic ovary syndrome. Cardiol. J. 24, 364–373 (2017).

    Article  PubMed  Google Scholar 

  192. Berbrier, D. E. et al. Effects of androgen excess and body mass index on endothelial function in women with polycystic ovary syndrome. J. Appl. Physiol. 134, 868–878 (2023).

    Article  CAS  PubMed  Google Scholar 

  193. 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  PubMed  Google Scholar 

  194. Lakhani, K., Hardiman, P. & Seifalian, A. M. Intima-media thickness of elastic and muscular arteries of young women with polycystic ovaries. Atherosclerosis 175, 353–359 (2004).

    Article  CAS  PubMed  Google Scholar 

  195. Manneras-Holm, L. et al. Coagulation and fibrinolytic disturbances in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 96, 1068–1076 (2011).

    Article  PubMed  Google Scholar 

  196. Shoemaker, J. K., Klassen, S. A., Badrov, M. B. & Fadel, P. J. Fifty years of microneurography: learning the language of the peripheral sympathetic nervous system in humans. J. Neurophysiol. 119, 1731–1744 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Lambert, E. A. et al. Sympathetic activation and endothelial dysfunction in polycystic ovary syndrome are not explained by either obesity or insulin resistance. Clin. Endocrinol. 83, 812–819 (2015).

    Article  CAS  Google Scholar 

  198. Shorakae, S. et al. Inter-related effects of insulin resistance, hyperandrogenism, sympathetic dysfunction and chronic inflammation in PCOS. Clin. Endocrinol. 89, 628–633 (2018).

    Article  CAS  Google Scholar 

  199. Sverrisdottir, Y. B., Mogren, T., Kataoka, J., Janson, P. O. & Stener-Victorin, E. Is polycystic ovary syndrome associated with high sympathetic nerve activity and size at birth? Am. J. Physiol. Endocrinol. Metab. 294, E576–E581 (2008). This study was the first to demonstrate that women with PCOS have increased muscle sympathetic nerve activity with testosterone and cholesterol as independent predictors for the elevated activity, which may contribute to the increased cardiovascular risk in the syndrome.

    Article  CAS  PubMed  Google Scholar 

  200. Manneras, L., Cajander, S., Lonn, M. & Stener-Victorin, E. Acupuncture and exercise restore adipose tissue expression of sympathetic markers and improve ovarian morphology in rats with dihydrotestosterone-induced PCOS. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R1124–1131 (2009).

    Article  PubMed  Google Scholar 

  201. Stener-Victorin, E., Jedel, E., Janson, P. O. & Sverrisdottir, Y. B. Low-frequency electroacupuncture and physical exercise decrease high muscle sympathetic nerve activity in polycystic ovary syndrome. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R387–395 (2009).

    Article  CAS  PubMed  Google Scholar 

  202. Ely, B. R. et al. Heat therapy reduces sympathetic activity and improves cardiovascular risk profile in women who are obese with polycystic ovary syndrome. Am. J. Physiol. Regul. Integr. Comp. Physiol. 317, R630–R640 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Mahfoud, F. et al. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation 123, 1940–1946 (2011).

    Article  CAS  PubMed  Google Scholar 

  204. Schlaich, M. P. et al. Renal denervation: a potential new treatment modality for polycystic ovary syndrome? J. Hypertens. 29, 991–996 (2011).

    Article  CAS  PubMed  Google Scholar 

  205. Young, C. N., Deo, S. H., Chaudhary, K., Thyfault, J. P. & Fadel, P. J. Insulin enhances the gain of arterial baroreflex control of muscle sympathetic nerve activity in humans. J. Physiol. 588, 3593–3603 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Ketel, I. J. et al. Greater arterial stiffness in polycystic ovary syndrome (PCOS) is an obesity–but not a PCOS-associated phenomenon. J. Clin. Endocrinol. Metab. 95, 4566–4575 (2010).

    Article  CAS  PubMed  Google Scholar 

  207. Ollila, M. M. et al. Effect of polycystic ovary syndrome on cardiac autonomic function at a late fertile age: a prospective Northern Finland Birth Cohort 1966 study. BMJ Open 9, e033780 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Philbois, S. V. et al. Women with polycystic ovarian syndrome exhibit reduced baroreflex sensitivity that may be associated with increased body fat. Arq. Bras. Cardiol. 112, 424–429 (2019).

    PubMed  PubMed Central  Google Scholar 

  209. Qu, X. & Donnelly, R. Sex hormone-binding globulin (SHBG) as an early biomarker and therapeutic target in polycystic ovary syndrome. Int. J. Mol. Sci. 21, 8191 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Rock, K. L., Latz, E., Ontiveros, F. & Kono, H. The sterile inflammatory response. Annu. Rev. Immunol. 28, 321–342 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Polderman, T. J. et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat. Genet. 47, 702–709 (2015).

    Article  CAS  PubMed  Google Scholar 

  212. Jiang, X., Deng, Q. & Stener-Victorin, E. Is there a shared genetic basis and causal relationship between polycystic ovary syndrome and psychiatric disorders: evidence from a comprehensive genetic analysis. Hum. Reprod. 36, 2382–2391 (2021).

    Article  CAS  PubMed  Google Scholar 

  213. Hu, M. et al. Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring. Proc. Natl Acad. Sci. USA 112, 14348–14353 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Manti, M. et al. Maternal androgen excess and obesity induce sexually dimorphic anxiety-like behavior in the offspring. FASEB J. 32, 4158–4171 (2018).

    Article  CAS  PubMed  Google Scholar 

  215. Fitzgerald, E., Hor, K. & Drake, A. J. Maternal influences on fetal brain development: the role of nutrition, infection and stress, and the potential for intergenerational consequences. Early Hum. Dev. 150, 105190 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Palm, C. V. B. et al. Prenatal androgen exposure and traits of autism spectrum disorder in the offspring: Odense child cohort. J. Autism Dev. Disord. 53, 1053–1065 (2023).

    Article  PubMed  Google Scholar 

  217. Dalgaard, C. M. et al. Maternal polycystic ovary syndrome and attention deficit hyperactivity disorder in offspring at 3 years of age: Odense child cohort. Acta Obstet. Gynecol. Scand. 100, 2053–2065 (2021).

    Article  CAS  PubMed  Google Scholar 

  218. Chen, X., Kong, L., Piltonen, T. T., Gissler, M. & Lavebratt, C. Association of polycystic ovary syndrome or anovulatory infertility with offspring psychiatric and mild neurodevelopmental disorders: a Finnish population-based cohort study. Hum. Reprod. 35, 2336–2347 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Robinson, S. L. et al. The associations of maternal polycystic ovary syndrome and hirsutism with behavioral problems in offspring. Fertil. Steril. 113, 435–443 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  220. Tian, X. et al. Sexual function in Chinese women with different clinical phenotypes of polycystic ovary syndrome. Gynecol. Endocrinol. 39, 2221736 (2023).

    Article  PubMed  Google Scholar 

  221. Mojahed, B. S., Ghajarzadeh, M., Khammar, R. & Shahraki, Z. Depression, sexual function and sexual quality of life in women with polycystic ovary syndrome (PCOS) and healthy subjects. J. Ovarian Res. 16, 105 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  222. Noroozzadeh, M., Ramezani Tehrani, F., Bahri Khomami, M. & Azizi, F. A comparison of sexual function in women with polycystic ovary syndrome (PCOS) whose mothers had PCOS during their pregnancy period with those without PCOS. Arch. Sex. Behav. 46, 2033–2042 (2017).

    Article  PubMed  Google Scholar 

  223. Silva, M. S. B. et al. Female sexual behavior is disrupted in a preclinical mouse model of PCOS via an attenuated hypothalamic nitric oxide pathway. Proc. Natl Acad. Sci. USA 119, e2203503119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Joham, A. E. et al. Polycystic ovary syndrome. Lancet Diabetes Endocrinol. 10, 668–680 (2022).

    Article  CAS  PubMed  Google Scholar 

  225. Teede, H. J. et al. Recommendations from the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. Fertil. Steril. 110, 364–379 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Pena, A. S. et al. Adolescent polycystic ovary syndrome according to the international evidence-based guideline. BMC Med. 18, 72 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Tay, C. T. et al. Updated adolescent diagnostic criteria for polycystic ovary syndrome: impact on prevalence and longitudinal body mass index trajectories from birth to adulthood. BMC Med. 18, 389 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  228. Dong, J. & Rees, D. A. Polycystic ovary syndrome: pathophysiology and therapeutic opportunities. BMJ Med. 2, e000548 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  229. Urakami, T. Maturity-onset diabetes of the young (MODY): current perspectives on diagnosis and treatment. Diabetes Metab. Syndr. Obes. 12, 1047–1056 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Kataoka, J. et al. Weight management interventions in women with and without PCOS: a systematic review. Nutrients 9, 996 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  231. Lim, S. S. et al. Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst. Rev. 3, CD007506 (2019).

    PubMed  Google Scholar 

  232. Moran, L. J. et al. C-reactive protein before and after weight loss in overweight women with and without polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 92, 2944–2951 (2007).

    Article  CAS  PubMed  Google Scholar 

  233. American Diabetes Association Professional Practice Committee. 3. Prevention or delay of type 2 diabetes and associated comorbidities: standards of medical care in diabetes-2022. Diabetes Care 45, S39–S45 (2022).

    Article  Google Scholar 

  234. Chiavaroli, L. et al. DASH dietary pattern and cardiometabolic outcomes: an umbrella review of systematic reviews and meta-analyses. Nutrients 11, 338 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Ge, L. et al. Comparison of dietary macronutrient patterns of 14 popular named dietary programmes for weight and cardiovascular risk factor reduction in adults: systematic review and network meta-analysis of randomised trials. BMJ 369, m696 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  236. Papadaki, A., Nolen-Doerr, E. & Mantzoros, C. S. The effect of the Mediterranean diet on metabolic health: a systematic review and meta-analysis of controlled trials in adults. Nutrients 12, 3342 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Sievenpiper, J. L. Low-carbohydrate diets and cardiometabolic health: the importance of carbohydrate quality over quantity. Nutr. Rev. 78, 69–77 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  238. Benham, J. L. et al. Exercise training and reproductive outcomes in women with polycystic ovary syndrome: a pilot randomized controlled trial. Clin. Endocrinol. 95, 332–343 (2021).

    Article  Google Scholar 

  239. Ribeiro, V. B. et al. Effects of continuous and intermittent aerobic physical training on hormonal and metabolic profile, and body composition in women with polycystic ovary syndrome: a randomized controlled trial. Clin. Endocrinol. 93, 173–186 (2020).

    Article  CAS  Google Scholar 

  240. Carlsson, L. M. S. et al. Life expectancy after bariatric surgery in the Swedish obese subjects study. N. Engl. J. Med. 383, 1535–1543 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  241. Eisenberg, D. et al. 2022 American Society for Metabolic and Bariatric Surgery (ASMBS) and International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO): indications for metabolic and bariatric surgery. Surg. Obes. Relat. Dis. 18, 1345–1356 (2022).

    Article  PubMed  Google Scholar 

  242. Hu, L. et al. Efficacy of bariatric surgery in the treatment of women with obesity and polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 107, e3217–e3229 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  243. Tatarchuk, T. et al. The effect of gastric sleeve resection on menstrual pattern and ovulation in premenopausal women with classes III-IV obesity. Obes. Surg. 32, 599–606 (2022).

    Article  PubMed  Google Scholar 

  244. Melin, J. et al. The impact of metformin with or without lifestyle modification versus placebo on polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Eur. J. Endocrinol. 189, S37–S63 (2023).

    Article  PubMed  Google Scholar 

  245. Ge, J. J., Wang, D. J., Song, W., Shen, S. M. & Ge, W. H. The effectiveness and safety of liraglutide in treating overweight/obese patients with polycystic ovary syndrome: a meta-analysis. J. Endocrinol. Invest. 45, 261–273 (2022).

    Article  CAS  PubMed  Google Scholar 

  246. Teede, H. et al. Effect of the combined oral contraceptive pill and/or metformin in the management of polycystic ovary syndrome: a systematic review with meta-analyses. Clin. Endocrinol. 91, 479–489 (2019).

    Article  CAS  Google Scholar 

  247. Elkind-Hirsch, K. E., Chappell, N., Shaler, D., Storment, J. & Bellanger, D. Liraglutide 3 mg on weight, body composition, and hormonal and metabolic parameters in women with obesity and polycystic ovary syndrome: a randomized placebo-controlled-phase 3 study. Fertil. Steril. 118, 371–381 (2022). This study showed that GLP1 analogue is superior to placebo in reducing body weight and hyperandrogenism as well as improving cardiometabolic variables in women with PCOS.

    Article  CAS  PubMed  Google Scholar 

  248. Carmina, E. & Longo, R. A. Semaglutide treatment of excessive body weight in obese PCOS patients unresponsive to lifestyle programs. J. Clin. Med. 12, 5921 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Fonseka, S. et al. Effectiveness of low-dose ethinylestradiol/cyproterone acetate and ethinylestradiol/desogestrel with and without metformin on hirsutism in polycystic ovary syndrome: a randomized, double-blind, triple-dummy study. J. Clin. Aesthet. Dermatol. 13, 18–23 (2020).

    PubMed  PubMed Central  Google Scholar 

  250. Forslund, M. et al. Different kinds of oral contraceptive pills in polycystic ovary syndrome: a systematic review and meta-analysis. Eur. J. Endocrinol. 189, S1–S16 (2023).

    Article  PubMed  Google Scholar 

  251. Melin, J. et al. Metformin and combined oral contraceptive pills in the management of polycystic ovary syndrome: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 109, e817–e836 (2023).

    Article  PubMed Central  Google Scholar 

  252. Bhandari, M. et al. Effects of bariatric surgery on people with obesity and polycystic ovary syndrome: a large single center study from India. Obes. Surg. 32, 3305–3312 (2022).

    Article  PubMed  Google Scholar 

  253. Lullo, J. J. et al. Incidence of androgenic dermatologic side effects following placement of a levonorgestrel intrauterine device for menorrhagia: a survey-based study. J. Am. Acad. Dermatol. 79, 364–365 (2018).

    Article  PubMed  Google Scholar 

  254. King, L., Gajarawala, S. & McCrary, M. D. Endometrial cancer and obesity: addressing the awkward silence. JAAPA 36, 28–31 (2023).

    Article  PubMed  Google Scholar 

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

    Article  Google Scholar 

  256. Benito, E. et al. Fertility and pregnancy outcomes in women with polycystic ovary syndrome following bariatric surgery. J. Clin. Endocrinol. Metab. 105, dgaa439 (2020).

    Article  PubMed  Google Scholar 

  257. Legro, R. S. et al. Randomized controlled trial of preconception interventions in infertile women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 100, 4048–4058 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. 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  PubMed  Google Scholar 

  259. de Wilde, M. A. et al. Increased rates of complications in singleton pregnancies of women previously diagnosed with polycystic ovary syndrome predominantly in the hyperandrogenic phenotype. Fertil. Steril. 108, 333–340 (2017).

    Article  PubMed  Google Scholar 

  260. Wang, R. et al. First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis. Hum. Reprod. Update 25, 717–732 (2019).

    Article  CAS  PubMed  Google Scholar 

  261. Wang, R. Treatment strategies for women with WHO group II anovulation: systematic review and network meta-analysis. BMJ 356, j138 (2017); erratum 379, o2436 (2022).

  262. Legro, R. S. et al. Letrozole or clomiphene for infertility in the polycystic ovary syndrome. N. Engl. J. Med. 371, 1463–1464 (2014).

    Article  PubMed  Google Scholar 

  263. Pundir, J. et al. Risk of foetal harm with letrozole use in fertility treatment: a systematic review and meta-analysis. Hum. Reprod. Update 27, 474–485 (2021).

    Article  CAS  PubMed  Google Scholar 

  264. Bordewijk, E. M. et al. Long-term outcomes of switching to gonadotrophins versus continuing with clomiphene citrate, with or without intrauterine insemination, in women with normogonadotropic anovulation and clomiphene failure: follow-up study of a factorial randomized clinical trial. Hum. Reprod. 38, 421–429 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Chen, Z. J. et al. Fresh versus frozen embryos for infertility in the polycystic ovary syndrome. N. Engl. J. Med. 375, 523–533 (2016).

    Article  PubMed  Google Scholar 

  266. Chen, N. et al. Risk factors associated with monozygotic twinning in offspring conceived by assisted reproductive technology. Hum. Reprod. Open 2023, hoad035 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  267. Zhang, B. et al. Obstetric complications after frozen versus fresh embryo transfer in women with polycystic ovary syndrome: results from a randomized trial. Fertil. Steril. 109, 324–329 (2018).

    Article  PubMed  Google Scholar 

  268. Magnusson, A. et al. Endometrial preparation protocols prior to frozen embryo transfer — convenience or safety? Reprod. Biomed. Online 48, 103587 (2023).

    Article  PubMed  Google Scholar 

  269. Gilchrist, R. B. et al. A fresh start for IVM: capacitating the oocyte for development using pre-IVM. Hum. Reprod. Update 30, 3–25 (2023).

    Article  Google Scholar 

  270. Pham, H. H. et al. Cumulative live birth rate after oocyte in vitro maturation with a pre-maturation step in women with polycystic ovary syndrome or high antral follicle count. J. Assist. Reprod. Genet. 40, 827–835 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  271. Stein, I. F. Multiple pregnancy following wedge resection in the Stein-Leventhal syndrome. Int. J. Fertil. 9, 343–350 (1964).

    CAS  PubMed  Google Scholar 

  272. Nahuis, M. J. et al. Long-term follow-up of laparoscopic electrocautery of the ovaries versus ovulation induction with recombinant FSH in clomiphene citrate-resistant women with polycystic ovary syndrome: an economic evaluation. Hum. Reprod. 27, 3577–3582 (2012).

    Article  CAS  PubMed  Google Scholar 

  273. Bayram, N., van Wely, M., Kaaijk, E. M., Bossuyt, P. M. & van der Veen, F. Using an electrocautery strategy or recombinant follicle stimulating hormone to induce ovulation in polycystic ovary syndrome: randomised controlled trial. BMJ 328, 192 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Baradwan, S. et al. Transvaginal needle versus laparoscopic ovarian drilling in hormonal profile and pregnancy outcomes of polycystic ovary syndrome: a systematic review and meta-analysis. J. Gynecol. Obstet. Hum. Reprod. 52, 102606 (2023).

    Article  PubMed  Google Scholar 

  275. Dokras, A. et al. Weight loss and lowering androgens predict improvements in health-related quality of life in women with PCOS. J. Clin. Endocrinol. Metab. 101, 2966–2974 (2016). Weight loss and oral contraceptives improve HRQoL as well as depressive and anxiety symptoms and when combined they offer further benefits in women with overweight and obesity and PCOS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Jiskoot, G. et al. Long-term effects of a three-component lifestyle intervention on emotional well-being in women with polycystic ovary syndrome (PCOS): a secondary analysis of a randomized controlled trial. PLoS ONE 15, e0233876 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Cooney, L. G. et al. Cognitive-behavioral therapy improves weight loss and quality of life in women with polycystic ovary syndrome: a pilot randomized clinical trial. Fertil. Steril. 110, 161–171 e161 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  278. Melson, E. et al. A systematic review of models of care for polycystic ovary syndrome highlights the gap in the literature, especially in developing countries. Front. Endocrinol. 14, 1217468 (2023).

    Article  Google Scholar 

  279. Behboodi Moghadam, Z., Fereidooni, B., Saffari, M. & Montazeri, A. Measures of health-related quality of life in PCOS women: a systematic review. Int. J. Womens Health 10, 397–408 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  280. Karjula, S. et al. Population-based data at ages 31 and 46 show decreased HRQoL and life satisfaction in women with PCOS symptoms. J. Clin. Endocrinol. Metab. 105, 1814–1826 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  281. Cronin, L. 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).

    CAS  PubMed  Google Scholar 

  282. 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  PubMed  Google Scholar 

  283. Williams, S., Sheffield, D. & Knibb, R. C. The polycystic ovary syndrome quality of life scale (PCOSQOL): development and preliminary validation. Health Psychol. Open 5, 2055102918788195 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  284. Saei Ghare Naz, M. et al. Adolescents’ polycystic ovary syndrome health-related quality of life questionnaire (APQ-20): development and psychometric properties. Eur. J. Pediatr. 182, 2393–2407 (2023).

    Article  PubMed  Google Scholar 

  285. Azziz, R. et al. Recommendations for epidemiologic and phenotypic research in polycystic ovary syndrome: an androgen excess and PCOS society resource. Hum. Reprod. 34, 2254–2265 (2019).

    Article  CAS  PubMed  Google Scholar 

  286. Al Wattar, B. H. et al. Harmonising research outcomes for polycystic ovary syndrome: an international multi-stakeholder core outcome set. Hum. Reprod. 35, 404–412 (2020).

    Article  PubMed  Google Scholar 

  287. Kiconco, S. et al. PCOS phenotype in unselected populations study (P-PUP): protocol for a systematic review and defining PCOS diagnostic features with pooled individual participant data. Diagnostics 11, 1953 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  288. Gibson-Helm, M., Dokras, A., Karro, H., Piltonen, T. & Teede, H. J. Knowledge and practices regarding polycystic ovary syndrome among physicians in Europe, North America, and internationally: an online questionnaire-based study. Semin. Reprod. Med. 36, 19–27 (2018).

    Article  PubMed  Google Scholar 

  289. Schünemann, H., Brożek, J., Guyatt, G. & Oxman, A. (eds) GRADE Handbook (GRADE Working Group, 2013).

  290. James, D. E., Stockli, J. & Birnbaum, M. J. The aetiology and molecular landscape of insulin resistance. Nat. Rev. Mol. Cell Biol. 22, 751–771 (2021).

    Article  CAS  PubMed  Google Scholar 

  291. Di Guardo, F., Ciotta, L., Monteleone, M. & Palumbo, M. Male equivalent polycystic ovarian syndrome: hormonal, metabolic, and clinical aspects. Int. J. Fertil. Steril. 14, 79–83 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  293. Sanke, S., Chander, R., Jain, A., Garg, T. & Yadav, P. A comparison of the hormonal profile of early androgenetic alopecia in men with the phenotypic equivalent of polycystic ovarian syndrome in women. JAMA Dermatol. 152, 986–991 (2016).

    Article  PubMed  Google Scholar 

  294. Starka, L., Duskova, M., Cermakova, I., Vrbikova, J. & Hill, M. Premature androgenic alopecia and insulin resistance. Male equivalent of polycystic ovary syndrome? Endocr. Regul. 39, 127–131 (2005).

    CAS  PubMed  Google Scholar 

  295. Crisosto, N. et al. Reproductive and metabolic features during puberty in sons of women with polycystic ovary syndrome. Endocr. Connect. 6, 607–613 (2017). This study further supports that not only daughters but also sons of women with PCOS present with metabolic and minor reproductive dysfunctions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Torchen, L. C. et al. Increased antimullerian hormone levels and other reproductive endocrine changes in adult male relatives of women with polycystic ovary syndrome. Fertil. Steril. 106, 50–55 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  298. Baillargeon, J. P. & Carpentier, A. C. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  299. Sam, S., Coviello, A. D., Sung, Y. A., Legro, R. S. & Dunaif, A. Metabolic phenotype in the brothers of women with polycystic ovary syndrome. Diabetes Care 31, 1237–1241 (2008).

    Article  CAS  PubMed  Google Scholar 

  300. Sam, S., Sung, Y. A., Legro, R. S. & Dunaif, A. Evidence for pancreatic β-cell dysfunction in brothers of women with polycystic ovary syndrome. Metabolism 57, 84–89 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Karthik, S. et al. Cardiovascular disease risk in the siblings of women with polycystic ovary syndrome. Hum. Reprod. 34, 1559–1566 (2019).

    Article  CAS  PubMed  Google Scholar 

  302. Subramaniam, K., Tripathi, A. & Dabadghao, P. Familial clustering of metabolic phenotype in brothers of women with polycystic ovary syndrome. Gynecol. Endocrinol. 35, 601–603 (2019).

    Article  CAS  PubMed  Google Scholar 

  303. Joham, A. E., Boyle, J. A., Ranasinha, S., Zoungas, S. & Teede, H. J. Contraception use and pregnancy outcomes in women with polycystic ovary syndrome: data from the Australian Longitudinal Study on Women’s Health. Hum. Reprod. 29, 802–808 (2014).

    Article  CAS  PubMed  Google Scholar 

  304. Dokras, A. et al. Androgen excess- polycystic ovary syndrome society: position statement on depression, anxiety, quality of life, and eating disorders in polycystic ovary syndrome. Fertil. Steril. 109, 888–899 (2018).

    Article  PubMed  Google Scholar 

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Acknowledgements

E.S.-V. is supported by the Swedish Medical Research Council: project no. 2022-00550 (ESV); Distinguished Investigator Grant – Endocrinology and Metabolism, Novo Nordisk Foundation: NNF22OC0072904 and project grant NNF19OC0056647; Diabetes Foundation: DIA2022-708; Karolinska Institutet KID funding: 2023-0005 and 2020-00990; and Regional Agreement on Medical Training and Clinical Research between the Stockholm County Council and the Karolinska Institutet: 20190079. M.O.G. is supported by the Eris M. Field Chair in Diabetes Research and NIDDK P30-DK063481. H.T. is supported by Australian NHMRC Fellowship 2009326 and the Centre for Research Excellence.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden

    Elisabet Stener-Victorin

  2. Monash Centre for Health Research and Implementation, Monash Health and Monash University, Melbourne, Victoria, Australia

    Helena Teede

  3. Robinson Research Institute, Adelaide Medical School, Adelaide, South Australia, Australia

    Robert J. Norman

  4. Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, PA, USA

    Richard Legro

  5. Department of Public Health Science, Penn State College of Medicine, Hershey, PA, USA

    Richard Legro

  6. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Mark O. Goodarzi

  7. Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA

    Anuja Dokras

  8. Division of Reproductive Endocrinology & Infertility, Department of Obstetrics and Gynecology, Erasmus MC, Rotterdam, Netherlands

    Joop Laven

  9. Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    Kathleen Hoeger

  10. Department of Obstetrics and Gynecology, Research Unit of Clinical Medicine, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland

    Terhi T. Piltonen

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Contributions

Introduction (E.S.-V.); Epidemiology (T.T.P., H.T., A.D. and E.S.-V.); Mechanisms/pathophysiology (E.S.-V., M.O.G., J.L., R.J.N. and T.T.P.); Diagnosis, screening and prevention (H.T.); Management (K.H., J.L., R.L., T.T.P. and A.D.); Quality of life (A.D.); Outlook (E.S.-V., H.T., R.J.N., R.L., M.O.G., A.D., J.L., K.H. and T.T.P.) and overview of the Primer (E.S.-V.).

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Nature Reviews Disease Primers thanks Vasantha Padmanabhan, who co-reviewed with Katherine Hollaran; Fahimeh Teherani; Han Zhao, who co-reviewed with ZiJiang Chen; and the other, anonymous, reviewer(s) for their contribution to the peer-review of this work.

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Stener-Victorin, E., Teede, H., Norman, R.J. et al. Polycystic ovary syndrome. Nat Rev Dis Primers 10, 27 (2024). https://doi.org/10.1038/s41572-024-00511-3

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