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Molecular Mechanisms in the Etiology of Polycystic Ovary Syndrome (PCOS): A Multifaceted Hypothesis Towards the Disease with Potential Therapeutics

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Abstract

Among the premenopausal women, Polycystic Ovary Syndrome (PCOS) is the most prevalent endocrinopathy affecting the reproductive system and metabolic rhythms leading to disrupted menstrual cycle. Being heterogeneous in nature it is characterized by complex symptomology of oligomennorhoea, excess of androgens triggering masculine phenotypic appearance and/or multiple follicular ovaries. The etiology of this complex disorder remains somewhat doubtful and the researchers hypothesize multisystem links in the pathogenesis of this disease. In this review, we attempt to present several hypotheses that tend to contribute to the etiology of PCOS. Metabolic inflexibility, aberrant pattern of gonadotropin signaling along with the evolutionary, genetic and environmental factors have been discussed. Considered a lifelong endocrinological implication, no universal treatment is available for PCOS so far however; multiple drug therapy is often advised along with simple life style intervention is mainly advised to manage its cardinal symptoms. Here we aimed to present a summarized view of pathophysiological links of PCOS with potential therapeutic strategies.

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Abbreviations

NIH:

National Institutes of Health

HA:

Hyperandrogenism

OD:

Ovarian dysfunction

PCOM:

Polycystic ovarian morphology

AE:

Androgen Excess-PCOS Society

I.R:

Insulin resistance

LH:

Luteinizing hormone

FSH:

Follicle stimulating hormone

References

  1. Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018;14(5):270.

    Article  PubMed  Google Scholar 

  2. Escobar-Morreale HF. Defining PCOS: A syndrome with an intrinsic heterogeneous nature. Polycystic Ovary Syndrome: Elsevier; 2022. p. 3–13.

  3. Yazdani, A. Polycystic ovarian syndrome. Examination Obstetrics and Gynaecology. 2010:21.

  4. Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol. 2014;6:1.

    Google Scholar 

  5. Teede H, Deeks A, Moran L. Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med. 2010;8(1):1–10.

    Article  Google Scholar 

  6. Sanchez-Garrido MA, Tena-Sempere M. Metabolic dysfunction in polycystic ovary syndrome: pathogenic role of androgen excess and potential therapeutic strategies. Mol Metab. 2020;35:100937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hasan M, Sultana S, Sohan M, Parvin S, Rahman MA, Hossain MJ, et al. Prevalence and associated risk factors for mental health problems among patients with polycystic ovary syndrome in Bangladesh: a nationwide cross: sectional study. PLoS ONE. 2022;17(6):e0270102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Deeks A, Gibson-Helm M, Paul E, Teede H. Is having polycystic ovary syndrome a predictor of poor psychological function including anxiety and depression? Hum Reprod. 2011;26(6):1399–407.

    Article  CAS  PubMed  Google Scholar 

  9. Stein IF. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 1935;29:181–91.

    Article  Google Scholar 

  10. Hoeger KM, Dokras A, Piltonen T. Update on PCOS: consequences, challenges, and guiding treatment. J Clin Endocrinol Metab. 2021;106(3):e1071–83.

    Article  PubMed  Google Scholar 

  11. Zawadzski J. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. Polycystic Ovary Syndrome. 1992:39–50.

  12. Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018;33(9):1602–18.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertility and sterility. 2012;97(1):28–38.

  14. Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L, Azziz R. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril. 2016;106(1):6–15.

    Article  PubMed  Google Scholar 

  15. Mykhalchenko K, Lizneva D, Trofimova T, Walker W, Suturina L, Diamond MP, et al. Genetics of polycystic ovary syndrome. Expert Rev Mol Diagn. 2017;17(7):723–33.

    Article  CAS  PubMed  Google Scholar 

  16. Stener-Victorin E, Padmanabhan V, Walters KA, Campbell RE, Benrick A, Giacobini P, et al. Animal models to understand the etiology and pathophysiology of polycystic ovary syndrome. Endocr Rev. 2020;41(4):538–76.

    Article  Google Scholar 

  17. Barthelmess EK, Naz RK. Polycystic ovary syndrome: current status and future perspective. Front Biosci (Elite Ed). 2014;6:104.

    PubMed  Google Scholar 

  18. Azziz R. How PCOS came into its own. Elsevier; 2021.

  19. Bozdag G, Mumusoglu S, Zengin D, Karabulut E, Yildiz BO. The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2016;31(12):2841–55.

    Article  PubMed  Google Scholar 

  20. Ding T, Hardiman PJ, Petersen I, Wang F-F, Qu F, Baio G. The prevalence of polycystic ovary syndrome in reproductive-aged women of different ethnicity: a systematic review and meta-analysis. Oncotarget. 2017;8(56):96351.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Goodarzi MO, Quiñones MJ, Azziz R, Rotter JI, Hsueh WA, Yang H. Polycystic ovary syndrome in Mexican-Americans: prevalence and association with the severity of insulin resistance. Fertil Steril. 2005;84(3):766–9.

    Article  PubMed  Google Scholar 

  22. Wolf WM, Wattick RA, Kinkade ON, Olfert MD. Geographical prevalence of polycystic ovary syndrome as determined by region and race/ethnicity. Int J Environ Res Public Health. 2018;15(11):2589.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004;89(6):2745–9.

    Article  CAS  PubMed  Google Scholar 

  24. Knochenhauer E, Key T, Kahsar-Miller M, Waggoner W, Boots L, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998;83(9):3078–82.

    CAS  PubMed  Google Scholar 

  25. Azziz R. Introduction: determinants of polycystic ovary syndrome. Fertil Steril. 2016;106(1):4–5.

    Article  PubMed  Google Scholar 

  26. Liu J, Wu Q, Hao Y, Jiao M, Wang X, Jiang S, et al. Measuring the global disease burden of polycystic ovary syndrome in 194 countries: Global Burden of Disease Study 2017. Hum Reprod. 2021;36(4):1108–19.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Naal H, El Koussa M, El Hamouch M, Hneiny L, Saleh S. A systematic review of global health capacity building initiatives in low-to middle-income countries in the Middle East and North Africa region. Glob Health. 2020;16(1):1–16.

    Article  Google Scholar 

  28. Miazgowski T, Martopullo I, Widecka J, Miazgowski B, Brodowska A. National and regional trends in the prevalence of polycystic ovary syndrome since 1990 within Europe: the modeled estimates from the Global Burden of Disease Study 2016. Arch Med Sci: AMS. 2021;17(2):343.

    Article  PubMed  Google Scholar 

  29. Bharali MD, Rajendran R, Goswami J, Singal K, Rajendran V. Prevalence of polycystic ovarian syndrome in India: a systematic review and meta-analysis. Cureus. 2022;14(12).

  30. Sharma P, Kaur M, Kumar S, Khetarpal P. A cross-sectional study on prevalence of menstrual problems, lifestyle, mental health, and PCOS awareness among rural and urban population of Punjab, India. J Psychosom Obstet Gynecol. 2022;43(3):349–58.

    Article  Google Scholar 

  31. Barber T. Why are women with polycystic ovary syndrome obese? Br Med Bull. 2022;1:11.

    Article  Google Scholar 

  32. Joharatnam J, Barber TM, Webber L, Conway GS, McCarthy MI, Franks S. Determinants of dyslipidaemia in probands with polycystic ovary syndrome and their sisters. Clin Endocrinol. 2011;74(6):714–9.

    Article  Google Scholar 

  33. Long C, Feng H, Duan W, Chen X, Zhao Y, Lan Y, et al. Prevalence of polycystic ovary syndrome in patients with type 2 diabetes: a systematic review and meta-analysis. Frontiers in Endocrinology. 2022:2091.

  34. Riestenberg C, Jagasia A, Markovic D, Buyalos RP, 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. 2022;107(2):575–85.

    Article  PubMed  Google Scholar 

  35. Oktem O, Urman B. Understanding follicle growth in vivo. Hum Reprod. 2010;25(12):2944–54.

    Article  PubMed  Google Scholar 

  36. Rosenfield RL, Ehrmann DA. The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev. 2016;37(5):467–520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Falck B. Site of production of oestrogen in rat ovary as studied in micro-transplants. Acta Physiol Scand. 1960;47(4):1–101.

    Article  Google Scholar 

  38. Kiriakidou M, Mcallister JM, Sugawara T, Strauss J 3rd. Expression of steroidogenic acute regulatory protein (StAR) in the human ovary. J Clin Endocrinol Metab. 1996;81(11):4122–8.

    CAS  PubMed  Google Scholar 

  39. Miller WL. Molecular biology of steroid hormone synthesis. Endocr Rev. 1988;9(3):295–318.

    Article  CAS  PubMed  Google Scholar 

  40. Penning TM. Molecular endocrinology of hydroxysteroid dehydrogenases. Endocr Rev. 1997;18(3):281–305.

    CAS  PubMed  Google Scholar 

  41. Hanukoglu I. Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis. J Steroid Biochem Mol Biol. 1992;43(8):779–804.

    Article  CAS  PubMed  Google Scholar 

  42. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32(1):81–151.

    Article  CAS  PubMed  Google Scholar 

  43. Kirschner MA, Bardin CW. Androgen production and metabolism in normal and virilized women. Metabolism. 1972;21(7):667–88.

    Article  CAS  PubMed  Google Scholar 

  44. Longcope C, Johnston C Jr. Androgen and estrogen dynamics in pre-and postmenopausal women: a comparison between smokers and nonsmokers. J Clin Endocrinol Metab. 1988;67(2):379–83.

    Article  CAS  PubMed  Google Scholar 

  45. Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM, Graham-Lorence S, et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev. 1994;15(3):342–55.

    CAS  PubMed  Google Scholar 

  46. Walters K, Allan C, Handelsman D. Androgen actions and the ovary. Biol Reprod. 2008;78(3):380–9.

    Article  CAS  PubMed  Google Scholar 

  47. Escobar-Morreale HF, Luque-Ramírez M, San Millán JL. The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome. Endocr Rev. 2005;26(2):251–82.

    Article  CAS  PubMed  Google Scholar 

  48. Anakwe OO, Payne AH. Noncoordinate regulation of de novo synthesis of cytochrome P-450 cholesterol side-chain cleavage and cytochrome P-450 17α-hydroxylase/C17-20 lyase in mouse Leydig cell cultures: Relation to steroid production. Mol Endocrinol. 1987;1(9):595–603.

    Article  CAS  PubMed  Google Scholar 

  49. Fauser BC, Pache TD, Lamberts SW, Hop WC, de Jong FH, Dahl KD. Serum bioactive and immunoreactive luteinizing hormone and follicle-stimulating hormone levels in women with cycle abnormalities, with or without polycystic ovarian disease. J Clin Endocrinol Metab. 1991;73(4):811–7.

    Article  CAS  PubMed  Google Scholar 

  50. Abbott D, Barnett D, Bruns C, Dumesic D. Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? Hum Reprod Update. 2005;11(4):357–74.

    Article  CAS  PubMed  Google Scholar 

  51. Fernández-Real J-M, Ricart W. Insulin resistance and inflammation in an evolutionary perspective: the contribution of cytokine genotype/phenotype to thriftiness. Diabetologia. 1999;42(11):1367–74.

    Article  PubMed  Google Scholar 

  52. Khan MJ, Ullah A, Basit S. Genetic basis of polycystic ovary syndrome (PCOS): current perspectives. Appl Clin Genet. 2019;12:249.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Kosova G, Urbanek M. Genetics of the polycystic ovary syndrome. Mol Cell Endocrinol. 2013;373(1–2):29–38.

    Article  CAS  PubMed  Google Scholar 

  54. Cooper HE, Spellacy W, Prem K, Cohen W. Hereditary factors in the Stein-Leventhal syndrome. Am J Obstet Gynecol. 1968;100(3):371–87.

    Article  CAS  PubMed  Google Scholar 

  55. Vink J, Sadrzadeh S, Lambalk C, Boomsma D. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab. 2006;91(6):2100–4.

    Article  CAS  PubMed  Google Scholar 

  56. Waterworth DM, Bennett ST, Gharani N, McCarthy MI, Hague S, Batty S, et al. Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet. 1997;349(9057):986–90.

    Article  CAS  PubMed  Google Scholar 

  57. Taylor SI, Cama A, Accili D, Barbetti F, Quon MJ, Sierra MDLL, et al. Mutations in the insulin receptor gene. Endocr Rev. 1992;13(3):566–95.

    Article  CAS  PubMed  Google Scholar 

  58. Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet. 2007;39(6):724–6.

    Article  CAS  PubMed  Google Scholar 

  59. Barber T, Bennett A, Groves C, Sovio U, Ruokonen A, Martikainen H, et al. Association of variants in the fat mass and obesity associated (FTO) gene with polycystic ovary syndrome. Diabetologia. 2008;51(7):1153–8.

    Article  CAS  PubMed  Google Scholar 

  60. Ackerman C, Garcia O, Legro R, Dunaif A, Urbanek M. SHBG (TAAAA) n is associated with serum SHBG in a PCOS case-control cohort. Endocr Rev. 2011;32:P2–66.03.

  61. Shi Y, Zhao H, Shi Y, Cao Y, Yang D, Li Z, et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet. 2012;44(9):1020–5.

    Article  CAS  PubMed  Google Scholar 

  62. Chen Z-J, Zhao H, He L, Shi Y, Qin Y, Shi Y, et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16. 3, 2p21 and 9q33. 3. Nat Genet. 2011;43(1):55–9.

  63. Gao J, Xue J-D, Li Z-C, Zhou L, Chen C. The association of DENND1A gene polymorphisms and polycystic ovary syndrome risk: a systematic review and meta-analysis. Arch Gynecol Obstet. 2016;294:1073–80.

    Article  CAS  PubMed  Google Scholar 

  64. Day F, Karaderi T, Jones MR, Meun C, He C, Drong A, et al. Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLoS Genet. 2018;14(12):e1007813.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Feng C, Lv P-P, Yu T-T, Jin M, Shen J-M, Wang X, et al. The association between polymorphism of INSR and polycystic ovary syndrome: a meta-analysis. Int J Mol Sci. 2015;16(2):2403–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet. 2008;40(5):638–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Cui L, Zhao H, Zhang B, Qu Z, Liu J, Liang X, et al. Genotype–phenotype correlations of PCOS susceptibility SNPs identified by GWAS in a large cohort of Han Chinese women. Hum Reprod. 2013;28(2):538–44.

    Article  CAS  PubMed  Google Scholar 

  68. Tian Y, Li J, Su S, Cao Y, Wang Z, Zhao S, et al. PCOS-GWAS susceptibility variants in THADA, INSR, TOX3, and DENND1A are associated with metabolic syndrome or insulin resistance in women with PCOS. Front Endocrinol. 2020;11:274.

    Article  Google Scholar 

  69. Greenaway J, Lawler J, Moorehead R, Bornstein P, Lamarre J, Petrik J. Thrombospondin-1 inhibits VEGF levels in the ovary directly by binding and internalization via the low density lipoprotein receptor-related protein-1 (LRP-1). J Cell Physiol. 2007;210(3):807–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Dapas M, Lin FT, Nadkarni GN, Sisk R, Legro RS, Urbanek M, et al. Distinct subtypes of polycystic ovary syndrome with novel genetic associations: an unsupervised, phenotypic clustering analysis. PLoS Med. 2020;17(6):e1003132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LC. The insulin-related ovarian regulatory system in health and disease. Endocr Rev. 1999;20(4):535–82.

    Article  CAS  PubMed  Google Scholar 

  72. Diamanti-Kandarakis E, Papavassiliou AG. Outstanding questions. Trends Mol Med. 2006;7(12):324–32.

    Article  Google Scholar 

  73. Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018;98(4):2133–223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang J, Wu D, Guo H, Li M. Hyperandrogenemia and insulin resistance: the chief culprit of polycystic ovary syndrome. Life Sci. 2019;236:116940.

    Article  CAS  PubMed  Google Scholar 

  75. Munir I, Yen H-W, Geller DH, Torbati D, Bierden RM, Weitsman SR, et al. Insulin augmentation of 17α-hydroxylase activity is mediated by phosphatidyl inositol 3-kinase but not extracellular signal-regulated kinase-1/2 in human ovarian theca cells. Endocrinology. 2004;145(1):175–83.

    Article  CAS  PubMed  Google Scholar 

  76. Zhang Y, Sun X, Sun X, Meng F, Hu M, Li X, et al. Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus. Sci Rep. 2016;6(1):1–15.

    Google Scholar 

  77. Diamanti-Kandarakis E, Papavassiliou AG. Molecular mechanisms of insulin resistance in polycystic ovary syndrome. Trends Mol Med. 2006;12(7):324–32.

    Article  CAS  PubMed  Google Scholar 

  78. Ciaraldi TP, Morales AJ, Hickman MG, Odom-Ford R, Olefsky JM, Yen SS. Cellular insulin resistance in adipocytes from obese polycystic ovary syndrome subjects involves adenosine modulation of insulin sensitivity. J Clin Endocrinol Metab. 1997;82(5):1421–5.

    CAS  PubMed  Google Scholar 

  79. Feng C, Jin Z, Chi X, Zhang B, Wang X, Sun L, et al. SHBG expression is correlated with PI3K/AKT pathway activity in a cellular model of human insulin resistance. Gynecol Endocrinol. 2018;34(7):567–73.

    Article  CAS  PubMed  Google Scholar 

  80. Malini N, George KR. Evaluation of different ranges of LH: FSH ratios in polycystic ovarian syndrome (PCOS)–Clinical based case control study. Gen Comp Endocrinol. 2018;260:51–7.

    Article  CAS  PubMed  Google Scholar 

  81. Burghen GA, Givens JR, Kitabchi AE. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab. 1980;50(1):113–6.

    Article  CAS  PubMed  Google Scholar 

  82. Matalliotakis I, Kourtis A, Koukoura O, Panidis D. Polycystic ovary syndrome: etiology and pathogenesis. Arch Gynecol Obstet. 2006;274(4):187–97.

    Article  CAS  PubMed  Google Scholar 

  83. Nestler JE, Jakubowicz DJ, Falcon de Vargas A, Brik C, Quintero N, Medina F. 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. 1998;83(6):2001–5.

  84. Tosi F, Negri C, Brun E, Castello R, Faccini G, Bonora E, et al. Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women. Eur J Endocrinol. 2011;164(2):197.

    Article  CAS  PubMed  Google Scholar 

  85. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012;33(6):981–1030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Corbould A, Kim Y-B, Youngren JF, Pender C, Kahn BB, Lee A, 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. 2005;288(5):E1047–54.

    Article  CAS  PubMed  Google Scholar 

  87. Lan C-W, Chen M-J, Tai K-Y, Danny C, Yang Y-C, Jan P-S, et al. Functional microarray analysis of differentially expressed genes in granulosa cells from women with polycystic ovary syndrome related to MAPK/ERK signaling. Sci Rep. 2015;5(1):1–10.

    Article  Google Scholar 

  88. Song X, Shen Q, Fan L, Yu Q, Jia X, Sun Y, et al. Dehydroepiandrosterone-induced activation of mTORC1 and inhibition of autophagy contribute to skeletal muscle insulin resistance in a mouse model of polycystic ovary syndrome. Oncotarget. 2018;9(15):11905.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Butts SF, Seifer DB, Koelper N, Senapati S, Sammel MD, Hoofnagle AN, et al. Vitamin D deficiency is associated with poor ovarian stimulation outcome in PCOS but not unexplained infertility. J Clin Endocrinol Metab. 2019;104(2):369–78.

    Article  PubMed  Google Scholar 

  90. Wikiera B, Zubkiewicz-Kucharska A, Nocoń-Bohusz J, Noczyńska A. Metabolic disorders in polycystic ovary syndrome. Pediatr Endocrinol Diabetes Metab. 2017;23(4).

  91. Spinedi E, Cardinali DP. The polycystic ovary syndrome and the metabolic syndrome: a possible chronobiotic-cytoprotective adjuvant therapy. International journal of endocrinology. 2018;2018.

  92. Monte A, Barros V, Santos J, Menezes V, Cavalcante A, Gouveia B, et al. Immunohistochemical localization of insulin-like growth factor-1 (IGF-1) in the sheep ovary and the synergistic effect of IGF-1 and FSH on follicular development in vitro and LH receptor immunostaining. Theriogenology. 2019;129:61–9.

    Article  CAS  PubMed  Google Scholar 

  93. Martins F, Saraiva M, Celestino J, Bruno J, Almeida A, Cunha R, et al. Expression of protein and mRNA encoding Insulin Growth Factor-I (IGF-I) in goat ovarian follicles and the influence of IGF-I on in vitro development and survival of caprine preantral follicles. Anim Reprod. 2018;7(4):349–61.

    Google Scholar 

  94. Stanek MB, Borman SM, Molskness TA, Larson JM, Stouffer RL, Patton PE. Insulin and insulin-like growth factor stimulation of vascular endothelial growth factor production by luteinized granulosa cells: comparison between polycystic ovarian syndrome (PCOS) and non-PCOS women. J Clin Endocrinol Metab. 2007;92(7):2726–33.

    Article  CAS  PubMed  Google Scholar 

  95. Zeng X, Xie Y-j, Liu Y-t, Long S-l, Mo Z-c. Polycystic ovarian syndrome: correlation between hyperandrogenism, insulin resistance and obesity. Clin Chim Acta. 2020;502:214–21.

  96. Ng EHY, Chan CCW, Yeung WSB, Ho PC. Comparison of ovarian stromal blood flow between fertile women with normal ovaries and infertile women with polycystic ovary syndrome. Hum Reprod. 2005;20(7):1881–6.

    Article  PubMed  Google Scholar 

  97. Hong H, Branham WS, Ng HW, Moland CL, Dial SL, Fang H, et al. Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and α-fetoprotein. Toxicol Sci. 2015;143(2):333–48.

    Article  CAS  PubMed  Google Scholar 

  98. Sheikh IA, Turki RF, Abuzenadah AM, Damanhouri GA, Beg MA. Endocrine disruption: computational perspectives on human sex hormone-binding globulin and phthalate plasticizers. PLoS ONE. 2016;11(3):e0151444.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Rutkowska AZ, Diamanti-Kandarakis E. Polycystic ovary syndrome and environmental toxins. Fertil Steril. 2016;106(4):948–58.

    Article  CAS  PubMed  Google Scholar 

  100. Koch CA, Diamanti-Kandarakis E. Introduction to endocrine disrupting chemicals–is it time to act? Rev Endocr Metab Disord. 2015;16(4):269–70.

    Article  PubMed  Google Scholar 

  101. Dirinck E, Dirtu A, Jorens P, Malarvannan G, Covaci A, Van Gaal L. Pivotal role for the visceral fat compartment in the release of persistent organic pollutants during weight loss. J Clin Endocrinol Metab. 2015;100(12):4463–71.

    Article  CAS  PubMed  Google Scholar 

  102. Rehan M, Ahmad E, Sheikh IA, Abuzenadah AM, Damanhouri GA, Bajouh OS, et al. Androgen and progesterone receptors are targets for bisphenol A (BPA), 4-Methyl-2, 4-bis-(P-Hydroxyphenyl) Pent-1-Ene—a potent metabolite of BPA, and 4-Tert-Octylphenol: a computational insight. PLoS ONE. 2015;10(9):e0138438.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Papalou O, M Victor V, Diamanti-Kandarakis E. Oxidative stress in polycystic ovary syndrome. Curr Pharm Des. 2016;22(18):2709–22.

  104. Patel S, Zhou C, Rattan S, Flaws JA. Effects of endocrine-disrupting chemicals on the ovary. Biol Reprod. 2015;93(1):20, 1–9.

  105. Rutkowska A, Rachoń D. Bisphenol A (BPA) and its potential role in the pathogenesis of the polycystic ovary syndrome (PCOS). Gynecol Endocrinol. 2014;30(4):260–5.

    Article  CAS  PubMed  Google Scholar 

  106. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, Van Der Saag PT, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology. 1998;139(10):4252–63.

    Article  CAS  PubMed  Google Scholar 

  107. Thomas P, Dong J. Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: a potential novel mechanism of endocrine disruption. J Steroid Biochem Mol Biol. 2006;102(1–5):175–9.

    Article  CAS  PubMed  Google Scholar 

  108. Zhou W, Liu J, Liao L, Han S, Liu J. Effect of bisphenol A on steroid hormone production in rat ovarian theca-interstitial and granulosa cells. Mol Cell Endocrinol. 2008;283(1–2):12–8.

    Article  CAS  PubMed  Google Scholar 

  109. Déchaud H, Ravard C, Claustrat F, de la Perrière AB, Pugeat M. Xenoestrogen interaction with human sex hormone-binding globulin (hSHBG) 1. Steroids. 1999;64(5):328–34.

    Article  PubMed  Google Scholar 

  110. Kandaraki E, Chatzigeorgiou A, Livadas S, Palioura E, Economou F, Koutsilieris M, et al. Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS. J Clin Endocrinol Metab. 2011;96(3):E480–4.

    Article  CAS  PubMed  Google Scholar 

  111. Yokota H, Iwano H, Endo M, Kobayashi T, Inoue H, Ikushiro S-i, et al. Glucuronidation of the environmental oestrogen bisphenol A by an isoform of UDP-glucuronosyltransferase, UGT2B1, in the rat liver. Biochem J. 1999;340(2):405–9.

  112. Holtcamp W. Obesogens: an environmental link to obesity. National Institute of Environmental Health Sciences; 2012.

  113. Maradonna F, Evangelisti M, Gioacchini G, Migliarini B, Olivotto I, Carnevali O. Assay of vtg, ERs and PPARs as endpoint for the rapid in vitro screening of the harmful effect of Di-(2-ethylhexyl)-phthalate (DEHP) and phthalic acid (PA) in zebrafish primary hepatocyte cultures. Toxicol In Vitro. 2013;27(1):84–91.

    Article  CAS  PubMed  Google Scholar 

  114. Lind PM, Roos V, Rönn M, Johansson L, Ahlström H, Kullberg J, et al. Serum concentrations of phthalate metabolites are related to abdominal fat distribution two years later in elderly women. Environ Health. 2012;11(1):1–8.

    Article  Google Scholar 

  115. Masuno H, Iwanami J, Kidani T, Sakayama K, Honda K. Bisphenol a accelerates terminal differentiation of 3T3-L1 cells into adipocytes through the phosphatidylinositol 3-kinase pathway. Toxicol Sci. 2005;84(2):319–27.

    Article  CAS  PubMed  Google Scholar 

  116. A Polyzos S, Kountouras J, Deretzi G, Zavos C, S Mantzoros C. The emerging role of endocrine disruptors in pathogenesis of insulin resistance: a concept implicating nonalcoholic fatty liver disease. Curr Mol Med. 2012;12(1):68–82.

  117. Alonso-Magdalena P, Morimoto S, Ripoll C, Fuentes E, Nadal A. The estrogenic effect of bisphenol A disrupts pancreatic β-cell function in vivo and induces insulin resistance. Environ Health Perspect. 2006;114(1):106–12.

    Article  CAS  PubMed  Google Scholar 

  118. Menale C, Grandone A, Nicolucci C, Cirillo G, Crispi S, Di Sessa A, et al. Bisphenol A is associated with insulin resistance and modulates adiponectin and resistin gene expression in obese children. Pediatr Obes. 2017;12(5):380–7.

    Article  PubMed  Google Scholar 

  119. Carré J, Gatimel N, Moreau J, Parinaud J, Léandri R. Does air pollution play a role in infertility?: a systematic review. Environ Health. 2017;16(1):1–16.

    Article  Google Scholar 

  120. Wang J, Xie P, Kettrup A, Schramm K-W. Inhibition of progesterone receptor activity in recombinant yeast by soot from fossil fuel combustion emissions and air particulate materials. Sci Total Environ. 2005;349(1–3):120–8.

    Article  CAS  PubMed  Google Scholar 

  121. Takeda K, Tsukue N, Yoshida S. Endocrine-disrupting activity of chemicals in diesel exhaust and diesel exhaust particles. Environ Sci: Int J Environ Physiol Toxicol. 2004;11(1):33–45.

    CAS  Google Scholar 

  122. Palacio J, Iborra A, Ulcova-Gallova Z, Badia R, Martinez P. The presence of antibodies to oxidative modified proteins in serum from polycystic ovary syndrome patients. Clin Exp Immunol. 2006;144(2):217–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol. 2012;10(1):1–31.

    Article  Google Scholar 

  124. Murri M, Luque-Ramírez M, Insenser M, Ojeda-Ojeda M, Escobar-Morreale HF. Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. Hum Reprod Update. 2013;19(3):268–88.

    Article  CAS  PubMed  Google Scholar 

  125. Lin S-Y, Yang Y-C, Chang CY-Y, Lin C-C, Hsu W-H, Ju S-W, et al. Risk of polycystic ovary syndrome in women exposed to fine air pollutants and acidic gases: a nationwide cohort analysis. Int J Environ Res Public Health. 2019;16(23):4816.

  126. González F. Inflammation in polycystic ovary syndrome: underpinning of insulin resistance and ovarian dysfunction. Steroids. 2012;77(4):300–5.

    Article  PubMed  Google Scholar 

  127. Kshetrimayum C, Sharma A, Mishra VV, Kumar S. Polycystic ovarian syndrome: environmental/occupational, lifestyle factors; an overview. J Turkish German Gynecol Assoc. 2019;20(4):255.

    Article  CAS  Google Scholar 

  128. Cooper GS, Klebanoff MA, Promislow J, Brock JW, Longnecker MP. Polychlorinated biphenyls and menstrual cycle characteristics. Epidemiology. 2005:191–200.

  129. Farr S, Cooper G, Cai J, Savitz D, Sandler D. Pesticide use and menstrual cycle characteristics among premenopausal women in the Agricultural Health Study. Am J Epidemiol. 2004;160(12):1194–204.

    Article  CAS  PubMed  Google Scholar 

  130. Mendola P, Messer LC, Rappazzo K. Science linking environmental contaminant exposures with fertility and reproductive health impacts in the adult female. Fertil Steril. 2008;89(2):e81–94.

    Article  PubMed  Google Scholar 

  131. Caldwell AS, Edwards MC, Desai R, Jimenez M, Gilchrist RB, Handelsman DJ, et al. Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome. Proc Natl Acad Sci. 2017;114(16):E3334–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Moore AM, Campbell RE. The neuroendocrine genesis of polycystic ovary syndrome: a role for arcuate nucleus GABA neurons. J Steroid Biochem Mol Biol. 2016;160:106–17.

    Article  CAS  PubMed  Google Scholar 

  133. Moore AM, Prescott M, Marshall CJ, Yip SH, Campbell RE. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. Proc Natl Acad Sci. 2015;112(2):596–601.

    Article  CAS  PubMed  Google Scholar 

  134. Hrabovszky E, Liposits Z. Afferent neuronal control of type-I gonadotropin releasing hormone neurons in the human. Front Endocrinol. 2013;4:130.

    Article  Google Scholar 

  135. Kaiser UB, Jakubowiak A, Steinberger A, Chin WW. Differential effects of gonadotropin-releasing hormone (GnRH) pulse frequency on gonadotropin subunit and GnRH receptor messenger ribonucleic acid levels in vitro. Endocrinology. 1997;138(3):1224–31.

    Article  CAS  PubMed  Google Scholar 

  136. Wildt L, Häusler A, Marshall G, Hutchison J, Plant T, Belchetz P, et al. Frequency and amplitude of gonadotropin-releasing hormone stimulation and gonadotropin secretion in the rhesus monkey. Endocrinology. 1981;109(2):376–85.

    Article  CAS  PubMed  Google Scholar 

  137. Chang RJ. The reproductive phenotype in polycystic ovary syndrome. Nat Clin Pract Endocrinol Metab. 2007;3(10):688–95.

    Article  CAS  PubMed  Google Scholar 

  138. Gilling-Smith C, Willis DS, Beard RW, Franks S. Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries. J Clin Endocrinol Metab. 1994;79(4):1158–65.

    CAS  PubMed  Google Scholar 

  139. Jonard S, Dewailly D. The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest. Hum Reprod Update. 2004;10(2):107–17.

    Article  PubMed  Google Scholar 

  140. Taylor AE, McCourt B, Martin KA, Anderson EJ, Adams JM, Schoenfeld D, et al. Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1997;82(7):2248–56.

    CAS  PubMed  Google Scholar 

  141. Campbell R. Defining the gonadotrophin-releasing hormone neuronal network: transgenic approaches to understanding neurocircuitry. J Neuroendocrinol. 2007;19(7):561–73.

    Article  CAS  PubMed  Google Scholar 

  142. Skorupskaite K, George JT, Anderson RA. The kisspeptin-GnRH pathway in human reproductive health and disease. Hum Reprod Update. 2014;20(4):485–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Young J, George JT, Tello JA, Francou B, Bouligand J, Guiochon-Mantel A, et al. Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications. Neuroendocrinology. 2013;97(2):193–202.

    Article  CAS  PubMed  Google Scholar 

  144. Han S-K, Gottsch ML, Lee KJ, Popa SM, Smith JT, Jakawich SK, et al. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci. 2005;25(49):11349–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Pielecka-Fortuna J, Chu Z, Moenter SM. Kisspeptin acts directly and indirectly to increase gonadotropin-releasing hormone neuron activity and its effects are modulated by estradiol. Endocrinology. 2008;149(4):1979–86.

    Article  CAS  PubMed  Google Scholar 

  146. Roseweir AK, Kauffman AS, Smith JT, Guerriero KA, Morgan K, Pielecka-Fortuna J, et al. Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci. 2009;29(12):3920–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Li X-F, Kinsey-Jones JS, Cheng Y, Knox AM, Lin Y, Petrou NA, et al. Kisspeptin signalling in the hypothalamic arcuate nucleus regulates GnRH pulse generator frequency in the rat. PLoS ONE. 2009;4(12):e8334.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Clarkson J, Han SY, Piet R, McLennan T, Kane GM, Ng J, et al. Definition of the hypothalamic GnRH pulse generator in mice. Proc Natl Acad Sci. 2017;114(47):E10216–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Herbison AE. The gonadotropin-releasing hormone pulse generator. Endocrinology. 2018;159(11):3723–36.

    Article  CAS  PubMed  Google Scholar 

  150. Bianco SD, Kaiser UB. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol. 2009;5(10):569–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349(17):1614–27.

    Article  CAS  PubMed  Google Scholar 

  152. Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S, et al. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med. 2008;358(7):709–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Silveira L, Noel S, Silveira-Neto A, Abreu A, Brito V, Santos M, et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab. 2010;95(5):2276–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Labarrere CA, Woods J, Hardin J, Campana G, Ortiz M, Jaeger B, et al. Early prediction of cardiac allograft vasculopathy and heart transplant failure. Am J Transpl. 2011;11(3):528–35.

    Article  CAS  Google Scholar 

  155. Ruddenklau A, Campbell RE. Neuroendocrine impairments of PCOS. Endocrinology.

  156. Walters KA, Gilchrist RB, Ledger WL, Teede HJ, Handelsman DJ, Campbell RE. New perspectives on the pathogenesis of PCOS: neuroendocrine origins. Trends Endocrinol Metab. 2018;29(12):841–52.

    Article  CAS  PubMed  Google Scholar 

  157. Jeon YE, Lee KE, Jung JA, Yim SY, Kim H, Seo SK, et al. Kisspeptin, leptin, and retinol-binding protein 4 in women with polycystic ovary syndrome. Gynecol Obstet Invest. 2013;75(4):268–74.

    Article  CAS  PubMed  Google Scholar 

  158. Wang T, Han S, Tian W, Zhao M, Zhang H. Effects of kisspeptin on pathogenesis and energy metabolism in polycystic ovarian syndrome (PCOS). Gynecol Endocrinol. 2019;35(9):807–10.

    Article  CAS  PubMed  Google Scholar 

  159. Kawwass JF, Sanders KM, Loucks TL, Rohan LC, Berga SL. Increased cerebrospinal fluid levels of GABA, testosterone and estradiol in women with polycystic ovary syndrome. Hum Reprod. 2017;32(7):1450–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Tata B, Mimouni NEH, Barbotin A-L, Malone SA, Loyens A, Pigny P, et al. Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood. Nat Med. 2018;24(6):834–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Caldwell A, Middleton L, Jimenez M, Desai R, McMahon A, Allan C, et al. Characterization of reproductive, metabolic, and endocrine features of polycystic ovary syndrome in female hyperandrogenic mouse models. Endocrinology. 2014;155(8):3146–59.

    Article  CAS  PubMed  Google Scholar 

  162. Moore AM, Prescott M, Campbell RE. Estradiol negative and positive feedback in a prenatal androgen-induced mouse model of polycystic ovarian syndrome. Endocrinology. 2013;154(2):796–806.

    Article  CAS  PubMed  Google Scholar 

  163. Hogg K, Wood C, McNeilly AS, Duncan WC. The in utero programming effect of increased maternal androgens and a direct fetal intervention on liver and metabolic function in adult sheep. PLoS ONE. 2011;6(9):e24877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Silva MS, Prescott M, Campbell RE. Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS. JCI insight. 2018;3(7).

  165. Sullivan SD, Moenter SM. Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder. Proc Natl Acad Sci. 2004;101(18):7129–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Wawrzkiewicz-Jałowiecka A, Kowalczyk K, Trybek P, Jarosz T, Radosz P, Setlak M, et al. In Search of new therapeutics—molecular aspects of the PCOS pathophysiology: genetics, hormones, metabolism and beyond. Int J Mol Sci. 2020;21(19):7054.

    Article  PubMed  PubMed Central  Google Scholar 

  167. Carmina E, Lobo RA. Polycystic ovary syndrome (PCOS): arguably the most common endocrinopathy is associated with significant morbidity in women. J Clin Endocrinol Metab. 1999;84(6):1897–9.

    Article  CAS  PubMed  Google Scholar 

  168. McAllister JM, Legro RS, Modi BP, Strauss JF III. Functional genomics of PCOS: from GWAS to molecular mechanisms. Trends Endocrinol Metab. 2015;26(3):118–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Escobar-Morreale H, Carmina E, Dewailly D, Gambineri A, Kelestimur F, Moghetti P, et al. Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update. 2012;18(2):146–70.

    Article  CAS  PubMed  Google Scholar 

  170. Squibb B-M. Bristol-Myers Squibb Labeling VANIQA. US Food & Drug Administration. 2000.

  171. Tartagni MV, Alrasheed H, Damiani GR, Montagnani M, Maria A, De Pergola G, et al. Intermittent low-dose finasteride administration is effective for treatment of hirsutism in adolescent girls: a pilot study. J Pediatr Adolesc Gynecol. 2014;27(3):161–5.

    Article  PubMed  Google Scholar 

  172. Lachelin G, Leblanc H, Yen S. The inhibitory effect of dopamine agonists on LH release in women. J Clin Endocrinol Metab. 1977;44(4):728–32.

    Article  CAS  PubMed  Google Scholar 

  173. Leyden J, Stein-Gold L, Weiss J. Why topical retinoids are mainstay of therapy for acne. Dermatol Ther. 2017;7(3):293–304.

    Article  Google Scholar 

  174. van Zuuren EJ, Fedorowicz Z, Schoones J. Interventions for female pattern hair loss. Cochrane Database Syst Rev. 2016(5).

  175. Araviiskaia E, Dréno B. The role of topical dermocosmetics in acne vulgaris. J Eur Acad Dermatol Venereol. 2016;30(6):926–35.

    Article  CAS  PubMed  Google Scholar 

  176. Gold MH, Goldberg DJ, Nestor MS. Current treatments of acne: Medications, lights, lasers, and a novel 650-μs 1064-nm Nd: YAG laser. J Cosmet Dermatol. 2017;16(3):303–18.

    Article  PubMed  Google Scholar 

  177. Dinh QQ, Sinclair R. Female pattern hair loss: current treatment concepts. Clin Interv Aging. 2007;2(2):189.

    PubMed  PubMed Central  Google Scholar 

  178. Anitua E, Pino A, Martinez N, Orive G, Berridi D. The effect of plasma rich in growth factors on pattern hair loss: a pilot study. Dermatol Surg. 2017;43(5):658–70.

    Article  CAS  PubMed  Google Scholar 

  179. Izquierdo D, Foyouzi N, Kwintkiewicz J, Duleba AJ. Mevastatin inhibits ovarian theca–interstitial cell proliferation and steroidogenesis. Fertil Steril. 2004;82:1193–7.

    Article  CAS  PubMed  Google Scholar 

  180. Liu R, Zhang C, Shi Y, Zhang F, Li L, Wang X, et al. Dysbiosis of gut microbiota associated with clinical parameters in polycystic ovary syndrome. Front Microbiol. 2017;8:324.

    PubMed  PubMed Central  Google Scholar 

  181. Sherman SB, Sarsour N, Salehi M, Schroering A, Mell B, Joe B, et al. Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis. Gut Microbes. 2018;9(5):400–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Ahmadi S, Jamilian M, Karamali M, Tajabadi-Ebrahimi M, Jafari P, Taghizadeh M, et al. Probiotic supplementation and the effects on weight loss, glycaemia and lipid profiles in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Hum Fertil. 2017;20(4):254–61.

    Article  CAS  Google Scholar 

  183. Heshmati J, Farsi F, Yosaee S, Razavi M, Rezaeinejad M, Karimie E, et al. The effects of probiotics or synbiotics supplementation in women with polycystic ovarian syndrome: a systematic review and meta-analysis of randomized clinical trials. Probiotics Antimicrobial Proteins. 2019;11:1236–47.

    Article  CAS  PubMed  Google Scholar 

  184. Shoaei T, Heidari-Beni M, Tehrani HG, Esmaillzadeh A, Askari G. Effects of probiotic supplementation on pancreatic β-cell function and c-reactive protein in women with polycystic ovary syndrome: a randomized double-blind placebo-controlled clinical trial. Int J Prevent Med. 2015;6.

  185. Gholizadeh Shamasbi S, Dehgan P, Mohammad-Alizadeh Charandabi S, Aliasgarzadeh A, Mirghafourvand M. The effect of resistant dextrin as a prebiotic on metabolic parameters and androgen level in women with polycystic ovarian syndrome: a randomized, triple-blind, controlled, clinical trial. Eur J Nutr. 2019;58:629–40.

    Article  CAS  PubMed  Google Scholar 

  186. Thomson RL, Buckley JD, Lim SS, Noakes M, Clifton PM, Norman RJ, et al. Lifestyle management improves quality of life and depression in overweight and obese women with polycystic ovary syndrome. Fertil Steril. 2010;94(5):1812–6.

    Article  PubMed  Google Scholar 

  187. Panidis D, Tziomalos K, Papadakis E, Vosnakis C, Chatzis P, Katsikis I. Lifestyle intervention and anti-obesity therapies in the polycystic ovary syndrome: impact on metabolism and fertility. Endocrine. 2013;44(3):583–90.

    Article  CAS  PubMed  Google Scholar 

  188. Escobar-Morreale HF, Santacruz E, Luque-Ramírez M, Botella Carretero JI. Prevalence of ‘obesity-associated gonadal dysfunction’in severely obese men and women and its resolution after bariatric surgery: a systematic review and meta-analysis. Hum Reprod Update. 2017;23(4):390–408.

    Article  CAS  PubMed  Google Scholar 

  189. Naderpoor N, Shorakae S, de Courten B, Misso ML, Moran LJ, Teede HJ. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis. Hum Reprod Update. 2015;21(5):560–74.

    Article  CAS  PubMed  Google Scholar 

  190. Pedersen AJ, Stage TB, Glintborg D, Andersen M, Christensen MMH. The pharmacogenetics of metformin in women with polycystic ovary syndrome: a randomized trial. Basic Clin Pharmacol Toxicol. 2018;122(2):239–44.

    Article  CAS  PubMed  Google Scholar 

  191. Morley LC, Tang T, Yasmin E, Norman RJ, Balen AH. Insulin‐sensitising drugs (metformin, rosiglitazone, pioglitazone, D‐chiro‐inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2017(11).

  192. Laganà AS, Rossetti P, Sapia F, Chiofalo B, Buscema M, Valenti G, et al. Evidence-based and patient-oriented inositol treatment in polycystic ovary syndrome: changing the perspective of the disease. Int J Endocrinol Metab. 2017;15(1).

  193. Cabrera-Cruz H, Oróstica L, Plaza-Parrochia F, Torres-Pinto I, Romero C, Vega M. The insulin-sensitizing mechanism of myo-inositol is associated with AMPK activation and GLUT-4 expression in human endometrial cells exposed to a PCOS environment. Am J Physiol-Endocrinol Metab. 2020;318(2):E237–48.

    Article  CAS  PubMed  Google Scholar 

  194. Zhang N, Liu X, Zhuang L, Liu X, Zhao H, Shan Y, et al. Berberine decreases insulin resistance in a PCOS rats by improving GLUT4: Dual regulation of the PI3K/AKT and MAPK pathways. Regul Toxicol Pharmacol. 2020;110:104544.

    Article  CAS  PubMed  Google Scholar 

  195. Niafar M, Pourafkari L, Porhomayon J, Nader N. A systematic review of GLP-1 agonists on the metabolic syndrome in women with polycystic ovaries. Arch Gynecol Obstet. 2016;293(3):509–15.

    Article  CAS  PubMed  Google Scholar 

  196. Van Can J, Sloth B, Jensen C, Flint A, Blaak E, Saris W. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int J Obes. 2014;38(6):784–93.

    Article  Google Scholar 

  197. Barnett A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int J Clin Pract. 2006;60(11):1454–70.

    Article  CAS  PubMed  Google Scholar 

  198. Javed Z, Papageorgiou M, Deshmukh H, Rigby AS, Qamar U, Abbas J, et al. Effects of empagliflozin on metabolic parameters in polycystic ovary syndrome: a randomized controlled study. Clin Endocrinol. 2019;90(6):805–13.

    Article  CAS  Google Scholar 

  199. dehghani Firouzabadi R, Aflatoonian A, Modarresi S, Sekhavat L, MohammadTaheri S. Therapeutic effects of calcium & vitamin D supplementation in women with PCOS. Complement Ther Clin Pract. 2012;18(2):85–8.

  200. Tarfeen N, Nisa KU, Ahmad MB, Waza AA, Ganai BA. Metabolic and genetic association of vitamin D with calcium signaling and insulin resistance. Indian J Clin Biochem. 2022:1–11.

  201. Irani M, Minkoff H, Seifer DB, Merhi Z. Vitamin D increases serum levels of the soluble receptor for advanced glycation end products in women with PCOS. J Clin Endocrinol Metab. 2014;99(5):E886–90.

    Article  CAS  PubMed  Google Scholar 

  202. Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, et al. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016;2(1):1–18.

    Article  Google Scholar 

  203. Andersson K. The levonorgestrel intrauterine system: more than a contraceptive. Eur J Contracept Reprod Health Care. 2001;6(sup1):15–22.

    Article  CAS  PubMed  Google Scholar 

  204. Balen AH, Morley LC, Misso M, Franks S, Legro RS, Wijeyaratne CN, et al. The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Hum Reprod Update. 2016;22(6):687–708.

    Article  PubMed  Google Scholar 

  205. Mumusoglu S, Yildiz BO. Polycystic ovary syndrome phenotypes and prevalence: differential impact of diagnostic criteria and clinical versus unselected population. Curr Opin Endocrine Metab Res. 2020;12:66–71.

    Article  Google Scholar 

  206. Azziz R. Polycystic ovary syndrome. Obstet Gynecol. 2018;132(2):321–36.

    Article  PubMed  Google Scholar 

  207. Pugliese A, Miceli D. The insulin gene in diabetes. Diabetes Metab Res Rev. 2002;18(1):13–25.

    Article  CAS  PubMed  Google Scholar 

  208. Urbanek M, Woodroffe A, Ewens K, Diamanti-Kandarakis E, Legro R, Strauss Iii J, et al. Candidate gene region for polycystic ovary syndrome on chromosome 19p13. 2. J Clin Endocrinol Metab. 2005;90(12):6623–9.

  209. Gonzalez A, Abril E, Roca A, Aragón MJ, Figueroa MJ, Velarde P, et al. CAPN10 alleles are associated with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87(8):3971–6.

    Article  CAS  PubMed  Google Scholar 

  210. Christopoulos P, Mastorakos G, Gazouli M, Deligeoroglou E, Katsikis I, Diamanti-Kandarakis E, et al. Study of association of IRS-1 and IRS-2 genes polymorphisms with clinical and metabolic features in women with polycystic ovary syndrome. Is there an impact? Gynecol Endocrinol. 2010;26(9):698–703.

  211. Batarfi AA, Filimban N, Bajouh OS, Dallol A, Chaudhary AG, Bakhashab S. MC4R variants rs12970134 and rs17782313 are associated with obese polycystic ovary syndrome patients in the Western region of Saudi Arabia. BMC Med Genet. 2019;20(1):1–7.

    Article  CAS  Google Scholar 

  212. Zhang W, Wei D, Sun X, Li J, Yu X, Shi Y, et al. Family-based analysis of adiponectin gene polymorphisms in Chinese Han polycystic ovary syndrome. Fertil Steril. 2014;101(5):1419–23.

  213. Diamanti-Kandarakis E, Bartzis MI, Bergiele AT, Tsianateli TC, Kouli CR. Microsatellite polymorphism (tttta) n at − 528 base pairs of gene CYP11α influences hyperandrogenemia in patients with polycystic ovary syndrome. Fertil Steril. 2000;73(4):735–41.

    Article  CAS  PubMed  Google Scholar 

  214. Gharani N, Waterworth DM, Batty S, White D, Gilling-Smith C, Conway GS, et al. Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet. 1997;6(3):397–402.

    Article  CAS  PubMed  Google Scholar 

  215. Wickenheisser JK, Quinn PG, Nelson VL, Legro RS, Strauss JF III, McAllister JM. Differential activity of the cytochrome P450 17α-hydroxylase and steroidogenic acute regulatory protein gene promoters in normal and polycystic ovary syndrome theca cells. J Clin Endocrinol Metab. 2000;85(6):2304–11.

    CAS  PubMed  Google Scholar 

  216. Rosenfield RL, Barnes RB, Jose’F C, Lucky AW. Dysregulation of cytochrome P450c17α as the cause of polycystic ovarian syndrome. Fertil Steril. 1990;53(5):785–91.

  217. Mehdizadeh A, Kalantar SM, Sheikhha MH, Aali BS, Ghanei A. Association of SNP rs. 2414096 CYP19 gene with polycystic ovarian syndrome in Iranian women. Int J Reprod BioMedicine. 2017;15(8):491.

  218. Witchel SF, Kahsar-Miller M, Aston CE, White C, Azziz R. Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess. Fertil Steril. 2005;83(2):371–5.

    Article  CAS  PubMed  Google Scholar 

  219. Shaikh N, Dadachanji R, Meherji P, Shah N, Mukherjee S. Polymorphisms and haplotypes of insulin-like factor 3 gene are associated with risk of polycystic ovary syndrome in Indian women. Gene. 2016;577(2):180–6.

    Article  CAS  PubMed  Google Scholar 

  220. Marioli DJ, Saltamavros AD, Vervita V, Koika V, Adonakis G, Decavalas G, et al. Association of the 17-hydroxysteroid dehydrogenase type 5 gene polymorphism (− 71A/G HSD17B5 SNP) with hyperandrogenemia in polycystic ovary syndrome (PCOS). Fertil Steril. 2009;92(2):648–52.

    Article  CAS  PubMed  Google Scholar 

  221. Yan J, Tian Y, Gao X, Cui L, Ning Y, Cao Y, et al. A genome-wide association study identifies FSHR rs2300441 associated with follicle-stimulating hormone levels. Clin Genet. 2020;97(6):869–77.

    Article  CAS  PubMed  Google Scholar 

  222. Tian Y, Zhao H, Chen H, Peng Y, Cui L, Du Y, et al. Variants in FSHB are associated with polycystic ovary syndrome and luteinizing hormone level in Han Chinese women. J Clin Endocrinol Metab. 2016;101(5):2178–84.

    Article  CAS  PubMed  Google Scholar 

  223. Pierre A, Peigné M, Grynberg M, Arouche N, Taieb J, Hesters L, et al. Loss of LH-induced down-regulation of anti-Müllerian hormone receptor expression may contribute to anovulation in women with polycystic ovary syndrome. Hum Reprod. 2013;28(3):762–9.

    Article  CAS  PubMed  Google Scholar 

  224. Thathapudi S, Kodati V, Erukkambattu J, Addepally U, Qurratulain H. Association of luteinizing hormone chorionic gonadotropin receptor gene polymorphism (rs2293275) with polycystic ovarian syndrome. Genet Test Mol Biomarkers. 2015;19(3):128–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Zheng M-X, Li Y, Hu R, Wang F-M, Zhang X-M, Guan B. Anti-Müllerian hormone gene polymorphism is associated with androgen levels in Chinese polycystic ovary syndrome patients with insulin resistance. J Assist Reprod Genet. 2016;33(2):199–205.

    Article  PubMed  PubMed Central  Google Scholar 

  226. Deswal R, Yadav A, Dang AS. Sex hormone binding globulin-an important biomarker for predicting PCOS risk: a systematic review and meta-analysis. Syst Biol Reprod Med. 2018;64(1):12–24.

    Article  CAS  PubMed  Google Scholar 

  227. Deepika M, Reddy KR, Yashwanth A, Rani VU, Latha KP, Jahan P. TNF-α haplotype association with polycystic ovary syndrome–a South Indian study. J Assist Reprod Genet. 2013;30(11):1493–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Vural P, Değirmencioğlu S, Saral NY, Akgül C. Tumor necrosis factor α (− 308), interleukin-6 (− 174) and interleukin-10 (− 1082) gene polymorphisms in polycystic ovary syndrome. Eur J Obst Gynecol Reprod Biol. 2010;150(1):61–5.

    Article  CAS  Google Scholar 

  229. Wehr E, Trummer O, Giuliani A, Gruber H-J, Pieber TR, Obermayer-Pietsch B. Vitamin D-associated polymorphisms are related to insulin resistance and vitamin D deficiency in polycystic ovary syndrome. Eur J Endocrinol. 2011;164(5):741.

    Article  CAS  PubMed  Google Scholar 

  230. Hayes MG, Urbanek M, Ehrmann DA, Armstrong LL, Lee JY, Sisk R, et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun. 2015;6(1):1–13.

    Article  CAS  Google Scholar 

  231. Manna P, Jain SK. Vitamin D up-regulates glucose transporter 4 (GLUT4) translocation and glucose utilization mediated by cystathionine-γ-lyase (CSE) activation and H2S formation in 3T3L1 adipocytes. J Biol Chem. 2012;287(50):42324–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Louwers YV, Stolk L, Uitterlinden AG, Laven JS. Cross-ethnic meta-analysis of genetic variants for polycystic ovary syndrome. J Clin Endocrinol Metab. 2013;98(12):E2006–12.

    Article  CAS  PubMed  Google Scholar 

  233. Zhang Y, Movva VC, Williams MS, Lee MTM. Polycystic ovary syndrome susceptibility loci inform disease etiological heterogeneity. J Clin Med. 2021;10(12):2688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Dakshinamoorthy J, Jain PR, Ramamoorthy T, Ayyappan R, Balasundaram U. Association of GWAS identified INSR variants (rs2059807 & rs1799817) with polycystic ovarian syndrome in Indian women. Int J Biol Macromol. 2020;144:663–70.

    Article  CAS  PubMed  Google Scholar 

  235. Hwang J-Y, Lee E-J, Jin Go M, Sung Y-A, Lee HJ, Heon Kwak S, et al. Genome-wide association study identifies GYS2 as a novel genetic factor for polycystic ovary syndrome through obesity-related condition. J Hum Genet. 2012;57(10):660–4.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are highly indebted to the Centre of Research for development (CORD) and Department of Environmental Sciences, University of Kashmir for providing the necessary facilities. This work didn’t receive any specific funding from any agency. However, the author KN is a recipient of MANF (MANF UGC Beneficiary Code: BININ01671381).

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Authors and Affiliations

  1. Department of Environmental Science, University of Kashmir, Srinagar, 190006, India

    Khair Ul Nisa

  2. Centre of Research for Development (CORD), University of Kashmir, Srinagar, 190006, India

    Khair Ul Nisa, Najeebul Tarfeen & Bashir Ahmad Ganai

  3. Department of Endocrinology, Government Medical College, Shireen Bagh, Srinagar, 190010, India

    Shahnaz Ahmad Mir

  4. Multidisciplinary Research Unit (MRU), Government Medical Collage (GMC), Srinagar, 190010, India

    Ajaz Ahmad Waza

  5. Department of Biochemistry, University of Kashmir, Srinagar, 190006, India

    Mir Bilal Ahmad

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  5. Mir Bilal Ahmad
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Contributions

Khair Ul Nisa and Bashir Ahmad Ganai conceived and designed this review. Khair Ul Nisa, Najeebul Tarfeen, Shahnaz Ahmad Mir, Ajaz Ahmad Waza, and Mir Bilal Ahmad collected the literature for this review. Khair Ul Nisa wrote the manuscript draft. Bashir Ahmad Ganai and Shahnaz Ahmad Mir edited this manuscript. All the authors gave final shape to this manuscript.

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Correspondence to Bashir Ahmad Ganai.

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Nisa, K.U., Tarfeen, N., Mir, S.A. et al. Molecular Mechanisms in the Etiology of Polycystic Ovary Syndrome (PCOS): A Multifaceted Hypothesis Towards the Disease with Potential Therapeutics. Ind J Clin Biochem 39, 18–36 (2024). https://doi.org/10.1007/s12291-023-01130-7

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