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The Role of Genetics, Epigenetics and Lifestyle in Polycystic Ovary Syndrome Development: the State of the Art

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Abstract

Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disease affecting about 20–25% of women in reproductive age. Different mechanisms could contribute to the development of its typical clinical features (i.e. hirsutism, acne, oligo-amenorrhea, alopecia). Some genetic and epigenetic aspects and lifestyle changes seem to be involved in PCOS development. In this review, we shall summarize data from principal studies evaluating the impact of major genetic, epigenetic and environmental factors on the appearance of this female disorder. Literature review and analysis of the most relevant data until May 2020. Current data suggest the importance of genetics and epigenetics in the appearance of PCOS. Several genes, including those related to adrenal and ovarian steroidogenesis as well as those associated with hormonal response to gonadotrophins, androgens and insulin, have been demonstrated to be associated with PCOS. Besides, the phenomenon of methylation of genes and the presence of specific microRNA (miRNA) could take part in PCOS aetiology. Intrauterine exposure to androgens, glucocorticoids and/or some stressful conditions for foetus could contribute to the development of PCOS and other disorders observed in adolescence and later (e.g. premature adrenarche, atypical puberty, metabolic syndrome). Emerging studies report a theoretical role of endocrine disruptors, intestinal dysbiosis and Advanced Glycation End products (AGEs) in PCOS. PCOS is a polygenic and multifactorial hormonal and metabolic dysfunction. An appropriate knowledge of personal and/or family history, lifestyle and nutritional habits of PCOS patients has a great importance to early identify and manage this syndrome.

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References

  1. 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. Journal of Clinical Endocrinology and Metabolism. 2004;89(6):2745–9.

    Article  CAS  PubMed  Google Scholar 

  2. 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. 2004;81(1):19–25.

    Article  Google Scholar 

  3. Zeng X, Xie YJ, Liu YT, Long SL, Mo ZC. Polycystic ovarian syndrome: correlation between hyperandrogenism, insulin resistance and obesity. Clin Chim Acta pii. 2019;S0009-8981(19):32118–7.

    Google Scholar 

  4. Macut D, Bjekić-Macut J, Rahelić D, Doknić M. Insulin and the polycystic ovary syndrome. Diabetes Res Clin Pract. 2017;130:163–70.

    Article  CAS  PubMed  Google Scholar 

  5. Moghetti P. Insulin Resistance and polycystic ovary syndrome. Curr Pharm Des. 2016;22(36):5526–34.

    Article  CAS  PubMed  Google Scholar 

  6. Patel S. Polycystic ovary syndrome (PCOS), an inflammatory, systemic, lifestyle endocrinopathy. J Steroid Biochem Mol Biol. 2018;182:27–36.

    Article  CAS  PubMed  Google Scholar 

  7. Barber TM, Hanson P, Weickert MO, Franks S. Obesity and polycystic ovary syndrome: implications for pathogenesis and novel management strategies. Clin Med Insights Reprod Health. 2019;13:1179558119874042.

    Article  PubMed  Google Scholar 

  8. Zhao Y, Qiao J. Ethnic differences in the phenotypic expression of polycystic ovary syndrome. Steroids. 2013;78(8):755–60.

    Article  CAS  PubMed  Google Scholar 

  9. Azziz R. Diagnostic criteria for polycystic ovary syndrome: a reappraisal. Fertil Steril. 2005;83(5):1343–6.

    Article  PubMed  Google Scholar 

  10. Belenkaia LV, Lazareva LM, Walker W, Lizneva DV, Suturina LV. Criteria, phenotypes and prevalence of polycystic ovary syndrome. Minerva Ginecol. 2019;71(3):211–23.

    Article  PubMed  Google Scholar 

  11. Crosignani PG, Nicolosi AE. Polycystic ovarian disease: heritability and heterogeneity. Hum Reprod Update. 2001;7(1):3–7.

    Article  CAS  PubMed  Google Scholar 

  12. Diamanti-Kandarakis E, Alexandraki K, Bergiele A, Kandarakis H, Mastorakos G, Aessopos A. Presence of metabolic risk factors in non-obese PCOS sisters: evidence of heritability of insulin resistance. J Endocrinol Invest. 2004;27(10):931–6.

    Article  CAS  PubMed  Google Scholar 

  13. Vipin VP, Dabadghao P, Shukla M, Kapoor A, Raghuvanshi AS, Ramesh V. Cardiovascular disease risk in first-degree relatives of women with polycystic ovary syndrome. Fertil Steril. 2016;105(5):1338–44.

    Article  PubMed  Google Scholar 

  14. Yilmaz B, Vellanki P, Ata B, Yildiz BO. Diabetes mellitus and insulin resistance in mothers, fathers, sisters, and brothers of women with polycystic ovary syndrome: a systematic review and meta-analysis. Fertil Steril. 2018;110(3):523–33.

    Article  PubMed  Google Scholar 

  15. Kahsar-Miller MD, Nixon C, Boots LR, Go RC, Azziz R. Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS. Fertil Steril. 2001;75(1):53–8.

    Article  CAS  PubMed  Google Scholar 

  16. Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A. 1998;95(25):14956–60.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Hiam D, Moreno-Asso A, Teede HJ, Laven JSE, Stepto NK, Moran LJ, et al. The genetics of polycystic ovary syndrome: an overview of candidate gene systematic reviews and genome-wide association studies. J Clin Med. 2019;8(10).

  19. Khan MJ, Ullah A, Basit S. Genetic basis of polycystic ovary syndrome (PCOS): current perspectives. Appl Clin Genet. 2019;12:249–60.

    Article  PubMed  Google Scholar 

  20. 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 

  21. Gambineri A, Vicennati V, Genghini S, Tomassoni F, Pagotto U, Pasquali R, et al. Genetic variation in 11beta-hydroxysteroid dehydrogenase type 1 predicts adrenal hyperandrogenism among lean women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91(6):2295–302.

    Article  CAS  PubMed  Google Scholar 

  22. Wickenheisser JK, Quinn PG, Nelson VL, Legro RS, Strauss JF 3rd, McAllister JM. Differential activity of the cytochrome P450 17alpha-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 

  23. Tee MK, Speek M, Legeza B, Modi B, Teves ME, McAllister JM, et al. Alternative splicing of DENND1A, a PCOS candidate gene, generates variant 2. Mol Cell Endocrinol. 2016;434:25–35.

    Article  CAS  PubMed  Google Scholar 

  24. McAllister JM, Modi B, Miller BA, Biegler J, Bruggeman R, Legro RS, et al. Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype. Proc Natl Acad Sci USA. 2014;111(15):E1519–27.

    Article  CAS  PubMed  Google Scholar 

  25. Dapas M, Sisk R, Legro RS, Urbanek M, Dunaif A, Hayes MG. Family-based quantitative trait meta-analysis implicates rare noncoding variants in DENND1A in polycystic ovary syndrome. J Clin Endocrinol Metab. 2019;104:3835–50. https://doi.org/10.1210/jc.2018-02496.

    Article  Google Scholar 

  26. Walters KA, Rodriguez Paris V, Aflatounian A, Handelsman DJ. Androgens and ovarian function: translation from basic discovery research to clinical impact. J Endocrinol. 2019;242(2):R23–50.

    Article  CAS  PubMed  Google Scholar 

  27. Gur EB, Karadeniz M, Turan GA. Fetal programming of polycystic ovary syndrome. World J Diabetes. 2015;6(7):936–42.

    Article  PubMed  Google Scholar 

  28. Day FR, Hinds DA, Tung JY, Stolk L, Styrkarsdottir U, Saxena R, et al. Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat Commun. 2015;6:8464.

    Article  CAS  PubMed  Google Scholar 

  29. Peng Y, Zhang W, Yang P, Tian Y, Su S, Zhang C, et al. ERBB4 confers risk for polycystic ovary syndrome in Han Chinese. Sci Rep. 2017;7:42000.

    Article  CAS  PubMed  Google Scholar 

  30. Xia JY, Tian W, Yin GH, Yan H. Association of Rs13405728, Rs12478601, and Rs2479106 single nucleotide polymorphisms and in vitro fertilization and embryo transfer efficacy in patients with polycystic ovarian syndrome: a case control genome-wide association study. Kaohsiung J Med Sci. 2019;35(1):49–55.

    Article  PubMed  Google Scholar 

  31. Laven JSE. Follicle stimulating hormone receptor (FSHR) polymorphisms and polycystic ovary syndrome (PCOS). Front Endocrinol (Lausanne). 2019;12(10):23.

    Article  Google Scholar 

  32. Tong Y, Liao WX, Roy AC, Ng SC. Association of AccI polymorphism in the follicle-stimulating hormone beta gene with polycystic ovary syndrome. Fertil Steril. 2000;74(6):1233–6.

    Article  CAS  PubMed  Google Scholar 

  33. 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 

  34. Deswal R, Nanda S, Dang AS. Association of luteinizing hormone and LH receptor gene polymorphism with susceptibility of Polycystic ovary syndrome. Syst Biol Reprod Med. 2019;65(5):400–8.

    Article  CAS  PubMed  Google Scholar 

  35. Zhang Y, Ho K, Keaton JM, Hartzel DN, Day F, Justice AE, et al. A genome-wide association study of polycystic ovary syndrome identified from electronic health records. Am J Obstet Gynecol. 2020;223(4):559.e1–559.e21.

    Article  CAS  Google Scholar 

  36. Li T, Zhao H, Zhao X, Zhang B, Cui L, Shi Y, et al. Identification of YAP1 as a novel susceptibility gene for polycystic ovary syndrome. J Med Genet. 2012;49(4):254–7.

    Article  CAS  PubMed  Google Scholar 

  37. Moorthy JD, 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. 2019;144:663–70. https://doi.org/10.1016/j.ijbiomac.2019.10.235.

    Article  CAS  Google Scholar 

  38. 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 

  39. 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 

  40. Goodarzi MO, Shah NA, Antoine HJ, Pall M, Guo X, Azziz R. Variants in the 5alpha-reductase type 1 and type 2 genes are associated with polycystic ovary syndrome and the severity of hirsutism in affected women. J Clin Endocrinol Metab. 2006;91(10):4085–91.

    Article  CAS  PubMed  Google Scholar 

  41. Graupp M, Wehr E, Schweighofer N, Pieber TR, Obermayer-Pietsch B. Association of genetic variants in the two isoforms of 5α-reductase, SRD5A1 and SRD5A2, in lean patients with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2011;157(2):175–9.

    Article  CAS  PubMed  Google Scholar 

  42. Jordan CD, Bohling SD, Charbonneau NL, Sakai LY. Fibrillins in adult human ovary and polycystic ovary syndrome: is fibrillin-3 affected in PCOS? J Histochem Cytochem. 2010;58(10):903–15.

    Article  CAS  PubMed  Google Scholar 

  43. Tan S, Scherag A, Janssen OE, Hahn S, Lahner H, Dietz T, et al. Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS). BMC Med Genet. 2010;11:12.

    Article  PubMed  Google Scholar 

  44. Branavan U, Wijesundera S, Chandrasekaran V, Arambepola C, Wijeyaratne C. In depth analysis of the association of FTO SNP (rs9939609) with the expression of classical phenotype of PCOS: a Sri Lankan study. BMC Med Genet. 2020;21(1):30.

    Article  CAS  PubMed  Google Scholar 

  45. 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 

  46. Goodarzi MO, Jones MR, Li X, Chua AK, Garcia OA, Chen YD, et al. Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J Med Genet. 2012;49(2):90–5.

    Article  CAS  PubMed  Google Scholar 

  47. Chen L, Hu LM, Wang YF, Yang HY, Huang XY, Zhou W, et al. Genome-wide association study for SNPs associated with PCOS in human patients. Exp Ther Med. 2017;14(5):4896–900.

    CAS  PubMed  Google Scholar 

  48. 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 (Lausanne). 2020;11:274.

    Article  Google Scholar 

  49. Pau CT, Mosbruger T, Saxena R, Welt CK. Phenotype and tissue expression as a function of genetic risk in polycystic ovary syndrome. PLoS One. 2017;12(1):e0168870.

    Article  PubMed  Google Scholar 

  50. Sun Y, Yuan Y, Yang H, Li J, Feng T, Ouyang Y, et al. Association between common genetic variants and polycystic ovary syndrome risk in a Chinese Han population. J Clin Res Pediatr Endocrinol. 2016;8(4):405–10.

    Article  PubMed  Google Scholar 

  51. Yu J, Ding C, Guan S, Wang C. Association of single nucleotide polymorphisms in the RAB5B gene 3’UTR region with polycystic ovary syndrome in Chinese Han women. Biosci Rep. 2019;39(5):BSR20190292.

    Article  CAS  PubMed  Google Scholar 

  52. Jiao X, Chen W, Zhang J, Wang W, Song J, Chen D, et al. Variant alleles of the ESR1, PPARG, HMGA2, and MTHFR genes are associated with polycystic ovary syndrome risk in a Chinese population: a case-control study. Front Endocrinol (Lausanne). 2018;9:504.

    Article  PubMed  Google Scholar 

  53. Li M, Zhao H, Zhao SG, Wei DM, Zhao YR, Huang T, et al. The HMGA2-IMP2 pathway promotes granulosa cell proliferation in polycystic ovary syndrome. J Clin Endocrinol Metab. 2019;104(4):1049–59.

    Article  PubMed  Google Scholar 

  54. Zhai J, Liu J, Cheng X, Li S, Hong Y, Sun K, et al. Zinc finger gene 217 (ZNF217) promoted ovarian hyperstimulation syndrome (OHSS) through regulating E2 synthesis and inhibiting thrombospondin-1 (TSP-1). Sci Rep. 2017;7(1):3245.

    Article  PubMed  Google Scholar 

  55. Zhai J, Li S, Cheng X, Chen ZJ, Li W, Du Y. A candidate pathogenic gene, zinc finger gene 217 (ZNF217), may contribute to polycystic ovary syndrome through prostaglandin E2. Acta Obstet Gynecol Scand. 2020;99(1):119–26.

    Article  CAS  PubMed  Google Scholar 

  56. VÁzquez-martÍnez ER, Gómez-Viais YI, García-Gómez E, Reyes-Mayoral C, Reyes-Muñoz E, Camacho-Arroyo I, Cerbón MA. DNA methylation in the pathogenesis of polycystic ovary syndrome. Reproduction. 2019;158:R27–40. https://doi.org/10.1530/REP-18-0449.

    Article  Google Scholar 

  57. Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nature reviews Genetics. 2012;13(7):484–92.

    Article  CAS  PubMed  Google Scholar 

  58. Concha CF, Sir PT, Recabarren SE, Pérez BF. Epigenetics of polycystic ovary syndrome. Rev Med Chil. 2017;145(7):907–15.

  59. Pan JX, Tan YJ, Wang FF, Hou NN, Xiang YQ, Zhang JY, Liu Y, Qu F, Meng Q, Xu J, Sheng JZ, Huang HF. Aberrant expression and DNA methylation of lipid metabolism genes in PCOS: a new insight into its pathogenesis. Clin Epigenetics. 2018;10:6. https://doi.org/10.1186/s13148-018-0442-y.

  60. Hiam D, Simar D, Laker R, Altıntaş A, Gibson-Helm M, Fletcher E, Moreno-Asso A, Trewin AJ, Barres R, Stepto NK. Epigenetic reprogramming of immune cells in women with PCOS impact genes controlling reproductive function. J Clin Endocrinol Metab. 2019;104(12):6155–70.

  61. Echiburú B, Milagro F, Crisosto N, Pérez-Bravo F, Flores C, Arpón A, et al. DNA Methylation in promoter regions of genes involved in the reproductive and metabolic function of children born to women with PCOS. Epigenetics. 2020;1-17.

  62. Wroblewski A, Strycharz J, Swiderska E, Drewniak K, Drzewoski J, Szemraj J, et al. Molecular insight into the interaction between epigenetics and leptin in metabolic disorders. Nutrients. 2019;11(8).

  63. Sagvekar P, Kumar P, Mangoli V, Desai S, Mukherjee S. DNA methylome profiling of granulosa cells reveals altered methylation in genes regulating vital ovarian functions in polycystic ovary syndrome. Clin Epigenetics. 2019;11(1):61.

    Article  PubMed  Google Scholar 

  64. Chen B, Xu P, Wang J, Zhang C. The role of MiRNA in polycystic ovary syndrome (PCOS). Gene. 2019;706:91–6.

    Article  CAS  PubMed  Google Scholar 

  65. Huang X, Liu C, Hao C, Tang Q, Liu R, Lin S, et al. Identification of altered microRnas in cumulus cells of PCOS patients: microRNA-509-3p promotes oestradiol secretion by targeting MAP3K8. Reproduction. 2016;151(6):643–55.

    Article  CAS  PubMed  Google Scholar 

  66. Yao L, Li M, Hu J, Wang W, Gao M. MiRNA-335-5p negatively regulates granulosa cell proliferation via SGK3 in PCOS. Reproduction. 2018;156(5):439–49.

    CAS  PubMed  Google Scholar 

  67. Chen YH, Heneidi S, Lee JM, Layman LC, Stepp DW, Gamboa GM, et al. miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance. Diabetes. 2013;62(7):2278–86.

    Article  CAS  PubMed  Google Scholar 

  68. Chuang TY, Wu HL, Chen CC, Gamboa GM, Layman LC, Diamond MP, et al. MicroRNA-223 expression is upregulated in insulin resistant human adipose tissue. J Diabetes Res. 2015;2015:1–8. https://doi.org/10.1155/2015/943659.

    Article  Google Scholar 

  69. McAllister JM, Han AX, Modi BP, Teves ME, Mavodza GR, Anderson ZL, et al. miRNA profiling reveals miRNA-130b-3p mediates DENND1A variant 2 expression and androgen biosynthesis. Endocrinology. 2019;160(8):1964–81.

    Article  CAS  PubMed  Google Scholar 

  70. Rashad NM, Ateya MA, Saraya YS, Elnagar WM, Helal KF, Lashin ME, et al. Association of miRNA - 320 expression level and its target gene endothelin-1 with the susceptibility and clinical features of polycystic ovary syndrome ovarian. Res. 2019;12(1):39.

    Google Scholar 

  71. Filippou P, Homburg R. Is foetal hyperexposure to androgens a cause of PCOS? Hum Reprod Update. 2017;23(4):421–32.

    Article  CAS  PubMed  Google Scholar 

  72. Barnes RB, Rosenfield RL, Ehrmann DA, Cara JF, Cuttler L, Levitsky LL, et al. Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women. J Clin Endocrinol Metab. 1994;79(5):1328–33.

    CAS  PubMed  Google Scholar 

  73. Raperport C, Homburg R. The source of polycystic ovarian syndrome. Clin Med Insights Reprod Health. 2019;13:117955811987146. https://doi.org/10.1177/1179558119871467.

    Article  Google Scholar 

  74. Tata B, Mimouni NEH, Barbotin AL, 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  Google Scholar 

  75. Tadaion Far F, Jahanian Sadatmahalleh S, Ziaei S, Kazemnejad A. Comparison of the umbilical cord Blood’s anti-Mullerian hormone level in the newborns of mothers with polycystic ovary syndrome (PCOS) and healthy mothers. J Ovarian Res. 2019;12(1):111.

    Article  PubMed  Google Scholar 

  76. Köninger A, Kampmeier A, Schmidt B, Frank M, Strowitzki T, Kimmig R, et al. Trends in anti-Müllerian hormone concentrations across different stages of pregnancy in women with polycystic ovary syndrome. Reprod Biomed Online. 2018;37(3):367–74.

    Article  PubMed  Google Scholar 

  77. Xita N, Tsatsoulis A. Review: fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical, and genetic association studies. J Clin Endocrinol Metab. 2006;91(5):1660–6.

    Article  CAS  PubMed  Google Scholar 

  78. Abbott DH, Kraynak M, Dumesic DA, Levine JE. In utero androgen excess: a developmental commonality preceding polycystic ovary syndrome? Front Horm Res. 2019;53:1–17.

    Article  CAS  PubMed  Google Scholar 

  79. Baculescu N. The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS. J Med Life. 2013;6(1):18–25.

    CAS  PubMed  Google Scholar 

  80. Maliqueo M, Lara HE, Sánchez F, Echiburú B, Crisosto N, Sir-Petermann T. Placental steroidogenesis in pregnant women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2013;166(2):151–5.

    Article  CAS  PubMed  Google Scholar 

  81. Sun M, Maliqueo M, Benrick A, Johansson J, Shao R, Hou L, et al. Maternal androgen excess reduces placental and fetal weights, increases placental steroidogenesis, and leads to long-term health effects in their female offspring. Am J Physiol Endocrinol Metab. 2012;303(11):E1373–85.

    Article  CAS  PubMed  Google Scholar 

  82. Conway G, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Franks S, Gambineri A, et al. The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur J Endocrinol. 2014;171(4):P1–29.

    Article  CAS  PubMed  Google Scholar 

  83. de Melo AS, Dias SV, Cavalli Rde C, Cardoso VC, Bettiol H, Barbieri MA, et al. Pathogenesis of polycystic ovary syndrome: multifactorial assessment from the foetal stage to menopause. Reproduction. 2015;150(1):R11–24.

    Article  PubMed  Google Scholar 

  84. Ibáñez L, de Zegher F, Potau N. Premature pubarche, ovarian hyperandrogenism, hyperinsulinism and the polycystic ovary syndrome: from a complex constellation to a simple sequence of prenatal onset. J Endocrinol Invest. 1998;21(9):558–66.

    Article  PubMed  Google Scholar 

  85. Fulghesu AM, Manca R, Loi S, Fruzzetti F. Insulin resistance and hyperandrogenism have no substantive association with birth weight in adolescents with polycystic ovary syndrome. Fertil Steril. 2015;103(3):808–14.

    Article  CAS  PubMed  Google Scholar 

  86. Legro RS, Roller RL, Dodson WC, Stetter CM, Kunselman AR, Dunaif A. Associations of birthweight and gestational age with reproductive and metabolic phenotypes in women with polycystic ovarian syndrome and their first-degree relatives. J Clin Endocrinol Metab. 2010;95(2):789–99.

    Article  CAS  PubMed  Google Scholar 

  87. Gambineri A, Pelusi C, Vicennati V, Pagotto U, Pasquali R. Obesity and the polycystic ovary syndrome. Int J Obes Relat Metab Disord. 2002;26(7):883–96.

    Article  CAS  PubMed  Google Scholar 

  88. Catalano PM, Shankar K. Obesity and pregnancy: mechanisms of short term and long-term adverse consequences for mother and child. BMJ. 2017;356:j1.

    Article  PubMed  Google Scholar 

  89. Fishman SL, Sonmez H, Basman C, Singh V, Poretsky L. The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review. Mol Med. 2018;24(1):59.

    Article  PubMed  Google Scholar 

  90. Gill V, Kumar V, Singh K, Kumar A, Kim JJ. Advanced glycation end products (AGEs) may be a link between modern diet and health. Biomolecules. 2019;9. https://doi.org/10.3390/biom9120888.

  91. Merhi Z, Kandaraki EA, Diamanti-Kandarakis E. Implications and future perspectives of AGEs in PCOS pathophysiology. Trends Endocrinol Metab. 2019;30(3):150–62.

    Article  CAS  PubMed  Google Scholar 

  92. Merhi Z. Advanced glycation end products and their relevance in female reproduction. Hum Reprod. 2014;29(1):135–45.

    Article  CAS  PubMed  Google Scholar 

  93. Lin PH, Chang CC, Wu KH, Shih CK, Chiang W, Chen HY, et al. Dietary glycotoxins, advanced glycation end products, inhibit cell proliferation and progesterone secretion in ovarian granulosa cells and mimic PCOS-like symptoms. Biomolecules. 2019;9. https://doi.org/10.3390/biom9080327.

  94. Garg D, Merhi Z. Relationship between advanced glycation end products and steroidogenesis in PCOS. Reprod Biol Endocrinol. 2016;14(1):71.

    Article  PubMed  Google Scholar 

  95. Diamanti-Kandarakis E, Katsikis I, Piperi C, Kandaraki E, Piouka A, Papavassiliou AG, et al. Increased serum advanced glycation end-products is a distinct finding in lean women with polycystic ovary syndrome (PCOS) Clin. Endocrinol. 2008;69:634–41.

    Article  CAS  Google Scholar 

  96. Tantalaki E, Piperi C, Livadas S, Kollias A, Adamopoulos C, Koulouri A, et al. Impact of dietary modification of advanced glycation end products (AGEs) on the hormonal and metabolic profile of women with polycystic ovary syndrome (PCOS). Hormones. 2014;13:65–73.

    Article  PubMed  Google Scholar 

  97. Faghfoori Z, Fazelian S, Shadnoush M, Goodarzi R. Nutritional management in women with polycystic ovary syndrome: a review study diabetes. Metab Syndr. 2017;11(Suppl 1):S429–32.

    Article  Google Scholar 

  98. Rutkowska AZ, Diamanti-Kandarakis E. Do advanced glycation end products (AGEs) contribute to the comorbidities of polycystic ovary syndrome (PCOS)? Curr Pharm Des. 2016;22(36):5558–71.

    Article  CAS  PubMed  Google Scholar 

  99. Crunkhorn S. Role of the gut microbiota in PCOS. Nat Rev Drug Discov. 2019;18(9):668.

    PubMed  Google Scholar 

  100. Silva MSB, Giacobini P. Don’t trust your gut: when gut microbiota disrupt fertility. Cell Metab. 2019;30(4):616–8.

    Article  CAS  PubMed  Google Scholar 

  101. Zeng B, Lai Z, Sun L, Zhang Z, Yang J, Li Z, et al. Structural and functional profiles of the gut microbial community in polycystic ovary syndrome with insulin resistance (IR-PCOS): a pilot study. Res Microbiol. 2019;170(1):43–52.

    Article  CAS  PubMed  Google Scholar 

  102. 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  Google Scholar 

  103. Torres PJ, Siakowska M, Banaszewska B, Pawelczyk L, Duleba AJ, Kelley ST, et al. Gut microbial diversity in women with polycystic ovary syndrome correlates with hyperandrogenism. J Clin Endocrinol Metab. 2018;103(4):1502–11.

    Article  PubMed  Google Scholar 

  104. Insenser M, Murri M, Del Campo R, Martínez-García MÁ, Fernández-Durán E, Escobar-Morreale HF. Gut microbiota and the polycystic ovary syndrome: influence of sex, sex hormones, and obesity. J Clin Endocrinol Metab. 2018;103(7):2552–62.

    Article  PubMed  Google Scholar 

  105. Hossein Rashidi B, Amanlou M, Behrouzi Lak T, Ghazizadeh M, Haghollahi F, Bagheri M, et al. The association between bisphenol A and polycystic ovarian syndrome: a case-control study. Acta Med Iran. 2017;55(12):759–64.

    PubMed  Google Scholar 

  106. 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 

  107. Palioura E, Kandaraki E, Diamanti-Kandarakis E. Endocrine disruptors and polycystic ovary syndrome: a focus on Bisphenol A and its potential pathophysiological aspects. Horm Mol Biol Clin Investig. 2014;17(3):137–44.

    CAS  PubMed  Google Scholar 

  108. Hu Y, Wen S, Yuan D, Peng L, Zeng R, Yang Z, et al. The association between the environmental endocrine disruptor bisphenol A and polycystic ovary syndrome: a systematic review and meta-analysis. Gynecol Endocrinol. 2018;34(5):370–7.

    Article  CAS  PubMed  Google Scholar 

  109. Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, et al. on behalf of the International PCOS Network Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Human Reproduction. 2018;33(9):1602–18.

    Article  PubMed  Google Scholar 

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  1. Department of Gynecology and Obstetrics, University of Florence, Florence, Italy

    Vincenzina Bruni

  2. Department of Women and Child Health, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy

    Anna Capozzi & Stefano Lello

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  1. Vincenzina Bruni
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  2. Anna Capozzi
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Bruni, V., Capozzi, A. & Lello, S. The Role of Genetics, Epigenetics and Lifestyle in Polycystic Ovary Syndrome Development: the State of the Art. Reprod. Sci. 29, 668–679 (2022). https://doi.org/10.1007/s43032-021-00515-4

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