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A brief insight into the etiology, genetics, and immunology of polycystic ovarian syndrome (PCOS)

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Abstract

Polycystic ovarian syndrome (PCOS) is a prevailing endocrine and metabolic disorder occurring in about 6–20% of females in reproductive age. Most symptoms of PCOS arise early during puberty. Since PCOS involves a combination of signs and symptoms, thus it is considered as a heterogeneous disorderliness. The most accepted diagnostic criteria is Rotterdam criteria which involves two of the latter three features: (a) hyperandrogenism, (b) oligo- or an-ovulation, and (c) polycystic ovaries. The persistent hormonal imbalance leads to multiple small antral follicles formation and irregular menstrual cycle, ultimately causing infertility among females. Insulin resistance, cardiovascular diseases, abdominal obesity, psychological disorders, infertility, and cancer are also related to PCOS. These pathophysiologies associated with PCOS are interrelated with each other. Hyperandrogenism causes insulin resistance and hyperglycemia, leading to ROS formation, oxidative stress, and abdominal adiposity. In consequence, inflammation, ROS production, insulin resistance, and hyperandrogenemia also increase. Elevation of AGEs in the body either produced endogenously or consumed from diet exaggerates PCOS symptoms and is also related to ovarian dysfunction. This review summarizes how AGE formation, inflammation, and oxidative stress are significantly essential in PCOS progression. Alterations during prenatal development like exposure to excess AMH, androgens, or toxins (bisphenol-A, endocrine disruptors, etc.) may also be the etiologic mechanism behind PCOS. Although the etiology of this disorder is unclear, environmental and genetic factors are primarily involved. Physical inactivity, as well as unhealthy eating habits, has a vital role in the progression of PCOS. This review outlines a collection of specific genes phenotypically linked with PCOS. Furthermore, beneficial effect of metformin in maintaining endocrine abnormalities and ovarian function is also mentioned. Kisspeptin is a protein which helps in onset of puberty and increases GnRH pulsatile release during ovulation as well as role of KNDy neurons in GnRH pulsatile signal required for reproduction are also elaborated. This review also focuses on the immunology related to PCOS involving chronic low-grade inflammation, and how the alterations within the follicular microenvironment are intricated in the development of infertility in PCOS patients. How PCOS develops following antiepileptic and psychiatric medication is also expanded in this review. Initiation of antiandrogen treatment in early age (≤ 25 years) might be helpful in spontaneous conception in PCOS women. The role of BMP (bone morphogenetic proteins) in folliculogenesis and their expression in oocytes and granulosa cells are also explained. GDF8 and SERPINE1 expression in PCOS is given in detail.

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References

  1. A. Szilagyi and I. Szabo, “Endocrine characteristics of polycystic ovary syndrome (PCOS),” IJEB Vol.41(07) [July 2003], 2003, Accessed: Jan. 18, 2022. [Online]. Available: http://nopr.niscair.res.in/handle/123456789/17119

  2. Balen AH, 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. https://doi.org/10.1093/HUMUPD/DMW025.

    Article  Google Scholar 

  3. Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nature Rev Endocrinol. 2018;14(5):270–84.

    Article  Google Scholar 

  4. R. Azziz et al., “Polycystic ovary syndrome,” Nature Reviews Disease Primers 2016 2:1 https://doi.org/10.1038/nrdp.2016.57.

  5. Witchel SF, Oberfield SE, Peña AS. Polycystic ovary syndrome: pathophysiology, presentation, and treatment with emphasis on adolescent girls. J Endocr Soc. 2019;3(8):1545–73. https://doi.org/10.1210/JS.2019-00078.

    Article  CAS  Google Scholar 

  6. Mehreen TS, Ranjani H, Kamalesh R, Ram U, Anjana RM, Mohan V. Prevalence of polycystic ovarian syndrome among adolescents and young women in India. J Diabetol. 2022;12(3):319. https://doi.org/10.4103/JOD.JOD_105_20.

    Article  Google Scholar 

  7. M. F. Yii, C. E. D. Lim, X. Luo, W. S. F. Wong, N. C. L. Cheng, and X. Zhan, “Polycystic ovarian syndrome in adolescence,” https://doi.org/10.1080/09513590903015551 2009 25 10:634–639 https://doi.org/10.1080/09513590903015551.

  8. Bronstein J, Tawdekar S, Liu Y, Pawelczak M, David R, Shah B. Age of onset of polycystic ovarian syndrome in girls may be earlier than previously thought. J Pediatr Adolesc Gynecol. 2011;24(1):15–20. https://doi.org/10.1016/J.JPAG.2010.06.003.

    Article  Google Scholar 

  9. S. Balaji et al., “Urban rural comparisons of polycystic ovary syndrome burden among adolescent girls in a hospital setting in India,” BioMed Research International 2015 https://doi.org/10.1155/2015/158951

  10. Dumesic DA, Meldrum DR, Katz-Jaffe MG, Krisher RL, Schoolcraft WB. Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health. Fertil Steril. 2015;103(2):303–16. https://doi.org/10.1016/J.FERTNSTERT.2014.11.015.

    Article  Google Scholar 

  11. Liu Y, et al. Oxidative stress markers in the follicular fluid of patients with polycystic ovary syndrome correlate with a decrease in embryo quality. J Assist Reprod Genet. 2021;38(2):471–7. https://doi.org/10.1007/S10815-020-02014-Y/TABLES/5.

    Article  CAS  Google Scholar 

  12. Y. Dincer, T. Akcay, T. Erdem, E. Ilker Saygili, and S. Gundogdu, “DNA damage, DNA susceptibility to oxidation and glutathione level in women with polycystic ovary syndrome,” 65 8:721–728 2009 https://doi.org/10.1080/00365510500375263

  13. K. Polak, A. Czyzyk, T. Simoncini, and B. Meczekalski, “New markers of insulin resistance in polycystic ovary syndrome,” J Endocrinol Investi 2016 https://doi.org/10.1007/S40618-016-0523-8

  14. Manco M, et al. Insulin dynamics in young women with polycystic ovary syndrome and normal glucose tolerance across categories of body mass index. PLoS ONE. 2014;9(4):e92995. https://doi.org/10.1371/JOURNAL.PONE.0092995.

    Article  Google Scholar 

  15. Kirchengast S, Huber J. Body composition characteristics and body fat distribution in lean women with polycystic ovary syndrome. Hum Reprod. 2001;16(6):1255–60. https://doi.org/10.1093/HUMREP/16.6.1255.

    Article  CAS  Google Scholar 

  16. 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. https://doi.org/10.1093/HUMUPD/DMS059.

    Article  CAS  Google Scholar 

  17. Goodarzi MO, Azziz R. Diagnosis, epidemiology, and genetics of the polycystic ovary syndrome. Best Pract Res Clin Endocrinol Metab. 2006;20(2):193–205. https://doi.org/10.1016/J.BEEM.2006.02.005.

    Article  CAS  Google Scholar 

  18. B. C. J. M. Fauser et al., “Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group,” Fertil Steril,97 1 2012, https://doi.org/10.1016/J.FERTNSTERT.2011.09.024.

  19. Azziz R, et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009;91(2):456–88. https://doi.org/10.1016/J.FERTNSTERT.2008.06.035.

    Article  Google Scholar 

  20. G. Conway, … D. D.-E. journal of, and undefined 2014, “The polycystic ovary syndrome: a position statement from the European Society of Endocrinology,” eje.bioscientifica.com, Accessed: Aug. 20, 2022. [Online]. Available: https://eje.bioscientifica.com/view/journals/eje/171/4/P1.xml

  21. R. Legro, S. Arslanian, … D. E.-T. J. of, and undefined 2013, “Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline,” academic.oup.com, Accessed: Aug. 20, 2022. [Online]. Available: https://academic.oup.com/jcem/article-abstract/98/12/4565/2833703

  22. “National Institute of Health (NIH)-Evidence based... - Google Scholar.” https://scholar.google.co.in/scholar?hl=en&as_sdt=0%2C5&q=National+Institute+of+Health+%28NIH%29-Evidence+based+workshop+on+Polycystic+Ovary+Syndrome+%282012%29&btnG= (accessed Aug. 20, 2022).

  23. 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. https://doi.org/10.1016/S0015-0282(00)01662-9.

    Article  CAS  Google Scholar 

  24. R. S. Legro, D. Driscoll, J. F. Strauss, J. Fox, and A. Dunaif, “Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome,” Proceedings of the National Academy of Sciences, 95, 25, 1998.

  25. Ajmal N, Khan SZ, Shaikh R. Polycystic ovary syndrome (PCOS) and genetic predisposition: a review article. Eur J Obstet Gynecol Reproduct Biol. 2019;3:100060. https://doi.org/10.1016/J.EUROX.2019.100060.

    Article  CAS  Google Scholar 

  26. de Andrade VHL, et al. Current aspects of polycystic ovary syndrome: a literature review. Rev Assoc Med Bras. 2016;62(9):867–71. https://doi.org/10.1590/1806-9282.62.09.867.

    Article  Google Scholar 

  27. V. Nelson-Degrave, … J. W.-M., and undefined 2005, “Alterations in mitogen-activated protein kinase kinase and extracellular regulated kinase signaling in theca cells contribute to excessive androgen production in,” academic.oup.com, Accessed: Aug. 20, 2022. [Online]. Available: https://academic.oup.com/mend/article-abstract/19/2/379/2741316

  28. Willis D, Mason H, Gilling-Smith C, Franks S. Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab. 1996;81(1):302–9. https://doi.org/10.1210/JCEM.81.1.8550768.

    Article  CAS  Google Scholar 

  29. da Silva BB, et al. Morphological and morphometric analysis of the adrenal cortex of androgenized female rats. Gynecol Obstet Invest. 2007;64(1):44–8. https://doi.org/10.1159/000098956.

    Article  Google Scholar 

  30. A. Dunaif and C. B. Book, “Insulin resistance in the polycystic ovary syndrome,” Clinical Research in Diabetes and Obesity, 249–274, 1997, https://doi.org/10.1007/978-1-4757-3906-0_14.

  31. R. Dumitrescu, C. Mehedintu, I. Briceag, V. L. Purcarea, and D. Hudita, “The polycystic ovary syndrome: an update on metabolic and hormonal mechanisms,” Journal of Medicine and Life, vol. 8, no. 2, p. 142, Apr. 2015, Accessed: Jan. 20, 2022. [Online]. Available: /pmc/articles/PMC4392092/

  32. Chun S. Relationship between early follicular serum estrone level and other hormonal or ultrasonographic parameters in women with polycystic ovary syndrome. Gynecol Endocrinol. 2020;36(2):143–7. https://doi.org/10.1080/09513590.2019.1633296.

    Article  CAS  Google Scholar 

  33. DeVane GW, Czekala NM, Judd HL, Yen SSC. Circulating gonadotropins, estrogens, and androgens in polycystic ovarian disease. Am J Obstet Gynecol. 1975;121(4):496–500. https://doi.org/10.1016/0002-9378(75)90081-2.

    Article  CAS  Google Scholar 

  34. E. Doh et al., “The relationship between adiposity and insulin sensitivity in african women living with the polycystic ovarian syndrome: a clamp study,” International Journal of Endocrinology, vol. 2016, https://doi.org/10.1155/2016/9201701.

  35. R. Pasquali and A. Gambineri, “New perspectives on the definition and management of polycystic ovary syndrome,” Journal of Endocrinological Investigation 2018 41:10, vol. 41 10:1123–1135, 2018, https://doi.org/10.1007/S40618-018-0832-1.

  36. Burger HG. Androgen production in women. Fertil Steril. 2002;77(4):3–5. https://doi.org/10.1016/S0015-0282(02)02985-0.

    Article  Google Scholar 

  37. Moll GW, Rosenfield RL. Plasma free testosterone in the diagnosis of adolescent polycystic ovary syndrome. J Pediatr. 1983;102(3):461–4. https://doi.org/10.1016/S0022-3476(83)80678-7.

    Article  Google Scholar 

  38. van Hooff MHA, Voorhorst FJ, Kaptein MBH, Hirasing RA, Koppenaal C, Schoemaker J. Polycystic ovaries in adolescents and the relationship with menstrual cycle patterns, luteinizing hormone, androgens, and insulin. Fertil Steril. 2000;74(1):49–58. https://doi.org/10.1016/S0015-0282(00)00584-7.

    Article  Google Scholar 

  39. 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. https://doi.org/10.1210/ER.2015-1104.

    Article  CAS  Google Scholar 

  40. Bulsara J, Patel P, Soni A, Acharya S. A review: brief insight into polycystic ovarian syndrome. Endocr Metab Sci. 2021;3:100085. https://doi.org/10.1016/J.ENDMTS.2021.100085.

    Article  CAS  Google Scholar 

  41. D. E. Moller and J. S. Flier, “Detection of an alteration in the insulin-receptor gene in a patient with insulin resistance, Acanthosis nigricans, and the polycystic ovary syndrome (type A insulin resistance),” 319, 23:1526–1529 2010, https://doi.org/10.1056/NEJM198812083192306.

  42. S. Toosy, R. Sodi, and J. M. Pappachan, “Lean polycystic ovary syndrome (PCOS): an evidence-based practical approach,” Journal of Diabetes & Metabolic Disorders 2018 17:2 277–285 2018 https://doi.org/10.1007/S40200-018-0371-5.

  43. Aversa A, et al. Fundamental concepts and novel aspects of polycystic ovarian syndrome: expert consensus resolutions. Front Endocrinol. 2020;11:516. https://doi.org/10.3389/FENDO.2020.00516.

    Article  Google Scholar 

  44. Hannon TS, Janosky J, Arslanian SA. longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Pediatric Research. 2006;60(6):759–63. https://doi.org/10.1203/01.pdr.0000246097.73031.27.

    Article  CAS  Google Scholar 

  45. Caprio S. Insulin: the other anabolic hormone of puberty. Acta Pædiatrica. 1999;88(433):84–7. https://doi.org/10.1111/J.1651-2227.1999.TB14410.X.

    Article  CAS  Google Scholar 

  46. Fridlyand LE, Philipson LH. Reactive species and early manifestation of insulin resistance in type 2 diabetes. Diabetes Obes Metab. 2006;8(2):136–45. https://doi.org/10.1111/J.1463-1326.2005.00496.X.

    Article  CAS  Google Scholar 

  47. Seow KM, Juan CC, Hsu YP, Hwang JL, Huang LW, Ho LT. Amelioration of insulin resistance in women with PCOS via reduced insulin receptor substrate-1 Ser312 phosphorylation following laparoscopic ovarian electrocautery. Hum Reprod. 2007;22(4):1003–10. https://doi.org/10.1093/HUMREP/DEL466.

    Article  CAS  Google Scholar 

  48. Corbould 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):51–5. https://doi.org/10.1152/AJPENDO.00361.2004/ASSET/IMAGES/LARGE/ZH10050520890006.JPEG.

    Article  Google Scholar 

  49. Chen L, Xu WM, Zhang D. Association of abdominal obesity, insulin resistance, and oxidative stress in adipose tissue in women with polycystic ovary syndrome. Fertil Steril. 2014;102(4):1167-1174.e4. https://doi.org/10.1016/J.FERTNSTERT.2014.06.027.

    Article  CAS  Google Scholar 

  50. J. L. Evans, B. A. Maddux, and I. D. Goldfine, “The molecular basis for oxidative stress-induced insulin resistance,” https://home.liebertpub.com/ars, 7, 7–8:1040–1052, 2005, https://doi.org/10.1089/ARS.2005.7.1040.

  51. González F, Rote NS, Minium J, Kirwan JP. reactive oxygen species-induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91(1):336–40. https://doi.org/10.1210/JC.2005-1696.

    Article  Google Scholar 

  52. V. M. Victor, M. Rocha, E. Sola, C. Banuls, K. Garcia-Malpartida, and A. Hernandez- Mijares, “Oxidative stress, endothelial dysfunction and atherosclerosis,” Current Pharmaceutical Design, 15, 26:2988–3002, 2009, https://doi.org/10.2174/138161209789058093

  53. Sabuncu T, Vural H, Harma M, Harma M. Oxidative stress in polycystic ovary syndrome and its contribution to the risk of cardiovascular disease☆. Clin Biochem. 2001;34(5):407–13. https://doi.org/10.1016/S0009-9120(01)00245-4.

    Article  CAS  Google Scholar 

  54. Ziech D, Franco R, Pappa A, Panayiotidis MI. Reactive oxygen species (ROS)––induced genetic and epigenetic alterations in human carcinogenesis. Mutat Res/Fundam Mol Mechan Mutagen. 2011;711(1–2):167–73. https://doi.org/10.1016/J.MRFMMM.2011.02.015.

    Article  CAS  Google Scholar 

  55. Donkena KV, Young CYF, Tindall DJ. oxidative stress and dna methylation in prostate cancer. Obstet Gynecol Int. 2010;2010:1–14. https://doi.org/10.1155/2010/302051.

    Article  CAS  Google Scholar 

  56. Franco R, Schoneveld O, Georgakilas AG, Panayiotidis MI. Oxidative stress, DNA methylation and carcinogenesis. Cancer Lett. 2008;266(1):6–11. https://doi.org/10.1016/J.CANLET.2008.02.026.

    Article  CAS  Google Scholar 

  57. March WA, Moore VM, Willson KJ, Phillips DIW, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25(2):544–51. https://doi.org/10.1093/HUMREP/DEP399.

    Article  Google Scholar 

  58. T. Zuo, M. Zhu, and W. Xu, “Roles of oxidative stress in polycystic ovary syndrome and cancers,” Oxidative Medicine and Cellular Longevity, vol. 2016, 2016, https://doi.org/10.1155/2016/8589318.

  59. Ozata M, et al. Increased oxidative stress and hypozincemia in male obesity. Clin Biochem. 2002;35(8):627–31. https://doi.org/10.1016/S0009-9120(02)00363-6.

    Article  CAS  Google Scholar 

  60. Couillard C, et al. Circulating levels of oxidative stress markers and endothelial adhesion molecules in men with abdominal obesity. J Clin Endocrinol Metab. 2005;90(12):6454–9. https://doi.org/10.1210/JC.2004-2438.

    Article  CAS  Google Scholar 

  61. Hu Y, Zhao Y, Ren D, Guo J, Luo Y, Yang X. Hypoglycemic and hepatoprotective effects of d - chiro -inositol-enriched tartary buckwheat extract in high fructose-fed mice. Food Funct. 2015;6(12):3760–9. https://doi.org/10.1039/C5FO00612K.

    Article  CAS  Google Scholar 

  62. Castro MC, Massa ML, Arbeláez LG, Schinella G, Gagliardino JJ, Francini F. Fructose-induced inflammation, insulin resistance and oxidative stress: a liver pathological triad effectively disrupted by lipoic acid. Life Sci. 2015;137:1–6. https://doi.org/10.1016/J.LFS.2015.07.010.

    Article  CAS  Google Scholar 

  63. Repaci A, Gambineri A, Pasquali R. The role of low-grade inflammation in the polycystic ovary syndrome. Mol Cell Endocrinol. 2011;335(1):30–41. https://doi.org/10.1016/J.MCE.2010.08.002.

    Article  CAS  Google Scholar 

  64. González F, Rote NS, Minium J, Kirwan JP. Evidence of proatherogenic inflammation in polycystic ovary syndrome. Metab. 2009;58(7):954–62. https://doi.org/10.1016/J.METABOL.2009.02.022.

    Article  Google Scholar 

  65. Yilmaz M, et al. The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome. Hum Reprod. 2005;20(12):3333–40. https://doi.org/10.1093/HUMREP/DEI258.

    Article  CAS  Google Scholar 

  66. Piotrowski PC, et al. Antioxidants inhibit expression of genes involved in testosterone production by theca-interstitial cells. Fertil Steril. 2005;84:S7. https://doi.org/10.1016/J.FERTNSTERT.2005.07.016.

    Article  Google Scholar 

  67. Diamanti-Kandarakis E, Christakou C, Marinakis E. Phenotypes and enviromental factors: their influence in PCOS. Curr Pharm Des. 2012;18(3):270–82. https://doi.org/10.2174/138161212799040457.

    Article  CAS  Google Scholar 

  68. Piperi C, Adamopoulos C, Dalagiorgou G, Diamanti-Kandarakis E, Papavassiliou AG. Crosstalk between advanced glycation and endoplasmic reticulum stress: emerging therapeutic targeting for metabolic Diseases. J Clin Endocrinol Metab. 2012;97(7):2231–42. https://doi.org/10.1210/JC.2011-3408.

    Article  CAS  Google Scholar 

  69. Garg D, Merhi Z. Advanced glycation end products: link between diet and ovulatory dysfunction in PCOS? Nutrients. 2015;7(12):10129–44. https://doi.org/10.3390/NU7125524.

    Article  CAS  Google Scholar 

  70. Diamanti-Kandarakis E, et al. Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries. Histochem Cell Biol. 2007;127:581–9. https://doi.org/10.1007/s00418-006-0265-3.

    Article  CAS  Google Scholar 

  71. Basta G. Receptor for advanced glycation endproducts and atherosclerosis: from basic mechanisms to clinical implications. Atherosclerosis. 2008;196(1):9–21. https://doi.org/10.1016/J.ATHEROSCLEROSIS.2007.07.025.

    Article  CAS  Google Scholar 

  72. Tantalaki E, 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(1):65–73. https://doi.org/10.1007/BF03401321.

    Article  Google Scholar 

  73. Diamanti-Kandarakis E, Piperi C, Kalofoutis A, Creatsas G. Increased levels of serum advanced glycation end-products in women with polycystic ovary syndrome. Clin Endocrinol. 2005;62(1):37–43. https://doi.org/10.1111/J.1365-2265.2004.02170.X.

    Article  CAS  Google Scholar 

  74. Vlassara H, et al. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc Natl Acad Sci. 2002;99(24):15596–601. https://doi.org/10.1073/PNAS.242407999.

    Article  CAS  Google Scholar 

  75. Uribarri J, et al. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J Gerontol Series A. 2007;62(4):427–33. https://doi.org/10.1093/GERONA/62.4.427.

    Article  Google Scholar 

  76. Cai W, di Gao Q, Zhu L, Peppa M, He C, Vlassara H. Oxidative stress-inducing carbonyl compounds from common foods: novel mediators of cellular dysfunction. Mol Med. 2002;8(7):337–46. https://doi.org/10.1007/BF03402014/FIGURES/5.

    Article  CAS  Google Scholar 

  77. Tatone C, Eichenlaub-Ritter U, Amicarelli F. Dicarbonyl stress and glyoxalases in ovarian function. Biochem Soc Trans. 2014;42(2):433–8. https://doi.org/10.1042/BST20140023.

    Article  CAS  Google Scholar 

  78. Unoki H, Yamagishi S. Advanced glycation end products and insulin resistance. Curr Pharm Des. 2008;14(10):987–9. https://doi.org/10.2174/138161208784139747.

    Article  CAS  Google Scholar 

  79. Merhi Z. Advanced glycation end products and their relevance in female reproduction. Hum Reprod. 2014;29(1):135–45. https://doi.org/10.1093/HUMREP/DET383.

    Article  CAS  Google Scholar 

  80. Koyama H, et al. Plasma level of endogenous secretory RAGE is associated with components of the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol. 2005;25(12):2587–93. https://doi.org/10.1161/01.ATV.0000190660.32863.cd.

    Article  CAS  Google Scholar 

  81. Ueno H, et al. Receptor for advanced glycation end-products (RAGE) regulation of adiposity and adiponectin is associated with atherogenesis in apoE-deficient mouse. Atherosclerosis. 2010;211(2):431–6. https://doi.org/10.1016/J.ATHEROSCLEROSIS.2010.04.006.

    Article  CAS  Google Scholar 

  82. P. Pigny, S. Jonard, … Y. R.-T. J. of C., and undefined 2006, “Serum anti-Mullerian hormone as a surrogate for antral follicle count for definition of the polycystic ovary syndrome,” academic.oup.com, Accessed: Aug. 20, 2022. [Online]. Available: https://academic.oup.com/jcem/article-abstract/91/3/941/2843410

  83. C. Cook, Y. Siow, A. Brenner, M. F.-F. and sterility, and undefined 2002, “Relationship between serum müllerian-inhibiting substance and other reproductive hormones in untreated women with polycystic ovary syndrome and normal,” Elsevier, Accessed: Aug. 20, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0015028201029442?casa_token=3ObG0fuGhhUAAAAA:ffl0nsmfH5O14HW73cx-pjnR6AKND3wtBrE_Fem1J7RWz111t5uJqetqOOB7b23MjfNEsY7PeQ38

  84. L. Pellatt, L. Hanna, M. Brincat, … R. G.-T. J. of, and undefined 2007, “Granulosa cell production of anti-Mullerian hormone is increased in polycystic ovaries,” academic.oup.com, Accessed: Aug. 20, 2022. [Online]. Available: https://academic.oup.com/jcem/article-abstract/92/1/240/2598594

  85. Pigny P, et al. Elevated serum level of anti-mullerian hormone in patients with polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest. J Clin Endocrinol Metab. 2003;88(12):5957–62. https://doi.org/10.1210/JC.2003-030727.

    Article  CAS  Google Scholar 

  86. M. Goodarzi, D. Dumesic, … G. C.-N. reviews, and undefined 2011, “Polycystic ovary syndrome: etiology, pathogenesis and diagnosis,” nature.com, Accessed: Aug. 21, 2022. [Online]. Available: https://www.nature.com/articles/nrendo.2010.217

  87. Tata B, et al. Elevated prenatal anti-Mullerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood. Nat Med. 2018;24(6):834–7. https://doi.org/10.1038/S41591-018-0035-5.

    Article  CAS  Google Scholar 

  88. N. Mimouni, I. Paiva, A. Barbotin, F. T.-C. metabolism, and undefined 2021, “Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process,” Elsevier, Accessed: Aug. 21, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S1550413121000048

  89. L. Moore, T. Le, G. F.- Neuropsychopharmacology, and undefined 2013, “DNA methylation and its basic function,” nature.com, Accessed: Aug. 21, 2022. [Online]. Available: https://www.nature.com/articles/npp2012112

  90. R. Tal, D. Seifer, M. Khanimov, … H. M.-A. journal of, and undefined 2014, “Characterization of women with elevated antimüllerian hormone levels (AMH): correlation of AMH with polycystic ovarian syndrome phenotypes and assisted,” Elsevier, Accessed: Aug. 21, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0002937814001689

  91. R. Homburg, A. Ray, P. Bhide, A. Gudi, A. S.-… Reproduction, and undefined 2013, “The relationship of serum anti-Mullerian hormone with polycystic ovarian morphology and polycystic ovary syndrome: a prospective cohort study,” academic.oup.com, Accessed: Aug. 21, 2022. [Online]. Available: https://academic.oup.com/humrep/article-abstract/28/4/1077/653152

  92. Y. Lin et al., “Antimüllerian hormone and polycystic ovary syndrome,” Elsevier, Accessed: Aug. 21, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0015028211005863?casa_token=qb4h0HFI1noAAAAA:Od82bVmuVqtLcNfJlQkGjcPuNVgY-Ptj2N6QM2VcyynJt-TcHxkjQgRMD9TB68hJClVDQTr82HY

  93. A. Piouka, D. Farmakiotis, I. Katsikis, D. Macut, S. Gerou, and D. Panidis, “Anti-Müllerian hormone levels reflect severity of PCOS but are negatively influenced by obesity: Relationship with increased luteinizing hormone levels,” American Journal of Physiology - Endocrinology and Metabolism, 296, 2, 2009, https://doi.org/10.1152/AJPENDO.90684.2008.

  94. Eldar-Geva T, et al. Serum anti-Mullerian hormone levels during controlled ovarian hyperstimulation in women with polycystic ovaries with and without hyperandrogenism. Hum Reprod. 2005;20(7):1814–9. https://doi.org/10.1093/HUMREP/DEH873.

    Article  CAS  Google Scholar 

  95. “Elevated serum level of anti-mullerian hormone in patients with polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest,” academic.oup.com, Accessed: Aug. 21, 2022. [Online]. Available: https://academic.oup.com/jcem/article-abstract/88/12/5957/2661509

  96. Abbott DH, Barnett DK, Bruns CM, Dumesic DA. Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? Hum Reprod Update. 2005;11(4):357–74. https://doi.org/10.1093/HUMUPD/DMI013.

    Article  CAS  Google Scholar 

  97. Hines M, Golombok S, Rust J, Johnston KJ, Golding J. Testosterone during pregnancy and gender role behavior of preschool children: a longitudinal, population study. Child Dev. 2002;73(6):1678–87. https://doi.org/10.1111/1467-8624.00498.

    Article  Google Scholar 

  98. R. Hart, D. Sloboda, D. Doherty, R. N.-F. and sterility, and undefined 2010, “Circulating maternal testosterone concentrations at 18 weeks of gestation predict circulating levels of antimüllerian hormone in adolescence: a prospective,” Elsevier, Accessed: Aug. 21, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0015028209043192?casa_token=w61Hv4KIJ3gAAAAA:BrYdCIuHRtNjgg607BUfC_sKuz4L0X7fqWWYQTAKc6h4Yn29mwqO4BQFvA5v-RiyKTtgzQ9TI9Y

  99. Webber LJ, et al. Formation and early development of follicles in the polycystic ovary. Lancet. 2003;362(9389):1017–21. https://doi.org/10.1016/S0140-6736(03)14410-8.

    Article  CAS  Google Scholar 

  100. Palomba S, et al. Pervasive developmental disorders in children of hyperandrogenic women with polycystic ovary syndrome: a longitudinal case-control study. Clin Endocrinol. 2012;77(6):898–904. https://doi.org/10.1111/J.1365-2265.2012.04443.X.

    Article  CAS  Google Scholar 

  101. M. Maliqueo, H. E. Lara, F. Sá nchez, B. rbara Echiburú, N. Crisosto, and T. Sir-Petermann, “Placental steroidogenesis in pregnant women with polycystic ovary syndrome,” Elsevier, 2013, https://doi.org/10.1016/j.ejogrb.2012.10.015.

  102. E. Kandaraki, … A. C.-T. J. of, and undefined 2011, “Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS,” academic.oup.com, Accessed: Aug. 21, 2022. [Online]. Available: https://academic.oup.com/jcem/article-abstract/96/3/E480/2597282

  103. L. Akin et al., “The endocrine disruptor bisphenol A may play a role in the aetiopathogenesis of polycystic ovary syndrome in adolescent girls.,” Acta Paediatrica (Oslo, Norway : 1992), 104, 4:e171–7, 2015, https://doi.org/10.1111/APA.12885

  104. A. Rutkowska, E. D.-K.-F. and sterility, and undefined 2016, “Polycystic ovary syndrome and environmental toxins,” Elsevier, Accessed: Aug. 21, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0015028216627280

  105. D. Micic, V. Popovic, M. Nesovic, … M. S.-J. of steroid, and undefined 1988, “Androgen levels during sequential insulin euglycemic clamp studies in patients with polycystic ovary disease,” Elsevier, Accessed: Aug. 21, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/0022473188903445

  106. A. Dumont, G. Robin, D. D. Endocrinology, D. and, and undefined 2018, “Anti-müllerian hormone in the pathophysiology and diagnosis of polycystic ovarian syndrome,” journals.lww.com, 2018, https://doi.org/10.1097/MED.0000000000000445

  107. S. Franks, C. Gilling-Smith, N. Gharani, and M. McCarthy, “Pathogenesis of polycystic ovary syndrome: evidence for a genetically determined disorder of ovarian androgen production,”, 3, 2:77–79, 2009, https://doi.org/10.1080/1464727002000198731

  108. Gharani N, et al. Association of the steroid synthesis gene Cyp11a with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet. 1997;6(3):397–402. https://doi.org/10.1093/HMG/6.3.397.

    Article  CAS  Google Scholar 

  109. Reddy KR, et al. CYP11A1 microsatellite (tttta)n polymorphism in PCOS women from South India. J Assist Reprod Genet. 2014;31(7):857–63. https://doi.org/10.1007/S10815-014-0236-X/TABLES/3.

    Article  Google Scholar 

  110. Zhang CW, et al. Association between polymorphisms of the CYP11A1 gene and polycystic ovary syndrome in Chinese women. Mol Biol Rep. 2012;39(8):8379–85. https://doi.org/10.1007/S11033-012-1688-7/TABLES/7.

    Article  CAS  Google Scholar 

  111. Rosenfield RL, Barnes RB, Cara JF, Lucky AW. Dysregulation of cytochrome P450c17α as the cause of polycystic ovarian syndrome. Fertil Steril. 1990;53(5):785–91. https://doi.org/10.1016/S0015-0282(16)53510-9.

    Article  CAS  Google Scholar 

  112. Rosenfield RL, Barnes RB, Ehrmann DA. Studies of the nature of 17-hydroxyprogesterone hyperresonsiveness to gonadotropin-releasing hormone agonist challenge in functional ovarian hyperandrogenism. J Clin Endocrinol Metab. 1994;79(6):1686–92. https://doi.org/10.1210/JCEM.79.6.7989476.

    Article  CAS  Google Scholar 

  113. Carey AH, et al. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet. 1994;3(10):1873–6. https://doi.org/10.1093/HMG/3.10.1873.

    Article  CAS  Google Scholar 

  114. Zhang LH, Rodriguez H, Ohno S, Miller WL. Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci. 1995;92(23):10619–23. https://doi.org/10.1073/PNAS.92.23.10619.

    Article  CAS  Google Scholar 

  115. D. W. Nebert et al., “The P450 gene superfamily: recommended nomenclature,” http://www.liebertpub.com/dna, 6, 1:1–11, 2009, https://doi.org/10.1089/DNA.1987.6.1.

  116. S. Chen et al., “Human Aromatase: cDNA cloning, southern blot analysis, and assignment of the gene to chromosome 15,” http://www.liebertpub.com/dna, 7, 1:27–38, 2009, https://doi.org/10.1089/DNA.1988.7.27.

  117. Harada N, et al. Biochemical and molecular genetic analyses on placental aromatase (P-450AROM) deficiency. J Biol Chem. 1992;267(7):4781–5. https://doi.org/10.1016/S0021-9258(18)42900-6.

    Article  CAS  Google Scholar 

  118. Ito Y, Fisher CR, Conte FA, Grumbach MM, Simpson ER. Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries. Proc Natl Acad Sci. 1993;90(24):11673–7. https://doi.org/10.1073/PNAS.90.24.11673.

    Article  CAS  Google Scholar 

  119. Jakimiuk AJ, Weitsman SR, Brzechffa PR, Magoffin DA. Aromatase mRNA expression in individual follicles from polycystic ovaries. Mol Hum Reprod. 1998;4(1):1–8. https://doi.org/10.1093/MOLEHR/4.1.1.

    Article  CAS  Google Scholar 

  120. J. L. Jin et al., “Association between CYP19 gene SNP rs2414096 polymorphism and polycystic ovary syndrome in Chinese women.,” BMC Med Genet, 10, 1:139, 2009, https://doi.org/10.1186/1471-2350-10-139/TABLES/3.

  121. Escobar-Morreale H, Pazos F, Potau N, Garcia-Robles R, Sancho JM, Varela C. Ovarian suppression with triptorelin and adrenal stimulation with adrenocorticotropin in functional hyperadrogenism: role of adrenal and ovarian cytochrome P450c17α. Fertil Steril. 1994;62(3):521–30. https://doi.org/10.1016/S0015-0282(16)56940-4.

    Article  CAS  Google Scholar 

  122. Azziz R, Bradley EL, Potter HD, Boots LR. Adrenal androgen excess in women: lack of a role for 17-hydroxylase and 17,20-lyase dysregulation. J Clin Endocrinol Metab. 1995;80(2):400–5. https://doi.org/10.1210/JCEM.80.2.7852496.

    Article  CAS  Google Scholar 

  123. 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. https://doi.org/10.1016/J.FERTNSTERT.2004.10.027.

    Article  CAS  Google Scholar 

  124. D. B. Lubahn, D. R. Joseph, P. M. Sullivan, H. F. Willard, F. S. French, and E. M. Wilson, “Cloning of human androgen receptor complementary dna and localization to the X chromosome,” Science (1979), 240, 4850:327–330, 1988, https://doi.org/10.1126/SCIENCE.3353727.

  125. Mifsud A, Ramirez S, Yong EL. Androgen receptor gene cag trinucleotide repeats in anovulatory infertility and polycystic ovaries. J Clin Endocrinol Metab. 2000;85(9):3484–8. https://doi.org/10.1210/JCEM.85.9.6832.

    Article  CAS  Google Scholar 

  126. Edmunds SEJ, Stubbs AP, Santos AA, Wilkinson ML. Estrogen and androgen regulation of sex hormone binding globulin secretion by a human liver cell line. J Steroid Biochem Mol Biol. 1990;37(5):733–9. https://doi.org/10.1016/0960-0760(90)90358-R.

    Article  CAS  Google Scholar 

  127. Nestler JE, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1991;72(1):83–9. https://doi.org/10.1210/JCEM-72-1-83.

    Article  CAS  Google Scholar 

  128. Selby C. Sex hormone binding globulin: origin, function and clinical significance. Ann Clin Biochem. 1990;27(6):532–41. https://doi.org/10.1177/000456329002700603.

    Article  Google Scholar 

  129. Bérubé D, Séralini GE, Gagné R, Hammond GL. Localization of the human sex hormone-binding globulin gene (SHBG) to the short arm of chromosome 17 (17p12→p13). Cytogenet Genome Res. 1990;54(1–2):65–7. https://doi.org/10.1159/000132958.

    Article  Google Scholar 

  130. Xita N, Tsatsoulis A, Chatzikyriakidou A, Georgiou I. Association of the (TAAAA)n repeat polymorphism in the sex hormone-binding globulin (SHBG) gene with polycystic ovary syndrome and relation to SHBG serum levels. J Clin Endocrinol Metab. 2003;88(12):5976–80. https://doi.org/10.1210/JC.2003-030197.

    Article  CAS  Google Scholar 

  131. Wickham EP, Ewens KG, Legro RS, Dunaif A, Nestler JE, Strauss JF. Polymorphisms in the SHBG gene influence serum SHBG levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2011;96(4):E719–27. https://doi.org/10.1210/JC.2010-1842.

    Article  CAS  Google Scholar 

  132. C. Chen, J. Smothers, A. Lange, J. E. Nestler, J. F. Strauss, and E. P. Wickham, “Sex hormone-binding globulin genetic variation: associations with type 2 diabetes mellitus and polycystic ovary syndrome,” Minerva Endocrinol, vol. 35, no. 4, p. 271, Dec. 2010, Accessed: Jan. 24, 2022. [Online]. Available: /pmc/articles/PMC3683392/

  133. Furui K, et al. Identification of two point mutations in the gene coding luteinizing hormone (LH) beta-subunit, associated with immunologically anomalous LH variants. J Clin Endocrinol Metab. 1994;78(1):107–13. https://doi.org/10.1210/JCEM.78.1.7904610.

    Article  CAS  Google Scholar 

  134. Okuda K, Yamada T, Imoto H, Komatsubara H, Sugimoto O. Antigenic Alteration of an Anomalous Human Luteinizing Hormone Caused by Two Chorionic Gonadotropin-Type Amino-Acid Substitutions. Biochem Biophys Res Commun. 1994;200(1):584–90. https://doi.org/10.1006/BBRC.1994.1488.

    Article  CAS  Google Scholar 

  135. Haavisto AM, Pettersson K, Bergendahl M, Virkamäki A, Huhtaniemi I. Occurrence and biological properties of a common genetic variant of luteinizing hormone. J Clin Endocrinol Metab. 1995;80(4):1257–63. https://doi.org/10.1210/JCEM.80.4.7714098.

    Article  CAS  Google Scholar 

  136. Roy AC, Liao WX, Chen Y, Arulkumaran S, Ratnam SS. Identification of seven novel mutations in LH β-subunit gene by SSCP. Mol Cellular Biochem. 1996;165(2):151–3. https://doi.org/10.1007/BF00229477.

    Article  CAS  Google Scholar 

  137. Takahashi K, et al. Influence of missense mutation and silent mutation of LHβ-subunit gene in Japanese patients with ovulatory disorders. Eur J Human Genet. 2003;11(5):402–8. https://doi.org/10.1038/sj.ejhg.5200968.

    Article  CAS  Google Scholar 

  138. Franks S, Gharani N, McCarthy M. Candidate genes in polycystic ovary syndrome. Hum Reprod Update. 2001;7(4):405–10. https://doi.org/10.1093/HUMUPD/7.4.405.

    Article  CAS  Google Scholar 

  139. A. Al-Hayawi, “The FSHR polymorphisms association with polycystic ovary syndrome in women of Erbil, Kurdistan in North of Iraq”, https://doi.org/10.30526/2017.IHSCICONF.1799.

  140. Gorsic LK, et al. Pathogenic Anti-Müllerian hormone variants in polycystic ovary syndrome. J Clin Endocrinol Metab. 2017;102(8):2862–72. https://doi.org/10.1210/JC.2017-00612.

    Article  Google Scholar 

  141. Knight PG, Glister C. Potential local regulatory functions of inhibins, activins and follistatin in the ovary. Reprod. 2001;121(4):503–12. https://doi.org/10.1530/REP.0.1210503.

    Article  CAS  Google Scholar 

  142. Guo Q, Kumar TR, Woodruff T, Hadsell LA, Demayo FJ, Matzuk MM. Overexpression of mouse follistatin causes reproductive defects in transgenic mice. Mol Endocrinol. 1998;12(1):96–106. https://doi.org/10.1210/MEND.12.1.0053.

    Article  CAS  Google Scholar 

  143. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38(9):1165–74. https://doi.org/10.2337/DIAB.38.9.1165.

    Article  CAS  Google Scholar 

  144. Munir I, 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. Endocrinol. 2004;145(1):175–83. https://doi.org/10.1210/EN.2003-0329.

    Article  CAS  Google Scholar 

  145. N. Cataldo, L. Giudice, L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice, “The insulin-related ovarian regulatory system in health and disease,” 1999, https://doi.org/10.1210/edrv.20.4.0374.

  146. Junien C, van Heyningen V. Report of the committee on the genetic constitution of chromosome 11. Cytogenet Genome Res. 1990;55(1–4):153–69. https://doi.org/10.1159/000133007.

    Article  CAS  Google Scholar 

  147. Bell GI, Selby MJ, Rutter WJ. The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences. Nature. 1982;295(5844):31–5. https://doi.org/10.1038/295031a0.

    Article  CAS  Google Scholar 

  148. Waterworth DM, et al. Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet. 1997;349(9057):986–90. https://doi.org/10.1016/S0140-6736(96)08368-7.

    Article  CAS  Google Scholar 

  149. Goldfine ID. The insulin receptor: molecular biology and transmembrane signaling. Endocr Rev. 1987;8(3):235–55. https://doi.org/10.1210/EDRV-8-3-235.

    Article  CAS  Google Scholar 

  150. Sorbara LR, et al. Absence of insulin receptor gene mutations in three insulin-resistant women with the polycystic ovary syndrome. Metabolism. 1994;43(12):1568–74. https://doi.org/10.1016/0026-0495(94)90018-3.

    Article  CAS  Google Scholar 

  151. Talbot JA, Bicknell EJ, Rajkhowa M, Krook A, O’Rahilly S, Clayton RN. Molecular scanning of the insulin receptor gene in women with polycystic ovarian syndrome. J Clin Endocrinol Metab. 1996;81(5):1979–83. https://doi.org/10.1210/JCEM.81.5.8626868.

    Article  CAS  Google Scholar 

  152. Tucci S, et al. Evidence for association of polycystic ovary syndrome in caucasian women with a marker at the insulin receptor gene locus. J Clin Endocrinol Metab. 2001;86(1):446–9. https://doi.org/10.1210/JCEM.86.1.7274.

    Article  CAS  Google Scholar 

  153. Urbanek M, et al. Candidate gene region for polycystic ovary syndrome on chromosome 19p13.2. J Clin Endocrinol Metab. 2005;90(12):6623–9. https://doi.org/10.1210/JC.2005-0622.

    Article  CAS  Google Scholar 

  154. Siegel S, et al. A C/T single nucleotide polymorphism at the tyrosine kinase domain of the insulin receptor gene is associated with polycystic ovary syndrome. Fertil Steril. 2002;78(6):1240–3. https://doi.org/10.1016/S0015-0282(02)04241-3.

    Article  Google Scholar 

  155. White MF. IRS proteins and the common path to diabetes. Am J Physiol - Endocrinol Metab. 2002;283(3):46–53. https://doi.org/10.1152/AJPENDO.00514.2001/ASSET/IMAGES/LARGE/H10920962005.JPEG.

    Article  Google Scholar 

  156. “G972R polymorphism of IRS-1 in women with polycystic ovary syndrome - ProQuest.” https://www.proquest.com/openview/1eb37ce5cc2b3d46b73650d49adb6791/1?pq-origsite=gscholar&cbl=48469 (accessed Jan. 30, 2022).

  157. Dilek S, Ertunc D, Tok EC, Erdal EM, Aktas A. Association of Gly972Arg variant of insulin receptor substrate-1 with metabolic features in women with polycystic ovary syndrome. Fertil Steril. 2005;84(2):407–12. https://doi.org/10.1016/J.FERTNSTERT.2005.01.133.

    Article  CAS  Google Scholar 

  158. Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R. Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J. 2001;15(12):2099–111. https://doi.org/10.1096/FJ.01-0009REV.

    Article  CAS  Google Scholar 

  159. P. Gual, Y. le Marchand-Brustel, J. T.- Biochimie, and undefined 2005, “Positive and negative regulation of insulin signaling through IRS-1 phosphorylation,” Elsevier, Accessed: Aug. 21, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0300908404001981

  160. Paz K, et al. A molecular basis for insulin resistance. J Biol Chem. 1997;272(47):29911–8. https://doi.org/10.1074/jbc.272.47.29911.

    Article  CAS  Google Scholar 

  161. H. Kanety, R. Feinstein, M. Papa, … R. H.-J. of B., and undefined 1995, “Tumor necrosis factor α-induced phosphorylation of insulin receptor substrate-1 (IRS-1): POSSIBLE MECHANISM FOR SUPPRESSION OF INSULIN,” ASBMB, Accessed: Aug. 21, 2022. [Online]. Available: https://www.jbc.org/article/S0021-9258(18)89979-3/abstract

  162. Yu C, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem. 2002;277(52):50230–6. https://doi.org/10.1074/jbc.M200958200.

    Article  CAS  Google Scholar 

  163. P. Gual, T. Gonzalez, T. Grémeaux, … R. B.-J. of B., and undefined 2003, “Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes,” ASBMB, Accessed: Aug. 21, 2022. [Online]. Available: https://www.jbc.org/article/S0021-9258(20)84607-9/abstract

  164. Potashnik R, Bloch-Damti A, Bashan N, Rudich A. IRS1 degradation and increased serine phosphorylation cannot predict the degree of metabolic insulin resistance induced by oxidative stress. Diabetologia. 2003;46(5):639–48. https://doi.org/10.1007/S00125-003-1097-5/FIGURES/7.

    Article  CAS  Google Scholar 

  165. A. Dunaif, J. Xia, C. Book, … E. S.-T. J. of clinical, and undefined 1995, “Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary,” Am Soc Clin Investig, Accessed: Aug. 21, 2022. [Online]. Available: https://www.jci.org/articles/view/118126

  166. Corbould 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):51–5. https://doi.org/10.1152/AJPENDO.00361.2004.

    Article  Google Scholar 

  167. A. Corbould, H. Zhao, S. Mirzoeva, F. Aird, and A. Dunaif, “Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome,” Diabetes, vol. 55, no. 3, pp. 751–760, Mar. 2006, Accessed: Aug. 21, 2022. [Online]. Available: https://go.gale.com/ps/i.do?p=AONE&sw=w&issn=00121797&v=2.1&it=r&id=GALE%7CA143248675&sid=googleScholar&linkaccess=fulltext

  168. E. Velazquez, S. Mendoza, T. Hamer, F. S.- Metabolism, and undefined 1994, “Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating,” Elsevier, Accessed: Aug. 21, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/0026049594902097

  169. R. Dumitrescu, “Metformin-clinical pharmacology in PCOs,” Journal of Medicine and Life, vol. 8, pp. 187–192.

  170. H. Escobar-Morreale, … E. C.-H. reproduction, and undefined 2012, “Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society,” academic.oup.com, Accessed: Aug. 21, 2022. [Online]. Available: https://academic.oup.com/humupd/article-abstract/18/2/146/618266

  171. Dunaif A. Drug Insight: Insulin-sensitizing drugs in the treatment of polycystic ovary syndrome - a reappraisal. Nat Clin Pract Endocrinol Metab. 2008;4(5):272–83. https://doi.org/10.1038/NCPENDMET0787.

    Article  CAS  Google Scholar 

  172. K. Blomquist, V. Milsom, R. Barnes, … A. B.-C., and undefined 2012, “Metabolic syndrome in obese men and women with binge eating disorder: developmental trajectories of eating and weight-related behaviors,” Elsevier, Accessed: Aug. 21, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0010440X12000272

  173. T Tang RJ Norman AH Balen JM Lord 2003 Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome Cochrane Database Syst Revhttps://doi.org/10.1002/14651858.CD003053

  174. G. Attia, W. Rainey, B. C.-F. and sterility, and undefined 2001, “Metformin directly inhibits androgen production in human thecal cells,” Elsevier, Accessed: Aug. 21, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0015028201019756?casa_token=kndwMryayKIAAAAA:lZrv1YXr-yJzXhJGMshXQx12j6blX0mdSjJF0myv0603DHP9XWYFSxcvTR6wUXeQO7XOJMdcya8

  175. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334(9):574–9. https://doi.org/10.1056/NEJM199602293340906.

    Article  CAS  Google Scholar 

  176. S. Thatcher, E. J.-F. and sterility, and undefined 2006, “Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin,” Elsevier, Accessed: Aug. 21, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0015028205042123?casa_token=OpclRqBuXV8AAAAA:LPjTc3bOEsCb5N0B0mrzb47b8dIUCV4uwhK3RpnFozx9JWfhzRv8iBCTXr6VMFbkWxIIPpGE9qM

  177. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod. 2002;17(11):2858–64. https://doi.org/10.1093/HUMREP/17.11.2858.

    Article  CAS  Google Scholar 

  178. R. Norman, J. Wang, W. H.-C. O. in Obstetrics, and undefined 2004, “Should we continue or stop insulin sensitizing drugs during pregnancy?,” journals.lww.com, Accessed: Aug. 21, 2022. [Online]. Available: https://journals.lww.com/co-obgyn/fulltext/2004/06000/should_we_continue_or_stop_insulin_sensitizing.7.aspx?casa_token=fkq-L3704Q0AAAAA:UXhl-h-gdaFui3IMGmuE0kZhlxWUVrnPCKD3-SxagZCdvFMLLPTSJJxh787DInABN-KLWi08qmiX_YaDqQHa7vHywaiQIQ

  179. Sreenan SK, et al. Calpains play a role in insulin secretion and action. Diabetes. 2001;50(9):2013–20. https://doi.org/10.2337/DIABETES.50.9.2013.

    Article  CAS  Google Scholar 

  180. Y. Horikawa et al., “Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus,” Nature Genetics 2000 26:2, vol. 26, no. 2, pp. 163–175, Oct. 2000, doi: https://doi.org/10.1038/79876.

  181. Gonzalez A, et al. CAPN10 alleles are associated with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87(8):3971–6. https://doi.org/10.1210/JCEM.87.8.8793.

    Article  CAS  Google Scholar 

  182. Gonzalez A, et al. Specific CAPN10 gene haplotypes influence the clinical profile of polycystic ovary patients. J Clin Endocrinol Metab. 2003;88(11):5529–36. https://doi.org/10.1210/JC.2003-030322.

    Article  CAS  Google Scholar 

  183. H. F. Escobar-Morreale, B. Peral, G. Villuendas, R. M. Calvo, J. Sancho, and J. L. San Millán, “Common single nucleotide polymorphisms in intron 3 of the calpain-10 gene influence hirsutism,” Fertility and Sterility, vol. 77, no. 3, pp. 581–587, Mar. 2002, doi: https://doi.org/10.1016/S0015-0282(01)03206-X.

  184. Willer CJ, et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet. 2009;41(1):25. https://doi.org/10.1038/NG.287.

    Article  CAS  Google Scholar 

  185. Cai X, Liu C, Mou S. Association between fat mass- and obesity- associated (FTO) gene polymorphism and polycystic ovary syndrome: a meta-analysis. PLoS ONE. 2014;9(1):e86972. https://doi.org/10.1371/JOURNAL.PONE.0086972.

    Article  Google Scholar 

  186. Rangwala SM, Lazar MA. Peroxisome proliferator-activated receptor γ in diabetes and metabolism. Trends Pharmacol Sci. 2004;25(6):331–6. https://doi.org/10.1016/J.TIPS.2004.03.012.

    Article  CAS  Google Scholar 

  187. Vidal-Puig AJ, et al. Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Investig. 1997;99(10):2416–22. https://doi.org/10.1172/JCI119424.

    Article  CAS  Google Scholar 

  188. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1996;81(9):3299–306. https://doi.org/10.1210/JCEM.81.9.8784087.

    Article  CAS  Google Scholar 

  189. Azziz R, et al. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab. 2001;86(4):1626–32. https://doi.org/10.1210/JCEM.86.4.7375.

    Article  CAS  Google Scholar 

  190. Meirhaeghe A, Amouyel P. Impact of genetic variation of PPARγ in humans. Mol Genet Metab. 2004;83(1–2):93–102. https://doi.org/10.1016/J.YMGME.2004.08.014.

    Article  CAS  Google Scholar 

  191. Urbanek M, et al. Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Proc Natl Acad Sci. 1999;96(15):8573–8. https://doi.org/10.1073/PNAS.96.15.8573.

    Article  CAS  Google Scholar 

  192. Hahn S, et al. The peroxisome proliferator activated receptor gamma Pro12Ala polymorphism is associated with a lower hirsutism score and increased insulin sensitivity in women with polycystic ovary syndrome. Clin Endocrinol. 2005;62(5):573–9. https://doi.org/10.1111/J.1365-2265.2005.02261.X.

    Article  CAS  Google Scholar 

  193. Qu F, et al. A molecular mechanism underlying ovarian dysfunction of polycystic ovary syndrome: hyperandrogenism induces epigenetic alterations in the granulosa cells. J Mol Med. 2012;90(8):911–23. https://doi.org/10.1007/S00109-012-0881-4/FIGURES/5.

    Article  CAS  Google Scholar 

  194. Meczekalski B, Katulski K, Podfigurna-Stopa A, Czyzyk A, Genazzani AD. Spontaneous endogenous pulsatile release of kisspeptin is temporally coupled with luteinizing hormone in healthy women. Elsevier. 2016;105:1345-1350.e2. https://doi.org/10.1016/j.fertnstert.2016.01.029.

    Article  CAS  Google Scholar 

  195. Katulski K, Podfigurna A, Czyzyk A, Meczekalski B, Genazzani AD. Kisspeptin and LH pulsatile temporal coupling in PCOS patients. Endocrine. 2018;61(1):149–57. https://doi.org/10.1007/S12020-018-1609-1.

    Article  CAS  Google Scholar 

  196. E. A. Coutinho and A. S. Kauffman, “The role of the brain in the pathogenesis and physiology of polycystic ovary syndrome (PCOS),” Medical Sciences, 7, 8:84, 2019, https://doi.org/10.3390/MEDSCI7080084.

  197. R. Goodman, M. Lehman, J. Smith, … L. C.-, and undefined 2007, “Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B,” academic.oup.com, Accessed: Aug. 21, 2022. [Online]. Available: https://academic.oup.com/endo/article-abstract/148/12/5752/2501543

  198. A. M. Moore, L. M. Coolen, and M. N. Lehman, “In vivo imaging of the GnRH pulse generator reveals a temporal order of neuronal activation and synchronization during each pulse,” Proc Natl Acad Sci U S A, 119, 6, 2022, https://doi.org/10.1073/PNAS.2117767119.

  199. J. Kawwass, K. Sanders, … T. L.-H., and undefined 2017, “Increased cerebrospinal fluid levels of GABA, testosterone and estradiol in women with polycystic ovary syndrome,” academic.oup.com, Accessed: Aug. 21, 2022. [Online]. Available: https://academic.oup.com/humrep/article-abstract/32/7/1450/3770406

  200. 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. https://doi.org/10.1073/PNAS.0308058101.

    Article  CAS  Google Scholar 

  201. A. Moore, M. Prescott, R. C.- Endocrinology, and undefined 2013, “Estradiol negative and positive feedback in a prenatal androgen-induced mouse model of polycystic ovarian syndrome,” academic.oup.com, Accessed: Aug. 21, 2022. [Online]. Available: https://academic.oup.com/endo/article-abstract/154/2/796/2423496

  202. Moore AM, Prescott M, Marshall CJ, Yip SH, Campbell RE, McEwen BS. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. Proc Natl Acad Sci U S A. 2015;112(2):596–601. https://doi.org/10.1073/PNAS.1415038112/SUPPL_FILE/PNAS.201415038SI.PDF.

    Article  CAS  Google Scholar 

  203. S. Chhabra, C. McCartney, … R. Y.-T. J. of, and undefined 2005, “Progesterone inhibition of the hypothalamic gonadotropin-releasing hormone pulse generator: evidence for varied effects in hyperandrogenemic adolescent girls,” academic.oup.com, Accessed: Aug. 21, 2022. [Online]. Available: https://academic.oup.com/jcem/article-abstract/90/5/2810/2836855

  204. McCartney CR, Campbell RE, Marshall JC, Moenter SM. The role of gonadotropin-releasing hormone neurons in polycystic ovary syndrome. J Neuroendocrinol. 2022. https://doi.org/10.1111/JNE.13093).

    Article  Google Scholar 

  205. C. Eagleson, M. Gingrich, … C. P.-T. J. of, and undefined 2000, “Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and,” academic.oup.com, Accessed: Aug. 21, 2022. [Online]. Available: https://academic.oup.com/jcem/article-abstract/85/11/4047/2852619

  206. Dulka EA, Burger LL, Moenter SM. Ovarian androgens maintain high GnRH neuron firing rate in adult prenatally-androgenized female mice. Endocrinology. 2020;161(1):1–14. https://doi.org/10.1210/endocr/bqz038.

    Article  CAS  Google Scholar 

  207. M. Silva, M. Prescott, R. C.-J. insight, and undefined 2018, “Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS,” ncbi.nlm.nih.gov, Accessed: Aug. 21, 2022. [Online]. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928858/

  208. Wang C, Wen Y-X, Mai Q-Y. Impact of metabolic disorders on endometrial receptivity in patients with polycystic ovary syndrome. Exp Ther Med. 2022;23(3):221. https://doi.org/10.3892/ETM.2022.11145).

    Article  Google Scholar 

  209. G. F. Erickson and S. Shimasaki, “The spatiotemporal expression pattern of the bone morphogenetic protein family in rat ovary cell types during the estrous cycle,” Reproductive Biology and Endocrinology, 1, 2003, https://doi.org/10.1186/1477-7827-1-9

  210. S. Shimasaki, R. Moore, … F. O.-E., and undefined 2004, “The bone morphogenetic protein system in mammalian reproduction,” academic.oup.com, Accessed: Aug. 22, 2022. [Online]. Available: https://academic.oup.com/edrv/article-abstract/25/1/72/2355266

  211. Elvin JA, Yan C, Matzuk MM. Oocyte-expressed TGF-β superfamily members in female fertility. Mol Cell Endocrinol. 2000;159(1–2):1–5. https://doi.org/10.1016/S0303-7207(99)00185-9.

    Article  CAS  Google Scholar 

  212. Baarends WM, et al. Anti-müllerian hormone and anti-müllerian hormone type II receptor messenger ribonucleic acid expression in rat ovaries during postnatal development, the estrous cycle, and gonadotropin-induced follicle growth. Endocrinol. 1995;136(11):4951–62. https://doi.org/10.1210/ENDO.136.11.7588229.

    Article  CAS  Google Scholar 

  213. von Schalburg KR, Mccarthy SP, Rise ML, Hutson JC, Davidson WS, Koop BF. Expression of morphogenic genes in mature ovarian and testicular tissues: potential stem-cell niche markers and patterning factors. Wiley Online Library. 2006;73(2):142–52. https://doi.org/10.1002/mrd.20359.

    Article  CAS  Google Scholar 

  214. A. Bourret et al., “BMP system expression in GCs from polycystic ovary syndrome women and the in vitro effects of BMP4, BMP6, and BMP7 on GC steroidogenesis,” researchgate.net, 2012, https://doi.org/10.1530/EJE-12-0891.

  215. A. Fatehi, R. van den Hurk, B. C.- Theriogenology, and undefined 2005, “Expression of bone morphogenetic protein2 (BMP2), BMP4 and BMP receptors in the bovine ovary but absence of effects of BMP2 and BMP4 during IVM on bovine,” Elsevier, Accessed: Aug. 22, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0093691X04001645

  216. J. Visser, F. de Jong, … J. L.-, and undefined 2006, “Anti-Mullerian hormone: a new marker for ovarian function,” rep.bioscientifica.com, Accessed: Aug. 22, 2022. [Online]. Available: https://rep.bioscientifica.com/view/journals/rep/131/1/1310001.xml

  217. E. L. A. F. van Houten, J. S. E. Laven, Y. v. Louwers, A. McLuskey, A. P. N. Themmen, and J. A. Visser, “Bone morphogenetic proteins and the polycystic ovary syndrome,” Journal of Ovarian Research, 6, 1:1–4, 2013, https://doi.org/10.1186/1757-2215-6-32/TABLES/1.

  218. Y. Han et al., “Mesenchymal stem cells for regenerative medicine,” mdpi.com, 2019, https://doi.org/10.3390/cells8080886.

  219. J. Zhang et al., “The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy,” Stem Cell Research and Therapy, vol. 6, no. 1, Dec. 2015, doi: https://doi.org/10.1186/S13287-015-0240-9.

  220. M. Ullah, D. D. Liu, and A. S. Thakor, “Mesenchymal stromal cell homing: mechanisms and strategies for improvement,” iScience, 15:421–438, 2019, https://doi.org/10.1016/J.ISCI.2019.05.004.

  221. Chapel A, et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J Gene Med. 2003;5(12):1028–38. https://doi.org/10.1002/JGM.452.

    Article  Google Scholar 

  222. A. J. Braga Osorio Gomes Salgado et al., “Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine,” Current Stem Cell Research & Therapy, 5, 2:103–110, 2010, https://doi.org/10.2174/157488810791268564.

  223. Fan XL, Zhang Y, Li X, Fu QL. Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell Mol Life Sci. 2020;77(14):2771–94. https://doi.org/10.1007/S00018-020-03454-6.

    Article  CAS  Google Scholar 

  224. Q. Xie et al., “Mesenchymal stem cells alleviate DHEA-induced polycystic ovary syndrome (PCOS) by inhibiting inflammation in mice,” hindawi.com, Accessed: Aug. 22, 2022. [Online]. Available: https://www.hindawi.com/journals/sci/2019/9782373/

  225. Z. KALHORI, M. AZADBAKHT, M. SOLEIMANI MEHRANJANI, and M. A. SHARIATZADEH, “Improvement of the folliculogenesis by transplantation of bone marrow mesenchymal stromal cells in mice with induced polycystic ovary syndrome,” Cytotherapy, 20, 12:1445–1458, 2018, https://doi.org/10.1016/J.JCYT.2018.09.005

  226. R. M. Chugh et al., “Mesenchymal stem cell therapy ameliorates metabolic dysfunction and restores fertility in a PCOS mouse model through interleukin-10,” Stem Cell Research and Therapy, 12, 1, 2021, https://doi.org/10.1186/S13287-021-02472-W.

  227. Marti N, Bouchoucha N, Sauter KS, Flück CE. Resveratrol inhibits androgen production of human adrenocortical H295R cells by lowering CYP17 and CYP21 expression and activities. PLoS ONE. 2017;12(3):e0174224. https://doi.org/10.1371/JOURNAL.PONE.0174224.

    Article  Google Scholar 

  228. P Kempná G Hofer P Mullis CF-M Pharmacology undefined, 2007 Pioglitazone inhibits androgen production in NCI-H295R cells by regulating gene expression of CYP17 and HSD3B2 ASPET 2006https://doi.org/10.1124/mol.106.028902

  229. I. Dilogo, J. Fiolin, P. A.-A. S. Letters, and undefined 2018, “Osteogenic potency of secretome bone marrow derived mesenchymal stem cells: a literature review,” ingentaconnect.com, Accessed: Aug. 22, 2022. [Online]. Available: https://www.ingentaconnect.com/contentone/asp/asl/2018/00000024/00000008/art00148

  230. Polacek M, Bruun J-A, Elvenes J, Figenschau Y, Martinez I. The secretory profiles of cultured human articular chondrocytes and mesenchymal stem cells: implications for autologous cell transplantation strategies. Cell Transplant. 2011;20:1381–93. https://doi.org/10.3727/096368910X550215.

    Article  Google Scholar 

  231. Hashimoto O, Moore RK, Shimasaki S. Posttranslational processing of mouse and human BMP-15: potential implication in the determination of ovulation quota. Proc Natl Acad Sci. 2005;102(15):5426–31. https://doi.org/10.1073/PNAS.0409533102.

    Article  CAS  Google Scholar 

  232. Yoshino O, et al. The function of bone morphogenetic proteins in the human ovary. Springer. 2011;10(1):1–7. https://doi.org/10.1007/s12522-010-0072-3.

    Article  CAS  Google Scholar 

  233. N. Xu et al., “Epigenetic mechanism underlying the development of polycystic ovary syndrome (PCOS)-like phenotypes in prenatally androgenized rhesus monkeys,” PLoS ONE, 6, 11, 2011, https://doi.org/10.1371/JOURNAL.PONE.0027286.

  234. A. A. Bremer, “Polycystic ovary syndrome in the pediatric population,” https://home.liebertpub.com/met, vol. 8, no. 5, pp. 375–394, Oct. 2010, doi: https://doi.org/10.1089/MET.2010.0039.

  235. R. Rosenfield, D. E.-E. reviews, and undefined 2016, “The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited,” academic.oup.com, Accessed: Aug. 22, 2022. [Online]. Available: https://academic.oup.com/edrv/article-abstract/37/5/467/2567094

  236. Zhang J, et al. Effect of bone morphogenetic protein-2 on proliferation and apoptosis of gastric cancer cells. Int J Med Sci. 2012;9(2):184. https://doi.org/10.7150/IJMS.3859.

    Article  CAS  Google Scholar 

  237. J. Hardwick, G. van den Brink, S. B.- Gastroenterology, and undefined 2004, “Bone morphogenetic protein 2 is expressed by, and acts upon, mature epithelial cells in the colon,” Elsevier, Accessed: Aug. 22, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0016508503017359

  238. R. Chugh, H. Park, S. Esfandyari, … A. E.-I. journal of, and undefined 2021, “Mesenchymal stem cell-conditioned media regulate steroidogenesis and inhibit androgen secretion in a PCOS cell model via BMP-2,” mdpi.com, Accessed: Aug. 22, 2022. [Online]. Available: https://www.mdpi.com/1243468

  239. M. Sewer, M. W.- Endocrinology, and undefined 2002, “Adrenocorticotropin/cyclic adenosine 3′, 5′-monophosphate-mediated transcription of the human CYP17 gene in the adrenal cortex is dependent on phosphatase,” academic.oup.com, Accessed: Aug. 22, 2022. [Online]. Available: https://academic.oup.com/endo/article-abstract/143/5/1769/2989540

  240. P. Kempná, G. Hofer, P. Mullis, C. F.-M. Pharmacology, and undefined 2007, “Pioglitazone inhibits androgen production in NCI-H295R cells by regulating gene expression of CYP17 and HSD3B2,” ASPET, Accessed: Aug. 22, 2022. [Online]. Available: https://molpharm.aspetjournals.org/content/71/3/787.short

  241. Huang X, et al. Modulation of expression of 17-Hydroxylase/17,20 lyase (CYP17) and P450 aromatase (CYP19) by inhibition of MEK1 in a human ovarian granulosa-like tumor cell line. Gynecol Endocrinol. 2016;32(3):201–5. https://doi.org/10.3109/09513590.2015.1106470.

    Article  Google Scholar 

  242. F. Diomede et al., “Non-cytokine protein profile of the mesenchymal stem cell secretome that regulates the androgen production pathway,” mdpi.com, 2022, doi: https://doi.org/10.3390/ijms23094633.

  243. C. DeUgarte, A. Bartolucci, R. A.-F. and sterility, and undefined 2005, “Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment,” Elsevier, Accessed: Aug. 22, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0015028205003730?casa_token=5wfGPsSz3xUAAAAA:kvoTklN6j9wD9udaRIAdKHWe6XQn-ItidYYoUWLB76_9p34ULtUGXm-WLyOZRdppdVwCPVjUf7g

  244. M. Ángeles Martínez-García, S. Moncayo, M. Insenser, F. Álvarez-Blasco, M. Luque-Ramírez, and H. F. Escobar-Morreale, “Metabolic cytokines at fasting and during macronutrient challenges: influence of obesity, female androgen excess and sex,” mdpi.com, vol. 11, p. 2566, 2019, doi: https://doi.org/10.3390/nu11112566.

  245. 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. https://doi.org/10.1210/ER.2011-1034.

    Article  CAS  Google Scholar 

  246. A. C. McPherron, A. M. Lawler, and S. J. Lee, “Regulation of skeletal muscle mass in mice by a new TGF-p superfamily member,” Nature 1997 387:6628, vol. 387, no. 6628, pp. 83–90, May 1997, doi: https://doi.org/10.1038/387083a0.

  247. H. Chang, J. Qiao, P. L.-H. reproduction update, and undefined 2017, “Oocyte–somatic cell interactions in the human ovary—novel role of bone morphogenetic proteins and growth differentiation factors,” academic.oup.com, Accessed: Aug. 22, 2022. [Online]. Available: https://academic.oup.com/humupd/article-abstract/23/1/1/2334872

  248. McPherron AC, Lee S-J. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Investig. 2002;109(5):595–601. https://doi.org/10.1172/JCI13562.

    Article  CAS  Google Scholar 

  249. Park JJ, Berggren JR, Hulver MW, Houmard JA, Hoffman EP. GRB14, GPD1, and GDF8 as potential network collaborators in weight loss-induced improvements in insulin action in human skeletal muscle. Physiol Genomics. 2006;27(2):114–21. https://doi.org/10.1152/PHYSIOLGENOMICS.00045.2006.

    Article  CAS  Google Scholar 

  250. L. Bai, W. Wang, Y. Xiang, S. Wang, … S. W.-M. T.-N., and undefined 2021, “Aberrant elevation of GDF8 impairs granulosa cell glucose metabolism via upregulating SERPINE1 expression in patients with PCOS,” Elsevier, Accessed: Aug. 22, 2022. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S2162253120303619

  251. S. Risal et al., “Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome,” Nature Medicine 2019 25:12, vol. 25, no. 12, pp. 1894–1904, Dec. 2019, doi: https://doi.org/10.1038/s41591-019-0666-1.

  252. Y. Shi et al., “Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome,” Nature Genetics 2012 44:9, vol. 44, no. 9, pp. 1020–1025, Aug. 2012, doi: https://doi.org/10.1038/ng.2384.

  253. Z. Chen et al., “Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16. 3, 2p21 and 9q33. 3,” nature.com, Accessed: Aug. 22, 2022. [Online]. Available: https://www.nature.com/articles/ng.732

  254. Wood JR, Dumesic DA, Abbott DH, Strauss JF. Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis. J Clin Endocrinol Metab. 2007;92(2):705–13. https://doi.org/10.1210/JC.2006-2123.

    Article  CAS  Google Scholar 

  255. Haouzi D, Assou S, Monzo C, Vincens C, Dechaud H, Hamamah S. Altered gene expression profile in cumulus cells of mature MII oocytes from patients with polycystic ovary syndrome. Hum Reprod. 2012;27(12):3523–30. https://doi.org/10.1093/HUMREP/DES325.

    Article  CAS  Google Scholar 

  256. J. Li et al., “Molecular features of polycystic ovary syndrome revealed by transcriptome analysis of oocytes and cumulus cells,” Frontiers in Cell and Developmental Biology, vol. 9, Sep. 2021, doi: https://doi.org/10.3389/FCELL.2021.735684/FULL.

  257. Francisco V, et al. Adipokines: Linking metabolic syndrome, the immune system, and arthritic diseases. Biochem Pharmacol. 2019;165:196–206. https://doi.org/10.1016/J.BCP.2019.03.030.

    Article  CAS  Google Scholar 

  258. van Elten TM, et al. Preconception lifestyle intervention reduces long term energy intake in women with obesity and infertility: a randomised controlled trial 11 Medical and Health Sciences 1117 Public Health and Health Services 11 Medical and Health Sciences 1111 Nutrition and Dietetics. Int J Behav Nutr Phys Act. 2019;16(1):1–10. https://doi.org/10.1186/S12966-018-0761-6/FIGURES/3.

    Article  Google Scholar 

  259. Talukdar S, et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nature Med. 2012;18(9):1407–12. https://doi.org/10.1038/nm.2885.

    Article  CAS  Google Scholar 

  260. N. J. Su et al., “The peripheral blood transcriptome identifies dysregulation of inflammatory response genes in polycystic ovary syndrome,” https://doi.org/10.1080/09513590.2017.1418851, 34, 7:584–588, 2017, https://doi.org/10.1080/09513590.2017.1418851.

  261. González F. Inflammation in polycystic ovary syndrome: underpinning of insulin resistance and ovarian dysfunction. Steroids. 2012;77(4):300–5. https://doi.org/10.1016/J.STEROIDS.2011.12.003.

    Article  Google Scholar 

  262. Bilbo SD, Klein SL. special issue: the neuroendocrine-immune axis in health and disease. Horm Behav. 2012;62(3):187–90. https://doi.org/10.1016/J.YHBEH.2012.06.005.

    Article  Google Scholar 

  263. Li R, Albertini DF. The road to maturation: somatic cell interaction and self-organization of the mammalian oocyte. Nature Rev Mol Cell Biol. 2013;14(3):141–52. https://doi.org/10.1038/nrm3531.

    Article  CAS  Google Scholar 

  264. L. A. Jaffe and J. R. Egbert, “Regulation of mammalian oocyte meiosis by intercellular communication within the ovarian follicle,” http://dx.doi.org/https://doi.org/10.1146/annurev-physiol-022516-034102, 79, 237–260, 2017, https://doi.org/10.1146/ANNUREV-PHYSIOL-022516-034102.

  265. Boots CE, Jungheim ES. Inflammation and human ovarian follicular dynamics. Sem Reprod Med. 2015;33(4):270–5. https://doi.org/10.1055/S-0035-1554928/ID/JR00947A-42.

    Article  CAS  Google Scholar 

  266. Duffy DM, Ko C, Jo M, Brannstrom M, Curry TE. Ovulation: parallels with inflammatory processes. Endocr Rev. 2019;40(2):369–416. https://doi.org/10.1210/ER.2018-00075.

    Article  Google Scholar 

  267. Fitzgerald KA, Kagan JC. Toll-like receptors and the control of immunity. Cell. 2020;180(6):1044–66. https://doi.org/10.1016/J.CELL.2020.02.041.

    Article  CAS  Google Scholar 

  268. Barton GM, Kagan JC. A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nature Rev Immunol. 2009;9(8):535–42. https://doi.org/10.1038/nri2587.

    Article  CAS  Google Scholar 

  269. K. Hoshino et al., “Cutting Edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the lps gene product,” The Journal of Immunology, 162, 7, 1999

  270. K. v. Swanson, M. Deng, and J. P. Y. Ting, “The NLRP3 inflammasome: molecular activation and regulation to therapeutics,” Nature Reviews Immunology, 19, 8:477–489, 2019, https://doi.org/10.1038/s41577-019-0165-0

  271. Zhao C, Zhao W. NLRP3 inflammasome—a key player in antiviral responses. Front Immunol. 2020;11:211. https://doi.org/10.3389/FIMMU.2020.00211/BIBTEX.

    Article  CAS  Google Scholar 

  272. M. H. Park and J. T. Hong, “Roles of NF-κB in cancer and inflammatory diseases and their therapeutic approaches,” Cells 2016, 5, 15, 5, 2, 15, 2016, https://doi.org/10.3390/CELLS5020015

  273. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol Cell. 2002;10(2):417–26. https://doi.org/10.1016/S1097-2765(02)00599-3.

    Article  CAS  Google Scholar 

  274. Popovic M, Sartorius G, Christ-Crain M. Chronic low-grade inflammation in polycystic ovary syndrome: is there a (patho)-physiological role for interleukin-1? Seminars in Immunopathology. 2019;41(4):447–59. https://doi.org/10.1007/S00281-019-00737-4/FIGURES/2.

    Article  Google Scholar 

  275. Li S, Zhang L, Wei N, Tai Z, Yu C, Xu Z. Research progress on the effect of epilepsy and antiseizure medications on PCOS through HPO Axis. Front Endocrinol. 2021;12:1710. https://doi.org/10.3389/FENDO.2021.787854/BIBTEX.

    Article  Google Scholar 

  276. L. Jin, J. Yu, Y. Chen, H. Pang, J. Sheng, and H. Huang, “Polycystic ovary syndrome and risk of five common psychiatric disorders among European women: a two-sample Mendelian randomization study,” Frontiers in Genetics, 12, 2021, https://doi.org/10.3389/FGENE.2021.689897/FULL

  277. T. Sir-Petermann, M. Maliqueo, … E. C.-T. J. of, and undefined 2007, “Early metabolic derangements in daughters of women with polycystic ovary syndrome,” academic.oup.com, Accessed: Aug. 22, 2022. [Online]. Available: https://academic.oup.com/jcem/article-abstract/92/12/4637/2597088

  278. Ibáñez L, Potau N, Zampolli M, RiquÉ S, Saenger P, Carrascosa A. Hyperinsulinemia and decreased insulin-like growth factor-binding protein-1 are common features in prepubertal and pubertal girls with a history of premature pubarche. J Clin Endocrinol Metab. 1997;82(7):2283–8. https://doi.org/10.1210/JCEM.82.7.4084.

    Article  Google Scholar 

  279. S. Persson, E. Elenis, S. Turkmen, … M. K.-H., and undefined 2019, “Fecundity among women with polycystic ovary syndrome (PCOS)—a population-based study,” academic.oup.com, Accessed: Aug. 22, 2022. [Online]. Available: https://academic.oup.com/humrep/article-abstract/34/10/2052/5556931

  280. E. Elenis, E. Desroziers, S. Persson, I. Sundström Poromaa, and R. E. Campbell, “Early initiation of anti-androgen treatment is associated with increased probability of spontaneous conception leading to childbirth in women with polycystic ovary syndrome: a population-based multiregistry cohort study in Sweden,” Human Reproduction, 36, 5:1427–1435, 2021, https://doi.org/10.1093/HUMREP/DEAA357

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar, Pradesh -202002, India

    Sana Siddiqui, Somaiya Mateen, Rizwan Ahmad & Shagufta Moin

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  1. Sana Siddiqui
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The idea for this review article was given by Shagufta Moin and Somaiya Mateen; the literature search and data analysis were performed by Sana Siddiqui; this review article was drafted by Sana Siddiqui and Rizwan Ahmad; the work was critically revised by Somaiya Mateen and Shagufta Moin.

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Correspondence to Shagufta Moin.

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Siddiqui, S., Mateen, S., Ahmad, R. et al. A brief insight into the etiology, genetics, and immunology of polycystic ovarian syndrome (PCOS). J Assist Reprod Genet 39, 2439–2473 (2022). https://doi.org/10.1007/s10815-022-02625-7

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