Pathophysiological mechanisms of gonadotropins– and steroid hormones–related genes in etiology of polycystic ovary syndrome

Document Type : Review Article

Authors

1 Department of Animal Science, College of Agriculture, Shiraz University, Shiraz, Iran

2 Research and Clinical Center for Infertility, Yazd Reproduction Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

3 The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran

Abstract

Objective(s): Polycystic ovary syndrome (PCOS) is an endocrinopathy in women, which, unlike its impact on fertility and health of women, there is no clear understanding about the causal mechanisms of this pathogenesis. The aim of this review paper is to investigate the pathophysiological pathways affecting the PCOS etiology, based on functions of gonadotropins– and steroid hormones–related genes.
Materials and Methods: Due to different hormonal and metabolic signs of this complex disorder, different hypotheses are mentioned about etiology of this syndrome. Because of the heterogeneity of the reasons given for this syndrome and the spread of the effective genes in its pathophysiology, most of genes affected by sex-related hormonal imbalances are examined for discriminative diagnosis. For this purpose, published articles and reviews dealing with genetic evaluation of PCOS in women in peer-reviewed journals in PubMed and Google Scholar databases were included in this review.
Results: In previous studies, it has been well demonstrated that PCOS in some individuals have a genetic origin. Pathophysiological functions of genes are primarily responsible for the synthesis of proteins that have role in PCOS before hyperandrogenism including GnRHR, FSHβ, FSHR, LHCGR, CYP19A1, HSD17B, AR and SHBG, and their effects in PCOS of human have been confirmed.
Conclusion: Hormonal imbalances are the first reason mentioned in PCOS etiology, and usually characterized with menstrual irregularities in PCOS women. Hyperandrogenism and gonadotropin secretion disorders are shown in PCOS condition, which are related to steroidogenesis pathways and hypothalamic–pituitary–ovarian axis disturbances, respectively.

Keywords

Main Subjects


1. De Leo V, Musacchio M, Cappelli V, Massaro M, Morgante G, Petraglia F. Genetic, hormonal and metabolic aspects of PCOS: an update. Reprod Biol Endocrinol 2016;14:38-54.
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 (PCOS). Hum Reprod 2004;19:41-47.
3. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. Criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an androgen excess society guideline. J Clin Endocrinol Metab 2006;91:4237-4245.
4. Fenichel P, Rougier C, Hieronimus S, Chevalier N. Which origin for polycystic ovaries syndrome: Genetic, environmental or both? Ann Endocrinol 2017;78:176-185.
5. Guo M, Chen Z, Eijkemans M, Goverde A, Fauser B, Macklon N. Comparison of the phenotype of Chinese versus Dutch Caucasian women presenting with polycystic ovary syndrome and oligo/amenorrhoea. Hum Reprod 2012;27:1481-1488.
6. Strauss III JF, McAllister JM, Urbanek M. Persistence pays off for PCOS gene prospectors. J Clin Endocrinol Metab 2012;97:2286-2288.
7. Deligeoroglou E, Kouskouti C, Christopoulos P. The role of genes in the polycystic ovary syndrome: predisposition and mechanisms. Gynecol Endocrinol 2009;25:603-609.
8. Roland AV, Moenter SM. Reproductive neuroendocrine dysfunction in polycystic ovary syndrome: insight from animal models. Front Neuroendocrinol 2014;35:494-511.
9. Shaaban Z, Jafarzadeh Shirazi MR, Nooranizadeh MH, Tamadon A, Rahmanifar F, Ahmadloo S, et al. Decrease in arginine-phenylalanine-amide-related peptide-3 gene expression of dorsomedial hypothalamic nucleus in constant light exposure model of polycystic ovarian syndrome. Int J Fertil Steril 2018;12:43-50.
10. Rosenfield RL, Ehrmann DA. The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev 2016;37:467-520.
11. Luque-Ramírez M, San Millán JL, Escobar-Morreale HF. Genomic variants in polycystic ovary syndrome. Clin Chim Acta 2006;366:14-26.
12. Nestler JE. Modulation of aromatase and P450 cholesterol side-chain cleavage enzyme activities of human placental cytotrophoblasts by insulin and insulin-like growth factor I. Endocrinology 1987;121:1845-1852.
13. Sir-Petermann T, Maliqueo M, Angel B, Lara H, Perez-Bravo F, Recabarren S. Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum Reprod 2002;17:2573-2579.
14. Kosova G, Urbanek M. Genetics of the polycystic ovary syndrome. Mol Cell Endocrinol 2013;373:29-38.
15. Roldán B, San Millán JL, Escobar-Morreale HF. Genetic basis of metabolic abnormalities in polycystic ovary syndrome. Am J Pharmacogenomics 2004;4:93-107.
16. Goodarzi MO, Azziz R. Diagnosis, epidemiology, and genetics of the polycystic ovary syndrome. Best Practice & Research: Clin Endocrinol Metabol 2006;20:193-205.
17. Barber TM, Franks S. Genetics of polycystic ovary syndrome. Front Horm Res 2013;40:28-39.
18. Jones MR, Goodarzi MO. Genetic determinants of polycystic ovary syndrome: progress and future directions. Fertil Steril 2016;106:25-32.
19. Chen Z-J, Zhao H, He L, Shi Y, Qin Y, Shi Y, et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16. 3, 2p21 and 9q33. 3. Nat Genet 2011;43:55-59.
20. Shi Y, Zhao H, Shi Y, Cao Y, Yang D, Li Z, et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet 2012;44:1020-1025.
21. 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.
22. Welt CK, Styrkarsdottir U, Ehrmann DA, Thorleifsson G, Arason G, Gudmundsson JA, et al. Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry. J Clin Endocrinol Metab 2012;97:E1342-E1347.
23. Brower MA, Jones MR, Rotter JI, Krauss RM, Legro RS, Azziz R, et al. Further investigation in europeans of susceptibility variants for polycystic ovary syndrome discovered in genome-wide association studies of Chinese individuals. J Clin Endocrinol Metab 2015;100:E182-E186.
24. Moore AM, Campbell RE. The neuroendocrine genesis of polycystic ovary syndrome: a role for arcuate nucleus GABA neurons. J Steroid Biochem Mol Biol 2016;160:106-117.
25. Carmel P, Araki S, Ferin M. Pituitary stalk portal blood collection in rhesus monkeys: evidence for pulsatile release of gonadotropin-releasing hormone (GnRH). Endocrinology 1976;99:243-248.
26. Barzegar MH, Khazali H, Kalantar SM, Khoradmehr A. The comparative effect of Citrullus colocynthis hydro-alcoholic extract (CCT) and metformin on morphometric ovarian follicles disorders in estradilol valerate Iinduced PCOS rats. Galen Med J 2018;7:In press.
27. Medissa H, Hunter J. Polycystic ovary syndrome: its not just infertility. Am Fam Physician 2000;62:1079-1088.
28. Shoham Z, Jacobs HS, Insler V. Luteinizing hormone: its role, mechanism of action, and detrimental effects when hypersecreted during the follicular phase. Fertil Steril 1993;59:1153-1161.
29. Dufau ML. The luteinizing hormone receptor. Annu Rev Physiol 1998;60:461-496.
30. Almawi WY, Hubail B, Arekat DZ, Al-Farsi SM, Al-Kindi SK, Arekat MR, et al. Leutinizing hormone/choriogonadotropin receptor and follicle stimulating hormone receptor gene variants in polycystic ovary syndrome. J Assist Reprod Genet 2015;32:607-614.
31. Sheikhha MH, Kalantar SM, Ghasemi N. Genetics of polycystic ovary syndrome. Int J Reprod BioMed 2007;5:1-5.
32. Ubuka T, Morgan K, Pawson AJ, Osugi T, Chowdhury VS, Minakata H, et al. Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis. PLoS ONE 2009;4:e8400.
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;101:2178-2184.
34. Caburet S, Fruchter RB, Legois B, Fellous M, Shalev S, Veitia RA. A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome. Eur J Endocrinol 2017;176:K9-K14.
35. Li Q, Yang G, Wang Y, Zhang X, Sang Q, Wang H, et al. Common genetic variation in the 3′-untranslated region of gonadotropin-releasing hormone receptor regulates gene expression in cella and is associated with thyroid function, insulin secretion as well as insulin sensitivity in polycystic ovary syndrome patients. Hum Genet 2011;129:553-561.
36. Batista MCP, de Fatima Duarte E, dos Reis Borba MD, Zingler E, Mangussi-Gomes J, dos Santos BTA, et al. Trp28Arg/Ile35Thr LHB gene variants are associated with elevated testosterone levels in women with polycystic ovary syndrome. Gene 2014;550:68-73.
37. El‐Shal AS, Zidan HE, Rashad NM, Abdelaziz AM, Harira MM. Association between genes encoding components of the Leutinizing hormone/Luteinizing hormone–choriogonadotrophin receptor pathway and polycystic ovary syndrome in Egyptian women. IUBMB life 2016;68:23-36.
38. Hayes MG, Urbanek M, Ehrmann DA, Armstrong LL, Lee JY, Sisk R, et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun 2015;6:7502.
39. Liaqat I, Jahan N, Krikun G, Taylor HS. Genetic polymorphisms in Pakistani women with polycystic ovary syndrome. Reprod Sci 2015;22:347-357.
40. Goodarzi MO, Jones MR, Li X, Chua AK, Garcia OA, Chen Y-DI, et al. Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J Med Genet 2011;49:90-95.
41. Eriksen MB, Brusgaard K, Andersen M, Tan Q, Altinok ML, Gaster M, et al. Association of polycystic ovary syndrome susceptibility single nucleotide polymorphism rs2479106 and PCOS in Caucasian patients with PCOS or hirsutism as referral diagnosis. Eur J Obstet Gynecol Reprod Biol 2012;163:39-42.
42. Bassiouny YA, Rabie WA, Hassan AA, Darwish RK. Association of the luteinizing hormone/choriogonadotropin receptor gene polymorphism with polycystic ovary syndrome. Gynecological Endocrinol 2014;30:428-430.
43. Thathapudi S, Kodati V, Erukkambattu J, Addepally U, Qurratulain H. Association of luteinizing hormone chorionic gonadotropin receptor gene polymorphism (rs2293275) with polycystic ovarian syndrome. Genet Test Mol Biomarkers 2015;19:128-132.
44. Chen D-J, Ding R, Cao J-Y, Zhai J-X, Zhang J-X, Ye D-Q. Two follicle-stimulating hormone receptor polymorphisms and polycystic ovary syndrome risk: a meta-analysis. Eur J Obstet Gynecol Reprod Biol 2014;182:27-32.
45. Kambalachenu H, Durairaj Paul S, Nellepalli S, Venkatachalam P. Study on follicle stimulating hormone receptor gene polymorphism in South Indian women with polycystic ovarian syndrome. Am J Med 2013;4:160-167.
46. Saxena R, Georgopoulos N, Braaten T, Bjonnes A, Koika V, Panidis D, et al. Han Chinese polycystic ovary syndrome risk variants in women of European ancestry: relationship to FSH levels and glucose tolerance. Hum Reprod 2015;30:1454-1459.
47. Abdel-Aziz A, El-Sokkary A, El-Refaeey A, El-Sokkary M, Osman H, El-Saeed RA. Association between follicle stimulating hormone receptor (FSHR) polymorphism and polycystic ovary syndrome among Egyptian women. Int J Biochem Res Rev 2015;5:198-206.
48. Qiu L, Liu J, Hei Q-m. Association between two polymorphisms of follicle stimulating hormone receptor gene and susceptibility to polycystic ovary syndrome: a meta-analysis. Chin Med Sci J 2015;30:44-50.
49. Jones M, Wilson S, Mullin B, Mead R, Watts G, Stuckey B. Polymorphism of the follistatin gene in polycystic ovary syndrome. Mol Human Reprod 2007;13:237-241.
50. Tucci S, Futterweit W, Concepcion ES, Greenberg DA, Villanueva R, Davies TF, 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;86:446-449.
51. Dasgupta S, Pisapati S, Kudugunti N, Kathragadda A, Godi S, Reddy M. Does follistatin gene have any direct role in the manifestation of polycystic ovary syndrome in Indian women? J Postgrad Med 2012;58:190-193.
52. Wang B, Zhou S, Wang J, Liu J, Ni F, Yan J, et al. Identification of novel missense mutations of GDF9 in Chinese women with polycystic ovary syndrome. Reprod Biomed Online 2010;21:344-348.
53. Kaiser UB. GnRH receptor signalling. Endocr Abst 2012;29 S25.21.
54. Cohen DP, Stein EM, Li Z, Matulis CK, Ehrmann DA, Layman LC. Molecular analysis of the gonadotropin-releasing hormone receptor in patients with polycystic ovary syndrome. Fertil Steril 1999;72:360-363.
55. Barzegar MH, Khazali H, Kalantar SM, Khoradmehr A. Effect of Citrullus colocynthis hydro-alcoholic extract on hormonal and folliculogenesis process in estradiol valerate-induced PCOS rat model: An experimental study. Int J Reprod Biomed 2017;15:661-668.
56. Fan QR, Hendrickson WA. Structure of human follicle-stimulating hormone in complex with its receptor. Nature 2005;433:269-277.
57. Meduri G, Bachelot A, Cocca M, Vasseur C, Rodien P, Kuttenn F, et al. Molecular pathology of the FSH receptor: new insights into FSH physiology. Mol Cell Endocrinol 2008;282:130-142.
58. Shimoda C, Koh E, Yamamoto K, Matsui F, Sugimoto K, Sin HS, et al. Single nucleotide polymorphism analysis of the folliclestimulating hormone (FSH) receptor in Japanese with male infertility: identification of codon combination with heterozygous variations of the two discrete FSH receptor gene. Endocr J 2009;56:859-865.
59. Capalbo A, Sagnella F, Apa R, Fulghesu A, Lanzone A, Morciano A, et al. The 312N variant of the luteinizing hormone/choriogonadotropin receptor gene (LHCGR) confers up to 2· 7‐fold increased risk of polycystic ovary syndrome in a Sardinian population. Clin Endocrinol 2012;77:113-119.
60. Sang Q, Zhang S, Zou S, Wang H, Feng R, Li Q, et al. Quantitative analysis of follistatin (FST) promoter methylation in peripheral blood of patients with polycystic ovary syndrome. Reprod Biomed Online 2013;26:157-163.
61. Schneyer A, Sidis Y, Xia Y, Saito S, del Re E, Lin HY, et al. Differential actions of follistatin and follistatin-like 3. Mol Cell Endocrinol 2004;225:25-28.
62. Phillips DJ, de Kretser DM. Follistatin: a multifunctional regulatory protein. Front Neuroendocrinol 1998;19:287-322.
63. Tsutsui K, Saigoh E, Ukena K, Teranishi H, Fujisawa Y, Kikuchi M, et al. A novel avian hypothalamic peptide inhibiting gonadotropin release. Biochem Biophys Res Commun 2000;275:661-667.
64. Salehi MS, Tamadon A, Jafarzadeh Shirazi MR, Namavar MR, Zamiri MJ. The role of arginine-phenylalanine-amide-related peptides in mammalian reproduction. Int J Fertil Steril 2015;9:268-276.
65. Zhang Y, Li S, Liu Y, Lu D, Chen H, Huang X, et al. Structural diversity of the GnIH/GnIH receptor system in teleost: its involvement in early development and the negative control of LH release. Peptides 2010;31:1034-1043.
66. Jafarzadeh Shirazi MR, Pazoohi F, Zamiri MJ, Salehi MS, Namavar MR, Tamadon A, et al. Expression of RFamide-related peptide in the dorsomedial nucleus of hypothalamus during the estrous cycle of rats. Physiol Pharmacol 2013;17:72-79.
67. Kriegsfeld LJ, Mei DF, Bentley GE, Ubuka T, Mason AO, Inoue K, et al. Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals. Proc Natl Acad Sci U S A Biol Sci 2006;103:2410-2415.
68. Rizwan MZ, Porteous R, Herbison AE, Anderson GM. Cells expressing RFamide-related peptide-1/3, the mammalian gonadotropin-inhibitory hormone orthologs, are not hypophysiotropic neuroendocrine neurons in the rat. Endocrinology 2008;150:1413-1420.
69. Clarke IJ, Sari IP, Qi Y, Smith JT, Parkington HC, Ubuka T, et al. Potent action of RFamide-related peptide-3 on pituitary gonadotropes indicative of a hypophysiotropic role in the negative regulation of gonadotropin secretion. Endocrinology 2008;149:5811-5821.
70. Jafarzadeh Shirazi M, Zamiri M, Salehi M, Moradi S, Tamadon A, Namavar M, et al. Differential expression of RFamide-related peptide, a mammalian gonadotrophin-inhibitory hormone orthologue, and kisspeptin in the hypothalamus of Abadeh ecotype does during breeding and anoestrous seasons. J Neuroendocrinol 2014;26:186-194.
71. Jafarzadeh Shirazi MR, Namavar MR, Tamadon A. Expression of gonadotropin inhibitory hormone in the preoptic area and its relation with phases of estrous cycle of ewe. Physiol Pharmacol 2011;15:90-96.
72. Jafarzadeh Shirazi MR, Tamadon A. Intermediary role of kisspeptin in the stimulation of gonadotropin-releasing hormone neurons by estrogen in the preoptic area of sheep brain. Physiol Pharmacol 2010;14:41-47.
73. Jafarzadeh Shirazi MR, Tamadon A, Namavar MR. Coexpression of gonadotropin inhibitory hormone with Agouti-related peptide in the neurons of arcuate nucleus of ewe hypothalamus. Physiol Pharmacol 2011;15:201-209.
74. Ubuka T, Inoue K, Fukuda Y, Mizuno T, Ukena K, Kriegsfeld LJ, et al. Identification, expression, and physiological functions of Siberian hamster gonadotropin-inhibitory hormone. Endocrinology 2012;153:373-385.
75. Ubuka T, Lai H, Kitani M, Suzuuchi A, Pham V, Cadigan PA, et al. Gonadotropin‐inhibitory hormone identification, cDNA cloning, and distribution in rhesus macaque brain. J Comp Neurol 2009;517:841-855.
76. Salehi MS, Shirazi MRJ, Zamiri MJ, Pazhoohi F, Namavar MR, Niazi A, et al. Hypothalamic expression of KiSS1 and RFamide-related peptide-3 mRNAs during the estrous cycle of rats. Int J Fertil Steril 2013;6:304-309.
77. Asadi Yousefabad SL, Tamadon A, Rahmanifar F, Jafarzadeh Shirazi MR, Sabet Sarvestani F, Tanideh N, et al. Lactation effect on the mRNAs expression of RFRP-3 and KiSS-1 in dorsomedial and arcuate nuclei of the rat hypothalamus. Physiol Pharmacol 2013;17:277-285.
78. Jahanara M, Tamadon A, Jafarzadeh Shirazi MR, Rahmanifar F, Sabet Sarvestani F, Tanideh N, et al. Long term malnutrition and mRNAs expression of RFRP-3 and KiSS-1 in hypothalamus of female ovariectomized rats. Physiol Pharmacol 2014;17:370-378.
79. Sarvestani FS, Tamadon A, Koohi-Hosseinabadi O, Nezhad SM, Rahmanifar F, Shirazi MRJ, et al. Expression of RFamide-related peptide-3 (RFRP-3) mRNA in dorsomedial hypothalamic nucleus and KiSS-1 mRNA in arcuate nucleus of rat during pregnancy. Int J Fertil Steril 2014;8:333.
80. Ayachi S, Simonin F. Involvement of mammalian RF-amide peptides and their receptors in the modulation of nociception in rodents. Front Endocrinol 2014;5:158.-170.
81. Nooranizadeh MH, Rahmanifar F, Jafarzadeh Shirazi MR, Ahmadloo S, Shaaban Z, Tamadon A, et al. Enhancement of melanocortin-4 receptor (MC4R) and constancy of kiss1 mRNAs expression in the hypothalamic arcuate nucleus in a model of polycystic ovary syndrome rat. Galen Med J 2018;7:e1070.
82. Kumar A, Woods KS, Bartolucci AA, Azziz R. Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2005;62:644-649.
83. Marcondes JAM, Hayashida SA, Barcellos CR, Rocha MP, Maciel GA, Baracat EC. Metabolic syndrome in women with polycystic ovary syndrome: prevalence, characteristics and predictors. Arq Bras Endocrinol Metabol 2007;51:972-979.
84. Petry CJ, Ong KK, Michelmore KF, Artigas S, Wingate DL, Balen AH, et al. Association of aromatase (CYP 19) gene variation with features of hyperandrogenism in two populations of young women. Hum Reprod 2005;20:1837-1843.
85. 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;88:5976-5980.
86. Park J-M, Lee E-J, Ramakrishna S, Cha D-H, Baek K-H. Association study for single nucleotide polymorphisms in the CYP17A1 gene and polycystic ovary syndrome. Int J Mol Med 2008;22:249-254.
87. Banerjee U, Dasgupta A, Khan A, Ghosh MK, Roy P, Rout JK, et al. A cross-sectional study to assess any possible linkage of C/T polymorphism in CYP17A1 gene with insulin resistance in non-obese women with polycystic ovarian syndrome. Indian J Med Res 2016;143:739-747.
88. Jones MR, Italiano L, Wilson SG, Mullin BH, Mead R, Dudbridge F, et al. Polymorphism in HSD17B6 is associated with key features of polycystic ovary syndrome. Fertil Steril 2006;86:1438-1446.
89. Jones MR, Mathur R, Cui J, Guo X, Azziz R, Goodarzi MO. Independent confirmation of association between metabolic phenotypes of polycystic ovary syndrome and variation in the type 6 17β-hydroxysteroid dehydrogenase gene. J Clin Endocrinol Metab 2009;94:5034-5038.
90. Zhang X-L, Zhang C-W, Xu P, Liang F-J, Che Y-N, Xia Y-J, et al. SNP rs2470152 in CYP19 is correlated to aromatase activity in Chinese polycystic ovary syndrome patients. Mol Med Rep 2012;5:245-249.
91. 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;6:397-402.
92. Reddy KR, Deepika M, Supriya K, Latha KP, Rao SL, Rani VU, et al. CYP11A1 microsatellite (tttta) n polymorphism in PCOS women from South India. J Assist Reprod Genet 2014;31:857-863.
93. Shan B, Zhou L, Yang S, Yan M, Wang Z, Ouyang Y, et al. Association between polycystic ovary syndrome (PCOS) and CYP11A1 polymorphism in Hainan, China: a case-control study. Int J Clin Experiment Pathol 2016;9:230-236.
94. Yu M, Feng R, Sun X, Wang H, Wang H, Sang Q, et al. Polymorphisms of pentanucleotide repeats (tttta) n in the promoter of CYP11A1 and their relationships to polycystic ovary syndrome (PCOS) risk: a meta-analysis. Mol Biol Rep 2014;41:4435-4445.
95. Xu P, Zhang X, Xie G, Zhang C, Shen S, Zhang X, et al. The (TTTA) n polymorphism in intron 4 of CYP19 and the polycystic ovary syndrome risk in a Chinese population. Mol Biol Rep 2013;40:5041-5047.
96. Gambineri A, Vicennati V, Genghini S, Tomassoni F, Pagotto U, Pasquali R, et al. Genetic variation in 11β-hydroxysteroid dehydrogenase type 1 predicts adrenal hyperandrogenism among lean women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:2295-2302.
97. Li L, Gu Z-P, Bo Q-M, Wang D, Yang X-S, Cai G-H. Association of CYP17A1 gene-34T/C polymorphism with polycystic ovary syndrome in Han Chinese population. Gynecological Endocrinol 2015;31:40-43.
98. Lecke SB, Morsch DM, Spritzer PM. CYP19 gene expression in subcutaneous adipose tissue is associated with blood pressure in women with polycystic ovary syndrome. Steroids 2011;76:1383-1388.
99. Xita N, Lazaros L, Georgiou I, Tsatsoulis A. CYP19 gene: a genetic modifier of polycystic ovary syndrome phenotype. Fertil Steril 2010;94:250-254.
100. Nagarajeshwari C, Unnisa W, Nalini S, Jahan P, M.L.N D, Ranjith R, Rani U. Androgen associated gene polymorphism(s) in women with polycystic ovary syndrome from South Indian population. 12th Royan Congress on Reproductive Biomedicine and 6th Royan Nursing and Midwifery Seminar. 2011;Supplement 1: 0-0 2011-08-23.
101. Jin J-L, Sun J, Ge H-J, Cao Y-X, Wu X-K, Liang F-J, et al. Association between CYP19 gene SNP rs2414096 polymorphism and polycystic ovary syndrome in Chinese women. BMC Med Genet 2009;10:139.
102. Mutib MT, Hamdan FB, Al-Salihi AR. Effect of CYP19 Gene on Polycystic Ovary Syndrome Phenotype in Iraqi Women. Iraqi J Med Sci 2015;13:272-278.
103. Mostafa RA, Al-Sherbeeny MM, Abdelazim IA, Fahmy AA, Farghali MM, Abdel-Fatah MA, et al. Relation between aromatase gene CYP19 variation and hyperandrogenism in polycystic ovary syndrome Egyptian women. J Infertil Reprod Biol 2016;4:1-5.
104. Mehdizadeh A, Kalantar SM, Sheikhha MH, Aali BS, Ghanei A. Association of SNP rs. 2414096 CYP19 gene with polycystic ovarian syndrome in Iranian women. Int J Reprod BioMed 2017;15:491-496.
105. Diamanti-Kandarakis E, Bartzis MI, Bergiele AT, Tsianateli TC, Kouli CR. Microsatellite polymorphism (tttta) n at− 528 base pairs of gene CYP11α influences hyperandrogenemia in patients with polycystic ovary syndrome. Fertil Steril 2000;73:735-741.
106. Gaasenbeek M, Powell BL, Sovio U, Haddad L, Gharani N, Bennett A, et al. Large-scale analysis of the relationship between CYP11A promoter variation, polycystic ovarian syndrome, and serum testosterone. J Clin Endocrinol Metabol 2004;89:2408-2413.
107. San Millán JL, Sancho J, Calvo RM, Escobar-Morreale HF. Role of the pentanucleotide (tttta) n polymorphism in the promoter of the CYP11a gene in the pathogenesis of hirsutism. Fertil Steril 2001;75:797-802.
108. Wang Y, Wu X, Cao Y, Yi L, Chen J. A microsatellite polymorphism (tttta) n in the promoter of the CYP11a gene in Chinese women with polycystic ovary syndrome. Fertil Steril 2006;86:223-226.
109. Li T, Guijin Z. Role of the pentanucleotide (tttta) n polymorphisms of CYP 11α gene in the pathogenesis of hyperandrogenism in chinese women with polycystic ovary syndrome. J Huazhong Univ Sci Technolog Med Sci 2005;25:212-214.
110. Lim SK. Polymorphism of CYP17 and CYP11α for polycystic ovary syndrome in a Korean population. Genes Genom 2002;24:343-348.
111. Diamanti-Kandarakis E, Bartzis MI, Zapanti ED, Spina GG, Filandra FA, Tsianateli TC, et al. Polymorphism T-->C (-34 bp) of gene CYP17 promoter in Greek patients with polycystic ovary syndrome. Fertil Steril 1999;71:431-435.
112. Prapas N, Karkanaki A, Prapas I, Kalogiannidis I, Katsikis I, Panidis D. Genetics of polycystic ovary syndrome. Hippokratia 2009;13:216-223.
113. Comim F, Teerds K, Hardy K, Franks S. Increased protein expression of LHCG receptor and 17α-hydroxylase/17-20-lyase in human polycystic ovaries. Hum Reprod 2013;28:3086-3092.
114. Blomquist CH. Kinetic analysis of enzymic activities: prediction of multiple forms of 17β-hydroxysteroid dehydrogenase. J Steroid Biochem Mol Biol 1995;55:515-524.
115. Doldi N, Grossi D, Destefani A, Gessi A, Ferrari A. Polycystic ovary syndrome: evidence for reduced 3β-hydroxysteroid dehydrogenase gene expression in human luteinizing granulosa cells. Gynecological Endocrinol 2000;14:32-37.
116. Carbunaru G, Prasad P, Scoccia B, Shea P, Hopwood N, Ziai F, et al. The hormonal phenotype of nonclassic 3β-hydroxysteroid dehydrogenase (HSD3B) deficiency in hyperandrogenic females is associated with insulin-resistant polycystic ovary syndrome and is not a variant of inherited HSD3B2 deficiency. J Clin Endocrinol Metab 2004;89:783-794.
117. Qin K, Ehrmann DA, Cox N, Refetoff S, Rosenfield RL. Identification of a functional polymorphism of the human type 5 17β-hydroxysteroid dehydrogenase gene associated with polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:270-276.
118. Marioli DJ, Saltamavros AD, Vervita V, Koika V, Adonakis G, Decavalas G, et al. Association of the 17-hydroxysteroid dehydrogenase type 5 gene polymorphism (-71A/G HSD17B5 SNP) with hyperandrogenemia in polycystic ovary syndrome (PCOS). Fertil Steril 2009;92:648-652.
119. Ju R, Wu W, Fei J, Qin Y, Tang Q, Wu D, et al. Association analysis between the polymorphisms of HSD17B5 and HSD17B6 and risk of polycystic ovary syndrome in Chinese population. Europ J Endocrinol 2015;172:227-233.
120. Wood JR, Nelson VL, Ho C, Jansen E, Wang CY, Urbanek M, et al. The molecular phenotype of polycystic ovary syndrome (PCOS) theca cells and new candidate PCOS genes defined by microarray analysis. J Biol Chem 2003;278:26380-26390.
121. Hickey T, Chandy A, Norman R. The androgen receptor CAG repeat polymorphism and X-chromosome inactivation in Australian Caucasian women with infertility related to polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:161-165.
122. Apparao K, Lovely LP, Gui Y, Lininger RA, Lessey BA. Elevated endometrial androgen receptor expression in women with polycystic ovarian syndrome. Biol Reprod 2002;66:297-304.
123. Catteau-Jonard S, Jamin SP, Leclerc A, Gonzalès J, Dewailly D, di Clemente N. Anti-Mullerian hormone, its receptor, FSH receptor, and androgen receptor genes are overexpressed by granulosa cells from stimulated follicles in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93:4456-4461.
124. Baculescu N. The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS. J Med Life 2013;6:18-25.
125. Lin LH, Baracat MC, Maciel GA, Soares JM, Baracat EC. Androgen receptor gene polymorphism and polycystic ovary syndrome. Int J Gynecol Obst 2013;120:115-118.
126. Shah NA, Antoine HJ, Pall M, Taylor KD, Azziz R, Goodarzi MO. Association of androgen receptor CAG repeat polymorphism and polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93:1939-1945.
127. Mifsud A, Ramirez S, Yong E. Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries. J Clin Endocrinol Metabol 2000;85:3484-3488.
128. Jääskeläinen J, Korhonen S, Voutilainen R, Hippeläinen M, Heinonen S. Androgen receptor gene CAG length polymorphism in women with polycystic ovary syndrome. Fertil Steril 2005;83:1724-1728.
129. Schüring A, Welp A, Gromoll J, Zitzmann M, Sonntag B, Nieschlag E, et al. Role of the CAG repeat polymorphism of the androgen receptor gene in polycystic ovary syndrome (PCOS). Exp Clin Endocrinol Diabetes 2012;120:73-79.
130. Ferk P, Teran N, Gersak K. The (TAAAA) n microsatellite polymorphism in the SHBG gene influences serum SHBG levels in women with polycystic ovary syndrome. Hum Reprod 2006;22:1031-1036.
131. Ackerman C, Garcia O, Legro R, Dunaif A, Urbanek M. SHBG (TAAAA) n is associated with serum SHBG in a PCOS case-control cohort. Endocr Rev 2011;32:P2-66.03.
132. Moran L, Teede H, Noakes M, Clifton PM, Norman R, Wittert G. Sex hormone binding globulin, but not testosterone, is associated with the metabolic syndrome in overweight and obese women with polycystic ovary syndrome. J Endocrinol Invest 2013;36:1004-1010.
133. Martínez-García MÁ, Gambineri A, Alpañés M, Sanchón R, Pasquali R, Escobar-Morreale HF. Common variants in the sex hormone-binding globulin gene (SHBG) and polycystic ovary syndrome (PCOS) in Mediterranean women. Hum Reprod 2012;27:3569-3576.
134. Kahsar-Miller MD, Conway-Myers BA, Boots LR, Azziz R. Steroidogenic acute regulatory protein (StAR) in the ovaries of healthy women and those with polycystic ovary syndrome. Am J Obstet Gynecol 2001;185:1381-1387.
135. Nazouri AS, Khosravifar M, Akhlaghi AA, Shiva M, Afsharian P. No relationship between most polymorphisms of steroidogenic acute regulatory (StAR) gene with polycystic ovarian syndrome. Int J Reprod BioMed 2015;13:771.