Pathophysiologic mechanisms of obesity- and chronic inflammation-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, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

3 Reproductive Biomedicine Research Center, Royan Institute, Tehran, Iran

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

10.22038/ijbms.2019.14029

Abstract

Objective(s): One of the common heterogeneous reproductive disorders in women of childbearing age is polycystic ovary syndrome (PCOS). It is characterized by lack of fertility due to anovulatory cycles, hyperandrogenemia, polycystic ovaries, hyperinsulinemia, and obesity. Both reproductive anomalies and metabolic disorders are involved in PCOS pathology. Although the role of increased levels of androgens in initiation of PCOS is almost proven, mechanisms of PCOS pathophysiology are not clear. Here we discuss roles of altered metabolic conditions, obesity, and chronic inflammation in PCOS pathophysiology.
Materials and Methods: In this review, we attempted to identify genes related to obesity and chronic inflammation aspects of PCOS and their physiological functions to explain the pathways that are regulated by these genes and can be a prominent function in PCOS predisposition. 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: Obesity and chronic inflammation are not prominent diagnostic features of PCOS, but they play an important role in exacerbating metabolic and hyperandrogenic states. ADIPOQ, FTO TGFβ, and DENND1A as the main obesity- and chronic inflammation-related genes have roles in PCOS pathophysiology.
Conclusion: It seems that genes related to obesity pathology in genomic research association, are related to metabolic aspects and body mass index in PCOS patients. Genomes have roles in chronic inflammation, followed by obesity, in the pathogenesis of PCOS.

Keywords


1. Azziz R. PCOS in 2015: New insights into the genetics of polycystic ovary syndrome. Nat Rev Endocrinol. 2016;12:74.
2. Vink J, Sadrzadeh S, Lambalk C, Boomsma D. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab. 2006;91:2100-2104.
3. 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.
4. 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.
5. 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. 2012;49:90-95.
6. 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.
7. Mutharasan P, Galdones E, Peñalver Bernabé B, Garcia OA, Jafari N, Shea LD, et al. Evidence for chromosome 2p16. 3 polycystic ovary syndrome susceptibility locus in affected women of European ancestry. J Clin Endocrinol Metab. 2013;98:E185-E190.
8. 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.
9. Diamanti-Kandarakis E, Piperi C. Genetics of polycystic ovary syndrome: searching for the way out of the labyrinth. Hum Reprod Update. 2005;11:631-643.
10. Escobar-Morreale HF, San Millán JL. Abdominal adiposity and the polycystic ovary syndrome. Trends Endocrinol Metab. 2007;18:266-272.
11. Huber-Buchholz M-M, Carey D, Norman R. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab. 1999;84:1470-1474.
12. van Dam EW, Roelfsema F, Veldhuis JD, Hogendoorn S, Westenberg J, Helmerhorst FM, et al. Retention of estradiol negative feedback relationship to LH predicts ovulation in response to caloric restriction and weight loss in obese patients with polycystic ovary syndrome. Am J Physiol Endocrinol Metab. 2004;286:E615-E620.
13. Duleba AJ, Dokras A. Is PCOS an inflammatory process? Fertil Steril. 2012;97:7-12.
14. Escobar-Morreale H, Villuendas G, Botella-Carretero J, Sancho J, San Millan J. Obesity, and not insulin resistance, is the major determinant of serum inflammatory cardiovascular risk markers in pre-menopausal women. Diabetologia. 2003;46:625-633.
15. Pasquali R, Gambineri A. The Endocrine Impact of Obesity and Body Habitus in the Polycystic Ovary Syndrome.  Androgen Excess Disorders in Women: Springer; 2006. p. 283-291.
16. Cresswell J, Barker D, Osmond C, Egger P, Phillips D, Fraser R. Fetal growth, length of gestation, and polycystic ovaries in adult life. Lancet. 1997;350:1131-1135.
17. Attie AD, Scherer PE. Adipocyte metabolism and obesity. J Lipid Res. 2009;50:S395-S399.
18. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115:1111-1119.
19. Shaaban Z, Khoradmehr A, Jafarzadeh Shirazi MR, Tamadon A. Pathophysiological mechanisms of gonadotropins–and steroid hormones–related genes in etiology of polycystic ovary syndrome. Iran J Basic Med Sci. 2019;22:3-16.
20. Lee YS. Consequences of childhood obesity. Ann Acad Med Singapore. 2009;38:75-77.
21. Barber TM, Franks S. Genetics of polycystic ovary syndrome.  Polycystic Ovary Syndrome. 40: Karger Publishers; 2013. p. 28-39.
22. Fenichel P, Rougier C, Hieronimus S, Chevalier N, editors. Which origin for polycystic ovaries syndrome: genetic, environmental or both? Ann Endocrinol; 2017: Elsevier.
23. Legro RS, editor Obesity and PCOS: implications for diagnosis and treatment. Semin Reprod Med; 2012: NIH Public Access.
24. Luque-Ramírez M, San Millán JL, Escobar-Morreale HF. Genomic variants in polycystic ovary syndrome. Clin Chim Acta. 2006;366:14-26.
25. Beatriz Motta A. The role of obesity in the development of polycystic ovary syndrome. Curr Pharm Des. 2012;18:2482-2491.
26. Xiong W, Lin Y, Xu L, Tamadon A, Zou S, Tian F, et al. Circulatory microRNA 23a and microRNA 23b and polycystic ovary syndrome (PCOS): the effects of body mass index and sex hormones in an Eastern Han Chinese population. J Ovarian Resh. 2017;10:10.
27. Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med. 2001;111:607-613.
28. Zhao J, Hu Z, Cai L, Liu L, Jiang X, Wu L, et al. Association between single nucleotide polymorphisms of sterol regulatory element binding protein-2 and liver X receptor α gene and risk of polycystic ovary syndrome in a Chinese Han population. Cell Biochem Biophys. 2014;70:1421-1426.
29. Jia H, Yu L, Guo X, Gao W, Jiang Z. Associations of adiponectin gene polymorphisms with polycystic ovary syndrome: a meta-analysis. Endocrine. 2012;42:299-306.
30. Zhang W, Wei D, Sun X, Li J, Yu X, Shi Y, et al. Family-based analysis of adiponectin gene polymorphisms in Chinese Han polycystic ovary syndrome. Fertil Steril. 2014;101:1419-1423. e1413.
31. Baba T, Endo T, Sata F, Nagasawa K, Honnma H, Kitajima Y, et al. The contributions of resistin and adiponectin gene single nucleotide polymorphisms to the genetic risk for polycystic ovary syndrome in a Japanese population. Gynecol Endocrinol. 2009;25:498-503.
32. Xian L, He W, Pang F, Hu Y. ADIPOQ gene polymorphisms and susceptibility to polycystic ovary syndrome: a HuGE survey and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2012;161:117-124.
33. Zhang N, Shi Y-H, Hao C-F, Gu HF, Li Y, Zhao Y-R, et al. Association of+ 45G15G (T/G) and+ 276 (G/T) polymorphisms in the ADIPOQ gene with polycystic ovary syndrome among Han Chinese women. Eur J Endocrinol. 2008;158:255-260.
34. Li L, Yun J-H, Lee J-H, Song S, Choi B-C, Baek K-H. Association study of+ 45G15G (T/G) and+ 276 (G/T) polymorphisms in the adiponectin gene in patients with polycystic ovary syndrome. Int J Mol Med. 2011;27:283-287.
35. Barber T, Bennett A, Groves C, Sovio U, Ruokonen A, Martikainen H, et al. Association of variants in the fat mass and obesity associated (FTO) gene with polycystic ovary syndrome. Diabetologia. 2008;51:1153-1158.
36. Ewens KG, Jones MR, Ankener W, Stewart DR, Urbanek M, Dunaif A, et al. FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome. PLoS ONE. 2011;6:e16390.
37. Wehr E, Schweighofer N, Möller R, Giuliani A, Pieber TR, Obermayer-Pietsch B. Association of FTO gene with hyperandrogenemia and metabolic parameters in women with polycystic ovary syndrome. Metabolism. 2010;59:575-580.
38. Song DK, Lee H, Oh J-Y, Hong YS, Sung Y-A. FTO gene variants are associated with PCOS susceptibility and hyperandrogenemia in young Korean women. Diabetes Metab J. 2014;38:302-310.
39. Yuan H, Zhu G, Wang F, Wang X, Guo H, Shen M. Interaction between common variants of FTO and MC4R is associated with risk of PCOS. Reprod Biol Endocrinol. 2015;13:55.
40. Bradnová O, Vejražková D, Vaňková M, Lukášová P, Včelák J, Stanická S, et al. Metabolic and hormonal consequencies of the obesity risk” MC4R variant (rs12970134) in Czech women. Physiol Res. 2015;64: S187-S195.
41. Ranjzad F, Mahmoudi T, Shemirani AI, Mahban A, Nikzamir A, Vahedi M, et al. A common variant in the adiponectin gene and polycystic ovary syndrome risk. Mol Biol Rep. 2012;39:2313-2319.
42. Zaki M, Kholoussi S, Ismail S, Raouf HA, Helwa I, Hassan N, et al. Metabolic abnormalities in young Egyptian women with polycystic ovary syndrome and their relation to ADIPOQ gene variants and body fat phenotype. Egyptian J Med Hum Gen. 2015;16:367-374.
43. Stratigopoulos G, Padilla SL, LeDuc CA, Watson E, Hattersley AT, McCarthy MI, et al. Regulation of Fto/Ftm gene expression in mice and humans. Am J Physiol Regul Integr Comp Physiol. 2008;294:R1185-R1196.
44. Attaoua R, El Mkadem SA, Radian S, Fica S, Hanzu F, Albu A, et al. FTO gene associates to metabolic syndrome in women with polycystic ovary syndrome. Biochem Biophys Res Commun. 2008;373:230-234.
45. Grant SF, Bradfield JP, Zhang H, Wang K, Kim CE, Annaiah K, et al. Investigation of the locus near MC4R with childhood obesity in Americans of European and African ancestry. Obesity. 2009;17:1461-1465.
46. Yang Y-k, Dickinson CJ, Zeng Q, Li J-Y, Thompson DA, Gantz I. Contribution of melanocortin receptor exoloops to Agouti-related protein binding. J Biol Chem. 1999;274:14100-14106.
47. Sarvestani FS, Tamadon A, Hematzadeh A, Jahanara M, Shirazi MRJ, Moghadam A, et al. Expression of melanocortin-4 receptor and agouti-related peptide mRNAs in arcuate nucleus during long term malnutrition of female ovariectomized rats. Iran J Basic Med Sci. 2015;18:104-107.
48. Zandi MR, Jafarzadeh Shirazi MR, Tamadon A, Akhlaghi A, Salehi MS, Niazi A, et al. Hypothalamic expression of melanocortin-4 receptor and agouti-related peptide mRNAs during the estrous cycle of rats. Int J Mol Cell Med. 2014;3:183-189.
49. Asadi-Yousefabad S-L, Sabet Sarvestani F, Tamadon A, Jafarzadeh Shirazi MR, Ahmadloo S, Moghadam A, et al. Agouti-related peptide and melanocortin-4 receptor mRNAs expressions in arcuate nucleus during the pregnancy and lactation of rats. Vet Arh. 2015;85:689-700.
50. Nooranizadeh MH, Rahmanifar F, Ahmadloo S, Shaaban Z, Shirazi MRJ, Tamadon A. 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.
51. Raghow R, Yellaturu C, Deng X, Park EA, Elam MB. SREBPs: the crossroads of physiological and pathological lipid homeostasis. Trends Endocrinol Metab. 2008;19:65-73.
52. Wild RA, Rizzo M, Clifton S, Carmina E. Lipid levels in polycystic ovary syndrome: systematic review and meta-analysis. Fertil Steril. 2011;95:1073-1079.
53. Zhao C, Dahlman-Wright K. Liver X receptor in cholesterol metabolism. J Endocrinol. 2010;204:233-240.
54. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109:1125-1131.
55. Malin SK, Kirwan JP, Sia CL, González F. Glucose-stimulated oxidative stress in mononuclear cells is related to pancreatic β-cell dysfunction in polycystic ovary syndrome. J Clin Endocrinol Metab. 2014;99:322-329.
56. Ojeda-Ojeda M, Murri M, Insenser M, F Escobar-Morreale H. Mediators of low-grade chronic inflammation in polycystic ovary syndrome (PCOS). Curr Pharm Des. 2013;19:5775-5791.
57. González F. Inflammation in polycystic ovary syndrome: underpinning of insulin resistance and ovarian dysfunction. Steroids. 2012;77:300-305.
58. Spritzer PM, Lecke SB, Satler F, Morsch DM. Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome. Reproduction. 2015;149:R219-R227.
59. Deligeoroglou E, Kouskouti C, Christopoulos P. The role of genes in the polycystic ovary syndrome: predisposition and mechanisms. Gynecol Endocrinol. 2009;25:603-609.
60. Vural P, Değirmencioğlu S, Saral NY, Akgül C. Tumor necrosis factor α (− 308), interleukin-6 (− 174) and interleukin-10 (− 1082) gene polymorphisms in polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2010;150:61-65.
61. 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.
62. Gao J, Xue J-D, Li Z-C, Zhou L, Chen C. The association of DENND1A gene polymorphisms and polycystic ovary syndrome risk: a systematic review and meta-analysis. Arch Gynecol Obstet. 2016;294:1073-1080.
63. Bao S, Cai J-H, Yang S-Y, Ren Y, Feng T, Jin T, et al. Association of DENND1A gene polymorphisms with polycystic ovary syndrome: a meta-analysis. J Clin Res Pediatr Endocrinol. 2016;8:135.
64. Dallel M, Sarray S, Douma Z, Hachani F, Al-Ansari AK, Letaifa DB, et al. Differential association of DENND1A genetic variants with polycystic ovary syndrome in Tunisian but not Bahraini Arab women. Gene. 2018;647:79-84.
65. Li Y, Liu H, Zhao H, Xu C, Zhao Y, Ma J, et al. Association of AQP8 in women with PCOS. Reprod Biomed Online. 2013;27:419-422.
66. Li T, Zhao H, Zhao X, Zhang B, Cui L, Shi Y, et al. Identification of YAP1 as a novel susceptibility gene for polycystic ovary syndrome. J Med Genet. 2012;49:254-257.
67. Diao X, Han T, Zhang Y, Ma J, Shi Y, Chen Z-J. Family association study between tumour necrosis factor a gene polymorphisms and polycystic ovary syndrome in Han Chinese. Reprod Biomed Online. 2014;29:581-587.
68. Yang J, Zhong T, Xiao G, Chen Y, Liu J, Xia C, et al. Polymorphisms and haplotypes of the TGF-β1 gene are associated with risk of polycystic ovary syndrome in Chinese Han women. Eur J Obstet Gynecol Reprod Biol. 2015;186:1-7.
69. Peral Bn, San Millán JL, Castello R, Moghetti P, Escobar-Morreale HcF. The methionine 196 arginine polymorphism in exon 6 of the TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary syndrome and hyperandrogenism. J Clin Endocrinol Metab. 2002;87:3977-3983.
70. Tumu VR, Govatati S, Guruvaiah P, Deenadayal M, Shivaji S, Bhanoori M. An interleukin-6 gene promoter polymorphism is associated with polycystic ovary syndrome in South Indian women. J Assist Reprod Genet. 2013;30:1541-1546.
71. Guo R, Zheng Y, Yang J, Zheng N. Association of TNF-alpha, IL-6 and IL-1beta gene polymorphisms with polycystic ovary syndrome: a meta-analysis. BMC Genetics. 2015;16:5.
72. Deligeoroglou E, Vrachnis N, Athanasopoulos N, Iliodromiti Z, Sifakis S, Iliodromiti S, et al. Mediators of chronic inflammation in polycystic ovarian syndrome. Gynecol Endocrinol. 2012;28:974-978.
73. Xiong Y-l, Liang X-y, Yang X, Li Y, Wei L-n. Low-grade chronic inflammation in the peripheral blood and ovaries of women with polycystic ovarian syndrome. Eur J Obstet Gynecol Reprod Biol. 2011;159:148-150.
74. Kim YY, Tamadon A, Ku S-Y. Potential use of antiapoptotic proteins and noncoding RNAs for efficient in vitro follicular maturation and ovarian bioengineering. Tissue Eng Part B Rev. 2017;23:142-158.
75. Hotamisligil G. The role of TNFα and TNF receptors in obesity and insulin resistance. J Intern Med. 1999;245:621-625.
76. González F, Sia CL, Bearson DM, Blair HE. Hyperandrogenism induces a proinflammatory TNFα response to glucose ingestion in a receptor-dependent fashion. J Clin Endocrinol Metab. 2014;99:E848-E854.
77. Szczuko M, Zapałowska-Chwyć M, Maciejewska D, Drozd A, Starczewski A, Stachowska E. High glycemic index diet in PCOS patients. The analysis of IGF I and TNF-α pathways in metabolic disorders. Med Hypotheses. 2016;96:42-47.
78. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α-and obesity-induced insulin resistance. Science. 1996;271:665-670.
79. Spaczynski RZ, Arici A, Duleba AJ. Tumor necrosis factor-α stimulates proliferation of rat ovarian theca-interstitial cells. Biol Reprod. 1999;61:993-998.
80. Hong L, Zhang Y, Wang Q, Han Y, Teng X. Effects of interleukin 6 and tumor necrosis factor-α on the proliferation of porcine theca interna cells: Possible role of these cytokines in the pathogenesis of polycystic ovary syndrome. Taiwan J Obstet Gynecol. 2016;55:183-187.
81. Fernández-Real JM, Gutiérrez C, Ricart W, Castiñeira Ma-J, Vendrell J, Richart C. Plasma levels of the soluble fraction of tumor necrosis factor receptors 1 and 2 are independent determinants of plasma cholesterol and LDL-cholesterol concentrations in healthy subjects. Atherosclerosis. 1999;146:321-327.
82. Peral B, San Millán JL, Castello R, Moghetti P, Escobar-Morreale HcF. The methionine 196 arginine polymorphism in exon 6 of the TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary syndrome and hyperandrogenism. J Clin Endocrinol Metab. 2002;87:3977-3983.
83. Päth Gn, Bornstein SR, Ehrhart-Bornstein M, Scherbaum WA. Interleukin-6 and the interleukin-6 receptor in the human adrenal gland: expression and effects on steroidogenesis. J Clin Endocrinol Metab. 1997;82:2343-2349.
84. Marat AL, Dokainish H, McPherson PS. DENN domain proteins: regulators of Rab GTPases. J Biol Chem. 2011;286:13791-13800.
85. Tee MK, Speek M, Legeza B, Modi B, Teves ME, McAllister JM, et al. Alternative splicing of DENND1A, a PCOS candidate gene, generates variant 2. Mol Cell Endocrinol. 2016;434:25-35.
86. McAllister JM, Modi B, Miller BA, Biegler J, Bruggeman R, Legro RS, et al. Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype. Proc Natl Acad Sci U S A. 2014:201400574.