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Current Women`s Health Reviews

Editor-in-Chief

ISSN (Print): 1573-4048
ISSN (Online): 1875-6581

Review Article

Polycystic Ovary Syndrome and Infertility: From Molecular Perspective

Author(s): Masoumeh Ghafarzadeh*

Volume 16, Issue 3, 2020

Page: [182 - 187] Pages: 6

DOI: 10.2174/1573404816999200408122039

Price: $65

Abstract

Polycystic ovary syndrome (PCOS) is one of the major endocrine abnormalities in women. It is associated with the dysfunction of androgen metabolism, elevation in insulin resistance and impaired fertility. In addition, it is characterized by polycystic ovaries, chronic anovulation, hyperandrogenism, chronic low-grade inflammation and type 2 diabetes. Furthermore, the studies have indicated that PCOS is associated with higher rates of obesity and central adiposity, which are partly responsible for the clinical severity of PCOS. Over the years, PCOS has been associated with infertility in women, as it is responsible for subfertility and increases the risk of pregnancy-related complications like gestational diabetes, hypertensive disorders, and premature delivery. The pathogenesis of PCOS remains ambiguous, however PI3K-Akt and retinoid signaling pathways are known to be involved mechanisms. In this review, we will give a comprehensive summary based on the possible association of PI3K-Akt and retinoid signaling pathways in PCOS-related infertility.

Keywords: Polycystic ovary syndrome, PI3K-Akt signaling pathway, infertility, retinoid signaling pathway, endocrine abnormalities, hypertensive disorders.

Graphical Abstract

[1]
Yari F, Ghafarzadeh M, Vahabi S, Khadish A. The efficacy of adding dexamethazone to clomiphene citrate in the treatment of polycystic ovary syndrome and infertility. Iran J Reprod Med 2014; 12(6): 93.
[2]
Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev 2015; 36(5): 487-525.
[http://dx.doi.org/10.1210/er.2015-1018] [PMID: 26426951]
[3]
Kandaraki E, Chatzigeorgiou A, Livadas S, et al. Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS. J Clin Endocrinol Metab 2011; 96(3): E480-4.
[http://dx.doi.org/10.1210/jc.2010-1658] [PMID: 21193545]
[4]
Chakraborty P, Goswami SK, Rajani S, et al. Recurrent pregnancy loss in polycystic ovary syndrome: role of hyperhomocysteinemia and insulin resistance. PLoS One 2013; 8(5) e64446.
[http://dx.doi.org/10.1371/journal.pone.0064446] [PMID: 23700477]
[5]
Palomba S, Falbo A, Russo T, et al. Uterine blood flow in pregnant patients with polycystic ovary syndrome: relationships with clinical outcomes. BJOG 2010; 117(6): 711-21.
[http://dx.doi.org/10.1111/j.1471-0528.2010.02525.x] [PMID: 20236107]
[6]
Loverro G, Vicino M, Lorusso F, Vimercati A, Greco P, Selvaggi L. Polycystic ovary syndrome: relationship between insulin sensitivity, sex hormone levels and ovarian stromal blood flow. Gynecol Endocrinol 2001; 15(2): 142-9.
[PMID: 11379011]
[7]
Savaris RF, Groll JM, Young SL, et al. Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles. J Clin Endocrinol Metab 2011; 96(6): 1737-46.
[http://dx.doi.org/10.1210/jc.2010-2600] [PMID: 21411543]
[8]
Villavicencio A, Goyeneche A, Telleria C, et al. Involvement of Akt, Ras and cell cycle regulators in the potential development of endometrial hyperplasia in women with polycystic ovarian syndrome. Gynecol Oncol 2009; 115(1): 102-7.
[http://dx.doi.org/10.1016/j.ygyno.2009.06.033] [PMID: 19631369]
[9]
Moore AM, Prescott M, Marshall CJ, Yip SH, Campbell RE. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. Proc Natl Acad Sci USA 2015; 112(2): 596-601.
[http://dx.doi.org/10.1073/pnas.1415038112] [PMID: 25550522]
[10]
Priyadarshani A, Chuttani K, Mittal G, Bhatnagar A. Radiolabeling, biodistribution and gamma scintigraphy of noscapine hydrochloride in normal and polycystic ovary induced rats. J Ovarian Res 2010; 3(1): 10.
[http://dx.doi.org/10.1186/1757-2215-3-10] [PMID: 20420718]
[11]
Dafopoulos K, Venetis C, Pournaras S, Kallitsaris A, Messinis IE. Ovarian control of pituitary sensitivity of luteinizing hormone secretion to gonadotropin-releasing hormone in women with the polycystic ovary syndrome. Fertil Steril 2009; 92(4): 1378-80.
[http://dx.doi.org/10.1016/j.fertnstert.2009.04.033] [PMID: 19467538]
[12]
Lorzadeh N, Samimi S, Birjandi M. Association of fetal gender with maternal serum β-hCG and testosterone in normotensive and preeclamptic pregnancies. IJOGI 2010; 13(1): 13-9.
[13]
Rojas J, Chávez M, Olivar L, et al. Polycystic ovary syndrome, insulin resistance, and obesity: navigating the pathophysiologic labyrinth. Int J Reprod Med 2014; 2014 719050.
[http://dx.doi.org/10.1155/2014/719050] [PMID: 25763405]
[14]
Sekar N, Garmey JC, Veldhuis JD. Mechanisms underlying the steroidogenic synergy of insulin and luteinizing hormone in porcine granulosa cells: joint amplification of pivotal sterol-regulatory genes encoding the low-density lipoprotein (LDL) receptor, steroidogenic acute regulatory (stAR) protein and cytochrome P450 side-chain cleavage (P450scc) enzyme. Mol Cell Endocrinol 2000; 159(1-2): 25-35.
[http://dx.doi.org/10.1016/S0303-7207(99)00203-8] [PMID: 10687849]
[15]
Lorzadeh N, Kazemi Rad S. MomenNasab M, Lorzadeh M, Safa M. The effects of daily fluoxetine in treatment of premenstrual dysphoric disorder. IJOGI 2006; 9(2): 39-46.
[16]
Hendrix AO, Selgrade JF. Bifurcation analysis of a menstrual cycle model reveals multiple mechanisms linking testosterone and classical PCOS. J Theor Biol 2014; 361: 31-40.
[http://dx.doi.org/10.1016/j.jtbi.2014.07.020] [PMID: 25079709]
[17]
Baculescu N. The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS. J Med Life 2013; 6(1): 18-25.
[PMID: 23599814]
[18]
De Leo V, Musacchio MC, Cappelli V, Massaro MG, Morgante G, Petraglia F. Genetic, hormonal and metabolic aspects of PCOS: an update. Reprod Biol Endocrinol 2016; 14(1): 38.
[http://dx.doi.org/10.1186/s12958-016-0173-x] [PMID: 27423183]
[19]
Song L, Li D, Gu Y, et al. MicroRNA-126 targeting PIK3R2 inhibits NSCLC A549 cell proliferation, migration, and invasion by regulation of PTEN/PI3K/AKT pathway. Clin Lung Cancer 2016; 17(5): e65-75.
[http://dx.doi.org/10.1016/j.cllc.2016.03.012] [PMID: 27236384]
[20]
Gao YF, Zhang MN, Wang TX, Wu TC, Ai RD, Zhang ZS. Hypoglycemic effect of D-chiro-inositol in type 2 diabetes mellitus rats through the PI3K/Akt signaling pathway. Mol Cell Endocrinol 2016; 433: 26-34.
[http://dx.doi.org/10.1016/j.mce.2016.05.013] [PMID: 27212205]
[21]
Long M, Zhou J, Li D, Zheng L, Xu Z, Zhou S. Long-term over-expression of neuropeptide Y in hypothalamic paraventricular nucleus contributes to adipose tissue insulin resistance partly via the Y5 receptor. PLoS One 2015; 10(5) e0126714.
[http://dx.doi.org/10.1371/journal.pone.0126714] [PMID: 25993471]
[22]
Højlund K. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance. Dan Med J 2014; 61(7): B4890.
[PMID: 25123125]
[23]
Lewandowski KC, Dąbrowska K, Brzozowska M, Kawalec J, Lewiński A. Metformin paradoxically worsens insulin resistance in SHORT syndrome. Diabetol Metab Syndr 2019; 11: 81.
[http://dx.doi.org/10.1186/s13098-019-0477-z] [PMID: 31583022]
[24]
Thauvin-Robinet C, Auclair M, Duplomb L, et al. PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. Am J Hum Genet 2013; 93(1): 141-9.
[http://dx.doi.org/10.1016/j.ajhg.2013.05.019] [PMID: 23810378]
[25]
Yang M, Ren Y, Lin Z, et al. Krüppel-like factor 14 increases insulin sensitivity through activation of PI3K/Akt signal pathway. Cell Signal 2015; 27(11): 2201-8.
[http://dx.doi.org/10.1016/j.cellsig.2015.07.019] [PMID: 26226221]
[26]
Sharma BR, Kim HJ, Rhyu DY. Caulerpa lentillifera extract ameliorates insulin resistance and regulates glucose metabolism in C57BL/KsJ-db/db mice via PI3K/AKT signaling pathway in myocytes. J Transl Med 2015; 13(1): 62.
[http://dx.doi.org/10.1186/s12967-015-0412-5] [PMID: 25889508]
[27]
Jiang L, Huang J, Chen Y, et al. Identification of several circulating microRNAs from a genome-wide circulating microRNA expression profile as potential biomarkers for impaired glucose metabolism in polycystic ovarian syndrome. Endocrine 2016; 53(1): 280-90.
[http://dx.doi.org/10.1007/s12020-016-0878-9] [PMID: 26860517]
[28]
Rivero R, Garin CA, Ormazabal P, et al. Protein expression of PKCZ (Protein Kinase C Zeta), Munc18c, and Syntaxin-4 in the insulin pathway in endometria of patients with polycystic ovary syndrome (PCOS). Reprod Biol Endocrinol 2012; 10(1): 17.
[http://dx.doi.org/10.1186/1477-7827-10-17] [PMID: 22390153]
[29]
Restuccia DF, Hynx D, Hemmings BA. Loss of PKBβ/Akt2 predisposes mice to ovarian cyst formation and increases the severity of polycystic ovary formation in vivo. Dis Model Mech 2012; 5(3): 403-11.
[http://dx.doi.org/10.1242/dmm.008136] [PMID: 22275470]
[30]
Sun X, Su Y, He Y, et al. New strategy for in vitro activation of primordial follicles with mTOR and PI3K stimulators. Cell Cycle 2015; 14(5): 721-31.
[http://dx.doi.org/10.1080/15384101.2014.995496] [PMID: 25590233]
[31]
Kim E, Seok HH, Lee SY, et al. Correlation between expression of glucose transporters in granulosa cells and oocyte quality in women with polycystic ovary syndrome. Endocrinol Metab (Seoul) 2014; 29(1): 40-7.
[http://dx.doi.org/10.3803/EnM.2014.29.1.40] [PMID: 24741453]
[32]
Fukuda S, Orisaka M, Tajima K, Hattori K, Kotsuji F. Luteinizing hormone-induced Akt phosphorylation and androgen production are modulated by MAP Kinase in bovine theca cells. J Ovarian Res 2009; 2(1): 17.
[http://dx.doi.org/10.1186/1757-2215-2-17] [PMID: 19917087]
[33]
Zhao Y, Zhang C, Huang Y, et al. Up-regulated expression of WNT5a increases inflammation and oxidative stress via PI3K/AKT/NF-κB signaling in the granulosa cells of PCOS patients. J Clin Endocrinol Metab 2015; 100(1): 201-11.
[http://dx.doi.org/10.1210/jc.2014-2419] [PMID: 25303486]
[34]
Shah KN, Patel SS. Phosphatidylinositide 3-kinase inhibition: A new potential target for the treatment of polycystic ovarian syndrome. Pharm Biol 2016; 54(6): 975-83.
[http://dx.doi.org/10.3109/13880209.2015.1091482] [PMID: 26459667]
[35]
Zhang HY, Zhang YF, Han YK, Xue FX, Zhao XH, Zhang XL. [Activation and significance of the PI3K/Akt pathway in endometrium with polycystic ovary syndrome patients]. Zhonghua Fu Chan Ke Za Zhi 2012; 47(1): 19-23.
[PMID: 22455688]
[36]
Matulonis U, Vergote I, Backes F, et al. Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma. Gynecol Oncol 2015; 136(2): 246-53.
[http://dx.doi.org/10.1016/j.ygyno.2014.12.019] [PMID: 25528496]
[37]
Ferreira GD, Germeyer A, de Barros Machado A, et al. Metformin modulates PI3K and GLUT4 expression and Akt/PKB phosphorylation in human endometrial stromal cells after stimulation with androgen and insulin. Eur J Obstet Gynecol Reprod Biol 2014; 175: 157-62.
[http://dx.doi.org/10.1016/j.ejogrb.2014.01.009] [PMID: 24480115]
[38]
Yari F, Ghafarzadeh M, Tarahi M. Effect of soy supplementation on hot flushes in postmenopausal women. YAFTEH 2000; 2(4-5): 43-6.
[39]
Yari F, Ghafarzadeh M. Androgen level in patients with preeclampsia. YAFTEH 2001; 3(10): 39-41.
[40]
Xu H, Zhou Y, Liu Y, et al. Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis. J Endocrinol 2016; 229(2): 133-44.
[http://dx.doi.org/10.1530/JOE-15-0409] [PMID: 26941037]
[41]
Jia J, Bai J, Liu Y, et al. Association between retinol-binding protein 4 and polycystic ovary syndrome: a meta-analysis. Endocr J 2014; 61(10): 995-1002.
[http://dx.doi.org/10.1507/endocrj.EJ14-0186] [PMID: 25069671]
[42]
Wickenheisser JK, Nelson-DeGrave VL, Hendricks KL, Legro RS, Strauss JF III, McAllister JM. Retinoids and retinol differentially regulate steroid biosynthesis in ovarian theca cells isolated from normal cycling women and women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90(8): 4858-65.
[http://dx.doi.org/10.1210/jc.2005-0330] [PMID: 15914525]
[43]
Akbari S, Janani F, Changavi F, Ayazi M, Ghafarzadeh M. Beta-human chorionic gonadotropin (βHCG) levels in pre-eclamptic and normotensive pregnant women. YAFTEH 2005; 7(3-4): 57-62.
[44]
Wood JR, Ho CK, Nelson-Degrave VL, McAllister JM, Strauss JF III. The molecular signature of polycystic ovary syndrome (PCOS) theca cells defined by gene expression profiling. J Reprod Immunol 2004; 63(1): 51-60.
[http://dx.doi.org/10.1016/j.jri.2004.01.010] [PMID: 15284005]
[45]
Marti N, Galván JA, Pandey AV, et al. Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome. Mol Cell Endocrinol 2017; 441: 116-23.
[http://dx.doi.org/10.1016/j.mce.2016.07.029] [PMID: 27471004]
[46]
Wood JR, Nelson VL, Ho C, 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(29): 26380-90.
[http://dx.doi.org/10.1074/jbc.M300688200] [PMID: 12734205]

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