Table of Contents Author Guidelines Submit a Manuscript
Genetics Research International
Volume 2018, Article ID 7624932, 12 pages
https://doi.org/10.1155/2018/7624932
Review Article

Genetic Variants Associated with Hyperandrogenemia in PCOS Pathophysiology

Department of Molecular Endocrinology, National Institute for Research in Reproductive Health, J.M. Street, Parel, Mumbai 400012, India

Correspondence should be addressed to Srabani Mukherjee; ni.ser.hrrin@seejrehkum

Received 30 August 2017; Accepted 18 January 2018; Published 18 February 2018

Academic Editor: Fabio M. Macciardi

Copyright © 2018 Roshan Dadachanji et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Polycystic ovary syndrome is a multifactorial endocrine disorder whose pathophysiology baffles many researchers till today. This syndrome is typically characterized by anovulatory cycles and infertility, altered gonadotropin levels, obesity, and bulky multifollicular ovaries on ultrasound. Hyperandrogenism and insulin resistance are hallmark features of its complex pathophysiology. Hyperandrogenemia is a salient feature of PCOS and a major contributor to cosmetic anomalies including hirsutism, acne, and male pattern alopecia in affected women. Increased androgen levels may be intrinsic or aggravated by preexisting insulin resistance in women with PCOS. Studies have reported augmented ovarian steroidogenesis patterns attributed mainly to theca cell hypertrophy and altered expression of key enzymes in the steroidogenic pathway. Candidate gene studies have been performed in order to delineate the association of polymorphisms in genes, which encode enzymes in the intricate cascade of steroidogenesis or modulate the levels and action of circulating androgens, with risk of PCOS development and its related traits. However, inconsistent findings have impacted the emergence of a unanimously accepted genetic marker for PCOS susceptibility. In the current review, we have summarized the influence of polymorphisms in important androgen related genes in governing genetic predisposition to PCOS and its related metabolic and reproductive traits.

1. Introduction

Polycystic ovary syndrome affects scores of women worldwide with a prevalence of nearly 6–10% of premenopausal women [1]. Typical features of PCOS comprise distorted gonadotropin ratios, chronic anovulation, and subsequently irregular menstrual cycles, insulin resistance, increased androgen levels, and appearance of polycystic ovarian morphology upon ultrasound imaging [2]. Besides reproductive anomalies, these women are at an increased risk of developing type II diabetes, metabolic syndrome, and cardiovascular diseases (CVD), with subclinical markers being detected at earlier ages. While a clear-cut origin of PCOS has not emerged to explain its underlying pathophysiology, androgen excess and insulin resistance are reported to be the pivotal pathogenic drivers which extend reproductive, metabolic, and cosmetic consequences to affected women. The ovary remains the primary source of hyperandrogenism in women with PCOS which is mainly attributed to thecal cell hyperplasia leading to intense ovarian steroidogenesis. Evidence suggests that hyperandrogenism is an important factor in promoting anovulation due to follicular arrest [3] and high androgen level has been linked to reduced oocyte developmental competence and maturation rates. Further testosterone has been correlated with fertilization rates, embryo development, and miscarriage rates in women with PCOS [4]. Adrenal androgen excess has been reported in 20–30% of women with PCOS possibly due to defects in cortisol metabolism or common steroid pathway biosynthesis enzymes [5]. Apart from modifying reproductive outcomes, hyperandrogenemia also predicts severity of cardiometabolic profiles and CVD risk [6]. A recent meta-analysis has accentuated that hyperandrogenemia unfavourably influences the incidence of dyslipidemia, indices of insulin resistance, and metabolic syndrome risk [7]. The possibility of a genetic basis of hyperandrogenemia in PCOS has been recognized early [8] and candidate gene studies investigating the association of genes involved in androgen synthesis and action have strengthened this concept further [9, 10]. In the present review, we have outlined studies detailing the association of polymorphisms in these genes with PCOS susceptibility and its related traits.

2. General Steroid Metabolism

Ovary, the chief organ of interest is endowed with important functions of maintaining the female reproductive physiology. These include timely development of ovarian follicles and production of mature oocytes as well as the steroid hormones synthesis [11]. Steroidogenesis comprises processes by which the precursor cholesterol is converted to biologically active steroid hormones. Steroidogenic enzymes are responsible for the biosynthesis of various steroid hormones including glucocorticoids, mineralocorticoids, progestins, androgens, and estrogens. They consist of several specific cytochrome P450 enzymes (CYPs), hydroxysteroid dehydrogenases (HSDs), and steroid reductases [12]. De novo synthesis of all steroid hormones starts with the conversion of cholesterol to pregnenolone by CYP11A (cholesterol side-chain cleavage) [13]. CYP11A is bound to the inner membrane of the mitochondrion and is found in all steroid producing organs and tissues [12]. Pregnenolone is converted to progesterone by 3β-hydroxysteroid dehydrogenase (3β-HSD), found in both mitochondria and smooth endoplasmic reticulum. 3β-HSD is widely distributed in steroidogenic and nonsteroidogenic tissues and consists of two isoenzymes, which are regulated in a tissue-specific manner [1417]. The type 2 3β-HSD is predominantly expressed in steroidogenic tissues such as adrenal, testis, and ovary, whereas type 1 is found in placenta and in nonsteroidogenic tissues such as liver, kidney, and skin. Pregnenolone and progesterone form the precursors for all other steroid hormones.

In the ovary, steroidogenesis is a well-regulated process governed by the gonadotropins and signaling mechanisms occurring in the ovarian cells. Androgen synthesis predominantly takes place in thecal cells which have LH receptors and subsequent signaling and activation of CYP17 enzyme convert pregnenolone and progesterone to dehydroepiandrosterone (DHEA) and androstenedione, respectively. These androgens are further acted upon by CYP19 aromatase enzymes present in the FSH stimulated granulosa cells to estrogens which are essential for normal physiological functions of the human ovary.

3. Hyperandrogenemia and PCOS

The most common clinical manifestation of hyperandrogenism in women is hirsutism and excessive terminal hair growth in androgen-dependent areas of the body. Other clinical manifestations of hyperandrogenism include acne vulgaris, weight gain, menstrual irregularities, and acanthosis nigricans [1]. Hyperandrogenemia has been the common feature included in all three mainly proposed and employed diagnostic criteria put forward by the National Institute of Health in 1990, consensus criteria by the American Society for Reproductive Medicine (ASRM) and the European Society of Human Reproduction and Embryology (ESHRE) at Rotterdam in 2003, and more recently the Androgen Excess Society in 2006, which has asserted the inclusion of presence of clinical and/or biochemical hyperandrogenism to be imperative in diagnosis of PCOS. A controversial opinion regarding the inclusion of hyperandrogenism was debated at the 2012 joint meeting of ASRM and ESHRE whereupon it was noted that it was a significant predictor for diagnosis and prognosis of the syndrome and its accompanying metabolic maladies, thus forming an important criterion for inclusion into multicentric studies in PCOS [18].

PCOS is now considered as a disorder of androgen excess [19, 20]. In women with PCOS, there is increased gonadotropin-releasing hormone (GnRH) pulse frequency which favours increased LH secretion over that of follicle stimulating hormone (FSH) [21]. Under control of high pulsatile release of LH, the theca cells upregulate the expression of steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage (P450scc), 3β-hydroxysteroid dehydrogenase (3β-HSD), and cytochrome P450c17 (CYP17) and increase steroidogenic activity in the theca cells [22], thereby producing androstenedione. This action is further enhanced in a synergistic fashion by the high levels of insulin commonly observed in PCOS women. Androstenedione is then converted by aromatase to estrogen in the granulosa cells under the influence of pituitary FSH. However, there is relative deficit in FSH secretion which often results in impaired and arrested follicular development and reduced aromatase activity, thereby resulting in excess androgen accumulation and hyperandrogenemia in PCOS women.

Polycystic ovaries typically consist of numerous follicles arrested primarily in the preantral and antral stages with thecal hyperplasia and follicular fluid accumulation subsequently forming cyst-like structures which line the periphery of the ovary giving it a string of pearls-like appearance. Increased ovarian stromal volume along with many fluid filled follicles make these ovaries enlarged, a common morphological feature observed in PCOS women. In addition to thickened thecal layers, these follicles show increased steroidogenic activity. Insulin resistance, another major player in PCOS pathophysiology, intensifies the steroid inducing action of LH and indirectly increases LH pulse amplitude and progressively worsens this hyperandrogenemia. Insulin may also act directly via the insulin receptors on the ovary to augment ovarian steroidogenesis [23] and may also stimulate P450c17α activity in ovary and adrenal glands of PCOS women [24]. Insulin indirectly exacerbates hyperandrogenemia by reducing hepatic biosynthesis of sex hormone binding globulin and increasing the free and bioavailable testosterone levels. This creates a precarious physiologic environment of hormonal imbalance promoted by a sequence of hyperinsulinemia followed by hyperandrogenemia [23]. Coupled with lowered aromatase activity and diminished conversion of testosterone to estrogen, the circulating androgen pool continues to grow. Long-term cultures of theca and granulosa cells demonstrated significantly increased enzymatic activities of P450c17α and 3βHSD in PCOS theca cells with subsequent increased synthesis of testosterone precursors compared to normal cells [25, 26]. Follicular hyperandrogenemia induces marked changes in methylation status of essential genes for reproduction and development such as PPARγ, HDAC3, and NCOR1 [27]. Increased activity of both 17 and 20 lyase in the Δ4 pathway and 3β-hydroxysteroid dehydrogenase II combined with low aromatase activity was documented in hyperandrogenic PCOS women. Thus, the heterogeneity in androgenic phenotype may be attributed to differential activity of important enzymes in the steroidogenic pathway [28].

While the metabolic derangements of PCOS have mainly been attributed to the insulin resistance and obesity frequently present in these women, increased abdominal adiposity develops as a consequence of hyperandrogenemia. Sensitive indicators of hyperandrogenism include total and free testosterone and androstenedione levels, and free androgen index (FAI) which are capable of predicting phenotype heterogeneity and severity [29]. Recently use of mass spectrometry based techniques such as liquid chromatography- and gas chromatography-MS/MS for serum and urinary steroid hormone profiling have led to more accurate measurements of androgen levels in women with PCOS and have been hailed as the gold standard for testosterone assay by the Endocrine Society [30]. These techniques have enabled researchers to accurately measure low concentrations of testosterone (<5 nmol/l) and prevent inaccurate measurement due to cross-reactivity with DHEAS as seen in immunoassay methods [31]. This has led to assignment of lower cut-off values for total and free testosterone [32], thereby improving diagnosis and subclassification of PCOS women [33]. However hirsutism scores do not necessarily correlate with steroid concentrations measured in affected women [29]. Further, PCOS women showing biochemical androgen excess are more prone to reduced insulin sensitivity and dysglycemia [34], number of menstrual cycles in a year, elevated cardiovascular disease markers, dyslipidemia, and heightened predisposition to metabolic syndrome [35].

Experimental evidence strongly implicates the role of hyperandrogenic intrauterine hormonal milieu in influencing the development of PCOS-like reproductive and metabolic features in monkey and sheep animal models. Prenatally androgenized ewes showed early increase in LH secretion, coupled with progressive loss in reproductive cyclicity and ovulatory failure [36], increased number of primary follicles [37], and persistent follicular cysts [38] along with upregulation of steroidogenic genes such as StAR, CYP11A, and CYP17 in thecal cells of female offspring [39]. Similarly, female rhesus monkeys prenatally exposed to testosterone demonstrate LH hypersecretion, anovulation, and polyfollicular ovaries with increased follicular recruitment with impaired oocyte developmental competence [40]. Moreover, maternal or fetal exposure to high doses of androgens has been reported to alter pancreatic morphology, particularly beta cell development, which may contribute to insulin resistance and consequent hyperinsulinemia in rhesus monkeys and sheep models [41, 42]. Adrenal androgen excess has also been reported in prenatally androgenized nonhuman primate models for PCOS as indicated by elevated basal circulating levels of DHEA and DHEAS. Furthermore, treatment with thiazolidinedione-based insulin sensitizers ameliorates adrenal steroidogenesis along with reducing insulin resistance [43]. Women with PCOS were more likely to give birth to small for gestational age infants which has been associated with increased maternal testosterone levels [44]. Findings of high AMH levels in daughters born to women with PCOS suggest altered follicular development from an early age [45]. Familial prevalence of PCOS and its associated phenotypes provides evidence of possible maternal transmission and genetic inheritance of this disorder [10]. Maternal heritability had significant effects on the prevalence of fasting dysglycemia in women with PCOS [46]. These studies support prenatal activation and fetal programming which passes PCOS-like traits in subsequent generations. Xita et al. have elegantly hypothesized that exposure to androgen excess encourages fetal programming of PCOS by altering phenotypic expression of reproductive and metabolic tissues and results in altered differentiation of thecal cells, LH hypersecretion, and male-type fat distribution in female offspring. Moreover genotypes related to regulating androgen levels, activity and bioavailability in PCOS mothers can modulate the extent of androgen exposure in utero [47]. Epigenetic changes and subsequently altered gene expression and maternal nutrition have also been found to influence fetal programming [4749]. On the other hand, it was also shown that increased maternal androgen levels may not induce PCOS in female fetus provided normal placental aromatization activity is maintained [49]. Altogether, these findings highlight the role of hyperandrogenism in critical windows of fetal development in modifying PCOS susceptibility.

PCOS is also thus regarded as a form of functional ovarian hyperandrogenism, where all the above-mentioned aberrations contribute towards not only the reproductive dysfunctions but also the metabolic anomalies observed in these women (Figure 1).

Figure 1: Overview of pathophysiology of PCOS. Androgen biosynthesis is a well-orchestrated process occurring in the ovary mediated by an enzymatic cascade under stimulation by pituitary LH. In PCOS, accumulation of small antral follicles with thecal hyperplasia along with overexpression of steroidogenic enzymes results in elevated testosterone levels. In contrast, downregulation of aromatase enzymes decreases testosterone to estradiol conversion, leading to release of large amounts of circulating testosterone. In addition, women with PCOS display insulin resistance coupled with compensatory hyperinsulinemia. Insulin acts directly on the ovary, via its receptors, as well as synergistically with LH to enhance androgen production. On the other hand, insulin acts indirectly via decreasing hepatic biosynthesis of sex hormone binding globulin, thereby raising biologically available testosterone levels. The hyperandrogenic phenotype is typically characterized by arrest in folliculogenesis and consequent anovulatory infertility and cosmetic problems such as hirsutism, acne, and androgenic alopecia. It also contributes to increased incidence of metabolic disorders including insulin resistance, dyslipidemia, metabolic syndrome, and cardiovascular disease.

4. Genetics of PCOS

PCOS has a strong genetic component as evidenced by clustering of PCOS in families as well as PCOS-like features in both male and female relatives of affected women [1]. Approaches such as twin studies and linkage studies have been employed in order to decipher the contribution of heritability in this multifactorial disorder. Linkage studies of 37 candidate genes predicted strong association of follistatin and nominal association of CYP11A1 gene in affected siblings with hyperandrogenemia and PCOS related traits. This same study established strong genetic association of D19S884 allelic marker near INSR gene with PCOS, by transmission disequilibrium test [50]. Association studies of candidate genes involved in pathways related to the etiology of the syndrome and its associated anomalies have garnered interest from the research community to try and pinpoint the significance of genetic predisposition in manifestation of this syndrome [10]. Polymorphisms of genes involved in pathways including insulin signaling, gonadotropin regulation, chronic inflammation, and energy homeostasis have been studied [10]; however, the exact role of these susceptibility genes has not yet been established. Single nucleotide polymorphisms (SNPs) reveal functional changes due to the fact that amino acid variations or modulation of gene expression and candidate gene approaches are helpful in deciphering the impact of differential frequency distribution in healthy and diseased population. Simultaneously, while candidate gene approaches have been studied in relatively smaller populations, genome-wide association studies have revolutionized the study of PCOS genetics. Previously we have reviewed the genes involved in insulin action and regulation with PCOS susceptibility and related traits [51]. Given the importance of androgens in female reproductive health and PCOS development, in the current review, we will be concentrating on polymorphisms in genes involved in androgen synthesis, action, and bioavailability.

CYP11A1 Gene. CYP11A1 on 15q23-24 encodes the enzyme P450 cholesterol side-chain cleavage that catalyzes the rate limiting step of ovarian steroidogenesis, that is, the conversion of cholesterol to pregnenolone [52, 53]. Theca cells derived from PCOS ovaries and propagated in long-term culture demonstrate increased CYP11A expression compared to normal theca cells [54, 55]. An early linkage study carried out in 20 families showed involvement of CYP11A locus in PCOS development and subsequently association of 5′UTR (TTTTA)n pentanucleotide repeats in hirsute PCOS women [56]. Positive association of pentanucleotide repeat alleles with PCOS susceptibility were confirmed subsequently in women from United States [57], South India [58], and Greece [59] and nominally in women from United Kingdom [60]. Wang et al. have demonstrated that different allele combinations may increase or decrease the risk of PCOS in Chinese women [61]. In contrast to earlier findings, no association was reported in Spanish [62], Chinese [63, 64], Argentinian [65], Indian [53], and Czech [66] women with PCOS. A recent meta-analysis confirmed strong association of this (TTTTA)n repeat polymorphism of CYP11A with increased risk of PCOS in Caucasian population [67]. Furthermore, another meta-analysis indicated that carriers of 4 repeats had increased risk considering the recessive model while carriers of 6 repeats showed decreased risk of PCOS considering the dominant model [68]. Conflicting reports regarding the association of these pentanucleotide repeats with PCOS related traits are available. Increased testosterone levels have been reported in carriers of short alleles in women with PCOS [53, 59] while no effect of allele dose was seen on CYP11A transcription [57] or serum androgen levels in another studies [57, 60, 63]. What is more this repeat polymorphism shows significant relationship with metabolic traits including obesity [61], higher waist-hip ratio, decreased AUC glucose values [64], alleviated dyslipidemia [66], and decreased FSH levels [66]. Another polymorphism, rs4077582, showed significant association in Chinese women with PCOS [69, 70] as well as altered testosterone and LH levels [70]. One more polymorphism, namely, rs11632698, showed both positive [69] and negative [70] association with PCOS risk in Chinese women. Together, these studies imply CYP11A to be a promising genetic biomarker for PCOS.

CYP17 Gene. The CYP17 gene at 10q24.3 encodes cytochrome P450 enzyme with 17-hydroxylase activity, which converts pregnenolone and progesterone into 17-hydroxypregnenolone and 17-hydroxyprogesterone, respectively. The 17,20-lyase activity subsequently converts these steroids to dehydroepiandrosterone (DHEA) and 4-androstenedione [10]. The vast majority of studies have focused on a widely studied polymorphism at −34 position (−34 T/C) in the promoter, which creates an additional Sp1 transcription factor binding site, thereby regulating expression of CYP17 and consequently androgen levels [71]. In 1994, Carey et al. showed significant association of this polymorphism with PCO and male pattern baldness in a family-based study [72]; however, these findings were not persistent when they increased the sample size [73]. On similar lines, this polymorphism was not found to be a significant factor for PCOS development in British [74], Slovenian [75], Polish [76], American [77, 78], Korean [79], Chilean [80], Chinese [81], Thai [82], and Indian [83] women with PCOS or even in Turkish adolescents [84]. In contrast, Indian women with PCOS showed significantly increased frequency of C allele [53]. This polymorphism impacts the hyperandrogenic phenotype in women with PCOS [53, 65, 81]. Interestingly, this polymorphism negatively influenced metabolic traits including obesity [80, 82], waist circumference [80], and insulin resistance [80]. A meticulous meta-analysis taking into consideration all studies revealed that this variant was not associated with risk of PCOS development when considering any genetic model or even after stratification by country and ethnicity. Furthermore, amongst studies which were in Hardy-Weinberg equilibrium, significantly increased risk was seen considering the dominant genetic model. However, they suggest sample size may also influence these associations as shown by increased risk in small sample compared to large sample studies [85].

CYP19 Gene. The aromatase p450 enzyme, essential for synthesis of estrogen from androgens, is encoded by CYP19 gene on chromosome 15q21.2 [86]. Reduced aromatase activity in both lean and obese women with PCOS has reported [87] and activity is further inhibited by hyperandrogenemia [28]. Yang et al. have demonstrated decreased aromatase expression concomitant with increased levels of testosterone in follicular fluid derived from PCOS women [88]. Promoter hypermethylation and reduced CYP19A1 mRNA and protein levels were evident in PCOS ovaries, suggesting repressed aromatase expression [89]. An intronic variant rs2414096 was shown to be significantly associated with increased risk of PCOS development and with increased estradiol to testosterone ratio (E2/T), FSH levels, and age of menarche in Han Chinese women [90]. Raised PCOS symptom score and changes in circulating estradiol and testosterone concentrations were observed in adolescent girls in the UK carrying this polymorphism [91]. Additionally, certain promoter variants were independently associated with PCOS symptom score in UK adolescents [92]. The rs2414096 polymorphism lacked association with PCOS or with alterations in hormonal and metabolic variables after undergoing a 6-month treatment regime of oral contraceptives in both anovulatory and ovulatory PCOS women [93]. Another common polymorphism, a tetranucleotide repeat polymorphism (TTTA)n in the fourth intron related to suboptimal aromatase activity [94], has been investigated. Reports are available indicating that short allele repeats, predominantly consisting of seven repeats, are prevalent in Greek [9496] and Han Chinese [97] women with PCOS compared to controls. These short repeat alleles were associated with hormonal parameters including increased testosterone levels, high LH : FSH ratios [94], and reduced reproductive markers such as number of large follicles and total oocyte count [95]. Interestingly, these alleles predicted successful pregnancy following assisted reproductive technique intervention [95]. Carriers of 11 repeat alleles are also commonly found in Chinese women with PCOS [97, 98] which influence lipid metabolism [97]. Another polymorphism, rs2470152, did not affect PCOS risk but the heterozygous TC genotype was found to be significantly associated with increased testosterone levels with decreased E2/T ratio, suggesting role of this polymorphism in regulating aromatase activity [99]. A missense polymorphism, Arg264Cys, increases aromatase activity and affects PCOS susceptibility [100]. However, the above findings indicate a definite role of this gene in PCOS outcome.

AR Gene. The androgen receptor (AR) gene located on the X chromosome encodes the AR, which consists of a poorly conserved N terminal domain containing highly polymorphic CAG repeats [101]. An inverse correlation has been demonstrated between CAG repeat number and AR transactivation efficiency [102]. An interesting case study reported that a woman carrying a heterozygous AR gene mutation gave birth to a baby with androgen insensitivity syndrome suggesting plausible repercussions on reproductive outcomes associated with AR gene mutations [103] and not only with repeat lengths. AR has been primarily localized in the theca interna cells of preantral follicles, granulosa cells of preantral and antral follicles, and both theca and granulosa cells of dominant follicles [104]. Inconsistent associations of the differences in number of CAG repeats in exon 1 have been reported with PCOS prevalence. It has later been ascertained that short AR CAG repeats were more frequent in PCOS cases and may possibly be linked to PCOS onset in both Chinese and Caucasian populations [100, 105108]. This may contribute to the inherent hyperandrogenic phenotype commonly seen in women with PCOS by increasing AR activity and enhancing androgen sensitivity to even low circulating levels of testosterone, thereby promoting hirsutism, acne, and irregular cycles [106, 109]. Anovulatory normoandrogenic PCOS women showed a significant trend towards short CAG repeat length indicating increased intrinsic androgen sensitivity [110]. Furthermore, they found that Indian women showed comparatively shorter repeat lengths compared to Chinese women, indicating possible role of ethnic variation [110]. No association of AR CAG repeat lengths with PCOS was reported in Indian [111], Slovene [112], Korean [113], Croatian, [114] and Finnish women [115]. A few studies have indicated that CAG repeat lengths may also modify both testosterone and insulin resistance parameters in women with PCOS despite failing to show association with PCOS risk. This CAG repeat polymorphism was found to be a significant predictor of serum circulating testosterone levels in Croatian [114], Brazilian [116], Chinese [101] and Korean [113] women with PCOS. German women carrying short CAG repeats presented with increased testosterone which in turn aggravated insulin resistance in these women suggesting a putative effect of CAG repeats as an underlying mechanism of hyperandrogenemia induced insulin resistance [117]. In contrast, infertile Australian PCOS women showed preferential expression of long CAG repeat alleles compared to fertile PCOS women [118]. Meta-analyses examining the relationship between CAG repeat lengths at AR and PCOS risk have concluded that they may not be major determining factors in PCOS etiology [111, 119, 120]. Apart from CAG repeat, other groups have concluded that a GGN repeat polymorphism and rs6152G/A polymorphism were also significantly associated with PCOS in Chinese women [121, 122]. Thus, AR polymorphisms may exacerbate the hyperandrogenic phenotype of women with PCOS.

SHBG Gene. Sex hormone binding globulin (SHBG) is primarily synthesized in the liver, binds androgens, and estrogen with high affinity, thereby lowering circulating steroid hormones and rendering them biologically unavailable to target tissues [123]. Several polymorphisms in the SHBG gene located on chromosome 17 have been shown to alter hepatic biosynthesis, plasma levels, and plasma clearance efficiency of SHBG, thereby regulating the distribution of sex steroid hormones [123]. Two novel coding region mutations were discovered in a woman showing severe SHBG deficiency, one which resulted in abnormal glycosylation and the other to truncated SHBG synthesis. This led to remarkably low SHBG levels with elevated circulating free testosterone concentrations [124]. The putative genetic contribution of SHBG polymorphisms was further supported by evidence of association of longer TAAAA repeats with late onset of menarche [125] and decreased SHBG levels in hirsute French women [126]. Long TAAAA repeat alleles failed to show association with PCOS risk in Croatian [127], Slovenian [128], French [126], and Chinese [129] women. However Greek women with PCOS had significantly greater frequency of long repeat alleles compared to controls [130]. An inverse association between TAAAA repeat polymorphism alone [126128, 130] or coupled with short AR CAG repeats [96] and SHBG serum levels has been established. Greek women with PCOS having long SHBG alleles coupled with short CYP19 alleles demonstrated low SHBG levels and increased testosterone levels with raised FAI, DHEAS and T/E2 ratios [96]. A meta-analysis was unable to draw a conclusive association between the TAAAA repeat polymorphism with PCOS risk indicating that it may not be a reliable predictor of PCOS onset [131]. A functional missense polymorphism in exon 8 causes an amino acid change from aspartic acid to asparagine (D327N), delays SHBG half-life, and influences the metabolism of SHBG [126]. Another missense polymorphism, E326K lowered SHBG levels in women with PCOS independently of BMI, androgen, and insulin related traits [132]. Family-based and case-control association studies have found that rs1799941 and rs727428 in SHBG gene influenced SHBG metabolism in American and Mediterranean women with PCOS [133, 134], but not PCOS risk [133]. A recent study in Bahraini women has concluded that haplotypes spanning six polymorphisms were associated with either increased or decreased PCOS susceptibility [135] rekindling interest in SHBG gene polymorphisms in PCOS susceptibility.

StAR Gene. The StAR gene located on chromosome 8p11.2 encodes the steroidogenic acute regulatory protein which binds to and facilitates uptake of cholesterol into mitochondria of cells for steroidogenesis. However a pilot study carried out in Iranian women investigating seven known polymorphisms showed no significant association with PCOS risk [136].

HSD17B5 Gene. The enzyme type 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5) is instrumental in converting androstenedione to testosterone in theca cells and adrenal glands [137]. The −71A/G polymorphism in the promoter region was revealed for the first time by Qin et al., who also investigated its prevalence in a population of ethnically diverse PCOS women. Here they found that this variant was associated with PCOS susceptibility in Caucasian but not in African American women with PCOS [138]. It also modulates testosterone biosynthesis and thereby plasma testosterone levels [138]. Subsequent studies failed to find this association in Greek [139] and Caucasian [140] women with PCOS. Intronic polymorphism rs12529 affected testosterone levels but PCOS risk remained unchanged in Chinese women. On the other hand, rs1937845 not only increased risk of PCOS development but also increased homeostasis model assessment of β-cell function (HOMA-B) index and testosterone levels in these women [137]. In Brazilian women with PCOS, improvement in hyperandrogenic phenotype could be attributed to treatment regimen with oral contraceptive pills but not HSD17B5 polymorphisms [141].

INSL3 Gene. Insulin-like factor 3 (INSL3) is localized in the thecal cells and corpus luteum of the ovary. A pioneering study by Glister et al. established the role of INSL3-RXFP2 signaling in maintaining androgen production by the ovarian theca cells [142]. Recently, women with PCOS were reported to have increased serum INSL3 levels [143145]. INSL3 polymorphisms may have an important role in modulating ovarian steroidogenesis and hence contribute to the pathogenesis of PCOS. To the best of our knowledge, our group has conducted the first case-control association study investigating relationship between INSL3 polymorphisms and its haplotypes with PCOS susceptibility and its related traits in a well characterized cohort of Indian women with PCOS [146]. Our study showed that the A/G rs6523 polymorphism present in exon 1 of INSL3 was significantly associated with PCOS susceptibility. Other coding region polymorphisms along with the rs6543 SNP affect both the metabolic and hyperandrogenemia related traits of PCOS in both controls and women with PCOS. These polymorphisms have differential influence depending on the physiological state present [146]. No other studies have been attempted to replicate this association till date.

5. Conclusion

PCOS remains an endocrine enigma even today characterized by adverse hormonal perturbations raising metabolic and gynecological concerns in affected women. Genetic factors work in tandem with environmental signals contributing to its pathogenesis. A hallmark feature of PCOS remains augmented androgen synthesis and consequent circulating levels which is frequently associated with cosmetic complaints including hirsutism, acne, and alopecia. The ovary remains the primary source of hyperandrogenism in women with PCOS. Thecal cell hyperplasia coupled with enhanced steroidogenic potential of androgen pathway enzymes may contribute to excess androgen production in ovaries of affected women. The current review has encapsulated salient findings from candidate gene based association studies of polymorphisms in genes involved in steroidogenesis as well as androgen levels and action which are presumed to govern PCOS susceptibility and phenotypic heterogeneity of the disorder. However, candidate gene studies have not provided conclusive results due to different diagnostic criteria, the likely contribution of multiple genes, differences in lifestyle, environmental factors, and the sample size studied. On the other hand, genome-wide association studies (GWAS) empower researchers with the capacity to explore thousands of variants across the entire genome in both case and control participants to uncover association of genetic variants with complex disease in an unbiased manner. The notable GWAS studies in Chinese populations have essentially offered several loci mapping to DENND1A, THADA, LHCGR, FSHR, INSR, TOX3, YAP1, RAB5B, c9orf3, HMGA2, and SUMO1P1/ZNF217 involved in steroidogenesis, gonadotropin action and regulation, follicular development, insulin signaling and type 2 diabetes mellitus (T2DM), calcium signaling, and endocytosis [147, 148]. Of these loci, DENND1A has been implicated as a driving force for PCOS hyperandrogenemia. Overexpression in normal ovaries was found to upregulate ovarian steroidogenesis whereas knockdown decreases steroid synthesis by reducing transcription of CYP11A1 and CYP17 [149]. Interestingly, alternative splicing of DENND1A to produce v.2 variant is supposed to be important in PCOS development [150] and DENND1A v.2 was highly concentrated in theca cells of ovaries of women with PCOS [149]. On the other hand, although DENDD1A v.1 was abundant in the NCI-H295 adrenal steroidogenic cell line, overexpression of v.2 increased expression of CYP17 and CYP11A enzymes [150]. The association of the LHCGR locus with PCOS in GWAS [148] strengthens the rationale that alteration in receptor expression could contribute to LH hyperstimulation, thereby enhancing steroidogenesis. Findings from GWAS in European population has highlighted the significant association of gene polymorphisms in FDFT1 and GATA4 involved in cholesterol synthesis and a potent regulator of steroidogenic gene transcription, respectively, suggesting altered androgen synthesis [151]. Thus while candidate genes have offered substantial evidence to strengthen the role of genetic variants in modulating PCOS hyperandrogenism, GWAS has provided new clues which need to be explored in greater detail in different ethnic populations. Selection of suitable candidate genes should continue in order to successfully delineate the genetic underpinnings of a multigenic complex disorder like PCOS. These would pave the way for establishing genetic predisposition profiles which could be harnessed for designing therapeutic management strategies in future.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors acknowledge the financial assistance provided by University Grants Commission to Roshan Dadachanji for pursuing her doctoral studies. The authors gratefully acknowledge NIRRH (REV/526/08-2017) for providing necessary support.

References

  1. M. O. Goodarzi, D. A. Dumesic, G. Chazenbalk, and R. Azziz, “Polycystic ovary syndrome: etiology, pathogenesis and diagnosis,” Nature Reviews Endocrinology, vol. 7, no. 4, pp. 219–231, 2011. View at Publisher · View at Google Scholar · View at Scopus
  2. H. Teede, A. Deeks, and L. Moran, “Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan,” BMC Medicine, vol. 8, article 41, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. S. Jonard and D. Dewailly, “The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest,” Human Reproduction Update, vol. 10, no. 2, pp. 107–117, 2004. View at Publisher · View at Google Scholar · View at Scopus
  4. J. Qiao and H. L. Feng, “Extra- and intra-ovarian factors in polycystic ovary syndrome: Impact on oocyte maturation and embryo developmental competence,” Human Reproduction Update, vol. 17, no. 1, pp. 17–33, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. M. O. Goodarzi, E. Carmina, and R. Azziz, “DHEA, DHEAS and PCOS,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 145, pp. 213–225, 2015. View at Publisher · View at Google Scholar · View at Scopus
  6. N. M. P. Daan, Y. V. Louwers, M. P. H. Koster et al., “Cardiovascular and metabolic profiles amongst different polycystic ovary syndrome phenotypes: who is really at risk?” Fertility and Sterility, vol. 102, no. 5, pp. 1444.e3–1451.e3, 2014. View at Publisher · View at Google Scholar
  7. R. Yang, S. Yang, R. Li, P. Liu, J. Qiao, and Y. Zhang, “Effects of hyperandrogenism on metabolic abnormalities in patients with polycystic ovary syndrome: A meta-analysis,” Reproductive Biology and Endocrinology, vol. 14, no. 1, article no. 67, 2016. View at Publisher · View at Google Scholar · View at Scopus
  8. R. S. Legro, D. Driscoll, J. F. Strauss III, J. Fox, and A. Dunaif, “Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 95, no. 25, pp. 14956–14960, 1998. View at Publisher · View at Google Scholar · View at Scopus
  9. N. Xita, I. Georgiou, and A. Tsatsoulis, “The genetic basis of polycystic ovary syndrome,” European Journal of Endocrinology, vol. 147, no. 6, pp. 717–725, 2002. View at Publisher · View at Google Scholar · View at Scopus
  10. N. Prapas, A. Karkanaki, I. Prapas, I. Kalogiannidis, I. Katsikis, and D. Panidis, “Genetics of polycystic ovary syndrome,” Hippokratia, vol. 13, no. 4, pp. 216–223, 2009. View at Google Scholar · View at Scopus
  11. E. A. McGee and A. J. W. Hsueh, “Initial and cyclic recruitment of ovarian follicles,” Endocrine Reviews, vol. 21, no. 2, pp. 200–214, 2000. View at Publisher · View at Google Scholar · View at Scopus
  12. W. L. Miller, “Molecular biology of steroid hormone synthesis,” Endocrine Reviews, vol. 9, no. 3, pp. 295–318, 1988. View at Publisher · View at Google Scholar · View at Scopus
  13. K. L. Parker and B. P. Schimmer, “Transcriptional regulation of the genes encoding the cytochrome P-450 steroid hydroxylases,” in Vitamins and Hormones, vol. 51, pp. 339–370, 1995. View at Publisher · View at Google Scholar
  14. S. Gingras, S. Côté, and J. Simard, “Multiple signal transduction pathways mediate interleukin-4-induced 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase in normal and tumoral target tissues,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 76, no. 1-5, pp. 213–225, 2001. View at Publisher · View at Google Scholar · View at Scopus
  15. S. Leers-Sucheta, K.-I. Morohashi, J. I. Mason, and M. H. Melner, “Synergistic activation of the human type II 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase promoter by the transcription factor steroidogenic factor-1/adrenal 4-binding protein and phorbol ester,” The Journal of Biological Chemistry, vol. 272, no. 12, pp. 7960–7967, 1997. View at Publisher · View at Google Scholar · View at Scopus
  16. J. I. Mason, D. S. Keeney, I. M. Bird et al., “The regulation of 3β-hydroxysteroid dehydrogenase expression,” Steroids, vol. 62, no. 1, pp. 164–168, 1997. View at Publisher · View at Google Scholar · View at Scopus
  17. J. Simard, M.-L. Ricketts, S. Gingras, P. Soucy, F. A. Feltus, and M. H. Melner, “Molecular biology of the 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase gene family,” Endocrine Reviews, vol. 26, no. 4, pp. 525–582, 2005. View at Publisher · View at Google Scholar · View at Scopus
  18. L. Gianaroli, C. Racowsky, J. Geraedts, M. Cedars, A. Makrigiannakis, and R. A. Lobo, “Best practices of ASRM and ESHRE: A journey through reproductive medicine,” Fertility and Sterility, vol. 98, no. 6, pp. 1380–1394, 2012. View at Publisher · View at Google Scholar · View at Scopus
  19. R. Azziz, “Androgen excess is the key element in polycystic ovary syndrome,” Fertility and Sterility, vol. 80, no. 2, pp. 252–254, 2003. View at Publisher · View at Google Scholar · View at Scopus
  20. E. Diamanti-Kandarakis, J. Papailiou, and S. Palimeri, “Hyperandrogenemia: pathophysiology and its role in ovulatory dysfunction in PCOS,” Pediatric Endocrinology Reviews, vol. 3, supplement 1, pp. 198–204, 2006. View at Google Scholar · View at Scopus
  21. S. K. Blank, C. R. McCartney, K. D. Helm, and J. C. Marshall, “Neuroendocrine effects of androgens in adult polycystic ovary syndrome and female puberty,” Seminars in Reproductive Medicine, vol. 25, no. 5, pp. 352–359, 2007. View at Publisher · View at Google Scholar · View at Scopus
  22. E. Diamanti-Kandarakis, G. Argyrakopoulou, F. Economou, E. Kandaraki, and M. Koutsilieris, “Defects in insulin signaling pathways in ovarian steroidogenesis and other tissues in polycystic ovary syndrome (PCOS),” The Journal of Steroid Biochemistry and Molecular Biology, vol. 109, no. 3–5, pp. 242–246, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. S. Mukherjee and A. Maitra, “Molecular & genetic factors contributing to insulin resistance in polycystic ovary syndrome,” Indian Journal of Medical Research, vol. 131, pp. 743–760, 2010. View at Google Scholar
  24. G. N. Allahbadia and R. Merchant, “Polycystic ovary syndrome and impact on health,” Middle East Fertility Society Journal, vol. 16, no. 1, pp. 19–37, 2011. View at Publisher · View at Google Scholar · View at Scopus
  25. V. L. Nelson, K. Qin, R. L. Rosenfield et al., “The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome,” The Journal of Clinical Endocrinology & Metabolism, vol. 86, no. 12, pp. 5925–5933, 2001. View at Publisher · View at Google Scholar
  26. K. Takayama, T. Fukaya, H. Sasano et al., “Immunohistochemical study of steroidogenesis and cell proliferation in polycystic ovarian syndrome,” Human Reproduction, vol. 11, no. 7, pp. 1387–1392, 1996. View at Publisher · View at Google Scholar · View at Scopus
  27. F. Qu, F.-F. Wang, R. Yin et al., “A molecular mechanism underlying ovarian dysfunction of polycystic ovary syndrome: Hyperandrogenism induces epigenetic alterations in the granulosa cells,” Journal of Molecular Medicine, vol. 90, no. 8, pp. 911–923, 2012. View at Publisher · View at Google Scholar · View at Scopus
  28. S. F. De Medeiros, J. S. Barbosa, and M. M. W. Yamamoto, “Comparison of steroidogenic pathways among normoandrogenic and hyperandrogenic polycystic ovary syndrome patients and normal cycling women,” Journal of Obstetrics and Gynaecology Research, vol. 41, no. 2, pp. 254–263, 2015. View at Publisher · View at Google Scholar · View at Scopus
  29. R. Pasquali, L. Zanotti, F. Fanelli et al., “Defining hyperandrogenism in women with polycystic ovary syndrome: a challenging perspective,” The Journal of Clinical Endocrinology & Metabolism, vol. 101, no. 5, pp. 2013–2022, 2016. View at Publisher · View at Google Scholar
  30. W. Rosner, R. J. Auchus, R. Azziz, P. M. Sluss, and H. Raff, “Position statement: Utility, limitations, and pitfalls in measuring testosterone: An endocrine society position statement,” The Journal of Clinical Endocrinology & Metabolism, vol. 92, no. 2, pp. 405–413, 2007. View at Publisher · View at Google Scholar · View at Scopus
  31. J. H. Barth, H. P. Field, E. Yasmin, and A. H. Balen, “Defining hyperandrogenism in polycystic ovary syndrome: Measurement of testosterone and androstenedione by liquid chromatography-tandem mass spectrometry and analysis by receiver operator characteristic plots,” European Journal of Endocrinology, vol. 162, no. 3, pp. 611–615, 2010. View at Publisher · View at Google Scholar · View at Scopus
  32. W. A. Salameh, M. M. Redor-Goldman, N. J. Clarke, R. Mathur, R. Azziz, and R. E. Reitz, “Specificity and predictive value of circulating testosterone assessed by tandem mass spectrometry for the diagnosis of polycystic ovary syndrome by the National Institutes of Health 1990 criteria,” Fertility and Sterility, vol. 101, no. 4, pp. 1135.e2–1141.e2, 2014. View at Publisher · View at Google Scholar · View at Scopus
  33. L. M. Bloem, K.-H. Storbeck, P. Swart, T. Du Toit, L. Schloms, and A. C. Swart, “Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 153, article no. 4400, pp. 80–92, 2015. View at Publisher · View at Google Scholar · View at Scopus
  34. M. W. O'Reilly, A. E. Taylor, N. J. Crabtree et al., “Hyperandrogenemia predicts metabolic phenotype in polycystic ovary syndrome: the utility of serum androstenedione,” The Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 3, pp. 1027–1036, 2014. View at Google Scholar
  35. Y.-A. Sung, J.-Y. Oh, H. Chung, and H. Lee, “Hyperandrogenemia is implicated in both the metabolic and reproductive morbidities of polycystic ovary syndrome,” Fertility and Sterility, vol. 101, no. 3, pp. 840–845, 2014. View at Publisher · View at Google Scholar · View at Scopus
  36. R. A. Birch, V. Padmanabhan, D. L. Foster, W. P. Unsworth, and J. E. Robinson, “Prenatal programming of reproductive neuroendocrine function: Fetal androgen exposure produces progressive disruption of reproductive cycles in sheep,” Endocrinology, vol. 144, no. 4, pp. 1426–1434, 2003. View at Publisher · View at Google Scholar · View at Scopus
  37. R. A. Fordslike, K. Hardy, L. Bull et al., “Disordered follicle decelopment in ovaries of prenatally androgenized ewes,” Journal of Endocrinology, vol. 192, no. 2, pp. 421–428, 2007. View at Publisher · View at Google Scholar · View at Scopus
  38. M. Manikkam, T. L. Steckler, K. B. Welch, E. K. Inskeep, and V. Padmanabhan, “Fetal programming: Prenatal testosterone treatment leads to follicular persistence/luteal defects; partial restoration of ovarian function by cyclic progesterone treatment,” Endocrinology, vol. 147, no. 4, pp. 1997–2007, 2006. View at Publisher · View at Google Scholar · View at Scopus
  39. K. Hogg, J. M. Young, E. M. Oliver, C. J. Souza, A. S. McNeilly, and W. C. Duncan, “Enhanced thecal androgen production is prenatally programmed in an ovine model of polycystic ovary syndrome,” Endocrinology, vol. 153, no. 1, pp. 450–461, 2012. View at Publisher · View at Google Scholar · View at Scopus
  40. D. A. Dumesic, D. H. Abbott, and V. Padmanabhan, “Polycystic ovary syndrome and its developmental origins,” Reviews in Endocrine and Metabolic Disorders, vol. 8, no. 2, pp. 127–141, 2007. View at Publisher · View at Google Scholar · View at Scopus
  41. L. E. Nicol, T. D. O'Brien, D. A. Dumesic, T. Grogan, A. F. Tarantal, and D. H. Abbott, “Abnormal infant islet morphology precedes insulin resistance in PCOS-like monkeys,” PLoS ONE, vol. 9, no. 9, Article ID 0106527, 2014. View at Publisher · View at Google Scholar · View at Scopus
  42. M. Rae, C. Grace, K. Hogg et al., “The pancreas is altered by in utero androgen exposure: implications for clinical conditions such as polycystic ovary syndrome (PCOS),” PLoS ONE, vol. 8, no. 2, Article ID e56263, 2013. View at Publisher · View at Google Scholar · View at Scopus
  43. D. Abbott, R. Zhou, I. Bird, D. Dumesic, and A. Conley, “Fetal programming of adrenal androgen excess: Lessons from a nonhuman primate model of polycystic ovary syndrome,” Endocrine Development, vol. 13, pp. 145–158, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. T. Sir-Petermann, C. Hitchsfeld, M. Maliqueo et al., “Birth weight in offspring of mothers with polycystic ovarian syndrome,” Human Reproduction, vol. 20, no. 8, pp. 2122–2126, 2005. View at Publisher · View at Google Scholar · View at Scopus
  45. T. Sir-Petermann, E. Codner, M. Maliqueo et al., “Increased anti-müllerian hormone serum concentrations in prepubertal daughters of women with polycystic ovary syndrome,” The Journal of Clinical Endocrinology & Metabolism, vol. 91, no. 8, pp. 3105–3109, 2006. View at Publisher · View at Google Scholar · View at Scopus
  46. K. Kobaly, P. Vellanki, R. K. Sisk et al., “Parent-of-origin effects on glucose homeostasis in polycystic ovary syndrome,” The Journal of Clinical Endocrinology & Metabolism, vol. 99, no. 8, pp. 2961–2966, 2014. View at Publisher · View at Google Scholar · View at Scopus
  47. N. Xita and A. Tsatsoulis, “Review: fetal programming of polycystic ovary syndrome by androgen excess: Evidence from experimental, clinical, and genetic association studies,” The Journal of Clinical Endocrinology & Metabolism, vol. 91, no. 5, pp. 1660–1666, 2006. View at Publisher · View at Google Scholar · View at Scopus
  48. N. Xita and A. Tsatsoulis, “Fetal origins of the metabolic syndrome,” Annals of the New York Academy of Sciences, vol. 1205, pp. 148–155, 2010. View at Publisher · View at Google Scholar · View at Scopus
  49. D. A. Dumesic, M. O. Goodarzi, G. D. Chazenbalk, and D. H. Abbott, “Intrauterine environment and polycystic ovary syndrome,” Seminars in Reproductive Medicine, vol. 32, no. 3, pp. 159–165, 2014. View at Publisher · View at Google Scholar · View at Scopus
  50. M. Urbanek, R. S. Legro, D. A. Driscoll et al., “Thirty-seven candidate genes for polycystic ovary syndrome: Strongest evidence for linkage is with follistatin,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 96, no. 15, pp. 8573–8578, 1999. View at Publisher · View at Google Scholar · View at Scopus
  51. N. Shaikh, R. Dadachanji, and S. Mukherjee, “Genetic markers of polycystic ovary syndrome: emphasis on insulin resistance,” International Journal of Medical Genetics, vol. 2014, Article ID 478972, 10 pages, 2014. View at Publisher · View at Google Scholar
  52. W. L. Miller, “Androgen biosynthesis from cholesterol to DHEA,” Molecular and Cellular Endocrinology, vol. 198, no. 1-2, pp. 7–14, 2002. View at Publisher · View at Google Scholar · View at Scopus
  53. M. Pusalkar, P. Meherji, J. Gokral, S. Chinnaraj, and A. Maitra, “CYP11A1 and CYP17 promoter polymorphisms associate with hyperandrogenemia in polycystic ovary syndrome,” Fertility and Sterility, vol. 92, no. 2, pp. 653–659, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. V. L. Nelson, R. S. Legro, J. F. Strauss III, and J. M. McAllister, “Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries,” Molecular Endocrinology, vol. 13, no. 6, pp. 946–957, 1999. View at Publisher · View at Google Scholar · View at Scopus
  55. J. K. Wickenheisser, J. M. Biegler, V. L. Nelson-DeGrave, R. S. Legro, J. F. Strauss III, and J. M. McAllister, “Cholesterol side-chain cleavage gene expression in theca cells: augmented transcriptional regulation and mRNA stability in polycystic ovary syndrome,” PLoS ONE, vol. 7, no. 11, Article ID e48963, 2012. View at Publisher · View at Google Scholar · View at Scopus
  56. N. Gharani, D. M. Waterworth, S. Batty et al., “Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism,” Human Molecular Genetics, vol. 6, no. 3, pp. 397–402, 1997. View at Publisher · View at Google Scholar · View at Scopus
  57. S. Daneshmand, S. R. Weitsman, A. Navab, A. J. Jakimiuk, and D. A. Magoffin, “Overexpression of theca-cell messenger RNA in polycystic ovary syndrome does not correlate with polymorphisms in the cholesterol side-chain cleavage and 17α-hydroxylase/C17-20 lyase promoters,” Fertility and Sterility, vol. 77, no. 2, pp. 274–280, 2002. View at Publisher · View at Google Scholar · View at Scopus
  58. K. R. Reddy, M. L. N. Deepika, K. Supriya et al., “CYP11A1 microsatellite (tttta)n polymorphism in PCOS women from South India,” Journal of Assisted Reproduction and Genetics, vol. 31, no. 7, pp. 857–863, 2014. View at Publisher · View at Google Scholar · View at Scopus
  59. E. Diamanti-Kandarakis, M. I. Bartzis, A. T. Bergiele, T. C. Tsianateli, and C. R. Kouli, “Microsatellite polymorphism (tttta)(n) at –-528 base pairs of gene CYP11α influences hyperandrogenemia in patients with polycystic ovary syndrome,” Fertility and Sterility, vol. 73, no. 4, pp. 735–741, 2000. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Gaasenbeek, B. L. Powell, U. Sovio et al., “Large-scale analysis of the relationship between CYP11A Promoter variation, polycystic ovarian syndrome, and serum testosterone,” The Journal of Clinical Endocrinology & Metabolism, vol. 89, no. 5, pp. 2408–2413, 2004. View at Publisher · View at Google Scholar · View at Scopus
  61. Y. Wang, X. Wu, Y. Cao, L. Yi, and J. Chen, “A microsatellite polymorphism (tttta)n in the promoter of the CYP11a gene in Chinese women with polycystic ovary syndrome,” Fertility and Sterility, vol. 86, no. 1, pp. 223–226, 2006. View at Publisher · View at Google Scholar · View at Scopus
  62. J. L. San Millán, J. Sancho, R. M. Calvo, and H. F. Escobar-Morreale, “Role of the pentanucleotide (tttta)n polymorphism in the promoter of the CYP11a gene in the pathogenesis of hirsutism,” Fertility and Sterility, vol. 75, no. 4, pp. 797–802, 2001. View at Publisher · View at Google Scholar · View at Scopus
  63. T. Li and Z. Guijin, “Role of the pentanucleotide (tttta)n polymorphisms of CYP11α gene in the pathogenesis of hyperandrogenism in chinese women with polycystic ovary syndrome,” Journal of Huazhong University of Science and Technology (Medical Sciences), vol. 25, no. 2, pp. 212–214, 2005. View at Publisher · View at Google Scholar
  64. C. F. Hao, H. C. Bao, N. Zhang, H. F. Gu, and Z. J. Chen, “Evaluation of association between the CYP11alpha promoter pentannucleotide (TTTTA)n polymorphism and polycystic ovarian syndrome among Han Chinese women,” Neuroendocrinology Letters, vol. 30, no. 1, pp. 56–60, 2009. View at Google Scholar
  65. M. S. Perez, G. E. Cerrone, H. Benencia, N. Marquez, E. De Piano, and G. D. Frechtel, “Polymorphism in CYP11α and CYP17 genes and the etiology of hyperandrogenism in patients with polycystic ovary syndrome,” Medicina (B Aires), vol. 68, no. 2, pp. 129–134, 2008. View at Google Scholar · View at Scopus
  66. S. Prazakova, M. Vankova, O. Bradnova et al., “(TTTTA), polymorphism in the promoter of the CYP11A1 gene in the pathogenesis of polycystic ovary syndrome,” Casopis Lekaru Ceskych, vol. 149, no. 11, pp. 520–525, 2010. View at Google Scholar
  67. W. Shen, T. Li, Y. Hu, H. Liu, and M. Song, “Common polymorphisms in the CYP1A1 and CYP11A1 genes and polycystic ovary syndrome risk: A meta-analysis and meta-regression,” Archives of Gynecology and Obstetrics, vol. 289, no. 1, pp. 107–118, 2014. View at Publisher · View at Google Scholar · View at Scopus
  68. M. Yu, R. Feng, X. Sun 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,” Molecular Biology Reports, vol. 41, no. 7, pp. 4435–4445, 2014. View at Publisher · View at Google Scholar · View at Scopus
  69. G. H. Gao, Y. X. Cao, L. Yi, Z. L. Wei, Y. P. Xu, and C. Yang, “Polymorphism of CYP11A1 gene in Chinese patients with polycystic ovarian syndrome,” Zhonghua Fu Chan Ke Za Zhi, vol. 45, no. 3, pp. 191–196, 2010. View at Google Scholar
  70. C.-W. Zhang, X.-L. Zhang, Y.-J. Xia et al., “Association between polymorphisms of the CYP11A1 gene and polycystic ovary syndrome in Chinese women,” Molecular Biology Reports, vol. 39, no. 8, pp. 8379–8385, 2012. View at Publisher · View at Google Scholar · View at Scopus
  71. L. Sharp, A. H. Cardy, S. C. Cotton, and J. Little, “CYP17 gene polymorphisms: Prevalence and associations with hormone levels and related factors. A HuGE review,” American Journal of Epidemiology, vol. 160, no. 8, pp. 729–740, 2004. View at Publisher · View at Google Scholar · View at Scopus
  72. A. H. Carey, D. Waterworth, K. Patel et al., “Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17,” Human Molecular Genetics, vol. 3, no. 10, pp. 1873–1876, 1994. View at Publisher · View at Google Scholar · View at Scopus
  73. N. Gharani, D. M. Waterworth, R. Williamson, and S. Franks, “5 Polymorphism of the CYP17 gene is not associated with serum testosterone levels in women with polycystic ovaries,” The Journal of Clinical Endocrinology & Metabolism, vol. 81, no. 11, p. 4174, 1996. View at Publisher · View at Google Scholar · View at Scopus
  74. K. Techatraisak, G. S. Conway, and G. Rumsby, “Frequency of a polymorphism in the regulatory region of the 17α-hydroxylase-17,20-lyase (CYP17) gene in hyperandrogenic states,” Clinical Endocrinology, vol. 46, no. 2, pp. 131–134, 1997. View at Publisher · View at Google Scholar · View at Scopus
  75. M. Liović, J. Preželj, A. Kocijančič, G. Majdič, and R. Komel, “CYP17 gene analysis in hyperandrogenised women with and without exaggerated 17-hydroxyprogesterone response to ovarian stimulation,” Journal of Endocrinological Investigation, vol. 20, no. 4, pp. 189–193, 1997. View at Publisher · View at Google Scholar · View at Scopus
  76. B. Marszalek, M. Laciski, N. Babych et al., “Investigations on the genetic polymorphism in the region of CYP17 gene encoding 5-UTR in patients with polycystic ovarian syndrome,” Gynecological Endocrinology, vol. 15, no. 2, pp. 123–128, 2001. View at Publisher · View at Google Scholar · View at Scopus
  77. A. K. Chua, R. Azziz, and M. O. Goodarzi, “Association study of CYP17 and HSD11B1 in polycystic ovary syndrome utilizing comprehensive gene coverage,” Molecular Human Reproduction, vol. 18, no. 6, pp. 320–324, 2012. View at Publisher · View at Google Scholar · View at Scopus
  78. M. Kahsar-Miller, L. R. Boots, A. Bartolucci, and R. Azziz, “Role of a CYP17 polymorphism in the regulation of circulating dehydroepiandrosterone sulfate levels in women with polycystic ovary syndrome,” Fertility and Sterility, vol. 82, no. 4, pp. 973–975, 2004. View at Publisher · View at Google Scholar · View at Scopus
  79. J.-M. Park, E.-J. Lee, S. Ramakrishna, D.-H. Cha, and K.-H. Baek, “Association study for single nucleotide polymorphisms in the CYP17A1 gene and polycystic ovary syndrome,” International Journal of Molecular Medicine, vol. 22, no. 2, pp. 249–254, 2008. View at Publisher · View at Google Scholar · View at Scopus
  80. B. Echiburú, F. Pérez-Bravo, M. Maliqueo, F. Sánchez, N. Crisosto, and T. Sir-Petermann, “Polymorphism T → C (-34 base pairs) of gene CYP17 promoter in women with polycystic ovary syndrome is associated with increased body weight and insulin resistance: a preliminary study,” Metabolism, vol. 57, no. 12, pp. 1765–1771, 2008. View at Publisher · View at Google Scholar · View at Scopus
  81. L. Li, Z.-P. Gu, Q.-M. Bo, D. Wang, X.-S. Yang, and G.-H. Cai, “Association of CYP17A1 gene -34T/C polymorphism with polycystic ovary syndrome in Han Chinese population,” Gynecological Endocrinology, vol. 31, no. 1, pp. 40–43, 2015. View at Publisher · View at Google Scholar · View at Scopus
  82. K. Techatraisak, C. Chayachinda, T. Wongwananuruk et al., “No association between CYP17 -34T/C polymorphism and insulin resistance in Thai polycystic ovary syndrome,” Journal of Obstetrics and Gynaecology Research, vol. 41, no. 9, pp. 1412–1417, 2015. View at Publisher · View at Google Scholar · View at Scopus
  83. U. Banerjee, A. Dasgupta, A. Khan 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 Journal of Medical Research, vol. 143, no. 9, pp. 739–747, 2016. View at Publisher · View at Google Scholar · View at Scopus
  84. T. Unsal, E. Konac, E. Yesilkaya et al., “Genetic polymorphisms of FSHR, CYP17, CYP1A1, CAPN10, INSR, SERPINE1 genes in adolescent girls with polycystic ovary syndrome,” Journal of Assisted Reproduction and Genetics, vol. 26, no. 4, pp. 205–216, 2009. View at Publisher · View at Google Scholar · View at Scopus
  85. Y. Li, F. Liu, S. Luo, H. Hu, X.-H. Li, and S.-W. Li, “Polymorphism T→C of gene CYP17 promoter and polycystic ovary syndrome risk: A meta-analysis,” Gene, vol. 495, no. 1, pp. 16–22, 2012. View at Publisher · View at Google Scholar · View at Scopus
  86. S. E. Bulun, K. Takayama, T. Suzuki, H. Sasano, B. Yilmaz, and S. Sebastian, “Organization of the human aromatase P450 (CYP19) gene,” Seminars in Reproductive Medicine, vol. 22, no. 1, pp. 5–9, 2004. View at Publisher · View at Google Scholar · View at Scopus
  87. J. Chen, S. Shen, Y. Tan et al., “The correlation of aromatase activity and obesity in women with or without polycystic ovary syndrome,” Journal of Ovarian Research, vol. 8, no. 1, article 11, pp. 1–6, 2015. View at Publisher · View at Google Scholar · View at Scopus
  88. F. Yang, Y.-C. Ruan, Y.-J. Yang et al., “Follicular hyperandrogenism downregulates aromatase in luteinized granulosa cells in polycystic ovary syndrome women,” Reproduction, vol. 150, no. 4, pp. 289–296, 2015. View at Publisher · View at Google Scholar · View at Scopus
  89. Y.-Y. Yu, C.-X. Sun, Y.-K. Liu, Y. Li, L. Wang, and W. Zhang, “Promoter methylation of CYP19A1 gene in chinese polycystic ovary syndrome patients,” Gynecologic and Obstetric Investigation, vol. 76, no. 4, pp. 209–213, 2013. View at Publisher · View at Google Scholar · View at Scopus
  90. J.-L. Jin, J. Sun, H.-J. Ge et al., “Association between CYP19 gene SNP rs2414096 polymorphism and polycystic ovary syndrome in Chinese women,” BMC Medical Genetics, vol. 10, p. 139, 2009. View at Publisher · View at Google Scholar · View at Scopus
  91. C. J. Petry, K. K. Ong, K. F. Michelmore et al., “Association of aromatase (CYP 19) gene variation with features of hyperandrogenism in two populations of young women,” Human Reproduction, vol. 20, no. 7, pp. 1837–1843, 2005. View at Publisher · View at Google Scholar · View at Scopus
  92. C. J. Petry, K. K. Ong, K. F. Michelmore et al., “Associations between common variation in the aromatase gene promoter region and testosterone concentrations in two young female populations,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 98, no. 4-5, pp. 199–206, 2006. View at Publisher · View at Google Scholar · View at Scopus
  93. P. S. Maier and P. M. Spritzer, “Aromatase gene polymorphism does not influence clinical phenotype and response to oral contraceptive pills in polycystic ovary syndrome women,” Gynecologic and Obstetric Investigation, vol. 74, no. 2, pp. 136–142, 2012. View at Publisher · View at Google Scholar · View at Scopus
  94. N. Xita, L. Lazaros, I. Georgiou, and A. Tsatsoulis, “CYP19 gene: a genetic modifier of polycystic ovary syndrome phenotype,” Fertility and Sterility, vol. 94, no. 1, pp. 250–254, 2010. View at Publisher · View at Google Scholar · View at Scopus
  95. L. Lazaros, N. Xita, E. Hatzi et al., “CYP19 gene variants affect the assisted reproduction outcome of women with polycystic ovary syndrome,” Gynecological Endocrinology, vol. 29, no. 5, pp. 478–482, 2013. View at Publisher · View at Google Scholar · View at Scopus
  96. N. Xita, I. Georgiou, L. Lazaros, V. Psofaki, G. Kolios, and A. Tsatsoulis, “The synergistic effect of sex hormone-binding globulin and aromatase genes on polycystic ovary syndrome phenotype,” European Journal of Endocrinology, vol. 158, no. 6, pp. 861–865, 2008. View at Publisher · View at Google Scholar · View at Scopus
  97. C. F. Hao, N. Zhang, Q. Qu, X. Wang, H. F. Gu, and Z. J. Chen, “Evaluation of the association between the CYP19 tetranucleotide (TTTA)n polymorphism and polycystic ovarian syndrome(PCOS) in Han Chinese women,” Neuroendocrinology Letters, vol. 31, no. 3, pp. 370–374, 2010. View at Google Scholar
  98. P. Xu, X. L. Zhang, G. B. Xie et al., “The (TTTA)n polymorphism in intron 4 of CYP19 and the polycystic ovary syndrome risk in a Chinese population,” Molecular Biology Reports, vol. 40, no. 8, pp. 5041–5047, 2013. View at Publisher · View at Google Scholar · View at Scopus
  99. X.-L. Zhang, C.-W. Zhang, P. Xu et al., “SNP rs2470152 in CYP19 is correlated to aromatase activity in Chinese polycystic ovary syndrome patients,” Molecular Medicine Reports, vol. 5, no. 1, pp. 245–249, 2012. View at Publisher · View at Google Scholar · View at Scopus
  100. H. Wang, Q. Li, T. Wang et al., “A common polymorphism in the human aromatase gene alters the risk for polycystic ovary syndrome and modifies aromatase activity in vitro,” Molecular Human Reproduction, vol. 17, no. 6, pp. 386–391, 2011. View at Publisher · View at Google Scholar · View at Scopus
  101. C. Y. Peng, H. J. Xie, Z. F. Guo et al., “The association between androgen receptor gene CAG polymorphism and polycystic ovary syndrome: a case-control study and meta-analysis,” Journal of Assisted Reproduction and Genetics, vol. 31, no. 9, pp. 1211–1219, 2014. View at Publisher · View at Google Scholar · View at Scopus
  102. N. L. Chamberlain, E. D. Driver, and R. L. Miesfeld, “The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function,” Nucleic Acids Research, vol. 22, no. 15, pp. 3181–3186, 1994. View at Publisher · View at Google Scholar · View at Scopus
  103. H. Nam, C. Kim, M. Cha, J. Kim, B. Kang, and H. Yoo, “Polycystic ovary syndrome woman with heterozygous androgen receptor gene mutation who gave birth to a child with androgen insensitivity syndrome,” Obstetrics & Gynecology Science, vol. 58, no. 2, pp. 179–182, 2015. View at Publisher · View at Google Scholar
  104. K. A. Walters, C. M. Allan, and D. J. Handelsman, “Androgen actions and the ovary,” Biology of Reproduction, vol. 78, no. 3, pp. 380–389, 2008. View at Publisher · View at Google Scholar · View at Scopus
  105. L. H. Lin, M. C. P. Baracat, G. A. R. MacIel, J. M. Soares Jr., and E. C. Baracat, “Androgen receptor gene polymorphism and polycystic ovary syndrome,” International Journal of Gynecology and Obstetrics, vol. 120, no. 2, pp. 115–118, 2013. View at Publisher · View at Google Scholar · View at Scopus
  106. A. N. Schüring, A. Welp, J. Gromoll et al., “Role of the CAG repeat polymorphism of the androgen receptor gene in polycystic ovary syndrome (PCOS),” Experimental and Clinical Endocrinology & Diabetes, vol. 120, no. 2, pp. 73–79, 2012. View at Publisher · View at Google Scholar · View at Scopus
  107. N. A. Shah, H. J. Antoine, M. Pall, K. D. Taylor, R. Azziz, and M. O. Goodarzi, “Association of androgen receptor CAG repeat polymorphism and polycystic ovary syndrome,” The Journal of Clinical Endocrinology & Metabolism, vol. 93, no. 5, pp. 1939–1945, 2008. View at Publisher · View at Google Scholar · View at Scopus
  108. Y. Xia, Y. Che, X. Zhang et al., “Polymorphic CAG repeat in the androgen receptor gene in polycystic ovary syndrome patients,” Molecular Medicine Reports, vol. 5, no. 5, pp. 1330–1334, 2012. View at Publisher · View at Google Scholar · View at Scopus
  109. F. Van Nieuwerburgh, D. Stoop, P. Cabri, M. Dhont, D. Deforce, and P. De Sutter, “Shorter CAG repeats in the androgen receptor gene may enhance hyperandrogenicity in polycystic ovary syndrome,” Gynecological Endocrinology, vol. 24, no. 12, pp. 669–673, 2008. View at Publisher · View at Google Scholar · View at Scopus
  110. A. Mifsud, S. Ramirez, and E. L. Yong, “Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries,” The Journal of Clinical Endocrinology & Metabolism, vol. 85, no. 9, pp. 3484–3488, 2000. View at Publisher · View at Google Scholar · View at Scopus
  111. S. Rajender, S. J. Carlus, S. K. Bansal et al., “Androgen Receptor CAG Repeats Length Polymorphism and the Risk of Polycystic Ovarian Syndrome (PCOS),” PLoS ONE, vol. 8, no. 10, Article ID e75709, 2013. View at Publisher · View at Google Scholar · View at Scopus
  112. P. Ferk, M. P. Perme, N. Teran, and K. Gersak, “Androgen receptor gene (CAG)n polymorphism in patients with polycystic ovary syndrome,” Fertility and Sterility, vol. 90, no. 3, pp. 860–863, 2008. View at Publisher · View at Google Scholar · View at Scopus
  113. J. J. Kim, S. H. Choung, Y. M. Choi, S. H. Yoon, S. H. Kim, and S. Y. Moon, “Androgen receptor gene CAG repeat polymorphism in women with polycystic ovary syndrome,” Fertility and Sterility, vol. 90, no. 6, pp. 2318–2323, 2008. View at Publisher · View at Google Scholar · View at Scopus
  114. L. Skrgatic, D. P. Baldani, J. Z. Cerne, P. Ferk, and K. Gersak, “CAG repeat polymorphism in androgen receptor gene is not directly associated with polycystic ovary syndrome but influences serum testosterone levels,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 128, no. 3-5, pp. 107–112, 2012. View at Publisher · View at Google Scholar · View at Scopus
  115. J. Jääskeläinen, S. Korhonen, R. Voutilainen, M. Hippeläinen, and S. Heinonen, “Androgen receptor gene CAG length polymorphism in women with polycystic ovary syndrome,” Fertility and Sterility, vol. 83, no. 6, pp. 1724–1728, 2005. View at Publisher · View at Google Scholar · View at Scopus
  116. P. D. Ramos Cirilo, F. E. Rosa, M. F. Moreira Ferraz, C. A. Rainho, A. Pontes, and S. R. Rogatto, “Genetic polymorphisms associated with steroids metabolism and insulin action in polycystic ovary syndrome,” Gynecological Endocrinology, vol. 28, no. 3, pp. 190–194, 2012. View at Publisher · View at Google Scholar · View at Scopus
  117. M. Möhlig, A. Jürgens, J. Spranger et al., “The androgen receptor CAG repeat modifies the impact of testosterone on insulin resistance in women with polycystic ovary syndrome,” European Journal of Endocrinology, vol. 155, no. 1, pp. 127–130, 2006. View at Publisher · View at Google Scholar · View at Scopus
  118. T. Hickey, A. Chandy, and R. J. Norman, “The androgen receptor CAG repeat polymorphism and X-Chromosome inactivation in australian caucasian women with infertility related to polycystic ovary syndrome,” The Journal of Clinical Endocrinology & Metabolism, vol. 87, no. 1, pp. 161–165, 2002. View at Publisher · View at Google Scholar
  119. T. Zhang, W. Liang, M. Fang, J. Yu, Y. Ni, and Z. Li, “Association of the CAG repeat polymorphisms in androgen receptor gene with polycystic ovary syndrome: A systemic review and meta-analysis,” Gene, vol. 524, no. 2, pp. 161–167, 2013. View at Publisher · View at Google Scholar · View at Scopus
  120. R. Wang, M. O. Goodarzi, T. Xiong, D. Wang, R. Azziz, and H. Zhang, “Negative association between androgen receptor gene CAG repeat polymorphism and polycystic ovary syndrome? A systematic review and meta-analysis,” Molecular Human Reproduction, vol. 18, no. 10, pp. 498–509, 2012. View at Publisher · View at Google Scholar · View at Scopus
  121. C. Y. Peng, X. Y. Long, and G. X. Lu, “Association of AR rs6152G/A gene polymorphism with susceptibility to polycystic ovary syndrome in Chinese women,” Reproduction, Fertility and Development, vol. 22, no. 5, pp. 881–885, 2010. View at Publisher · View at Google Scholar · View at Scopus
  122. C. Yuan, C. Gao, Y. Qian et al., “Polymorphism of CAG and GGN repeats of androgen receptor gene in women with polycystic ovary syndrome,” Reproductive BioMedicine Online, vol. 31, no. 6, pp. 790–798, 2015. View at Publisher · View at Google Scholar · View at Scopus
  123. G. L. Hammond, “Plasma steroid-binding proteins: Primary gatekeepers of steroid hormone action,” Journal of Endocrinology, vol. 230, no. 1, pp. R13–R25, 2016. View at Publisher · View at Google Scholar · View at Scopus
  124. K. N. Hogeveen, P. Cousin, M. Pugeat, D. Dewailly, B. Soudan, and G. L. Hammond, “Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction,” The Journal of Clinical Investigation, vol. 109, no. 7, pp. 973–981, 2002. View at Publisher · View at Google Scholar · View at Scopus
  125. N. Xita, A. Tsatsoulis, I. Stavrou, and I. Georgiou, “Association of SHBG gene polymorphism with menarche,” Molecular Human Reproduction, vol. 11, no. 6, pp. 459–462, 2005. View at Publisher · View at Google Scholar · View at Scopus
  126. P. Cousin, L. Calemard-Michel, H. Lejeune et al., “Influence of SHBG gene pentanucleotide TAAAA repeat and D327N polymorphism on serum sex hormone-binding globulin concentration in hirsute women,” The Journal of Clinical Endocrinology & Metabolism, vol. 89, no. 2, pp. 917–924, 2004. View at Publisher · View at Google Scholar · View at Scopus
  127. D. P. Baldani, L. Skrgatic, J. Z. Cerne, S. K. Oguic, B. M. Gersak, and K. Gersak, “Association between serum levels and pentanucleotide polymorphism in the sex hormone binding globulin gene and cardiovascular risk factors in females with polycystic ovary syndrome,” Molecular Medicine Reports, vol. 11, no. 5, pp. 3941–3947, 2015. View at Publisher · View at Google Scholar
  128. P. Ferk, N. Teran, and K. Gersak, “The (TAAAA)n microsatellite polymorphism in the SHBG gene influences serum SHBG levels in women with polycystic ovary syndrome,” Human Reproduction, vol. 22, no. 4, pp. 1031–1036, 2007. View at Publisher · View at Google Scholar · View at Scopus
  129. J. L. Zhao, Z. J. Chen, Y. R. Zhao et al., “Study on the (TAAAA)n repeat polymorphism in sex hormone-binding globulin gene and the SHBG serum levels in putative association with the glucose metabolic status of Chinese patients suffering from polycystic ovarian syndrome in Shandong province,” Zhonghua Yi Xue Yi Chuan Xue Za Zhi, vol. 22, no. 6, pp. 644–647, 2005. View at Google Scholar
  130. N. Xita, A. Tsatsoulis, A. Chatzikyriakidou, and I. Georgiou, “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,” The Journal of Clinical Endocrinology & Metabolism, vol. 88, no. 12, pp. 5976–5980, 2003. View at Publisher · View at Google Scholar · View at Scopus
  131. W. Fan, S. Li, Q. Chen, and Z. Huang, “Association between the (TAAAA)n SHBG polymorphism and PCOS: A systematic review and meta-analysis,” Gynecological Endocrinology, vol. 29, no. 7, pp. 645–650, 2013. View at Publisher · View at Google Scholar · View at Scopus
  132. B. Hacihanefioǧlu, B. Aybey, Y. Hakan Özön, H. Berkil, and K. Karşidaǧ, “Association of anthropometric, androgenic and insulin-related features with polymorphisms in exon 8 of SHBG gene in women with polycystic ovary syndrome,” Gynecological Endocrinology, vol. 29, no. 4, pp. 361–364, 2013. View at Publisher · View at Google Scholar · View at Scopus
  133. E. P. Wickham III, K. G. Ewens, R. S. Legro, A. Dunaif, J. E. Nestler, and J. F. Strauss III, “Polymorphisms in the SHBG gene influence serum SHBG levels in women with polycystic ovary syndrome,” The Journal of Clinical Endocrinology & Metabolism, vol. 96, no. 4, pp. E719–E727, 2011. View at Publisher · View at Google Scholar · View at Scopus
  134. M. Á. Martínez-García, A. Gambineri, M. Alpañés, R. Sanchón, R. Pasquali, and H. F. Escobar-Morreale, “Common variants in the sex hormone-binding globulin gene (SHBG) and polycystic ovary syndrome (PCOS) in Mediterranean women,” Human Reproduction, vol. 27, no. 12, pp. 3569–3576, 2012. View at Publisher · View at Google Scholar · View at Scopus
  135. T. M. Abu-Hijleh, E. Gammoh, A. S. Al-Busaidi et al., “Common variants in the sex hormone-binding globulin (SHBG) gene influence SHBG levels in women with polycystic ovary syndrome,” Annals of Nutrition and Metabolism, vol. 68, no. 1, pp. 66–74, 2016. View at Publisher · View at Google Scholar · View at Scopus
  136. A.-S. Nazouri, M. Khosravifar, A.-A. Akhlaghi, M. Shiva, and P. Afsharian, “No relationship between most polymorphisms of steroidogenic acute regulatory (StAR) gene with polycystic ovarian syndrome,” Iranian Journal of Reproductive Medicine, vol. 13, no. 12, pp. 771–778, 2015. View at Google Scholar · View at Scopus
  137. R. Ju, W. Wu, J. Fei et al., “Association analysis between the polymorphisms of HSD17B5 and HSD17B6 and risk of polycystic ovary syndrome in Chinese population,” European Journal of Endocrinology, vol. 172, no. 3, pp. 227–233, 2015. View at Publisher · View at Google Scholar · View at Scopus
  138. K. Qin, D. A. Ehrmann, N. Cox, S. Refetoff, and R. L. Rosenfield, “Identification of a functional polymorphism of the human type 5 17β-hydroxysteroid dehydrogenase gene associated with polycystic ovary syndrome,” The Journal of Clinical Endocrinology & Metabolism, vol. 91, no. 1, pp. 270–276, 2006. View at Publisher · View at Google Scholar · View at Scopus
  139. D. J. Marioli, A. D. Saltamavros, V. Vervita et al., “Association of the 17-hydroxysteroid dehydrogenase type 5 gene polymorphism (-71A/G HSD17B5 SNP) with hyperandrogenemia in polycystic ovary syndrome (PCOS),” Fertility and Sterility, vol. 92, no. 2, pp. 648–652, 2009. View at Publisher · View at Google Scholar · View at Scopus
  140. M. O. Goodarzi, M. R. Jones, H. J. Antoine, M. Pall, Y.-D. I. Chen, and R. Azziz, “Nonreplication of the type 5 17β-hydroxysteroid dehydrogenase gene association with polycystic ovary syndrome,” The Journal of Clinical Endocrinology & Metabolism, vol. 93, no. 1, pp. 300–303, 2008. View at Publisher · View at Google Scholar · View at Scopus
  141. P. S. Maier, S. S. Mattiello, L. Lages, and P. M. Spritzer, “17-hydroxysteroid dehydrogenase type 5 gene polymorphism (-71A/G HSD17B5 SNP) and treatment with oral contraceptive pills in PCOS women without metabolic comorbidities,” Gynecological Endocrinology, vol. 28, no. 8, pp. 606–610, 2012. View at Publisher · View at Google Scholar · View at Scopus
  142. C. Glister, L. Satchell, R. A. D. Bathgate et al., “Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 110, no. 15, pp. E1426–E1435, 2013. View at Publisher · View at Google Scholar · View at Scopus
  143. R. Anand-Ivell, K. Tremellen, Y. Dai et al., “Circulating insulin-like factor 3 (INSL3) in healthy and infertile women,” Human Reproduction, vol. 28, no. 11, pp. 3093–3102, 2013. View at Publisher · View at Google Scholar · View at Scopus
  144. A. Gambineri, L. Patton, O. Prontera et al., “Basal insulin-like factor 3 levels predict functional ovarian hyperandrogenism in the polycystic ovary syndrome,” Journal of Endocrinological Investigation, vol. 34, no. 9, pp. 685–691, 2011. View at Publisher · View at Google Scholar · View at Scopus
  145. D. Szydlarska, W. Grzesiuk, A. Trybuch, A. Kondracka, I. Kowalik, and E. Bar-Andziak, “Insulin-like factor 3—a new hormone related to polycystic ovary syndrome?” Endokrynologia Polska, vol. 63, no. 5, pp. 356–361, 2012. View at Google Scholar · View at Scopus
  146. N. Shaikh, R. Dadachanji, P. Meherji, N. Shah, and S. Mukherjee, “Polymorphisms and haplotypes of insulin-like factor 3 gene are associated with risk of polycystic ovary syndrome in Indian women,” Gene, vol. 577, no. 2, pp. 180–186, 2016. View at Publisher · View at Google Scholar · View at Scopus
  147. Z.-J. Chen, H. Zhao, L. He et al., “Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3,” Nature Genetics, vol. 43, no. 1, pp. 55–59, 2011. View at Publisher · View at Google Scholar · View at Scopus
  148. Y. Shi, H. Zhao, Y. Shi et al., “Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome,” Nature Genetics, vol. 44, no. 9, pp. 1020–1025, 2012. View at Publisher · View at Google Scholar · View at Scopus
  149. J. M. McAllister, R. S. Legro, B. P. Modi, and J. F. Strauss, “Functional genomics of PCOS: From GWAS to molecular mechanisms,” Trends in Endocrinology & Metabolism, vol. 26, no. 3, pp. 118–124, 2015. View at Publisher · View at Google Scholar · View at Scopus
  150. M. K. Tee, M. Speek, B. Legeza et al., “Alternative splicing of DENND1A, a PCOS candidate gene, generates variant 2,” Molecular and Cellular Endocrinology, vol. 434, pp. 25–35, 2016. View at Publisher · View at Google Scholar · View at Scopus
  151. M. G. Hayes, M. Urbanek, D. A. Ehrmann et al., “Corrigendum: Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations,” Nature Communications, vol. 6, Article ID 7502, 2015. View at Publisher · View at Google Scholar · View at Scopus