Background: Polycystic ovary syndrome (PCOS) is a multifactorial endocrine disorder characterized by anovulation, hyperandrogenism, and polycystic ovarian morphology. The pathophysiology of PCOS is not clear; however, disturbance in hypothalamic-pituitary-ovarian axis and abnormal steroidogenesis along with genetic and environmental factors act as main contributors to this disorder. Main text: Hyperandrogenism, the hallmark feature of PCOS, is clinically manifested as hirsutism, acne, and alopecia. Excessive androgen production by ovaries as well as from adrenals contributes to hyperandrogenism. Abnormalities in the neuroendocrine system like increased pulse frequency of gonadotropin-releasing hormone, stimulating the pituitary for excessive production of luteinizing hormone than that of follicle-stimulating hormone is seen in PCOS women. Excess LH stimulates ovarian androgen production, whereas a relative deficit in FSH impairs follicular development. The imbalance in LH: FSH causes proliferation of ovarian theca cells leading to increased steroidogenesis, and ultimately leading to hyperandrogenism in PCOS women. Various genetic factors have been shown to be associated with abnormal steroidogenesis. CYP genes involved in steroidogenesis play an important role in androgen production and are considered as key players in hyperandrogenism in PCOS. Conclusion: Polymorphisms in CYP genes can aggravate the hyperandrogenic phenotype in women with PCOS by either upregulating or downregulating their expression, thus increasing androgens further. However, this hypothesis needs to be validated by further studies.

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Background: Polycystic ovary syndrome (PCOS) is commonly associated with metabolic abnormalities such as hyperinsulinemia, insulin resistance and obesity. The genetic variants of genes regulating insulin action, expression and regulation are suggested as possible factors involved in development and severity of clinical manifestations in PCOS. Aim: We investigated whether IRS-1Gly972Arg (rs1801278) polymorphism is associated with increased risk of PCOS in Kashmiri women. The correlation of various clinical, metabolic and hormonal markers with rs1801278 single nucleotide polymorphism was analyzed. The genotypic–phenotypic association of clinical manifestations of PCOS with the tested genetic variant was also assessed. Results: There were no significant differences in allele frequency (OR = 0.87, CI = 0.59–1.29, χ2 = 0.456, p = 0.499) or genotypic distribution (χ2 = 3.73, p = 0.15) between PCOS women and controls. No significant association was also found in the dominant (OR = 1.63, χ2 = 0.377, p = 0.53), recessive (OR = 0.79, χ2 = 1.01, p = 0.31) or heterozygote vs. homozygote (OR = 1.34, χ2 = 1.53, p = 0.22) genotype model analysis. The genotype–phenotype correlation analysis showed that the Arg allele was significantly associated with increased central adiposity markers hip circumference (p = 0.012), and body adiposity index BAI (p = 0.002) in the recessive model in PCOS women. The two-hour glucose (p = 0.04) and insulin resistance marker HOMA (p = 0.44) were significantly higher in Arg allele carriers. The androgen excess markers dehydroepiandrosterone sulfate DHEAS (p = 0.02), Ferriman–Gallwey score (p = 0.012), prevalence of acne, alopecia and hirsutism (all p < 0.01) were significantly elevated in the wild-type GG genotype. Conclusions:IRS-1Gly972Arg genetic variant does not increase the risk of PCOS in Kashmiri women. However, this polymorphism is associated with clinical manifestations of insulin resistance, obesity and hyperandrogenism, suggesting its possible role in variable phenotypic manifestations of PCOS.