دانلود رایگان مقاله انگلیسی انواع ژنتیک مرتبط با هیپرآندروژنیسم در پاتوفیزیولوژی PCOS - هینداوی 2018

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.

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 Genetics Research International 7 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].