An update of genetic basis of PCOS pathogenesis

Abstract

Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder that affects 5-20% of reproductive age women. PCOS clinical symptoms include hirsutism, menstrual dysfunction, infertility, obesity and metabolic syndrome. There is a wide heterogeneity in clinical manifestations and metabolic complications. The pathogenesis of PCOS is not fully elucidated, but four aspects seem to contribute to the syndrome to different degrees: increased ovarian and/or adrenal androgen secretion, partial folliculogenesis arrest, insulin resistance and neuroendocrine axis dysfunction. A definitive etiology remains to be elucidated, but PCOS has a strong heritable component indicated by familial clustering and twin studies. Genome Wide Association Studies (GWAS) have identified several new risk loci and candidate genes for PCOS. Despite these findings, the association studies have explained less than 10% of heritability. Therefore, we could speculate that different phenotypes and subphenotypes are caused by rare private genetic variants. Modern genetic studies, such as whole exome and genome sequencing, will help to clarify the contribution of these rare genetic variants on different PCOS phenotypes. Arch Endocrinol Metab. 2018;62(3):352-61.

Transgenerational Inheritance of Reproductive and Metabolic Phenotypes in PCOS Rats

“…In PCOS girls, neuroendocrine disorders occur after the onset of puberty, characterized by a rapid luteinizing hormone (LH) pulse frequency (8). Due to its familial clustering and peripubertal onset, PCOS is characterized as an autosomal dominant genetic disease (9). Polycystic ovaries, testosterone levels, paternal metabolic syndrome (MBS) and type 2 diabetes mellitus (T2DM)-related defects in insulin secretion and action are all genetic factors for PCOS (4,(9)(10)(11).…”

Expression and Contribution of Insulin Signaling Pathway to the Development of Polycystic Ovary Syndrome

“…Inborn abnormal factors, such as genetic defect and gene mutation, and other acquired factors, like lifestyle, obesity, and environment, can all cause IR by affecting PI3K/PKB signaling pathway. It was found that with the increase of free fatty acids in blood, they were converted into acy-CoA, DAG was increased, PKC was activated, serine residues in IRS-1 were phosphorylated, tyrosine phosphorylation in IRS-1 was decreased, PI3K activation was disturbed, and GLUT4 translocation to cell surface was affected, thus reducing insulin-mediated glucose utilization [3,13,17]. The increase of free fatty acids leads to the increase of lipids in muscle, which in turn interferes with the use and storage of insulin to glucose and causes IR.…”

“…This signaling from insulin receptor down to the end-mediated substrates of insulin action involves many aspects of cell metabolism [3,[17][18][19][20]. Any link of insulin signaling impairment can lead to IR, which is closely related to the impairment of key molecules in the signaling of insulin, insulin receptor, insulin receptor substrate, PI3K, and GLUT4, specifically divided into the following three aspects [3,[17][18][19][20]: First, pre-receptor IR. The mutation of insulin gene leads to the changes of insulin primary structure and the decrease of biological activity, resulting in body IR.…”

“…Insulin deficiency refers to a series of abnormal metabolic processes that occur when insulin binds to receptors and transmits signals to cells, which is the main cause of IR in PCOS patients. The physiological effect of insulin on glucose is the result of key enzyme activation such as insulin-dependent GLUT4 and G-kinase and glycogen synthase, and the defects in the structure or function of these enzymes can lead to IR [3,13,[17][18][19][20][21]. Increased serine phosphorylation of insulin receptor may weaken the tyrosine kinase activity of insulin receptor, which may be the mechanism of post-receptor deficiency in PCOS patients.…”

Modern approaches to diagnostics of hyperandrogenism distributed forms in reproductive aged women

“…рис. 2).Постулюються такі механізми: ↑ активність нейронів гонадотропін-рилізинг-гормону → гіперплазія тека-клітин → ↑ синтезу андрогенів яєчниками[8] ; генетично детерміновані стероїдогенні дефекти яєчників, наднирників, метаболічних ефектів інсуліну[9] ; ↑ рівня інсуліну → ↑ чутливості тека-клітин до лютеїнізуючого гормону (ЛГ) → ↑ їхньої стероїдогенної активності → ↑ синтезу андрогенів яєчниками[10][11][12]…”