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.

Figure 1. Ovarian steroidogenesis. (A) Normal ovarian steroid synthesis. (B) PCOS ovarian steroid synthesis. In comparison to normal theca cells, PCOS theca cells show increased expression of LH receptor and increased expression of CYP17A1 gene, leading to enhance of 17α-hydroxylase and 17,20-lyase activity, and amplifying androgen synthesis. Exogenous factors, such as hyperinsulinemia and IGFs are modulatory hormones that can disrupt normal intra-ovarian regulatation of steroidogenesis.

Figure 2. Role of AMH in folliculogenesis. AMH has an inibitory effect on initial recruitment of primary follicles, on FSH-dependent follicular maturation and selection of dominant follicle, and on FSH-induced aromatase expression on granulosa cells, reducing the conversion of testosterone into estradiol. Higher AMH levels in PCOS patients turns the follicles more resistant to FSH action, culminating in inhibition of follicular maturarion and ovulation, and in inhibiton of aromatase expression, and consequently, leading to hyperandrogenism. Adapted from Azziz and cols. 2016 (1).

Figure 3. Schematic components of PCOS pathogenesis. Four main physiologic mechanisms contribute to PCOS pathogenesis: hyperandrogenism (HY), insulin resistance (IR), folliculogenesis dysfunction (FC), and neuroendocrine axis dysfunction (ND). These mechanisms contribute to each phenotype in different degrees. The classical phenotype shows alterations in all four mechanism, being HY and IR the main ones (A). In the ovulatory phenotype, HY and ND predominate and folliculogenesis seems not compromised (B). In contrast, in the normoandrogenic phenotype, FC seems to play the most important role in the pathogenesis, while HY is not present (C).