Genetic Variants Associated with Hyperandrogenemia in PCOS Pathophysiology

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.