Polycystic Ovary Syndrome, Insulin Resistance, and Obesity: Navigating the Pathophysiologic Labyrinth

Figure 3

Mechanisms for obesity-mediated potentiation of hyperandrogenemia in polycystic ovary syndrome. SAT = subcutaneous adipose tissue; VAT = visceral adipose tissue; HHAA = hypothalamus-hypophysis-adrenal-axis; C = cortisol; GCR = glucocorticoid receptor; DHEA = dehydroepiandrosterone; LH = luteinizing hormone; FSH = follicle-stimulating hormone; GC = granulosa cells; TC = teca cells; Ch = carbohydrate; AGE = advanced glycation end products; SHBG = sex hormone binding globulin. In PCOS, obesity may potentiate hyperandrogenemia through several mechanisms. Aside from hyperinsulinemia-mediated effects of IR, increased adiposity leads to faster cortisol metabolism, which results in hyperactivation of the HHAA and thus increased DHEA synthesis. Competitive binding to GCR by GC-produced progesterone derives into diminished cortisol binding to GCR, reinforcing HHAA activation. High adiposity also leads to greater aromatase expression in adipocytes, which allows for increased extraovarian estrogen synthesis. In turn, this causes an elevated LH/FSH ratio, prompting hyperplasia of GC and TC, which then synthesizes greater amounts of progesterone and testosterone, respectively. Hyperleptinemia and leptin resistance result in alterations of LH secretion, as well as downregulation of ovarian collagenases, and promotion of a chronic inflammatory state. Carbohydrate-rich diets may induce oxidative stress in circulating mononuclear blood cells and thus chronic inflammation. Lipid-rich diets have been reported to increase testosterone synthesis and downregulate SHBG synthesis, resulting in hyperandrogenemia. These diets also favor endogenous and exogenous AGE deposition, which results in overall ovarian tissue damage.