Treating Inflammation in PCOS to Ameliorate Ovarian Dysfunction



 DESCRIPTION (provided by applicant): Polycystic Ovary Syndrome (PCOS) is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovaries. Insulin resistance is a common feature of PCOS, and the resultant hyperinsulinemia has been theorized to promote hyperandrogenism in the disorder. However, 30-50% of women with PCOS who are lean do not have insulin resistance. Women with PCOS also exhibit chronic low-grade inflammation. We have shown that in PCOS, glucose ingestion activates nuclear factor κB (NFκB), the cardinal signal of inflammation culminating in upregulation of the inflammation pathway within mononuclear cells (MNC). This phenomenon is independent of excess adiposity and is highly correlated with circulating androgens. In addition, in vitro exposure to proinflammatory stimuli is capable of directly stimulating ovarian theca cell androgen production. Salicylate administration has been shown to suppress NFκB activation, and the nonacetylated form of salicylate is well tolerated in humans. The proposed research is a randomized double-blind placebo-controlled study of 90 women with PCOS. Forty-five subjects with PCOS (15 lean without insulin resistance (IR), 15 lean with IR and 15 obese) receiving salsalate, a nonacetylated salicylate, at an oral dose of 3-4 gm daily for 12 weeks will be compared with 45 age- and body-composition-matched control women with PCOS receiving placebo. The overarching hypothesis is that inflammation contributes to ovarian dysfunction, independent of excess adiposity or IR. The specific aims are, I: To examine the effect of salsalate administration on the ovarian capacity to secrete androgen on and insulin sensitivity in PCOS. II: To examine the effect of salsalate administration on the inflammatory response of mononuclear cells induced by lipid ingestion and glucose infusion in PCOS. The approach involves evaluation of ovarian androgen secretion in response to human chorionic gonadotropin administration and insulin sensitivity during the euglycemic phase of a two-step pancreatic clamp along with ovulation monitoring before and after salsalate administration. The inflammatory response of MNC to lipid ingestion and the hyperglycemic phase of the two-step clamp will also be evaluated during treatment by measuring reactive oxygen species, the RNA and protein content of inflammation markers, nuclear factor κB activation and cytokine release in culture. It is our expectation that women wit PCOS receiving salsalate will exhibit decreased ovarian androgen secretion and reduced inflammation regardless of degree of adiposity or IR status. These results will be significant because they will show that in PCOS, treatment with a non-steroidal anti-inflammatory agent directly attenuates ovarian androgen secretion and inflammation triggered by dietary components. This will lead to important advances in the therapy of PCOS that will ameliorate androgen excess and by reducing inflammation.