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 ?B (NF?B), 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 NF?B 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 ?B 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.

Public Health Relevance

Polycystic Ovary Syndrome (PCOS) is a common endocrine abnormality affecting as many as 15% of premenopausal women regardless of ethnicity; and is characterized by hyperandrogenism and chronic anovulation that predispose to the development of infertility, endometrial carcinoma, and disfiguring skin manifestations such as hirsutism, acne and temporal balding. Insulin resistance and the compensatory hyperinsulinemia are also common findings in PCOS that have been previously linked to the poorly understood mechanism of ovarian dysfunction in this disorder. This study will characterize the molecular mechanism by which dietary components such as lipid and glucose exacerbate low-grade inflammation in PCOS, and the ability of a non-steroidal anti-inflammatory agent to directly reduce ovarian androgen secretion independent of insulin resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK107605-01A1
Application #
9122848
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Bremer, Andrew
Project Start
2016-04-01
Project End
2020-02-29
Budget Start
2016-04-01
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202