Project 176516

The polycystic ovary syndrome (PCOS) is a frequent disorder characterized by increased male hormone levels (hyperandrogenemia). We have shown that insulin contributes to hyperandrogenemia even in PCOS women with normal insulin levels and that PPARgamma agonists (a medication) might improve this. Our hypothesis is that women develop PCOS in part because of increased action of insulin on male hormones production. We further propose that this defect might be reversed by PPARgamma agonists (PPARg-a) and induced by some types of fat. Our objectives are (1) to reverse this increased insulin action on male hormones production in PCOS women with a PPARg-a; (2) to induce this increased insulin action on male hormones production in normal female dogs with saturated fat; and (3) to investigate mechanisms involved in fat and PPARg-a effects with cultured cells. AIM 1: We will study 16 normal and 16 PCOS women with normal weight and insulin levels, and 36 obese PCOS women. Glucose tolerance and insulin sensitivity testing will be performed at baseline and repeated in PCOS women after 8-week treatment with medications reducing insulin levels or with rosiglitazone (a PPARg-a). AIM 2: Male hormones will be measured in 20 female dogs exposed to high intravascular fat or saline, plus 10 pre-treated for 8 weeks with rosiglitazone before exposure to fat. AIM 3: Cells producing male hormones will be cultured from the adrenals and the ovaries of these dogs and 20 human adrenals. These cells will be studied for male hormones response to insulin, with or without saturated fat and/or PPARg-a, and for cellular mechanisms of observed alterations. Thus, our program will be the first to assess in details the role of insulin and fat in PCOS hyperandrogenemia, and potential mechanisms. Thus, this proposal will help found new treatments for this frequent and disabling condition, including future researches on the benefits of changing dietary fat content.