Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder frequently associated with infertility secondary to anovulation, hirsutism secondary to elevated androgens and metabolic abnormalities such as insulin resistance and adverse lipoprotein profiles. Insulin resistance is the most significant feature of the metabolic disturbance in women with PCOS. Hyperinsulinemia has been implicated as a causative agent in the anovulation, hyperandrogenism and adverse lipid profiles characteristic of this disorder. No studies have evaluated directly the role of chronic insulin sensitization on daily reproductive hormone dynamics in women with PCOS who respond to metformin with reinstitution of ovulatory cycles. We hypothesize that metformin, by acting on the liver and increasing sex hormone binding globulin (SHBG), induces a temporary estrogen-lowering effect, opening the feedback loop to the hypothalmic-pituitary gonadal axis and allowing elevation in FSH to induce ovulation. In order to test this hypothesis, two specific aims are proposed:
in Aim 1, we will perform a single blind sequential study of metformin versus placebo in obese women with PCOS. In order to determine whether metformin has a direct effect on hepatic glucose output, we will perform a three dose, hyperinsulinemic, euglycemic clamp study before and after metformin.
This aim will establish whether or not a hepatic site of action of metformin is prominent in women with PCOS.
In Aim 2, we will assess the day to day dynamics of urinary LH, FSH, estrone conjugates and pregnanediol glucuronide in overnight urine collections from placebo and metformin treated obese women with PCOS studied over a two month period of time. The eventual goal of these studies are to clarify the interaction between the metabolic and reproductive aspects of the polycystic ovary syndrom and to generate further hypotheses which will allow us to test these critical interactions. Linkage of improvements in insulin resistance with recovery of ovulation in women with PCOS will allow us to better target both short and long term preventive treatment strategies for women with this common endocrine condition.
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