The overall hypothesis of this proposal is that insulin resistance is the fundamental pathophysiologic defect in women with polycystic ovary syndrome (PCOS), and therefore interventions to improve it are most likely to result in spontaneous ovulation and a singleton term pregnancy in infertile PCOS women. The primary aim is to identify the most effective form of ovulation induction in PCOS women that will result in a full term singleton intrauterine pregnancy with the safest profile. We propose to perform a multicenter-randomized trial of two methods of ovulation induction in clomiphene-resistant PCOS women (failure to either ovulate or conceive after an adequate trial of clomiphene). The women will be randomized to either gonadotropin or metformin treatment. Gonadotropins are the current standard method of ovulation induction in clomiphene resistant PCOS women and directly stimulate ovarian follicular development. The large cohort of arrested antral follicles and the unique pathophysiology of insulin resistance in PCOS places these women at particular risk for ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy with this form of therapy. Metformin achieves ovulation through improvement in insulin sensitivity and suppression of hepatic gluconeogenesis. These changes induce secondary effects of decreased circulating insulin, androgens and gonadotropins, increased sex hormone binding globulin, and increased ovulatory function. PCOS women will be identified on the basis of unexplained hyperandrogenemic chronic anovulation, without other health problems, and no other major infertility factor. We hypothesize that the treatment arm that improves insulin sensitivity will be more likely to result in monofollicular ovulation and thus singleton pregnancy, and less likely to result in the complications of ovulation induction including multiple pregnancy and OHSS. This study could have a major impact on infertility in PCOS women while avoiding the risks and costly burden of OHSS and multiple pregnancy.
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