This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The polycystic ovary syndrome is a poorly understood disorder that affects approximately 6-10% of women of reproductive age. Polycystic ovary syndrome (PCOS) is characterized by excess circulating androgen levels and chronic anovulation. The fundamental pathophysiologic defect is unknown, but PCOS is characterized by insulin resistance and compensatory hyperinsulinemia. The evidence for this has been consistent and overwhelming. Insulin resistance has been found in PCOS women of many racial and ethnic groups implying both that it is a universal characteristic and that a common defect may underlie its prevalence. Improving Insulin Sensitivity in PCOS: Improvements in insulin sensitivity in PCOS women, either through lifestyle changes or through pharmaceutical intervention, have consistently resulted in a marked improvement in the reproductive and metabolic abnormalities in PCOS. Resumption of ovulation occurs in up to 60-70% of PCOS women. The longest and most varied published experience (in terms of number of studies) with any agent that improves insulin sensitivity in PCOS women has been with metformin, brand name Glucophage. Metformin was approved for the treatment of type II diabetes by the FDA in 1994, but was used clinically for close to 20 years in other parts of the world. Metformin is a biguanide that works primarily by suppressing hepatic gluconeogenesis, but it also improves insulin sensitivity in the periphery (primarily skeletal muscle). Its use in PCOS women has been accompanied by a reduction in circulating insulin levels, a decrease in androgen levels and resumption of menses. These beneficial effects have been noted in both lean and obese PCOS women. Randomized studies with metformin have consistently shown improvement in insulin action and lowered serum androgens in PCOS women. The purpose of this study is to determine the safety and efficacy of clomiphene citrate (Clomid, Serophene), metformin XR (extended release form of metformin with brand name Glucophage XR), or combined therapy of the two in achieving pregnancy. We hypothesize that success rates will step down as follows: combined clomiphene citrate/metformin XR metformin XR clomiphene citra
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