Although great strides have been made in achieving ovulation in women with PCOS, one of the most important remaining clinical problems is the pregnancy shortfall that is seen regardless of the ovulation induction agent or regimen employed. A likely mechanism for this pregnancy shortfall appears to be an unfavorable follicular microenvironment, characterized by high levels of androgens. The goals of this study are to: a) evaluate the responses of PCOS patients to more complete and reliable suppression of both ovarian and adrenal androgens: b) to provide critical information about the follicular microenvironment in PCOS in response to these experimental manipulations by taking advantage of the unique opportunities for direct access presented by IVF; c) validate methodology to unambiguously identify different subtypes of PCOS patients and d) to utilize this new information to maximize conception rates and fashion more rational protocols for ovulation induction. To accomplish these goals, several lines of investigation are planned. The first Specific Aim is a pharmacokinetic study examining two doses of leuprolide acetate, as well as a GnRH antagonist given daily for 14 days in PCOS women. Critical information on dose and duration effects of leuprolide acetate vs Nal-Glu will be obtained, as well as information on the impact of BMI and possibly patient subset on the pituitary response to GnRH agonists and antagonists. In the second Specific Aim, three different pretreatments focusing on androgen suppression will be evaluated for women with PCCS prior to IVF with detailed information obtained on serum and follicular fluid dynamics, as well as other cycle endpoints such as oocyte number and quality, fertilization rate, and pregnancy rate. Finally, since our previous analysis of subtypes of PCOS required intensive biochemical characterization, the third Specific Aim will evaluate the use of urine samples as surrogates for frequent blood sampling studies, to simplify valuation of subtypes of PCOS patients and their response to therapeutic interventions.
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