CLOMIPHENE, METFORMIN XR, AND COMBINED CC/METFXR FOR INFERTILITY IN PCOS WOMEN

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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 purpose of this study is to determine the safety and efficacy of clomiphene citrate, metformin XR, or combined therapy of the two treatments in achieving pregnancy and a live birth. Polycystic ovary syndrome (PCOS) is characterized by excess circulating androgen levels and chronic anovulation. PCOS is characterized by insulin resistance and compensatory higher insulin levels. Studies have shown that improvements in insulin sensitivity through lifestyle or pharmaceutical interventions have consistently resulted in a marked improvement in the reproductive and metabolic abnormalities in PCOS. This treatment results in the resumption of ovulation in 60-70% of PCOS women. There are numerous studies which suggest that metformin improves insulin sensitivity in PCOS women. When metformin was used to induce ovulation and was compared to clomiphene citrate alone, metformin achieved a significantly higher ovulation rate than clomiphene citrate alone. The women in this study were only followed for 35 day on metformin, but achieved a 35% ovulation rate in this time frame. Other studies which have followed women on metformin for a longer period of time have also noted substantial improvement. Few studies have addressed the issue of pregnancy in PCOS women on metformin. Those studies that have were limited by their observational nature and small sample size. The preliminary evidence suggests that metformin is well-tolerated and results in pregnancy without known adverse events. Recently, a new sustained release form of metformin has become available. There are no published reports of the efficacy and tolerability of this new medication, metformin XR, in infertile women with PCOS. This study will test varying medications to see if improving the way your body uses insulin (metformin) or pituitary simulation of the ovaries (clomiphene) or both will most likely result in a successful pregnancy. This study is a multicenter, double-blind, randomized trial designed to determine the most effective method of achieving a live birth in infertile PCOS women. Patients will be randomized to one of three treatment strategies: 1) metformin XR alone, 2) clomiphene citrate alone, or 3) combined metformin XR and clomiphene citrate. The combination of these two drugs is not FDA approved for ovulation induction (causing the release an egg to increase the chances of becoming pregnant), however both drugs are commonly used medications to achieve pregnancy in women with PCOS. All visits will take place at the GCRC. Subjects will be asked to participate and will be involved in the informed consent process. A baseline visit will establish the existence of PCOS, the subject's medical history and physical health, and physical examination. Patients who agree to participate will be asked to have her partner provide a semen sample. This test is necessary to rule out other possible infertility factors. The couple will also be offered pre-conception counseling during the baseline evaluation in order to increase the likelihood of conception. During Visit 2 the patient will be randomized to one of three study groups. Subjects will be asked to participate in weekly visits to the GCRC for close monitoring of adverse events, ovulation, and pregnancy. An ultrasound may be performed if the subject's indications warrant this procedure. A final study visit will occur after the completion of the study or pregnancy, whichever come first. During this visit, final blood test will be performed to check liver and kidney function and to measure hormones such as insulin.