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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。本研究的目的是确定克罗米芬、二甲双胍XR或两种治疗的联合治疗在实现妊娠和活产方面的安全性和有效性。 多囊卵巢综合征（PCOS）的特征是循环雄激素水平过高和慢性无排卵。PCOS的特征是胰岛素抵抗和代偿性高胰岛素水平。研究表明，通过生活方式或药物干预改善胰岛素敏感性，一贯导致PCOS的生殖和代谢异常明显改善。这种治疗导致60-70%的PCOS妇女恢复排卵。 有许多研究表明二甲双胍可以改善PCOS女性的胰岛素敏感性。当使用二甲双胍诱导排卵并与单独使用克罗米芬进行比较时，二甲双胍获得的排卵率显著高于单独使用克罗米芬。这项研究中的妇女只接受了35天的二甲双胍随访，但在这段时间内达到了35%的排卵率。其他研究对服用二甲双胍的女性进行了较长时间的随访，也发现了实质性的改善。很少有研究涉及二甲双胍治疗PCOS女性的妊娠问题。这些研究受到其观察性质和小样本量的限制。初步证据表明，二甲双胍耐受性良好，可导致妊娠，且无已知不良事件。最近，一种新的持续释放形式的二甲双胍已成为可用的。目前还没有关于这种新药二甲双胍XR在PCOS不孕妇女中的疗效和耐受性的报道。这项研究将测试不同的药物，看看是否改善你的身体使用胰岛素（二甲双胍）或垂体卵巢模拟（克罗米酚）或两者兼而有之的方式将最有可能导致成功怀孕。 本研究是一项多中心、双盲、随机试验，旨在确定不孕PCOS妇女实现活产的最有效方法。患者将被随机分配至三种治疗策略之一：1）二甲双胍XR单药治疗，2）克罗米芬单药治疗，或3）二甲双胍XR和克罗米芬联合治疗。这两种药物的组合未被FDA批准用于诱导排卵（导致释放卵子以增加怀孕的机会），但这两种药物都是PCOS女性怀孕的常用药物。所有访视将在GCRC进行。将要求受试者参与并参与知情同意过程。基线访视将确定PCOS的存在、受试者的病史和身体健康以及体格检查。同意参加的患者将被要求让她的伴侣提供精液样本。这项测试是必要的，以排除其他可能的不孕因素。在基线评估期间，这对夫妇还将接受孕前咨询，以增加受孕的可能性。访视2期间，患者将被随机分配至三个研究组之一。将要求受试者参加每周一次的GCRC访视，以密切监测不良事件、排卵和妊娠。如果受试者的适应症需要进行超声检查，则可以进行超声检查。最终研究访视将在研究完成或妊娠后进行，以先发生者为准。在此次访视期间，将进行最终血液检查，以检查肝脏和肾脏功能，并测量激素，如胰岛素。

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.