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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。本研究的目的是确定克罗米芬、二甲双胍XR或两种疗法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。多囊卵巢综合征的特点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，一直能显著改善多囊卵巢综合征的生殖和代谢异常。这种治疗使60%-70%的多囊卵巢综合征妇女恢复排卵。有大量研究表明，二甲双胍可以改善多囊卵巢综合征患者的胰岛素敏感性。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，二甲双胍的排卵率明显高于单独使用克罗米芬。这项研究中的女性只接受了35天的二甲双胍治疗，但在这段时间内排卵率达到了35%。其他对女性服用二甲双胍进行更长时间跟踪的研究也注意到了显著的改善。很少有研究涉及服用二甲双胍的多囊卵巢综合征患者的怀孕问题。这些研究因其观察性和样本量小而受到限制。初步证据表明，二甲双胍耐受性良好，在怀孕期间没有已知的不良事件。最近，一种新的二甲双胍缓释形式已经问世。目前还没有关于这种新药二甲双胍XR对患有多囊卵巢综合征的不孕妇女的疗效和耐受性的报道。这项研究将测试不同的药物，看看改善你的身体使用胰岛素(二甲双胍)或脑下垂体模拟卵巢(克罗米芬)的方式是否最有可能导致成功怀孕。这项研究是一项多中心、双盲、随机试验，旨在确定对不孕不育的多囊卵巢综合征妇女实现活产的最有效方法。患者将被随机分成三种治疗策略之一：1)单独使用二甲双胍XR，2)单独使用克罗米芬，或3)联合使用二甲双敏XR和克罗米芬。这两种药物的组合没有被FDA批准用于诱导排卵(导致释放卵子以增加怀孕的机会)，但这两种药物都是多囊卵巢综合征妇女怀孕的常用药物。所有访问将在GCRC进行。受试者将被要求参加，并将参与知情同意过程。基线检查将确定多囊卵巢综合征的存在，受试者的病史和身体健康状况，以及体检。同意参与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，这对夫妇还将接受受孕前咨询，以增加受孕的可能性。在访问2期间，患者将被随机分为三个研究组之一。受试者将被要求参加每周对GCRC的访问，密切监测不良事件、排卵和怀孕。如果受试者的适应症需要这样做，就可以进行超声波检查。最后一次学习访问将在完成学习或怀孕后进行，以先到者为准。在这次访问期间，将进行最后的血液测试，以检查肝和肾功能，并测量胰岛素等激素。

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.