Treatment of Hyperandrogenism vs. Insulin Resistance in Infertile PCOS Women

描述（由申请人提供）：多囊卵巢综合征（PCOS）是女性无排卵性不孕症的最常见原因，患有PCOS的女性患妊娠并发症（如妊娠糖尿病和先兆子痫）的风险增加。PCOS给我们的经济带来了重大的医疗保健负担，仅在美国每年就花费5亿美元用于不孕症治疗。高雄激素血症（HA）和肥胖加重胰岛素抵抗（IR）是该综合征的特征，也是治疗的靶点，但哪一个应该是主要的焦点尚不清楚。我们假设，改善PCOS不孕妇女活产率的关键是纠正HA，避免后期妊娠并发症的关键是通过强化减肥计划改善IR。第一阶段将是一个随机试验的三个孕前干预（持续4个月）。PCOS不孕妇女（N=246，Penn State约150，U Penn约100）：A.药物联合干预（西布曲明），代餐，和生活方式改变以改善IR B）连续OCP 4个月以改善HA和C）两者的组合，以改善HA和IR。这将是随后的排卵诱导与克罗米芬柠檬酸盐在所有受试者多达4个周期（第二阶段）。此时，所有治疗组将遵循标准化饮食和运动方案。本试验的主要结局将是三个治疗组的累积活产率（其次是排卵率），我们建议从治疗A到C逐步增加。我们还将在I期和II期研究PCOS表型的变化，并将在两个治疗组（III期）研究所有妊娠受试者在妊娠三个月的葡萄糖耐量和血压变化。本试验的目的是确定HA与IR的相对作用，以及联合治疗PCOS女性不孕症和预防妊娠并发症的作用。我们将调整现有的药物和治疗方法，以确定有利的风险效益比治疗PCOS不孕妇女。我们的试验是新颖和重要的，因为我们正在研究从怀孕前到怀孕到分娩的PCOS女性。该项目组建了一个独特的多学科团队，在各自领域积累了丰富的经验，并履行了NIH路线图的任务，以开发临床干预措施，改善以患者为导向的结果。 公共卫生相关性：多囊卵巢综合征（PCOS）是美国女性中最常见的内分泌疾病，也是女性不孕的主要原因。这种疾病的最佳治疗方法尚不清楚，该提案将研究减肥的影响，用避孕药减少女性雄激素，并结合使用PCOS女性的妊娠率和妊娠并发症发生率。我们的目标是开发安全有效的治疗方法，以改善PCOS女性不孕症的治疗，但研究结果可以推广到所有PCOS女性。

DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility among women, and women with PCOS are at increased risk for pregnancy complications such as gestational diabetes and pre-eclampsia. PCOS results in a significant health care burden to our economy with an estimated $500 million spent annually in the U.S. on infertility treatment alone. Both hyperandrogenism (HA) and obesity exacerbated insulin resistance (IR) are characteristic of the syndrome, and are targets for treatment, but which should be the predominant focus is unknown. We hypothesize that the key to improving the live birth rate in infertile women with PCOS is to correct HA, and the key to avoiding later pregnancy complications is to improve IR with an intense weight loss program. Phase I will be a randomized trial of three preconception interventions (lasting 4 mos.) in infertile women with PCOS (N=246, ~150 at Penn State and ~100 at U Penn): A) a combined intervention of medication (sibutramine), meal replacements, and lifestyle modficiation to improve IR B) continuous OCP for 4 months to improve HA and C) the combination of both to improve HA and IR. This will be followed by ovulation induction with clomiphene citrate in all subjects for up to 4 cycles (Phase II). All treatment arms will follow standardized diet and exercise regimens at this point. The primary outcome of the trial will be the cumulative live birth rates of the three treatment groups (and secondarily ovulation rates) which we propose will increase stepwise from Treatment A thru C. We will also examine changes in the PCOS phenotype during Phase I and II and will study all pregnant subjects by trimester in pregnancy for changes in glucose tolerance and blood pressure in the two treatment arms (Phase III). The goal of this trial is to establish the relative roles of HA versus IR and in combination in treating infertility and preventing pregnancy complications in women with PCOS. We will adapt existing medications and treatments with an established favorable risk benefit ratio to the treatment of infertile women with PCOS. Our trial is novel and important because we are studying women with PCOS across the continuum from pre-conception to conception to delivery. This project has assembled a unique multidisciplinary team bridging vast experience in their respective areas, and fulfills the mandates of the NIH roadmap to develop clinical interventions that improve patient oriented outcomes. PUBLIC HEALTH RELEVANCE: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women in the U.S. and is the leading cause of infertility in women. The best treatment for this disorder is unknown and this proposal will examine the effects of weight loss, reducing female androgens with the birth control pill, and using both in combination on pregnancy rates and pregnancy complication rates in women with PCOS. Our goal is to develop safe and effective treatments to improve the treatment of infertility in women with PCOS, but the findings can be generalized to all women with PCOS.