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的最常见原因，患有PCOS的女性发生妊娠并发症的风险增加，如妊娠糖尿病和先兆子痫。多囊卵巢综合征给我们的经济带来了巨大的医疗负担，据估计，美国每年仅在不孕症治疗上就花费了5亿美元。高雄激素症（HA）和肥胖加重胰岛素抵抗（IR）都是该综合征的特征，也是治疗的目标，但哪一个应该是主要的焦点尚不清楚。我们假设提高PCOS不孕妇女活产率的关键是纠正HA，避免妊娠后期并发症的关键是通过高强度的减肥计划改善IR。第一阶段将是一项随机试验，在患有PCOS的不孕妇女中进行三种孕前干预（持续4个多月）（N=246, Penn State = 150, U Penn = 100）： a)药物（西布曲明）、代餐和改变生活方式的联合干预，以改善IR； B)连续4个月的OCP，以改善HA； C)两者结合，以改善HA和IR。随后，所有受试者使用柠檬酸克罗米芬诱导排卵长达4个周期（II期）。在这一点上，所有治疗组都将遵循标准化的饮食和运动方案。试验的主要结果将是三个治疗组的累计活产率（和次级排卵率），我们建议从治疗A到c逐步增加。我们还将检查PCOS表型在I期和II期的变化，并将研究所有怀孕受试者在妊娠三个月时的葡萄糖耐量和血压变化（III期）。本试验的目的是确定HA与IR的相对作用，并联合治疗多囊卵巢综合征妇女的不孕症和预防妊娠并发症。我们将调整现有的药物和治疗方法，建立有利的风险效益比，以治疗不孕妇女多囊卵巢综合征。我们的试验新颖而重要，因为我们研究的是从孕前到怀孕到分娩的多囊卵巢综合征妇女。该项目组建了一个独特的多学科团队，在各自的领域积累了丰富的经验，并履行了NIH路线图的任务，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紊乱，也是导致女性不孕的主要原因。这种疾病的最佳治疗方法尚不清楚，本提案将研究减肥，减少避孕药中的雌性雄激素，以及将两者结合使用对多囊卵巢综合征女性的怀孕率和妊娠并发症发生率的影响。我们的目标是开发安全有效的治疗方法来改善PCOS女性不孕不育的治疗，但研究结果可以推广到所有的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.