Treatment of Hyperandrogenism vs. Insulin Resistance in Infertile PCOS Women

描述(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的女性患妊娠并发症(如妊娠期糖尿病和先兆子痫)的风险增加。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，美国每年仅在不孕不育治疗上就花费了5亿美元。高雄激素血症(HA)和肥胖加重的胰岛素抵抗(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病灶尚不清楚。我们推测，提高多囊卵巢综合征不孕妇女活产率的关键是纠正HA，避免晚期妊娠并发症的关键是通过强化减肥计划来提高IR。第一阶段将是一项随机试验，包括三种先入为主的干预措施(持续4个月)。对于患有多囊卵巢综合征的不孕妇女(N=246，宾夕法尼亚州立大学~150，宾夕法尼亚大学~100)：A)药物(西布曲明)、膳食替代和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。随后将在所有受试者中使用克罗米芬诱导排卵，最多4个周期(第二阶段)。在这一点上，所有治疗部队都将遵循标准化的饮食和锻炼方案。试验的主要结果将是三个治疗组的累积活产率(以及二次排卵率)，我们建议从治疗A到治疗C逐步增加。我们还将检查第一阶段和第二阶段PCOS表型的变化，并将在怀孕三个月期间研究所有受试者两个治疗组中葡萄糖耐量和血压的变化(第三阶段)。这项试验的目的是确定HA和IR在治疗多囊卵巢综合征妇女不孕症和预防妊娠并发症方面的相对作用。我们将调整现有的药物和治疗方法，使其具有既定的有利风险效益比，用于治疗患有多囊卵巢综合征的不孕妇女。我们的试验是新颖而重要的，因为我们正在研究从受孕前到受孕到分娩的整个过程中患有多囊卵巢综合征的女性。该项目组建了一支独特的多学科团队，弥合了各自领域的丰富经验，并履行了NIH路线图的任务，开发了改善以患者为导向的结果的临床干预措施。公共卫生相关性：多囊卵巢综合征(PCOS)是美国女性最常见的内分泌疾病，也是导致女性不孕的主要原因。治疗这种疾病的最佳方法尚不清楚，这项提案将研究减肥、使用避孕药减少女性雄激素以及两者联合使用对多囊卵巢综合征女性妊娠率和妊娠并发症的影响。我们的目标是开发安全有效的治疗方法来改善多囊卵巢综合征女性不孕症的治疗，但这一发现可以推广到所有患有多囊卵巢综合征的女性。

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.