The COMET-PCOS trial - Comparing the effects of Oral Contraceptive Pills versus Metformin in the medical management of overweight/obese women with Polycystic Ovary Syndrome

背景：多囊卵巢综合征(PCOS)是育龄期最常见的内分泌疾病 女人。代谢综合征(METS)是一系列心脏代谢危险因素，是一个主要的健康问题 在患有多囊卵巢综合征的年轻女性中患病率很高(20%-40%)。令人惊讶的是，对于 超重/肥胖妇女没有尝试怀孕，导致冲突的最佳治疗 口服避孕药(OCP)和二甲双胍在妇女中的临床使用指南和处方模式 多囊卵巢综合征的长期治疗。尽管口服避孕药改善了月经不规律，降低了雄激素，但它们可能 与体重、血清甘油三酯水平和血压增加有关。在OWL-PCOS研究中，我们 最近发现，OCP的这些不利代谢影响在超重/肥胖女性中加剧， 多囊卵巢综合征。另一方面，二甲双胍具有良好的代谢特征，但改善效果较差 月经规律与降低雄激素。这一难题突出表明，需要确定全面的 和安全的治疗，同时改善这一高危人群的代谢状况。 具体目标和方法：在具体目标1中，我们提出了一项实用的随机临床试验(COMET- PCOS)比较口服环磷酰胺、二甲双胍和口服环磷酰胺+二甲双胍对糖尿病患病率变化的影响 240例超重/肥胖多囊卵巢综合征患者治疗6个月后的METS。基于我们来自OWL的数据- 多囊卵巢综合征，我们假设小剂量口服环磷酰胺的使用将显著增加甲硫氨酸的风险，而二甲双胍 单独使用或二甲双胍+口服避孕药将分别导致蛋氨酸减少或略有增加。我们的次要 AIMS将研究与大都会运动试验的各个组成部分相关的创新机械途径。为 例如，为了准确了解OCP对血脂异常(血清升高)的矛盾影响 甘油三酯和高密度脂蛋白水平)，这是多囊卵巢综合征最常见的代谢异常，我们将评估高密度脂蛋白 通过测量反向胆固醇流出和核磁共振测量脂蛋白颗粒大小和数量来发挥功能 光谱学。在具体目标2中，我们将准确定义OCP的影响(通过减少雄激素)和 二甲双胍(通过改善胰岛素敏感性)或两者兼而有之对内脏脂肪分布、糖耐量、 炎性细胞因子和脂肪因子。 摘要：多囊卵巢综合征和甲型肝炎的存在显著增加了长期发病率、财务和 年轻女性的情感负担。我们精心设计和充足动力的研究可能会提供 支持OCP+二甲双胍联合使用和避免OCP单独使用的证据 患有多囊卵巢综合征的超重/肥胖妇女。这些发现将显著改变目前的临床实践，即 根据病人和医生的喜好。此外，我们的次要目标将是创新的 旨在专门比较和了解代谢改变的病理生理学 与OCP和二甲双胍的使用有关。

Background: Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in reproductive age women. Metabolic syndrome (MetS), a constellation of cardiometabolic risk factors, is a major health problem with a high prevalence in young women with PCOS (20-40%). Surprisingly, there is no consensus on the optimal treatment of overweight/obese women with PCOS not attempting pregnancy, resulting in conflicting clinical guidelines and prescribing patterns for the use of oral contraceptive pills (OCP) and metformin in the long term treatment of PCOS. Although OCP improve menstrual irregularity and lower androgens, they may be associated with increase in weight, serum triglycerides levels and blood pressure. In the OWL-PCOS study, we recently found that these adverse metabolic effects of OCP are exacerbated in overweight/obese women with PCOS. Metformin on the other hand, has a favorable metabolic profile but is less effective in improving menstrual regularity and reducing androgens. This conundrum highlights the need to identify comprehensive and safe treatments, whilst improving the metabolic profile in this high risk population. Specific Aims and Methods: In Specific Aim 1 we propose a pragmatic randomized clinical trial (COMET- PCOS) to compare the effects of OCP versus metformin versus OCP+metformin on change in prevalence of MetS after 6 months treatment in 240 overweight/obese women with PCOS. Based on our data from OWL- PCOS, we hypothesize that low dose OCP use will significantly increase the risk of MetS, while metformin alone or metformin+OCP use will result in a decrease or modest increase in MetS respectively. Our secondary aims will examine innovative mechanistic pathways associated with individual components of MetS. For example, to precisely understand the paradoxical effects of OCP on dyslipidemia (increased serum triglycerides and HDL-C levels), the commonest metabolic abnormality in PCOS, we will assess HDL-C function by measuring reverse cholesterol efflux, and lipoprotein particle size and number by NMR spectroscopy. In Specific Aim 2 we will precisely define the impact of OCP (by decreasing androgens) and metformin (by improving insulin sensitivity) or both on change in visceral fat distribution, glucose tolerance, inflammatory cytokines and adipokines. Summary: The presence of both PCOS and MetS adds significantly to long term morbidities, financial and emotional burden in young women. Our well-designed and adequately powered study will likely provide evidence favoring the use of OCP+metformin combination and avoiding use of OCP alone in management of overweight/obese women with PCOS. These findings will significantly change current clinical practice which is based on patient and physician preferences. Further, our secondary aims will be innovative as they are targeted at specifically comparing and understanding the pathophysiology of the metabolic alterations associated with use of OCP and metformin.