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

COMET-PCOS 试验 - 比较口服避孕药与二甲双胍在超重/肥胖多囊卵巢综合症女性医疗管理中的效果

• 批准号: 9286789
• 负责人: ANUJA DOKRAS
• 金额: $ 60.01万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9286789
• 关键词: Adipocytes; Affect; Aftercare; Age; Androgens; Apolipoproteins; Blood Pressure; Body Weight; Body Weight decreased; Body fat; Cardiovascular Diseases; Caucasians; Cholesterol; Chronic Disease; Clinical; Combined Modality Therapy; Conflict (Psychology); Consensus; Data; Development; Diabetes Mellitus; Dual-Energy X-Ray Absorptiometry; Dyslipidemias; Emotional; Endocrine System Diseases; Endocrinologist; Fatty acid glycerol esters; Functional disorder; Funding; Glucose; Guidelines; Gynecologist; Health; High Density Lipoproteins; High Prevalence; Hirsutism; Hyperandrogenism; Hypertriglyceridemia; IL6 gene; Individual; Inflammation; Inflammatory; Insulin; Insulin Resistance; International; Irregular Menstruation; Leptin; Lipids; Lipoproteins; Low Dose Oral Contraceptives; Measures; Medical; Metabolic; Metabolic syndrome; Metformin; Methods; Morbidity - disease rate; NMR Spectroscopy; National Institute of Child Health and Human Development; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Oral Contraceptives; Overweight; Particle Size; Pathway interactions; Patients; Pattern; Periodicity; Pharmaceutical Preparations; Phenotype; Physicians; Polycystic Ovary Syndrome; Population; Pregnancy; Prevalence; Prevention strategy; Preventive treatment; Public Health; Race; Randomized; Randomized Clinical Trials; Risk; Risk Factors; Serum; Serum Markers; Surveys; System; TNF gene; Techniques; Testing; Triglycerides; Visceral; Weight; Woman; adipokines; adiponectin; arm; base; cardiometabolic risk; clinical practice; cytokine; design; evidence based guidelines; glucose tolerance; high risk population; improved; inflammatory marker; innovation; insulin sensitivity; intervention effect; metabolic profile; pediatrician; pill; preference; racial difference; reproductive; trial comparing; young woman

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.

背景：多囊卵巢综合征（PCOS）是生殖时代最常见的内分泌障碍 女性。代谢综合征（MetS）是心脏代谢危险因素的星座，是一个主要的健康问题 患有PCOS的年轻女性（20-40％）的患病率很高。令人惊讶的是，关于 对超重/肥胖女性患有PCOS未尝试怀孕的最佳治疗，导致冲突 使用口服避孕药（OCP）和二甲双胍的临床准则和处方模式 PCOS的长期处理。尽管OCP改善了月经不规则性和较低的雄激素，但它们可能是 与体重增加，血清甘油三酸酯水平和血压有关。在OWL-PCOS研究中，我们 最近发现，在超重/肥胖的女性中，OCP的这些不良代谢作用加剧了 PCOS。另一方面，二甲双胍具有良好的代谢概况，但在改善方面的有效性较差 月经的规律性和减少雄激素。这个难题强调了确定全面的必要性 和安全的治疗，同时改善了这种高风险人群的代谢特征。 特定目的和方法：在特定目的1中，我们提出了一项务实的随机临床试验（彗星 - PCOS）比较OCP与二甲双胍与OCP+二甲双胍对变化的影响的影响 在240个超重/肥胖女性患有PCOS的240名超重女性治疗6个月后。基于我们的数据 PCOS，我们假设低剂量的OCP使用将大大增加大都能蛋白的风险 单独或二甲双胍+OCP的使用将分别导致MetS的减少或适度增加。我们的次要 AIMS将检查与MetS各个组件相关的创新机械途径。为了 例如，准确理解OCP对血脂异常的悖论作用（血清增加 甘油三酸酯和HDL-C水平），PCOS中最常见的代谢异常，我们将评估HDL-C 通过测量反向胆固醇外排和NMR的脂蛋白粒度和数量来实现功能 光谱法。在特定目标2中，我们将精确地定义OCP的影响（通过减少雄激素）和 二甲双胍（通过提高胰岛素敏感性）或在内脏脂肪分布，葡萄糖耐受性的变化方面都 炎症细胞因子和脂肪因子。 摘要：PCOS和METS的存在大大增加了长期病毒，财务和 年轻女性的情感负担。我们精心设计和充分的动力研究可能会提供 有利于使用OCP+二甲双胍组合并避免单独使用OCP的证据 超重/肥胖女性患有PCOS。这些发现将大大改变当前的临床实践 基于患者和医师的偏好。此外，我们的次要目标将是创新的 针对特定比较和理解代谢改变的病理生理学 与OCP和二甲双胍的使用相关。