Role of semaglutide in restoring ovulation in youth and adults with polycystic ovary syndrome

多囊卵巢综合征（PCOS）是女性最常见的内分泌疾病之一， 青春期不排卵和生殖功能障碍因超重而恶化。PCOS女性 也降低了胰岛素敏感性（IS），这将肥胖和生殖异常结合在一起。肥胖是 以及过量的睾酮和胰岛素是子宫内膜癌的危险因素，继发于缺乏 排卵周期与子宫内膜的过度激素刺激。尽管发病率很高， 与PCOS相关的合并症的严重性，缺乏广泛有效的治疗选择。素样 肽-1受体激动剂（GLP-1 RA）增加餐后胰岛素分泌并调节肠道和 下丘脑激素反应抑制食欲并导致体重减轻。GLP-1 RA被批准用于治疗 糖尿病，高剂量的话，肥胖关于较旧和效力较低的GLP-1 RA（如依塞那肽或 利拉鲁肽在PCOS女性中具有改善月经频率和降低血清 睾酮.我们的初步结果后，4个月的治疗与更有效的和口服制剂GLP- 1例患有PCOS和肥胖的青少年患者中，semaglutide的RA表现出较低的餐后血糖， 胰岛素曲线向更正常模式转变，从而改善口服处置指数。审判时间太短了 持续时间，以评估生殖功能障碍，虽然有降低血清睾酮和 与试验前4个月相比，近一半的患者月经频率有所改善。青少年有 IS低于成人，糖尿病或肥胖青年对GLP-1 RA的反应低于成人。工作是需要在 长期、更有效的GLP-1 RA治疗在PCOS +肥胖女性中的作用，特别是在 生殖寿命此外，在了解GLP-1的潜在特征预测方面存在差距 RA反应，限制了将GLP-1 RA纳入PCOS个性化治疗计划的能力。 我们的首要假设是，减肥和代谢改善是改善 PCOS患者的生殖健康本申请的目的将在以下背景下执行： 为期一年的临床试验经过4个月的观察期，无论是没有药物治疗或二甲双胍治疗，我们 将使用Semaglutide治疗12-35岁肥胖和PCOS女性10个月，以诱导体重 减少和改善排卵和降低睾丸激素。我们的目标是：SA 1）定量排卵频率之前， 在PCOS女性中，semaglutide给药后。SA 2）联合用药后定量排卵频率 Semaglutide +二甲双胍治疗。SA 3）Semaglutide的排卵反应将与基线相关 特征和对治疗的代谢反应。这项研究将确定目前的生殖影响， 这种常见的高风险疾病的可用药物，有可能立即改变健康状况 结果。我们还将确定治疗反应的预测因素，作为开发高质量 为PCOS +肥胖患者提供个性化治疗计划。

Polycystic ovary syndrome (PCOS), one of the most common endocrinopathies in women, presents with anovulation in adolescence and reproductive dysfunction is worsened by excess weight. Females with PCOS also have lowered insulin sensitivity (IS), which integrates obesity and reproductive abnormalities. Obesity as well as excess testosterone and insulin are risk factors for endometrial carcinoma, secondary to the lack of ovulatory cycles with excess hormonal stimulation of the endometrium. Despite the high prevalence and gravity of comorbidities associated with PCOS, widely effective therapeutic options are lacking. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) increase post-prandial insulin secretion and modulate gut and hypothalamic hormone responses to suppress appetite and cause weight loss. GLP-1 RA are approved to treat diabetes, and in higher doses, obesity. Limited data on older and less potent GLP-1 RA, such as exenatide or liraglutide, in women with PCOS are promising with improved menstrual frequency and lowered serum testosterone. Our initial results following 4 months of treatment with a more potent and oral formulation GLP- 1 RA, semaglutide, in adolescents with PCOS and obesity demonstrated lower post-prandial glucose, a shifted insulin curve to a more normal pattern with a resultant improved oral disposition index. The trial is too short of duration to assess reproductive dysfunction, although there is a trend for decreased serum testosterone and nearly half had improved menses frequency compared to the 4 months prior to the trial. Adolescents have lower IS than adults, and youth with diabetes or obesity respond less to GLP-1 RA than adults. Work is needed on the role of longer-term, more potent GLP-1 RA treatment in women with PCOS + obesity, especially across the reproductive lifespan. Further, there is a gap in understanding the underlying features predictive of GLP-1 RA response, limiting the ability to include GLP-1 RA in a personalized therapy plan for PCOS. Our overarching hypothesis is that weight loss and metabolic improvements are required to improve reproductive health in individuals with PCOS. The aims of this application will be performed in the context of a year-long clinical trial. After a 4-month observation period of either no medication or metformin treatment, we will treat females aged 12-35 years with obesity and PCOS for 10 months with semaglutide to induce weight loss and improve ovulation and lower testosterone. We aim to: SA1) Quantitate ovulation frequency before and after semaglutide in females with PCOS. SA2) Quantitate ovulation frequency following combination treatment with semaglutide + metformin. SA3) The ovulation response to semaglutide will relate to baseline characteristics and metabolic response to therapy. This study will define the reproductive impact of currently available medications on this common, high-risk disease, with the potential to immediately change health outcomes. We will also identify predictors of treatment response, as a step towards developing high-quality personalized treatment plans for those with PCOS + obesity.