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，以 超重会加重青春期无排卵和生殖功能障碍。女性多囊卵巢综合征 还降低了胰岛素敏感性(IS)，它包括肥胖和生殖异常。肥胖就像 此外，过量的睾丸素和胰岛素是子宫内膜癌的危险因素，继而缺乏 子宫内膜激素刺激过多的排卵周期。尽管流行率很高， 与多囊卵巢综合征相关的严重并发症，缺乏广泛有效的治疗选择。类胰高血糖素 多肽-1受体激动剂(GLP-1RA)促进餐后胰岛素分泌，调节肠道和 下丘脑荷尔蒙反应抑制食欲，导致体重减轻。GLP-1类风湿性关节炎获准治疗 糖尿病，以及更高剂量的肥胖症。有关较旧和效力较低的GLP-1 RA的有限数据，如艾塞那肽或 利拉鲁肽治疗多囊卵巢综合征妇女有望改善月经频率和降低血清水平 睾丸激素。我们使用更有效的口服制剂GLP治疗4个月后的初步结果- 在患有多囊卵巢综合征和肥胖症的青少年中，1RA，Semagluide，表现为餐后血糖降低，a 胰岛素曲线向更正常的模式转变，从而改善了口腔倾向指数。审判时间太短了 评估生殖功能障碍的持续时间，尽管有血清睾酮和 与试验前的4个月相比，近一半的人月经频率有所改善。青少年有 低于成年人，患有糖尿病或肥胖症的青少年对GLP-1RA的反应比成年人更少。工作是需要的 更长期、更有效的GLP-1 RA治疗对患有PCOS+肥胖症的女性的作用，特别是在 生殖寿命。此外，对GLP-1的潜在预测功能的理解也存在差距 RA反应，限制了将GLP-1 RA纳入PCOS个性化治疗计划的能力。 我们最重要的假设是，减肥和新陈代谢的改善是必须的。 多囊卵巢综合征患者的生殖健康。本应用程序的目标将在 为期一年的临床试验。在4个月的观察期后，无论是不服用药物还是二甲双胍治疗，我们 将用赛马路德治疗12-35岁患有肥胖症和多囊卵巢综合征的女性10个月以诱导体重 减少和改善排卵，降低睾丸素。我们的目标是：1)量化排卵频率 患有多囊卵巢综合征的女性患者服用赛马路德后。SA2)量化合并后的排卵频率 赛马路德+二甲双胍治疗。SA3)赛马路德的排卵反应与基线有关 治疗的特点和代谢反应。这项研究将定义目前对生殖的影响 治疗这种常见、高风险疾病的可用药物有可能立即改变健康 结果。我们还将确定治疗反应的预测因素，作为开发高质量的 针对PCOS+肥胖者的个性化治疗计划。

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.