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

索马鲁肽在青少年和成人多囊卵巢综合征恢复排卵中的作用

• 批准号: 10587181
• 负责人: Melanie G Cree
• 金额: $ 54.11万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587181
• 关键词: Acne; Adolescence; Adolescent; Adult; Age; Agonist; Androgens; Anovulation; Body Weight decreased; Characteristics; Clinical; Clinical Trials; Combined Modality Therapy; Compensatory Hyperinsulinemia; Data; Desire for food; Diabetes Mellitus; Dose; Endometrial Carcinoma; Endometrium; Enrollment; Female; Formulation; Frequencies; Functional disorder; GLP-I receptor; Glucose; Health; Hemorrhage; High Prevalence; Hirsutism; Hormonal; Hour; Hyperandrogenism; Hypergravity; Hypothalamic Hormones; Individual; Insulin; Life Style; Longevity; Luteinizing Hormone; Measures; Menstrual cycle; Menstruation; Metabolic; Metabolic Diseases; Metformin; Methods; Modeling; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Oligomenorrhea; Oral; Outcome; Ovulation; Ovulation Induction; Pattern; Persons; Pharmaceutical Preparations; Physiology; Polycystic Ovary Syndrome; Prediction of Response to Therapy; Progesterone; Puberty; Reproductive Health; Risk; Risk Factors; Role; Secondary to; Serum; Testosterone; Weight; Woman; Work; Youth; aged; androgen excess; arm; comorbidity; disorder risk; efficacious treatment; exenatide; experience; girls; high risk; hormonal contraception; improved; indexing; insulin secretion; insulin sensitivity; liraglutide; loss of function; metabolic phenotype; metabolic profile; mullerian-inhibiting hormone; personalized medicine; predicting response; prevent; reproductive; reproductive function; reproductive outcome; response; subcutaneous; therapeutically effective; trait; treatment planning; treatment response; trend; urinary

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.

多囊卵巢综合征（PCOS）是女性最常见的内分泌疾病之一，表现为 体重过重会加剧青春期无排卵和生殖功能障碍。患有多囊卵巢综合症的女性 胰岛素敏感性（IS）也降低，其中包括肥胖和生殖异常。肥胖如 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 子宫内膜受到过多激素刺激的排卵周期。尽管患病率很高并且 由于 PCOS 相关合并症的严重性，缺乏广泛有效的治疗选择。胰高血糖素样 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，高剂量则导致肥胖。关于较旧且效力较低的 GLP-1 RA（例如艾塞那肽或 利拉鲁肽对于患有 PCOS 的女性来说有望改善月经频率并降低血清水平 睾酮。我们使用更有效的口服制剂 GLP 治疗 4 个月后的初步结果- 1 RA（索马鲁肽）在患有 PCOS 和肥胖的青少年中表现出较低的餐后血糖，这是一种转变 胰岛素曲线变得更加正常，从而改善口腔处置指数。审判时间太短 评估生殖功能障碍的持续时间，尽管存在血清睾酮下降和 与试验前 4 个月相比，近一半的月经频率有所改善。青少年有 IS 低于成年人，患有糖尿病或肥胖的青少年对 GLP-1 RA 的反应低于成年人。需要工作 长期、更有效的 GLP-1 RA 治疗对 PCOS + 肥胖女性的作用，尤其是 生殖寿命。此外，在理解 GLP-1 的潜在预测特征方面存在差距 RA 反应，限制了将 GLP-1 RA 纳入 PCOS 个性化治疗计划的能力。 我们的总体假设是，需要减轻体重和改善代谢来改善 多囊卵巢综合症患者的生殖健康。该应用程序的目标将在 为期一年的临床试验。经过 4 个月的不用药或二甲双胍治疗观察期后，我们 将使用索马鲁肽治疗 12-35 岁患有肥胖症和多囊卵巢综合症的女性 10 个月以诱导体重 减少并改善排卵并降低睾酮水平。我们的目标是： SA1) 之前定量排卵频率 以及患有 PCOS 的女性服用索马鲁肽后。 SA2) 定量组合后的排卵频率 索马鲁肽+二甲双胍治疗。 SA3) 对索马鲁肽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 针对这种常见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，作为开发高质量的一步 为 PCOS + 肥胖患者制定个性化治疗计划。