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病之一， 过多的重量会使青春期和生殖功能障碍的缺乏症恶化。有PCOS的女性 还降低了胰岛素敏感性（IS），这整合了肥胖和生殖异常。肥胖症 以及过量的睾丸激素和胰岛素是子宫内膜癌的危险因素，其次是缺乏 子宫内膜过量激素刺激的排卵周期。尽管患病率很高， 缺乏与PCOS相关的合并症的重力，缺乏广泛有效的治疗选择。胰高血糖素状 肽-1受体激动剂（GLP-1 RA）增加了餐后胰岛素的分泌并调节肠道和 下丘脑激素对抑制食欲的反应并导致体重减轻。 GLP-1 RA被批准用于治疗 糖尿病和更高剂量的肥胖症。较旧且有效的GLP-1 RA的数据有限，例如艾烯肽或 Liraglutide，有PCOS的女性有望有所改善，血清降低了血清 睾丸激素。在4个月后，我们的最初结果，以更有效和口服的配方GLP- 1 Ra，semaglutide，患有PCOS和肥胖症的青少年表现出较低的餐后葡萄糖，一种移动 胰岛素曲线达到更正常的模式，结果改善了口服性格指数。审判太短了 持续时间以评估生殖功能障碍，尽管血清睾丸激素和 与试验前的4个月相比，将近一半的月经频率提高了。青少年有 低于成年人，糖尿病或肥胖症的青年对GLP-1 RA的反应少于成年人。需要工作 关于PCOS +肥胖女性长期，更有效的GLP-1 RA治疗的作用，尤其是在跨越 生殖寿命。此外，理解GLP-1的基本特征存在差距 RA响应，限制了将GLP-1 RA包括在PCOS的个性化治疗计划中的能力。 我们的总体假设是需要减肥和代谢改善以改善 PCOS患者的生殖健康。该应用程序的目的将在 为期一年的临床试验。经过4个月的无药物或二甲双胍治疗的观察期，我们 将用肥胖和PCOS治疗12-35岁的女性使用Semaglutide持续10个月以诱发体重 损失和改善排卵和较低的睾丸激素。我们的目标是：SA1）定量排卵频率 在患有PCOS的女性中，半熟肽后。 SA2）组合后定量排卵频率 用半卢比 +二甲双胍治疗。 SA3）排卵对半卢比德的反应将与基线有关 对治疗的特征和代谢反应。这项研究将定义当前的生殖影响 这种常见的高风险疾病的可用药物，有可能立即改变健康 结果。我们还将确定治疗反应的预测指标，这是发展高质量的一步 PCOS +肥胖者的个性化治疗计划。