Project 3: Primary Prevention and Uterine Preservation in Premenopausal Women with Obesity and Endometrial Hyperplasia/Cancer

项目总结/摘要 在美国，每年约65，000名被诊断患有子宫内膜癌的女性中，高达90%的人超重或肥胖。 肥胖是子宫内膜癌的主要病因，高达60%的子宫内膜癌病例是由肥胖引起的。这在很大程度上是因为， 肥胖促进子宫内膜非典型增生（AEH）的发展，AEH是1级子宫内膜增生的前兆。 癌如果在这些阶段之一诊断，患者可以进行子宫切除术治疗，这是100% 有效预防/治疗子宫内膜癌。然而，子宫切除术往往是不可接受的， 希望保持生育能力的绝经前妇女。相反，这些患者通常用 孕激素，最常见的是通过左炔诺孕酮释放宫内节育器（IUD）。然而，高达41%的 服用抗肿瘤药物的妇女最终会复发并需要子宫切除术。此外，不到12%的 选择这种选择的妇女继续活产，可能是因为肥胖和通常的共同- 胰岛素抵抗的发生损害生育能力。由于体重减轻本身也可以逆转AEH和1级子宫内膜 癌症，一个理想的治疗绝经前妇女希望未来的生育能力将同时 提供一种带有有效减肥策略的子宫内节育器沿着。早期发现、预防和 人口科学项目包括两项随机对照试验，测试总体假设， 联合使用阿托伐他汀和治疗性或行为性减肥干预， 比单独使用雷公藤多甙更好地保护子宫。目的1是确定雷公藤多甙加a 行为减肥干预，使子宫保留和预防绝经前癌症 患有AEH或1级子宫内膜癌的女性。目的2是确定胰高血糖素样肽1的功效 受体激动剂加雷公藤多甙加行为减肥干预，以保留子宫， 绝经前AEH妇女的癌症预防。本试验中的治疗药物由 用于治疗肥胖症。探索性目的3是鉴定反映对曲马多蛋白加 减肥.如果该项目确定了有效的战略，就可以广泛实施， 患有AEH或1级子宫内膜癌的绝经前妇女，以避免癌症并保护其子宫 未来的生育能力。

PROJECT SUMMARY/ ABSTRACT Up to 90% of the ~65,000 women diagnosed with endometrial cancer each year in the U.S. are overweight or obese, and up to 60% of endometrial cancer cases are attributed to obesity. This is, in large part, because obesity promotes development of atypical endometrial hyperplasia (AEH), a precursor of grade 1 endometrial cancer. If diagnosed at one of these stages, a patient can be treated with hysterectomy, which is 100% effective in preventing/curing endometrial cancer. However, hysterectomy is often unacceptable to premenopausal women who would like to retain fertility. Instead, such patients are commonly treated with progestin, most commonly via a levonorgestrel-releasing intrauterine device (IUD). However, up to 41% of women on progestin eventually experience relapse and require a hysterectomy. Moreover, fewer than 12% of women who choose this option go on to have a live birth, likely because obesity and the commonly co- occurring insulin resistance impair fertility. As weight loss alone can also reverse AEH and grade 1 endometrial cancer, an ideal treatment for premenopausal women desiring future fertility would be to simultaneously provide a progestin IUD along with an effective weight loss strategy. This Early detection, Prevention and Population Science project includes two randomized controlled trials testing the overall hypothesis that combined treatment with progestin and either therapeutic or behavioral weight loss interventions leads to greater uterine preservation than progestin use alone. Aim 1 is to determine the efficacy of progestin plus a behavioral weight loss intervention to allow uterine preservation and cancer prevention in premenopausal women with AEH or grade 1 endometrial cancer. Aim 2 is to determine the efficacy of a glucagon-like peptide 1 receptor agonist plus progestin plus a behavioral weight loss intervention to allow uterine preservation and cancer prevention in premenopausal women with AEH. The therapeutic drug in this trial is approved by the FDA for treating obesity. Exploratory Aim 3 is to identify biomarkers that reflect response to progestin plus weight loss. If this project identifies effective strategies, they can be widely implemented to allow premenopausal women with AEH or grade 1 endometrial cancer to both avoid cancer and preserve their uterus for future fertility.