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

项目摘要/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，高达60%的子宫内膜癌病例归因于肥胖。这在很大程度上是因为 肥胖促进非典型子宫内膜增生症(AEH)的发展，AEH是1级子宫内膜的先兆 癌症。如果在这些阶段中的一个阶段确诊，患者可以进行子宫切除术，这是100%的 有效预防/治疗子宫内膜癌。然而，子宫切除术通常是不能接受的 想要保留生育能力的绝经前女性。取而代之的是，这类患者通常被用 孕激素，最常见的是通过释放左炔诺孕酮的宫内节育器(IUD)。然而，高达41%的 服用孕激素的女性最终会复发，需要进行子宫切除术。此外，只有不到12%的人 选择这个选项的女性继续活着分娩，很可能是因为肥胖和通常的 发生胰岛素抵抗会损害生育能力。AS单独减肥也可以逆转AEH和1级子宫内膜 癌症，对于希望未来生育的绝经前女性来说，理想的治疗方法是同时 提供孕激素宫内节育器以及有效的减肥策略。这一早期发现、预防和 人口科学项目包括两个随机对照试验，检验总体假设 联合使用孕激素和治疗性或行为性减肥干预可导致 比单独使用孕激素能更好地保存子宫。目的1是确定孕激素联合 绝经前行为减肥干预使子宫保育和癌症预防 患有AEH或1级子宫内膜癌的女性。目的2是确定一种胰高血糖素样肽1的疗效 受体激动剂+孕激素+行为减肥干预，允许子宫保存和 绝经前AEH患者的癌症预防。这项试验中的治疗药物由美国食品和药物管理局批准 FDA用于治疗肥胖症。探索性目标3是确定反映孕激素+反应的生物标记物。 减肥。如果这个项目确定了有效的战略，它们可以被广泛实施，以允许 患有AEH或1级子宫内膜癌的绝经前妇女既可避免癌症，又可保留子宫 为未来的生育做准备。

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.