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.