Primary Prevention and Uterine Preservation in Premenopausal Women With Obesity and Endometrial Hyperplasia

Inclusion Criteria: Diagnosis of histologically confirmed complex atypical endometrial hyperplasia. Patients with a previous diagnosis of AEH who are already being followed with conservative management with oral or LNG-IUD progestin therapy are eligible provided they have not previously been on a GLP-1R agonist within 3 months prior to enrollment. For patients with a previous diagnosis of AEH who have been placed on progestin prior to study entry, the duration of IUD or oral progestin use prior to trial entry should be less than or equal to 6 months. Premenopausal woman with a uterus. At least 18 years of age and no more than 45 years of age. Interested in uterine preservation/fertility-sparing treatment. BMI ≥ 30 kg/m2. Prior or current receipt of progestin is allowed as above. Willingness to undergo placement of LNG-IUD at the time of study entry. Prior or current receipt of metformin is allowed. Ability to understand and willingness to sign an IRB approved written informed consent document. Exclusion Criteria: Prior use of GLP-1 receptor agonist (exenatide, liraglutide, or other) or pramlintide or any DPP-4 inhibitor in the 3 months prior to date of registration. History of type 1 or type 2 diabetes. Acute decompensation of glycemic control. Acute coronary or cerebrovascular event in the previous 30 days. Currently planned coronary, carotid, or peripheral artery revascularization. Chronic heart failure (NYHA class IV). Evidence of renal dysfunction as defined by creatinine clearance < 60 ml/minute. History of solid organ transplant or awaiting solid organ transplant. Current, active treatment for any malignant neoplasm with chemotherapy or radiation. Family or personal history of multiple endocrine neoplasia syndrome type 2 (MEN 2) or familial medullary thyroid carcinoma (MTC). A history of allergic reactions attributed to compounds of similar chemical or biologic composition to progestin, semaglutide, or other agents used in the study. History of diabetic retinopathy. Recent history of pancreatitis, defined as less than 4 weeks prior to enrollment. History of suicidal attempts or active suicidal ideation. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. Pregnant and/or breastfeeding. Participants must have a negative serum pregnancy test within 7 days of date of registration. Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL, they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration, or they are receiving anti-retrovirals that affect progestin levels. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.