Impact of GLP-1 RA plus progestin therapy on fertility-sparing management of endometrial intraepithelial neoplasia and endometrial cancer.

OBJECTIVE: We examined whether the addition of GLP-1RA to progestin therapy reduced the risk of hysterectomy in patients with endometrial intraepithelial neoplasia (EIN) and endometrial cancer (EC) in the U.S. managed with fertility-sparing management. METHODS: Women ≤45 years old at EIN/EC diagnosis were identified in the TriNetX Research Collaborative Network (1/1/2017-12/01/2025). Patients initiating GLP-1 RA plus progestins (megestrol acetate, medroxyprogesterone acetate, or levonorgestrel-releasing intrauterine device) formed the GLP-1 RA + progestin group and were compared with the progestin-only group. Groups were 1:1 propensity-score matched (PSM) for demographics, BMI, HbA1c, type 2 diabetes, comorbidities, medication use, healthcare utilization, and EIN/EC. Patients were followed up for 6, 12, and 18 months from treatment initiation until the occurrence of hysterectomy; loss to follow-up; or December 1, 2025. Hazard ratios (HRs) with 95% confidence intervals (CI) were estimated using Cox proportional hazards regression. Analyses for subgroups, head-to-head comparisons were also performed. RESULTS: After 1:1 PSM (n = 432 in each group), hysterectomy occurred in 10.2% of the GLP-1RA + progestin group versus 23.4% in the matched progestin-only group (HR 0.41, 95% CI 0.29-0.58) at 18 months, with significant reductions observed as early as 6 months. This protective association was consistent across subgroups, including younger patients (<40 years), EC diagnosis, progestin type (LNG-IUD or oral progestins), and GLP-1RA type (semaglutide or tirzepatide). CONCLUSION: Adjunct GLP-1 receptor agonist therapy was associated with reduced hysterectomy risk in EIN and EC, supporting prospective fertility-sparing studies.