Phase 2 semaglutide GLP-1 receptor agonist + LNG-IUD progestin for fertility-sparing endometrial neoplasia

This Phase 2, single-arm conservative-management study tests whether combining a levonorgestrel-releasing IUD (local progestin that activates the progesterone receptor in the endometrium), semaglutide 2.4 mg (Novo Nordisk; a GLP-1 receptor agonist that improves insulin resistance and promotes weight loss), and a structured weight-loss program can increase complete pathologic response rates in reproductive-age patients with endometrial atypical hyperplasia/EIN or FIGO grade 1 endometrioid endometrial cancer who want to preserve fertility. Participants receive LNG-IUD placement at baseline, take semaglutide per standard titration to 2.4 mg weekly, and complete lifestyle coaching during 6 months of active therapy followed by 6 months of follow-up, with hysteroscopy/endometrial sampling used to confirm response and durability. The scientific angle is an “endometrium + metabolism” strategy: obesity and hyperinsulinemia are common in this population, so adding a potent weight-loss/insulin-sensitizing agent could plausibly deepen or stabilize progesterone-driven regressions compared with intrauterine progestin alone. Today’s care for confirmed EAH/EIN and early grade 1 disease is usually hysterectomy for definitive cure; for fertility-sparing candidates, conservative progestin therapy (often LNG-IUD or oral progestins) with close surveillance is used, but relapse and progesterone resistance remain practical problems this combination aims to reduce.