Semaglutide 2.4 mg plus LNG-IUD hypothesized to improve uterine preservation in obese women with endometrial hyperplasia

Endometrial hyperplasia, particularly atypical forms, is a precursor to endometrial cancer, often driven by unopposed estrogen and exacerbated by obesity. Current management includes hysterectomy, which is effective but not ideal for premenopausal women desiring uterine preservation. Progestin therapy, typically via a levonorgestrel intrauterine device (LNG-IUD), offers a uterine-sparing option by counteracting estrogen's effects on the endometrium. However, response rates can be suboptimal, especially in obese patients. This trial explores whether combining the metabolic benefits of a GLP-1R agonist with progestin therapy can enhance treatment efficacy and improve patient outcomes.

This phase II clinical trial investigates the efficacy of combined treatment in premenopausal women diagnosed with endometrial hyperplasia and obesity who wish to preserve their uterus. Participants will be randomized to receive either semaglutide 2.4 mg weekly via subcutaneous injection alongside an LNG-IUD, or an LNG-IUD alone. The study aims to compare the likelihood of uterine preservation, sustained weight loss, improvements in endometrial and metabolomic responses to progestin, and overall quality of life between the two groups. This design directly tests the hypothesis that adding a GLP-1R agonist can augment the established benefits of LNG-IUD.

The investigators hypothesize that the combined treatment arm, featuring semaglutide 2.4 mg and LNG-IUD, will demonstrate superior outcomes compared to LNG-IUD alone. Specifically, they expect an improved likelihood of uterine preservation, a critical endpoint for this patient population. The trial also anticipates that the combination therapy will lead to significant and sustained weight loss, a known benefit of semaglutide, which could indirectly improve endometrial health. Furthermore, the hypothesis includes an improved endometrial and metabolomic response to progestin, suggesting a synergistic effect on the underlying disease pathology. Finally, participants in the combination group are expected to report an improved quality of life. These are the primary hypothesized findings guiding the study's design and expected results.

The core hypothesis is that combined semaglutide 2.4 mg and LNG-IUD treatment will result in improved likelihood of uterine preservation, sustained weight loss, and enhanced endometrial and metabolomic response.