Fertility-preserving therapy in EC/AEH: impact of weight and body fat changes, and interim analysis of a randomized trial

The main objective of this study is to evaluate the impact of therapeutic regimens and visceral fat dynamics on complete remission rates in fertility-preserving management of atypical endometrial hyperplasia (AEH) and early endometrial cancer (EC) and to identify modifiable predictors of treatment efficacy. This interim analysis is based on data from an ongoing, prospective, open-label randomized controlled trial (Chinese Clinical Trial Registry ChiCTR2200067099). Conducted in accordance with the pre-specified study protocol, the analysis included the first 73 enrolled participants, who were randomized to either GnRH-a combined with daily letrozole or high-dose oral progestins (medroxyprogesterone acetate or megestrol acetate). All patients received standardized lifestyle interventions (diet and exercise). The exploratory aim was to assess the association between early changes in body composition - measured using the InBody 770 analyzer over 12 weeks - and treatment response. Multivariate logistic regression analyses were performed to assess the association between treatment outcomes and changes in weight and body fat distribution. In this interim analysis, 73 patients were enrolled, including 31 patients with AEH (42.5%) and 42 patients with EC (57.5%). After 12 weeks of treatment, 40 patients achieved CR, while 33 cases did not. After implementing positive education and lifestyle interventions, patients experienced reductions in weight and indicators of body fat distribution after 12 weeks of treatment. The gonadotropin-releasing hormone agonist plus aromatase inhibitors (GnRH-a + AIs) group showed a significantly higher complete response rate than the megestrol acetate/medroxyprogesterone acetate (MA/MPA) group (75.6 vs 28.1%; risk difference: 0.48, 95% CI: 0.27-0.68). After adjustment for covariates, each 1 cm increase in baseline hip circumference was associated with 7.187-fold higher odds of complete response rate (OR = 7.19, 95% CI: 1.03-50.41, P = 0.047). Conversely, progestin therapy (vs GnRH-a + AIs) was associated with 92.7% lower odds of CR rate (OR = 0.07, 95% CI: 0.02-0.35, P = 0.001). Furthermore, a reduction in visceral fat area (per 1 cm2 decrease) was associated with 35.9% higher odds of complete response (OR = 1.36, 95% CI: 1.02-1.81, P = 0.034). Conversely, progestin therapy (vs GnRH-a + AIs) was associated with 89.2% lower odds of CR rate (OR = 0.108, 95% CI: 0.015-0.773, P = 0.027). We found that treatment regimen selection critically influences therapeutic outcomes in fertility-sparing management. Our study shows that reducing visceral fat area substantially improves treatment efficacy, making it a key indicator for predicting treatment effects. This study is part of a registered clinical trial (Chinese Clinical Trial Registry ID: ChiCTR2200067099; registered December 27, 2022).