Fat reduction mediates the efficacy of intensive lifestyle interventions on fertility‐sparing treatment in overweight patients with endometrial cancer and intraepithelial neoplasia

INTRODUCTION: Fertility-sparing treatment (FST) for endometrial cancer (EC), and its precursor, endometrial intraepithelial neoplasia (EIN), is gaining attention. However, being overweight impairs the therapeutic efficacy of FST. We analyzed the association of intensive lifestyle intervention (ILI)-based weight management with clinical outcomes in overweight patients with EC/EIN undergoing FST. MATERIAL AND METHODS: This retrospective study at the Obstetrics & Gynecology Hospital of Fudan University included overweight patients with EC/EIN who received FST. Patients were categorized into the intervention group and the control group based on their weight management approach. The primary outcomes were the complete remission (CR) rate at 24 weeks and body composition changes, including weight, body fat mass (BFM), visceral fat area (VFA), and skeletal muscle mass (SMM); the secondary outcomes were the relapse rate, pregnancy rate, and live birth rate. Cox regression models were performed and hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Mediation analysis was conducted and mediated effects with proportions were calculated. RESULTS: A total of 141 patients were retrospectively analyzed: 97 (68.8%) cases were in the intervention group undergoing ILIs and 44 (31.2%) cases were in the control group. The intervention group demonstrated significant reductions in weight (-4.2% vs. +1.5%), BFM (-8.3% vs. +3.6%), and VFA (-6.7% vs. +3.9%) (all p < 0.001). The 24-week CR rate was higher in the intervention group (44.3% vs. 25.0%, p = 0.026), with ILIs identified as an independent protective factor (HR 2.13, 95% CI 1.08-4.22, p = 0.030). A parabolic relationship was observed between weight change and CR rate (p-nonlinear = 0.038), peaking at a 3.0% weight reduction. Patients with BFM loss (48.5% vs. 28.8%, p = 0.047) or VFA loss (51.8% vs. 27.3%, p = 0.010) presented higher CR rates. Mediation analysis revealed that both VFA and BFM partially mediated the effects of ILIs (14.2% and 19.3% of the total effect). Among patients attempting natural pregnancy, the intervention group showed a strong trend toward a higher pregnancy rate (81.8% vs. 46.2%, p = 0.066). CONCLUSIONS: ILI-based weight management, particularly targeting fat reduction, is associated with enhanced FST efficacy in overweight EC/EIN patients. Our findings advocate the integration of body composition-guided ILIs into standardized FST protocols.