Efficacy and safety of the levonorgestrel-releasing intrauterine system compared with oral progestogens for endometrial hyperplasia: a systematic review and meta-analysis of randomized controlled trials

Objective To compare the efficacy and safety of the levonorgestrel-releasing intrauterine system (LNG-IUS) with oral progestogens for histologic regression of endometrial hyperplasia using randomized controlled trial data. Methods A systematic review and meta-analysis of randomized controlled trials was conducted. The primary outcome was histologic regression. Log risk ratios (RRs) were pooled with inverse-variance random-effects models using restricted maximum likelihood (REML) estimation of τ² and Hartung-Knapp confidence intervals; a 95% prediction interval was calculated. Prespecified subgroup analyses and exploratory meta-regression by follow-up duration and oral progestogen type were performed. Safety outcomes were summarized narratively because reporting was heterogeneous. Results Twelve randomized controlled trials involving 1,199 randomized participants were included. LNG-IUS was associated with a higher likelihood of histologic regression than oral progestogens (RR, 1.21; 95% CI, 1.14–1.29; I² = 21.7%; 95% prediction interval, 1.08–1.36). The association was present in non-atypical hyperplasia (RR, 1.28; 95% CI, 1.14–1.44) and in the combined mixed-or-atypical subgroup (RR, 1.19; 95% CI, 1.10–1.28), which should not be interpreted as a pure atypical-hyperplasia estimate. Exploratory meta-regression did not identify follow-up duration (ratio of RRs per month, 0.996; 95% CI, 0.988–1.004; P = 0.310) or oral progestogen type (omnibus F(3, 8) = 0.58; P = 0.642) as statistically significant effect modifiers. Egger-type testing was not statistically significant ( P = 0.137), but with 12 trials it had limited ability to exclude publication bias. Conclusions In randomized trial data with extractable event counts, LNG-IUS was associated with higher histologic regression than oral progestogens. Safety evidence was insufficient for a comparative pooled conclusion, and treatment selection should account for histologic risk, surveillance feasibility, fertility goals, and patient preference. Trial registration INPLASY202690020