Metformin as an Adjunct to Fertility-Sparing Treatment in Atypical Endometrial Hyperplasia and Early-Stage Endometrioid Endometrial Cancer: Narrative Review.

Objective: This study aims to evaluate the potential role of metformin as an adjunct to fertility-sparing treatment strategies for women with atypical endometrial hyperplasia/endometrial intraepithelial neoplasia (AEH/EIN) and early-stage endometrioid endometrial cancer (EEC), with particular emphasis on oncologic and reproductive outcomes. Methods: A systematic search of PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library was conducted from database inception through May 2026. Eligible studies included randomized controlled trials, prospective studies, and retrospective cohort studies evaluating metformin-containing fertility-sparing treatment regimens in women with AEH/EIN or early-stage EEC. Owing to substantial clinical and methodological heterogeneity in study design, treatment protocols, metformin dosage, follow-up duration, and outcome reporting, a quantitative meta-analysis was considered inappropriate, and the findings were synthesized narratively. Results: Eight publications represented approximately 795 unique patients after accounting for overlapping cohorts. Complete response was reported in 63/92 patients overall (69%) in Acosta-Torres et al., including 23/34 (68%) receiving progestin plus metformin, and in 61/63 (97%) receiving medroxyprogesterone acetate plus metformin in Mitsuhashi et al. Reported recurrence rates ranged from 13.1% to 34.2%. Live births occurred in 2/34 (6%) metformin-treated patients in Acosta-Torres et al., 14/31 (45%) women wished to conceive in Mitsuhashi et al., and 29/79 (36.7%) patients overall in Jing et al. Differences in populations, assessment times, and reproductive denominators limited direct comparisons and attribution of benefit to metformin. Conclusions: Current evidence suggests that metformin may have a promising adjunctive role in fertility-sparing treatment for women with AEH/EIN and early-stage EEC, particularly among patients with obesity, insulin resistance, polycystic ovary syndrome, or other metabolic risk factors. Nevertheless, the overall body of evidence should be interpreted with caution because of substantial heterogeneity across studies, the predominance of retrospective designs, and the limited number of prospective randomized trials. Well-designed multicenter randomized controlled trials are required to define the optimal role of metformin, identify the patients most likely to benefit, and establish standardized treatment strategies before routine incorporation into clinical practice can be recommended.