Efficacy of combined metformin plus progestin therapy versus progestin monotherapy in endometrial hyperplasia: a randomized clinical trial.

Progesterone is the standard therapy for endometrial hyperplasia, but the added benefit of metformin on histological remission and metabolic outcomes remains unclear. This study aims to compare the efficacy and safety of progestin monotherapy versus metformin plus progestin therapy in women with endometrial hyperplasia. The trial design is a single-center, open-label, parallel-group, randomized clinical trial conducted at Kosar Hospital, Qazvin, Iran, between May 2023 and July 2024. One hundred women aged 18-55 years with histologically confirmed endometrial hyperplasia were randomized 1:1 to receive progestin alone (n = 50) or metformin plus progestin (n = 50). Progestin monotherapy was administered as megestrol acetate 40 mg daily (atypical hyperplasia) or medroxyprogesterone acetate 10 mg/day cyclically (non-atypical). The combination group received the same progestin regimen plus metformin 500 mg twice daily for 3 months. All participants completed follow-up. At 3 months, histological remission was achieved in 82% (41/50) of the progestin group and 76% (38/50) of the combination group (adjusted RR 0.94; 95% CI 0.76-1.16; p = 0.56). At 6 months, remission rates were 92% and 88%, respectively (adjusted RR 0.98; 95% CI 0.86-1.11; p = 0.76). Addition of metformin was associated with a statistically significant but very modest reduction in BMI over 6 months (adjusted mean difference - 0.15 kg/m2; 95% CI - 0.25 to - 0.06; p = 0.001), without significant effects on fasting blood glucose (FBS). No Grade ≥ 3 or serious adverse events occurred; mild gastrointestinal adverse events were more frequent in the progestin plus metformin group. In this randomized clinical trial, the addition of metformin (1000 mg/day) to progestin therapy was not associated with a statistically significant difference in histological remission at 6 months compared with progestin monotherapy in women with endometrial hyperplasia. Future trials with patient stratification by metabolic and clinical characteristics may clarify subgroups that could benefit from adjunctive metformin. Iranian Registry of Clinical Trials (IRCT20230128057254N1), retrospectively registered on October 30, 2023.