A Randomized Clinical Trial of Levonorgestrel Intrauterine System with or without Metformin for Treatment of Endometrial Hyperplasia without Atypia in Indian Women

BACKGROUND: Endometrial cancer is the second most frequent genital malignancy in women, which is showing a constant rise all over world. Endometrial hyperplasia is the precursor of endometrial cancer. Levonorgestrel intrauterine system is the first line management in patients with endometrial hyperplasia without atypia. Metformin has shown to reverse endometrial hyperplasia, but its effectiveness and safety in endometrial hyperplasia is uncertain. OBJECTIVE: To compare the efficacy in terms of histopathological response, clinical response and safety at the end of 6 months in patients with endometrial hyperplasia without atypia managed with levonorgestrel intrauterine system alone versus patients managed with levonorgestrel intrauterine system plus metformin. METHODS: The randomized control trial was conducted on 51 cases of endometrial hyperplasia without atypia. Twenty-five subjects were prescribed metformin 500mg twice daily with levonorgestrel intrauterine system and 26 subjects, with levonorgestrel intrauterine system only for 6 months. At the end of 6 months, endometrial sampling was performed for histopathological response. RESULTS: Clinical response was observed in 23 of 25 subjects in metformin group and 22 of 24 in levonorgestrel only group. The metformin group responded significantly with amenorrhea (p= 0.0053), while levonorgestrel only group responded with regular cycles (p=0.027). At the end of study, of 46 subjects available for histopathological evaluation, 100% subjects in metformin group and 95.45% in levonorgestrel only group (p=0.47826) showed complete response. The metformin group had a significant reduction in body mass index at end of study [P = 0∙023, 95% confidence interval (-1.7802, -0.1418)]. CONCLUSION: No significant difference in regression of endometrial hyperplasia was observed on adjunctive use of metformin but a significant reduction in BMI was observed. Use of metformin in obese patients may improve the treatment response.