Abstract
To assess the efficacy of metformin in megestrol acetate (MA)-based fertility-sparing treatment for patients with atypical endometrial hyperplasia (AEH) and endometrioid endometrial cancer (EEC). A randomised, single-centre, open-label, controlled trial conducted between October 2013 and December 2017. Shanghai OBGYN Hospital of Fudan University, China. A total of 150 patients (18-45years old) with primary AEH or well-differentiated EEC were randomised into an MA group (n=74) and an MA plus metformin group (n=76). Patients with AEH or EEC were firstly stratified, then randomised to receive MA (160mg orally, daily) or MA (160mg orally, daily) plus metformin (500mg orally, three times a day). The primary efficacy parameter was the cumulate complete response (CR) rate within 16weeks of treatment (16w-CR rate); the secondary efficacy parameters were 30w-CR rate and adverse events. The 16w-CR rate was higher in the metformin plus MA group than in the MA-only group (34.3 versus 20.7%, odds ratio [OR]2.0, 95% confidence interval [CI]0.89-4.51, P=0.09) but the difference was more significant in 102 AEH patients (39.6 versus 20.4%, OR2.56, 95% CI 1.06-6.21, P=0.04). This effect of metformin was also significant in non-obese (51.4 versus 24.3%, OR3.28, 95% CI1.22-8.84, P=0.02) and insulin-sensitive (54.8 versus 28.6%, OR3.04, 95% CI1.03-8.97, P=0.04) subgroups of AEH women. No significant result was found in secondary endpoints. As a fertility-sparing treatment, metformin plus MA was associated with a higher early CR rate compared with MA alone in AEH patients. For AEH patients, metformin plus MA might be a better fertility-sparing treatment to achieve a higher early CR rate compared with MA alone.
Highlights
Progestin therapy is widely accepted as the main fertility-sparing treatment for young women with atypical endometrial hyperplasia (AEH) and well-differentiated endometrioid endometrial cancer (EEC)
[odds ratios (OR)] 2.0, 95% confidence interval [CI] 0.89–4.51, P = 0.09) but the difference was more significant in 102 AEH patients (39.6 versus 20.4%, OR 2.56, 95% CI 1.06–6.21, P = 0.04)
As a fertility-sparing treatment, metformin plus megestrol acetate (MA) was associated with a higher early complete response (CR) rate compared with MA alone in AEH patients
Summary
Progestin therapy is widely accepted as the main fertility-sparing treatment for young women with atypical endometrial hyperplasia (AEH) and well-differentiated endometrioid endometrial cancer (EEC). Basic and clinical research supports the use of metformin in the fertility-sparing treatment for AEH and EEC patients.[3,4,5,6,7,8,9,10] Metformin has been demonstrated to suppress the growth of breast, ovarian, prostate and endometrial cancer cells via altering glucose metabolism and inhibiting the PI3K-AKT-mTOR signalling pathway.[3,4,5,6,7,8] metformin has been shown to increase expression of the progesterone receptor and sensitise progestin-resistant endometrial cancer cells to medroxyprogesterone (MPA)-induced apoptosis.[9,10] The latest meta-analysis showed an anti-cancer role of metformin after reviewing all the eligible articles (n = 19) on metformin use in AEH and endometrial cancer (EC).[7] In spite of the high heterogeneity of the analysed studies, metformin was suggested to synergise with progestin by reversing AEH to normal endometrial histology, reducing cancerprogression biomarkers and improving overall survival for EC patients.[7] Notably, a phase II non-controlled trial reported that metformin plus MPA led to a CR rate of 81% and a recurrence rate of 10% in obese women with AEH and early EC.[8] it is logical to hypothesise that metformin would improve the early CR rate of progestin-based fertilitypreserving therapy for AEH and EEC patients
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