Effect of oral phytoestrogens on endometrial thickness and breast density of perimenopausal and postmenopausal women: A systematic review and meta-analysis

Background: Phytoestrogens constitute an alternative, non-pharmacologic approach for the management of menopausal symptoms. However, few studies have focused on their safety, specifically in relation to endometrial thickness and breast density. Aim: To systematically search for and quantitatively synthesize the evidence regarding the effect of phytoestrogens on endometrial thickness and breast density in perimenopausal and postmenopausal women. Methods: Randomized controlled trials (RCTs) examining the effect of phytoestrogens compared with placebo or menopausal hormone therapy (MHT) on endometrial thickness and/or breast density in perimenopausal or postmenopausal women were searched for in the MEDLINE, CENTRAL and Scopus databases as well as gray literature sources until October 31, 2018. Main outcomes were the change from baseline in endometrial thickness and breast density. Statistical analysis was performed with RevMan 5.3, using R language and Open Meta-Analyst software. Results: The meta-analysis for endometrial thickness included 30 RCTs (with a total of 3497 women), and that for breast density four RCTs (with a total of 674 women). Phytoestrogens did not affect endometrial thickness compared with placebo [weighted mean difference (WMD) -0.04 mm, 95% confidence interval (CI) -0.18 to 0.11, I-2 66%] or MHT (WMD -1.40 mm, 95% CI - 2.98 to 0.18, I-2 84%). In addition, phytoestrogens did not affect breast density compared with placebo [standardized mean difference (SMD) - 0.76, 95% CI - 1.54 to 0.2, I-2 95%). Conclusion: Phytoestrogens have no effect on endometrial thickness or breast density, when administered at various doses and for various durations, in perimenopausal and postmenopausal women. However, the high heterogeneity of the studies makes it necessary to conduct RCTs with less risk of systematic error.