Effect of Soy Isoflavones on Measures of Estrogenicity: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Despite recommendations to increase plant food consumption for public and planetary health and the role that soy foods can play in plant-predominant diets, controversies around the effects of soy foods, especially soy isoflavones, are a barrier to their intake. Given their cardioprotective effects and ability to alleviate menopausal symptoms, addressing these concerns is particularly relevant to women. This systematic review and meta-analysis of randomized controlled trials aimed to determine the effect of soy isoflavones on measures of estrogenicity in postmenopausal women. MEDLINE, Embase, and Cochrane Library were searched through August 2024 for randomized trials >= 3-mo investigating soy isoflavones compared with non-isoflavone controls in postmenopausal women. Outcomes included endometrial thickness (ET), vaginal maturation index (VMI), follicle-stimulating hormone (FSH), and estradiol. Independent authors extracted data and assessed risk of bias. Grading of Recommendations, Assessment, Development and Evaluation was used to assess certainty of evidence. We included 40 trials (52 trial comparisons, n = 3285) assessing the effect of a median reported dose of 75 mg/d of soy isoflavones in substitution for non-isoflavone controls over a median of 24 wk. Soy isoflavones had no statistically significant effect on any measure of estrogenicity; ET [mean difference, -0.22 mm (95% confidence interval, -0.45, 0.01 mm), P-MD = 0.059], VMI [2.31 (-2.14, 6.75), P-MD = 0.310], FSH [-0.02 IU/L (-2.39, 2.35 IU/L), P-MD = 0.987], and estradiol [1.61 pmol/L (-1.17, 4.38 pmol/L), P-MD = 0.256]. The certainty of evidence was high to moderate for all outcomes. Current evidence suggests that soy isoflavones do not exhibit estrogenic effects compared with non-isoflavone controls on 4 measures of estrogenicity in postmenopausal women. This synthesis supports that soy isoflavones likely act as selective estrogen receptor modulators, differing clinically from the hormone estrogen. Addressing public health concerns may promote soy foods as high-quality plant protein sources with low environmental impact and cost, particularly benefiting postmenopausal women and aligning with sustainable dietary patterns and guidelines.