Effect of soy isoflavones on measures of estrogenicity: A systematic review and meta-analysis of randomized trials

Abstract

Background Despite dietary recommendations to consume more plant foods for public and planetary health and the role that soy foods can play in plant-predominant diets, controversies around the effects of soy foods and their components, especially isoflavones, are a barrier to their intake. Given the cardioprotective effects and ability to alleviate menopausal symptoms, addressing this issue is particularly relevant to women. We therefore undertook a systematic review and meta-analysis of randomized controlled trials in postmenopausal women to determine the effect of soy isoflavones on measures of estrogenicity. Methods MEDLINE, Embase, and Cochrane Library were searched through July 2023 for randomized controlled trials 3-months investigating soy isoflavones versus non-isoflavone controls in postmenopausal women. The four outcomes included endometrial thickness (ET), vaginal maturation index (VMI), follicle-stimulating hormone (FSH), and estradiol. Independent authors extracted data and assessed risk of bias. GRADE (grading of recommendations assessment, development, and evaluation) was used to assess certainty of evidence. Results We included 40 trials (52 trial comparisons, n=3285) assessing the effect of a median daily dose of 75 mg of soy isoflavones in substitution for non-isoflavone control over a median of 24 weeks. Isoflavones had no statistically significant effects on any of the measures of estrogenicity; ET (mean difference, -0.22mm [95% confidence interval, -0.45 to 0.01mm], P_MD=0.059), VMI (2.31 [-2.14 to 6.75], P_MD=0.310), FSH (-0.02IU/L [-2.39 to 2.35IU/L], P_MD=0.987), and estradiol (1.61pmol/L [-1.17 to 4.38pmol/L], P_MD=0.256). The certainty of evidence was high-to-moderate for all outcomes. Conclusion Current evidence provides a good indication that soy isoflavones do not have an estrogenic effect versus non-isoflavone controls on 4 measures of estrogenicity in postmenopausal women. This synthesis supports the classification of soy isoflavones as selective estrogen receptor modulators and that isoflavones differ clinically from the hormone estrogen where no assumptions about the health effects of soy foods or isoflavones should be based on an understanding of the effects of the hormone estrogen. Addressing public health concerns around soy foods may support their intake as high-quality plant protein foods with low environmental impact and cost, especially relevant for postmenopausal women, and aligning with sustainable dietary patterns and guidelines. Registration: PROSPERO (CRD42023439239)