Two-Week Dietary Soy Supplementation Has an Estrogenic Effect on Normal Premenopausal Breast

Abstract

Introduction: Isoflavones are hypothesized to protect against breast cancer, but it is not clear whether they act as oestrogens or anti-oestrogens in breast tissue. Our aim was to determine the effects of taking a red clover-derived isoflavone supplement daily for 1 year on mammographic breast density. Effects on oestradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), lymphocyte tyrosine kinase activity and menopausal symptoms were also assessed.Methods: A total of 205 women (age range 49-65 years) with Wolfe P2 or DY mammographic breast patterns were randomly assigned to receive either a red clover-derived isoflavone tablet (26 mg biochanin A, 16 mg formononetin, 1 mg genistein and 0.5 mg daidzein) or placebo. Change in mammographic breast density, serum oestradiol, FSH, LH, menopausal symptoms and lymphocyte tyrosine kinase activity from baseline to 12 months were assessed.Results: A total of 177 women completed the trial. Mammographic breast density decreased in both groups but the difference between the treatment and placebo was not statistically significant. There was a significant interaction between treatment group and oestrogen receptor (ESR1) PvuII polymorphism for the change in estimated percentage breast density (mean ± standard deviation): TT isoflavone 1.4 ± 12.3% and TT placebo -9.6 ± 14.2%; CT isoflavone -5.2 ± 12.0% and CT placebo -2.8 ± 10.3%; and CC isoflavone -3.4 ± 9.7% and CC placebo -1.1 ± 9.5%. There were no statistically significant treatment effects on oestradiol, FSH, or LH (assessed only in postmenopausal women), or on lymphocyte tyrosine kinase activity. Baseline levels of menopausal symptoms were low, and there were no statistically significant treatment effects on frequency of hot flushes or other menopausal symptoms. Conclusion:In contrast to studies showing that conventional hormone replacement therapies increase mammographic breast density, the isoflavone supplement did not increase mammographic breast density in this population of women. Furthermore, there were no effects on oestradiol, gonadotrophins, lymphocyte tyrosine kinase activity, or menopausal symptoms.

Disposition of soy isoflavones in normal human breast tissue

“…Although differences in the time of sampling, dosing regimen, and formulation (36) often hamper sound comparisons between dietary intervention trials, the hydrolyzed serum and tissue isoflavone concentrations observed in this study were in agreement with previous reports on human breast exposure (18,19,37) and prostate exposure (28). Isoflavone tissue concentrations were lower than the corresponding serum concentrations (19,28).…”

“…Isoflavone tissue concentrations were lower than the corresponding serum concentrations (19,28). Moreover, the consistent lack of a correlation between serum and tissue concentrations (18,19) suggests that isoflavone serum concentrations do not predict tissue disposition. Nevertheless, the G/D ratios correlated well between the different samples and reflected the composition of the isoflavone preparations (28).…”

“…In particular, ques-tions regarding the absorption, metabolism, and distribution of these compounds in the target tissue need to be clarified because these processes highly determine whether isoflavones may elicit protective or rather adverse responses with respect to breast carcinogenesis. Two studies (18,19) quantified isoflavones in human nipple aspirate fluid and/or breast-tissue homogenates after soy supplementation. However, only total concentrations after enzymatic hydrolysis were reported, even though the conjugation to glucuronic acid and/or sulfate moieties is known to alter the pharmacologic profiles of genistein and daidzein (20).…”

Genistein and Cancer: Current Status, Challenges, and Future Directions

“…These controversial results have been confirmed in human clinical studies, in which, in some cases, purified genistein did not exert any adverse estrogenic effects on breast tissue when consumed at a dose of 54 mg/d (164,165), whereas others found proestrogenic effects of dietary soy supplementation on breast tissue (166)(167)(168). Thus, considering the agonist activity of genistein against ER-a, its use in women with established ER-positive breast cancers must be carefully considered.…”

Mammographic breast density as a biomarker of effects of isoflavones on the female breast

“…[5] reported an increase in the presence of epithelial hyperplasia in nipple aspirate fluid from premenopausal and postmenopausal women following a 6-month soy protein intervention, and Hargreaves et al . [6] reported changes in estrogen-regulated proteins in nipple aspirate fluid that were indicative of an estrogenic response among premenopausal women following a 14-day soy protein intervention. Interestingly, Hargreaves et al .…”