Red Clover-Derived Isoflavones and Mammographic Breast Density: A Double-Blind, Randomized, Placebo-Controlled Trial [ISRCTN42940165]

Charlotte Atkinson; Ruth ML Warren; Evis Sala; Mitch Dowsett; Alison M Dunning; Catherine S Healey; Shirley Runswick; Nicholas E Day; Sheila A Bingham


Breast Cancer Res. 2004;6(3) 

In This Article

Abstract and Introduction

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.

Isoflavones are biologically active compounds that are naturally present in foods of plant origin. They have received considerable attention because of their potential cancer preventive, cardioprotective and bone sparing effects, and because of their potential to provide relief from menopausal symptoms.[1,2] Soybeans are particularly rich sources of isoflavones such as daidzein and genistein,[3] and intakes of isoflavones are markedly higher among Asian populations than in Western ones, largely resulting from soy consumption patterns.[4,5] It is widely perceived that exposure to isoflavones is beneficial because rates of breast cancer and other hormone-dependent conditions are lower in Asian than in Western countries.[6,7,8] However, isoflavones can act as weak oestrogens, and two intervention studies with soy have provided evidence for stimulatory effects of isoflavones on breast tissue.[9,10]

Mammographic breast density, characterized by the relative proportions of radiolucent fat and radiodense connective and epithelial tissue within the breast, has consistently been associated with risk for breast cancer. In a review of case–control studies,[11] odds ratios for breast cancer among women with the highest versus the lowest extents of density ranged from 2.1 to 6.0. The mechanism underlying this relationship has not been fully explained, but it has been suggested that breast density provides an index of current and past hormonal and reproductive events that modulate risk for breast cancer.[12] In support of this, studies have shown that breast density increases when a woman begins hormone replacement therapy (HRT) and decreases when she discontinues,[13,14,15,16,17,18] and anti-oestrogens such as tamoxifen reduce breast density.[19,20,21] As a result of such findings, we suggested that breast density can act as a biomarker of oestrogenic or anti-oestrogenic effects of a given treatment on breast tissue.[22]

Diet has been shown to influence breast density, potentially through effects on endogenous hormone levels. For example, a low-fat, high-carbohydrate intervention significantly reduced breast density[23]; however, an inverse association has also been reported between breast density and saturated fat intake.[24] In a cross-sectional study of diet and mammographic density, total protein and carbohydrate intake was significantly and positively associated with breast density, and among postmenopausal women there was a significant positive association between total meat intake and breast density.[25] More recently, data from a cross-sectional study of soy food intakes and mammographic densities[26] indicated the presence of a significant trend toward higher percentage density through increasing quartiles of soy intake, but a small study of a soy isoflavone supplement[27] did not significantly alter breast density after 1 year of treatment.

Here, we report the results of a randomized, placebo-controlled trial that was conducted to determine the effects of a red clover-derived isoflavone supplement, taken daily for 1 year, on mammographic breast density. In addition, effects on circulating levels of oestradiol, gonadotrophins, lymphocyte tyrosine kinase activity, and menopausal symptoms are reported, and interactions between treatment group and polymorphisms in CYP17, CYP19, and oestrogen receptor (ESR1) genes.


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