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Clinical Trial
. 2004;6(3):R170-9.
doi: 10.1186/bcr773. Epub 2004 Feb 24.

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

Free PMC article
Clinical Trial

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

Charlotte Atkinson et al. Breast Cancer Res. .
Free PMC article


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.


Figure 1
Figure 1
Flow chart describing progress of participants through trial. *Includes two women who completed the trial but were excluded from all analyses because they had taken an oral contraceptive (OC) or were being treated for alcoholism. **Includes one woman who was excluded from all analyses because she had taken an OC, two women who had mammograms taken before the end of the study, and one woman who did not attend her follow-up mammogram. HRT, hormone replacement therapy.
Figure 2
Figure 2
Urinary isoflavone (sum of daidzein, genistein, formononetin and biochanin A) excretion at baseline, midway, and at the end of the study, excluding samples with < 70% or > 110% para-amino benzoic acid recovery. Error bars represent ± standard error of the mean. Numbers at each evaluation were as follows: baseline, 66 and 72 in the isoflavone and placebo groups, respectively; 6 months, 70 and 73; and 12 months, 76 and 79. The difference in isoflavone excretion between treatment groups was not statistically significant at baseline (P = 0.23), but differences between treatment groups at 6 and 12 months were highly significant (P < 0.001 and P < 0.001).
Figure 3
Figure 3
Estimated percentage density (and 95% confidence intervals) at baseline and follow up by treatment group (77 women in the isoflavone group and 85 in the placebo; P = 0.82).

Comment in

  • Isoflavones and women's health.
    Powles T. Powles T. Breast Cancer Res. 2004;6(3):140-2. doi: 10.1186/bcr796. Epub 2004 Apr 6. Breast Cancer Res. 2004. PMID: 15084236 Free PMC article.

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