Combined HRT is associated with an increased risk for breast cancer [42
] and an increase in mammographic breast density [13
]. Soy and phyto-oestrogens have been proposed as potential natural alternatives to HRT [45
], but there are only limited data from small studies on the effect of isoflavones on breast density. In the largest and longest study conducted thus far, we did not observe a significant effect of the clover-derived isoflavone supplement, taken daily for 1 year, on mammographic breast density. This is in agreement with a small, exploratory study conducted in 30 premenopausal women [27
], in which there were no significant effects of a soy isoflavone supplement, providing 100 mg/day isoflavones for 12 months, on mammographic breast density. In that study, there was a slight increase in percentage density among women taking the isoflavone supplement, but differences between the intervention and placebo groups were not statistically significant. In the present study, breast density decreased to a similar extent in both treatment groups. This was presumably due to natural changes over time because an inverse relationship between breast density and age exists (for review [11
]). The decrease in percentage density was of a similar magnitude to that seen among control individuals in other studies [20
] but was not as great as the decreases seen with anti-oestrogens such as tamoxifen [20
An attractive hypothesis for the potential chemopreventive actions of isoflavones is via modulation of endocrine function. However, the literature is conflicting with regard to the effects of soy intakes on circulating levels of oestradiol in both premenopausal and postmenopausal women; some studies have reported decreases, increases, or little effect [9
]. In a recent study of premenopausal women [54
], consumption of soymilk from which the isoflavones had been removed resulted in a decrease in oestradiol, suggesting that soy protein rather than soy isoflavones may be responsible for the reduction in circulating levels of oestradiol seen in some studies.
Reported effects of soy intakes on gonadotrophins have also been inconsistent, with limited data showing either no effect [49
] or decreases in FSH and LH with soy supplementation [53
]. Despite the fact that this was one of the longest and largest studies to have investigated the effects of an isoflavone supplement on the hormonal status of postmenopausal women, we did not observe a significant effect of the isoflavone supplement on circulating levels of oestradiol, FSH or LH.
Phyto-oestrogens have been postulated to have several other anticancer effects and, because of the possible role of genistein as an inhibitor of protein tyrosine kinase activity [56
], we investigated levels of lymphocyte tyrosine kinase activity. However, we were unable to show significant differences between treatment groups for the change in the levels of lymphocyte tyrosine kinase activity.
Soy and phyto-oestrogens have received considerable attention because of their potential role in relieving menopausal symptoms, but their efficacy in such a role remains to be fully established. Short-term intervention studies among women experiencing frequent hot flushes have shown reductions in the frequency and/or severity of hot flushes with soy consumption, but also among control individuals [57
], whereas others have shown little or no effect [60
]. However, in a recent study of women experiencing more than five hot flushes per day, all study participants were given a placebo tablet in a single-blind, 4-week run-in phase, and during the subsequent 12-week double-blind phase the frequency of hot flushes was reduced by 44% in the women taking two Promensil tablets per day; no further reduction occurred in the placebo group [64
]. In our study, the occurrence of hot flushes and the severity of menopausal symptoms decreased to a similar extent in both treatment groups, suggesting natural improvement over time. It is possible that the lack of a significant treatment effect may, in part, have been due to our study population; women were not selected for the study on the basis of suffering from severe or frequent hot flushes and/or other menopausal symptoms. As a result, baseline levels of menopausal symptoms were relatively low, which presumably limited the room for improvement in the study.
Polymorphisms in genes involved in sex hormone metabolism and in genes that encode hormone receptors may have an effect on the production of and exposure to sex hormones, and on the subsequent activation of genes that are responsive to sex hormones. We investigated interactions between treatment and selected polymorphisms in the CYP17 and CYP19 genes, both of which are involved in the sex hormone biosynthesis pathway, and the oestrogen receptor (ESR1) gene. Polymorphisms in these genes have been associated with risk for breast cancer in some but not all studies [65
]. We saw interesting potential gene–treatment effects for the changes in breast density and ESR1 polymorphism and FSH and CYP19 polymorphism, but the study was not powered to investigate these interactions and a larger study is needed to confirm these findings.
Using the PABA check method as an independent marker of compliance, and urinary excretion of isoflavones, compliance with study procedures appeared to be excellent. However, a potential limitation of this study is that, although the study size was based on a case–control study of tamoxifen and breast density [19
], changes in breast density among control individuals in this study were greater than anticipated. In addition, our findings may not be generalizable to the population as a whole. We did not include women in this study who were taking HRT at the time of recruitment (approximately one-third of women in the UK between the ages of 50 and 64 years use HRT [67
]), and we only selected women with Wolfe P2 or DY breast patterns (which comprised approximately 60% of all mammograms classified for recruitment purposes). A further limitation of the study is that several statistical tests were carried out, and some of the statistically significant findings may have been due to chance.