Soybean isoflavones are commonly classified as phytoestrogens.1,2 The estrogenic properties of isoflavones were first recognized nearly seven decades ago3 although the term “phytoestrogen” was not widely used in reference to isoflavones until the 1970s.4 In the early days of isoflavone research, determining estrogenic activity was based on reproductive effects in animals, and often specifically, uterotrophic effects in immature animals.3,5
However, more sophisticated methods of determining estrogenicity have been developed and include assessment of direct interaction with estrogen receptors (ERs). That is, relative estrogen potency was based on in vitro binding to ERs.6 Typically, potency was based on the concentration of a given ligand such as isoflavones that was required to dislodge 50% of estradiol from the ER (which eventually became known as ERa). From the get-go, there was debate and discussion about whether isoflavones were estrogen agonists (pro-estrogens) or estrogen antagonists (anti-estrogens) and the circumstances under which these properties would be exhibited.6 This debate and discussion continues today.
Speculation was that isoflavones would function in vivo as anti-estrogens in a high estrogen environment (e.g., premenopausal women) and as estrogens in a low estrogen environment (e.g., postmenopausal women). This potentially could occur because isoflavones would dislodge more potent endogenous estrogens from ERs in premenopausal women but in postmenopausal women, the main effect would come from their binding to ERs. Therefore, in theory, isoflavones could combat the effects of high estrogen levels in premenopausal women but mitigate the effects of the reduction in estrogen synthesis that occurs in postmenopausal women.
Evidence indicating isoflavones alleviate menopausal hot flashes,7 which was first hypothesized in 1992,8 is consistent with this theory although acceptance of this schematic might allow for the possibility that isoflavones could increase breast cancer risk in postmenopausal women. However, although tamoxifen and aromatase inhibitors, drugs which inhibit estrogen action, are widely used chemotherapeutic options for the treatment of ER+ breast cancer,9 it is not clear that estrogen therapy increases breast cancer risk.10
The identification of the second ERb in 199611 complicated the initial view of the actions of isoflavones because binding to ERb, in general, counters the proliferative effects of ERa binding.12 Because isoflavones preferentially bind to ERb,13,14 isoflavones began to be thought of as selective estrogen receptor modulators (SERMs).15,16 SERMs exert estrogen-like effects in some tissues but have either no effects or anti-estrogenic effects in others.15 The identification of ERb led to the notion that the actions of isoflavones were determined not so much by circulating estrogen levels but by the relative proportion of each type of ER in tissues.15
In the end, the most relevant characterization of isoflavone action is based on the clinical evidence. There is scant evidence in humans that isoflavones function as anti-estrogens in premenopausal women. In fact, it is difficult to point to any clinical study demonstrating this is the case. One exception may be newly published research from the University of Texas Medical Branch.17
In this 2-year trial, isoflavones reduced MRI assessed fibroglandular breast tissue (FGBT), which is suggestive of a reduction in breast cancer risk.18 FGBT typically increases over time in premenopausal women due to the high circulating levels of estrogen. It is possible that isoflavones were not working via interaction with ERs as isoflavones have pleiotropic effects.19 Also, the daily dose (136.6 mg) of isoflavones in this study is higher than the dose used in most clinical trials and represents the amount of isoflavones provided by about 6-7 servings of tofu.
Finally, direct evidence that isoflavones function as estrogen agonists in postmenopausal women is not as forthcoming as one might expect given their classification as phytoestrogens. As noted, isoflavones appear to alleviate hot flashes, which is also the case for the hormone estrogen and conjugated equine estrogens.20 However, in postmenopausal women, isoflavones don’t affect the vaginal maturation index21 or levels of follicle stimulating hormone levels,22 whereas estrogen affects both of these endpoints.
In summary, isoflavones are complicated molecules. Their effects are still not fully understood, but what is known is that many of the initial assumptions about isoflavones have not held up to the results of subsequently published research.
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