Do Isoflavones Exert Estrogen-Like Effects in Women?
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.
References
1. Barnes S. Soy isoflavones–phytoestrogens and what else? J Nutr 2004;134:1225S-8S.
2. Setchell KD. Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones. Am J Clin Nutr 1998;68:1333S-46S.
3. Carter MW, Matrone G, Smart WWGJ. Effect of genistein on reproduction of the mouse. J Nutr 1955;55:639-45.
4. Leopold AS, Erwin M, Oh J, Browning B. Phytoestrogens: adverse effects on reproduction in California quail. Science 1976;191:98-100.
5. Cheng E, Story CD, Yoder L, Hale WH, Burroughs W. Estrogenic activity of isoflavone derivatives extracted and prepared from soybean oil meal. Science 1953;118:164-5.
6. Folman Y, Pope GS. The interaction in the immature mouse of potent oestrogens with coumestrol, genistein and other utero-vaginotrophic compounds of low potency. J Endocrinol 1966;34:215-25.
7. Taku K, Melby MK, Kronenberg F, Kurzer MS, Messina M. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause 2012;19:776-90.
8. Adlercreutz H, Hamalainen E, Gorbach S, Goldin B. Dietary phyto-oestrogens and the menopause in Japan. Lancet 1992;339:1233.
9. Lumachi F, Santeufemia DA, Basso SM. Current medical treatment of estrogen receptor-positive breast cancer. World J Biol Chem 2015;6:231-9.
10. Chlebowski RT, Anderson GL, Aragaki AK, Manson JE, Stefanick ML, Pan K, Barrington W, Kuller LH, Simon MS, Lane D, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the women’s health initiative randomized clinical trials. JAMA 2020;324:369-80.
11. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A 1996;93:5925-30.
12. Paruthiyil S, Parmar H, Kerekatte V, Cunha GR, Firestone GL, Leitman DC. Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res 2004;64:423-8.
13. Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997;138:863-70.
14. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 1998;139:4252-63.
15. Oseni T, Patel R, Pyle J, Jordan VC. Selective estrogen receptor modulators and phytoestrogens. Planta Med 2008;74:1656-65.
16. Setchell KD. Soy isoflavones–benefits and risks from nature’s selective estrogen receptor modulators (SERMs). J Am Coll Nutr 2001;20:354S-62S.
17. Lu LW, Chen NW, Brunder DG, Nayeem F, Nagamani M, Nishino TK, Anderson KE, Khamapirad T. Soy isoflavones decrease fibroglandular breast tissue measured by magnetic resonance imaging in premenopausal women: A 2-year randomized double-blind placebo controlled clinical trial. Clin Nutr ESPEN 2022;52:158-68.
18. Engmann NJ, Golmakani MK, Miglioretti DL, Sprague BL, Kerlikowske K, Breast Cancer Surveillance C. Population-attributable risk proportion of clinical risk factors for breast cancer. JAMA oncology 2017;3:1228-36.
19. Bernatoniene J, Kazlauskaite JA, Kopustinskiene DM. Pleiotropic Effects of Isoflavones in Inflammation and Chronic Degenerative Diseases. Int J Mol Sci 2021;22.
20. Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review. JAMA 2004;291:1610-20.
21. Levis S, Strickman-Stein N, Ganjei-Azar P, Xu P, Doerge DR, Krischer J. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: A randomized, double-blind trial. Arch Intern Med 2011;171:1363-9.
22. Carmignani LO, Pedro AO, Costa-Paiva LH, Pinto-Neto AM. The effect of dietary soy supplementation compared to estrogen and placebo on menopausal symptoms: a randomized controlled trial. Maturitas 2010;67:262-9.
This blog is sponsored by SNI Global and U.S. Soy.