Over the past 30 years the health effects of soyfoods have been rigorously investigated. Approximately 2,000 soy-related peer-reviewed papers are published annually. Much of this research can be attributed to soyfoods being uniquely rich sources of isoflavones. This point is illustrated by the mean daily isoflavone intake of 30 to 50 mg among older individuals in Japan1,2 whereas in the United States3 and Europe,4 per capita intake is less than 3 mg. Isoflavones have been purported to exert several health benefits, from reducing cancer risk5,6 to alleviating menopausal symptoms7 and improving memory. 8 On the other hand, some concerns about possible adverse effects of isoflavones have arisen, although a recently published comprehensive technical review concluded that neither soyfoods nor isoflavones exert endocrine-disrupting effects.9
The three isoflavones in soybeans—genistein (molecular weight, 270 g/mol), daidzein (molecular weight, 254.2 g/mol) and glycitein (molecular weight, 284.3 g/mol) — and their respective glycosides (the predominate form in soybeans and unfermented soyfoods) account for approximately 50, 40 and 10%, respectively, of the total soybean isoflavone content.10 In fermented soyfoods, such as miso, tempeh and natto, to varying degrees isoflavones are present as aglycones.10 The degree to which the glycosides are converted to aglycones depends upon the bacteria used and duration of fermentation.11,12
Isoflavones have a similar chemical structure to estrogen, bind to estrogen receptors (ERs), and exert estrogen-like effects under certain experimental conditions. For this reason, they are commonly classified as phytoestrogens. The potency of isoflavones relative to estrogen is difficult to assess. Potency is typically discussed in terms of relative binding affinity (RBA) and compared to 17b-estradiol, with the latter arbitrarily set at 100. Depending on the isoflavone and ER, estimates range from isoflavones being only about 1/1,000th as potent13 to nearly as potent.14 However, RBA does not completely capture potency. The effect of any given ligand on a specific tissue depends upon the conformational shape of the ligand-receptor complex, the ERa:ERβ ratio and the types of co-activators and co-repressors in cells. Also, there may be isoflavone metabolites formed within cells that are more or less potent than their parent compound.15,16
Importantly, isoflavones differ from the hormone estrogen at both the molecular and clinical level and are classified not just as phytoestrogens, but also as selective estrogen receptor modulators (SERMs).17 Depending upon the tissue, SERMs can have estrogen agonistic effects, antagonistic effects, or no effects at all in tissues affected by estrogen. The tissue selectivity of isoflavones is thought to be at least partly due to their preferential binding to and activation of ERβ in comparison to ERa.17 In general, activation of ERa and ERβ are seen as exerting proliferative and anti-proliferative effects, respectively.18
Isoflavones may also exert effects independent of their interaction with estrogen receptors.19 In fact, it was recognition of the ability of genistein to inhibit in vitro the activity of tyrosine protein kinase, an enzyme overexpressed in many cancer cell lines, which first sparked interest in the chemopreventive effects of isoflavones and soyfoods.20,21 However, it is not clear whether blood or tissue isoflavone concentrations in people consuming isoflavones reach the levels necessary to elicit ER-independent effects.
Unlike the aglycones, isoflavone glycosides cannot be absorbed due to their higher hydrophilicity and higher molecular mass.22 They become bioavailable and can be absorbed only when hydrolyzed,23 which can occur along the entire length of the gastrointestinal tract, but mostly, they are hydrolyzed in the jejunum24 by brush border membrane and b-glucosidases,25 such as lactase-phlorizin hydrolase, which are active from relatively early life.26 Once the glycosides are hydrolyzed, the resulting aglycone can be absorbed via passive diffusion;27 typically this occurs within 1–2 hours.28,29.
According to European Food Safety Authority (EFSA), no estimate of absolute bioavailability of isoflavones in humans can be given although EFSA concluded bioavailability was low.30 There is a biphasic isoflavone appearance pattern in plasma and urine of humans after the consumption of soy or purified isoflavone preparations with peak isoflavone levels occurring 1–2 hours and again 4–8 hours after intake.24,31-34
Finally, traditional soyfoods contain approximately 3.5 mg of isoflavones per gram of protein.1 whereas more refined soy products, such as soy protein isolate and soy protein concentrate, can lose as much as 90% of their isoflavone content during processing.10 On average, traditional soyfoods contain 20–30 mg of isoflavones per serving (for example, 250 ml of soymilk made from whole soybeans or 100 g of tofu).1
- Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer 2006;55:1-12.
- Konishi K, Wada K, Yamakawa M, Goto Y, Mizuta F, Koda S, Uji T, Tsuji M, Nagata C. Dietary soy intake is inversely associated with risk of type 2 diabetes in Japanese women but not in men. J Nutr 2019;149:1208-14.
- Bai W, Wang C, Ren C. Intakes of total and individual flavonoids by US adults. Int J Food Sci Nutr 2014;65:9-20.
- Zamora-Ros R, Knaze V, Lujan-Barroso L, Kuhnle GG, Mulligan AA, Touillaud M, Slimani N, Romieu I, Powell N, Tumino R, et al. Dietary intakes and food sources of phytoestrogens in the European Prospective Investigation into Cancer and Nutrition (EPIC) 24-hour dietary recall cohort. Eur J Clin Nutr 2012;66:932-41.
- Applegate CC, Rowles JL, Ranard KM, Jeon S, Erdman JW. Soy consumption and the risk of prostate cancer: An updated systematic review and meta-analysis. Nutrients 2018;10.
- Okekunle AP, Gao J, Wu X, Feng R, Sun C. Higher dietary soy intake appears inversely related to breast cancer risk independent of estrogen receptor breast cancer phenotypes. Heliyon 2020;6:e04228.
- 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.
- Cui C, Birru RL, Snitz BE, Ihara M, Kakuta C, Lopresti BJ, Aizenstein HJ, Lopez OL, Mathis CA, Miyamoto Y, et al. Effects of soy isoflavones on cognitive function: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev 2020;78:134-44.
- Messina M, Mejia SB, Cassidy A, Duncan A, Kurzer M, Nagato C, Ronis M, Rowland I, Sievenpiper J, Barnes S. Neither soyfoods nor isoflavones warrant classification as endocrine disruptors: a technical review of the observational and clinical data. Crit Rev Food Sci Nutr 2021:1-57.
- Murphy PA, Barua K, Hauck CC. Solvent extraction selection in the determination of isoflavones in soy foods. Journal of chromatography B, Analytical technologies in the biomedical and life sciences 2002;777:129-38.
- Chien HL, Huang HY, Chou CC. Transformation of isoflavone phytoestrogens during the fermentation of soymilk with lactic acid bacteria and bifidobacteria. Food Microbiol 2006;23:772-8.
- Lee IH, Chou CC. Distribution profiles of isoflavone isomers in black bean kojis prepared with various filamentous fungi. J Agric Food Chem 2006;54:1309-14.
- Jiang Y, Gong P, Madak-Erdogan Z, Martin T, Jeyakumar M, Carlson K, Khan I, Smillie TJ, Chittiboyina AG, Rotte SC, et al. Mechanisms enforcing the estrogen receptor beta selectivity of botanical estrogens. FASEB J 2013;27:4406-18.
- 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.
- Arora A, Nair MG, Strasburg GM. Antioxidant activities of isoflavones and their biological metabolites in a liposomal system. Arch Biochem Biophys 1998;356:133-41.
- Kulling SE, Honig DM, Metzler M. Oxidative metabolism of the soy isoflavones daidzein and genistein in humans in vitro and in vivo. J Agric Food Chem 2001;49:3024-33.
- Oseni T, Patel R, Pyle J, Jordan VC. Selective estrogen receptor modulators and phytoestrogens. Planta Med 2008;74:1656-65.
- 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.
- Spagnuolo C, Russo GL, Orhan IE, Habtemariam S, Daglia M, Sureda A, Nabavi SF, Devi KP, Loizzo MR, Tundis R, et al. Genistein and cancer: Current status, challenges, and future directions. Adv Nutr 2015;6:408-19.
- Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N, Shibuya M, Fukami Y. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 1987;262:5592-5.
- Akiyama T, Ogawara H. Use and specificity of genistein as inhibitor of protein-tyrosine kinases. Methods Enzymol 1991;201:362-70.
- Hur HG, Lay JO, Jr., Beger RD, Freeman JP, Rafii F. Isolation of human intestinal bacteria metabolizing the natural isoflavone glycosides daidzin and genistin. Arch Microbiol 2000;174:422-8.
- Setchell KD. Absorption and metabolism of soy isoflavones-from food to dietary supplements and adults to infants. J Nutr 2000;130:654S-5S.
- Zubik L, Meydani M. Bioavailability of soybean isoflavones from aglycone and glucoside forms in American women. Am J Clin Nutr 2003;77:1459-65.
- Nemeth K, Plumb GW, Berrin JG, Juge N, Jacob R, Naim HY, Williamson G, Swallow DM, Kroon PA. Deglycosylation by small intestinal epithelial cell beta-glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans. Eur J Nutr 2003;42:29-42.
- Day AJ, Canada FJ, Diaz JC, Kroon PA, McLauchlan R, Faulds CB, Plumb GW, Morgan MR, Williamson G. Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase. FEBS Lett 2000;468:166-70.
- Decroos K, Vanhemmens S, Cattoir S, Boon N, Verstraete W. Isolation and characterisation of an equol-producing mixed microbial culture from a human faecal sample and its activity under gastrointestinal conditions. Arch Microbiol 2005;183:45-55.
- King RA, Broadbent JL, Head RJ. Absorption and excretion of the soy isoflavone genistein in rats. J Nutr 1996;126:176-82.
- Sfakianos J, Coward L, Kirk M, Barnes S. Intestinal uptake and biliary excretion of the isoflavone genistein in rats. J Nutr 1997;127:1260-8.
- EFSA. EFSA ANS Panel (EFSA Panel on Food Additives and Nutrient Sources added to Food), 2015. Scientific opinion on the risk assessment for peri- and post-menopausal women taking food supplements containing isolated isoflavones. EFSA J. 13,4246 (342 pp). 2015.
- Fanti P, Sawaya BP, Custer LJ, Franke AA. Serum levels and metabolic clearance of the isoflavones genistein and daidzein in hemodialysis patients. J Am Soc Nephrol 1999;10:864-71.
- Franke AA, Yu MC, Maskarinec G, Fanti P, Zheng W, Custer LJ. Phytoestrogens in human biomatrices including breast milk. Biochem Soc Trans 1999;27:308-18.
- Setchell KD, Faughnan MS, Avades T, Zimmer-Nechemias L, Brown NM, Wolfe BE, Brashear WT, Desai P, Oldfield MF, Botting NP, et al. Comparing the pharmacokinetics of daidzein and genistein with the use of 13C-labeled tracers in premenopausal women. Am J Clin Nutr 2003;77:411-9.
- King RA, Bursill DB. Plasma and urinary kinetics of the isoflavones daidzein and genistein after a single soy meal in humans. Am J Clin Nutr 1998;67:867-72.