Phytoestrogens are naturally occurring nonsteroidal phenolic plant compounds that, due to their molecular structure and size, resemble vertebrate steroids estrogens. This review is focused on plant flavonoids isoflavones, which are ranked among the most estrogenic compounds. The main dietary sources of isoflavones for humans are soybean and soybean products, which contain mainly daidzein and genistein. When they are consumed, they exert estrogenic and/or antiestrogenic effects. Isoflavones are considered chemoprotective and can be used as an alternative therapy for a wide range of hormonal disorders, including several cancer types, namely breast cancer and prostate cancer, cardiovascular diseases, osteoporosis, or menopausal symptoms. On the other hand, isoflavones may also be considered endocrine disruptors with possible negative influences on the state of health in a certain part of the population or on the environment. This review deals with isoflavone classification, structure, and occurrence, with their metabolism, biological, and health effects in humans and animals, and with their utilization and potential risks.

Department of Biochemistry Faculty of Science Masaryk University Kotlarska 2 61137 Brno Czech Republic

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Kurzer M.S., Xu X. Dietary phytoestrogens. Annu. Rev. Nutr. 1997;17:353–381. doi: 10.1146/annurev.nutr.17.1.353. PubMed DOI

Bennetts H.W., Uuderwood E.J., Shier F.L. A specific breeding problem of sheep on subterranean clover pastures in Western Australia. Aust. Vet. J. 1946;22:2–12. doi: 10.1111/j.1751-0813.1946.tb15473.x. PubMed DOI

Mustonen E., Taponen S., Andersson M., Sukura A., Katila T., Taponen J. Fertility and growth of nulliparous ewes after feeding red clover silage with high phyto-oestrogen concentrations. Animal. 2014;8:1699–1705. doi: 10.1017/S175173111400161X. PubMed DOI

Lightfoot R.J., Croker K.P., Neil H.G. Failure of sperm transport in relation to ewe infertility following prolonged grazing on oestrogenic pastures. Aust. J. Agric. Res. 1968;18:755–765. doi: 10.1071/AR9670755. DOI

Rossiter R.C., Beck A.B. Physiological and ecological studies on the estrogenic isoflavones in subterranean clover (Trifolium subterraneum) I. Effects of temperature. Aust. J. Agric. Res. 1966;17:29–37. doi: 10.1071/AR9660029. DOI

Braden A., Hart N., Lamberton J. The estrogenic activity and metabolism of certain isoflavones in sheep. Aust. J. Agric. Res. 1967;18:335–348. doi: 10.1071/AR9670355. DOI

Nottle M.C. Composition of some urinary calculi of ruminants in Western Australia. Res. Vet. Sci. 1976;21:309–317. doi: 10.1016/S0034-5288(18)33341-1. PubMed DOI

Marrian G.F., Haslewood G.A. Equol, a new inactive phenol isolated from the ketohydroxyoestrin fraction of mares’ urine. Biochem. J. 1932;26:1227–1232. doi: 10.1042/bj0261227. PubMed DOI PMC

Marrian G.F., Beall D. The constitution of equol. Biochem. J. 1935;29:1586–1589. doi: 10.1042/bj0291586. PubMed DOI PMC

Shutt D., Braden A. The significance of equol in relation to the oestrogenic responses in sheep ingesting clover with a high formononetin content. Aust. J. Agric. Res. 1968;19:545. doi: 10.1071/AR9680545. DOI

Shutt D.A., Weston R.H., Hogan J.P. Quantitative aspects of phytoestrogen metabolism in sheep fed on subterranean clover (Trifolium subterraneum, cultivar Clare) or red clover (Trifolium pratense) Aust. J. Agric. Res. 1970;21:714–722. doi: 10.1071/AR9700713. DOI

Lundh T. Metabolism of Estrogenic Isoflavones in Domestic Animals. Proc. Soc. Exp. Biol. Med. 1995;208:33–39. doi: 10.3181/00379727-208-43828. PubMed DOI

Klyne W., Wright A.A. Steroids and other lipids of pregnant cow’s urine. J. Endocrinol. 1959;18:32–45. doi: 10.1677/joe.0.0180032. PubMed DOI

Chang H.H.-S., Robinson A.R., Common R.H. Excretion of Radioactive Daidzein and Equol as Monosulfates and Disulfates in the Urine of the Laying Hen. Can. J. Biochem. 1975;53:223–230. doi: 10.1139/o75-031. PubMed DOI

Blair R.M., Appt S.E., Franke A.A., Clarkson T.B. Treatment with antibiotics reduces plasma equol concentration in cynomolgus monkeys (Macaca fascicularis) J. Nutr. 2003;133:2262–2267. doi: 10.1093/jn/133.7.2262. PubMed DOI

Brown N.M., Setchell K.D. Animal models impacted by phytoestrogens in commercial chow: Implications for pathways influenced by hormones. Lab. Investig. 2001;81:735–747. doi: 10.1038/labinvest.3780282. PubMed DOI

Juniewicz P.E., Morell S.P., Moser A., Ewing L.L. Identification of phytoestrogens in the urine of male dogs. J. Steroid Biochem. 1988;31:987–994. doi: 10.1016/0022-4731(88)90343-3. PubMed DOI

Axelson M., Kirk D.N., Farrant R.D., Cooley G., Lawson A.M., Setchell K.D. The identification of the weak oestrogen equol [7-hydroxy-3-(4’-hydroxyphenyl)chroman] in human urine. Biochem. J. 1982;201:353–357. doi: 10.1042/bj2010353. PubMed DOI PMC

Committee on Toxicity Phytoestrogens and Health: COT Report. [(accessed on 25 July 2008)];2003 Available online: https://cot.food.gov.uk/sites/default/files/cot/phytoreport0503.pdf.

Setchell K.D.R., Brown N.M., Lydeking-Olsen E. The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. J. Nutr. 2002;132:3577–3584. doi: 10.1093/jn/132.12.3577. PubMed DOI

Dixon R.A. Legume Natural Products: Understanding and Manipulating Complex Pathways for Human and Animal Health. Plant Physiol. 2003;131:878–885. doi: 10.1104/pp.102.017319. PubMed DOI PMC

Ko K.-P. Isoflavones: Chemistry, Analysis, Functions and Effects on Health and Cancer. Asian Pac. J. Cancer Prev. 2014;15:7001–7010. doi: 10.7314/APJCP.2014.15.17.7001. PubMed DOI

Coward L., Barnes N.C., Setchell K.D.R., Barnes S. Genistein, daidzein, and their β-glycoside conjugates: Antitumor isoflavones in soybean foods from American and Asian diets. J. Agric. Food Chem. 1993;41:1961–1967. doi: 10.1021/jf00035a027. DOI

Bingham S.A., Atkinson C., Liggins J., Bluck L., Coward A. Phyto-oestrogens: Where are we now? Br. J. Nutr. 1998;79:393–406. doi: 10.1079/BJN19980068. PubMed DOI

Daems F., Romnee J.-M., Heuskin S., Froidmont É., Lognay G. Analytical methods used to quantify isoflavones in cow’s milk: A review. Dairy Sci. Technol. 2016;96:261–283. doi: 10.1007/s13594-015-0276-8. PubMed DOI PMC

Dakora F.D., Phillips D.A. Diverse functions of isoflavonoids in legumes transcend anti-microbial definitions of phytoalexins. Physiol. Mol. Plant Pathol. 1996;49:1–20. doi: 10.1006/pmpp.1996.0035. DOI

Bellou S., Karali E., Bagli E., Al-Maharik N., Morbidelli L., Ziche M., Adlercreutz H., Murphy C., Fotsis T. The isoflavone metabolite 6-methoxyequol inhibits angiogenesis and suppresses tumor growth. Mol. Cancer. 2012;11:35. doi: 10.1186/1476-4598-11-35. PubMed DOI PMC

Rípodas C., Via V.D., Aguilar O.M., Zanetti M.E., Blanco F.A. Knock-down of a member of the isoflavone reductase gene family impairs plant growth and nodulation in Phaseolus vulgaris. Plant Physiol. Biochem. 2013;68:81–89. doi: 10.1016/j.plaphy.2013.04.003. PubMed DOI

Subramanian S., Stacey G., Yu O. Endogenous isoflavones are essential for the establishment of symbiosis between soybean and Bradyrhizobium japonicum. Plant J. 2006;48:261–273. doi: 10.1111/j.1365-313X.2006.02874.x. PubMed DOI

Sukumaran A., McDowell T., Chen L., Renaud J., Dhaubhadel S. Isoflavonoid-specific prenyltransferase gene family in soybean: GmPT01, a pterocarpan 2-dimethylallyltransferase involved in glyceollin biosynthesis. Plant J. 2018;96:966–981. doi: 10.1111/tpj.14083. PubMed DOI

Liu Y., Hassan S., Kidd B.N., Garg G., Mathesius U., Singh K.B., Anderson J.P. Ethylene Signaling Is Important for Isoflavonoid-Mediated Resistance to Rhizoctonia solani in Roots of Medicago truncatula. Mol. Plant-Microbe Interact. 2017;30:691–700. doi: 10.1094/MPMI-03-17-0057-R. PubMed DOI

Hasanah Y., Nisa T.C., Armidin H., Hanum H. Isoflavone content of soybean [Glycine max (L). Merr.] cultivars with different nitrogen sources and growing season under dry land conditions. JAEID. 2015;109:5–17. doi: 10.12895/jaeid.20151.216. DOI

Adler S.A., Purup S., Hansen-Møller J., Thuen E., Steinshamn H. Phytoestrogens and Their Metabolites in Bulk-Tank Milk: Effects of Farm Management and Season. PLoS ONE. 2015;10:e0127187. doi: 10.1371/journal.pone.0127187. PubMed DOI PMC

Saloniemi H., Wähälä K., Nykanen-Kurki P., Kallela K., Saastamoinen I. Phytoestrogen Content and Estrogenic Effect of Legume Fodder. Exp. Biol. Med. 1995;208:13–17. doi: 10.3181/00379727-208-43825. PubMed DOI

Steinshamn H., Purup S., Thuen E., Hansen-Møller J. Effects of Clover-Grass Silages and Concentrate Supplementation on the Content of Phytoestrogens in Dairy Cow Milk. J. Dairy Sci. 2008;91:2715–2725. doi: 10.3168/jds.2007-0857. PubMed DOI

Butkutė B., Padarauskas A., Cesevičienė J., Taujenis L., Norkevičienė E. Phytochemical composition of temperate perennial legumes. Crop Pasture Sci. 2018;69:1020. doi: 10.1071/CP18206. DOI

Rizzo G., Baroni L. Soy, Soy Foods and Their Role in Vegetarian Diets. Nutrients. 2018;10:43. doi: 10.3390/nu10010043. PubMed DOI PMC

Bustamante-Rangel M., Delgado-Zamarreño M.M., Pérez-Martín L., Rodríguez-Gonzalo E., Domínguez-Álvarez J. Analysis of Isoflavones in Foods: Analysis of isoflavones in foods…. Compr. Rev. Food Sci. Food Saf. 2018;17:391–411. doi: 10.1111/1541-4337.12325. PubMed DOI

Frankenfeld C.L. Dairy consumption is a significant correlate of urinary equol concentration in a representative sample of US adults. Am. J. Clin. Nutr. 2011;93:1109–1116. doi: 10.3945/ajcn.111.011825. PubMed DOI

Andres S., Hansen U., Niemann B., Palavinskas R., Lampen A. Determination of the isoflavone composition and estrogenic activity of commercial dietary supplements based on soy or red clover. Food Funct. 2015;6:2017–2025. doi: 10.1039/C5FO00308C. PubMed DOI

Klyne W., Wright A.A. Steroids and other lipids of pregnant goat’s urine. Biochem. J. 1957;66:92–101. doi: 10.1042/bj0660092. PubMed DOI PMC

Miksicek R.J. Estrogenic Flavonoids: Structural Requirements for Biological Activity. Exp. Biol. Med. 1995;208:44–50. doi: 10.3181/00379727-208-43830. PubMed DOI

Nilsson A., Hill J.L., Davies H.L. An in vitro study of formononetin and biochanin A in rumen fluid from sheep. Biochim. Biophys. Acta. 1967;148:92–98. doi: 10.1016/0304-4165(67)90282-6. PubMed DOI

Dickinson J.M., Smith G.R., Randel R.D., Pemberton I.J. In vitro metabolism of formononetin and biochanin A in bovine rumen fluid. J. Anim. Sci. 1988;66:1969–1973. doi: 10.2527/jas1988.6681969x. PubMed DOI

Wocławek-Potocka I., Mannelli C., Boruszewska D., Kowalczyk-Zieba I., Waśniewski T., Skarżyński D.J. Diverse Effects of Phytoestrogens on the Reproductive Performance: Cow as a Model. Inter. J. Endocrinol. 2013;2013:1–15. doi: 10.1155/2013/650984. PubMed DOI PMC

Choi E.J., Kim G.-H. The antioxidant activity of daidzein metabolites, O-desmethylangolensin and equol, in HepG2 cells. Mol. Med. Rep. 2014;9:328–332. doi: 10.3892/mmr.2013.1752. PubMed DOI

Njåstad K.M., Adler S.A., Hansen-Møller J., Thuen E., Gustavsson A.-M., Steinshamn H. Gastrointestinal metabolism of phytoestrogens in lactating dairy cows fed silages with different botanical composition. J. Dairy Sci. 2014;97:7735–7750. doi: 10.3168/jds.2014-8208. PubMed DOI

Adams N.R. Detection of the effects of phytoestrogens on sheep and cattle. J. Anim. Sci. 1995;73:1509–1515. doi: 10.2527/1995.7351509x. PubMed DOI

Trnková A., Šancová K., Zapletalová M., Kašparovská J., Dadáková K., Křížová L., Lochman J., Hadrová S., Ihnatová I., Kašparovský T. Determination of in vitro isoflavone degradation in rumen fluid. J. Dairy Sci. 2018;101:5134–5144. doi: 10.3168/jds.2017-13610. PubMed DOI

Lundh T.J.O., Pettersson H.I., Martinsson K.A. Comparative levels of free and conjugated plant estrogens in blood plasma of sheep and cattle fed estrogenic silage. J. Agric. Food Chem. 1990;38:1530–1534. doi: 10.1021/jf00097a022. DOI

Urpi-Sarda M., Morand C., Besson C., Kraft G., Viala D., Scalbert A., Besle J.-M., Manach C. Tissue distribution of isoflavones in ewes after consumption of red clover silage. Arch. Biochem. Biophys. 2008;476:205–210. doi: 10.1016/j.abb.2008.05.002. PubMed DOI

Tucker H.A., Knowlton K.F., Meyer M.T., Khunjar W.O., Love N.G. Effect of diet on fecal and urinary estrogenic activity. J. Dairy Sci. 2010;93:2088–2094. doi: 10.3168/jds.2009-2657. PubMed DOI

Třináctý J., Křížová L., Schulzová V., Hajšlová J., Hanuš O. The effect of feeding soybean-derived phytoestogens on their concentration in plasma and milk of lactating dairy cows. Arch. Anim. Nutr. 2009;63:219–229. doi: 10.1080/17450390902859739. DOI

Mustonen E.A., Tuori M., Saastamoinen I., Taponen J., Wähälä K., Saloniemi H., Vanhatalo A. Equol in milk of dairy cows is derived from forage legumes such as red clover. Br. J. Nutr. 2009;102:1552–1556. doi: 10.1017/S0007114509990857. PubMed DOI

King R.A., Mano M.M., Head R.J. Assessment of isoflavonoid concentrations in Australian bovine milk samples. J. Dairy Res. 1998;65:479–489. doi: 10.1017/S0022029998002891. PubMed DOI

Höjer A., Adler S., Purup S., Hansen-Møller J., Martinsson K., Steinshamn H., Gustavsson A.-M. Effects of feeding dairy cows different legume-grass silages on milk phytoestrogen concentration. J. Dairy Sci. 2012;95:4526–4540. doi: 10.3168/jds.2011-5226. PubMed DOI

Sakakibara H., Viala D., Doreau M., Besle J.-M. Clover isoflavones move to cows’ milk; Proceedings of the 1st International Conference on Polyphenols and Health; Vichy, France. 18–21 November 2004; p. 296.

Flachowsky G., Hünerberg M., Meyer U., Kammerer D.R., Carle R., Goerke M., Eklund M. Isoflavone concentration of soybean meal from various origins and transfer of isoflavones into milk of dairy cows. J. Verbrauch. Lebensm. 2011;6:449–456. doi: 10.1007/s00003-011-0702-7. DOI

Křížová L., Třináctý J., Hajšlová J., Havlíková Š. The Effect of Technological Processing on the Content of Isoflavones in Bovine Milk and Dairy Products. In: Ng T.-B., editor. Soybean—Applications and Technology. InTech; Rijeka, Croatia: 2011. pp. 95–110.

Křížová L., Veselý A., Třináctý J., Schulzová V., Hurajová A., Hajšlová J., Kvasničková E., Havlíková Š. Changes in isoflavones concentrations in cheese during processing and ripening. Acta Univ. Agric. Silvic. Mendel. Brun. 2011;59:153–162. doi: 10.11118/actaun201159010153. DOI

Kasparovska J., Pecinkova M., Dadakova K., Krizova L., Hadrova S., Lexa M., Lochman J., Kasparovsky T. Effects of Isoflavone-Enriched Feed on the Rumen Microbiota in Dairy Cows. PLoS ONE. 2016;11:e0154642. doi: 10.1371/journal.pone.0154642. PubMed DOI PMC

Andersen C., Weisbjerg M.R., Hansen-Møller J., Sejrsen K. Effect of forage on the content of phyto-oestrogens in bovine milk. Animal. 2009;3:617–622. doi: 10.1017/S1751731108003698. PubMed DOI

Turner C.W. Estrogen Content of Colostrum and Milk of Dairy Cattle. J. Dairy Sci. 1958;41:630–640. doi: 10.3168/jds.S0022-0302(58)90976-7. DOI

Shennan D.B., Peaker M. Transport of milk constituents by the mammary gland. Physiol. Rev. 2000;80:925–951. doi: 10.1152/physrev.2000.80.3.925. PubMed DOI

Schwen R.J., Nguyen L., Jackson R.L. Elucidation of the metabolic pathway of S-equol in rat, monkey and man. Food Chem. Toxicol. 2012;50:2074–2083. doi: 10.1016/j.fct.2012.03.048. PubMed DOI

Whitehouse-Tedd K.M., Cave N.J., Ugarte C.E., Waldron L.A., Prasain J.K., Arabshahi A., Barnes S., Thomas D.G. Dietary isoflavone absorption, excretion, and metabolism in captive cheetahs (Acinonyx jubatus) J. Zoo Wildl. Med. 2011;42:658–670. doi: 10.1638/2011-0060.1. PubMed DOI

Marshall T. Clover disease: What do we know and what can we do. J. Dep. Agric. West. Aust. Ser. 4. 1973;14:2.

Sakakibara H., Viala D., Ollier A., Combeau A., Besle J.-M. Isoflavones in several clover species and in milk from goats fed clovers. Biofactors. 2004;22:237–239. doi: 10.1002/biof.5520220147. PubMed DOI

Woclawek-Potocka I., Bah M.M., Korzekwa A., Piskula M.K., Wiczkowski W., Depta A., Skarzynski D.J. Soybean-derived phytoestrogens regulate prostaglandin secretion in endometrium during cattle estrous cycle and early pregnancy. Exp. Biol. Med. 2005;230:189–199. doi: 10.1177/153537020523000305. PubMed DOI

Woclawek-Potocka I., Borkowski K., Korzekwa A., Okuda K., Skarzynski D.J. Phyto- and endogenous estrogens differently activate intracellular calcium ion mobilization in bovine endometrial cells. J. Reprod. Dev. 2006;52:731–740. doi: 10.1262/jrd.18057. PubMed DOI

Woclawek-Potocka I., Piskula M.K., Bah M., Siemieniuch M.J., Korzekwa A., Brzezicka E., Skarzynski D.J. Concentrations of isoflavones and their metabolites in the blood of pregnant and non-pregnant heifers fed soy bean. J. Reprod. Dev. 2008;54:358–363. doi: 10.1262/jrd.20013. PubMed DOI

Piotrowska K.K., Woclawek-Potocka I., Bah M.M., Piskula M.K., Pilawski W., Bober A., Skarzynski D.J. Phytoestrogens and their metabolites inhibit the sensitivity of the bovine corpus luteum to luteotropic factors. J. Reprod. Dev. 2006;52:33–41. doi: 10.1262/jrd.17054. PubMed DOI

Watzková J., Křížová L., Pavlík A., Schulzová V., Hajšlová J., Lojza J. The Effect of Soybean-Derived Phytoestrogens on Concentrations of Plasma Isoflavones, 15-keto-13,14-dihydroprostaglandin F2α and Progesterone in Dairy Cows. Acta Vet. Brno. 2010;79:525–532. doi: 10.2754/avb201079040525. DOI

Goff A.K. Steroid hormone modulation of prostaglandin secretion in the ruminant endometrium during the estrous cycle. Biol. Reprod. 2004;71:11–16. doi: 10.1095/biolreprod.103.025890. PubMed DOI

Asselin E., Goff A.K., Bergeron H., Fortier M.A. Influence of sex steroids on the production of prostaglandins F2α and E2 and response to oxytocin in cultured epithelial and stromal cells of the bovine endometrium. Biol. Reprod. 1996;54:371–379. doi: 10.1095/biolreprod54.2.371. PubMed DOI

Okuda K., Miyamoto Y., Skarzynski D.J. Regulation of endometrial prostaglandin F(2α) synthesis during luteolysis and early pregnancy in cattle. Domest. Anim. Endocrinol. 2002;23:255–264. doi: 10.1016/S0739-7240(02)00161-3. PubMed DOI

Woclawek-Potocka I., Bober A., Korzekwa A., Okuda K., Skarzynski D.J. Equol and para-ethyl-phenol stimulate prostaglandin F2α secretion in bovine corpus luteum: Intracellular mechanisms of action. Prostaglandins Other Lipid Mediat. 2006;79:287–297. doi: 10.1016/j.prostaglandins.2006.03.003. PubMed DOI

Shore L.S., Rios C., Marcus S., Bernstein M., Shemesh M. Relationship between peripheral estrogen concentrations at insemination and subsequent fetal loss in cattle. Theriogenology. 1998;50:101–107. doi: 10.1016/S0093-691X(98)00117-4. PubMed DOI

Kowalczyk-Zieba I., Woclawek-Potocka I., Piskula M.K., Piotrowska-Tomala K.K., Boruszewska D., Bah M.M., Siemieniuch M.J., Skarzynski D.J. Experimentally induced mastitis and metritis modulate soy bean derived isoflavone biotransformation in dairy cows. Theriogenology. 2011;76:1744–1755. doi: 10.1016/j.theriogenology.2011.07.010. PubMed DOI

Mohanty I., Senapati M.R., Jena D., Behera P.C. Ethnoveterinary importance of herbal galactogogues—A review. Vet. World. 2014;7:325–330. doi: 10.14202/vetworld.2014.325-330. DOI

Dewhurst R.J., Fisher W.J., Tweed J.K.S., Wilkins R.J. Comparison of grass and legume silages for milk production. 1. Production responses with different levels of concentrate. J. Dairy Sci. 2003;86:2598–2611. doi: 10.3168/jds.S0022-0302(03)73855-7. PubMed DOI

Vanhatalo A., Kuoppala K., Toivonen V., Shingfield K.J. Effects of forage species and stage of maturity on bovine milk fatty acid composition. Eur. J. Lipid Sci. Technol. 2007;109:856–867. doi: 10.1002/ejlt.200700023. DOI

Liu D.-Y., He S.-J., Jin E.-H., Liu S.-Q., Tang Y.-G., Li S.-H., Zhong L.-T. Effect of daidzein on production performance and serum antioxidative function in late lactation cows under heat stress. Livest. Sci. 2013;152:16–20. doi: 10.1016/j.livsci.2012.12.003. DOI

Moorby J.M., Fraser M.D., Theobald V.J., Wood J.D., Haresign W. The effect of red clover formononetin content on live-weight gain, carcass characteristics and muscle equol content of finishing lambs. Anim. Sci. 2004;79:303–313. doi: 10.1017/S1357729800090160. DOI

Speijers M.H.M., Fraser M.D., Theobald V.J., Haresign W. Effects of ensiled forage legumes on performance of store finishing lambs. Anim. Feed Sci. Technol. 2005;120:203–216. doi: 10.1016/j.anifeedsci.2005.02.027. DOI

Liu H.Y., Zhang C.Q. Effects of daidzein on messenger ribonucleic Acid expression of gonadotropin receptors in chicken ovarian follicles. Poult. Sci. 2008;87:541–545. doi: 10.3382/ps.2007-00274. PubMed DOI

Guo-zhen J., Li W. Effect of Daidzein on Ileum Microflora Biodiversity in Hy-Line Variety Brown Layers. J. Northeast Agric. Univ. 2014;21:31–36. doi: 10.1016/S1006-8104(15)30017-9. DOI

Etxeberria U., Fernández-Quintela A., Milagro F.I., Aguirre L., Martínez J.A., Portillo M.P. Impact of Polyphenols and Polyphenol-Rich Dietary Sources on Gut Microbiota Composition. J. Agric. Food Chem. 2013;61:9517–9533. doi: 10.1021/jf402506c. PubMed DOI

Setchell K.D.R., Brown N.M., Desai P., Zimmer-Nechemias L., Wolfe B.E., Brashear W.T., Kirschner A.S., Cassidy A., Heubi J.E. Bioavailability of Pure Isoflavones in Healthy Humans and Analysis of Commercial Soy Isoflavone Supplements. J. Nutr. 2001;131:1362S–1375S. doi: 10.1093/jn/131.4.1362S. PubMed DOI

Heinonen S., Wähälä K., Adlercreutz H. Identification of Isoflavone Metabolites Dihydrodaidzein, Dihydrogenistein, 6′-OH-O-dma, and cis-4-OH-equol in Human Urine by Gas Chromatography–Mass Spectroscopy Using Authentic Reference Compounds. Anal. Biochem. 1999;274:211–219. doi: 10.1006/abio.1999.4279. PubMed DOI

Sfakianos J., Coward L., Kirk M., Barnes S. Intestinal uptake and biliary excretion of the isoflavone genistein in rats. J. Nutr. 1997;127:1260–1268. doi: 10.1093/jn/127.7.1260. PubMed DOI

Setchell K.D.R., Faughnan M.S., Avades T., Zimmer-Nechemias L., Brown N.B., Wolfe B., Brashear W.T., Desai P., Oldfield M.F., Botting N.P., et al. Comparing the pharmacokinetics of daidzein and genistein using 13C-labeled tracers in premenopausal women. Am. J. Clin. Nutr. 2003;77:411–419. doi: 10.1093/ajcn/77.2.411. PubMed DOI

Hur H.-G., Lay J.O., Jr., Beger R.D., Freeman J.P., Rafii F. Isolation of human intestinal bacteria metabolizing the natural isoflavone glycosides daidzin and genistin. Arch. Microbiol. 2000;174:422–428. doi: 10.1007/s002030000222. PubMed DOI

Yerramsetty V., Gallaher D.D., Ismail B. Malonylglucoside Conjugates of Isoflavones Are Much Less Bioavailable Compared with Unconjugated β-Glucosidic Forms in Rats. J. Nutr. 2014;144:631–637. doi: 10.3945/jn.114.190801. PubMed DOI

Zubik L., Meydani M. Bioavailability of soybean isoflavones from aglycone and glucoside forms in American women. Am. J. Clin. Nutr. 2003;77:1459–1465. doi: 10.1093/ajcn/77.6.1459. PubMed DOI

Németh K., Plumb G.W., Berrin J.G., Juge N., Jacob R., Naim H.I., Williamson G., Swallow D.L., Kroon P.A. Deglycosylation by small intestinal epithelial cell β-glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans. Eur. J. Nutr. 2003;42:29–42. doi: 10.1007/s00394-003-0397-3. PubMed DOI

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. doi: 10.1007/s00203-004-0747-4. PubMed DOI

Ronis M.J., Little J.M., Barone G.W., Chen G., Radominska-Pandya A., Badger T.M. Sulfation of the isoflavones genistein and daidzein in human and rat liver and gastrointestinal tract. J. Med. Food. 2006;9:348–355. doi: 10.1089/jmf.2006.9.348. PubMed DOI

Hosoda K., Furuta T., Yokokawa A., Ishii K. Identification and quantification of daidzein-7-glucuronide-4’-sulfate, genistein-7-glucuronide-4’-sulfate and genistein-4’,7-diglucuronide as major metabolites in human plasma after administration of kinako. Anal. Bioanal. Chem. 2010;397:1563–1572. doi: 10.1007/s00216-010-3714-8. PubMed DOI

Barnes S. The biochemistry, chemistry and physiology of the isoflavones in soybeans and their food products. Lymphat. Res. Biol. 2010;8:89–98. doi: 10.1089/lrb.2009.0030. PubMed DOI PMC

Setchell K.D., Cassidy A. Dietary isoflavones: Biological effects and relevance to human health. J. Nutr. 1999;129:758S–767S. doi: 10.1093/jn/129.3.758S. PubMed DOI

Gaya P., Medina M., Sánchez-Jiménez A., Landete J. Phytoestrogen Metabolism by Adult Human Gut Microbiota. Molecules. 2016;21:1034. doi: 10.3390/molecules21081034. PubMed DOI PMC

Setchell K.D.R. Equol—Origins, actions, and clinical relevance of this specific soy isoflavone metabolite. J. Nutr. 2004;134:1235S–1236S.

Muthyala R.S., Ju Y.H., Sheng S., Williams L.D., Doerge D.R., Katzenellenbogen B.S., Helferich W.G., Katzenellenbogen J.A. Equol, a natural estrogenic metabolite from soy isoflavones: Convenient preparation and resolution of R- and S-equols and their differing binding and biological activity through estrogen receptors α and β. Bioorg. Med. Chem. 2004;12:1559–1567. doi: 10.1016/j.bmc.2003.11.035. PubMed DOI

Toro-Funes N., Morales-Gutiérrez F.J., Veciana-Nogués M.T., Vidal-Carou M.C., Spencer J.P.E., Rodriguez-Mateos A. The intracellular metabolism of isoflavones in endothelial cells. Food Funct. 2015;6:97–107. doi: 10.1039/C4FO00772G. PubMed DOI

Heinonen S.M., Hoikkala A., Wähälä K., Adlercreutz H. Metabolism of the soy isoflavones daidzein, genistein and glycitein in human subjects. Identification of new metabolites having an intact isoflavonoid skeleton. J. Steroid Biochem. Mol. Biol. 2003;87:285–299. doi: 10.1016/j.jsbmb.2003.09.003. PubMed DOI

Axelson M., Setchell K.D. The excretion of lignans in rats—Evidence for an intestinal bacterial source for this new group of compounds. FEBS Lett. 1981;123:337–342. doi: 10.1016/0014-5793(81)80322-5. PubMed DOI

Setchell K.D., Zimmer-Nechemias L., Cai J., Heubi J.E. Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet. 1997;350:23–27. doi: 10.1016/S0140-6736(96)09480-9. PubMed DOI

Setchell K.D., Zimmer-Nechemias L., Cai J., Heubi J.E. Isoflavone content of infant formulas and the metabolic fate of these phytoestrogens in early life. Am. J. Clin. Nutr. 1998;68:1453S–1461S. doi: 10.1093/ajcn/68.6.1453S. PubMed DOI

Rowland I.R., Wiseman H., Sanders T.A., Adlercreutz H., Bowey E.A. Interindividual variation in metabolism of soy isoflavones and lignans: Influence of habitual diet on equol production by the gut microflora. Nutr. Cancer. 2000;36:27–32. doi: 10.1207/S15327914NC3601_5. PubMed DOI

Braune A., Blaut M. Evaluation of inter-individual differences in gut bacterial isoflavone bioactivation in humans by PCR-based targeting of genes involved in equol formation. J. Appl. Microbiol. 2018;124:220–231. doi: 10.1111/jam.13616. PubMed DOI

Wu J., Oka J., Ezaki J., Ohtomo T., Ueno T., Uchiyama S., Toda T., Uehara M., Ishimi Y. Possible role of equol status in the effects of isoflavone on bone and fat mass in postmenopausal Japanese women: A double-blind, randomized, controlled trial. Menopause. 2007;14:866–874. doi: 10.1097/gme.0b013e3180305299. PubMed DOI

Frankenfeld C.L., Atkinson C., Thomas W.K., Gonzalez A., Jokela T., Wähälä K., Schwartz S.M., Li S.S., Lampe J.W. High concordance of daidzein-metabolizing phenotypes in individuals measured 1 to 3 years apart. Br. J. Nutr. 2005;94:873–876. doi: 10.1079/BJN20051565. PubMed DOI

Akaza H., Miyanaga N., Takashima N., Naito S., Hirao Y., Tsukamoto T., Fujioka T., Mori M., Kim W.-J., Song J.M., et al. Comparisons of percent equol producers between prostate cancer patients and controls: Case-controlled studies of isoflavones in Japanese, Korean and American residents. Jpn. J. Clin. Oncol. 2004;34:86–89. doi: 10.1093/jjco/hyh015. PubMed DOI

Franke A.A., Lai J.F., Halm B.M., Pagano I., Kono N., Mack W.J., Hodis H.N. Equol production changes over time in postmenopausal women. J. Nutr. Biochem. 2012;23:573–579. doi: 10.1016/j.jnutbio.2011.03.002. PubMed DOI PMC

Franke A.A., Lai J.F., Halm B.M. Absorption, distribution, metabolism, and excretion of isoflavonoids after soy intake. Arch. Biochem. Biophys. 2014;559:24–28. doi: 10.1016/j.abb.2014.06.007. PubMed DOI PMC

Frankenfeld C.L., McTiernan A., Tworoger S.S., Atkinson C., Thomas W.K., Stanczyk F.Z., Marcovina S.M., Weigle D.S., Weiss N.S., Holt V.L., et al. Serum steroid hormones, sex hormone-binding globulin concentrations, and urinary hydroxylated estrogen metabolites in post-menopausal women in relation to daidzein-metabolizing phenotypes. J. Steroid Biochem. Mol. Biol. 2004;88:399–408. doi: 10.1016/j.jsbmb.2004.01.006. PubMed DOI

Liu B., Qin L., Liu A., Uchiyama S., Ueno T., Li X., Wang P. Prevalence of the equol-producer phenotype and its relationship with dietary isoflavone and serum lipids in healthy Chinese adults. J. Epidemiol. 2010;20:377–384. doi: 10.2188/jea.JE20090185. PubMed DOI PMC

Setchell K.D.R., Cole S.J. Method of defining equol-producer status and its frequency among vegetarians. J. Nutr. 2006;136:2188–2193. doi: 10.1093/jn/136.8.2188. PubMed DOI

Redruello B., Guadamuro L., Cuesta I., Álvarez-Buylla J.R., Mayo B., Delgado S. A novel UHPLC method for the rapid and simultaneous determination of daidzein, genistein and equol in human urine. J. Chromatogr. B. 2015;1005:1–8. doi: 10.1016/j.jchromb.2015.09.029. PubMed DOI

Cassidy A. Plant Oestrogens and Their Relation to Hormonal Status in Women. Cambridge University; Cambridge, UK: 1991.

Lipovac M., Pfitscher A., Hobiger S., Laschitz T., Imhof M., Chedraui P., Jungbauer A. Red clover isoflavone metabolite bioavailability is decreased after fructooligosaccharide supplementation. Fitoterapia. 2015;105:93–101. doi: 10.1016/j.fitote.2015.06.011. PubMed DOI

Nielsen I.L.F., Williamson G. Review of the factors affecting bioavailability of soy isoflavones in humans. Nutr. Cancer. 2007;57:1–10. doi: 10.1080/01635580701267677. PubMed DOI

Cohen L.A., Crespin J.S., Wolper C., Zang E.A., Pittman B., Zhao Z., Holt P.R. Soy isoflavone intake and estrogen excretion patterns in young women: Effect of probiotic administration. In Vivo. 2007;21:507–512. PubMed

Elghali S., Mustafa S., Amid M., Manap M.Y.A.B.D., Ismail A., Abas F. Bioconversion of daidzein to equol by Bifidobacterium breve 15700 and Bifidobacterium longum BB536. J. Funct. Foods. 2012;4:736–745. doi: 10.1016/j.jff.2012.04.013. DOI

Shimada Y., Yasuda S., Takahashi M., Hayashi T., Morihiro M., Sato I., Abiru Y., Uchiyama S., Hishigaki H. Cloning and expression of a novel NADP(H)-dependent daidzein reductase, an enzyme involved in the metabolism of daidzein, from equol-producing Lactococcus strain 20–92. Appl. Environ. Microbiol. 2010;76:5892–5901. doi: 10.1128/AEM.01101-10. PubMed DOI PMC

Kim M., Kim S.-I., Han J., Wang X.-L., Song D.-G., Kim S.-U. Stereospecific Biotransformation of Dihydrodaidzein into (3S)-Equol by the Human Intestinal Bacterium Eggerthella Strain Julong 732. Appl. Environ. Microbiol. 2009;75:3062–3068. doi: 10.1128/AEM.02058-08. PubMed DOI PMC

Kim M., Lee J., Han J. Deglycosylation of isoflavone C-glycosides by newly isolated human intestinal bacteria. J. Sci. Food Agric. 2015;95:1925–1931. doi: 10.1002/jsfa.6900. PubMed DOI

Tamura M., Tsushida T., Shinohara K. Isolation of an isoflavone-metabolizing, Clostridium-like bacterium, strain TM-40, from human faeces. Anaerobe. 2007;13:32–35. doi: 10.1016/j.anaerobe.2006.10.001. PubMed DOI

Schoefer L., Mohan R., Braune A., Birringer M., Blaut M. Anaerobic C-ring cleavage of genistein and daidzein by Eubacterium ramulus. FEMS Microbiol. Lett. 2002;208:197–202. doi: 10.1111/j.1574-6968.2002.tb11081.x. PubMed DOI

Wang X.-L., Kim H.-J., Kang S.-I., Kim S.-I., Hur H.-G. Production of phytoestrogen S-equol from daidzein in mixed culture of two anaerobic bacteria. Arch. Microbiol. 2007;187:155–160. doi: 10.1007/s00203-006-0183-8. PubMed DOI

Ueno T., Uchiyama S. Identification of the specific intestinal bacteria capable of metabolising soy isoflavone to equol. (Abs.) Ann. Nutr. Metab. 2001;45:114.

Baber R.J. Phytoestrogens in health: The role of isoflavones. In: Preedy V.R., editor. Isoflavones: Chemistry, Analysis, Function and Effects. RCS Publishing; Cambridge, UK: 2013. pp. 3–13. Food and Nutritional Components in Focus.

Messina M., Kucuk O., Lampe J.W. An overview of the health effects of isoflavones with an emphasis on prostate cancer risk and prostate-specific antigen levels. J. AOAC Int. 2006;89:1121–1134. PubMed

Messina M., Hilakivi-Clarke L. Early intake appears to be the key to the proposed protective effects of soy intake against breast cancer. Nutr. Cancer. 2009;61:792–798. doi: 10.1080/01635580903285015. PubMed DOI

Shu X.O., Zheng Y., Cai H., Gu K., Chen Z., Zheng W., Lu W. Soy food intake and breast cancer survival. JAMA. 2009;302:2437–2443. doi: 10.1001/jama.2009.1783. PubMed DOI PMC

Carroll K.K. Review of clinical studies on cholesterol-lowering response to soy protein. J. Am. Diet. Assoc. 1991;91:820–827. PubMed

Teede H.J., Dalais F.S., Kotsopoulos D., Liang Y.L., Davis S., McGrath B.P. Dietary soy has both beneficial and potentially adverse cardiovascular effects: A placebo-controlled study in men and postmenopausal women. J. Clin. Endocrinol. Metab. 2001;86:3053–3060. doi: 10.1210/jc.86.7.3053. PubMed DOI

Hoie L.H., Guldstrand M., Sjoholm A., Graubaum H.J., Gruenwald J., Zunft H.J.F., Lueder W. Cholesterol-lowering effects of a new isolated soy protein with high levels of nondenaturated protein in hypercholesterolemic patients. Adv. Ther. 2007;24:439–447. doi: 10.1007/BF02849913. PubMed DOI

Ye Y.-B., Tang X.-Y., Verbruggen M.A., Su Y.-X. Soy isoflavones attenuate bone loss in early postmenopausal Chinese women: A single-blind randomized, placebo-controlled trial. Eur. J. Nutr. 2006;45:327–334. doi: 10.1007/s00394-006-0602-2. PubMed DOI

Lethaby A.E., Brown J., Marjoribanks J., Kronenberg F., Roberts H., Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst. Rev. 2007:CD001395. doi: 10.1002/14651858. PubMed DOI

Farquhar C.M., Marjoribanks J., Lethaby A., Lamberts Q., Suckling J.A., Cochrane HT Study Group Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst. Rev. 2005;2015:CD004143. doi: 10.1002/14651858. PubMed DOI

Turner R., Baron T., Wolffram S., Minihane A.M., Cassidy A., Rimbach G., Weinberg P.D. Effect of circulating forms of soy isoflavones on the oxidation of low density lipoprotein. Free Radic. Res. 2004;38:209–216. doi: 10.1080/10715760310001641854. PubMed DOI

Lund T.D., Munson D.J., Haldy M.E., Setchell K.D.R., Lephart E.D., Handa R.J. Equol is a novel anti-androgen that inhibits prostate growth and hormone feedback. Biol. Reprod. 2004;70:1188–1195. doi: 10.1095/biolreprod.103.023713. PubMed DOI

Nagel S.C., vom Saal F.S., Welshons W.V. Developmental effects of estrogenic chemicals are predicted by an in vitro assay incorporating modification of cell uptake by serum. J. Steroid Biochem. Mol. Biol. 1999;69:343–357. doi: 10.1016/S0960-0760(99)00078-3. PubMed DOI

Hilakivi-Clarke L., de Assis S. Fetal origins of breast cancer. Trends Endocrinol. Metab. 2006;17:340–348. doi: 10.1016/j.tem.2006.09.002. PubMed DOI

Wang Y., Man Gho W., Chan F.L., Chen S., Leung L.K. The red clover (Trifolium pratense) isoflavone biochanin A inhibits aromatase activity and expression. Br. J. Nutr. 2008;99:303–310. doi: 10.1017/S0007114507811974. PubMed DOI

Vitale D.C., Piazza C., Melilli B., Drago F., Salomone S. Isoflavones: Estrogenic activity, biological effect and bioavailability. Eur. J. Drug Metab. Pharmacokinet. 2013;38:15–25. doi: 10.1007/s13318-012-0112-y. PubMed DOI

Evers N.M., van de Klundert T.M.C., van Aesch Y.M., Wang S., de Roos W.K., Romano A., de Haan L.H.J., Murk A.J., Ederveen A.G.H., Rietjens I.M.C.M., et al. Human T47D-ERβ breast cancer cells with tetracycline-dependent ERβ expression reflect ERα/ERβ ratios in rat and human breast tissue. Toxicol. In Vitro. 2013;27:1753–1761. doi: 10.1016/j.tiv.2013.04.014. PubMed DOI

Mueller S.O., Simon S., Chae K., Metzler M., Korach K.S. Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor α (ERα) and ERβ in human cells. Toxicol. Sci. 2004;80:14–25. doi: 10.1093/toxsci/kfh147. PubMed DOI

Krebs E.E., Ensrud K.E., MacDonald R., Wilt T.J. Phytoestrogens for treatment of menopausal symptoms: A systematic review. Obstet. Gynecol. 2004;104:824–836. doi: 10.1097/01.AOG.0000140688.71638.d3. PubMed DOI

Howes L.G., Howes J.B., Knight D.C. Isoflavone therapy for menopausal flushes: A systematic review and meta-analysis. Maturitas. 2006;55:203–211. doi: 10.1016/j.maturitas.2006.03.008. PubMed DOI

Jou H.-J., Wu S.-C., Chang F.-W., Ling P.-Y., Chu K.S., Wu W.-H. Effect of intestinal production of equol on menopausal symptoms in women treated with soy isoflavones. Int. J. Gynaecol. Obstet. 2008;102:44–49. doi: 10.1016/j.ijgo.2008.01.028. PubMed DOI

Chandrareddy A., Muneyyirci-Delale O., McFarlane S.I., Murad O.M. Adverse effects of phytoestrogens on reproductive health: A report of three cases. Complement. Ther. Clin. Pract. 2008;14:132–135. doi: 10.1016/j.ctcp.2008.01.002. PubMed DOI

Anthony M.S., Clarkson T.B., Hughes C.L., Morgan T.M., Burke G.L. Soybean isoflavones improve cardiovascular risk factors without affecting the reproductive system of peripubertal rhesus monkeys. J. Nutr. 1996;126:43–50. doi: 10.1093/jn/126.1.43. PubMed DOI

Zhan S., Ho S.C. Meta-analysis of the effects of soy protein containing isoflavones on the lipid profile. Am. J. Clin. Nutr. 2005;81:397–408. doi: 10.1093/ajcn.81.2.397. PubMed DOI

Sacks F.M., Lichtenstein A., Van Horn L., Harris W., Kris-Etherton P., Winston M., American Heart Association Nutrition Committee Soy protein, isoflavones, and cardiovascular health: An American Heart Association Science Advisory for professionals from the Nutrition Committee. Circulation. 2006;113:1034–1044. doi: 10.1161/CIRCULATIONAHA.106.171052. PubMed DOI

Reynolds K., Chin A., Lees K.A., Nguyen A., Bujnowski D., He J. A meta-analysis of the effect of soy protein supplementation on serum lipids. Am. J. Cardiol. 2006;98:633–640. doi: 10.1016/j.amjcard.2006.03.042. PubMed DOI

Landmesser U., Hornig B., Drexler H. Endothelial function: A critical determinant in atherosclerosis? Circulation. 2004;109:II27–II33. doi: 10.1161/01.CIR.0000129501.88485.1f. PubMed DOI

Mäkelä S., Savolainen H., Aavik E., Myllärniemi M., Strauss L., Taskinen E., Gustafsson J.A., Häyry P. Differentiation between vasculoprotective and uterotrophic effects of ligands with different binding affinities to estrogen receptors α and β. Proc. Natl. Acad. Sci. USA. 1999;96:7077–7082. doi: 10.1073/pnas.96.12.7077. PubMed DOI PMC

Katz D.L., Evans M.A., Njike V.Y., Hoxley M.L., Nawaz H., Comerford B.P., Sarrel P.M. Raloxifene, soy phytoestrogens and endothelial function in postmenopausal women. Climacteric. 2007;10:500–507. doi: 10.1080/13697130701750123. PubMed DOI

Evans M., Njike V.Y., Hoxley M., Pearson M., Katz D.L. Effect of soy isoflavone protein and soy lecithin on endothelial function in healthy postmenopausal women. Menopause. 2007;14:141–149. doi: 10.1097/01.gme.0000227404.83686.1b. PubMed DOI

Teede H.J., Giannopoulos D., Dalais F.S., Hodgson J., McGrath B.P. Randomised, controlled, cross-over trial of soy protein with isoflavones on blood pressure and arterial function in hypertensive subjects. J. Am. Coll. Nutr. 2006;25:533–540. doi: 10.1080/07315724.2006.10719569. PubMed DOI

Liu X.X., Li S.H., Chen J.Z., Sun K., Wang X.J., Wang X.G., Hui R.T. Effect of soy isoflavones on blood pressure: A meta-analysis of randomized controlled trials. Nutr. Metab. Cardiovasc. Dis. 2012;22:463–470. doi: 10.1016/j.numecd.2010.09.006. PubMed DOI

Levine J.P. Effective strategies to identify postmenopausal women at risk for osteoporosis. Geriatrics. 2007;62:22–30. PubMed

Onoe Y., Miyaura C., Ohta H., Nozawa S., Suda T. Expression of estrogen receptor β in rat bone. Endocrinology. 1997;138:4509–4512. doi: 10.1210/endo.138.10.5575. PubMed DOI

Canalis E., Giustina A., Bilezikian J.P. Mechanisms of anabolic therapies for osteoporosis. N. Engl. J. Med. 2007;357:905–916. doi: 10.1056/NEJMra067395. PubMed DOI

Cheong J.M.K., Martin B.R., Jackson G.S., Elmore D., McCabe G.P., Nolan J.R., Barnes S., Peacock M., Weaver C.M. Soy isoflavones do not affect bone resorption in postmenopausal women: A dose-response study using a novel approach with 41Ca. J. Clin. Endocrinol. Metab. 2007;92:577–582. doi: 10.1210/jc.2006-0369. PubMed DOI PMC

Alekel D.L., Germain A.S., Peterson C.T., Hanson K.B., Stewart J.W., Toda T. Isoflavone-rich soy protein isolate attenuates bone loss in the lumbar spine of perimenopausal women. Am. J. Clin. Nutr. 2000;72:844–852. doi: 10.1093/ajcn/72.3.844. PubMed DOI

Arjmandi B.H., Lucas E.A., Khalil D.A., Devareddy L., Smith B.J., McDonald J., Arquitt A.B., Payton M.E., Mason C. One year soy protein supplementation has positive effects on bone formation markers but not bone density in postmenopausal women. Nutr. J. 2005;4:8. doi: 10.1186/1475-2891-4-8. PubMed DOI PMC

Chen Y.-M., Ho S.C., Lam S.S.H., Ho S.S.S., Woo J.L.F. Beneficial effect of soy isoflavones on bone mineral content was modified by years since menopause, body weight, and calcium intake: A double-blind, randomized, controlled trial. Menopause. 2004;11:246–254. doi: 10.1097/01.GME.0000094394.59028.46. PubMed DOI

Huang H.-Y., Yang H.-P., Yang H.-T., Yang T.-C., Shieh M.-J., Huang S.-Y. One-year soy isoflavone supplementation prevents early postmenopausal bone loss but without a dose-dependent effect. J. Nutr. Biochem. 2006;17:509–517. doi: 10.1016/j.jnutbio.2006.01.003. PubMed DOI

Ishimi Y. Dietary equol and bone metabolism in postmenopausal Japanese women and osteoporotic mice. J. Nutr. 2010;140:1373S–1376S. doi: 10.3945/jn.110.124842. PubMed DOI

Taku K., Melby M.K., Nishi N., Omori T., Kurzer M.S. Soy isoflavones for osteoporosis: An evidence-based approach. Maturitas. 2011;70:333–338. doi: 10.1016/j.maturitas.2011.09.001. PubMed DOI

Tousen Y., Ezaki J., Fujii Y., Ueno T., Nishimuta M., Ishimi Y. Natural S-equol decreases bone resorption in postmenopausal, non-equol-producing Japanese women: A pilot randomized, placebo-controlled trial. Menopause. 2011;18:563–574. doi: 10.1097/gme.0b013e3181f85aa7. PubMed DOI

Tousen Y., Ishiwata H., Ishimi Y., Ikegami S. Equol, a Metabolite of Daidzein, Is More Efficient than Daidzein for Bone Formation in Growing Female Rats. Phytother. Res. 2015;29:1349–1354. doi: 10.1002/ptr.5387. PubMed DOI

Fujioka M., Uehara M., Wu J., Adlercreutz H., Suzuki K., Kanazawa K., Takeda K., Yamada K., Ishimi Y. Equol, a metabolite of daidzein, inhibits bone loss in ovariectomized mice. J. Nutr. 2004;134:2623–2627. doi: 10.1093/jn/134.10.2623. PubMed DOI

Youlden D.R., Cramb S.M., Dunn N.A.M., Muller J.M., Pyke C.M., Baade P.D. The descriptive epidemiology of female breast cancer: An international comparison of screening, incidence, survival and mortality. Cancer Epidemiol. 2012;36:237–248. doi: 10.1016/j.canep.2012.02.007. PubMed DOI

Van Erp-Baart M.-A.J., Brants H.A.M., Kiely M., Mulligan A., Turrini A., Sermoneta C., Kilkkinen A., Valsta L.M. Isoflavone intake in four different European countries: The VENUS approach. Br. J. Nutr. 2003;89(Suppl. 1):S25–S30. doi: 10.1079/BJN2002793. PubMed DOI

Messina M., Nagata C., Wu A.H. Estimated Asian adult soy protein and isoflavone intakes. Nutr. Cancer. 2006;55:1–12. doi: 10.1207/s15327914nc5501_1. PubMed DOI

Messina M.J., Wood C.E. Soy isoflavones, estrogen therapy, and breast cancer risk: Analysis and commentary. Nutr. J. 2008;7:17. doi: 10.1186/1475-2891-7-17. PubMed DOI PMC

Shin H.-R., Joubert C., Boniol M., Hery C., Ahn S.H., Won Y.-J., Nishino Y., Sobue T., Chen C.-J., You S.-L., et al. Recent trends and patterns in breast cancer incidence among Eastern and Southeastern Asian women. Cancer Cause Control. 2010;21:1777–1785. doi: 10.1007/s10552-010-9604-8. PubMed DOI

Bardin A., Boulle N., Lazennec G., Vignon F., Pujol P. Loss of ERβ expression as a common step in estrogen-dependent tumor progression. Endocr. Relat. Cancer. 2004;11:537–551. doi: 10.1677/erc.1.00800. PubMed DOI PMC

Lazennec G., Bresson D., Lucas A., Chauveau C., Vignon F. ERβ inhibits proliferation and invasion of breast cancer cells. Endocrinology. 2001;142:4120–4130. doi: 10.1210/endo.142.9.8395. PubMed DOI PMC

Sotoca Covaleda A.M., van den Berg H., Vervoort J., van der Saag P., Ström A., Gustafsson J.-A., Rietjens I., Murk A.J. Influence of cellular ERα/ERβ ratio on the ERα-agonist induced proliferation of human T47D breast cancer cells. Toxicol. Sci. 2008;105:303–311. doi: 10.1093/toxsci/kfn141. PubMed DOI PMC

Islam M.A., Bekele R., Vanden Berg J.H.J., Kuswanti Y., Thapa O., Soltani S., van Leeuwen F.X.R., Rietjens I.M.C.M., Murk A.J. Deconjugation of soy isoflavone glucuronides needed for estrogenic activity. Toxicol. In Vitro. 2015;29:706–715. doi: 10.1016/j.tiv.2015.01.013. PubMed DOI

Horn-Ross P.L., John E.M., Canchola A.J., Stewart S.L., Lee M.M. Phytoestrogen intake and endometrial cancer risk. J. Natl. Cancer Inst. 2003;95:1158–1164. doi: 10.1093/jnci/djg015. PubMed DOI

Xu W.H., Zheng W., Xiang Y.B., Ruan Z.X., Cheng J.R., Dai Q., Gao Y.T., Shu X.O. Soya food intake and risk of endometrial cancer among Chinese women in Shanghai: Population based case-control study. BMJ. 2004;328:1285. doi: 10.1136/bmj.38093.646215.AE. PubMed DOI PMC

Murray M.J., Meyer W.R., Lessey B.A., Oi R.H., DeWire R.E., Fritz M.A. Soy protein isolate with isoflavones does not prevent estradiol-induced endometrial hyperplasia in postmenopausal women: A pilot trial. Menopause. 2003;10:456–464. doi: 10.1097/01.GME.0000063567.84134.D1. PubMed DOI

Messina M.J. Emerging evidence on the role of soy in reducing prostate cancer risk. Nutr. Rev. 2003;61:117–131. doi: 10.1301/nr.2003.apr.117-131. PubMed DOI

Lund T.D., Blake C., Bu L., Hamaker A.N., Lephart E.D. Equol an isoflavonoid: Potential for improved prostate health, in vitro and in vivo evidence. Reprod. Biol. Endocrinol. 2011;9:4. doi: 10.1186/1477-7827-9-4. PubMed DOI PMC

Adams K.F., Chen C., Newton K.M., Potter J.D., Lampe J.W. Soy isoflavones do not modulate prostate-specific antigen concentrations in older men in a randomized controlled trial. Cancer Epidemiol. Biomark. Prev. 2004;13:644–648. PubMed

Fischer L., Mahoney C., Jeffcoat A.R., Koch M.A., Thomas B.E., Valentine J.L., Stinchcombe T., Boan J., Crowell J.A., Zeisel S.H. Clinical characteristics and pharmacokinetics of purified soy isoflavones: Multiple-dose administration to men with prostate neoplasia. Nutr. Cancer. 2004;48:160–170. doi: 10.1207/s15327914nc4802_5. PubMed DOI

Yan L., Spitznagel E.L. Soy consumption and prostate cancer risk in men: A revisit of a meta-analysis. Am. J. Clin. Nutr. 2009;89:1155–1163. doi: 10.3945/ajcn.2008.27029. PubMed DOI

Chang H.C., Doerge D.R. Dietary genistein inactivates rat thyroid peroxidase in vivo without an apparent hypothyroid effect. Toxicol. Appl. Pharmacol. 2000;168:244–252. doi: 10.1006/taap.2000.9019. PubMed DOI

Messina M., Redmond G. Effects of soy protein and soybean isoflavones on thyroid function in healthy adults and hypothyroid patients: A review of the relevant literature. Thyroid. 2006;16:249–258. doi: 10.1089/thy.2006.16.249. PubMed DOI

Chorazy P.A., Himelhoch S., Hopwood N.J., Greger N.G., Postellon D.C. Persistent hypothyroidism in an infant receiving a soy formula: Case report and review of the literature. Pediatrics. 1995;96:148–150. PubMed

Dillingham B.L., McVeigh B.L., Lampe J.W., Duncan A.M. Soy protein isolates of varied isoflavone content do not influence serum thyroid hormones in healthy young men. Thyroid. 2007;17:131–137. doi: 10.1089/thy.2006.0206. PubMed DOI

Radović B., Mentrup B., Köhrle J. Genistein and other soya isoflavones are potent ligands for transthyretin in serum and cerebrospinal fluid. Br. J. Nutr. 2006;95:1171–1176. doi: 10.1079/BJN20061779. PubMed DOI

Hagen G.A., Solberg L.A. Brain and cerebrospinal fluid permeability to intravenous thyroid hormones. Endocrinology. 1974;95:1398–1410. doi: 10.1210/endo-95-5-1398. PubMed DOI

Köhrle J., Fang S.L., Yang Y., Irmscher K., Hesch R.D., Pino S., Alex S., Braverman L.E. Rapid effects of the flavonoid EMD 21388 on serum thyroid hormone binding and thyrotropin regulation in the rat. Endocrinology. 1989;125:532–537. doi: 10.1210/endo-125-1-532. PubMed DOI

Hillman G.G., Singh-Gupta V., Hoogstra D.J., Abernathy L., Rakowski J., Yunker C.K., Rothstein S.E., Sarkar F.H., Gadgeel S., Konski A.A., et al. Differential effect of soy isoflavones in enhancing high intensity radiotherapy and protecting lung tissue in a pre-clinical model of lung carcinoma. Radiother. Oncol. 2013;109:117–125. doi: 10.1016/j.radonc.2013.08.015. PubMed DOI PMC

Moosmann B., Behl C. The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties. Proc. Natl. Acad. Sci. USA. 1999;96:8867–8872. doi: 10.1073/pnas.96.16.8867. PubMed DOI PMC

Ruiz-Larrea M.B., Mohan A.R., Paganga G., Miller N.J., Bolwell G.P., Rice-Evans C.A. Antioxidant activity of phytoestrogenic isoflavones. Free Radic. Res. 1997;26:63–70. doi: 10.3109/10715769709097785. PubMed DOI

Amigo-Benavent M., Silván J.M., Moreno F.J., Villamiel M., Del Castillo M.D. Protein quality, antigenicity, and antioxidant activity of soy-based foodstuffs. J. Agric. Food Chem. 2008;56:6498–6505. doi: 10.1021/jf800697n. PubMed DOI

Yoon G.-A., Park S. Antioxidant action of soy isoflavones on oxidative stress and antioxidant enzyme activities in exercised rats. Nutr. Res. Pract. 2014;8:618–624. doi: 10.4162/nrp.2014.8.6.618. PubMed DOI PMC

Wiseman H., O’Reilly J.D., Adlercreutz H., Mallet A.I., Bowey E.A., Rowland I.R., Sanders T.A. Isoflavone phytoestrogens consumed in soy decrease F(2)-isoprostane concentrations and increase resistance of low-density lipoprotein to oxidation in humans. Am. J. Clin. Nutr. 2000;72:395–400. doi: 10.1093/ajcn/72.2.395. PubMed DOI

Djuric Z., Chen G., Doerge D.R., Heilbrun L.K., Kucuk O. Effect of soy isoflavone supplementation on markers of oxidative stress in men and women. Cancer Lett. 2001;172:1–6. doi: 10.1016/S0304-3835(01)00627-9. PubMed DOI

Monteiro N.E.S., Queirós L.D., Lopes D.B., Pedro A.O., Macedo G.A. Impact of microbiota on the use and effects of isoflavones in the relief of climacteric symptoms in menopausal women – A review. J. Funct. Foods. 2018;41:100–111. doi: 10.1016/j.jff.2017.12.043. DOI

Setchell K.D.R., Zhao X., Shoaf S.E., Ragland K. The pharmacokinetics of S-(-)equol administered as SE5-OH tablets to healthy postmenopausal women. J. Nutr. 2009;139:2037–2043. doi: 10.3945/jn.109.110874. PubMed DOI

Andersen C., Nielsen T.S., Purup S., Kristensen T., Eriksen J., Søegaard K., Sørensen J., Fretté X.C. Phyto-oestrogens in herbage and milk from cows grazing white clover, red clover, lucerne or chicory-rich pastures. Animal. 2009;3:1189–1195. doi: 10.1017/S1751731109004613. PubMed DOI

Nielsen T.S., Nørgaard J.V., Purup S., Fretté X.C., Bonefeld-Jørgensen E.C. Estrogenic activity of bovine milk high or low in equol using immature mouse uterotrophic responses and an estrogen receptor transactivation assay. Cancer Epidemiol. 2009;33:61–68. doi: 10.1016/j.canep.2009.04.003. PubMed DOI

Antignac J., Cariou R., LeBizec B., André F. New data regarding phytoestrogens content in bovine milk. Food Chem. 2004;87:275–281. doi: 10.1016/j.foodchem.2003.12.013. DOI

Krajčová A., Schulzová V., Lojza J., Křížová L., Hajšlová J. Phytoestrogens in bovine plasma and milk—LC-MS/MS analysis. Czech J. Food Sci. 2010;28:264–274. doi: 10.17221/138/2010-CJFS. DOI

Daems F., Jasselette C., Romnee J.-M., Planchon V., Lognay G., Froidmont É. Validating the use of an ultra-performance liquid chromatography with tandem mass spectrometry method to quantify equol in cow’s milk. Dairy Sci. Technol. 2015;95:303–319. doi: 10.1007/s13594-015-0209-6. DOI

Kuhnle G.G.C., Dell’Aquila C., Aspinall S.M., Runswick S.A., Mulligan A.A., Bingham S.A. Phytoestrogen content of foods of animal origin: Dairy products, eggs, meat, fish, and seafood. J. Agric. Food Chem. 2008;56:10099–10104. doi: 10.1021/jf801344x. PubMed DOI

Kašparovská J., Dadáková K., Lochman J., Hadrová S., Křížová L., Kašparovský T. Changes in equol and major soybean isoflavone contents during processing and storage of yogurts made from control or isoflavone-enriched bovine milk determined using LC-MS (TOF) analysis. Food Chem. 2017;222:67–73. doi: 10.1016/j.foodchem.2016.12.010. PubMed DOI

Atanassova N., McKinnell C., Fisher J., Sharpe R.M. Neonatal treatment of rats with diethylstilboestrol (DES) induces stromal-epithelial abnormalities of the vas deferens and cauda epididymis in adulthood following delayed basal cell development. Reproduction. 2005;129:589–601. doi: 10.1530/rep.1.00546. PubMed DOI

Franke A.A., Custer L.J. Daidzein and genistein concentrations in human milk after soy consumption. Clin. Chem. 1996;42:955–964. PubMed

Balakrishnan B., Thorstensen E.B., Ponnampalam A.P., Mitchell M.D. Transplacental transfer and biotransformation of genistein in human placenta. Placenta. 2010;31:506–511. doi: 10.1016/j.placenta.2010.03.007. PubMed DOI

Franke A.A., Custer L.J., Wang W., Shi C.Y. HPLC analysis of isoflavonoids and other phenolic agents from foods and from human fluids. Proc. Soc. Exp. Biol. Med. 1998;217:263–273. doi: 10.3181/00379727-217-44231. PubMed DOI

Irvine C.H., Shand N., Fitzpatrick M.G., Alexander S.L. Daily intake and urinary excretion of genistein and daidzein by infants fed soy- or dairy-based infant formulas. Am. J. Clin. Nutr. 1998;68:1462S–1465S. doi: 10.1093/ajcn/68.6.1462S. PubMed DOI

Lu L.J., Grady J.J., Marshall M.V., Ramanujam V.M., Anderson K.E. Altered time course of urinary daidzein and genistein excretion during chronic soya diet in healthy male subjects. Nutr. Cancer. 1995;24:311–323. doi: 10.1080/01635589509514420. PubMed DOI

Olea N., Olea-Serrano F., Lardelli-Claret P., Rivas A., Barba-Navarro A. Inadvertent exposure to xenoestrogens in children. Toxicol. Ind. Health. 1999;15:151–158. doi: 10.1191/074823399678846682. PubMed DOI

Talsness C., Grote K., Kuriyama S., Presibella K., Sterner-Kock A., Poça K., Chahoud I. Prenatal Exposure to the Phytoestrogen Daidzein Resulted in Persistent Changes in Ovarian Surface Epithelial Cell Height, Folliculogenesis, and Estrus Phase Length in Adult Sprague-Dawley Rat Offspring. J. Toxicol. Environ. Health Part A. 2015;78:635–644. doi: 10.1080/15287394.2015.1006711. PubMed DOI

Degen G.H., Janning P., Diel P., Michna H., Bolt H.M. Transplacental transfer of the phytoestrogen daidzein in DA/Han rats. Arch. Toxicol. 2002;76:23–29. doi: 10.1007/s00204-001-0305-7. PubMed DOI

Dinsdale E.C., Chen J., Ward W.E. Early life exposure to isoflavones adversely affects reproductive health in first but not second generation female CD-1 mice. J. Nutr. 2011;141:1996–2002. doi: 10.3945/jn.111.142281. PubMed DOI

Jefferson W.N., Patisaul H.B., Williams C.J. Reproductive consequences of developmental phytoestrogen exposure. Reproduction. 2012;143:247–260. doi: 10.1530/REP-11-0369. PubMed DOI PMC

Molzberger A.F., Vollmer G., Hertrampf T., Möller F.J., Kulling S., Diel P. In utero and postnatal exposure to isoflavones results in a reduced responsivity of the mammary gland towards estradiol. Mol. Nutr. Food Res. 2012;56:399–409. doi: 10.1002/mnfr.201100371. PubMed DOI

Kaludjerovic J., Chen J., Ward W.E. Early life exposure to genistein and daidzein disrupts structural development of reproductive organs in female mice. J. Toxicol. Environ. Health Part A. 2012;75:649–660. doi: 10.1080/15287394.2012.688482. PubMed DOI

Greathouse K.L., Bredfeldt T., Everitt J.I., Lin K., Berry T., Kannan K., Mittelstadt M.L., Ho S., Walker C.L. Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis. Mol. Cancer Res. 2012;10:546–557. doi: 10.1158/1541-7786.MCR-11-0605. PubMed DOI PMC

Piotrowska K., Baranowska-Bosiacka I., Marchlewicz M., Gutowska I., Noceń I., Zawiślak M., Chlubek D., Wiszniewska B. Changes in male reproductive system and mineral metabolism induced by soy isoflavones administered to rats from prenatal life until sexual maturity. Nutrition. 2011;27:372–379. doi: 10.1016/j.nut.2010.03.010. PubMed DOI

Wang W., Zhang W., Liu J., Sun Y., Li Y., Li H., Xiao S., Shen X. Metabolomic changes in follicular fluid induced by soy isoflavones administered to rats from weaning until sexual maturity. Toxicol. Appl. Pharmacol. 2013;269:280–289. doi: 10.1016/j.taap.2013.02.005. PubMed DOI

Fukaya T., Funayama Y., Muakami T., Sugawara J., Yajima A. Does apoptosis contribute follicular atresia and luteal regression in human ovary? Horm. Res. 1997;48(Suppl. 3):20–26. doi: 10.1159/000191296. PubMed DOI

Verdin E., Hirschey M.D., Finley L.W.S., Haigis M.C. Sirtuin regulation of mitochondria: Energy production, apoptosis, and signaling. Trends Biochem. Sci. 2010;35:669–675. doi: 10.1016/j.tibs.2010.07.003. PubMed DOI PMC

Rajah T.T., Peine K.J., Du N., Serret C.A., Drews N.R. Physiological concentrations of genistein and 17β-estradiol inhibit MDA-MB-231 breast cancer cell growth by increasing BAX/BCL-2 and reducing pERK1/2. Anticancer Res. 2012;32:1181–1191. PubMed

Tang S., Hu J., Meng Q., Dong X., Wang K., Qi Y., Chu C., Zhang X., Hou L. Daidzein induced apoptosis via down-regulation of Bcl-2/Bax and triggering of the mitochondrial pathway in BGC-823 cells. Cell Biochem. Biophys. 2013;65:197–202. doi: 10.1007/s12013-012-9418-2. PubMed DOI

Wang J., Xu J., Wang B., Shu F.R., Chen K., Mi M.T. Equol promotes rat osteoblast proliferation and differentiation through activating estrogen receptor. Genet. Mol. Res. 2014;13:5055–5063. doi: 10.4238/2014.July.4.21. PubMed DOI

Strom B.L., Schinnar R., Ziegler E.E., Barnhart K.T., Sammel M.D., Macones G.A., Stallings V.A., Drulis J.M., Nelson S.E., Hanson S.A. Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood. JAMA. 2001;286:807–814. doi: 10.1001/jama.286.7.807. PubMed DOI

Churella H.R., Borschel M.W., Thomas M.R., Breen M., Jacobs J. Growth and protein status of term infants fed soy protein formulas differing in protein content. J. Am. Coll. Nutr. 1994;13:262–267. doi: 10.1080/07315724.1994.10718407. PubMed DOI

Lasekan J.B., Ostrom K.M., Jacobs J.R., Blatter M.M., Ndife L.I., Gooch W.M., Cho S. Growth of newborn, term infants fed soy formulas for 1 year. Clin. Pediatr. 1999;38:563–571. doi: 10.1177/000992289903801001. PubMed DOI

Gilchrist J.M., Moore M.B., Andres A., Estroff J.A., Badger T.M. Ultrasonographic patterns of reproductive organs in infants fed soy formula: Comparisons to infants fed breast milk and milk formula. J. Pediatr. 2010;156:215–220. doi: 10.1016/j.jpeds.2009.08.043. PubMed DOI

Raman D.R., Williams E.L., Layton A.C., Burns R.T., Easter J.P., Daugherty A.S., Mullen M.D., Sayler G.S. Estrogen content of dairy and swine wastes. Environ. Sci. Technol. 2004;38:3567–3573. doi: 10.1021/es0353208. PubMed DOI

Hutchins S.R., White M.V., Hudson F.M., Fine D.D. Analysis of lagoon samples from different concentrated animal feeding operations for estrogens and estrogen conjugates. Environ. Sci. Technol. 2007;41:738–744. doi: 10.1021/es062234+. PubMed DOI

Dragomirescu A., Andoni M., Craina M. Endocrine disrupting compounds in environment—A review. J. Food. Agric. Environ. 2015;13:117–119. doi: 10.1234/4.2015.3904. DOI

Hoerger C.C., Wettstein F.E., Bachmann H.J., Hungerbühler K., Bucheli T.D. Occurrence and Mass Balance of Isoflavones on an Experimental Grassland Field. Environ. Sci. Technol. 2011;45:6752–6760. doi: 10.1021/es200567b. PubMed DOI

Hoerger C.C., Wettstein F.E., Hungerbühler K., Bucheli T.D. Occurrence and Origin of Estrogenic Isoflavones in Swiss River Waters. Environ. Sci. Technol. 2009;43:6151–6157. doi: 10.1021/es901034u. PubMed DOI

Kuster M., Azevedo D.A., López de Alda M.J., Aquino Neto F.R., Barceló D. Analysis of phytoestrogens, progestogens and estrogens in environmental waters from Rio de Janeiro (Brazil) Environ. Int. 2009;35:997–1003. doi: 10.1016/j.envint.2009.04.006. PubMed DOI

In Vitro Antibacterial Effect of the Methanolic Extract of the Korean Soybean Fermented Product Doenjang against Staphylococcus aureus

Production of Bovine Equol-Enriched Milk: A Review