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Phyto-oestrogens and osteoporosis: what is a safe dose?

  • Stephen Barnes (a1)


Hormone replacement therapy (HRT) for preventing loss of bone following the menopause is utilised by only 8–10% of possible users, largely due to a fear of increased risk of breast cancer. Plant oestrogen-like compounds (phyto-oestrogens) have been proposed as an alternative to HRT to prevent osteoporosis. One class of phyto-oestrogens (the isoflavones) is found in soya foods and red clover. The food industry is developing a wide variety of new foods containing soya to substantially increase isoflavone intake, as well as extracting isoflavones from soya and clover to use as additives to non-soya foods. Pharmaceutical companies are also preparing isoflavone extracts to be used in pill form. In each case the targeted delivery is ˜50mg of isoflavones/d. Is this dose of isoflavones safe? In this review of the current literature, it is concluded that isoflavones consumed orally and in doses below 2mg/kg body weight per d should be considered safe for most population groups. Whether these doses are sufficient to prevent osteoporosis is a separate matter.

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Corresponding author

*Corresponding author: Dr S. Barnes, fax + 1 205 934 6944, email


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Adlercreutz, H, Markkanen, H & Watanabe, S (1993) Plasma concentrations of phyto-oestrogens in Japanese men. Lancet 342, 12091210.
Akiyama, T, Ishida, J, Nakagawa, S, Ogawara, H, Watanabe, S, Itoh, N, Shibuya, M & Fukami, Y (1987) Genistein, a specific inhibitor of tyrosine-specific protein kinases. Journal of Biological Chemistry 262, 55925595.
Alexandersen, P, Toussaint, A, Christiansen, C, Devogelaer, JP, Roux, C, Fechtenbaum, J, Gennari, C & Reginster, JY (2001) Ipriflavone in the treatment of postmenopausal osteoporosis — a randomized controlled trial. Journal of the American Medical Association 285, 14821488.
Allred, CD, Allred, KF, Ju, YH, Virant, SM & Helferich, WG (2001 a) Soy diets containing varying amounts of genistein stimulate growth of oestrogen-dependent (MCF-7) tumors in a dose-dependent manner. Cancer Research 61, 50455050.
Allred, CD, Ju, YH, Allred, KF, Chang, J & Helferich, WG (2001 b) Dietary genistin stimulates growth of oestrogen-dependent breast cancer tumors similar to that observed with genistein. Carcinogenesis 22, 16671673.
Asthana, S, Baker, LD, Craft, S, Stanczyk, FZ, Veith, RC, Raskind, MA & Plymate, SR (2001) High-dose estradiol improves cognition for women with AD: results of a randomized study. Neurology 57, 605612.
Barnes, S (1997) The chemopreventive properties of soy isoflavonoids in animal models of breast cancer. Breast Cancer Research and Treatment 46, 169179.
Barnes, S (1998) Evolution of the history of soy and genistein. Proceedings of the Society for Experimental Biology and Medicine 217, 386392.
Barnes, S (2001) Oestrogens and their promiscuous receptors: con-fronting reality. Biochemical Society Transactions 29, 231236.
Barnes, S, Grubbs, C, Setchell, KDR & Carlson, J (1990) Soybeans inhibit mammary tumors in models of breast cancer. Progress in Clinical and Biological Research 347, 239253.
Barnes, S, Grubbs, C, Smith, M, Kirk, M & Lubet, R (2002) Greater renal clearance of daidzein and genistein accounts for the accumulation of equol in blood of soy-fed rats. Journal of Nutrition 132, 618S619S.
Barnes, S, Kim, H, Peterson, TG & Xu, J (1999) Isoflavones and cancer: the oestrogen paradox. Korean Soybean Digest 15, 8193.
Bayer, T, Colnot, T & Dekant, W (2001) Disposition and biotrans-formation of the oestrogenic isoflavone daidzein in rats. Toxicological Sciences 62, 205211.
Bennetts, HW, Underwood, EJ & Shier, FL (1946) A specific breeding problem of sheep on subterranean clover pasture I. Western Australia. Australian Veterinary Journal 22, 212.
Bieber, EJ & Barnes, RB (2001) Breast cancer and HRT — what are the data? International Journal of Fertility and Women's Medicine 46, 7378.
Boersma, B, Barnes, S, Kirk, M, Wang, C-C, Smith, M, Kim, H, Xu, J, Patel, R & Darley-Usmar, VM (2001) Soy isoflavonoids and cancer — metabolism at the target site. Mutation Research 480, 121127.
Bradbury, RB & White, DE (1951) The chemistry of subterranean clover. Part 1. Isolation of formononetin and genistein. Journal of the Chemical Society 34473449.
Brown, NM & Lamartiniere, CA (1995) Xeno-oestrogens alter mammary gland differentiation and cell proliferation in the rat. Environmental Health Perspectives 103, 708713.
Brown, NM & Setchell, KDR (2001) Animal models impacted by phyto-oestrogens in commercial chow: implications for path-ways influenced by hormones. Laboratory Investigation 81, 735747.
Busby, MG, Jeffcoat, AR, Bloedon, LT, Koch, MA, Black, T, Dix, KJ, Heizer, WD, Thomas, BF, Hill, JM, Crowell, JA & Zeisel, SH (2002) Clinical characteristics and pharmacokinetics of purified soy isoflavones: single-dose administration to healthy men. American Journal of Clinical Nutrition 75, 126136.
Casanova, M, You, L, Gaido, KW, Archibeque-Engle, S, Janszen, DB & Heck, HA (1999) Developmental effects of dietary phyto-oestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat oestrogen receptors alpha and beta in vitro. Toxicological Sciences 51, 236244.
Chang, HC & Doerge, DR (2000) Dietary genistein inactivates rat thyroid peroxidase in vivo without an apparent hypothyroid effect. Toxicology and Applied Pharmacology 168, 244252.
Chen, Z, Zheng, W, Custer, LJ, Dai, Q, Shu, XO, Jin, F & Franke, AA (1999) Usual dietary consumption of soy foods and its correlation with the excretion rate of isoflavonoids in overnight urine samples among Chinese women in Shanghai. Nutrition and Cancer 33, 8287.
Chin-Dusting, JP, Fisher, LJ, Lewis, TV, Piekarska, A, Nestel, PJ & Husband, A (2001) The vascular activity of some isoflavone metabolites: implications for a cardioprotective role. British Journal of Pharmacology 133, 595605.
Cohen, LA, Zhao, Z, Pittman, B & Scimeca, JA (2000) Effect of intact and isoflavone-depleted soy protein on NMU-induced rat mammary tumorigenesis. Carcinogenesis 21, 929935.
Coldham, NG, Howells, LC, Santi, A, Montesissa, C, Langlais, C, King, LJ, Macpherson, DD & Sauer, MJ (1999) Biotransformation of genistein in the rat: elucidation of metabolite structure by product ion mass fragmentology. Journal of Steroid Biochemistry and Molecular Biology 70, 169184.
Colditz, GA & Frazier, AL (1995) Models of breast cancer show that risk is set by events of early life: prevention efforts must shift focus. Cancer Epidemiology, Biomarkers & Prevention 4, 567571.
Coward, L, Kirk, M, Albin, N & Barnes, S (1996) Analysis of plasma isoflavones by reversed-phase HPLC-multiple reaction ion monitoring-mass spectrometry. Clinica Chimica Acta 247, 121142.
Davis, JN, Singh, B, Bhuiyan, M & Sarkar, FH (1998) Genistein-induced upregulation of p21WAFl, downregulation of cyclin B, and induction of apoptosis in prostate cancer cells. Nutrition and Cancer 32, 123131.
Day, AJ, Canada, FJ, Diaz, JC, Kroon, PA, Mclauchlan, R, Faulds, CB, Plumb, GW, Morgan, MRA & Williamson, G (2000) Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase. FEBS Letters 468, 166170.
Diel, P, Schulz, T, Smolnikar, K, Strunck, E, Vollmer, G & Michna, H (2000) Ability of xeno- and phyto-oestrogens to modulate expression of oestrogen-sensitive genes in rat Phyto-oestrogens and safety issues uterus: oestrogenicity profiles and uterotropic activity. Journal of Steroid Biochemistry and Molecular Biology 73, 110.
Diel, P, Smolnikar, K, Schulz, T, Laudenbach-Leschowski, U, Michna, H & Vollmer, G (2001) Phyto-oestrogens and carcino-genesis-differential effects of genistein in experimental models of normal and malignant rat endometrium. Human Reproduction 16, 9971006.
Divi, RL, Chang, HC & Doerge, DR (1997) Anti-thyroid isoflavones from soybean: isolation, characterization, and mechanisms of action. Biochemical Pharmacology 54, 10871096.
Divi, RL & Doerge, DR (1996) Inhibition of thyroid peroxidase by dietary flavonoids. Chemical Research in Toxicology 9, 1623.
File, SE, Jarrett, N, Fluck, E, Duffy, R, Casey, K & Wiseman, H (2001) Eating soya improves human memory. Psychopharmacology 157, 430436.
Fitzpatrick, M (2000) Soy formulas and the effects of isoflavones on the thyroid. New Zealand Medical Journal 113, 2426.
Fritz, WA, Coward, L, Wang, J & Lamartiniere, CA (1998) Dietary genistein: perinatal mammary cancer prevention, bioavailability and toxicity testing in the rat. Carcinogenesis 19, 21512158.
Gallo, D, Cantelmo, F, Distefano, M, Ferlini, C, Zannoni, GF, Riva, A, Morazzoni, P, Bombardelli, E, Mancuso, S & Scambia, G (1999) Reproductive effects of dietary soy in female Wistar rats. Food and Chemical Toxicology 37, 493502.
Gotoh, T, Yamada, K, Yin, H, Ito, A, Kataoka, T & Dohi, K (1998) Chemoprevention of N-nitroso-N-methylurea-induced rat mam-mary carcinogenesis by soy foods or biochanin A. Japanese Journal of Cancer Research 89, 137142.
Hawrylewicz, EJ, Zapata, JJ & Blair, WH (1995) Soy and experi-mental cancer: animal studies. Journal of Nutrition 12, Suppl. 3, 698S708S.
Horn-Ross, PL, Hoggatt, KJ & Lee, M (2002) Phyto-oestrogens and thyroid cancer risk. Journal of Nutrition, in press.
Hsieh, CY, Santell, RC, Haslam, SZ & Helferich, WG (1998) Oestrogenic effects of genistein on the growth of oestrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Research 58, 38333838.
Hwang, J, Sevanian, A, Hodis, HN & Ursini, F (2000) Synergistic inhibition of LDL oxidation by phyto-oestrogens and ascorbic acid. Free Radical Biology and Medicine 29, 7989.
Hymowitz, T (1990) Soybeans: the success story. In Advances in New Crops, pp. 159163 [Janick, J and Simon, JE, editors]. Portland, OR: Timber Press.
Jolleys, JV & Olesen, F (1996) A comparative study of prescribing of hormone replacement therapy in USA and Europe. Maturitas 23, 4753.
Jorgensen, M, Vendelbo, B, Skakkebaek, NE & Leffers, H (2000) Assaying oestrogenicity by quantitating the expression levels of endogenous oestrogen-regulated genes. Environmental Health Perspectives 108, 403412.
Ju, YH, Allred, CD, Allred, KF, Karko, KL, Doerge, DR & Helferich, WG (2001) Physiological concentrations of dietary genistein dose-dependently stimulate growth of oestrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice. Journal of Nutrition 131, 29572962.
Kim, H, Xia, H, Li, L & Gewin, J (2000) Attenuation of neurode-generation-relevant modifications of brain proteins by dietary soy. Biofactors 12, 243250.
Kimira, M, Arai, Y, Shimoi, K & Watanabe, S (1998) Japanese intake of flavonoids and isoflavonoids from foods. Journal of Epidemiology 8, 168175.
Klein, KO (1998) Isoflavones, soy-based infant formulas, and relevance to endocrine function. Nutrition Reviews 56, 193204.
Kuiper, GG, Carlsson, B, Grandien, K, Enmark, E, Haggblad, J, Nilsson, S & Gustafsson, JA (1997) Comparison of the ligand binding specificity and transcript tissue distribution of oestrogen receptors alpha and beta. Endocrinology 138, 863870.
Kulling, SE, Rosenberg, B, Jacobs, E & Metzler, M (1999) The phyto-oestrogens coumestrol and genistein induce structural chromosomal aberrations in cultured human peripheral blood lymphocytes. Archives of Toxicology 73, 5054.
Lamartiniere, CA, Moore, JB, Brown, NM, Thompson, R, Hardin, MJ & Barnes, S (1995) Genistein suppresses mammary cancer in rats. Carcinogenesis 16, 28332840.
Leopold, AS, Erwin, M, Oh, J & Browning, B (1976) Phyto-oestrogens: adverse effects on reproduction in California quail. Science 191, 98100.
Mant, JWF & Vessey, MP (1994) Ovarian and endometrial cancers. In Cancer Surveys — Trends in Cancer Incidence and Mortality, pp. 287307 [Doll, R, Fraumeni, JF Jr and Muir, CS, editors]. Plainville, NY: Cold Spring Harbor Laboratory Press.
Messina, M (1995) Isoflavone intakes by Japanese were overestimated. American Journal of Clinical Nutrition 62, 645.
Messina, MJ & Loprinzi, CL (2001) Soy for breast cancer survivors: a critical review of the literature. Journal of Nutrition 131, Suppl. 11, 3095S3108S.
Messina, MJ, Persky, V, Setchell, KD & Barnes, S (1994) Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutrition and Cancer 21, 113131.
Naciff, JM, Jump, ML, Torontali, SM, Carr, GJ, Tiesman, JP, Overmann, GJ & Daston, GP (2002) Gene expression profile induced by 17α-ethinyl estradiol, bisphenol A, and genistein in the developing female reproductive system of the rat. Toxicological Sciences 68, 184199.
Nakamura, Y, Tsuji, S & Tonogai, Y (2000) Determination of the levels of isoflavonoids in soybeans and soy-derived foods and estimation of isoflavonoids in the Japanese daily intake. Journal of AOAC International 83, 635650.
Nevton, CJ, Samuel, DL & James, VHT (1986) Aromatase activity and concentrations of cortisol, progesterone and testosterone in breast and abdominal adipose tissue. Journal of Steroid Biochemistry 24, 10331039.
Newbold, RR, Banks, EP, Bullock, B & Jefferson, WN (2001) Uterine adenocarcinoma in mice treated neonatally with genistein. Cancer Research 61, 43254328.
Pagliacci, MC, Smacchia, M, Migliorati, G, Grignani, F, Riccardi, C & Nicoletti, I (1994) Growth-inhibitory effects of the natural phyto-oestrogen genistein in MCF-7 human breast cancer cells. European Journal of Cancer 30A, 16751682.
Pan, Y, Anthony, M & Clarkson, TB (1999) Evidence for upregulation of brain-derived neurotrophic factor mRNA by soy phyto-oestrogens in the frontal cortex of retired breeder female rats. Neuroscience Letters 261, 1720.
Patel, RP, Boersma, B, Crawford, JH, Hogg, N, Kirk, M, Kalyanaraman, B, Parks, D, Barnes, S & Darley-Usmar, V (2001 a) Antioxidant mechanisms of isoflavones in lipid systems: paradoxical effects of peroxyl radical scavenging. Free Radical Biology and Medicine 31, 15701581.
Patel, RP, Chandler, RT, Kevil, CG, Kucik, D, Boersma, B, Barnes, S & Darley-Usmar, V (2001 b) Anti-inflammatory effects of soyisoflavones: inhibition of leukocyte–endothelial interactions. Free Radical Biology and Medicine 31, Suppl. 1, S35.
Pike, AC, Brzozowski, AM, Hubbard, RE, Bonn, T, Thorsell, AG, Engstrom, O, Ljunggren, J, Gustafsson, JA & Carlquist, M (1999) Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO Journal 18, 46084618.
Polednak, AP (1994) Projected numbers of cancers diagnosed in the US elderly population, 1990 through 2030. American Journal of Public Health 84, 13131316.
Reid, IR (1999) Pharmacological management of osteoporosis in postmenopausal women: a comparative review. Drugs and Aging 15, 349363.
Riggs, BL & Melton, LJ III (1995) The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone 17, Suppl. 5, 505S511S.
Ross, RK, Paganini-Hill, A, Wan, PC & Pike, MC (2000) Effect of hormone replacement therapy on breast cancer risk: oestrogen versus oestrogen plus progestin. Journal of the National Cancer Institute 92, 328332.
Sambrook, P, Kelly, P & Eisman, J (1993) Bone mass and ageing. Bailliére's Clinical Rheumatology 7, 445457.
Scheiber, MD & Rebar, RW (1999) Isoflavones and postmenopausal bone health: a viable alternative to oestrogen therapy? Menopause 6, 233241.
Setchell, KD, Brown, NM, Desai, P, Zimmer-Nechemias, L, Wolfe, BE, Brashear, WT, Kirschner, AS, Cassidy, A & Heubi, JE (2001) Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. Journal of Nutrition 131, Suppl. 4, 1362S1375S.
Setchell, KD, Gosselin, SJ, Welsh, MB, Johnston, JO, Balistreri, WF, Kramer, LW, Dresser, BL & Tarr, MJ (1987) Dietary oestrogens — a probable cause of infertility and liver disease in captive cheetahs. Gastroenterology 93, 225233.
Setchell, KD, Zimmer-Nechemias, L, Cai, J & Heubi, JE (1997) Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet 350, 2327.
Shao, ZM, Wu, J, Shen, ZZ & Barsky, SH (1998) Genistein inhibits both constitutive and EGF-stimulated invasion in ER-negative human breast carcinoma cell lines. Anticancer Research 18, 14351439.
Shimizu, H, Ross, RK, Bernstein, L, Yatani, R, Henderson, BE & Mack, TM (1991) Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. British Journal of Cancer 63, 963966.
Shutt, DA & Braden, AWH (1968) The significance of equol in relation to the oestrogenic responses in sheep ingesting clover with a high formononetin content. Australian Journal of Agricultural Research 19, 545553.
Strom, BL, Schinnar, R, Ziegler, EE, Barnhart, KT, Sammel, MD, Macones, GA, Stallings, VA, Drulis, JM, Nelson, SE & Hanson, SA (2001) Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood. Journal of the American Medical Association 286, 807814.
Uehara, M, Arai, Y, Watanabe, S & Adlercreutz, H (2000) Comparison of plasma and urinary phyto-oestrogens in Japanese and Finnish women by time-resolved fluoroimmunoassay. Biofactors 12, 217225.
Urban, D, Irwin, W, Kirk, M, Markiewicz, MA, Myers, R, Smith, M, Weiss, H, Grizzle, WE & Barnes, S (2001) The effect of isolated soy protein on plasma biomarkers in elderly men with elevated serum prostate specific antigen. Journal of Urology 165, 294300.
Wakai, K, Egami, I, Kato, K, Kawamura, T, Tamakoshi, A, Lin, Y, Nakayama, T, Wada, M & Ohno, Y (1999) Dietary intake and sources of isoflavones among Japanese. Nutrition and Cancer 33, 139145.
White, LR, Petrovitch, H, Ross, GW, Masaki, K, Hardman, J, Nelson, J, Davis, D & Markesbery, W (2000) Brain aging and midlife tofu consumption. Journal of the American College of Nutrition 19, 242255.
Willard, ST & Frawley, LS (1998) Phyto-oestrogens have agonistic and combinatorial effects on oestrogen-responsive gene expression in MCF-7 human breast cancer cells. Endocrine 8, 117121.


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Phyto-oestrogens and osteoporosis: what is a safe dose?

  • Stephen Barnes (a1)


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