Hostname: page-component-cd9895bd7-dk4vv Total loading time: 0 Render date: 2024-12-23T05:05:05.682Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  26 October 2011

Stephen Barnes
Stephen Barnes*
Affiliation:
Department of Pharmacology & Toxicology, and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
*
*Corresponding author: Dr S. Barnes, fax + 1 205 934 6944, email sbarnes@uab.edu
Rights & Permissions [Opens in a new window]

Extract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

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.

Keywords

Phyto-oestrogensIsoflavonesBlood levelsMechanisms
Type
Research Article
Information
British Journal of Nutrition , Volume 89 , Issue S1: Effects of Phyto-oestrogens on Bone Health: the VENUS Concerted Action , June 2003 , pp. S101 - S108
Copyright
Copyright © The Nutrition Society 2003

References

Adlercreutz, H, Markkanen, H & Watanabe, S (1993) Plasma concentrations of phyto-oestrogens in Japanese men. Lancet 342, 1209–1210.CrossRefGoogle ScholarPubMed
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, 5592–5595.CrossRefGoogle ScholarPubMed
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, 1482–1488.CrossRefGoogle ScholarPubMed
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, 5045–5050.Google Scholar
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, 1667–1673.CrossRefGoogle Scholar
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, 605–612.CrossRefGoogle ScholarPubMed
Barnes, S (1997) The chemopreventive properties of soy isoflavonoids in animal models of breast cancer. Breast Cancer Research and Treatment 46, 169–179.CrossRefGoogle ScholarPubMed
Barnes, S (1998) Evolution of the history of soy and genistein. Proceedings of the Society for Experimental Biology and Medicine 217, 386–392.CrossRefGoogle Scholar
Barnes, S (2001) Oestrogens and their promiscuous receptors: con-fronting reality. Biochemical Society Transactions 29, 231–236.CrossRefGoogle ScholarPubMed
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, 239–253.Google ScholarPubMed
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, 618S–619S.Google Scholar
Barnes, S, Kim, H, Peterson, TG & Xu, J (1999) Isoflavones and cancer: the oestrogen paradox. Korean Soybean Digest 15, 81–93.Google Scholar
Bayer, T, Colnot, T & Dekant, W (2001) Disposition and biotrans-formation of the oestrogenic isoflavone daidzein in rats. Toxicological Sciences 62, 205–211.CrossRefGoogle Scholar
Bennetts, HW, Underwood, EJ & Shier, FL (1946) A specific breeding problem of sheep on subterranean clover pasture I. Western Australia. Australian Veterinary Journal 22, 2–12.CrossRefGoogle ScholarPubMed
Bieber, EJ & Barnes, RB (2001) Breast cancer and HRT — what are the data? International Journal of Fertility and Women's Medicine 46, 73–78.Google ScholarPubMed
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, 121–127.CrossRefGoogle ScholarPubMed
Bradbury, RB & White, DE (1951) The chemistry of subterranean clover. Part 1. Isolation of formononetin and genistein. Journal of the Chemical Society 3447–3449.CrossRefGoogle Scholar
Brown, NM & Lamartiniere, CA (1995) Xeno-oestrogens alter mammary gland differentiation and cell proliferation in the rat. Environmental Health Perspectives 103, 708–713.Google Scholar
Brown, NM & Setchell, KDR (2001) Animal models impacted by phyto-oestrogens in commercial chow: implications for path-ways influenced by hormones. Laboratory Investigation 81, 735–747.CrossRefGoogle Scholar
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, 126–136.CrossRefGoogle ScholarPubMed
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, 236–244.CrossRefGoogle ScholarPubMed
Chang, HC & Doerge, DR (2000) Dietary genistein inactivates rat thyroid peroxidase in vivo without an apparent hypothyroid effect. Toxicology and Applied Pharmacology 168, 244–252.CrossRefGoogle ScholarPubMed
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, 82–87.CrossRefGoogle ScholarPubMed
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, 595–605.CrossRefGoogle ScholarPubMed
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, 929–935.CrossRefGoogle ScholarPubMed
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, 169–184.CrossRefGoogle ScholarPubMed
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, 567–571.Google ScholarPubMed
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, 121–142.CrossRefGoogle ScholarPubMed
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, 123–131.CrossRefGoogle Scholar
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, 166–170.CrossRefGoogle ScholarPubMed
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, 1–10.CrossRefGoogle Scholar
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, 997–1006.CrossRefGoogle ScholarPubMed
Divi, RL, Chang, HC & Doerge, DR (1997) Anti-thyroid isoflavones from soybean: isolation, characterization, and mechanisms of action. Biochemical Pharmacology 54, 1087–1096.CrossRefGoogle ScholarPubMed
Divi, RL & Doerge, DR (1996) Inhibition of thyroid peroxidase by dietary flavonoids. Chemical Research in Toxicology 9, 16–23.CrossRefGoogle ScholarPubMed
File, SE, Jarrett, N, Fluck, E, Duffy, R, Casey, K & Wiseman, H (2001) Eating soya improves human memory. Psychopharmacology 157, 430–436.CrossRefGoogle ScholarPubMed
Fitzpatrick, M (2000) Soy formulas and the effects of isoflavones on the thyroid. New Zealand Medical Journal 113, 24–26.Google ScholarPubMed
Fritz, WA, Coward, L, Wang, J & Lamartiniere, CA (1998) Dietary genistein: perinatal mammary cancer prevention, bioavailability and toxicity testing in the rat. Carcinogenesis 19, 2151–2158.CrossRefGoogle ScholarPubMed
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, 493–502.CrossRefGoogle ScholarPubMed
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, 137–142.CrossRefGoogle ScholarPubMed
Hawrylewicz, EJ, Zapata, JJ & Blair, WH (1995) Soy and experi-mental cancer: animal studies. Journal of Nutrition 12, Suppl. 3, 698S–708S.Google Scholar
Horn-Ross, PL, Hoggatt, KJ & Lee, M (2002) Phyto-oestrogens and thyroid cancer risk. Journal of Nutrition, in press.Google Scholar
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, 3833–3838.Google ScholarPubMed
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, 79–89.CrossRefGoogle ScholarPubMed
Hymowitz, T (1990) Soybeans: the success story. In Advances in New Crops, pp. 159–163 [Janick, J and Simon, JE, editors]. Portland, OR: Timber Press.Google Scholar
Jolleys, JV & Olesen, F (1996) A comparative study of prescribing of hormone replacement therapy in USA and Europe. Maturitas 23, 47–53.CrossRefGoogle ScholarPubMed
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, 403–412.Google Scholar
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, 2957–2962.CrossRefGoogle Scholar
Kim, H, Xia, H, Li, L & Gewin, J (2000) Attenuation of neurode-generation-relevant modifications of brain proteins by dietary soy. Biofactors 12, 243–250.CrossRefGoogle ScholarPubMed
Kimira, M, Arai, Y, Shimoi, K & Watanabe, S (1998) Japanese intake of flavonoids and isoflavonoids from foods. Journal of Epidemiology 8, 168–175.CrossRefGoogle ScholarPubMed
Klein, KO (1998) Isoflavones, soy-based infant formulas, and relevance to endocrine function. Nutrition Reviews 56, 193–204.CrossRefGoogle ScholarPubMed
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, 863–870.CrossRefGoogle ScholarPubMed
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, 50–54.CrossRefGoogle ScholarPubMed
Lamartiniere, CA, Moore, JB, Brown, NM, Thompson, R, Hardin, MJ & Barnes, S (1995) Genistein suppresses mammary cancer in rats. Carcinogenesis 16, 2833–2840.CrossRefGoogle ScholarPubMed
Leopold, AS, Erwin, M, Oh, J & Browning, B (1976) Phyto-oestrogens: adverse effects on reproduction in California quail. Science 191, 98–100.CrossRefGoogle ScholarPubMed
Mant, JWF & Vessey, MP (1994) Ovarian and endometrial cancers. In Cancer Surveys — Trends in Cancer Incidence and Mortality, pp. 287–307 [Doll, R, Fraumeni, JF Jr and Muir, CS, editors]. Plainville, NY: Cold Spring Harbor Laboratory Press.Google Scholar
Messina, M (1995) Isoflavone intakes by Japanese were overestimated. American Journal of Clinical Nutrition 62, 645.CrossRefGoogle ScholarPubMed
Messina, MJ & Loprinzi, CL (2001) Soy for breast cancer survivors: a critical review of the literature. Journal of Nutrition 131, Suppl. 11, 3095S–3108S.CrossRefGoogle Scholar
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, 113–131.CrossRefGoogle Scholar
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, 184–199.CrossRefGoogle ScholarPubMed
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, 635–650.CrossRefGoogle ScholarPubMed
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, 1033–1039.Google Scholar
Newbold, RR, Banks, EP, Bullock, B & Jefferson, WN (2001) Uterine adenocarcinoma in mice treated neonatally with genistein. Cancer Research 61, 4325–4328.Google ScholarPubMed
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, 1675–1682.CrossRefGoogle Scholar
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, 17–20.CrossRefGoogle ScholarPubMed
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, 1570–1581.CrossRefGoogle ScholarPubMed
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.Google Scholar
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, 4608–4618.CrossRefGoogle Scholar
Polednak, AP (1994) Projected numbers of cancers diagnosed in the US elderly population, 1990 through 2030. American Journal of Public Health 84, 1313–1316.CrossRefGoogle ScholarPubMed
Reid, IR (1999) Pharmacological management of osteoporosis in postmenopausal women: a comparative review. Drugs and Aging 15, 349–363.CrossRefGoogle ScholarPubMed
Riggs, BL & Melton, LJ III (1995) The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone 17, Suppl. 5, 505S–511S.CrossRefGoogle ScholarPubMed
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, 328–332.CrossRefGoogle ScholarPubMed
Sambrook, P, Kelly, P & Eisman, J (1993) Bone mass and ageing. Bailliére's Clinical Rheumatology 7, 445–457.CrossRefGoogle ScholarPubMed
Scheiber, MD & Rebar, RW (1999) Isoflavones and postmenopausal bone health: a viable alternative to oestrogen therapy? Menopause 6, 233–241.CrossRefGoogle Scholar
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, 1362S–1375S.CrossRefGoogle ScholarPubMed
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, 225–233.CrossRefGoogle ScholarPubMed
Setchell, KD, Zimmer-Nechemias, L, Cai, J & Heubi, JE (1997) Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet 350, 23–27.CrossRefGoogle ScholarPubMed
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, 1435–1439.Google ScholarPubMed
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, 963–966.CrossRefGoogle ScholarPubMed
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, 545–553.CrossRefGoogle Scholar
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, 807–814.CrossRefGoogle ScholarPubMed
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, 217–225.CrossRefGoogle Scholar
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, 294–300.CrossRefGoogle ScholarPubMed
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, 139–145.CrossRefGoogle ScholarPubMed
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, 242–255.CrossRefGoogle ScholarPubMed
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, 117–121.CrossRefGoogle Scholar