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Phytoestrogens and Prostate Disease¹

H. Adlercreutz², W. Mazur, P. Bartels, V.-V. Elomaa, S. Watanabe^*, K. Wähälä, M. Landström^**, E. Lundin^**,, A. Bergh^**, J.-E. Damber, P. Åman, A. Widmark, A. Johansson, J.-X. Zhang and G. Hallmans

Institute for Preventive Medicine, Nutrition and Cancer, Fokhälsan Research Center and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland; ^* Tokyo University of Agriculture, Tokyo, Japan; Department of Chemistry, University of Helsinki, Helsinki, Finland; ^** Departments of Pathology, Nutritional Research, Urology and Andrology, and Oncology, University of Umeå, Umeå, Sweden; and Department of Food Science, Swedish University of Agricultural Sciences, Uppsala, Sweden.

²To whom correspondence should be addressed.

	INTRODUCTION

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The mortality in prostate cancer is high in the Western world compared with countries in Asia, such as Japan, despite a similar incidence of latent and small or noninfiltrative prostate carcinomas (Le Marchand et al. 1994 , Severson et al. 1989 , Yatani et al. 1982 ). An abundance of animal fat and beef in the diet appears to be associated with increased risk for prostate cancer. Despite high fat intake, the prostate cancer incidence in Finland is lower than that in the United States but much higher than that in Japan. Because prostate cancer is hormone dependent, on the basis of studies in Japan, we hypothesized in 1985 that the diet in countries with low prostate cancer risk may contain higher amounts of cancer-protective compounds, such as phytoestrogens (lignans and isoflavonoids), affecting hormone metabolism or action (Adlercreutz 1990 ). Lignans occur in whole-grain bread, various seeds, berries, vegetables and tea; isoflavonoids occur mainly in soy beans and soy products. However, the mammalian lignan precursor secoisolariciresinol occurs also in significant amounts in soy beans (13–273 µg/100 g dry weight) and soy milk or drinks (10–20 µg/100 g).

Assaying lignans and isoflavonoids in urine by gas chromatography-mass spectrometry revealed very high total excretion in Japanese subjects consuming a traditional diet, intermediate levels in Finland, and low levels in the United States (Adlercreutz et al. 1995 ). However, the pattern was very different. Because of high soy intake, the Japanese subjects had 5–100 times higher levels of isoflavonoids (genistein, daidzein, and their metabolites) than did subjects living in the other countries; in Finland, the urinary excretion of lignans dominated, and was higher than that in both Japanese and American subjects.

In human prostate cancer cell studies, genistein and its precursor biochanin A inhibit cell growth at relatively high concentrations (Peterson and Barnes 1993 ). We have confirmed these effects on human prostate cancer cells in culture and have extended the studies to three different cell lines (LNCaP, DU-145 and PC-3) and to a number of other isoflavones, lignans and flavones, measuring also prostatic specific antigen both intracellularly and extracellularly. We found that some metabolites are even more active than the original soy isoflavones.

It is of interest that enterolactone is a normal, relatively abundant constituent of human semen and prostatic fluid (Morton et al. 1997 ). In rat experiments, soy in the diet prevented prostatitis in the rats for (Sharma et al. 1992 ).

Neonatal estrogenization of male mice by using diethylstilbestrol results in the development of dysplastic changes in the prostate, including lesions resembling prostatic intraperitoneal neoplasia in human prostates. At the age of 9 mo, 8 of 10 animals fed a soy-free diet showed severe dysplastic changes, but in a group receiving soy-containing diet, only 3 of 10 animals had severe dysplasia. This may be an antiestrogenic effect (Mäkelä et al. 1995 ).

In collaboration with Hallmans and co-workers at the University of Umeå, we conducted a series of experiments investigating the effect of dietary soy and rye bran on implanted rat or human prostate cancer in rats (Landström et al. 1998 ) and nude mice (unpublished), respectively. In the rat experiments Copenhagen Fisher F1 rats with transplanted R3327-PAP prostate tumors were used; the athymic nude BALB/cBom mice had transplanted androgen-sensitive human prostate cancer LNCaP cells. In the first rat experiment (25 rats/group), a significant delay of growth of the transplanted tumors was observed when the rats were fed either soy or rye bran (33% of the diet). Heating the rye bran did not affect the results. The rye bran diet caused a ninefold increase in the excretion of the lignan enterolactone, and a much greater amount of lignans was recovered in urine (280–450%) than expected on the basis of assays of the precursors matairesinol and secoisolariciresinol in the food. Only 1–13% of the dietary genistein and 11–28% of the daidzein were recovered in urine. In the experiment in nude mice, both soy and rye bran caused increased apoptosis of the tumors and inhibition of tumor growth. Combining the rye bran with a high fat diet abolished the effects.

The association of androgens with prostate cancer has long been known, but the role of the estrogens in prostate cancer development remains a controversial matter. Treatment of prostate cancer with estrogens results in inhibition of cancer growth, but estrogens have also been shown to be associated with growth of both benign prostatic hyperplasia and prostate cancer. On the other hand, Japanese subjects have lower prostate weights than do Western men at similar ages. Theoretically, dietary estrogens could therefore be both beneficial and deleterious with regard to prostate disease. However, it is possible that the beneficial effects of these compounds on prostate disease are mediated via mechanisms not involving the estrogen receptor. The possible mechanisms that could be involved are inhibition of tyrosine and other protein kinases, 3ß-hydroxysteroid dehydrogenase, 17ß-hydroxysteroid dehydrogenase, 5-reductase and aromatase. All of these effects have been demonstrated for phytoestrogens (Adlercreutz 1995 , Evans et al. 1995 ). It is concluded that dietary phytoestrogens are strong candidates for a role as protective compounds with regard to prostate diseases.

	FOOTNOTES

 
¹ Presented at the Third International Symposium on the Role of Soy in Preventing and Treating Chronic Disease, held in Washington, D.C., October 31–November 3, 1999. The symposium was sponsored by Archer Daniels Midland Co., Cargill Inc.-Protein Products, Central Soya, Co., Dr. Chung’s Food Company, Monsanto, Personal Care Products Company, Protein Technologies International, SoGood Int., Solbar Plant Extracts, SoyLife/Schouten, Whitehall-Robins Healthcare, the United Soybean Board and the following State Soybean Associations: Illinois Soybean Board, Indiana Soybean Board, Kentucky Soybean Promotion Board, Michigan Soybean Promotion Committee, Minnesota Soybean Research and Promotion Council, Nebraska Soybean Board, Ohio Soybean Council, South Dakota Soybean Research and Promotion Council. Publication of symposium proceedings was supported by educational grants from the United Soybean Board and the Soyfoods Association of North America. Guest Editor for this symposium was Mark Messina, Nutrition Matters, Inc., Port Townsend, WA.

	REFERENCES

TOP INTRODUCTION REFERENCES

 

1. Adlercreutz C.H.T., Goldin B. R., Gorbach S. L., Höckerstedt K.A.V., Watanabe S., Hämäläinen E. K., Markkanen M. H., Mäkelä T., H W|$$|, Adahälä K. T., Hase T. A., Fotsis T. Soybean phytoestrogen intake and cancer risk. J. Nutr. 1995;125:S757-S770

2. Adlercreutz H. Western diet and Western diseases: some hormonal and biochemical mechanisms and associations. Scand. J. Clin. Lab. Investig. 1990;50(suppl. 20):13-23

3. Adlercreutz H. Phytoestrogens: epidemiology and a possible role in cancer protection. Environ. Health Perspect. 1995;103:103-112

4. Evans B.A.J., Griffiths K., Morton M. S. Inhibition of 5-reductase in genital skin fibroblasts and prostate tissue by dietary lignans and isoflavonoids. J. Endocrinol. 1995;147:295-302[Abstract/Free Full Text]

5. Landström M., Zhang J. X., Hallmans G., Aman P., Bergh A., Damber J.-E., Mazur W., Wähälä K., Adlercreutz H. Inhibitory effects of soy and rye diets on the development of Dunning R3327 prostate adenocarcinoma in rats. Prostate 1998;36:151-161[Medline]

6. Le Marchand L., Kolonel L. N., Wilkens L. R., Myers B. C., Hirohata T. Animal fat consumption and prostate cancer—a prospective study in Hawaii. Epidemiology 1994;5:276-282[Medline]

7. Mäkelä S. I., Pylkkänen L. H., Santti R. S., Adlercreutz H. Dietary soybean may be antiestrogenic in male mice. J. Nutr. 1995;125:437-445

8. Morton M. S., Chan P. S. F., Cheng C., Blacklock N., Matosferreira A., Abranchesmonteiro L., Correia R., Lloyd S., Griffiths K. Lignans and isoflavonoids in plasma and prostatic fluid in men: samples from Portugal, Hong Kong, and the United Kingdom. Prostate 1997;32:122-128[Medline]

9. Peterson G., Barnes S. Genistein and biochanin-A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation. Prostate 1993;22:335-345[Medline]

10. Severson R. K., Nomura A.M.Y., Grove J. S., Stemmerman G. N. A prospective study of demographics and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Res 1989;49:1857-1860[Abstract/Free Full Text]

11. Sharma O. P., Adlercreutz H., Strandberg J. D., Zirkin B. R., Coffey D. S., Ewing L. L. Soy of dietary source plays a preventive role against pathogenesis of prostatitis in rats. J. Steroid Biochem. Mol. Biol. 1992;43:557-564[Medline]

12. Yatani R., Chigusa I., Akazaki K., Stemmerman G. N., Welsh R. A., Correa P. Geographic pathology of latent prostatic cancer. Int. J. Cancer 1982;29:611-616[Medline]

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