Summary and Conclusion

There are no known exogenous hormonal or non-hormonal exposures that are associated with prostate cancer risk, with the exception of "exposure" to a western life style (including a high fat diet), to an African American "environment", and, perhaps, to venereal disease, unknown factors related to farming, and employment in armed services and the nuclear industry. None of these associations point to specific chemicals, hormones, or other factors. In view of the high frequency of this malignancy in Western countries, this lack of known specific risk factors is remarkable and may indicate that there are many exogenous risk factors for prostate cancer which are too ubiquitous and overlapping to be detectable by epidemiologists. It is also possible that there are strong endogenous determinants of prostate cancer risk which are "overwhelming" most exogenous risk factors in epidemiological analyses. Androgenic hormones and androgen receptor mechanisms are prime candidates to be such important strong endogenous factors, but the epidemiological evidence for this is weak. There are some indications that muscle mass is positively correlated with risk, perhaps reflecting exposure to endogenous androgens or anabolic steroids. Elevation of bioavailable and bioactive androgens in the circulation and in the target tissue as an important risk factor is biologically highly plausible, and the results of several animal model studies strongly support this notion. Some of these experiments indicate that substantial enhancement of prostate carcinogenesis can be achieved by only very small elevations of circulating testosterone. This finding, if also valid for humans, may explain why the epidemiological associations between circulating androgen levels and prostate cancer are at best weak. There is also epidemiological evidence for increased transactivation activity of the androgen receptor to be associated with increased prostate cancer risk, both at the population and individual levels. However, more research is needed to confirm and further define these associations in humans, and to dissect further the biological mechanisms that underlie the increased risk that is probably associated with elevated circulating androgen levels and increased androgen receptor sensitivity.

African American men have a twofold higher risk than European American men, which is probably related to unknown environmental and genetic factors that may act though modifying their hormonal status. Indeed, circulating levels of androgens and, in men under 50 years, estrogens appear to be higher in African American men than in European American men. Such hormonal factors perhaps act as early as in utero, because circulating levels of androgens and estrogens have been reported to be higher in young men and pregnant African American women than in European American women.

Familial aggregation of prostate cancer risk is consistently observed and confers a considerable increased risk, but explains 10% or less of all cases. Putative susceptibility loci have been identified on chromosome 1q and the X chromosome, but there are no indications that these are related to hormonal factors. The role of hormones in familial aggregation of prostate cancer risk is unclear, since circulating testosterone levels appear to be lower in men with a family history of prostate cancer than in other men.

Hormonal stimulation of prostatic epithelial cell proliferation enhances the susceptibility of the rat prostate to chemical carcinogens. Testosterone at near-physiological plasma concentrations is a weak complete carcinogen and a strong tumor promotor for the rat prostate. The weak complete carcinogenic activity of androgens can perhaps be explained by their very strong tumor promoting activity. The precise mechanism of the tumor-inducing and -promoting activities of androgens for the rat prostate remains unknown. It is unlikely that chronic stimulation of prostatic cell proliferation rates by androgens is involved. However, it is conceivable that prostatic epithelial cells carrying critical genetic alterations have a selective growth advantage over normal cells and do not respond to androgens by differentiation, as normal cells would, but by proliferation.

Chronic exposure to testosterone plus 17^-estradiol is strongly carcinogenic for the dorsolateral prostate of some rat strains, while testosterone alone is only weakly carcinogenic. The mechanism of the carcinogenic effect of estrogen plus androgen in the rat prostate is incompletely understood, but it appears to in volve estrogen-generated oxidative stress and genotoxicity, in addition to androgen receptor- and estrogen receptor-mediated processes such as changes in sex steroid metabolism and receptor status. There is evidence for the presence of the enzyme aromatase in the human and rat prostate providing for a local source of estrogens, which in humans seems to increase in stromal cell activity with aging. Perinatal estrogen exposure is carcinogenic for the rodent male accessory sex glands. Hyperplastic and squamous metaplastic changes have been reported in human male genital tract tissues following prenatal DES exposure, suggesting that prenatal exposure to DES may also target the human prostate. The mechanisms of these prenatal estrogen effects are not clear but may involve permanently imprinted changes in hormone production and hormone sensitivity of prostatic tissues.

These observations lead to a multifactorial general hypothesis of prostate carcinogenesis in which androgens are strong tumor promotors acting via androgen receptor-mediated mechanisms to enhance the carcinogenic activity of endogenous genotoxic carcinogens, reactive estrogen metabolites, estrogen-and prostatitis-generated reactive oxygen species, and possibly unknown weak environmental carcinogens. In this concept, all of these processes are modulated by a variety of environmental factors such as diet and by genetic determinants such as hereditary susceptibility and polymorphic genes that encode for receptors and enzymes involved in the metabolism and action of steroid hormones. It is conceivable that environmental agents with hormonal activity are involved in prostate carcinogenesis, but their identity, role, and importance have not been defined.

Acknowledgement. This work was supported in part by NIH Grants No. CA58088 and CA 75293, and Center Grants No. CA13343 and ES 00260.

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