The Role of Sex Hormones in Prostate Cancer

Maarten C. Bosland

Departments of Environmental Medicine and Urology, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA E-mail: [email protected]

Prostate cancer is the most frequently diagnosed malignancy and second leading cause of cancer death in men in Western countries. Little is understood about its causes, but steroid hormones, particularly androgens, are suspected to play a major role. Human populations at high risk for prostate cancer may have slightly higher androgen production, circulating androgens, 5a-reductase activity, or androgen receptor transactivation activity than low-risk populations. Elevated circulating estrogens have been found in some high risk populations, such as African American men, suggesting estrogen involvement. Studies in rats have clearly demonstrated that testosterone is a weak complete carcinogen and a strong tumor promotor for the prostate, but the exact mechanisms of these activities are not clear. Treatment of rats with a combination of testosterone and 17^-estradiol can induce prostate cancer at high incidence, while androgens alone cause a low prostate cancer incidence, indicating involvement of estrogens as well. This effect may involve genotoxic activity of estrogens, as well as receptor-mediated changes in prostatic sex steroid metabolism and receptors. Aromatase in the prostate may provide a local source of estrogens. Perinatal estrogen exposure is carcinogenic for rodent male accessory sex glands. Hyperplastic/metaplastic changes have been reported in human prostatic tissues following prenatal DES exposure, indicating that this exposure also targets the human prostate. The mechanisms of prenatal estrogen effects may involve hormonal imprinting. A multifactorial hypothesis of the role of steroid hormones in prostate carcinogenesis may involve androgens as strong tumor promotors acting via androgen receptor-mediated mechanisms to enhance the carcinogenic activity of strong endogenous genotoxic carcinogens, such as reactive estrogen metabolites and reactive oxygen species, and possibly weak environmental carcinogens; these processes are modulated by 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.

Keywords. Androgens, Carcinogenesis, Epidemiology, Estrogens, Prostate, Prostate cancer, Steroid hormones

The Handbook of Environmental Chemistry Vol. 3, Part M Endocrine Disruptors, Part II (ed. by M. Metzler)

© Springer-Verlag Berlin Heidelberg 2002

1 Introduction 29

2 The Epidemiology of Prostate Cancer 30

2.1 General Risk Factors 30

2.2 Risk Factors Possibly Associated with Steroid Hormonal Factors . 31

2.2.1 Diet and Nutrition 31

2.2.2 Vasectomy 32

2.2.3 Sexual Factors 33

2.2.4 Physical Activity and Anthropometric Correlates of Risk 33

2.3 Epidemiological Studies of Endogenous Hormones and Hormone Metabolism 34

2.3.1 Steroid Hormonal Factors in Populations with Different Risk for Prostate Cancer 34

2.3.2 Comparisons of Steroid Hormonal Factors in Nested Case-

Control Studies 40

2.3.3 Critical Interpretation of the Studies 44

2.4 Epidemiology: Summary and Conclusions 46

3 Hormonal Induction of Prostate Cancer in Laboratory Animals . 47

3.1 Induction of Prostate Cancer with Sex Hormones 48

3.1.1 Androgens 48

3.1.2 Estrogen and Androgen Combinations 48

3.1.3 Perinatal Estrogen Exposure 49

3.2 Induction of Prostate Cancer with Chemical Carcinogens and Sex Hormones 50

3.2.1 Chemical Carcinogens Combined with Hormonal Stimulation of Cell Proliferation 50

3.2.2 Testosterone as Tumor Promotor of Prostate Carcinogenesis . . . 50

3.2.3 Effects of Androgens on Prostate Cancer Induction by Cadmium and Ionizing Radiation 51

3.3 Conclusions 51

4 Mechanisms of Hormonal Prostate Carcinogenesis 52

4.1 Androgens and Prostate Carcinogenesis 53

4.1.1 Stimulation of Cell Proliferation and Carcinogenic and Tumor-Promoting Effects of Androgens 53

4.1.2 Androgen Metabolism and Androgen Receptor Sensitivity . . . . 54

4.2 Estrogens and Prostate Carcinogenesis 55

4.2.1 Estrogen Receptor-Mediated Mechanisms 56

4.2.2 Non-Receptor Mechanisms 57

4.2.3 Perinatal Estrogen Exposure: Hormonal Imprinting 58

5 Summary and Conclusion 59

6 References 61

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