Endocrine Factors

Human prostate carcinomas are often androgen sensitive and react to hormonal therapy by temporary remission, followed by relapse to an androgen-insensitive state. These well-established features of prostate cancer strongly suggest that steroid hormones, particularly androgens, play a major role in human prostatic carcinogenesis, but the precise mechanisms by which androgens affect this process are unknown. In addition, the possible involvement of estrogenic hormones is not entirely clear.107 Estrogens induce mitosis of both normal and malignant prostatic epithelial cells in many species, including humans.108,109 An important metabolic pathway of the estrogens is the formation of hydroxylated estrogens.

Muti et al.,110 in a case-control study on urinary estrogen metabolites and prostate cancer risk, showed a protective effect of the metabolic pathway favoring 2-hydroxylation over 16-hydroxylation on risk of prostate cancer.

Two distinct lines of epidemiologic and basic science research have converged in the hypothesis that the somatotropic axis plays an important role in the development of prostate cancer. Insulin-like growth factor-1 (IGF-1) is an important hormone in the axis, conveying centrally regulated signals to the tissue level. IGF-1 is a mitogen that stimulates cell proliferation and inhibits apoptosis. Recent epidemiologic studies suggest an association between elevated blood levels of IGFs and risk of prostate cancer, although data are inconsistent across the studies.111112 Although it is well known that growth hormone (GH) is a major factor regulating IGF levels, there is no evidence about how the physiological mechanisms regulating GH secretion on the basis of IGF-1 serum concentration may change in the presence of prostate cancer. From experimental studies, it appears that GH might be involved in regulating prostate function. The coexpression of GH and its receptor demonstrated by Chopin and colleagues113 would enable an autocrine-paracrine pathway to exist in the prostate that would be able to stimulate prostate growth, either directly or indirectly via IGF production.

Briefly, scientific evidence suggests a multifactorial general hypothesis of prostate carcinogenesis, with androgens acting via androgen receptor-mediated mechanisms to enhance the carcinogenic activity of strong endogenous genotoxic carcinogens, such as reactive estrogen metabolites. In addition, the body of evidence is growing for a role of the IGF family members. In this hypothesis, all of these processes are modulated by a variety of environmental factors and genetic determinants.107

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