Testosterone as Tumor Promotor of Prostate Carcinogenesis

Long-term administration of testosterone to rats markedly enhances prostatic carcinogenesis following initial treatment with chemical carcinogens that target the prostate because of tissue-specific metabolism (DMAB and BOP) and/or concurrent hormonal stimulation of prostatic cell proliferation [69,70,191,196 -200,202,203,226]. The presence and magnitude of this enhancement appears to depend on several factors [190,191,197]. For example, after a single inj ection of BOP or MNU given to F344 rats without concurrent stimulation of prostatic cell proliferation, long-term testosterone treatment did not enhance prostatic carcinogenesis [200]. High incidences (66-83%) of adenocarcinomas of the dorsolateral and/or anterior prostate were induced by chronic treatment with testosterone following a single administration of MNU or BOP given during stimulation of prostatic cell proliferation in Wistar rats, or during and after ten repeated biweekly injections of DMAB in F344 rats [69, 70,190,191,197,199, 200,226]. This effect is somewhat strain-dependent, because when similar treat ments were given to Lobund Wistar rats, rather variable incidences of between 50 % and 97 % were reported by Pollard and co-workers [196,203,207], and only a 24% incidence was found by Hoover et al. [198].

The enhancing effect of testosterone on prostate carcinogenesis is remarkably confined to the dorsolateral and anterior prostate, and no tumors occur in the ventral prostate. Moreover, chronic testosterone treatment produces a shift of the site of DMAB- and BOP-induced carcinoma occurrence from exclusively the ventral lobe to predominantly the dorsolateral and anterior lobes [197,200, 226]. The dose-response relationship between testosterone dose and prostate carcinoma yield is very steep: elevation of circulating testosterone levels by less than 1.5-fold is sufficient for a near-maximal enhancement of the tumor response, and a two- to threefold elevation is sufficient for a maximal response; these concentrations are within the normal range of circulating testosterone levels in the rat [199]. Thus, testosterone is a powerful tumor promotor for the rat prostate.

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