Abstract
Epidemiological and experimental studies suggest that androgens influence colonic carcinogenesis. We investigated the effects of hormonal manipulations (surgical and chemical castration, hormone substitution) on colonic tumour development, tumour and mucosal histopathology, and epithelial proliferation in macroscopically normal colonic mucosa in male rats, after induction of chemical colon carcinogenesis by subcutaneous injections of azoxymethane (AOM). Chemical castration with cyproterone acetate, but not surgical castration, resulted in increased colonic tumorigenesis, which was accompanied by decreased crypt length, decreased number of cells per crypt, and increased crypt epithelial mitotic index in the right colon. Chemically castrated rats also had crypt hyperplasia and increased numbers of dysplastic foci in the left colon which were not seen with surgical castration. By contrast, rats given testosterone after surgical castration showed decreased colonic tumorigenesis with an increased proportion of tumours in the left colon and lower percentage of tumours with invasion. The grossly normal mucosa of the testosterone-substituted castrated rats showed decreased crypt length in the right colon similar to the other groups of castrated rats, but no significant increase in mitotic index. Our results suggest that the anti-androgenic progestin cyproterone is a potent enhancer of colonic tumorigenesis and epithelial proliferative abnormalities after AOM administration. Exogenous testosterone after castration alters tumour distribution and characteristics and suppresses epithelial proliferative abnormalities. Finally, androgen effects on the colonic mucosa are more prominent in the right than in the left colon, suggesting different influences of hormones on the epithelium of these anatomical sites.
Highlights
Human colonic carcinogenesis is thought to be influenced by androgens (Jacobson, 1984; Mehta et al, 1980)
This hypothesis is supported by the detection of specific androgen receptor proteins in human colonic tumour tissue (Alford et al, 1979)
Chemical induction of colonic carcinomas in rats has been found to provide a reliable model of colonic carcinogenesis in humans
Summary
Materials and methods glovesOnce injected, animals were left in the fume hood for 24 h. Group III animals were castrated at the same age and hormone-substituted with testosterone propionate (50 mg per kg body weight) in microcrystalline suspension s.c. three times a week. Group IV animals were chemically castrated with cyproterone acetate (50 mg per kg body weight) in microcrystalline suspension s.c. three times a week. Group V animals were castrated at 8 weeks of age and were administered the hormone vehicle. At week 23, hormone dose was reduced to I mg per kg body weight due to toxic effects, as expressed by a lethality of 40% in the castrated and testosterone-substituted group. Myri 53, a commonly used emulsifier, was supplied by Schering (Berlin, FRG). It is a polyethoxylic stearic acid with the chemical formula CP7H35COO (CH2CH20)40H
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