Effects of androgen manipulations on chemically induced colonic tumours and on macroscopically normal colonic mucosa in male Sprague-Dawley rats

Abstract

Summary 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.An important role for androgens in colonic carcinogenesis in humans has been suggested on the basis of detection of specific receptor proteins in human colorectal tissue (Odagiri et al., 1984, Jacobson 1984. Chemically induced colonic carcinogenesis models in rats have been used to study modulators of colonic carcinogenesis (Autrup & Williams, 1983). Some authors reported specific androgen receptor proteins in chemically induced colonic tumours (Mehta et al., 1980;Krelenbaum et al., 1984;Jacobson, 1984). In addition, hormonal manipulations have been reported to influence tumour yield (Balish et al., 1977;Moon & Fricks, 1977;Mehta et al., 1978;Izbicki et al., 1983). These findings seemed to support a possible role of androgens in colonic carcinogenesis.Recently, we reported the effects of hormonal manipulations on chemically induced colonic carcinogenesis and androgen receptors in macroscopically normal mucosa and colonic tumours (Izbicki et al., 1986). In the present publication we present our evaluation of the mechanisms of the observed effects. Materials and methods Experimental protocolTwo hundred 8-week-old male Sprague-Dawley rats weighing 230-275 g (Wiga, Sulzfeld, FRG) were randomly allocated to five groups ...

Population-based analysis of colorectal cancer risk after oophorectomy

“…In contrast, among men with prostate cancer, androgen deprivation therapy has been reported to increase the risk of colorectal cancer. In male rats, a protective effect of androgens has been reported.…”

Risk of Colorectal Cancer by Subsite in a Swedish Prostate Cancer Cohort

“…29 By contrast, an increased risk of colorectal adenocarcinoma due to androgen deprivation could be possible as the results from animal studies suggest that androgen may have a protective effect on the development of CRC. 30,31 Androgen receptors have also been found more frequently in the normal -as opposed to cancerous -mucosa in the colon. 31,32 Thus, orchiectomy or GnRH treatment would directly decrease androgen.…”

“…30,31 Androgen receptors have also been found more frequently in the normal -as opposed to cancerous -mucosa in the colon. 31,32 Thus, orchiectomy or GnRH treatment would directly decrease androgen.…”

Concordant colon tumors in monozygotic twins previously treated for prostate cancer

“…A more interesting possibility is that the colon tumors were somehow related to the dual-agent androgen deprivation therapy that both men had received. Androgen receptors are expressed in both healthy and neoplastic colon tissues [14], and data from various studies suggest that androgens exert protective effects in the colon [15][16][17][18][19]. For example, chemical castration has been shown to enhance chemically induced colon carcinogenesis in rats [19], and there is a large body of evidence indicating that androgen-receptor activation in colon cancer cells can repress canonical Wnt signalling (i.e., signalling through the beta-catenin/TCF pathway) [20][21][22], which-in its deregulated form-is believed to be responsible for the vast majority of colorectal cancers-familial and sporadic [23].…”