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Comparative Study
, 111 (46), 16514-9

Sex Disparity in Colonic Adenomagenesis Involves Promotion by Male Hormones, Not Protection by Female Hormones

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Comparative Study

Sex Disparity in Colonic Adenomagenesis Involves Promotion by Male Hormones, Not Protection by Female Hormones

James M Amos-Landgraf et al. Proc Natl Acad Sci U S A.

Abstract

It recently has been recognized that men develop colonic adenomas and carcinomas at an earlier age and at a higher rate than women. In the Apc(Pirc/+) (Pirc) rat model of early colonic cancer, this sex susceptibility was recapitulated, with male Pirc rats developing twice as many adenomas as females. Analysis of large datasets revealed that the Apc(Min/+) mouse also shows enhanced male susceptibility to adenomagenesis, but only in the colon. In addition, WT mice treated with injections of the carcinogen azoxymethane (AOM) showed increased numbers of colonic adenomas in males. The mechanism underlying these observations was investigated by manipulation of hormonal status. The preponderance of colonic adenomas in the Pirc rat model allowed a statistically significant investigation in vivo of the mechanism of sex hormone action on the development of colonic adenomas. Females depleted of endogenous hormones by ovariectomy did not exhibit a change in prevalence of adenomas, nor was any effect observed with replacement of one or a combination of female hormones. In contrast, depletion of male hormones by orchidectomy (castration) markedly protected the Pirc rat from adenoma development, whereas supplementation with testosterone reversed that effect. These observations were recapitulated in the AOM mouse model. Androgen receptor was undetectable in the colon or adenomas, making it likely that testosterone acts indirectly on the tumor lineage. Our findings suggest that indirect tumor-promoting effects of testosterone likely explain the disparity between the sexes in the development of colonic adenomas.

Keywords: androgens; animal models; colon cancer; estrogens; intestinal regionality.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Differential sex effect on the C57BL/6JD-ApcMin mouse phenotype. Male and female Min offspring from 57 litters were scored at sacrifice (90–120 d of age) for adenomas of the colon and small intestine. To minimize the effect of any variation among litters, the litters were selected as containing at least one Min animal of each sex. Tumor scoring was carried out as described previously (35), primarily by a single experienced observer (A.S.). Scatterplots were created for each sex for the small intestine (A) and colon (B). SI, small intestine.
Fig. 2.
Fig. 2.
Adenoma development in the Pirc rat is promoted by DHT and not affected by female hormones. (A) Numbers of adenomas in female Pirc rats are not affected by either OVX or OVX plus supplementation of female hormones. (B) Compared with sham-operated Pirc male rats, ORX reduces the numbers of adenomas to those observed in female rats. Treatment of ORX male Pirc rats with DHT causes an increase in the numbers of adenomas to levels seen in non-ORX males. Data are mean ± SEM. *P < 0.05; **P < 0.01.
Fig. 3.
Fig. 3.
Adenoma development is promoted by male hormones in the AOM mouse model. (A) Results of the male vs. female mouse experiment. In comparison with female mice, male mice have an increased adenoma burden. (B) Results of the ORX experiment. The numbers of adenomas in mice that underwent ORX are reduced compared with sham-operated mice. (C) Results of the testosterone supplementation experiment. Testosterone supplementation of male mice that had undergone ORX substantially increased the numbers of adenomas. Data are mean ± SEM. *P < 0.05; **P < 0.01.
Fig. 4.
Fig. 4.
IHC for androgen receptors in rat and mouse tissues. (A) Positive staining for the androgen receptor protein is seen in rare cells within the crypt and stroma of the mucosa. (B) Colonic adenomas show no staining for androgen receptor. (C) Diffuse staining is seen in the submucosa and muscularis in normal adjacent colon. (D) Positive control for androgen receptor staining in rat testis. (E) No positive staining for androgen receptor protein is seen in mouse colon. (F) Positive control for androgen receptor staining in mouse seminal vesicles.

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