Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-11, Vol.111 (46), p.16514-16519
• Main Authors: Amos-Landgraf, James M., Heijmans, Jarom, Wielenga, Mattheus C. B., Dunkin, Elisa, Krentz, Kathy J., Clipson, Linda, Ederveen, Antwan G., Groothuis, Patrick G., Mosselman, Sietse, Muncan, Vanesa, Hommes, Daniel W., Shedlovsky, Alexandra, Dove, William F., van den Brink, Gijs R.
• Format: Article
• Language: English
• Subjects: Adenoma; Adenoma - chemically induced; Adenoma - epidemiology; Adenoma - physiopathology; Adenoma - prevention & control; Adenomatous Polyposis Coli - epidemiology; Adenomatous Polyposis Coli - genetics; Adenomatous Polyposis Coli - physiopathology; Animal models; Animals; Animals, Congenic; Azoxymethane - toxicity; Biological Sciences; Carcinogens; Carcinogens - toxicity; Colon; Colonic Neoplasms - chemically induced; Colonic Neoplasms - epidemiology; Colonic Neoplasms - physiopathology; Colonic Neoplasms - prevention & control; Colorectal cancer; Dihydrotestosterone - toxicity; Disease Models, Animal; Estradiol - administration & dosage; Estradiol - pharmacology; Estrogens; Female; Genes, APC; Gonadal Steroid Hormones - physiology; Hormone Replacement Therapy; Hormones; Humans; Male; Medroxyprogesterone Acetate - administration & dosage; Medroxyprogesterone Acetate - pharmacology; Mice; Mice, Inbred C57BL; Mutation; Neoplasms, Hormone-Dependent - epidemiology; Neoplasms, Hormone-Dependent - physiopathology; Neoplasms, Hormone-Dependent - prevention & control; Orchiectomy; Organ Specificity; Ovariectomy; Postmenopause; Random Allocation; Rats; Rats, Inbred F344; Rats, Mutant Strains; Receptors, Androgen - biosynthesis; Receptors, Androgen - genetics; RNA, Messenger - analysis; Rodents; Sex Distribution; Small intestine; Species Specificity; Testosterone; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1323064111

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. Significance The age-adjusted incidence of colonic adenomas and colorectal cancer is higher in men than in women. In a careful analysis of two established animal models, we found that castration reduced, and testosterone supplementation restored, the number of adenomas in the male rat and mouse colon, whereas ovariectomy and replacement of female hormones had no measureable effect on colonic adenomagenesis. In Min mice, in which most of the tumors arise in the small intestine, this testosterone-dependent sexual dimorphism in mice was specific to the colon. Our results support a paradigm shift: Testosterone promotes early adenomagenesis through an indirect mechanism, explaining the enhanced susceptibility of males to colonic adenomagenesis in the human, rat, and mouse.