title: Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones.
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.
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology and Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706; amoslandgrafj@missouri.edu dove@oncology.wisc.edu.
authors.forename: James M
authors.initials: JM
authors.lastname: Amos-Landgraf
authors.affiliation: Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands;
authors.forename: Jarom
authors.initials: J
authors.lastname: Heijmans
authors.affiliation: Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands;
authors.forename: Mattheus C B
authors.initials: MC
authors.lastname: Wielenga
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology and.
authors.forename: Elisa
authors.initials: E
authors.lastname: Dunkin
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology and.
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Krentz
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology and.
authors.forename: Linda
authors.initials: L
authors.lastname: Clipson
authors.affiliation: Women's Health Department, Merck, Sharpe and Dohme, 5342 CC, Oss, The Netherlands; and.
authors.forename: Antwan G
authors.initials: AG
authors.lastname: Ederveen
authors.affiliation: Women's Health Department, Merck, Sharpe and Dohme, 5342 CC, Oss, The Netherlands; and.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Groothuis
authors.affiliation: Women's Health Department, Merck, Sharpe and Dohme, 5342 CC, Oss, The Netherlands; and.
authors.forename: Sietse
authors.initials: S
authors.lastname: Mosselman
authors.affiliation: Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands;
authors.forename: Vanesa
authors.initials: V
authors.lastname: Muncan
authors.affiliation: Center for Inflammatory Bowel Diseases, University of California, Los Angeles, CA 90095.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Hommes
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology and.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Shedlovsky
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology and Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706; amoslandgrafj@missouri.edu dove@oncology.wisc.edu.
authors.forename: William F
authors.initials: WF
authors.lastname: Dove
authors.affiliation: Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands;
authors.forename: Gijs R
authors.initials: GR
authors.lastname: van den Brink
mesh_terms: D000236:Adenoma / Q000139:chemically induced / Q000453:epidemiology* / Q000503:physiopathology / Q000517:prevention & control; D011125:Adenomatous Polyposis Coli / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D020296:Animals, Congenic; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000453:epidemiology* / Q000503:physiopathology / Q000517:prevention & control; D013196:Dihydrotestosterone / Q000633:toxicity*; D004195:Disease Models, Animal; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D017491:Genes, APC; D012739:Gonadal Steroid Hormones / Q000502:physiology*; D020249:Hormone Replacement Therapy; D006801:Humans; D008297:Male; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009376:Neoplasms, Hormone-Dependent / Q000453:epidemiology* / Q000503:physiopathology / Q000517:prevention & control; D009919:Orchiectomy; D009928:Organ Specificity; D010052:Ovariectomy; D017698:Postmenopause; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D011922:Rats, Mutant Strains; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics; D017678:Sex Distribution; D013045:Species Specificity
chemical_list: D002273:Carcinogens; D012739:Gonadal Steroid Hormones; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D004958:Estradiol; D017258:Medroxyprogesterone Acetate; D001397:Azoxymethane
keywords: androgens; animal models; colon cancer; estrogens; intestinal regionality