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.colon cancer | animal models | androgens | estrogens | intestinal regionality E pidemiologic studies have identified a number of factors that influence the risk of sporadic adenomas and colorectal cancer (CRC). Age, familial predisposition, racial background, diet, physical activity, obesity and the metabolic syndrome, smoking, and heavy alcohol use are all established risk factors for the development of CRC. In addition, the risk of CRC also shows sexual dimorphism, with a lower incidence and delayed onset in women (1, 2). Colonoscopic screening of asymptomatic individuals has corroborated male sex as a risk factor for the development of both adenomas and CRC in all age groups (3, 4); however, whether this disparity depends on protective factors in women, tumor-promoting factors in males, or both is unknown.A protective role of female hormones against the development of frank CRC is suggested by data from the Women's Health Initiative (WHI). In the WHI, two large randomized controlled trials examined the effects of hormonal replacement therapy on postmenopausal women over a 5-y period, using CRC development as one of the endpoints. The first study showed that combined treatment with both equine estrogen (E2) and medroxyprogesterone acetate (MPA) substantially reduced the risk of colorectal cancer compared with placebo (odds ratio, 0.63) after a 5-y follow-up (5). However, protection was not found in a second randomized cont...

Fibersol-2 induces apoptosis ofApc-deficient colorectal Cancer (SW480) cells and decreases polyp formation inApcMIN mice

“…Female Apc MIN/C mice typically show a higher intestinal tumor count compared to their male littermates. 35,37 In the present study a 2 factor ANOVA confirmed a significant prevalence for intestinal tumors in female mice (gender; F D 5.844, p D 0.017). At the same time, animals treated with 1% FS2 showed a significant reduction in total adenoma counts (FS2; F D5.985, pD0.015) compared to the water treated groups, but we found no interaction between gender and treatment (FD0.029, pD0.865) (see Table 1).…”

“…5. In the large intestine, the gender bios for polyposis is reversed 35,37 and in the tested groups the average count of polyps in males is significantly higher than the one in females (2 factor ANOVA gender; F D 13.230, p < 0.001). More importantly, a significant reduction in the number of polyps after the administration of 1%FS2 (2 factor ANOVA FS2; F D 3.920,p D 0.049), yet no interaction between gender and FS2 (F D 1.566, p D 0.212) was observed.…”

“…21 Apc MIN/C mice present pathological differences in the small-intestinal and colonic regions 33,34 as well as female and male specific variances. [35][36][37] Thus, FS2s anti-tumor activity was studied in both male and female Apc MIN/C mice. Three week old mice were given 1% final concentration of FS2 in the drinking water for a total duration of 9 weeks before euthanasia.…”

Cytotoxic Effects of Testosterone on Brain Cancer Cell Line (A172) in Cell Culture

“…This action is mediated by the androgen receptor (AR), which is expressed in large numbers by rat neuron cells; nonetheless, such findings have not yet been reported in humans [13]. It has also been demonstrated that testosterone may promote early colonic adenomagenesis in rats [14].…”

Possible Gender-Related Modulation by the ROCK1 Gene in Colorectal Cancer Susceptibility

“…The risk of CRC shows sexual dimorphism, with a significantly higher incidence rate in males than in females (2:1) [37]. It has been proposed that male hormones play a key role in the development of colonic adenomas [38]. Moreover, several reports describe a link between androgens and the ROCK signaling pathway [39,40,41].…”