Intestinal Tumorigenesis Is Not Affected by Progesterone Signaling in Rodent Models

Clinical data suggest that progestins have chemopreventive properties in the development of colorectal cancer. We set out to examine a potential protective effect of progestins and progesterone signaling on colon cancer development. In normal and neoplastic intestinal tissue, we found that the progesterone receptor (PR) is not expressed. Expression was confined to sporadic mesenchymal cells. To analyze the influence of systemic progesterone receptor signaling, we crossed mice that lacked the progesterone receptor (PRKO) to the ApcMin/+ mouse, a model for spontaneous intestinal polyposis. PRKO-ApcMin/+mice exhibited no change in polyp number, size or localization compared to ApcMin/+. To examine effects of progestins on the intestinal epithelium that are independent of the PR, we treated mice with MPA. We found no effects of either progesterone or MPA on gross intestinal morphology or epithelial proliferation. Also, in rats treated with MPA, injection with the carcinogen azoxymethane did not result in a difference in the number or size of aberrant crypt foci, a surrogate end-point for adenoma development. We conclude that expression of the progesterone receptor is limited to cells in the intestinal mesenchyme. We did not observe any effect of progesterone receptor signaling or of progestin treatment in rodent models of intestinal tumorigenesis

Oral contraceptives prevent the development of endometriosis in the chicken chorioallantoic membrane model

Background: Fundamental and genetic differences between women in the endometrium may cause some to develop endometriosis, whereas others (to not. Oral contraceptives (OC) may have in effect on the endometrium, rendering the development of endometriosis less likely. Study Design: Endometrium front women using CC (OCE) and menstrual endometrium (ME) from normal cycling women were transplanted onto the chicken chorioallantoic membrane (CAM), and endometriosis-like lesion formation was evalualed. Microarray gene expression profiling was performed to identify, differentially expressed genes in the endometrium front these groups. Microarray data were validated by real-time PCR. Results: Less endometriosis-like lesions were formed after transplantation of OCE than after transplantation of ME (p<.05). Most of the differentially expressed genes belong to the TGF beta superfamily. Real-time PCR validation revealed that inhibin beta A (INHBA) expression was significantly decreased in OCE its compared to ME. Conclusion: OC use affects the characteristics Of endometrium, rendering it less potent to develop into endometriosis. (C) 2008 Elsevier Inc. All rights reserved

Deoxyribonucleic acid methyltransferases and methyl-CpG-binding domain proteins in human endometrium and endometriosis

ObjectiveTo determine [1] expression levels of both DNA methyltransferases (DNMTs) and methyl-CpG-binding domain proteins (MBDs) in human endometrium throughout the menstrual cycle and in eutopic and ectopic endometrium of patients with endometriosis and [2] hormone responsiveness of DNMT and MBD expression in explant cultures of proliferative phase endometrium.DesignIn vitro study.SettingAcademic medical center.Patient(s)Premenopausal women with and without endometriosis.Intervention(s)Explant cultures of proliferative phase endometrium were treated with vehicle, 17β-E2, or a combination of E2 and P (E2 + P) for 24 hours.Main Outcome Measure(s)Expression levels of DNMT1, DNMT2, and DNMT3B and MBD1, MBD2, and MeCP2 with use of real-time quantitative polymerase chain reaction.Result(s)Expression levels of DNMT1 and MBD2 were significantly higher in secretory-phase endometrium compared with proliferative endometrium and menstrual endometrium. In explant cultures, treatment with E2 + P resulted in significant up-regulation of DNMT1 and MBD2. Expression levels of several DNMTs and MBDs were significantly lower in endometriotic lesions compared with eutopic endometrium of women with endometriosis and disease-free controls.Conclusion(s)These findings suggest a role for DNMTs and MBDs in the growth and differentiation of the human endometrium and support the notion that endometriosis may be an epigenetic disease

Antiangiogenesis therapy for endometriosis

It is known that angiogenesis is of pivotal importance for the development of endometriosis. However, in the treatment of endometriosis patients, prevention of endometriosis lesion development only will not be sufficient as a therapy. Treatment options, aimed at interfering with established lesions, have to be developed. In this study we evaluated whether inhibition of angiogenesis by angiostatic therapy is also effective in antagonizing the sustentation of endometriosis. We evaluated the effect of the angiostatic compounds antihuman vascular endothelial growth factor, TNP-470, endostatin, and anginex on the growth of established endometriosis lesions in the nude mouse model. We show that human endometrium in the proliferative endometrium is highly angiogenic and that vascular endothelial growth factor-A is the most important angiogenesis promotory factor. The angiostatic compounds significantly decreased microvessel densities and the number of established endometriosis lesions. In the remaining lesions, the number of pericyte-protected vessels is not different in control and treated mice; however, the number of unprotected vessels was significantly reduced in the groups treated with the angiostatic agents. Our data demonstrate that inhibitors of angiogenesis effectively interfere with the maintenance and growth of endometriosis by inhibiting angiogenesis. This suggests that the use of angiostatic agents may be promising as a therapy for endometriosis

Intestinal tumorigenesis is not affected by progesterone signaling in rodent models.

Clinical data suggest that progestins have chemopreventive properties in the development of colorectal cancer. We set out to examine a potential protective effect of progestins and progesterone signaling on colon cancer development. In normal and neoplastic intestinal tissue, we found that the progesterone receptor (PR) is not expressed. Expression was confined to sporadic mesenchymal cells. To analyze the influence of systemic progesterone receptor signaling, we crossed mice that lacked the progesterone receptor (PRKO) to the Apc(Min/+) mouse, a model for spontaneous intestinal polyposis. PRKO-Apc(Min/+) mice exhibited no change in polyp number, size or localization compared to Apc(Min/+). To examine effects of progestins on the intestinal epithelium that are independent of the PR, we treated mice with MPA. We found no effects of either progesterone or MPA on gross intestinal morphology or epithelial proliferation. Also, in rats treated with MPA, injection with the carcinogen azoxymethane did not result in a difference in the number or size of aberrant crypt foci, a surrogate end-point for adenoma development. We conclude that expression of the progesterone receptor is limited to cells in the intestinal mesenchyme. We did not observe any effect of progesterone receptor signaling or of progestin treatment in rodent models of intestinal tumorigenesis

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

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 adenoma