Study of the potential involvement of iron in the pathogenesis of peritoneal endometriosis

Endometriosis is defined by the presence of endometrial tissue outside the uterine cavity. Most studies on peritoneal endometriosis are based on the implantation theory of Sampson, postulating that, during the menses, retrograde reflux of endometrial cells through the fallopian tubes may lead to the implantation and growth of these cells within the peritoneal cavity. Several studies have demonstrated the presence of iron overload in the peritoneal cavity in case of endometriosis. Indeed, iron deposits are characteristic of endometriotic lesions and pelvic iron concentrations are higher in endometriosis patients. Iron could originate from lysis of erythrocytes carried into the pelvic cavity by retrograde menstruation. Our hypothesis is that iron may induce expression of pro-inflammatory proteins in the pelvic cavity and stimulate cell proliferation, promoting the development of peritoneal endometriosis. The objective of this thesis was to test the consequences of iron overload on endometriosis development. During the first phase of the thesis, we have set up an original in vitro cell culture protocol allowing to test the impact of iron on purified cultures of endometrial stromal and epithelial cells. Our results indicate that both cell types are able to incorporate iron from transferrin and to metabolize it to ferritin. This model enabled us to quantify and compare the constitutive and iron-induced expression of the pro-inflammatory molecules ICAM-1 and VCAM-1 by both endometrial cell types. In the second phase of the project, we have developed a nude mouse model, allowing a precise and reliable evaluation of the quantity and severity of endometriosis that may well prove to be useful for future pharmacological studies. Our in vivo study demonstrates that intraperitoneal injection of erythrocytes causes iron overload in lesions, peritoneal macrophages and fluid whereas iron chelation with desferrioxamine effectively reduces iron status. While iron overload does not appear to affect lesion establishment, our study strongly suggests that it may contribute to the further growth of endometriosis by promoting the proliferative activity of lesions. Treatment with an iron chelator could thus be beneficial in endometriosis to prevent iron overload in the pelvic cavity and decrease cellular proliferation in lesions.