Endometriosis, a Sequel of Diseased Eutopic Endometrium

Endometriosis is a disease, characterized by the occurrence of endometrial tissue outside of the uterine cavity, described to affect 6-10% of all women in reproductive age. Its occurrence is associated with chronic pelvic pain and/ or infertility. The diagnosis of endometriosis requires laparoscopy, i.e. much unnecessary surgery is performed in patients that retrospectively exhibit free of disease. Following diagnosis, the gold standard for treatment is based upon hormone administration and/ or surgical removal of lesions, with low or almost no proven effectivity. Thus, patients would benefit from detecting disease by simple and, thus, less invasive currettage instead of laparoscopy. To achieve this goal, it is mandatory to answer to the question how uterine endometrial tissue following retrograde menstruation is able to migrate towards and to invade extrauterine sites. However, it implies the existence of a not yet described mechanism responsible for this process. The presence of the disease in the pelvis has been attributed to attachment of endometrial fragments to the epithelium of the peritoneum, invasion of the epithelium, establishment of a blood supply, and generation of a suboptimum immune response that does not adequately clear the implants, resulting in continued survival and growth. Moreover, the endometrium of women with endometriosis is believed to be abnormally predisposed to successful establishment of ectopic disease. This view is compelling, especially since most women have some degree of retrograde menstruation but only 6-10% have endometriosis. Therefore it will be of great interest to investigate whether the cells of the endometrium of patients undergo modifications that can give reason of their readiness to displace. Presently, the only characteristic feature of the cells of patients` endometrium is a high aromatase activity but nothing is known about its precise impact on the development of endometriosis. Therefore it is our aim to determine whether and how aromatase affects cell motility, cell proliferation and cell survival by investigating the impact that increased production of endogenous estrogen exerts on ezrin, on the MAPK pathways and on Fas/FasL. Such a project gives us the additional possibility to investigate other facets of endometriosis, among all, how ectopic lesions survive apoptosis, but do not become metastatic. From this line of argumentation, our project comprises three parts: - Analysis of the mechanism by which pathological expression of aromatase affects cell migration capability of endometriotic cells and the investigation of whether this effect can be modulated by the eutopic vs. ectopic (i.e. peritoneum) localization; - Analysis of the involvement of the MAPK pathways, in promoting up-regulation of cell proliferation in endometriosis; - Investigation of whether increased cell migration can be linked to up-regulated cell proliferation by Raf-1; - Investigation of whether increased cell migration and up-regulated cell proliferation can down-regulate the extrinsic pathway of apoptosis.

Endometriosis is a disease, characterized by the occurrence of endometrial tissue outside of the uterine cavity, described to affect 6-10% of all women in reproductive age. Its occurrence is associated with chronic pelvic pain and/ or infertility. The diagnosis of endometriosis requires laparoscopy, i.e. much unnecessary surgery is performed in patients that retrospectively exhibit free of disease. Following diagnosis, the gold standard for treatment is based upon hormone administration and/ or surgical removal of lesions, with low or almost no proven effectivity. Thus, patients would benefit from detecting disease by simple and, thus, less invasive currettage instead of laparoscopy. To achieve this goal, it is mandatory to answer to the question how uterine endometrial tissue following retrograde menstruation is able to migrate towards and to invade extrauterine sites. However, it implies the existence of a not yet described mechanism responsible for this process. The presence of the disease in the pelvis has been attributed to attachment of endometrial fragments to the epithelium of the peritoneum, invasion of the epithelium, establishment of a blood supply, and generation of a suboptimum immune response that does not adequately clear the implants, resulting in continued survival and growth. Moreover, the endometrium of women with endometriosis is believed to be abnormally predisposed to successful establishment of ectopic disease. This view is compelling, especially since most women have some degree of retrograde menstruation but only 6-10% have endometriosis. Therefore it will be of great interest to investigate whether the cells of the endometrium of patients undergo modifications that can give reason of their readiness to displace. Presently, the only characteristic feature of the cells of patients` endometrium is a high aromatase activity but nothing is known about its precise impact on the development of endometriosis. Therefore it is our aim to determine whether and how aromatase affects cell motility, cell proliferation and cell survival by investigating the impact that increased production of endogenous estrogen exerts on ezrin, on the MAPK pathways and on Fas/FasL. Such a project gives us the additional possibility to investigate other facets of endometriosis, among all, how ectopic lesions survive apoptosis, but do not become metastatic. From this line of argumentation, our project comprises three parts: Analysis of the mechanism by which pathological expression of aromatase affects cell migration capability of endometriotic cells and the investigation of whether this effect can be modulated by the eutopic vs. ectopic (i.e. peritoneum) localization; Analysis of the involvement of the MAPK pathways, in promoting up-regulation of cell proliferation in endometriosis; Investigation of whether increased cell migration can be linked to up-regulated cell proliferation by Raf-1; Investigation of whether increased cell migration and up-regulated cell proliferation can down-regulate the extrinsic pathway of apoptosis.