Invasion promoting factors in endometriotic and endometrial tissue

Abstract

Endometriosis is a common gynaecologic disorder, affecting women of fertile age with pelvic pain and infertility, and is characterized by the presence of endometrial glands and stroma outside the uterine cavity. Retrograde shed endometrial fragments are presumed to adhere to pelvic structures and grow invasively, thereby creating endometriotic tissue.

Different factors might participate in the invasive process. The plasminogen activating system (PAs) is involved in tissue degradation and remodelling under both normal and pathological conditions. The activation of plasminogen, leading to the formation of plasmin, is catalyzed by tissue-type PA (tPA) or by urokinase plasminogen activator (uPA) when bound to its receptor uPAR. Receptor binding of uPA initiates pericellular proteolysis and cell migration, two processes required for tissue invasion. Two plasminogen activator inhibitors PAI-1 and PAI-2 regulate the plasminogen activating system. Plasmin, a highly potent protease, is able to degrade a broad spectrum of matrix and basement membrane proteins and plasmin also activates zymogens of other matrix-degrading proteases.

In this thesis we hypothesize that the PAs are important contributors both to menstrual shedding, endometrial adhesion and endometriotic invasion.

We investigated endometriotic and endometrial tissue as well as peritoneal fluid (PF) from women with endometriosis and used endometrium and PF from healthy women as controls. We analysed the concentrations of plasminogen activators and inhibitors and the IL-1beta, IL-6 and TNFalpha in homogenates of endometriotic and endometrial tissue as well as in peritoneal fluid and in culture medium from isolated, separated epithelial and stromal cells. With in situ hybridisation (ISH) and immunohistochemistry (IHC) we investigated in which type of cells, glandular and/or stromal cells, the mRNA and the protein for uPA, PAI-1 and uPAR were expressed in endometriotic and endometrial tissue samples. We found an up-regulation of mRNA for uPA, PAI-1 and uPAR and higher concentrations of uPA, and PAI-1 in endometriotic and endometrial tissue from women with endometriosis compared to endometrial tissue from control women.

These findings might be of importance for menstrual shedding and adhesion of viable endometrial fragments to other structures and for the invasive growth of endometriosis. The differences found between the three tissue types concerning IL-1beta, IL-6 and TNFalpha might have importance for the inflammatory reaction at the endometrial adhesion and in the growth regulation of endometriotic tissue. The higher level of PAI-2 in PF from women with endometriosis might be a consequence of the inflammatory process and contribute to the development of adherences in the peritoneal cavity.

Above all the studies have shown, that there is an important difference in the expression of the components of the PAs in endometrium from women with endometriosis compared to healthy endometrium supporting the hypothesis that ectopic endometrial invasion takes place at least partly as a consequence of a disturbed fibrinolytic activity in the eutopic endometrium.