[Frontiers in Bioscience 2, e48-52, August 1, 1997]

	[Frontiers in Bioscience 2, e48-52, August 1, 1997] Reprints PubMed CAVEAT LECTOR
	ENDOMETRIOSIS: A REVIEW OF ITS PATHOGENESIS Paul J.Q. van der Linden Deventer Ziekenhuis, Department of Obstetrics and Gynecology, P.O. Box 5001, 7400 GC Deventer, The Netherlands Received 6/15/97 Accepted 7/29/97 4. PREREQUISITE PROCESSES FOR THE IMPLANTATION THEORY 4.1 Retrograde menstruation Initially Watkins reported the occurrence of blood dripping from one or both fallopian tubes, when a laparotomy was performed during menstruation (24). Subsequently, the presence of blood in the peritoneal fluid during menstruation was visualy documented in healthy women, in women undergoing peritoneal dialysis, and in women with endometriosis (25, 26). It was also shown that tubal flushing leads to retrograde seeding of the endometrium (27). It was shown that in up to 59% of patients with and without endometriosis at various stages of the menstrual cycle the peritoneal fluid contains viable endometrial tissue (28-32). Kruitwagen and coworkers reported presence of viable endometrial cells in peritoneal fluid, most likely epithelial cells that could be cultured (30). It was suggested that the demonstration of blood in the pouch of Douglas at laparoscopy was inadequate to support retrograde menstruation, since only a weak correlation was found between blood staining of peritoneal fluid and the presence of endometrial cells (34). On the other hand, endometrial glands were reported in the peritoneal cavity after dilatation and curettage and after uterotubal irrigation (27, 28, 35, 36). Most studies demonstrated the presence of endometrial cells in peritoneal fluid, using Papanicolaou staining (31, 32, 34). This has the disadvantage that only rather large clusters of cells, resembling endometrial glandular and stromal tissue, can be used for recognition of endometrial tissue. Van der Linden and coworkers demonstrated presence of endometrial cells in peritoneal fluid using immunohistochemistry (37). They have compared the immunohistochemical staining properties of these cells to the cells present in endometrium, menstrual effluent, peritoneum and endometriotic lesions. Using epithelial markers, it was found that the staining characteristics of cells from menstrual effluent, endometrium, peritoneal fluid, and endometriotic lesions were remarkably similar. In women with patent tubes, peritoneal fluid contained single epithelial cells, rather than endometrial tissue fragments. However, these findings do not provide supporting evidence for the implantation theory. Furthermore, the anatomic distribution of endometriosis correlates very well with this theory (33). Taken together these data support the concept of retrograde menstruation. 4.2 Adhesion If retrograde menstruation is important in the pathogenesis of endometriosis, then at some point in time, endometrial tissue, either glands or stroma, should adhere to the peritoneum. In particular, in vivo studies showing the initial contact between just one or a couple of endometrial cells and the peritoneal lining are still lacking. In theory, either the glandular epithelial cells or stromal cells or both cell types are directly involved in the contact with the mesothelium of the peritoneum. Alternatively, both cell types are mutually influencing each other to allow this first contact. Another possibility could be direct contact of endometrial cells with the extracellular matrix. Both implantation of viable endometrial tissue fragments and induction of coelomic metaplasia by these fragments will require adhesion of endometrial cells to the peritoneal lining. Members of the integrin and cadherin family of proteins are expressed in endometriotic lesions and in cells and tissues that are potentially involved in the development of endometriosis (38, 39). Integrins alpha2beta1, alpha3beta1, alpha4beta1, alpha5beta1, and alpha6beta1 and E-cadherin were demonstrated to be expressed in endometriotic lesions as well as in cells and tissues that are potentially involved in the development of endometriosis (38). Regurgitated cells obtained from peritoneal fluid also expressed cell adhesion molecules, particularly E-cadherin and some beta1-integrins, but to a lesser extent from that present in the native tissue (38, 39). The expression pattern of cell adhesion molecules suggests that the loss of cell adhesion properties could be involved in the shedding of endometrial tissue during menstruation and the attachment of endometrial tissue fragments to the peritoneum. Possibly, they are first lost, only to return after establishment of the endometriotic lesion. In an in vitro model to investigate the adhesion between endometrial fragments and cells to an ECM covered by an intact epithelium, intact amniotic membranes were used (40). No adhesion of fragments of normal endometrium to intact epithelium was found, whereas these fragments readily adhered to amniotic membranes which were denuded of their epithelium. Peritoneum and amniotic membrane show a great similarity in structure and in morphological and immunohistochemical features (40). It was therefore suggested that an intact peritoneal mesothelium prevents adhesion between endometrial cells shed into the peritoneal cavity and the peritoneum (40). On the other hand, carcinoma cell lines did show adhesion to intact epithelium. This suggests that the adhesive behavior of endometrial carcinoma cells in the process of metastasis is different from that of normally shed endometrial fragments. Disruption of the peritoneal lining seems to be a prerequisite for adhesion of endometrial cells to the peritoneal wall. This is in accordance with the fact that endometrial tissue growing on the peritoneal surface with intact mesothelium has never been described (41). The findings of these studies support the contention that, in endometriosis, in particular in peritoneal endometriosis, a delicate equilibrium exists between attacking forces (retrograde menstruation) and protective mechanisms. On one hand, the amount and the nature of the regurgitated menstrual debris is important to the development of the disease (42). On the other hand, an intact peritoneal lining may be an important first line of defense. Additional protection is afforded by the collagenase-like activity of the peritoneal fluid and the active intra-abdominal milieu, characterized by activated macrophages (43). This milieu probably reduces endometrial tissue into single cells, that, in addition, have lost their functional cell adhesion properties. If this active peritoneal fluid is impaired in disposing of the regurgitated cells, or if the number of regurgitated cells is too large, the surviving cells can adhere to the exposed extracellular matrix in damaged peritoneal lining. How an intact mesothelium gets damaged is a matter still open for debate. The derangement of a normal immune mechanism may include the cell-mediated and humoral responses, the macrophages and cytokine network, autoantibodies, and the complement components (44). If all defense mechanisms fail, endometriosis will develop. It is postulated that minimal endometriosis is a normal condition which occurs intermittently in normal women. In contrast, endometriotic disease occurs as deeply infiltrating endometriosis, and cystic ovarian endometriosis (45).

[Frontiers in Bioscience 2, e48-52, August 1, 1997]
Reprints
PubMed
CAVEAT LECTOR

ENDOMETRIOSIS: A REVIEW OF ITS PATHOGENESIS

Paul J.Q. van der Linden

Deventer Ziekenhuis, Department of Obstetrics and Gynecology, P.O. Box 5001, 7400 GC Deventer, The Netherlands

Received 6/15/97 Accepted 7/29/97

4. PREREQUISITE PROCESSES FOR THE IMPLANTATION THEORY

4.1 Retrograde menstruation
Initially Watkins reported the occurrence of blood dripping from one or both fallopian tubes, when a laparotomy was performed during menstruation (24). Subsequently, the presence of blood in the peritoneal fluid during menstruation was visualy documented in healthy women, in women undergoing peritoneal dialysis, and in women with endometriosis (25, 26). It was also shown that tubal flushing leads to retrograde seeding of the endometrium (27). It was shown that in up to 59% of patients with and without endometriosis at various stages of the menstrual cycle the peritoneal fluid contains viable endometrial tissue (28-32). Kruitwagen and coworkers reported presence of viable endometrial cells in peritoneal fluid, most likely epithelial cells that could be cultured (30). It was suggested that the demonstration of blood in the pouch of Douglas at laparoscopy was inadequate to support retrograde menstruation, since only a weak correlation was found between blood staining of peritoneal fluid and the presence of endometrial cells (34). On the other hand, endometrial glands were reported in the peritoneal cavity after dilatation and curettage and after uterotubal irrigation (27, 28, 35, 36). Most studies demonstrated the presence of endometrial cells in peritoneal fluid, using Papanicolaou staining (31, 32, 34). This has the disadvantage that only rather large clusters of cells, resembling endometrial glandular and stromal tissue, can be used for recognition of endometrial tissue. Van der Linden and coworkers demonstrated presence of endometrial cells in peritoneal fluid using immunohistochemistry (37). They have compared the immunohistochemical staining properties of these cells to the cells present in endometrium, menstrual effluent, peritoneum and endometriotic lesions. Using epithelial markers, it was found that the staining characteristics of cells from menstrual effluent, endometrium, peritoneal fluid, and endometriotic lesions were remarkably similar. In women with patent tubes, peritoneal fluid contained single epithelial cells, rather than endometrial tissue fragments. However, these findings do not provide supporting evidence for the implantation theory. Furthermore, the anatomic distribution of endometriosis correlates very well with this theory (33). Taken together these data support the concept of retrograde menstruation.

4.2 Adhesion
If retrograde menstruation is important in the pathogenesis of endometriosis, then at some point in time, endometrial tissue, either glands or stroma, should adhere to the peritoneum. In particular, in vivo studies showing the initial contact between just one or a couple of endometrial cells and the peritoneal lining are still lacking. In theory, either the glandular epithelial cells or stromal cells or both cell types are directly involved in the contact with the mesothelium of the peritoneum. Alternatively, both cell types are mutually influencing each other to allow this first contact. Another possibility could be direct contact of endometrial cells with the extracellular matrix. Both implantation of viable endometrial tissue fragments and induction of coelomic metaplasia by these fragments will require adhesion of endometrial cells to the peritoneal lining.

Members of the integrin and cadherin family of proteins are expressed in endometriotic lesions and in cells and tissues that are potentially involved in the development of endometriosis (38, 39). Integrins alpha2beta1, alpha3beta1, alpha4beta1, alpha5beta1, and alpha6beta1 and E-cadherin were demonstrated to be expressed in endometriotic lesions as well as in cells and tissues that are potentially involved in the development of endometriosis (38). Regurgitated cells obtained from peritoneal fluid also expressed cell adhesion molecules, particularly E-cadherin and some beta1-integrins, but to a lesser extent from that present in the native tissue (38, 39). The expression pattern of cell adhesion molecules suggests that the loss of cell adhesion properties could be involved in the shedding of endometrial tissue during menstruation and the attachment of endometrial tissue fragments to the peritoneum. Possibly, they are first lost, only to return after establishment of the endometriotic lesion. In an in vitro model to investigate the adhesion between endometrial fragments and cells to an ECM covered by an intact epithelium, intact amniotic membranes were used (40).

No adhesion of fragments of normal endometrium to intact epithelium was found, whereas these fragments readily adhered to amniotic membranes which were denuded of their epithelium. Peritoneum and amniotic membrane show a great similarity in structure and in morphological and immunohistochemical features (40). It was therefore suggested that an intact peritoneal mesothelium prevents adhesion between endometrial cells shed into the peritoneal cavity and the peritoneum (40). On the other hand, carcinoma cell lines did show adhesion to intact epithelium. This suggests that the adhesive behavior of endometrial carcinoma cells in the process of metastasis is different from that of normally shed endometrial fragments. Disruption of the peritoneal lining seems to be a prerequisite for adhesion of endometrial cells to the peritoneal wall. This is in accordance with the fact that endometrial tissue growing on the peritoneal surface with intact mesothelium has never been described (41). The findings of these studies support the contention that, in endometriosis, in particular in peritoneal endometriosis, a delicate equilibrium exists between attacking forces (retrograde menstruation) and protective mechanisms. On one hand, the amount and the nature of the regurgitated menstrual debris is important to the development of the disease (42). On the other hand, an intact peritoneal lining may be an important first line of defense. Additional protection is afforded by the collagenase-like activity of the peritoneal fluid and the active intra-abdominal milieu, characterized by activated macrophages (43). This milieu probably reduces endometrial tissue into single cells, that, in addition, have lost their functional cell adhesion properties. If this active peritoneal fluid is impaired in disposing of the regurgitated cells, or if the number of regurgitated cells is too large, the surviving cells can adhere to the exposed extracellular matrix in damaged peritoneal lining. How an intact mesothelium gets damaged is a matter still open for debate. The derangement of a normal immune mechanism may include the cell-mediated and humoral responses, the macrophages and cytokine network, autoantibodies, and the complement components (44). If all defense mechanisms fail, endometriosis will develop. It is postulated that minimal endometriosis is a normal condition which occurs intermittently in normal women. In contrast, endometriotic disease occurs as deeply infiltrating endometriosis, and cystic ovarian endometriosis (45).