Human Reproduction, Vol. 16, No. 4, 605-607,
April 2001
© 2001 European Society of Human Reproduction and Embryology
The Mesothelium, Teflon or Velcro?
Mesothelium in endometriosis pathogenesis
1 Research Institute Growth and Development (GROW), Maastricht University, 2 Department of Obstetrics and Gynaecology and 3 Department of Pathology, Academisch Ziekenhuis Maastricht and Maastricht University, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
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Abstract |
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 Top Abstract IntroductionThe interaction between...The role of an...Menstruum as the aggressorConclusionsAcknowledgementsReferences |
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Sampson's transplantation theory for the pathogenesis of peritoneal endometriosis is widely accepted. The events that take place, however, on the cellular and subcellular level during the transition of endometrial tissue in the abdominal cavity into peritoneal endometriosis remain controversial. The mesothelium plays a central role in the debate on this subject.The interaction between endometrium and peritoneum has been studied in an in-vitro model using amnion, peritoneum and mesothelial cells in culture on the one hand and cyclic and menstrual endometrium on the other hand. The results of these studies indicate that (i) an intact mesothelial lining prevents adhesion of shed endometrial tissue, (ii) shed endometrial tissue adheres to the peritoneal extracellular matrix and (iii) menstrual effluent creates its own adhesion sites by damaging the mesothelial lining thus exposing the extracellular matrix. Therefore we conclude that the mesothelium has the properties of Teflon, while the extracellular matrix resembles Velcro.
Key words: adhesion/endometriosis/menstrual endometrium/meso-thelium/pathogenesis
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Introduction |
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TopAbstractIntroductionThe interaction between...The role of an...Menstruum as the aggressorConclusionsAcknowledgementsReferences |
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Endometriosis is the presence of functional endometrial glands and stroma in locations outside the uterine cavity. There are essentially three different forms of endometriosis: rectovaginal endometriosis or adenomyosis, ovarian cystic endometriosis and peritoneal endometriosis, each with its own pathogenesis, symptomatology, natural course of disease and hence treatment. The most accepted theory for the pathogenesis of peritoneal endometriosis is Sampson's transplantation theory (Sampson, 1927
). Considering the facts that nearly all women with patent Fallopian tubes harbour vital endometrial tissue in their peritoneal cavity during menstruation and that the majority of women have minimal to mild endometriosis as assessed during laparoscopy regardless of the indication for laparoscopy, it has been argued that all women at a given moment during their reproductive life have peritoneal endometriosis. Interestingly, nearly half a century ago, Scott already noted this: `If serial section of all pelvic tissue were feasible might not all 40 year old women with patent tubes and normal menstrual cycles regardless of parity reveal some endometriosis?' (Scott et al., 1953). As a consequence, this form of endometriosis should be considered physiological rather than a disease. In contrast, in a subset of women, for unknown reasons endometriosis becomes a disabling disease. Be this as it may, finding vital endometrial tissue in the abdominal cavity on the one hand and early lesions of peritoneal endometriosis on the other hand, does not give us much insight into the events that take place during the transition of endometrial tissue into endometriotic tissue. In other words, what happens at the encounter interface between the cells of the endometrial tissue and the peritoneal lining? Which cell types, the regurgitated endometrial epithelial glandular tissue or the stromal tissue, single cells or tissue fragments, are making the first contact with the mesothelial cells of the peritoneum? Or, alternatively, does the endometrium make direct contact with the submesothelial extracellular matrix, and if so, how does it pass through the mesothelial lining?
Does the mesothelium act as a barrier for the endometrium or is it receptive: Teflon or Velcro?
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The interaction between endometrium and peritoneum |
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TopAbstractIntroductionThe interaction between...The role of an...Menstruum as the aggressorConclusionsAcknowledgementsReferences |
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Since the interaction between endometrium and peritoneum cannot appropriately be studied in the human or in the known so-called animal models of endometriosis, we used an in-vitro model. In-vitro models have many advantages and one distinct disadvantage. Tissue manipulation can change properties of these tissues that may be critical to the function. At the same time one of these alterations proved to be of great value in our experiments as will be discussed below.
Working with the hypothesis that endometrium would have to attach to the peritoneal lining in order to form an endometriotic lesion we first showed that 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 (Van der Linden et al., 1994, 1995). Since the mere presence of cell adhesion molecules (CAMs) in endometrium, menstrual tissue and endometriotic lesions does not prove the functional role of CAMs in the attachment of endometrium to peritoneum, we developed a functional in-vitro model to study the interaction between endometrium and peritoneum. Cyclic (i.e. biopsied) as well as menstrual (i.e. spontaneously shed) endometrium was used. In the early experiments the amniotic membrane was used as a model for peritoneum, stripped and unstripped, i.e. devoid of the epithelial lining and with an intact epithelial lining. Using immunohistochemistry we showed the amniotic membrane to be similar to the peritoneum, at the epithelial and subepithelial level (Van der Linden et al., 1996). In later experiments fresh human peritoneum and cultured mesothelial cells, recovered from human omentum, were used.
Using the stripped and unstripped amnion model and early proliferative endometrium obtained with a Probet endometrial sampling device (Gynetic, Oisterwijk, The Netherlands), we showed that intact endometrial fragments, and not enzymatically digested epithelial and stromal cells, only adhered to the extracellular matrix side of the amnion and not to the epithelial side of the amnion, after culturing for 24 h. Adherence was assessed using immunohistochemistry and light microscopy (Van der Linden et al., 1996, 1998). Both stromal and epithelial cells showed adherence. The functional role of integrins in this adhesion process was corroborated by results of experiments that blocked the integrins (Koks et al., 2000a). The adhesion studies were extended in the same amniotic membrane model using scanning and transmission electron microscopy to determine the adhesion between endometrial fragments and the amnion (Groothuis et al., 1998). Again the endometrial fragments were seen at the extracellular matrix side of the amnion.
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The role of an intact mesothelium |
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TopAbstractIntroductionThe interaction between...The role of an...Menstruum as the aggressorConclusionsAcknowledgementsReferences |
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More interestingly, the use of the scanning electron microscope enabled us to make the following observation: the fragments that did adhere to the epithelial side of the amnion did so only at places where the epithelial lining was absent and/or, unintentionally, damaged. From the results of these experiments we tentatively concluded that an intact epithelial lining prevents the development of endometriosis. In order to corroborate this hypothesis we repeated the experiments with fresh peritoneum instead of amnion. Peritoneum was obtained during abdominal surgery for benign conditions and spread in six-well culture plates. Isolated endometrial fragments were layered on top and cultured for 24 hours. Comparable results were obtained. Endometrial fragments were seen where the epithelial lining showed breaches thus exposing the extracellular matrix (Groothuis et al., 1999
). These experiments were then repeated using menstrual endometrium instead of biopsied, proliferative or secretory endometrium, in order to mimic more closely the events that take place in vivo. Menstrual effluent was collected in a menstrual cup and was shown to contain vital endometrial tissue, in a sufficient quantity to use for adhesion studies (Koks et al., 1997). These adhesion studies using menstrual peritoneum and endometrium, confirmed by light and electron microscopy, our earlier findings that endometrial fragments do adhere at places where the epithelial layer of the peritoneum is damaged (Koks et al., 1999). An intact epithelial layer did not permit adhesion of endometrial fragments.
In a comparable experiment Witz and co-workers showed almost the same results and surprisingly came to the exact opposite conclusion (Witz et al., 1999). They used biopsied, cyclic (unfortunately not menstrual), mechanically dispersed, endometrium explanted on fresh human peritoneum and cultured it for 24 to 48 h. Using light and electron microscopy they showed that in 90% of instances the endometrium was on top of the extracellular matrix, while in 10% the mesothelium was present beneath the endometrium. These authors concluded that endometrium attaches to the mesothelium and rapidly invades through the mesothelium.
Results from experiments in cancer research underscore the importance of an intact mesothelial lining. The ability of human ovarian carcinoma cells derived from ascitic fluid to attach to a mesothelial cell monolayer grown on extracellular matrix or on extracellular matrix alone was quantitated by Niedbala and co-workers (1985) using 51Cr radio-labelled tumour cells. Tumour cell attachment was limited to areas of exposed extracellular matrix in lacerated mesothelium as assessed by phase contrast microscopy (Niedbala et al., 1985).
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Menstruum as the aggressor |
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TopAbstractIntroductionThe interaction between...The role of an...Menstruum as the aggressorConclusionsAcknowledgementsReferences |
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Based on the above mentioned studies we do not have much doubt that an intact mesothelial lining prevents adhesion of menstrual endometrial fragments to the peritoneal lining thus preventing the development of endometriosis. How can we reconcile this with the notion that endometriosis develops from time to time in all women with patent Fallopian tubes as we have mentioned in the first paragraph of this communication? Is the peritoneal lining damaged at regular, monthly, intervals? We have some evidence that this is the case. We observed that menstrual endometrium and not endometrium from the proliferative phase of the cycle caused damage to mesothelial cells in culture (Koks et al., 2000b
). It has to be noted that mesothelial damage has been shown as well in the course of metastasis. Kimura and co-workers (1985) studied the influence of cancerous ascites on peritoneal morphology in rats. The mesothelial cells were damaged and exfoliated markedly, thus giving way to the extracellular matrix. The factors that were shown to be damaging were found in the fraction containing low-molecular-weight substances (Kimura et al., 1985). Morphological changes of the mesothelium induced by tumour cells were observed in human ovarian carcinoma with the use of scanning electron microscopy, which included disruption of intercellular junctions leading to retraction of mesothelial cells, exposure of underlying extracellular matrix and attachment and proliferation of tumour cells (Niedbala et al., 1985).
We therefore tested the possible deleterious effect of the contents of menstrual effluent on mesothelial cells in co-culture with mesothelial cell monolayers. We showed that shed menstrual endometrium, menstrual endometrium in an insert, menstrual serum and conditioned medium of cultured menstrual tissue, lead to severe damage to the mesothelial cells. This suggests that the effect is at least partly paracrine in nature. The morphological changes were shown not to be primarily related to apoptosis or necrosis (Demir-Weusten et al., 2000).
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Conclusions |
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TopAbstractIntroductionThe interaction between...The role of an...Menstruum as the aggressorConclusionsAcknowledgementsReferences |
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The early events in the pathogenesis of peritoneal endometriosis are gradually being unveiled. During menstruation viable endometrium enters the abdominal cavity. Although the name suggests otherwise the abdominal cavity is a non-cavity, especially in the menstrual phase of the cycle, when peritoneal fluid is at its lowest volume. This leads to a close contact of the regurgitated menstrual endometrium with the peritoneal lining creating constant apposition of endometrium to mesothelium. After retrograde menstruation the contents of the menstruum cause damage to the mesothelium lining, thus exposing the extracellular matrix and creating adhesion sites for the endometrial tissue. Mesothelium has the properties of Teflon, the extracellular matrix resembles Velcro. However, the Teflon properties do not matter too much if we consider the findings that menstruum induces morphological changes in the mesothelial lining. The amount of menstruum and its composition, i.e. the ratio between glandular and stromal tissue, as well as the innate biological properties of the endometrium conceivably play an important role in the propensity to develop endometriosis. After adherence to the extracellular matrix, metalloproteinases of the endometrium itself start active remodelling of the extracellular matrix, leading to invasion of the endometrium into the submesothelial space of the peritoneum.
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Acknowledgements |
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Drs Van der Linden, Koks, Maas and Demir-Weusten have greatly contributed to the evolution of ideas as described in this debate.
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Notes |
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4 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Academisch Ziekenhuis Maastricht and Maastricht University, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands. E-mail: g.dunselman{at}og.unimaas.nl
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References |
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Demir-Weusten, A.Y., Groothuis, P.G., Dunselman, G.A. et al. (2000) Morphological changes in mesothelial cells induced by shed menstrual endometrium in vitro are not primarily due to apoptosis or necrosis. Hum. Reprod., 15, 1462–1468.
Groothuis, P.G., Koks, C.A., de Goeij, A.F. et al. (1998) Adhesion of human endometrium to the epithelial lining and extracellular matrix of amnion in vitro: an electron microscopic study. Hum. Reprod., 13, 2275–2281.
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