Extracellular matrix remodelling in the endometrium and its possible relevance to the pathogenesis of endometriosis

TABLE OF CONTENTSIntroduction 730Protease secretion in cell culture 731Proteases in patients with and withoutendometriosis 731Role of endometrial proteases and endometriosis 732Acknowledgements 734References 734Essential features of endometrial physiology involve theextracellular matrix (ECM). In the pathogenesis ofendometriosis, interactions of endometriosis cells withECM can be postulated. Two systems of secretedproteases in the endometrium, the plasmin(ogen)activator/inhibitor and the matrix metalloproteinasesand their inhibitors were examined in cell cultures ofuterine endometrial cells from women with and withoutendometriosis. Soluble urokinase receptor secretion isincreased, and mRNA transcription of tissue inhibitor ofmetalloproteinases-2 (TIMP-2) is upregulated byprogestin in endometriosis. These findings arecompatible with an altered ECM turnover in theendometrium of these patients that may explain a higherinvasive potential of retrogradely menstruatedendometrial fragments.Key words: endometrium/endometriosis/extracellularmatrix/pathogenesis/secreted proteasesIntroductionRemodelling of the extracellular matrix (ECM) is anessential process for physiological endometrial functionslike secretory transformation, implantation, decidualizationand menstruation. According to the theory of retrogrademenstruation (Sampson, 1925), which plausibly explainsmost pathophysiological and clinical aspects inendometriosis, uterine endometrium is the tissue of origin forendometriosis foci. With laparoscopies being increasinglyperformed, however, it has become evident that retrogrademenstruation must be regarded as a normal phenomenon(Halme et al., 1984), and Blumenkrantz et al. (1981)observed blood in peritoneal dialysates of women withpatent tubes at the time of menstruation. Even during theremainder of the menstrual cycle, some reflux ofendometrial cells into the peritoneal cavity seems to bephysiological, as reported by Bartosik et al. (1986).However, these authors found increased amounts ofendometrial cells in the peritoneal fluid of endometriosispatients after uterine irrigation. Leyendecker and co-workers(1996) recently demonstrated uterine hyperperistalsis anddysperistalsis to be present in patients with endometriosis,and suggested this phenomenon as a causal factor for bothreduced fertility (via an impaired sperm transport) and thedevelopment of endometriosis.Menstruation is initiated by oestrogen and progesteronewithdrawal and mediated at the molecular level, mainly bychanges in the expression of secreted proteases. Briefly, thereare two groups, one being the plasmin(ogen)activator/inhibitor system (also known as serine proteases),and the other being matrix metalloproteinases (which can beactivated by plasmin) and their tissue inhibitors (TIMPs;Tabibzadeh, 1996). The hormonal regulation and cellspecificity of TIMPs in human endometrium has recentlybeen described in detail (Zhang and Salamonsen, 1997). Anendometrial function which is even more important thanmenstruation, i.e. the implantation of the blastocyst, depends