Views and reviewsPathogenesis and pathophysiology of endometriosis
Section snippets
Histopathogenesis
A unifying theory regarding the origin of endometriosis has remained mystifyingly elusive. Instead, several theories (Fig. 1) have arisen to account for the disparate observations regarding pathogenesis, and these can generally be categorized as those proposing that implants originate from uterine endometrium and those proposing that implants arise from tissues other than the uterus. Intrinsic to these theories are inciting factors and genetic susceptibilities whose roles are beginning to be
Endometrial cell survival
The evidence for an innate or acquired condition of the endometrial cells as the predisposing factor toward implantation is compelling. The eutopic endometrium from women with endometriosis shares certain alterations with ectopic lesions that are not observed in the endometrium from healthy women. Up-regulation of the antiapoptotic gene BCL-2 has been shown in both eutopic and ectopic endometrium from affected women (31). In addition to decreased apoptosis, enhanced proliferation may confer a
Altered hormonal milieu: estrogen dependence and P resistance
Hormonal alterations may influence the ability of endometrial cells to proliferate, attach to the mesothelium, and/or evade immune-mediated clearance. Long appreciated clinically, the concept of endometriosis as an estrogen-dependent disorder is well supported by molecular evidence (46). A striking finding in endometriotic tissue relative to eutopic endometrium is the increased expression of the aromatase enzyme and decreased expression of 17β-hydroxysteroid dehydrogenase (17β-HSD) type 2 (47).
Evasion from immune clearance
Normally, refluxed endometrial tissue is cleared from the peritoneum by the immune system, and the dysregulation of this clearance mechanism has been implicated in the predisposition to implantation and growth of endometrial cells. Interestingly, larger tissue fragments as opposed to individual cells demonstrate an increased capacity to implant, presumably owing to the protection from immune clearance afforded the cells residing on the inner aspects of such fragments (52). Additionally, the
Endometrial cell attachment and invasion
Although endometriosis is a benign disorder, the process by which endometrial cells attach and invade surfaces shares features of malignancy. The ESC fraction is primarily involved in the interaction of endometrial tissue with the mesothelial cell lining of the peritoneum. A study using ESCs and peritoneal mesothelial cells from a variety of sources in an in vitro binding assay demonstrated that the source of the ESCs rather than the source of the peritoneal cells had the greatest impact on the
Lesional neuroangiogenesis/vasculogenesis and growth
A rich vascular supply is necessary for the development and sustenance of endometriotic lesions, particularly in the peritoneal microenvironment, which is relatively avascular compared with the eutopic endometrium. Neoangiogenesis and capillary recruitment are visibly associated with endometriotic lesions at laparoscopy, most notably in the context of the red vesicular phenotype (Fig. 2). In addition, nerves frequently accompany angiogenesis (neuroangiogensis), likely contributing to the pain
Inflammation
Increasing evidence supports the conceptualization of endometriosis as a pelvic inflammatory condition. In women with endometriosis, the peritoneal fluid is remarkable for an increased number of activated macrophages and important differences in the cytokine/chemokine profile (78). A proteomics approach identified a unique protein structurally similar to haptoglobin in the peritoneal fluid of patients with endometriosis (79). This protein was subsequently found to bind to macrophages, reduce
Lesional progression and sequelae
Clinical and molecular lines of evidence converge to support a stagewise phenotypic progression associated with peritoneal endometriotic lesions. These stages include red vesicular, black powder-burn, and fibrotic lesional phenotypes. Longitudinal placebo-controlled trials with second-look laparoscopy have demonstrated that 71%–83% of untreated lesions will progress or remain stable over a 12-month period 92, 93. The earliest lesion is the red vesicular subtype (Fig. 4A). Red vesicular lesions
Conclusion
Since the original clinical description of endometriosis, much has been accomplished in furthering our understanding of this debilitating disease. Although no theory of pathogenesis can account for all of the described manifestations of endometriosis, the retrograde menstruation theory has gained widespread acceptance as an explanation for the dissemination of endometrial cells. The exact factor or factors that orchestrate the survival and subsequent implantation of the displaced endometrium
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R.O.B. has nothing to disclose. L.C.G. has nothing to disclose.
Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health (NICHD/NIH) through cooperative agreement U54HD055764-06 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research (L.C.G.).