Pathophysiology and Immune Dysfunction in Endometriosis

Abstract

Endometriosis is an estrogen-dependent, chronic, proinflammatory disease prevalent in 10% of women of reproductive age worldwide. Characterized by the growth of endometrium-like tissue in aberrant locations outside of the uterus, it is responsible for symptoms including chronic pelvic pain, dysmenorrhea, and subfertility that degrade quality of life of women significantly. In Canada, direct and indirect economic cost of endometriosis amounts to 1.8 billion dollars, and this is elevated to 20 billion dollars in the United States. Despite decades of research, the etiology and pathophysiology of endometriosis still remain to be elucidated. This review aims to bring together the current understanding regarding the pathogenesis of endometriosis with specific focus on mechanisms behind vascularization of the lesions and the contribution of immune factors in facilitating lesion establishment and development. The role of hormones, immune cells, and cytokine signaling is highlighted, in addition to discussing the current pharmaceutical options available for management of pain symptoms in women with endometriosis.

Figure 1

An overview of immune cells and mediators involved in the promotion of neovascularization and endometriotic lesion growth on the peritoneal membrane. In women with endometriosis, high levels of angiogenic factors and inflammatory cytokines are found in the peritoneal fluid (PF). Development of blood vessels of the lesions depends on two processes: vasculogenesis and angiogenesis. Vasculogenesis is mediated by recruitment and incorporation of the bone marrow- (BM-) derived endothelial progenitor cells (EPCs) to proliferating blood vessels in the endometriotic lesions. Recruitment of BM-derived EPCs is facilitated by stromal cell-derived factor- (SDF-) 1. Vascular endothelial growth factor (VEGF) and other angiogenic factors including interleukin- (IL-) 6, IL-8, and tumor necrosis factor- (TNF-) α mediate the process of angiogenesis by activating angiogenic switch of endothelial cells. Local production of estradiol by the lesion maintains the expression of VEGF and promotes the production of VEGF and monocyte chemoattractant protein- (MCP-) 1 by the macrophages. In women with endometriosis, natural killer (NK) cell cytotoxicity is diminished, which may be due to increased expression of IL-10 in the PF. Immature dendritic cells (DCs) express VEGFR-2 on the surface and thus are theorized to play a role in angiogenesis by interacting with VEGF. The integrated role of immune cells and mediators is a complicated process and requires further studies to piece together the details available to fully appreciate their role in the pathogenesis of endometriosis.