Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies

Abstract

Endometriosis is an estrogen-dependent inflammatory disease that affects up to 10% of women of reproductive age and accounts for up to 50% of female infertility cases. It has been highly associated with poorer outcomes of assisted reproductive technology (ART), including decreased oocyte retrieval, lower implantation, and pregnancy rates. A better understanding of the pathogenesis of endometriosis-associated infertility is crucial for improving infertility treatment outcomes. Current theories regarding how endometriosis reduces fertility include anatomical distortion, ovulatory dysfunction, and niche inflammation-associated peritoneal or implantation defects. This review will survey the latest evidence on the role of inflammatory niche in the peritoneal cavity, ovaries, and uterus of endometriosis patients. Nonhormone treatment strategies that target these inflammation processes are also included. Furthermore, mesenchymal stem cell-based therapies are highlighted for potential endometriosis treatment because of their immunomodulatory effects and tropism toward inflamed lesion foci. Potential applications of stem cell therapy in treatment of endometriosis-associated infertility in particular for safety and efficacy are discussed.

Keywords: endometriosis; immunomodulation; infertility; inflammation; mesenchymal stem cell; niche.

Figure 1

Different inflammatory niche in (A) peritoneal cavity, (B) ovary, and (C) eutopic endometrium in endometriosis. The population of each immune cell type, the level of cytokine/hormone/protein expression, and the activation of cellular pathways are depicted by an up arrow or a down arrow to represent an increase or a decrease, respectively. BLyS, B lymphocyte stimulator; CC, cumulus cell; COX-2, cyclooxygenase 2; DC, dendritic cell; E2, estradiol; FF, follicular fluid; GC, granulosa cell; HGF, hepatocyte growth factor; IGF-I, insulin-like growth factor 1; IL, interleukin; LIF, leukemia inhibitory factor; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MIF, macrophage migration inhibitory factor; MMP, matrix metalloproteinases; NK, natural killer; P4, progesterone; PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; RANTES (CCL5), regulated on activation, normal T cell expressed and secreted; ROS, reactive oxygen species; sICAM-1, soluble intercellular adhesion molecule-1; TNF-α, tumor necrosis factor alpha; TGF-β, transforming growth factor beta; Th, T helper cell; Treg, regulatory T cell; VEGF, vascular endothelial growth factor.

Figure 2

Mesenchymal stem/stromal cell (MSC)-based therapy for treatment of endometriosis-associated infertility: safety and efficacy.