Characterising the immune cell phenotype of ectopic adenomyosis lesions compared with eutopic endometrium: A systematic review

Inflammation is implicated in the symptomatology and the pathogenesis of adenomyosis. Injury at the endo-myometrial interface causes inflammation and may facilitate the invasion of endometrium into the myometrium, forming adenomyosis lesions. Their presence causes local inflammation, resulting in heavy menstrual bleeding, chronic pelvic pain, and subfertility. Immunological differences have been described in the eutopic endometrium from women with adenomyosis compared to healthy endometrium, and differences are also expected in the adenomyotic lesions compared with the correctly sited eutopic endometrium. This systematic review retrieved relevant articles from three databases with additional manual citation chaining from inception to 24th October 2022. Twenty-two eligible studies were selected in accordance with PRISMA guidelines. Risk of bias assessments were performed, and the findings presented thematically. Ectopic endometrial stroma contained an increased density of macrophages compared with eutopic endometrium in adenomyosis. This was associated with an increase in pro-inflammatory cytokines (IL-6, IL-8, ILβ-1, C-X-C Motif Chemokine Receptor 1(CXCR1), Monocyte Chemoattractant Protein-1 (MCP-1)), and an imbalance of anti-inflammatory cytokines (IL-22, IL-37). Cells in ectopic lesions also contained a higher levels of toll-like receptors and immune-mediated enzymes. However, the studies were heterogeneous, with inconsistent reporting of immune cell density within epithelial or stromal compartments, and inclusion of samples from different menstrual cycle phases in the same group for analysis. A detailed understanding of the immune cell phenotypes present in eutopic and ectopic endometrium in adenomyosis and associated dysregulated inflammatory processes will provide further insight into the pathogenesis, to enable identification of fertility-sparing treatments as an alternative to hysterectomy.