*2.3. Pathophysiology of Endometriosis*

To date, the etiology and pathogenesis of endometriosis remains controversial. Multiple theories have been proposed to explain the pathogenesis of endometriosis [24,25,38]. Among the most recognized and reasonable are retrograde menstrual blood flow, coelomic metaplasia, and Müllerian remnants theories [21,24,39,53,54]. Amongst the various hypotheses, the one that has the greatest consensus is Sampsons' retrograde menstruation. Retrograde menstruation is the process in which endometrial cells and fragments of the tissue shed during menstrual bleeding and are transported into the peritoneal cavity due to the retroperistaltic movements of the fallopian tubes [21,24,53]. Implantation of these particles and subsequent proliferation during the menstrual cycle leads to the damage of pelvic organs at positions of implantation [21]. However, the hypothesis about the retrograde menstruation as a potential cause of endometriosis does not explain localization of endometrial tissue that can be found in rare cases of extragonadal endometriosis and endometriosis in male patients [26]. Another theory suggests that endometriosis develops due to endometrial cells transferred through the lymphatic system to other parts of the body, where they further grow and proliferate [21,24,26]. Additionally, it has been proposed that circulating blood cells originating from bone marrow differentiate into endometriotic tissue at various body sites [24,55]. Distant organ endometriosis, such as lung and brain endometriosis, is very rarely described and might be explained by vascular spread [21,24].

Meyer's hypothesis about coelomic metaplasia suggests development of endometriosis from the visceral epithelium, which can be converted to endometrial tissue by metaplastic processes [21,39].

More recent studies suggest that endometriosis is a pelvic inflammatory condition, so called "peritonitis without germs" [39,53]. This is based on the fact that the peritoneal fluid has an increased concentration of activated macrophages and an inflammatory profile in the cytokine/chemokine axis [39,56]. Cousins and Gargett in 2018 proposed that the human endometrium regenerates cyclically every month mediated by endometrial stem/progenitor cells such as CD140b+, CD146+, or SUSD2+ endometrial mesenchymal stem cells (eMSCs) [57]. N-cadherin + endometrial epithelial progenitor cells and side population cells may also contribute to the pathogenesis of the disease. They hypothesized that the eMSCs may have a role in the generation of progesterone-resistant phenotype endometrial stromal fibroblasts [39,57]. According to the other recent theories, deregulation of genes and the Wingless-related integration site (Wnt)/β-catenin signaling pathway would produce an aberration and the axial extension of the identity of the anterior-posterior patterning, whilst a deregulation of Hox genes and cofactor pre-B-cell leukemia homeobox 1 (Pbx1) produces an aberration in the segmentation of the mesoderm [21]. This

may cause aberrant placement of stem cells with endometrial phenotype and maintain them in a quiescent niche. Transcriptional activity induces the expression of vascular endothelial growth factor (VEGF) that stimulates the vascular endothelial cell. On the other hand, Müllerian inhibiting factor (MIF) induces endometrial cell mitosis, whose survival is supported by the activation of antiapoptotic gene B-cell lymphoma 2 (Bcl-2), by the degradation of the extracellular matrix by matrix metalloproteinases (MMPs) via intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion protein 1 (VCAM-1), creating the conditions for differentiation, adhesion, proliferation, and survival of ectopic endometrial cells [21]. This will lead to decreased apoptosis of ectopic endometrial-like cells [58–60], which escape from immune surveillance, and subsequently implant and proliferate. According to a recent review by Patel and colleagues, there is growing evidence that hormonal and immune factors create a pro-inflammatory microenvironment that support the persistence of endometriosis [61]. It is clear there is still much to learn about the nature and pathophysiology of endometriosis, and development of these theories could contribute to a greater understanding of the disease.
