Pathogenesis

The exact pathogenesis and pathophysiology of endometriosis are still not completely elucidated. Theories regarding the pathogenesis of endometriosis can generally be categorized as those proposing that implants originate from uterine endometrium by retrograde menstruation, lymphatic/haematogenous dissemination, or endo­metrial stem cell implantation and those proposing that implants arise from tissues other than the uterus by coelomic metaplasia or Mullerian remnant abnormalities (14).

The most widely accepted theory on the pathogenesis of endo­metriosis, proposed by Sampson in the 1920s, is that the disorder originates from retrograde sloughing of endometrial tissue through patent fallopian tubes into the peritoneal cavity (15). This theory is supported by the observation of higher prevalence of endomet­riosis in patients with obstructed or compromised outflow tracts (14). Furthermore, it has been established that intraperitoneal in­jection of menstrual blood or iatrogenic obstruction of the outflow tract in a nonhuman primate model results in endometriotic lesions within the peritoneal cavity (16, 17). Nevertheless, it is important to take into account that retrograde menstruation is observed in up to 90% of women and only 2-10% of women have endometriosis, suggesting that additional mechanisms are necessary for the devel­opment of endometriotic implants (14).

According to substantial evidence, the endometrium of women with endometriosis is abnormal due to a complex interplay of gen­etic, environmental, and immunological factors, resulting in the de­velopment of endometriotic lesions when retrograde menstruation occurs (15). Indeed, eutopic endometrium from women with endo­metriosis shares certain alterations with ectopic lesions that are not observed in the endometrium from healthy women (14). Studies comparing gene and protein expression in eutopic endometrium show differences in several pathways resulting in decreased apop­tosis and increased cell proliferation in patients with endometriosis (14).

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 (15). The eutopic endo­metrium from women with endometriosis was found to be more re­sistant to lysis by natural killer cells than the eutopic endometrium from women without disease (20-22). Compromised macrophage function in women with endometriosis may further contribute to decreased clearance of lesions (23). Further support for a funda­mentally altered immune system in the predisposition to endomet­riosis is derived from studies demonstrating a high concordance of autoimmune (systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome, and autoimmune thyroid disease) and atopic dis­ease (allergies, asthma, and eczema) in affected women (14).

The alterations in the immune system, endometrium, and peri­toneum resulting in decreased immunological clearance of refluxed endometrial tissue, increased cell survival, and higher chances of im­plantation in the peritoneum are important mechanisms to explain the initial development of endometriotic implants (14). Subsequent survival and growth of these implants is dependent on angiogen­esis and an altered hormonal environment (24).

Inflammation is another typical feature of endometriosis, as the presence of ectopic tissue in the peritoneal cavity is associated with overproduction of prostaglandins, cytokines, and chemokines (16). Macrophages infiltrating the ectopic lesions express typical markers of alternative activation, favouring the growth of the lesions and promoting their angiogenesis (12). Macrophages in the peritoneal cavity of affected women are known to accumulate iron, probably as a result of excessive pelvic blood collection (12). Non-protein­bound catalytic iron increases the generation of reactive oxygen species, which in turn favours the progression of endometriosis via peritoneal damage, exposure of submesothelial connective tissue, angiogenesis, and enhanced endometrial cell proliferation (12).

In summary, available evidence suggests that endometriosis ori­ginates from retrograde menstruation of endometrial tissue (15) (Figure 45.1). Intrinsic alterations in the immune system, endo­metrium, and peritoneum of patients with endometriosis result in implantation of this endometrial tissue on the peritoneal surface. Local changes in steroid production and angiogenesis support fur­ther growth of the lesions. This elicits an inflammatory response accompanied by development of adhesions, fibrosis, scarring, neur­onal infiltration, and anatomical distortion, resulting in pain and infertility (15).