Substantial evidence suggests that endometriosis is associated with a state of subclinical peritoneal inﬂammation, marked by an increased peritoneal ﬂuid volume, increased peritoneal ﬂuid white blood cell concentration (especially macrophages with increased activation status), and increased inﬂammatory cytokines, growth factors, and angiogenesispromoting substances. It is reported in baboons that subclinical peritoneal inﬂammation occurs during menstruation and after intrapelvic injection of endometrium (93). A higher basal activation status of peritoneal macrophages in women with endometriosis may impair fertility by reducing sperm motility, increasing sperm phagocytosis, or interfering with fertilization, possibly by increased secretion of cytokines such as tumor necrosis factor-α (TNF-α) (96–100). Tumor necrosis factor may facilitate the pelvic implantation of ectopic endometrium (99,100). The adherence of human endometrial stromal cells to mesothelial cells in vitro is increased by the pretreatment of mesothelial cells with physiologic doses of TNF-α (101). Macrophages or other cells may promote the growth of endometrial cells by secretion of growth and angiogenetic factors such as epidermal growth factor (EGF), macrophage-derived growth factor (MDGF), fibronectin, and adhesion molecules such as integrins (101–107). After attachment of endometrial cells to the peritoneum, subsequent invasion and growth appear to be regulated by matrix metalloproteinases (MMP) and their tissue inhibitors (108,109).
There is increasing evidence that local inﬂammation and secretion of prostaglandins (PG) is related to differences in endometrial aromatase activity between women with and without endometriosis. Expression of aromatase cytochrome P450 protein and mRNA is present in human endometriotic implants but not in normal endometrium, suggesting that ectopic endometrium produces estrogens, which may be involved in the tissue growth interacting with the estrogen receptor (110). Inactivation of 17β-estradiol is impaired in endometriotic tissues because of deficient expression of 17β-hydroxysteroid dehydrogenase type 2, which is normally expressed in eutopic endometrium in response to progesterone (111). The inappropriate aromatase expression in endometriosis lesions can be stimulated by prostaglandin E2 (PGE2). This reaction leads to local production of E2, which stimulates PGE2 production, resulting in a positive-feedback system between local inﬂammation and estrogen-driven local growth of ectopic endometrium (112).
The subclinical pelvic inﬂammatory status associated with endometriosis is reﬂected in the systemic circulation. Increased concentrations of C-reactive protein, serum amyloid A (SAA), TNF-α, membrane cofactor protein-1, interleukin-6 (IL-6), IL-8, and chemokine (C-C motif) receptor 1 (CCR1) are observed in peripheral blood samples of patients with endometriosis when compared with controls (113). This observation offers a basis for the development of noninvasive diagnostic tests.
Both hypothesis-driven research and system biology approaches using mRNA microarray and proteomic techniques studies show that eutopic endometrium is biologically different in women with endometriosis when compared to controls with respect to proliferation, apoptosis, angiogenesis, and inﬂammatory pathways (114–117). Several studies show a higher prevalence of nerve fibers and neurotrophic factors in the eutopic endometrium from women with endometriosis when compared to controls (46,118).