Clinical meaning
Endometriosis is defined by the presence of endometrial-like tissue (glands and stroma) outside the uterine cavity, most commonly on the pelvic peritoneum, ovaries (endometriomas), and rectovaginal septum. At the molecular level, Sampson's theory of retrograde menstruation provides the mechanical seeding mechanism - viable endometrial cells reflux through the fallopian tubes during menses - but immune dysregulation is required for implant survival. In healthy individuals, peritoneal macrophages and natural killer (NK) cells clear ectopic endometrial cells. In endometriosis, defective NK cell cytotoxicity (reduced expression of activating receptors NKG2D and NKp46) and altered macrophage polarization (shift from M1 pro-inflammatory to M2 reparative phenotype) allow implant survival. Ectopic implants secrete matrix metalloproteinases (MMP-2, MMP-9) that degrade the extracellular matrix, enabling tissue invasion and neovascularization via vascular endothelial growth factor (VEGF) overexpression. Local aromatase (CYP19A1) overexpression in ectopic stromal cells drives autonomous estrogen biosynthesis through intracrine signaling. Simultaneously, 17-beta-hydroxysteroid dehydrogenase type 2 (17β-HSD-2) - which normally inactivates estradiol to estrone - is downregulated due to progesterone resistance mediated by epigenetic silencing of progesterone receptor B (PR-B) via promoter hypermethylation. This creates a self-perpetuating estrogen-dominant...