Peritoneal Hypoxia as a Gatekeeper Between Physiologic Retrograde Menstruation and Pathologic Persistence in Endometriosis

Several hypotheses have been proposed to explain the establishment of endometriosis, of which retrograde menstruation remains the most widely accepted mechanism of dissemination. However, the mechanisms governing selective lesion establishment remain incompletely understood. Endometriosis affects ∼10% of reproductive-aged women, despite retrograde menstruation occurring in 76-90% of menstruating individuals. This discordance indicates that menstrual reflux is necessary but insufficient for disease development. We propose that transient, spatially restricted hypoxia functions as a biological gatekeeper determining whether refluxed endometrial fragments are cleared or establish persistent ectopic lesions. Menstrual shedding is an ischemia-reperfusion event characterized by hypoxia-inducible transcriptional activation; refluxed tissue therefore enters the peritoneal cavity in a hypoxia-primed state. In susceptible hosts, dysregulated microvascular responses and inflammatory oxygen consumption amplify local hypoxia, activating angiogenic, metabolic, endocrine, and neurotrophic programs that favor survival and invasion. Efficient oxygen restitution instead promotes immune-mediated clearance. We outline testable predictions and propose that, unlike prior work emphasizing hypoxia in established lesions, oxygen regulation may function as an early determinant of lesion fate, potentially resolving the long-standing paradox that retrograde menstruation is common whereas endometriosis develops in only a subset of women.