Endometriosis as a Chronic HIF-2α-Dominant Hypoxia–Fibrosis Syndrome: A Unified Mechanistic Framework and Rationale for Metabolic Repurposing

Authors:  Dr Graham Exelby¹,² & Dr Cris Beer¹,³. 2025.

¹MCMC-Research Collaborative, Gold Coast, Australia

² University of Queensland School of Medicine (Adjunct), Brisbane

³Integrative Gynaecology & Women’s Health, Gold Coast

Reviewed by Dr Valerio Vittone (PhD), Gold Coast

Abstract

Endometriosis is traditionally defined as ectopic endometrial-like tissue that evades immune clearance. Emerging molecular, vascular, and immunometabolic data suggest this view is incomplete. Evidence supports a model where endometriosis functions as a chronic hypoxia-locked, HIF-2α-dominant hypoxia–fibrosis syndrome sustained by PI3K/AKT hyperactivation, impaired PTEN and PEMT function, mast-cell and macrophage amplification, iron-driven oxidative stress, and structural lymphatic–venous obstruction.

This self-reinforcing microenvironment provides a mechanistic basis for aggressive angiogenesis, fibrosis, progesterone resistance, neuroangiogenesis, central sensitisation, high recurrence rates, and overlaps with Long COVID, POTS, and mast-cell activation syndrome. Among approved agents, dual GLP-1/GIP receptor agonists modulate multiple nodes in this network, providing a biologically plausible rationale for investigation in endometriosis. Any potential clinical effects remain unproven and require controlled trials. This synthesis integrates current evidence into a unified framework and highlights the need for phenotype-stratified, metabolism-guided clinical trials.

Full paper below

Endometriosis as a Chronic HIF-2α-Dominant Hypoxia–Fibrosis Syndrome- A Unified Mechanisti.

Download • 1.39MB