Revisiting estrogen-dependent signaling pathways in endometriosis: Potential targets for non-hormonal therapeutics

Endometriosis is an estrogen-dependent gynecologic disease. Endometriotic cells survive in oxidative stress and hypoxic environments. The aim of this review is to reconsider new therapeutic strategies for endometriosis by focusing on estrogen signaling, ROS production and scavenging, and mitochondrial metabolism. Each keyword alone or in combination was used to search from PubMed and Embase by applying the filters of the title and the publication years between January 2000 and May 2020. Abnormal epigenetic marks of estrogen receptors (ERs) in endometriosis cause overexpression of ERβ, progesterone resistance, inflammation, anti-apoptosis, and mitochondrial metabolic modification. In addition to hormonal action, estrogen is involved in various functions such as mitochondrial biosynthesis and energy metabolism. Estrogen works with its downstream target genes to modulate mitochondrial gene expression, regulate ROS production, and affect mitochondrial biology, including ATP production, antioxidant defenses, mitochondrial biosynthesis, quality control, and energy-transducing capacity. Endometriosis can shift mitochondrial metabolism from oxidative phosphorylation to aerobic glycolysis. This metabolic conversion suppresses ROS production and thus activates the survival signal of endometriotic cells. Therefore, molecules associated with aerobic glycolysis and mitochondrial metabolism are considered therapeutic targets for endometriosis. In conclusion, estrogen downstream target genes involved in mitochondrial metabolic biosynthesis may be potential targets for non-hormonal treatment of endometriosis.