Targeting Oxidative Stress Involved in Endometriosis and Its Pain

Abstract

Endometriosis is a common gynecological disorder seen in women and is characterized by chronic pelvic pain and infertility. This disorder is becoming more prevalent with increased morbidity. The etiology of endometriosis remains to be fully elucidated, which will lead to improved therapeutic options. In this review, we will evaluate the biochemical mechanisms leading to oxidative stress and their implication in the pathophysiology of endometriosis, as well as potential treatments that target these processes. A comprehensive exploration of previous research revealed that endometriosis is associated with elevated reactive oxygen species and oxidation products, decreased antioxidants and detoxification enzymes, and dysregulated iron metabolism. High levels of oxidative stress contributed to inflammation, extracellular matrix degradation, angiogenesis, and cell proliferation, which may explain its role in endometriosis. Endometriosis-associated pain was attributed to neurogenic inflammation and a feed-forward mechanism involving macrophages, pro-inflammatory cytokines, and pain-inducing prostaglandins. N-acetylcysteine, curcumin, melatonin, and combined vitamin C and E supplementation displayed promising results for the treatment of endometriosis, but further research is needed for their use in this population.

Keywords: antioxidant; ferroptosis; inflammation; pain.

Figure 1

Dysregulated Iron Homeostasis Leads to Oxidative Stress and Ferroptosis in Endometriosis. (A) Retrograde menstruation, a proposed mechanism for disruption of iron homeostasis in endometriosis, induces ectopic bleeding in the peritoneal cavity (PC). This causes erythrocyte degradation which releases free iron. High levels of iron promote increased transferrin saturation. (1) Transferrin binds to iron and delivers it to tissues where it binds to the transferrin receptor (TfR1). (2) The TfR1-Fe3+ complex enters the cell in an (3) endosome where acidification enables the separation of ferric iron (Fe3+) from the receptor. Six transmembrane epithelial antigens of the prostate 3 (STEAP3) catalyzes the conversion of ferric iron to ferrous iron (Fe2+). (4) Ferrous iron leaves the endosome and accumulates in the cytosolic iron pool. (5) Increased levels of iron in the cytosolic pool leads to increased levels of the intracellular iron storage protein, ferritin. (6) A portion of excess iron will undergo the Fenton reaction to generate free radicals which can damage lipids, proteins, and DNA. (B) This schematic represents a simplified diagram of ferroptosis, an-iron dependent mechanism of cell death. Ferroptosis occurs when glutathione-dependent antioxidant systems fail due to the accumulation of excessive reactive oxygen species (ROS). (7) There is decreased availability of reduced glutathione (GSH) due to excessive intracellular ROS. GSH is required for the conversion of lipid peroxides to non-toxic lipid alcohols by the enzyme glutathione peroxidase (GPX4). (8) Lipid peroxides accumulate and reduce membrane permeability and (9) promote the loss of mitochondrial cristae which contributes to mitochondrial outer membrane rupture. The intracellular accumulation of lipid peroxides and decreased total antioxidant capacity (TAC) eventually leads to cell death. Adapted from “Role of Lipin-1 in Modified-LDL Induced Pro-inflammatory Response”, by Biorender.com (2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 18 July 2022).

Figure 2

A simplified diagram of the etiology underlying iron-dependent oxidative stress characteristic of endometriosis.

Figure 3

The chemical structures of several key compounds discussed in the review which have been used for the treatment of endometriosis.

Figure 4

Potential therapeutic options for attenuating oxidative stress and inflammation in endometriosis. Elevated levels of TNF-a present in endometriosis activate the TNFR1-dependent signaling pathway which regulates the transcription of genes that prevent apoptosis and promote inflammation and cytokine production. Upregulation of this pathway leads to cell survival, proliferation, differentiation, and migration in endometriosis in comparison to controls. Oxidative stress resulting in elevated ROS increases the phosphorylation and degradation of IkB leading to nuclear translocation of NF-kB which activates gene expression. Curcumin and vitamin D supplementation may inhibit the phosphorylation of IkB preventing NF-kB nuclear translocation and expression of downstream targets. Omega-3 PUFAs and Vitamin C have the potential for reducing the activity of transcription factor NF-kB. Adapted from “Intracellular Layout—Nucleus and Endoplasmic Reticulum”, by Biorender.com (2022). Retrieved from https://app.biorender.com/biorender-templates (accessed on 18 July 2022).