Nonhormonal Treatment for Endometriosis Focusing on Redox Imbalance

Abstract

The aim of this review is to investigate the oxidant/antioxidant status and its regulatory mechanisms in patients with endometriosis and to summarize the antioxidant therapy as an alternative to hormonal therapy for endometriosis. 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 March 2020. Endometriosis is a chronic inflammatory disease characterized by repeated episodes of hemorrhage. Methemoglobin in repeated hemorrhage produces large amounts of superoxide anion via the autoxidation of hemoglobin. Excessive free-radical production causes redox imbalance, leading to inadequate antioxidant defenses and damage to endometrial cells, but may contribute to endometrial cell growth and survival through activation of various signaling pathways. In addition, to overcome excessive oxidative stress, estradiol participates in the induction of antioxidants such as superoxide dismutase in mitochondria. Several antioxidants that suppress free radicals may be effective in endometriosis-related pain. We searched for 23 compounds and natural substances that could reduce the pain caused by superoxide/reactive oxygen species in basic research and animal models. Next, we built a list of 16 drugs that were suggested to be effective against endometriosis other than hormone therapy in preclinical studies and clinical trials. Of the 23 and 16 drugs, 4 overlapping drugs could be potential candidates for clinically reducing endometriosis-related pain caused by superoxide anion/reactive oxygen species. These drugs include polyphenols (resveratrol and polydatin), dopamine agonists (cabergoline), and statins (simvastatin). However, no randomized controlled trials have evaluated the efficacy of these drugs. In conclusion, this review summarizes the following 2 points: superoxide anion generation by methemoglobin is enhanced in endometriosis, resulting in redox imbalance; and some compounds and natural substances that can suppress free radicals may be effective in endometriosis-related pain. Further randomized clinical trials based on larger series are mandatory to confirm the promising role of antioxidants in the nonhormonal management of endometriosis.

Effects of resveratrol on female reproduction: A review

“…Furthermore, RSV, like other polyphenols, has phytoestrogenic properties, that is, ability to bind and to affect steroid hormones receptors and to affect steroid‐dependent processes and diseases (Gambini et al, 2015; Nguyen, Savouret, Widerak, Corvol, & Rannou, 2017; Ortega & Duleba, 2015; van Duursen, 2017; Varoni, Lo Faro, Sharifi‐Rad, & Iriti, 2016; Zeng et al, 2020). RSV has antioxidant properties, which can be important in prevention of inflammation, malignant transformation and neurodegenerative diseases (Nagayasu, Imanaka, Kimura, Maruyama, & Kobayashi, 2021; Zeng et al, 2020). Moreover, RSV can bind and affect DNA methyltransferases and associated proteins responsible for DNA methylation resulting in activation of a number of genes (Mirza et al, 2013).…”

Clinicopathological characteristics, molecular features and novel diagnostic strategies for the detection of malignant transformation of endometriosis (Review)

“…Dual role of antioxidants in the different stages of malignant transformation of endometriosis. Nagayasu et al (34) presented a comprehensive review on the endogenous antioxidant defense systems in endometriosis. The generated ROS can be scavenged by enzymatic (e.g., superoxide dismutase [SOD], catalase, reduced glutathione [GSH], glutathione peroxidase [GPX], and thioredoxin) and non-enzymatic (e.g., estradiol, melatonin, vitamin E, and vitamin C) antioxidants (35,36).…”

Endometriosis: A Disease with Few Direct Treatment Options

“…Curcumin can significantly reduce the expression of COX-2, the production of TNF-α and IL-6, and decrease the epithelium-mesenchymal transition, essential for the development of endometriosis [64,108]. In addition, it can also reduce cell proliferation, decrease the size of endometriotic lesions, generate a reduction in matrix metalloproteinase-9 activity, and reduce VEGF expression, thus having an antiangiogenic character [126]. Chowdhury and collaborators demonstrated in their study that the effects of curcumin treatment on eutopic endometrial cells from endometriosis patients significantly reduce the secretion of inflammatory cytokines in these cells, also decreasing the phosphorylation of IKKα/β, NF-κB, STAT3, and JNK signaling pathways [127].…”

“…Puerarin is an isoflavonoid found in Pueraria lobata, used in the treatment of cardiovascular and neurological diseases. Due to its ability to inhibit aromatase enzyme activity in endometrial cells and suppress cell adhesion and proliferation, it constitutes a possible new treatment against endometriosis [126,128]. A study by Yu et al [129] showed that treatment with puerarin reduced the levels of estradiol and PGE2 in endometriotic rats, by inhibiting the aromatase enzyme P450 and COX-2, in addition to increasing the expression of 17β-HSD2, thus preventing the growth of endometrial tissue.…”

“…new treatment against endometriosis [126,128]. A study by Yu et al [129] showed that treatment with puerarin reduced the levels of estradiol and PGE2 in endometriotic rats, by inhibiting the aromatase enzyme P450 and COX-2, in addition to increasing the expression of 17β-HSD2, thus preventing the growth of endometrial tissue.…”