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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.

Currently, several endometriosis classification systems are available in clinical practice; however, no single classification system can predict the severity of all pre-and post-operative symptoms of endometriosis, such as pain, infertility and fibrosis. The aim of the present review was to reconcile the concepts of endometriosis classification and the molecular aspects of endometriosis. Each keyword alone or in combination was used to search by applying the filters of the title and the publication years between January, 2000 and December, 2019. Several classifications systems have been proposed to categorize the severity of endometriosis. The cause of pain is not only related to anatomic abnormalities, but also to the imbalance between sensory and sympathetic innervation due to the abnormal secretion of a variety of cytokines. Endometriosis-related infertility is a group of diseases manifesting with various morphological and functional abnormalities that negatively affect fertility. Diagnostic imaging, which primarily provides morphological information, has limitations as disease progression is not associated with the prevalence and severity of infertility. Changes in the microenvironment caused by endometriosis-induced inflammation and oxidative stress can lead to impaired fertility. In particular, proinflammatory mediators (cytokines, interleukins and immune dysfunction), oxidative stress markers (hemoglobin, heme, free iron, ROS and antioxidants), hormonal imbalance, proteolytic enzymes and soluble adhesion molecules all may be potential markers for predicting infertility. The major cell types involved in the development of endometriosis-associated fibrosis are platelets, various inflammatory cells, such as macrophages, T lymphocytes, B lymphocytes and natural killer (NK) cells, ectopic endometrial cells, and sensory nerve fibers. A variety of symptoms, such as pain, infertility and fibrosis, involve interrelated signaling mechanisms. Beyond the structural and functional changes that characterize a variety of symptoms, there may be interrelated, common signaling pathways. The present review highlights the molecular mechanisms involved in endometriosis-associated symptoms such as pain, infertility and fibrosis. In order to create a disease severity scoring system that can predict each symptom of endometriosis, not only anatomical findings, but also biochemical parameters, such as oxidative stress are required. Contents

<b><i>Objectives and Design:</i></b> Endometriosis-related pain can be caused by anatomical distortions as well as environmental factors such as inflammation and oxidative stress. The aim of this study is to investigate the relationship between the severity of dysmenorrhea in patients with ovarian endometrioma (OMA) and cyst fluid (CF) concentrations of irons, including total iron, heme iron, and free iron. <b><i>Method:</i></b> Eighty-three patients who were histologically diagnosed with OMA were enrolled in the Department of Gynecology, Nara Medical University Hospital, between 2013 and 2019. The patients were divided into 4 groups according to the severity of dysmenorrhea: no pain, mild, moderate, and severe. Iron concentration was measured by the inductively coupled plasma optical emission spectrometry method. <b><i>Results:</i></b> There were no significant differences among the 4 groups in variables such as age at diagnosis, preoperative CA125, preoperative CA19-9, cyst size, and tumor laterality (unilateral or bilateral). There was a positive correlation between the severity of dysmenorrhea and total iron (<i>p</i> &#x3c; 0.001) and heme iron (<i>p</i> = 0.016) concentrations. Multiple regression analyses revealed that the CF concentration of total iron (hazard ratio 18.75, 95% confidence interval: 2.26–155.35, <i>p</i> = 0.007) was a significant independent variable associated with the severity of dysmenorrhea. A receiver operating characteristic curve analysis showed that a total iron exceeding 290.8 mg/L was associated with severe dysmenorrhea with a sensitivity of 90.9% and a specificity of 65.7%. <b><i>Limitations:</i></b> This study excluded patients with adenomyosis, superficial endometriosis, or deep endometriosis, resulting in a smaller number of cases. Iron levels could not be compared to the endometriosis stage using the r-ASRM score. <b><i>Conclusions:</i></b> There is no clear evidence that iron predicts the severity of endometriosis-related pain. However, iron may be closely associated with dysmenorrhea.