{"paper_id":"9f0a858c-c82f-4ab6-9744-c19336376221","body_text":"Mini Review\nVolume 3 Issue 1 -March 2017\nDOI: 10.19080/JGWH.2017.03.555601\nJ Gynecol Women’s Health\nCopyright © All rights are reserved by Annika Sinha\nThe Role of Antioxidant Supplementation in \nEndometriosis Therapy\nAnnika Sinha* and Sajal Gupta\nCase Western Reserve University, USA\nSubmission: February 07, 2017; Published: March 07, 2017\n*Corresponding author: Annika Sinha, Case Western Reserve University, Cleveland, Ohio, USA, Email: \nJ Gynecol Women’s Health 3(1): JGWH.MS.ID.555601 (2017)\nIntroduction\nEndometriosis is a common benign disease characterized \nby extra-uterine implantation of endometrial-like tissue within \nthe ovaries, peritoneum, rectum, pelvis, and thoracic cavity. \nWhile some women remain asymptomatic, its symptoms and \nsigns include infertility, chronic pain, irregular bleeding, and \ndyspareunia in approximately 8% of women of reproductive \nage and up to 50% of infertile women [1,2]. While the \npathophysiologic mechanism of endometriosis is still unclear, \nthe disease is characterized by abnormal cellular proliferation, \ninvasion, and inflammation due to presence of reactive oxidative \nstress. These atypical processes underlie the signs and symptoms \nof this disease; therefore, treatment for endometriosis is targeted \nto address the various aspects of its pathogenesis.\nThe management of endometriosis is currently as \nrecommended by the European Society of Human Reproduction \n(ESHRE) guidelines [2]. These guidelines for endometriosis \ntherapy include oral contraceptive medications, GnRH agonists, \nprogestogens, analgesics, danazol, anti-progestogens, aromatase \ninhibitors, and conservative or non-conservative surgical \napproaches. The treatment approach for patients is highly \ndependent on the severity of the patient’s symptoms. Traditionally,  \n \nsurgical interventions, such as resection and nerve transection, \nare considered in patients with confirmed endometriosis who do \nnot respond to medical therapy [ASRM].Surgical methods aimed \nto removed endometriosis are considered more effective than \nnon-invasive means [1]. Surgery has been shown to significantly \nreduce pain, a major symptom of endometriosis [ASRM] and can \noffer improvements in fertility [1,3]. Though these interventions \nhave been shown to be effective, the relapse rate of endometriosis \npost-surgery, the most aggressive treatment, is still roughly 22% \nat 2 years and 40-50% after five years [4]. Though the current \ntherapeutic means offer benefits to patients, recent literature \non endometriosis treatment suggests that other novel medical \napproaches, especially in antioxidant therapy, may be able to \nsupplement the established treatment guidelines [3]. \nThe Role of Antioxidants \nAll Though the pathogenesis of endometriosis is still not fully \nelucidated, the disease is associated with oxidative stress and \nan abnormal increase in reactive oxidative species (ROS). ROS \nare volatile molecules that interact with biological molecules \nto activate apoptotic mechanisms and cell death [5]. ROS are \ntypically neutralized by physiological means; however, patients \n001\nJournal of\nGynecology and Women’s Health\nISSN 2474-7602\nAbstract \nEndometriosis is a benign, estrogen-dependent disorder, characterized by the presence of ectopic lesions in extra-uterine regions of body, \nincluding the ovaries, peritoneum, and even the thoracic cavity. Though the pathophysiology of endometriosis is relatively unknown, disease \nitself is characterized by cell survival, oxidative stress, cellular proliferation, excessive adhesion, inflammation, and angiogenesis [Matsuzaki]. \nThough endometriomas are not malignant, this atypical tissue can spread throughout the female reproductive tract, causing chronic pain, \ninfertility, and abnormal bleeding. Approximately 1 in 10 women suffer from endometriosis [1]. Despite the prevalence of endometriosis, \ncurrent treatment methods include surgery, oral contraceptives, gonadotropin-releasing hormone agonist therapy (GnRH), anti-inflammatory \nmedications, danazol, and aromatase inhibitors [1]. While these treatment methods aim to resects preexisting ectopic lesions, cause ovarian \nestrogen synthesis down regulation, and lessen cytokine-mediated inflammatory pain. Despite these interventions, endometriosis often can \nrecur after cessation of therapy; therefore, novel medical therapies, such as statins, metformin, and antioxidant therapy, could have the potential \nto alleviate the symptoms and progression of endometriosis. This article is a brief review of relevant and novel antioxidant treatments for \nendometriosis and their possibility to increase and improve treatment options. \n\n\nHow to cite this article:  nnika S, Sajal G. The Role of Antioxidant Supplementation in Endometriosis Therapy. J Gynecol Women’s Health. 2017; 3(1): \n555601. DOI: 10.19080/JGWH.2017.03.555601.002\nJournal of Gynecology and Women’s Health\nwith endometriosis have an altered balance of prooxidant \nand antioxidant molecules. For example, oxidative markers, \nsuch as Cu, ceruloplasmin, 8-hydroxyl-2-deoxyguanosine, \nand total oxidant status, may be elevated in endometriosis \npatients [6]. Moreover, serum total antioxidant status and thiol \nlevels were significantly lower (p<0.001) [7,8]. This evidence \ndemonstratesthat the low antioxidant levels may be integral to \nthe etiopathogenesis of endometriosis. Previous literature on \nantioxidant therapy suggests that the beneficial properties of \nantioxidants may reduce endometriosis-related symptoms and \noxidative damage. \nThe Evidence for Antioxidant Therapy\nBased on the role of oxidative stress in endometriosis, \nantioxidant use has been studied as a means to improve \npatient outcomes in endometriosis. Current research assesses \nthe antioxidant characteristics of vitamin E, vitamin C, \nepigallocatechin-3-gallate (EGCG), resveratrol, melatonin, \nandcerum oxide nanoparticles. Analysis of the antioxidative \nbenefits of these therapies were determined by outcomes both in \nanimal and human studies, such as symptomatic reduction, pain \nalleviation, lesion size reduction, and number of lesions. \nIn order to determine the effect of vitamin E and C, 46 women \nwith endometriosis-related pain were given a combination of \nvitamin E (1200 IU) and vitamin C (1000mg) for two months. \nVitamin E is a fat-soluble antioxidant that prevents the formation \nof the vitamin E radicals, and vitamin C was added to this regimen \nbecause it functions to recycle the vitamin E radial to vitamin E. \nAfter this randomized control trial, 43% of the patients reported \na reduction in chronic pelvic pain, suggesting that vitamin E and \nC may offer noticeable pain reduction even in short time frames \n(P=0.0055). The patients in the control group did not experience \nany decrease in pain [9]. While Santanam et al. [9] attributed \nthe effects of vitamin supplementation to its anti-oxidative and \nanti-inflammatory properties, there was no clear physiologic \nmechanism stated in the article. However, the work of Durak et \nal. [10], may offer some insight. In a rat model, experimentally \ninduces endometriotic cysts were treated with differing doses of \nvitamin C (0.5mg, 1.25mg, and 2.5mg) to determine if vitamin C \nsupplementation would alter the volume and weights of these \nlesions. The cysts from group treated with 2.5mg of vitamin C \nwere significantly reduced in weight and volume [10]. This \nevidence suggests that antioxidants, such as vitamin C, may \nreduce endometriosis symptoms by reducing lesion size. \nIn addition to vitamins, epigallocatechin-3-gallate (EGCG) \nmay also impact the size of endometriomas as well as selectively \ninhibit neovascularization in these lesions. EGCG is a commonly \nfound polyphenol in green tea. In other fields, it has been found \nto prevent tumor formation through initiating apoptosis and \ncell cycle arrest [11]. Therefore, Matsuzaki et al. [12] assessed \nits effect in endometriosis. Cell samples for 55 endometriosis \npatients were treated with EGCG and analyzed via rt-PCR, cell \nproliferation assays, in vitro migration and invasion assays. \nEGCG significantly reduced proliferation, cell migration, and \ninvasion of endometriotic cells [12]. Though EGCG appears to \noffer benefits for endometriosis patients, its low bioavailability \nthrough ingestion of pure EGCG or green tea consumption limits \nits use as a drug. \nLike EGCG, resveratrol, another natural therapy, may also \nimprove endometriosis symptoms. Resveratrol is known anti-\nproliferative agent and antioxidant found in grapes and red wine. \nRicci et al. [13] studied the effects of both EGCG and resveratrol on \nendometriosis as potential natural therapies. They investigated \nin a mouse model, 56 mice completed surgical induction of \nendometriosis and were treated with either resveratrol and \nEGCG for four weeks. Both interventions reduced the mean \nnumber and volume of established lesions (P<0.005). Though \nboth treatments were effective in decreasing cell proliferation, \nreducing vascular density, and increasing apoptosis, results due \nto resveratrol (p<0.01) were more significant than those due to \nEGCG (p<0.05) [13]. While the mechanism of action associated \nwith resveratrol is not completely understood, Amaya et al. \n[14] studied its dose-dependent impact on endometrium. In \naddition to its antioxidant properties, resveratrol functions \nas a phytoestrogen. It has different estrogen action based on \nconcentrations; in low concentrations, it acts agonistically. \nHowever, in high concentrations, it functions antagonistically. \nBecause endometriosis is an estrogen-dependent disease, \nhigh levels of resveratrol was shown to reduce proliferation of \nxenografts of human endometrium in mice [14].\nAnother naturally produced substance, melatonin, is also \nsuggested to have potent effects on endometriotic lesions. \nMelatonin has several properties, including free radical \nscavenging, stimulation of antioxidants, and increasing the \nefficacy of electron chain function [15,16]. In humans, it is \nproduced in the pineal gland, and has been shown to decrease \noxidative damage [15]. To understand the role of melatonin, \nYilmaz et al. [16], implanted endometriotic lesions in twenty rats \nand treated ten with melatonin and ten with saline (control). The \noutcome measures of this study were volume and weights of the \nlesions. In the experimental group, the lesion volume (p<0.01) \nand weights were significantly decreased (p<0.05), showing that \nmelatonin causes lesion regression [16]. \nAnother novel antioxidant therapy includes the use of cerium \noxide in order to impact the progression of endometriosis. \nCerium oxide has radical-scavenging characteristics that could \noffer benefit to endometriosis patients. Chaudhury et al. [17] \nutilized cerium oxide nanoparticles to improve endometriosis-\nrelated effects in a mice model. Mice with endometriosis treated \nwith cerium oxide nanoceria were found to have lower levels \nof ROS and higher levels of total antioxidant capacity (TAC). \nCerium oxide not only has antioxidant properties, but also has \nregenerative traits. This process of regeneration makes one \ndose of cerium oxide more appealing than the use of other \nantioxidants. While this study shows the effect of cerium oxide \n\nHow to cite this article: Annika S, Sajal G. The Role of Antioxidant Supplementation in Endometriosis Therapy. J Gynecol Women’s Health. 2017; 3(1): \n555601. DOI: 10.19080/JGWH.2017.03.555601.003\nJournal of Gynecology and Women’s Health\nYour next submission with Juniper Publishers    \n      will reach you the below assets\n• Quality Editorial service\n• Swift Peer Review\n• Reprints availability\n• E-prints Service\n• Manuscript Podcast for convenient understanding\n• Global attainment for your research\n• Manuscript accessibility in different formats \n         ( Pdf, E-pub, Full Text, Audio) \n• Unceasing customer service\n                      Track the below URL for one-step submission \n               https://juniperpublishers.com/online-submission.php\nThis work is licensed under Creative\nCommons Attribution 4.0 Licens\nDOI: 10.19080/JGWH.2017.03.555601\nnanoparticles in endometriosis, there is also a concern for \ntoxicity when using these nanoceria. \nConclusion\nEndometriosis is a chronic, estrogen-dependent condition \nthat affects nearly 10% of women of reproductive age, causing \npain, irregular bleeding, and infertility. This disease is treated by \nvarious medications, which function to reduce estrogen levels \nand inflammation, and surgery to remove the endometriotic \nlesions. However, despite this wide array of therapy, there \nis still high rate of relapse after surgery, the first line therapy \nfor symptomatic patients [4]. Because of this phenomenon, \nthere may be a need to improve outcomes for endometriosis \npatients. The current and previous literature focuses on the \nefficacy of antioxidant therapy in the treatment and mitigation \nof endometriosis. Antioxidants function by removing the free \nradial species, upregulating antioxidant enzymes, and reducing \noxidative damage. Relevant antioxidants include vitamin E and C, \nEGCG, resveratrol, melatonin, and cerium oxide. These molecules \nhave been shown to reduce the symptoms and progression of \nendometriosis mainly in experimental animal models. However \nthe studies highlight the potential of the antioxidants enlisted \nin the article for use in women with endometriosis. There is a \nneed for further well designed and adequately powered studies \nto assess the newer antioxidants in women suffering from this \ndebilitating disease.\nReferences\n1. Gupta S (2015) Endometriosis: a comprehensive update. Springer.\n2. Dunselman GAJ, Vermeulen N, Becker C, Hooghe TD, De Bie B, et al. \n(2014) ESHRE Guideline : Management of Women With Endometriosis. \nHum Reprod 29(3): 400-412.\n3. E Society, H Reproduction (2013) Management of women with \nendometriosis. p. 1-97.\n4. Guo S (2009) Recurrence of endometriosis and its control. Hum Reprod \nUpdate 15(4): 441-461.\n5. Ménézo Y, Dale B, Cohen M (2010) DNA damage and repair in human \noocytes and embryos: a review. Zygote 18(4): 357-365.\n6. Gupta S, Sinha A (2016) Potential Markers of Endometriosis : Latest \nUpdate. J Genit Syst Disord 5: 3.\n7. Turgut A, Özler A, Görük NY, Tunç SY, Lu OEĞ, et al. (2013) patients with \nadvanced-stage endometriosis. pp. 1472-1478.\n8. Choi YS, Cho S, Seo SK, Park JH, Kim SH, et al. (2015) Alteration \nin the intrafollicular thiol-redox system in infertile women with \nendometriosis. Reproduction 149(2): 155-162.\n9. Santanam N, Kavtaradze N, Murphy A, Dominguez C, Parthasarathy S \n(2013) Antioxidant supplementation reduces endometriosis-related \npelvic pain in humans. Transl Res 161(3): 189-195.\n10. Durak Y, Kokcu A, Kefeli M, Bildircin D, Çelik H, et al. Effect of vitamin C \non the growth of experimentally induced endometriotic cysts. J Obstet \nGynaecol Res 39(7): 1253-1258.\n11. Singh BN, Shankar S, Srivastava RK (2011) Green tea catechin, \nepigallocatechin-3-gallate (EGCG): Mechanisms, perspectives and \nclinical applications Catechin backbone. Biochem Pharmacol 82(12): \n1807-1821.\n12. Matsuzaki S, Darcha C (2014) Antifibrotic properties of epigallocatechin-\n3-gallate in endometriosis. Hum Reprod 29(8): 1677-1687.\n13. Singla JJ, Ricci AG, Olivares CN, Bilotas MA, Basto JI (2013) Natural \ntherapies assessment for the treatment of endometriosis. Hum Reprod \n28(1): 178-188.\n14. Amaya SC, Savaris RF, Filipovic CJ, Wise JD, Hestermann E, et al. (2015) \nResveratrol and Endometrium : A Closer Look at an Active Ingredient \nof Red Wine Using In Vivo and In Vitro Models. Reprod Sci 21(11): \n1362-1369.\n15. Reiter RJ, Tan D, Mayo JC, Sainz RM, Leon J (2003) Melatonin as \nan antioxidant : biochemical mechanisms and pathophysiological \nimplications in humans. Acta Biochem Pol 50(4): 1129-1146.\n16. Yilmaz B, Kilic S, Aksakal O, Egemen I, Tanrisever GG, et al. (2015) \nMelatonin causes regression of endometriotic implants in rats by \nmodulating angiogenesis, tissue levels of antioxidants and matrix \nmetalloproteinases. Arch Gynecol Obstet 292(1): 209-216.\n17. Chaudhury K, Singh AK, Das S, Kumar A, Seal S (2013) Mitigation \nof endometriosis using regenerative cerium oxide nanoparticles, \nNanomedicine Nanotechnology. NanoMedicine 9(3): 439-448.","source_license":"CC0","license_restricted":false}