Effect of Antioxidant Supplementation on Endometriosis-Related Pain: A Systematic Review

Purpose of Review This study was conducted to determine the effects of antioxidant supplementation on endometriosis-related chronic pelvic pain, dysmenorrhea, and dyspareunia.

PubMed/MEDLINE, Scopus, and Cochrane Library databases and the Google Scholar search engine were searched from early 2012 to 2022 using appropriate keywords for clinical trials receiving antioxidant supplements and reporting endometriosis-related pelvic pain (PROSPERO registration number CRD42022318924). The qualities of the included studies were evaluated using the Joanna Briggs Institute (JBI) Checklists Critical Appraisal Tools and the National Institutes of Health (NIH) quality assessment tool for before-after (Pre-Post) study with no control group. This systematic review was reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guideline.

In this systematic review, 8 studies (5 RCTs and 3 non-comparative trials) published in 2012–2022 were included.

The studies we included showed promising results in the use of antioxidants in endometriosis-related pain. However, many scientific studies are needed for clear statements. Similar content being viewed by others

Papers of particular interest, published recently, have been highlighted as: • Of importance World Health Organization ICD-11 for mortality and morbidity statistics. 2020. https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1838213761. Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020;382:1244–56. https://doi.org/10.1056/NEJMRA1810764. Agarwal SK, Chapron C, Giudice LC, Laufer MR, Leyland N, Missmer SA, Singh SS, Taylor HS. Clinical diagnosis of endometriosis: A call to action. Am J Obstet Gynecol. 2019;220(4):354.E1-354.E12. https://doi.org/10.1016/j.ajog.2018.12.039. Kim JH, Han E. Endometriosis and Female Pelvic Pain. Semin Reprod Med. 2018;36(2):143–51. https://doi.org/10.1055/s-0038-1676103. Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: Pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261–75. https://doi.org/10.1038/nrendo.2013.255. Ozawa Y, Murakami T, Terada Y, Yaegashi N, Okamura K, Kuriyama S, et al. Management of the pain associated with endometriosis: An update of the painful problems. Tohoku J Exp Med. 2006;210(3):175–88. https://doi.org/10.1620/tjem.210.175. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: Translational evidence of the relationship and implications. Hum Reprod Update. 2011;17(3):327–46. https://doi.org/10.1093/humupd/dmq050. Bloski T, Pierson R. Endometriosis and chronic pelvic pain: Unraveling the mystery behind this complex condition. Nurs Womens Health. 2008;12(5):382–95. https://doi.org/10.1111/j.1751-486x.2008.00362.x. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15:441–61. https://doi.org/10.1093/humupd/dmp007. Słopień R, Męczekalski B. Aromatase inhibitors in the treatment of endometriosis. Menopause Review/Przegląd Menopauzalny. 2016;15(1):43–7. https://doi.org/10.5114/pm.2016.58773. • Maddern J, Grundy L, Castro J, Brierley SM. Pain in endometriosis. Front Cell Neurosci. 2020;14:335. https://doi.org/10.3389/fncel.2020.590823. This review can provide more comprehensive information on the pathogenesis, diagnosis, and treatment of endometriosis. Brown J, Crawford TJ, Allen C, Hopewell S, Prentice A. Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev. 2017;1(1):CD004753. Published 2017 Jan 23. https://doi.org/10.1002/14651858.CD004753.pub4. Falcone T, Shakiba K, Bena JF, McGill KM, Minger J. Surgical treatment of endometriosis: A 7-year follow-up on the requirement for further surgery. Obstet Gynecol. 2008;111(6):1285–92. https://doi.org/10.1097/aog.0b013e3181758ec6. Carvalho LF, Samadder AN, Agarwal A, Fernandes LF, Abrao MS. Oxidative stress biomarkers in patients with endometriosis: Systematic review. Arch Gynecol Obstet. 2012;286(4):1033–40. https://doi.org/10.1007/s00404-012-2439-7. Augoulea A, Mastorakos G, Lambrinoudaki I, Christodoulakos G, Creatsas G. The role of the oxidative-stress in the endometriosis-related infertility. Gynecol Endocrinol. 2009;25(2):75–81. https://doi.org/10.1080/09513590802485012. Mier-Cabrera J, Aburto-Soto T, Burrola-Méndez S, Jiménez-Zamudio L, Tolentino MC, Casanueva E, Hernández-Guerrero C. Women with endometriosis improved their peripheral antioxidant markers after the application of a high antioxidant diet. Reprod Biol Endocrinol. 2009;28(7):54. https://doi.org/10.1186/1477-7827-7-54. Jamali N, Mostafavi-Pour Z, Zal F, Kasraeian M, Poordast T, Nejabat N. Antioxidant ameliorative effect of caffeic acid on the ectopic endometrial cells separated from patients with endometriosis. Taiwan J Obstet Gynecol. 2021;60(2):216–20. https://doi.org/10.1016/j.tjog.2020.12.003. Khodarahmian M, Amidi F, Moini A, Kashani L, Salahi E, Danaii-Mehrabad S, Nashtaei MS, Mojtahedi MF, Esfandyari S, Sobhani A. A randomized exploratory trial to assess the effects of resveratrol on VEGF and TNF-α 2 expression in endometriosis women. J Reprod Immunol. 2021;143:103248. https://doi.org/10.1016/j.jri. Lu X, Wu Z, Wang M, Cheng W. Effects of vitamin C on the outcome of in vitro fertilization-embryo transfer in endometriosis: A randomized controlled study. J Int Med Res. 2018;46(11):4624–33. https://doi.org/10.1177/0300060518786918. Schwertner A, Conceição Dos Santos CC, Costa GD, Deitos A, de Souza A, de Souza IC, Torres IL, da Cunha Filho JS, Caumo W. Efficacy of melatonin in the treatment of endometriosis: A phase II, randomized, double-blind, placebo-controlled trial. Pain. 2013;154(6):874–81. https://doi.org/10.1016/j.pain. Page MJ, McKenzie JE, Bossuyt PM, The PRISMA, et al. statement: An updated guideline for reporting systematic reviews. BMJ. 2020;2021:372. https://doi.org/10.1136/BMJ.N71. Sukan B, Akdevelioğlu Y, Sukan V. Effect of antioxidant supplementation on endometriosis related pelvic pain: Systematic review and meta-analysis. PROSPERO 2022 CRD42022318924. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022318924. Institute JB. critical-appraisal-tools - Critical Appraisal Tools. Center for Kliniske Retningslinjer. 2021. https://jbi.global/critical-appraisal-tools. NIH. Study quality assessment tools | NHLBI, NIH. National Heart, Lung, and Blood Institute. Published 2014. Accessed 22 Jun 2022. https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools. PRISMA. Retrieved April 6, 2022, from http://prisma-statement.org/prismastatement/flowdiagram.aspx. Santanam N, Kavtaradze N, Murphy A, Dominguez C, Parthasarathy S. Antioxidant supplementation reduces endometriosis-related pelvic pain in humans. Transl Res. 2013;161(3):189–95. https://doi.org/10.1016/j.trsl.2012.05.001. Amini L, Chekini R, Nateghi MR, et al. The effect of combined vitamin c and vitamin e supplementation on oxidative stress markers in women with endometriosis: A randomized, triple-blind placebo-controlled clinical trial. Pain Res Manag. 2021. https://doi.org/10.1155/2021/5529741. Ibrahim Abd El-Fadil Sehsah F, Taha Abd El-Fattah A, Mohammed Saeed A. The role of antioxidant supplementation in reducing the endometriosis related chronic pelvic pain in women. Al-Azhar Med J. 2022; 51(1): 121–34. https://doi.org/10.21608/amj.2022.212587. Amirsalari S, Behboodi Moghadam Z, Taghizadeh Z, et al. The effect of garlic tablets on the endometriosis-related pains: A randomized placebo-controlled clinical trial. Evid Based Complement Altern Med. 2021. https://doi.org/10.1155/2021/5547058. da Silva DM DM, Gross LA, Neto EPG, Lessey BA, Savaris RF. The use of resveratrol as an adjuvant treatment of pain in endometriosis: A randomized clinical trial. J Endocr Soc. 2017;1(4):359–69. https://doi.org/10.1210/js.2017-00053. Lete I, Mendoza N, de la Viuda E, Carmona F. Effectiveness of an antioxidant preparation with N-acetyl cysteine, alpha lipoic acid and bromelain in the treatment of endometriosis-associated pelvic pain: LEAP study. Eur J Obstet Gynecol Reprod Biol. 2018;228:221–4. https://doi.org/10.1016/j.ejogrb.2018.07.002. Caruso S, Iraci Sareri M, Casella E, Ventura B, Fava V, Cianci A. Chronic pelvic pain, quality of life and sexual health of women treated with palmitoylethanolamide and α-lipoic acid. Minerva Ginecol. 2015;67(5):413–9. Maia H, Haddad C, Pinheiro N, Casoy J. Advantages of the association of resveratrol with oral contraceptives for management of endometriosis-related pain. International Journal of Women’s Health. 2012;4(1):543–9. https://doi.org/10.2147/ijwh.s36825. Langley GB, Sheppeard H. The visual analogue scale: Its use in pain measurement. Rheumatol Int. 1985;5(4):145–8. https://doi.org/10.1007/BF00541514. Biberoglu KO, Behrman SJ. Dosage aspects of danazol therapy in endometriosis: Short term and long term effectiveness. Am J Obstet Gynecol. 1981;139:645–54. https://doi.org/10.1016/0002-9378(81)90478-6. Scutiero G, Iannone P, Bernardi G, et al. Oxidative stress and endometriosis: A systematic review of the literature. Oxid Med Cell Longev. 2017. https://doi.org/10.1155/2017/7265238. Latthe P, Latthe M, Say L, et al. WHO systematic review of prevalence of chronic pelvic pain: A neglected reproductive health morbidity. BMC Public Health. 2006;6:177. https://doi.org/10.1186/1471-2458-6-177. Ayorinde AA, Macfarlane GJ, Saraswat L, et al. Chronic pelvic pain in women: An epidemiological perspective. Womens Health (Lond). 2015;11(6):851–64. https://doi.org/10.2217/whe.15.30. • Horne AW, Saunders PTK, Abokhrais IM, et al. Top ten endometriosis research priorities in the UK and Ireland. Lancet. 2017;389(10085):2191–2. https://doi.org/10.1016/s0140-6736(17)31344-2. This article can help those who will study endometriosis to get an idea about priority areas. Ricci E, Viganò P, Cipriani S, et al. Physical activity and endometriosis risk in women with infertility or pain: Systematic review and meta-analysis. Medicine (Baltimore). 2016;95(40):e4957. https://doi.org/10.1097/md.0000000000004957. de Sousa TR, de Souza BC, Zomkowisk K, et al. The effect of acupuncture on pain, dyspareunia, and quality of life in Brazilian women with endometriosis: A randomized clinical trial. Complement Ther Clin Pract. 2016;25:114-. https://doi.org/10.1016/j.ctcp.2016.09.006. Armour M, Cave AE, Schabrun SM, Steiner GZ, Zhu X, Song J, Abbott J, Smith CA. Manual acupuncture plus usual care versus usual care alone in the treatment of endometriosis-related chronic pelvic pain: A randomized controlled feasibility study. J Altern Complement Med. 2021;27(10):841–9. https://doi.org/10.1089/acm.2021.0004. Ball E, Newton S, Kahan BC, et al. Smartphone app using mindfulness meditation for women with chronic pelvic pain (MEMPHIS): Protocol for a randomized feasibility trial. JMIR Res Protoc. 2018;7(1):e8. https://doi.org/10.2196/resprot.7720. Gonçalves AV, Barros NF, Bahamondes L. The practice of hatha yoga for the treatment of pain associated with endometriosis. J Altern Complement Med. 2017;23(1):45–52. https://doi.org/10.1089/acm.2015.0343. Almassinokiani F, Khodaverdi S, Solaymani-Dodaran M, Akbari P, Pazouki A. Effects of vitamin D on endometriosis-related pain: A double-blind clinical trial. Med Sci Monit. 2016;22:4960–6. https://doi.org/10.12659/msm.901838. Mehdizadehkashi A, Rokhgireh S, Tahermanesh K, Eslahi N, Minaeian S, Samimi M. The effect of vitamin D supplementation on clinical symptoms and metabolic profiles in patients with endometriosis. Gynecol Endocrinol. 2021;37(7):640–5. https://doi.org/10.1080/09513590.2021.1878138. Peng Bo. Fahad T Alotaibi, Sadaf Sediqi, Mohamed A Bedaiwy, Paul J Yong, Role of interleukin-1β in nerve growth factor expression, neurogenesis and deep dyspareunia in endometriosis. Hum Reprod. 2020;35(4):901–12. https://doi.org/10.1093/humrep/deaa017. Li S, Fu X, Wu T, Yang L, Hu C, Wu R. Role of interleukin-6 and its receptor in endometriosis. Med Sci Monit. 2017;23:3801–7. https://doi.org/10.12659/msm.905226. Senapati S, Clauw D, As-Sanie S. The relationship between serum tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) with pelvic pain symptoms in women with endometriosis. Fertil Steril. 2009;92(3):112. https://doi.org/10.1016/j.fertnstert.2009.07.1101. Smycz-Kubańska M, Kondera-Anasz Z, Sikora J, Wendlocha D, Królewska-Daszczyńska P, Englisz A, Janusz A, Janusz J, Mielczarek-Palacz A. The role of selected chemokines in the peritoneal fluid of women with endometriosis—participation in the pathogenesis of the disease. Processes. 2021;9(12):2229. https://doi.org/10.3390/pr9122229. Vodolazkaia A, Yesilyurt BT, Kyama CM, et al. Vascular endothelial growth factor pathway in endometriosis: Genetic variants and plasma biomarkers. Fertil Steril. 2016;105(4):988–96. https://doi.org/10.1016/j.fertnstert.2015.12.016. Szubert M, Rogut M, Ziętara M, Wierzbowski T, Wilczyński J, Czyż M. Expression of nerve growth factor (NGF) in endometrium as a potential biomarker for endometriosis – single tertiary care centre study. J Gynecol Obstet Hum Reprod. 2021;50(3):101895. https://doi.org/10.1016/j.jogoh.2020.101895. Cacciottola L, Donnez J, Dolmans M-M. Can endometriosis-related oxidative stress pave the way for new treatment targets? Int J Mol Sci. 2021;22(13):7138. https://doi.org/10.3390/ijms22137138. Ngô C, Chéreau C, Nicco C, et al. Reactive oxygen species controls endometriosis progression. Am J Pathol. 2009;175:225–34. https://doi.org/10.2353/ajpath.2009.080804. Öner-İyidoğan Y, Koçak H, Gürdöl F, Korkmaz D, Buyru F. Indices of oxidative stress in eutopic and ectopic endometria of women with endometriosis. Gynecol Obstet Invest. 2004;57(4):214–7. https://doi.org/10.1159/000076691. Forster R, Sarginson A, Velichkova A, Hogg C, Dorning A, Horne AW, Saunders PT, Greaves E. Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis. FASEB J. 2019;33:11210–22. https://doi.org/10.1096/fj.201900797r. Aich A, Afrin LB, Gupta K. Mast cell-mediated mechanisms of nociception. Int J Mol Sci. 2015;130:395–412. https://doi.org/10.3390/ijms161226151. Murphy AA, Santanam N, Morales AJ, Parthasarathy S. Lysophosphatidyl choline, a chemotactic factor for monocytes/T-lymphocytes is elevated in endometriosis. J Clin Endocrinol Metab. 1998;83(6):2110–3. https://doi.org/10.1210/JCEM.83.6.4823. Petean CC, Ferriani RA, dos Reis RM, de Moura MD, Jordão AA, Navarro PADAS. Lipid peroxidation and vitamin E in serum and follicular fluid of infertile women with peritoneal endometriosis submitted to controlled ovarian hyperstimulation: A pilot study. Fertil Steril. 2008;90(6):2080–5. https://doi.org/10.1016/j.fertnstert.2007.10.072. Singh AK, Chattopadhyay R, Chakravarty B, Chaudhury K. Markers of oxidative stress in follicular fluid of women with endometriosis and tubal infertility undergoing IVF. Reprod Toxicol. 2013;42:116–24. https://doi.org/10.1016/j.reprotox.2013.08.005. Mier-Cabrera J, Genera-García M, De la Jara-Díaz J, Perichart-Perera O, Vadillo-Ortega F, Hernández-Guerrero C. Effect of vitamins C and E supplementation on peripheral oxidative stress markers and pregnancy rate in women with endometriosis. Int J Gynaecol Obstet. 2008;100(3):252–6. https://doi.org/10.1016/J.IJGO.2007.08.018. Iwabuchi T, Yoshimoto C, Shigetomi H, Kobayashi H. Oxidative stress and antioxidant defense in endometriosis and its malignant transformation. Oxid Med Cell Longev. 2015;2015:848595. https://doi.org/10.1155/2015/848595. • Hayashi S, Nakamura T, Motooka Y, Ito F, Jiang L, Akatsuka S, Iwase A, Kajiyama H, Kikkawa F, Toyokuni S. Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice. Redox Biol. 2020;37:101726. https://doi.org/10.1016/j.redox.2020.101726. This animal study, which draws attention to the mechanism between endometriosis and infertility, explains that ovarian endometriosis created on a new model induces iron-catalyzed oxidative stress. Nahdi A, Hammami I, Kouidhi W, et al. Protective effects of crude garlic by reducing iron-mediated oxidative stress, proliferation and autophagy in rats. J Mol Hist. 2010;41:233–45. https://doi.org/10.1007/s10735-010-9283-5. Koseoglu M, Isleten F, Atay A, Kaplan YC. Effects of acute and subacute garlic supplement administration on serum total antioxidant capacity and lipid parameters in healthy volunteers. Phyther Res. 2010;24(3):374–8. https://doi.org/10.1002/ptr.2953. Desmawati D, Sulastri D. Phytoestrogens and their health effect. Open Access Maced J Med Sci. 2019;7(3):495–9. https://doi.org/10.3889/oamjms.2019.044. Chang HP, Chen YH. Differential effects of organosulfur compounds from garlic oil on nitric oxide and prostaglandin E2 in stimulated macrophages. Nutrition. 2005;21(4):530–6. https://doi.org/10.1016/J.NUT.2004.07.018. Xia N, Daiber A, Förstermann U, Li H. Antioxidant effects of resveratrol in the cardiovascular system. Br J Pharmacol. 2017;174(12):1633–46. https://doi.org/10.1111/bph.13492. Carrizzo A, Forte M, Damato A, et al. Antioxidant effects of resveratrol in cardiovascular, cerebral and metabolic diseases. Food Chem Toxicol. 2013;61:215–26. https://doi.org/10.1016/j.fct.2013.07.021. Gülçin I. Antioxidant properties of resveratrol: A structure-activity insight. Innov Food Sci Emerg Technol. 2010;11(1):210–8. https://doi.org/10.1016/j.ifset.2009.07.002. Rochette L, Ghibu S, Richard C, Zeller M, Cottin Y, Vergely C. Direct and indirect antioxidant properties of α-lipoic acid and therapeutic potential. Mol Nutr Food Res. 2013;57(1):114–25. https://doi.org/10.1002/mnfr.201200608. Di Nicuolo F, Castellani R, Nardone ADC, et al. Alpha-lipoic acid plays a role in endometriosis: New evidence on inflammasome-mediated interleukin production, cellular adhesion and invasion. Molecules. 2021;26(2). https://doi.org/10.3390/molecules26020288. Onat T, Çakır M. Ameliorative effect of alpha lipoic acid on endometriosis: An experimental model in rats. Med Bull Haseki. 2020;58:402–7. https://doi.org/10.4274/haseki.galenos.2020.6316. Pattanittum P, Kunyanone N, Brown J, et al. Dietary supplements for dysmenorrhoea. Cochrane Database Syst Rev. 2016;2016(3). https://doi.org/10.1002/14651858.CD002124.pub2. Showell MG, Mackenzie-Proctor R, Jordan V, Hart RJ. Antioxidants for female subfertility. 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About this article Cite this article Sukan, B., Akdevelioğlu, Y. & Sukan, V.N. Effect of Antioxidant Supplementation on Endometriosis-Related Pain: A Systematic Review. Curr Nutr Rep 11, 753–764 (2022). https://doi.org/10.1007/s13668-022-00432-1 Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s13668-022-00432-1