{"paper_id":"807e4846-0cd0-40aa-bf3b-39851ff974dd","body_text":"www.ogscience.org186\nIntroduction\nEndometriosis is a chronic inflammatory gynecological \ncondition characterized by the presence and growth of tis -\nsues similar to the endometrium outside the uterine cavity. \nIt affects at least 10% of women of reproductive age [1]. \nFurthermore, it frequently causes pelvic pain, dysmenorrhea, \ndyspareunia, and infertility, impairing patients’ quality of life \n[2]. Endometriosis is a multifaceted, symptomatic, pathobio\n-\nlogical, multisystem, and heterogeneous disease. Based on \nthe phenotype, it can be categorized into superficial perito\n-\nneal lesions, ovarian endometriomas, and deep-infiltrating \nendometriosis [3,4]. When addressing general endometriosis \nThe effect of antioxidant supplementation on \ndysmenorrhea and endometriosis-associated painful \nsymptoms: a systematic review and meta-analysis of \nrandomized clinical trials\nSaeed Baradwan, MD\n1\n, Abdulrahim Gari, MD\n2,3\n, Hussein Sabban, MD\n1,4\n, Majed Saeed Alshahrani, MD\n5\n,  \nKhalid Khadawardi, MD\n2\n, Ibtihal Abdulaziz Bukhari, MD\n6\n, Abdullah Alyousef, MD\n7\n,  \nAhmed Abu-Zaid, MD, PhD\n8\nDepartment of Obstetrics and Gynecology, \n1\nKing Faisal Specialist Hospital and Research Center, Jeddah, \n2\nCollege of Medicine, Umm Al-Qura Univer-\nsity, Makkah, \n3\nAl Salama Hospital, Jeddah, \n4\nFaculty of Medicine at Rabigh, King Abdulaziz University, Rabigh, \n5\nFaculty of Medicine, Najran University, \nNajran, \n6\nCollege of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, \n7\nKing Abdullah bin Abdulaziz University Hospital, Riyadh, \n8\nCol-\nlege of Medicine, Alfaisal University, Riyadh, Saudi Arabia\nThis study aimed to review randomized controlled trials (RCTs) investigating the effects of dietary antioxidant supple-\nments on the severity of endometriosis-related pain symptoms. The PubMed/Medline, Scopus, and Web of Science \ndatabases were searched until April 2022. Additionally, we manually searched the reference lists. Endpoints were \nsummarized as standardized mean difference (SMD) with 95% confidence intervals (CIs) in a random-effects model. \nThe I\n2\n statistic was used to assess heterogeneity. Ten RCTs were included in this meta-analysis. Overall, 10 studies were \nrelated to dysmenorrhea, four to dyspareunia, and four to pelvic pain. Antioxidants significantly reduced dysmenor-\nrhea (SMD, -0.48; 95% CI, -0.82 to -0.13; I\n2\n=75.14%). In a subgroup analysis, a significant reduction of dysmenorrhea \nwas observed only in a subset of trials that administered vitamin D (SMD, -0.59; 95% CI, -1.13 to -0.06; I\n2\n=69.59%) and \nmelatonin (SMD, -1.40; 95% CI, -2.47 to -0.32; I\n2\n=79.15%). Meta-analysis results also suggested that antioxidant sup-\nplementation significantly improved pelvic pain (SMD, -1.51; 95% CI, -2.74 to -0.29; I\n2\n=93.96%), although they seem \nnot to have a significant beneficial impact on the severity of dyspareunia. Dietary antioxidant supplementation seems \nto beneficially impact the severity of endometriosis-related dysmenorrhea (with an emphasis on vitamin D and mela\n-\ntonin) and pelvic pain. However, due to the relatively small sample size and high heterogeneity, the findings should \nbe interpreted cautiously, and the importance of further well-designed clinical studies cannot be overstated.\nKeywords: Antioxidant; Endometriosis; Dysmenorrhea; Dyspareunia; Pelvic pain\nArticles published in Obstet Gynecol Sci are open-access, distributed under the terms of \nthe Creative Commons Attribution Non-Commercial License (http://creativecommons.\norg/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, \nand reproduction in any medium, provided the original work is properly cited.\nCopyright © 2024 Korean Society of Obstetrics and Gynecology \nReview Article\nObstet Gynecol Sci 2024;67(2):186-198\nhttps://doi.org/10.5468/ogs.23210\neISSN 2287-8580\nReceived: 2023.08.25.   Revised: 2023.10.11.   Accepted: 2023.11.09.\nCorresponding author: Ahmed Abu-Zaid, MD, PhD\nDepartment of Obstetrics and Gynecology, College of Medicine, \nAlfaisal University, Al Zahrawi Street, Riyadh 11533, Saudi Arabia \nE-mail: aabuzaid@live.com\nhttps://orcid.org/0000-0003-2286-2181\n\n\nwww.ogscience.org 187\nSaeed Baradwan, et al. Antioxidants & gynecologic-related pain\nmanagement, three therapeutic modalities are commonly \navailable: I) medicinal treatment (e.g., painkillers, nonsteroi -\ndal anti-inflammatory drugs, combined oral contraceptives, \nprogestins, and gonadotropin-releasing hormone analogs); \nII) surgery (conservative or definitive); and III) assisted repro\n-\nductive technologies (such as in vitro  fertilization and intra -\ncytoplasmic sperm injection). It is crucial to emphasize the \ntimely administration of pain management, as therapeutic \ninertia portends the development of central sensitization (au-\ntonomous) [5-7]. Interestingly, reduction in oxidative stress \nis also a crucial alternative for endometriosis management. \nInflammation leads to an increased production of reactive \noxygen species (ROS), which play a fundamental role in the \nproliferation of endometriotic cells as well as in the develop-\nment, persistence, and progression of the disease [8]. Dietary \nmicro- and macro-nutrients and dietary factors are pivotal in \ncontrolling chronic diseases [9,10]. Dietary antioxidants exert \nbeneficial neutralizing effects against free radicals and ROS \nproduced by endometriotic cells. They demonstrate anti-\ninflammatory properties [11,12] and pro-apoptotic and anti-\nangiogenic actions and generally have a favorable safety pro\n-\nfile. Therefore, one could speculate that they may effectively \nreduce pain-inducing factors and improve endometriosis-\nassociated clinical symptoms [13-15].\nA growing body of literature has explored the impact of \ndifferent dietary antioxidants on endometriosis-related pain \n[15]. Antioxidant vitamins successfully reduce the intensity of \ndysmenorrhea, ameliorate dyspareunia and pelvic pain, and \nimprove the quality of life in patients with endometriosis. \nConsequently, therapy involving antioxidant vitamins may be \nconsidered an alternative treatment approach, independently \nor in conjunction with other methods, to alleviate endometri\n-\nosis-related pain [16]. Zheng et al. [16] showed that supple -\nmentation with vitamin E improved endometriosis-related \npelvic pain, whereas supplementation with vitamin D did \nnot. Some systematic reviews also reported no significant ef\n-\nfects of vitamin D on dysmenorrhea or non-cyclic pelvic pain \n[17]. Nevertheless, no systematic reviews or meta-analyses \nhave comprehensively summarized the effects of dietary \nantioxidants on endometriosis and dysmenorrhea. To bridge \nthis gap, we conducted a comprehensive systematic review \nand meta-analysis of randomized controlled trials (RCTs). We \naimed to investigate the duration response and the impact \nof administering various dietary antioxidant supplements, \nincluding vitamins D, C, E, and A, melatonin, curcumin, \nomega-3 fatty acids, resveratrol, zinc, copper, chromium, \nand selenium, separately or in different combinations, on the \nseverity of endometriosis-associated painful symptoms. The \nsymptoms evaluated include dysmenorrhea, dyspareunia, \nand chronic pelvic pain in women of reproductive age.\nMethods\nThis systematic review and meta-analysis of RCTs was perfor-\nmed according to the guidelines of the preferred reporting \nitems for systematic reviews and meta-analyses statement \nand the current recommendations of the Cochrane Collabo-\nration.\n1. Search strategy and study selection\nWe searched electronic research databases, including Sco -\npus, Web of Science (Science and Social Science Citation \nIndex), and PubMed/Medline, from their inception until April \n2022. In addition, we manually searched the reference lists \nand citations of the eight identified articles using Google \nScholar. We also contacted authors who had published in \nthis area to ensure we did not miss any relevant publications. \nSearch terms were set by the authors and adapted for use in \nother databases. There were no restrictions on the language \nor publication dates. Document with incomplete data or the \nauthor could not be reached was discarded. The search stra\n-\ntegy is described in detail in Supplementary Table 1. Two re-\nviewers (S.B. and A.G.) independently screened all identified \nrecords for potentially eligible studies after reading all titles \nand abstracts. The final inclusion criteria were determined af\n-\nter reading the full texts strictly. Disagreements were resolved \nthrough discussion with a third reviewer (A.A.).   \n2. Eligibility criteria\nThe eligibility criteria of the studies were formulated ac -\ncording to the participants, interventions, comparisons, \noutcomes, and study design criteria. I) Participants: women \nwith clinically and/or histologically confirmed endometriosis; \n \nII) intervention: supplementation with antioxidants (vitamins \nD, C, E, and A, melatonin, curcumin, omega-3 fatty acids, \nresveratrol, zinc, copper, chromium, and selenium, separately \nor in different combinations); III) comparators: antioxidant \nversus no treatment, antioxidant versus placebo; IV) out\n-\ncomes: severity of dysmenorrhea, dyspareunia and/or chronic \n\nwww.ogscience.org188\nVol. 67, No. 2, 2024\npelvic pain assessed by any pain assessment scale/tool; and  \nV) study design: a clinical randomized controlled study. Stu -\ndies meeting any of the following criteria were excluded: I) \npain caused by reasons other than endometriosis; II) non-ran-\ndomized clinical trials (e.g., conference abstracts, repeated \npublications, animal experiments, case reports, and reviews); \nand III) studies without available data for analysis.\n3. Data extraction and assessment of the quality of \nincluded studies\nTwo reviewers (H.S. and M.S.A.) independently extracted the \nfollowing data from the included trials: participant characteri\n-\nstics (e.g., age, diagnostic method, body mass index, and pa-\nrity), study characteristics (e.g., first author name, publication \nyear, region, study design, sample size, intervention type, and \nintervention characteristics), and study outcomes. The corres\n-\nponding authors were contacted for additional information. \nTwo reviewers (H.S. and M.S.A.) assessed the methodological \nquality of the included trials according to the Cochrane Han\n-\ndbook for Systematic Reviews of Interventions version 5.1.0 \n(Cochrane, London, England). Disagreements were resolved \nthrough discussion with a third reviewer (K.K.). Each trial was \nevaluated for seven items: random sequence generation, \nconcealed allocation, blinding of participants and personnel \n(performance bias), blinding of outcome assessment (detecti-\non bias), incomplete outcome data (attrition bias), selective \nreporting (reporting bias), and other biases; each item was \nrated as “high risk”, “low risk”, or “unclear”. \n4. Statistical analysis\nStata version 16 (Stata Corporation, College Station, TX, \nUSA) was used for the statistical analyses. All continuous \nFig. 1. The flow diagram of literature search and selection of studies. RCT, randomized controlled trials.\nRecords identified through  \ndatabase searching (n=134)\nAdditional records identified through \nother sources (n=8)\nRecords after duplicates removed \n(n=109)\nRecords screened\n(n=109)\nRecords excluded  \n(n=91)\nFull-text articles excluded, with \nreasons (n=8)\nHave no relevant variables (5) \nCombination with other \ntreatments (2)\nNot RCT (1)\nFull-text articles assessed  \nfor eligibility (n=18)\nStudies included in qualitative \nsynthesis (n=10)\nStudies included in quantitative \nsynthesis (meta-analysis)\n(n=10)\nIdentificationScreeningEligibilityIncluded\n\nwww.ogscience.org 189\nSaeed Baradwan, et al. Antioxidants & gynecologic-related pain\nTable 1. The main characteristics of the included studies\nStudy Country\nSample \nsize  \n(final \nanalysis)\nAntioxidant  \ntype Dosage Duration \n(weeks)\nAge\nEndometriosis \nstage Pain type \nPain  \nassessment \nmethod\nIntervention Placebo\nMean SD Mean SD\nSesti et al. (2007) \n[26]\nItaly 145 Mix - 24 29.1 3.9 31.1 4.1 III and I ↔ Dysmenorrhea VAS score\n↔ Dyspareunia\n↓ Pelvic pain\nLasco et al. (2012) \n[21]\nItaly 40 Vitamin D 300,000 IU 8 NM NM NM NM NM\n↓ Dysmenorrhea VAS score\nSchwertner et al. \n(2013) [25]\nBrazil 40 Melatonin 10 mg 8 36.76 6.4 37.63 5.5 All stages\n↓ Dysmenorrhea VAS score\nMendes da Silva et \nal. (2017) [23]\nBrazil 44 Resveratrol 40 mg 6 35.4 7.1 32.4 7 NM\n↔ Dysmenorrhea VAS score\nAlmassinokiani et \nal. (2016) [19]\nIran 40 Vitamin D 50,000 IU/\nweekly\n12 30.84 5.79 28.95 4.71 All stages ↔ Dysmenorrhea VAS score\n↔ Pelvic pain\nHoseinalizadeh \nand Cahichian \n(2018) [20]\nIran 40 Melatonin 5 mg 8 NM NM NM NM III and IV\n↓ Dysmenorrhea VAS score\n↓ Pelvic pain\nAbokhrais et al. \n(2020) [18]\nUK 30 Omega-3 1,000 mg/\ntwice a day\n8 35.43 8.57 36.08 9.59 All stages\n↔ Dysmenorrhea -Pain \n↔ Dyspareunia -Catastrophizing\n-Questionnaire\nNodler et al. (2020) \n[24]\nUSA 42 Omega-3 2,000 IU/day 24 20.01 2.7 20.1 3.5 All stages except \nstage III\n↔ Dysmenorrhea VAS score\nAmini et al. (2021) \n[13]\nIran 60 Mix (C and E) - C, 1,000 mg/\nday\n8 35.7 5.71 38.03 6.47 I to III\n↔ Dysmenorrhea VAS score\n↓ Dyspareunia\n- E, 800 IU/day ↓ Pelvic pain\nMehdizadehkashi \net al. (2021) [22]\nIran 60 Vitamin D 50,000 IU/each \n2 weeks\n12 34.8 7.1 35.6 7 NM\n↓ Dysmenorrhoea VAS score\n↔ Dyspareunia\n↓, this symbol is a sign of decreasing variables in the intervention group; ↔, this sign indicates no difference between the two groups.\nSD, standard deviation; VAS, visual analog scale; IU, international unit; NM, not mentioned. \n\nwww.ogscience.org190\nVol. 67, No. 2, 2024\nvariables were pooled by standard mean differences (SMDs) \nwith 95% confidence intervals (CIs). Heterogeneity was eva-\nluated using the Higgins’ I\n2\n statistic. I\n2\n statistics of 0-25%, \n25-50%, 50-75%, and >75% were suggestive of very low, \nlow, moderate, and high heterogeneity, respectively. We \nused a random-effects model to calculate individual study \nSMD and corresponding 95% CIs. In addition, a chi-square \ntest for heterogeneity was performed, and the P -values were \npresented. Exploration of the causes of heterogeneity was \nplanned using variations in the antioxidant type and durati\n-\non of the intervention. We performed sensitivity analyses to \nevaluate the robustness of pooled estimations after exclusion \nof every single trial through the “Leave-one-out method”. \nAdditionally, we assessed the risk of publication bias across \nstudies using counter-funnel plots of the outcomes. We used \nthe GRADEpro GDT software (Evidence Prime, Hamilton, \nON, USA) to formally assess the quality of evidence for sele\n-\ncted outcomes. We evaluated the outcomes considering the \nfollowing five criteria: risk of bias, inconsistency, indirectness, \nimprecision, and publication bias, and the level of evidence \nwas graded as very low, low, moderate, or high. The certain\n-\nty of the evidence evaluation is presented in Supplementary \nTable 2.\nResults\n1. Study selection\nInitially, 134 records were identified through a database sear-\nch, and eight additional records were identified through ot -\nher sources. All studies were then imported into EndNote X9 \nsoftware (Thomson Reuters, Philadelphia, PA, USA), 25 dupli\n-\ncates were removed, and 91 studies were removed after the \ntitle and abstract screening process; thus, 18 studies were \nscreened for eligibility in more detail. Finally, after detailed \ntitle, abstract, and full-text evaluations, 10 [13,18-26] RCTs \nwere included in this systematic review and meta-analysis. A \nflow diagram of the complete literature search and selection \nof studies is shown in Fig. 1.\n2. Study characteristics \nThe ethnicity of the study population varied among the stu -\ndies: Iran (n=4), Brazil (n=2), Italy (n=2), Britain (n=1), and \nthe United States (n=1). All the included trials, except one, \nwere published in English between 2007 and 2021. A total \nof 541 women aged 20-40 years were examined, with indivi\n-\ndual study sample sizes ranging from 30 to 145 participants. \nEndometriosis was confirmed by histopathology in all trials. \nSeven trials reported the endometriosis stage in the patients. \nThe characteristics of the included trials are summarized in \nTable 1. A summary of the risk of bias demonstrated that the \nmethodological quality of these trials was relatively desirable \n(Fig. 2). All participants in each trial were randomly allocated \nto groups using an adequate allocation procedure. The ran\n-\ndomization was unclear in both trials. Six trials stated that the \nallocation was concealed, one trial stated that it was unclear, \nand three trials were at high risk. Half of the trials used pa\n-\ntient masking, and the blinding of participants and personnel \nwas unclear in four trials. Thus, only one trial had a high risk \nof performance bias. Four trials reported appropriate blinding \nof the outcome assessment, whereas blinding was unclear \nFig. 2. The summary of risk of bias assessments. \nAbokhrais, 2020\nAlmassinokiani, 2016\nAmini, 2021\nHoseinalizadeh, 2018\nLasco, 2012 \nMehdizadehkashi, 2021\nMendes da silva, 2017\nNodler, 2020\nSchwertner, 2013\nSesti, 2007\nRandom sequence generation (selection bias)\nAllocation concealment (selection bias)\nBlinding of participants and personnel (performance bias)\nBlinding of outcome assessment (detection bias)\nIncomplete outcome data (attrition bias)\nSelective reporting (reporting bias)\nOther bias\n\nwww.ogscience.org 191\nSaeed Baradwan, et al. Antioxidants & gynecologic-related pain\nFig. 3. Forest plot of the effect of antioxidants on dysmenorrhea pain. N, number; SD, standard deviation; CI, confidence interval; FA, fatty \nacid.\nTreatment Control Hedges's g Weight (%)Study N Mean SD N Mean SD with 95% CI\nVitamin D\nMehdizadehkashi, 2021 30 -3.2 1.75 30 -1.9 2.71 -0.56 (-1.07, -0.05) 9.79\nNodler, 2020 27 -1.5 3.01 22 -1.6 2.94 0.03 (-0.52, 0.59) 9.43\nAlmassinokiani, 2016 19 -5.27 2.48 20 -3.69 2.94 -0.57 (-1.20, 0.06) 8.83\nLasco, 2012 20 -2.35 1.75 20 0.1 1.76 -1.37 (-2.05, -0.69) 8.43\nHeterogeneity: τ\n2\n=0.20, I\n2\n=69.59%, H\n2\n=3.29 -0.59 (-1.13, -0.06)\nTest of θi=θj: Q(3)=9.87, P=0.02\nOmega-3 FAs\nNodler, 2020 20 -0.7 3.15 22 -1.6 2.94 0.29 (-0.31, 0.89) 9.07\nAbokhrais, 2020 14 0.04 1.88 13 -0.67 2.47 0.32 (-0.42, 1.05) 7.97\nHeterogeneity: τ\n2\n=0.00, I\n2\n=0.00%, H\n2\n=1.00 0.30 (-0.16, 0.76)\nTest of θi=θj: Q(1)=0.00, P=0.96\nResveratrol\nMendes da Silva, 2017 22 -2.5 2.43 22 -1.5 3.13 -0.35 (-0.94, 0.23) 9.18\nHeterogeneity: τ\n2\n=0.00, I\n2\n=0.00%, H\n2\n=0.00 -0.35 (-0.94, 0.23)\nTest of θi=θj: Q(0)=-0.00, P=0.00\nMelatonin\nHoseinalizadeh, 2018 20 -3.85 1.37 20 -1.54 0.89 -1.96 (-2.70, -1.22) 7.91\nSchwertner, 2013 20 -3.741 2.21 20 1.98 1.75 -0.87 (-1.50, -0.23) 8.76\nHeterogeneity: τ\n2\n=0.47, I\n2\n=79.15%, H\n2\n=4.80  -1.40 (-2.47, -0.32)\nTest of θi=θj: Q(1)=4.80, P=0.03\nCombination\nSesti, 2007 35 -1.7 1.05 110 -1.5 1.25 -0.17 (-0.54, 0.21) 10.80\nAmini, 2021 30 -3.3 5.63 30 -1.95 3.11 -0.29 (-0.80, 0.21) 9.84\nHeterogeneity: τ\n2\n=0.00, I\n2\n=0.00%, H\n2\n=1.00 -0.21 (-0.51, 0.09)\nTest of θi=θj: Q(1)=0.16, P=0.69\n-0.48 (-0.82, -0.13)\nOverall\nHeterogeneity: τ\n2\n=0.26, I\n2\n=75.14%, H\n2\n=4.02\nTest of θi=θj: Q(10)=40.23, P=0.00\nTest of group differences: Qb(4)=11.52, P=0.02\nRandom-effects DerSimonian-Laird model\n-1 0 12-3\nFig. 4. Subgroup forest plot of the effect of antioxidants on dysmenorrhea pain. N, number; SD, standard deviation; CI, confidence inter -\nval.\nTreatment Control Hedges's g Weight (%)Study N Mean SD N Mean SD with 95% CI\n≤8 weeks\nMendes da Silva, 2017 22 -2.5 2.43 22 -1.5 3.13 -0.35 (-0.94, 0.23) 9.18\nAmini, 2021 30 -3.3 5.63 30 -1.95 3.11 -0.29 (-0.80, 0.21) 9.84\nAlmassinokiani, 2016 19 -5.27 2.48 20 -3.69 2.94 -0.57 (-1.20, 0.06) 8.83\nHoseinalizadeh, 2018 20 -3.85 1.37 20 -1.54 0.89 -1.96 (-2.70, -1.22) 7.91\nSchwertner, 2013 20 -3.741 2.21 20 -1.98 1.75 -0.87 (-1.50, -0.23) 8.76\nLasco, 2012 20 -2.35 1.75 20 0.1 1.76 -1.37 (-2.05, -0.69) 8.43\nAbokhrais, 2020 14 0.04 1.88 13 -0.67 2.47 0.32 (-0.42, 1.05) 7.97\nHeterogeneity: τ\n2\n=0.35, I\n2\n=77.16%, H\n2\n=4.38 -0.71 (-1.22, -0.21)\nTest of θi=θj: Q(6)=26.27, P=0.00\n>8 weeks\nMehdizadehkashi, 2021 30 -3.2 1.75 30 -1.9 2.71 -0.56 (-1.07, -0.05) 9.79\nNodler, 2020 27 -1.5 3.01 22 -1.6 2.94 0.03 (-0.52, 0.59) 9.43\nNodler, 2020 20 -0.7 3.15 22 -1.6 2.94 0.29 (-0.31, 0.89) 9.07\nSesti, 2007 35 -1.7 1.05 110 -1.5 1.25 -0.17 (-0.54, 0.21) 10.80\nHeterogeneity: τ\n2\n=0.04, I\n2\n=40.31%, H\n2\n=1.68 -0.13 (-0.45, 0.20)\nTest of θi=θj: Q(3)=5.03, P=0.17\n-0.48 (-0.82, -0.13)\nOverall\nHeterogeneity: τ\n2\n=0.26, I\n2\n=75.14%, H\n2\n=4.02\nTest of θi=θj: Q(10)=40.23, P=0.00\nTest of group differences: Qb(1)=3.69, P=0.05\nRandom-effects DerSimonian-Laird model\n-1 0 12-3\n\nwww.ogscience.org192\nVol. 67, No. 2, 2024\nin five trials. Only one trial had a high risk of detection bias. \nHalf the trials provided an intention-to-treat analysis. Three \ntrials were conducted for each protocol. Two trials had a \nhigh risk of attrition bias. All the trials were judged to have a \nlow risk of reporting bias. Finally, three trials were judged as \nunclear for other biases. All trials recorded sufficient data on \ndysmenorrhea; however, five of these trials provided insuf\n-\nficient data on pelvic pain, and four studies did not provide \nsufficient information on dyspareunia.\n3. The effect of antioxidants on dysmenorrhea\nPooling results from 10 trials that compared the effect of an-\ntioxidants versus placebo in terms of reducing dysmenorrhea \nsuggested that antioxidants significantly reduced dysmenorr\n-\nhea (SMD, -0.48; 95% CI, -0.82 to -0.13; P <0.001) (Fig. 3). \nHigh heterogeneity was detected between trials (P <0.001; \nI\n2\n=75.14%); however, there was no indication of publication \nbias affecting these findings (Egger’s regression intercept, \n-4.77; 95% CI, -12.17 to 2.62; P =0.178). In a subgroup \nanalysis, a significant difference was observed in the subset \nof trials that compared the effect of various antioxidants \non dysmenorrhea: vitamin D, omega-3 fatty acids, resve\n-\nratrol, melatonin, and a combination of antioxidants (Chi\n2\n, \n11.52; degree of differentiation, 4; P =0.02). There was a \nsignificant reduction in dysmenorrhea in the subset of trials \nthat administered vitamin D (SMD, -0.59; 95% CI, -1.13 \nto -0.06; P=0.02; I\n2\n=69.59%), and those that administered \nmelatonin (SMD, -1.40; 95% CI, -2.47 to -0.32; P =0.03; \nI\n2\n=79.15%; Fig. 3). No significant reduction in the severity \nof dysmenorrhea was observed in the subset of trials that \nadministered omega-3 fatty acids (SMD, 0.30; 95% CI, -0.16 \nto 0.76; P =0.96; I\n2\n=0%), resveratrol (SMD, -0.35; 95% CI, \n-0.94 to 0.23), or combination of antioxidants (SMD, -0.21; \n95% CI, -0.51 to 0.09; P =0.69; I\n2\n=0%; Fig. 3). A significant \nreduction in dysmenorrhea was observed in the subset of \ntrials that administered antioxidant supplementation for \n≤8 weeks (SMD, -0.71; 95% CI, -1.22 to -0.21; P <0.001; \nI\n2\n=77.16%). Conversely, no significant reduction was obser -\nved in the subset of trials with antioxidant supplementation \nlonger than 8 weeks (SMD, -0.13; 95% CI, -0.45 to 0.20; \nP=0.17; I\n2\n= 40.31%; Fig. 4). The sensitivity analysis indicated \nthat the exclusion of any individual trial did not significantly \nalter the overall results of the meta-analysis, revealing the \nhigh stability of the results (Supplementary Fig. 1). A funnel \nplot depicts a triangular region centered on the pooled SMD, \nin which 95% CI of study findings should fall if there is no \npublication bias and no heterogeneity in the underlying true \neffects (Supplementary Fig. 2).\nFig. 6. Forest plot of the effect of antioxidants on pelvic pain. N, number; SD, standard deviation; CI, confidence interval; REML, restricted \nmaximum likelihood.\nTreatment Control Hedges's g Weight (%)Study N Mean SD N Mean SD with 95% CI\nSesti, 2007 35 -3.8 0.98 110 -1.8 1.23 -1.69 (-2.12, -1.27) 25.93\nAmini, 2021 30 -5.38 2.41 30 0.17 1.73 -2.61 (-3.30, -1.93) 24.71\nAlmassinokiani, 2016 19 -3.21 2.98 20 -4.14 3.56 0.28 (-0.34, 0.89) 25.06\nHoseinalizadeh, 2018 20 -4.0 1.38 20 -1.57 0.89 -2.05 (-2.81, -1.30) 24.30\nOverall -1.51 (-2.74, -0.29)\nHeterogeneity: τ\n2\n=1.47, I\n2\n=93.96%, H\n2\n=16.56\nTest of θi=θj: Q(3)=44.69, P=0.00\nTest of θ=0: z=-2.42, P=0.02\nRandom-effects REML model\n-1 0 12-3\nFig. 5. Forest plot of the effect of antioxidants on dyspareunia pain. N, number; SD, standard deviation; CI, confidence interval.\nTreatment Control Hedges's g Weight (%)Study N Mean SD N Mean SD with 95% CI\nMehdizadehkashi, 2021 30 -2.3 2.46 30 -2.1 2.55 -0.08 (-0.58, 0.42) 25.57\nSesti, 2007 35 -2.2 1.15 110 -2.0 1.2 -0.17 (-0.55, 0.21) 26.40\nAmini et al, 2021 30 -5.08 2.48 30 -0.26 2.08 -2.08 ( -2.70, -1.46) 24.56\nAbokhrais et al, 2020 14 -0.03 2.37 13 -1.23 3.03 0.43 (-0.31, 1.17) 23.48\nOverall -0.47 (-1.40, 0.45)\nHeterogeneity: τ\n2\n=0.81, I\n2\n=91.61%, H\n2\n=11.92\nTest of θi=θj: Q(3)=35.76, P=0.00\nTest of θ=0: z=-1.00, P=0.32\nRandom-effects DerSimonian-Laird model\n-1 0 12-3\n\nwww.ogscience.org 193\nSaeed Baradwan, et al. Antioxidants & gynecologic-related pain\n4. The effect of antioxidants on dyspareunia\nTotal effectiveness was reported in four trials. Meta-analysis \nresults suggested that there was no significant difference \nin terms of dyspareunia levels when comparing antioxidant \nsupplementation and placebo (SMD, -0.47; 95% CI, -1.40 \nto 0.45; P=0.32; Fig. 5). High heterogeneity was detected \nbetween trials (I\n2\n= 91.61%; P<0.001). The sensitivity analysis \nindicated that excluding any individual trial did not signifi -\ncantly alter the overall results of the meta-analysis, revealing \nthe high stability of the results (Supplementary Fig. 3).\n5. The effect of antioxidants on pelvic pain\nPelvic pain was recorded in four trials. Meta-analysis results \nsuggested that antioxidant supplementation significantly \nimproved endometriosis-associated pelvic pain (SMD, -1.51; \n95% CI, -2.74 to -0.29; P =0.01; Fig. 6). High heterogeneity \nwas detected between trials (I\n2\n=93.96%; P<0.001). Sensitivi-\nty analysis showed that the pooled SMD varied considerably \nwith the omission of three trials; in particular, the exclusion \nof the study by Sesti et al. [26], Amini et al. [13], and Hosei\n-\nnalizadeh and Cahichian. [20] which accounted for approxi -\nmately 25.93%, 24.71%, and 24.30% of all weights in the \nmeta-analysis, resulted in a pooled SMD (95% CI) of -1.45 \n(-3.20 to 0.29), -1.15 (-2.56 to 0.26), and -1.34 (-3.00 to \n0.32), respectively (Supplementary Fig. 4).\n6. Quality of evidence\nWe were moderately confident in the outcomes of dysme -\nnorrhea because of the uncertainty regarding the risk of bias. \nWe had very little confidence in the outcomes of dyspareunia \nand pelvic pain because of some uncertainty regarding the \nrisk of bias, inconsistency (high heterogeneity), and imprecisi\n-\non (non-significant results) (Supplementary Table 2).\nConclusion\nNumerous studies have assessed the effectiveness of dietary \nand supplemental antioxidants for managing different types \nof pain in women with endometriosis. Previous systematic \nreviews and meta-analyses have reported inconsistent results. \nIn line with our findings, systematic reviews support the \npositive effects of antioxidants in improving endometriosis-\nassociated pain [16]. However, systematic reviews and meta-\nanalyses have indicated that certain antioxidant vitamins, \nsuch as vitamin D, may not efficiently alleviate pain in pa\n-\ntients [17]. Dysmenorrhea, dyspareunia, and chronic pelvic \npain stand out as the most prevalent issues in women of re\n-\nproductive age [27,28]. Our findings suggest that dietary and \nsupplemental antioxidant intake is associated with a notable \nreduction in dysmenorrhea and chronic pelvic pain. However, \nour meta-analysis did not reveal a significant effect of anti\n-\noxidant intake on dyspareunia in women with endometriosis.\nDietary antioxidants such as vitamin D, omega-3 fatty \nacids, and melatonin can have an interactive impact on \ndecreasing cellular damage induced by oxidative stress and \nROS [29-31]. Dietary antioxidants can neutralize the ROS and \noxidative damage associated with pain in endometriosis. The \ninvolvement of oxidative stress and related markers in the \ninitiation and progression of endometriotic complications \nhas been suggested in experimental studies [32]. Cultivated \nendometrial stromal cells were treated with antioxidants and \noxidative stress factors. The application of antioxidant agents \nresulted in a dose-dependent suppression of cell growth. In \ncontrast, control cells treated with oxidative stress factors ex\n-\nhibited increased endometrial stromal growth [33]. The most \naccepted mechanism for this effect is an antioxidant system \nthat removes free radicals and functions through superoxide \ndismutases that remove the superoxide anion and glutathi\n-\none peroxidase, which then removes hydrogen peroxide. In \nwomen with endometriosis, there is a diminished function of \nthe antioxidant system activity [34]. \nIt has been shown that the levels of most oxidative stress \nparameters are markedly enhanced in women with endome\n-\ntriosis compared with controls, and this is one of the main \nfactors contributing to pain in these patients [35,36]. Several \nrecent studies have shown that oxidative stress is positively \nassociated with the migration and proliferation of endome\n-\ntrial cells in the peritoneal cavity, thereby increasing the prob-\nability of endometriosis and infertility [32,37]. The correlation \nbetween ROS generation and endometriosis is verified and \nwidely investigated [38]. Moreover, it has been demonstrated \nthat ROS and their reactive oxygen precursors are essential in \nthe progression of pain in several etiologies [39]. Therefore, \ncontrol of ROS leads to pain relief in patients with endome\n-\ntriosis, and it has been widely reported that dietary antioxi -\ndant supplements can effectively decrease ROS levels [40,41]. \nIt was also observed that the increased ROS and enhanced \nproliferative potential in endometriotic cells were related to \nthe full stimulation and elevated levels of phosphorylated \n\nwww.ogscience.org194\nVol. 67, No. 2, 2024\nendoplasmic reticulum kinase (ERK), as previously detected in \ntumor cells [42]. In addition, enhanced ERK phosphorylation \nhas recently been reported in stromal cells of women with \nendometriosis [43]. Furthermore, there are links between \nROS generation, ERK activation, and endometriotic cell prolif-\neration [44]. It was also demonstrated that ERK activation is \nin response to different pro-inflammatory factors such as tu-\nmor necrosis factor-α and interleukin-1ß [45,46]. These two \npro-inflammatory markers are enhanced in the endometrium \nof women with endometriosis [47,48]. Pro-inflammatory \nmarkers have a pivotal role in the progression and develop -\nment of pain in patients with endometriosis [49,50]. In ad -\ndition, dietary antioxidant supplements have been shown to \nregulate pro-inflammatory cytokines efficiently [51]. \nRecent studies have also shown increased concentrations \nof other oxidative stress parameters in women with primary \ndysmenorrhea. Malondialdehyde (MDA) is an index of lipid \nperoxides [52]. MDA concentrations were higher in women \nwith endometriosis than in healthy controls [53]. Lipid per\n-\noxide levels were higher in peritoneal fluid samples from \nwomen with endometriosis than in healthy controls [34]. \nTherefore, a decrease in MDA levels may help control cell \nproliferation in endometriosis, and it has been demonstrated \nthat dietary antioxidants such as vitamin D and omega-3 \nfatty acids can decrease MDA levels [29,54]. \nRecent investigations have reported the elevated level of \niron in different parts of the peritoneal cavity of women \nwith endometriosis, including endometriotic lesions, mac\n-\nrophages, and peritoneal fluid, which basically proposes \ndysfunction of iron homeostasis in the peritoneal environ\n-\nment among this group of patients [55,56]. In women with \nendometriosis, elevated iron levels may result from the lysis \nof pelvic erythrocytes [57]. Retrograde menstruation leads to \nsevere hemolysis of erythrocytes accompanied by a disrup\n-\ntive or overwhelmed peritoneal elimination system, which \nenhances iron levels in the peritoneal environment, leading \nto the progression and growth of endometrial cells [58,59]. \nIron overload might have several cytotoxic effects because it \nreduces the equilibrium between free radical generation and \nthe antioxidant system, which can cause oxidative stress [60]. \nOur subgroup analysis indicated that vitamin D and mela\n-\ntonin were more effective in decreasing dysmenorrhea in \npatients with endometriosis. It has been demonstrated that \nvitamin D [61] and melatonin can efficiently decrease iron \ntoxicity complications [62,63]. \nThe effectiveness of vitamin D in reducing dysmenorrhea in \npatients with endometriosis is thought to be mechanistically \nlinked to its anti-inflammatory and immunomodulatory prop\n-\nerties [64]. Endometriosis is characterized by endometrial-\nlike tissue outside the uterus, causing inflammation and pain \nduring menstruation [65,66]. Vitamin D receptors exist in \nvarious cells, including those involved in immune responses \nand inflammation [67]. By binding to these receptors, vita -\nmin D may regulate the production of inflammatory media -\ntors such as cytokines and modulate immune system activity \n[68]. This regulatory effect is believed to mitigate the height-\nened inflammatory response associated with endometriosis \nand subsequently reduce the severity of dysmenorrhea [69]. \nAlthough the precise mechanisms are still under investiga\n-\ntion, emerging research suggests that maintaining optimal \nvitamin D levels may play a role in managing the pain and \ninflammation associated with endometriosis-related dysmen\n-\norrhea. On the other hand, melatonin, primarily recognized \nas a regulator of the sleep-wake cycle, also exhibits potent \nantioxidant properties [70]. Melatonin supplementation may \nbe beneficial in the context of endometriosis-related dysmen\n-\norrhea, where oxidative stress is pivotal to exacerbating pain \nand inflammation [25]. Endometriosis is associated with in\n-\ncreased ROS production, contributing to tissue damage and \nincreased pain sensitivity [8,71]. Melatonin functions as a \nfree radical scavenger and mitigates oxidative stress by neu\n-\ntralizing harmful molecules [72]. Therefore, the antioxidant \neffect of melatonin holds promise in reducing the severity of \ndysmenorrhea in patients with endometriosis [73]. By allevi\n-\nating the oxidative burden, melatonin may contribute to the \nmodulation of inflammatory responses and a subsequent de\n-\ncrease in pain perception, offering a supplementary avenue \nfor managing the discomfort associated with endometriosis-\nrelated menstrual pain [74].\nAdditionally, in the same context, vitamins C and E, similar \nto vitamin D and melatonin, are recognized for their role \nin regulating iron levels, preventing excess, or addressing \ndeficiency. This regulation aids in reducing oxidative stress \nbecause these vitamins function as antioxidants. However, \nperhaps due to the limited number of included studies that \nassessed the effectiveness of vitamins C and E, coupled with \nheterogeneous findings, we could not identify significant re\n-\nsults for these vitamins. Therefore, further large-scale studies \nare required.\n\nwww.ogscience.org 195\nSaeed Baradwan, et al. Antioxidants & gynecologic-related pain\n1. Strengths and limitations of the current review\nThis systematic review and meta-analysis has several limita -\ntions. The small number of included trials makes it difficult \nto draw a definitive conclusion regarding the effect of an -\ntioxidant supplements on dyspareunia in patients with en -\ndometriosis; therefore, these results should be interpreted \ncautiously. In addition, there are not enough trials in the lit\n-\nerature to cover all dietary antioxidant supplements that may \neffectively reduce endometriosis-associated pain symptoms. \nAnother limiting factor in the findings of this meta-analysis \nwas the heterogeneity of the study populations and the \ntypes of antioxidants included in the trials. Some researchers \nfailed to provide sufficient information on the selection crite\n-\nria and data regarding where the trials were performed.\nDietary antioxidant supplementation seemed to have a \nbeneficial effect on the severity of endometriosis-related \ndysmenorrhea (with an emphasis on vitamin D and melato\n-\nnin) and pelvic pain. In contrast, no significant reduction in \ndyspareunia was observed. However, the obtained findings \nshould be interpreted cautiously owing to the relatively small \nsample size and high heterogeneity between studies, and the \nimportance of further well-designed clinical studies cannot \nbe overstated.\nConflict of interest\nAll authors have no conflict of interest to declare.\nEthical approval\nNot applicable. \nPatient consent\nNot applicable.\nFunding information \nNone.\nReferences\n  1. Gordts S, Koninckx P , Brosens I. Pathogenesis of deep \nendometriosis. Fertil Steril 2017;108:872-85.e1.\n  2. Giudice LC. Clinical practice. Endometriosis. 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Therapeutic effects \nof melatonin on endometriosis, targeting molecular \npathways: current knowledge and future perspective. \nPathol Res Pract 2023;243:154368.","source_license":"CC0","license_restricted":false}