The association between Selenium and Epithelial Ovarian Cancer among women: A systematic review and meta-analysis

The association between Selenium and Epithelial Ovarian Cancer among women: A systematic review and meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review The association between Selenium and Epithelial Ovarian Cancer among women: A systematic review and meta-analysis KCM Perera, WND Perera, HTCS Abeysena This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9660701/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Ovarian cancer is the sixth most prevalent and fatal cancer among females worldwide. Antioxidants have been shown to have some proven anti-cancerous effects by limiting oxidative stress. Selenium is a powerful antioxidant, it also protects the cells from the destruction caused by peroxides. This study aimed to determine the association between Selenium and Epithelial Ovarian Cancer among women who have not had an oophorectomy. Methods and analysis: A comprehensive electronic search was carried out according to the prepared search strategy from the starting date of the PubMed/Medline, EMBASE, Scopus, Proquest, and Web of Science databases up to the 30 th of September 2022 without limitations related to language and publication status. All observational studies, cross-sectional analytical studies, ecological studies, randomised control studies, and non-randomised clinical trials were included in the systematic review. Studies were screened by COVIDENCE. The exposure of interest was high selenium intake from either food sources, supplements, or high selenium measures in blood and toenails. Data extraction was done. New Castle Ottawa Scale and the ROBINS-1 tool were used to assess the bias of selected studies. The narrative synthesis and meta-analysis were conducted. Results were displayed via forest plots. All analyses were conducted using STATA-17. Results: Nine studies (n=9) comprising 108,872 women were evaluated in the systematic review and meta-analysis. In narrative synthesis, there was a significant inverse association between Se and EOC, with high serum Se (n=2), diet by FFQ (n=2), food supplements (n=1), and oral supplements (n=1). There was no association between toenail Se and EOC. Based on four meta-analyses there was no significant association between Selenium from food sources(OR:0.68; 95%CI:0.39-1.17; p-value:0.167; I²:50.1%; Q value:4.01; p-value:0.135), food supplements (OR:0.83; 95%CI:0.56-1.24; p-value:0.37; I²:80.8%; Q value:20.78; p-value:0.000), biological samples (OR: 0.62; 95%CI:0.29-1.33; p-value:0.218; I²:37%; Q value:3.18; p-value:0.204), and diet and food supplement (OR:0.7; 95%CI:0.46-1.06; p-value:0.093; I²:0%; Q value:0.07; p-value:0.793) and Epithelial Ovarian Cancer. There was no publication bias in all four meta-analyses according to the funnel plots, Egger’s p-value (p≥0.05), and Begg’s p-value (p≥0.05). Conclusion Uniformity of controlling confounding bias among studies is a must to obtain the real association between Selenium and Epithelial Ovarian Cancer in this meta-analysis. Cancer ovarian epithelial association aetiology selenium Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Background Ovarian cancer is ranked as one of the sixth most prevalent and fatal cancers among women, and the 5-year survival rate is less than 40%. Around 165,000 new ovarian cancer cases and 100,000 deaths are diagnosed annually(1). Even though age-standardised incidence rates (ASR) are stable or falling in most of the developed countries, they are still rising in low and middle-income countries. In addition, due to the higher life expectancy of women now, the detection rate of ovarian cancer is high (2). More than 90% of ovarian cancers occurring in women over 40 years are epithelial. High-grade serous, low-grade serous, endometrioid, clear cell and mucinous carcinoma are the main 5 different histotypes of ovarian cancer in women (3). Even if it is classified as ovarian, a high proportion of high-grade serous cancers are now thought to originate from the fallopian tube (2). Lack of symptoms in the early-stages of ovarian cancer leads to a high mortality rate overall among women. In Australia, 66% of ovarian cancers were diagnosed within 1 month of the initial presentation, but for around 12 % of women, the diagnostic process took longer than 6 months, and this was more likely for those with lower incomes, those presenting with non-specific symptoms, or with more than one symptom (4). Transvaginal ultrasound and serum CA-125 testing can be effectively used at present to evaluate symptomatic women for ovarian cancer, but the United States Preventive Services Task Force (USPSTF) does not recommend routine screening for ovarian cancer using any method (5). Therefore, protective measures play a vital role in reducing ovarian cancer burden worldwide. In the ovaries, during the process of ovulation and luteinisation, free radicals are produced in excess and surrounding cells are exposed to excessive reactive oxidants. Antioxidants work by tracking down free radicals and neutralising their harmful effects. For proper physiological function, there should be a balance between free radicals and antioxidants. If an imbalance with excess free radicals overwhelms the body's ability to regulate them, a condition known as oxidative stress, ensues, which damages healthy cells and becomes cancerous(6). Therefore, limiting oxidative stress to the ovarian tissues could be considered a protective measure against ovarian cancer. Selenium (Se) is an essential dietary component and a powerful antioxidant for humans that fights against oxidative stress. The concentration of malondialdehyde (MDA), a lipid peroxidation product, was high in carcinomatous tissues. The basic function of Se in the organism is to be the cofactor of the enzyme Glutathion Peroxidase (GSH-Px), which protects the cells from the destruction caused by peroxides as it reduces already formed hydroperoxides to less reactive alcohol(7). Selenium is regarded as a protective agent against some selected cancers i.e., breast, lung, oesophagal, gastric, and prostate, but there was no such relationship with some other cancers, i.e. colorectal, bladder, and skin cancers(8). Several observational studies and some non-randomised clinical trials have assessed the relationship between selenium as an etiological factor and Epithelial Ovarian Cancer (EOC) risk among women. An inverse association for EOC was observed for the highest compared to the lowest tertile of Se intake from food sources (6, 8). In addition, women with the highest intakes of supplemental Se had an inverse association for EOC with no supplemental intake (9, 10). In contrast, some other studies have concluded that there is no inverse association between Se from food sources (11, 12), supplements (13) and serum concentration (14) with the incidence of ovarian cancer. So far, no published systematic reviews or meta-analyses have assessed the association between Se as an etiological factor and EOC risk. Epidemiological studies have shown some inconsistent results on the pre-mentioned association. Therefore, the objective of this systematic review and meta-analysis was to assess whether there is an inverse relationship between Se and EOC among women who have not had an oophorectomy, as such a relationship would have an impact on future preventive measures for ovarian cancer. Methodology Search strategy A search strategy was developed for PubMed and Medline, EMBASE, Scopus, Proquest, and Web of Science databases. A librarian of the University of Queensland was involved to develop the search strategy. Medical Subject Heading Terms (MeSH) and keywords were used in various combinations to develop search strategies. Search strategies were reviewed by all authors. A comprehensive electronic search was undertaken from the starting date of the databases up to the 30 th of September 2022, according to the prepared search strategies, without limitations related to the language and publication status, and the study protocol was registered at the PROSPERO(Annexure-1). Studies will be retrieved from the mentioned databases using the following search strategy, and the completed search strategy was attached as Annexure-2. (Selenium) AND ((((((((Epithelial Ovarian Cancer) OR (Ovarian Cancer)) OR (Gynaecological Malignancies)) OR (Ovarian Carcinoma)) OR (Ovarian tumour)) OR (Ovarian tumor)) OR (ovarian malignancy)) OR (female malignancies)) Sort by: Publication Date In addition, references of review articles, systematic reviews, meta-analyses, commentaries, editorials, meeting abstracts, and references of the included studies were evaluated for additional articles. Further, books related to gynaecological malignancies and hand searches of journals were done. And also searched for grey literature such as conference abstracts/proceedings, published lists of thesis and dissertations, and other literature outside of the main journal literature, where possible. Searched for unpublished outcomes and studies by searching informal sources, including meeting abstracts and Ph.D. theses, and contacting authors of included studies. Inclusion and Exclusion Criteria: Inclusion criteria We selected all observational studies (prospective/retrospective, case-control, and nested case-control) with provided adjusted risk estimates or provided data allowing the calculation of the risk estimates and 95% Confidence Interval (CI) for the association between Se and EOC, ecological studies, cross-sectional analytical studies, randomised control studies (RCTs) and non-randomised clinical trials. Studies published across all dates, times, and countries were included in the review. Studies published in other languages were translated into English by Google Translate. Exclusion criteria: Descriptive studies (i.e. case reports, case series, editorials, and opinion pieces) and animal studies were excluded from the review. Study selection Two review authors independently screened studies using COVIDENCE software for systematic reviews under the University of Queensland multiple systematic review license to identify the eligible studies according to the following procedure; Retrieved studies using the COVIDENCE software and removed duplicates Assessed the title and abstract of all studies and removed irrelevant ones Assessed the full text of all studies identified as possibly relevant Selected studies for the systematic review and meta-analysis Any inconsistencies between the two review authors over the eligibility of particular studies were resolved through discussion with a third reviewer. Quality assessment Two review authors independently used the New Castle Ottawa scale of quality assessment for observational studies and the ROBINS-1 tool of quality assessment for the non-clinical randomised study. Disagreements between the two review authors over the risk of bias in particular studies were resolved by discussion, with the involvement of the third review author where necessary. Data extraction Two review authors independently retrieved the following general study information, where available, from all included studies: author, publication year, study design, study setting; study population, participant demographics and baseline characteristics, details of the intervention and control conditions, recruitment and study completion rates, outcomes with risk estimates and 95%CIs, adjusted/matched factors for individual studies and times of outcome measurement, and information for the assessment of the risk of bias. Discrepancies were identified and resolved through discussion with the third author where necessary. As per the PRISMA-P expanded checklist 2020, We had cited studies that appeared to meet the inclusion, but which were excluded, and explained why they were excluded . Synthesis of the findings One review author had abstracted data into standard evidence tables; the second review author checked them for accuracy. The findings were synthesised via a narrative description in the first place. Quantitative synthesis for the pooling of data was done by meta-analysis. Heterogeneity between the studies in effect measures was assessed by using the I 2 statistic and Cochran”s Q test. The random effect inverse-variance model was used in the meta-analysis by STATA-17 with DerSimonian-Laird estimate of tau² and four meta-analyses were conducted between; Se from food sources, supplements, biological samples and diet and supplement and EOC among women. A subgroup analysis was conducted by reducing each study to substantial heterogeneity. The results were displayed via forest plots of log OR against log lower and log upper CIs. The existence of publication bias was also considered using the asymmetry of funnel plots, Egger̓s p-value and, Begg̓s p-value. All analyses were conducted using STATA-17. Results Out of the 652 articles retrieved and selected from the electronic databases, 145 studies were excluded due to duplication. In the next step, titles and abstracts of studies were screened and 405 irrelevant studies were removed; 102 studies were included in the full-text review and 29 studies were selected for data extraction. However, only 9 studies were considered eligible for the systematic review and meta-analysis. Performed a narrative synthesis and 4 separate meta-analyses were conducted based on selenium from food sources, supplements, biological samples and overall diet and supplements (Figure 1) . As per the PRISMA-P expanded checklist 2020, studies that had appeared to meet the inclusion criteria, but were excluded (n=20), were cited (Annexure- 3) and explained why they were excluded. Eligible studies were published from the starting date of the relevant database up to the 30 th of September 2022 in Washington country (n=1), Hawai and Los Angeles (n=1), Poland (n=2), and the USA (n=5) (Table 1). In these studies, data from 108,872 individuals (1930 subjects with ovarian cancers and 106942 control subjects) were reviewed. All data were synthesised based on the following research question: Is there an inverse relationship between Se (food sources, supplements, and measures of selenium in blood, serum, toenails, and other biological samples) and EOC risk among women who have not had an oophorectomy. Data were synthesised based on the study design, the intervention, and the association of Se and EOC. The study design There were 7 observational studies, including 2 nested case-control studies, 4 case-control studies, and 1 prospective cohort study, that presented the association between exposure and an outcome (Odds Ratio). One study of observational (prospective cohort) combined with an experimental trial presented the association between exposure and an outcome over time (Hazard Ratio). One study of a non-randomized clinical trial presented the ratio of the probability of an adverse outcome in an exposure group to the probability of an adverse outcome in an unexposed group (Relative risk). Two nested case-control studies were from Washington Country and Poland. Four case-control studies were from the USA, and Los Angeles, and Hawaii. One prospective cohort study was from the USA, and the study of a prospective cohort combined with an experimental trial was also from the USA. One study of a non-randomized clinical trial was from Poland. The intervention In case-control studies, cohort studies, and cohort studies combined with the clinical trial, the amount of Se that has been consumed in the diet or food supplement by the Food Frequency Questionnaire (FFQ) was the intervention, and the measurement of blood/serum concentration of Se was the intervention in nested case-control studies. An oral Se supplementation was the intervention for the non-randomised clinical trial. The association of Se and EOC Garland et al (1995) revealed that there is no association between the amount of Se that has been consumed in the diet and toenail selenium level among the members of the cohort and EOC among women (OR; 1.22, 95%CI; 0.44-3.88, p; 0.52). Helzlsouer et al (1996) was given an inverse association between the measurement of serum concentration of Se and the EOC diagnosed only after 4 years of blood collection (OR;0.23, 95%CI; 0.1-0.9, p;0.02) but there was no overall association between measurement of serum concentration of Se and the EOC (OR;0.58, 95%CI; 0.2-1.7, p;0.33). There was no association between the amount of Se that was consumed in the diet by FFQ in mucinous (OR; 0.78, 95%CI; 0.27-2.21, p; 0.18) and non-mucinous EOC (OR; 1.03, 95%CI; 0.6-1.8, p; 0.98) according to the study carried out by Tung et al (2005). The study carried out by Huzarski et al (2006) indicated that there is an inverse association between the amount of oral Se supplement and EOC (OR; 0.49, 95%CI; 0.35-0.69, p; 0.04). Thomson et al (2008) indicated that there is no association between the amount of Se consumed as a dietary supplement by interviewer-administered dietary supplement questionnaire and EOC (HR; 1.16, 95%CI; 0.91-1.48, p; 0.11). Fleischauer et al (2009) found no association between the amount of Se that has been consumed as a food supplement by FFQ between EOC cases and community controls (OR; 0.78, 95%CI; 0.46-1.34, p; 0.36) and total controls (OR; 0.9, 95%CI; 0.56-1.45, p; 0.64) as well. Gifkins et al. (2012) found an inverse association between the amount of Se that has been consumed from food in the diet by FFQ and EOC (OR; 0.41, 95%CI; 0.2-0.85, p; 0. 0.04) but there was a risk association of Se that has been consumed as a supplement in the diet by FFQ and EOC and it was reached to a significant level only after further adjusting smoking and physical activity (OR; 1.64, 95%CI; 1.05-2.56, p; 0.02). No association between Se has been consumed as food and dietary supplement by FFQ and EOC (OR; 0.75, 95%CI; 0.39-1.43, p; 0.3). Lubinski et al. (2017) found a significant inverse association between the measurement of Se concentration in the blood ≥110µĝ/l and EOC among women (OR; 0.32, 95%CI; 0.1-0.85, p; 0.033). Terry et al (2017) was given an inverse association between the amount of Se that has been consumed as a food supplement by FFQ and EOC (OR; 0.67, 95%CI; 0.46-0.97, p; 0.035). This inverse association was stronger in current smokers (OR; 0.13, 95%CI; 0.04-0.46, p; 0.001). In contrast, there was no association between the amount of Se that has been consumed in the diet by FFQ and EOC (OR; 0.66, 95%CI; 0.31-1.37, p; 0.1) and the amount of Se that has been consumed overall as a diet and food supplement by FFQ and EOC (OR; 0.67, 95%CI; 0.39-1.14, p; 0.1). Meta-analysis Selenium from food sources and EOC Based on the meta-analysis conducted on Se from food sources and EOC among women, there was no significant association between Se from food sources and EOC (OR: 0.68; 95%CI: 0.39-1.17; p-value:0.167; I²:50.1%; Q value:4.01; p-value:0.135) (Figure 2). As there was a mild substantial heterogeneity, subgroup analysis was conducted by reducing each study to see the changes in heterogeneity. Subgroup analysis 1; Meta-analysis between Tung (2005) and Gifkins (2012) increased heterogeneity further (I²:74.7%; p-value: 0.047). Subgroup analysis 2; Meta-analysis between Tung (2005) and Terry (2017) had reached 0 heterogeneity (I²:0.0%; p-value: 0.345). Subgroup analysis 3 Meta-analysis between Gifkins (2012) and Terry (2017) also reached 0 heterogeneity (I²:0.0%; p-value: 0.368). Publication bias was estimated using Begg̓s p-value (p≥0.05) and Egger̓s p-value (p≥0.05) and a funnel plot (Figure 3). Our findings revealed that there was no publication bias. 2. Selenium from food supplements and EOC Based on the meta-analysis conducted on Se from food supplements and EOC among women, there was no significant association between Se from food supplements and EOC (OR:0.83; 95%CI:0.56-1.24; p-value:0.37; I²:80.8%; Q value:20.78; p-value:0.000) (Figure 4). As there was substantial heterogeneity, subgroup analysis was conducted by reducing each study to see the changes in heterogeneity. Subgroup analysis 1 Meta-analysis between Fleischauer (2009), Terry (2017), Huzarski (2006), and Thomson (2008) decreased heterogeneity (I²:67.9%; p-value: 0.025). Subgroup analysis 2 Meta-analysis between Fleischauer (2009), Gifkins (2012), Huzarski (2006), and Thomson (2008) increased heterogeneity (I²:84.7%; p-value: 0.000). Subgroup analysis 3 Meta-analysis between Fleischauer (2009), Gifkins (2012), Terry (2017), and Thomson (2008) decreased heterogeneity (I²:69.3%; p-value: 0.021). Subgroup analysis 4 Meta-analysis between Fleischauer (2009), Gifkins (2012), Terry (2017), and Huzarski (2006) further increased heterogeneity (I²:83.5%; p-value: 0.000). Subgroup analysis 5 Meta-analysis between Gifkins (2012), Terry (2017), Huzarski (2006), and Thomson (2008) also further increased heterogeneity (I²:85.6%; p-value: 0.000). Publication bias was estimated using Begg̓ s p-value (p≥0.05) and Egger̓ s p-value (p≥0.05) and a funnel plot (Figure 5). Our findings revealed that there was no publication bias. 3. Selenium from biological samples and EOC Based on the meta-analysis conducted on Se from biological samples and EOC among women, there was no significant association between Se from biological samples and EOC (OR: 0.62; 95%CI:0.29-1.33; p-value:0.218; I²:37%; Q value:3.18; p-value:0.204) (Figure 6). Publication bias was estimated using Begg̓s p-value (p≥0.05) and Egger̓s p-value (p≥0.05) and a funnel plot (Figure 7). Our findings revealed that there was no publication bias. 4. Selenium from diet and food supplements and EOC Based on the meta-analysis conducted on Se from diet and food supplement and EOC among women, there was no significant association between Se from diet and food supplement and EOC (OR:0.7; 95%CI:0.46-1.06; p-value:0.093; I²:0%; Q value:0.07; p-value:0.793) (Figure 8). Publication bias was estimated using Begg̓s p-value (p≥0.05) and Egger̓s p-value (p≥0.05) and a funnel plot (Figure 9). Our findings revealed that there was no publication bias. Discussion Ovarian cancer is the most fatal of all gynecologic cancers ( 11 ). It usually detects at advanced stages, and treatment is unlikely to be curative, survival is poor. The majority of ovarian cancers had been diagnosed with metastasis as the symptoms of ovarian cancers are often non-specific ( 15 ). Due to the lack of recommended screening tools for ovarian cancer by the United States Preventive Services Task Force (USPTF), the identification of modifiable risk factors and preventive tools is essential to reduce ovarian cancer mortality and morbidity ( 2 ). Selenium is a micronutrient and powerful antioxidant, it reduces oxidative stress and ultimately prevents cell damage ( 16 ). There is some evidence that Se has a protective effect against some cancers (i.e. colon, prostate, lung, stomach and oesophagus) ( 8 ) but epidemiological studies have yielded inconsistent results on the association between Se and EOC risk. Some studies have given the inverse relationship between Se from food sources and EOC ( 6 , 8 ) while, some other studies found no association ( 9 , 12 ). Some were given an inverse relationship between Se from supplements ( 9 , 10 ) and EOC. In contrast, some other studies were given no association ( 11 , 20 ). Upon searching the literature, there were no systematic reviews and meta-analysis conducted so far on the association between Se and EOC risk. Though blood/serum levels of Se ( 14 , 17 ) and toenail levels of Se ( 18 ) were considered as proxy measures of Se intake from food sources and supplements when we assess the association of Se as an etiological factor for EOC, blood/serum levels or tissue levels of Se of diagnosed ovarian cancer cases in case-control studies were not suitable to include in the systematic review and meta-analysis and therefore they were excluded from the review. Only 9 studies were included in the final systematic review and meta-analysis. At first, a narrative synthesis was made. In the narrative synthesis, it was visible that some studies had given an inverse relationship between Se and EOC ( 6 , 9 , 10 , 17 ). In addition, a few more studies showed an inverse relationship in narrative synthesis between Se and EOC with some special adjustments ( 9 , 14 ). Four separate meta-analyses were conducted between Se from food sources, supplements, biological samples and diet and supplements and EOC, but none of them showed a significant inverse relationship. Two meta-analyses reported substantial heterogeneity. Meta-analysis between Se from food sources and EOC was given mild substantial heterogeneity (I² = 50.1%, p = 0.135). It was reduced, when we removed Gifkin et al (2012) and conducted a meta-analysis between Tung et al (2005) and Terry et al (2017) (I²= 0.0%, p = 0.345) and when we removed Tung et al (2005) and conducted meta-analysis between Gifkin et al (2012) and Terry et al (2017)(I²= 0.0%, p = 0.368). Meta-analysis between Se from supplements and EOC was given severe substantial heterogeneity (I² = 80.8%, p = 0.000). It was reduced, when we removed Gifkin et al (2012) and conducted a meta-analysis between Fleischauer et al (2009), Terry et al (2017), Huzarski et al (2006) and Thomson et al (2008) (I²= 67.9%, p = 0.025) and when we removed Huzarski et al (2006) and conducted meta-analysis between Fleischauer et al (2009), Gifkin et al (2012), Terry et al (2017), and Thomson et al (2008) (I²= 69.3%, p = 0.021). ¬ Limitations The major limitation of the study is the confounding bias of the studies selected for the systematic review and meta-analysis for the association between Se and EOC. It was not uniformly controlled in all selected studies for the review, which may have a significant impact on the results. ¬ Strengths The search strategy for electronic databases was created with the assistance of an expert librarian at the University of Queensland. To minimise the bias, two independent reviewers screened the title and abstracts of uploaded articles, screened the full text of selected articles, did the data extraction, assessed the risk of bias of included studies, and data synthesis and conflicts were resolved by the third review author were the strengths of this study. No limitations related to the language and publication status. Conclusions Though there was no true inverse relationship between Se and EOC in meta-analysis, there is strong evidence of a protective effect between Se and EOC in narrative synthesis. Confounding bias will play an important role in the true relationship between Se and EOC, and if the confounding bias were uniformly controlled in studies selected for the review, then the relationship between Se and EOC would have been different. Abbreviations Se Selenium EOC Epithelial Ovarian Cancer MeSH Medical Subject Heading Terms ASR Age- Standardized Rate USPSTF United States Preventive Service Task Force EMBASE Excerpta Medica data BASE PRISMA Preferred Reporting Items for Systematic Reviews and Meta-analysis STATA Statistics and Data FFQ Food Frequency Questionnaire CI Confidence Interval OR Odds ratio RR Relative risk HR Hazard ratio Declarations Ethical approval and consent to participate The need for ethical approval and consent was waived as the systematic review and meta-analysis are based on ethically approved and conducted studies only. It was not appropriate or possible to involve patients or the public in the design, conduct, reporting, or dissemination plans of our research. Consent for publication Not applicable Availability of data and materials The datasets used to analyze this systematic review and meta-analysis are available at the corresponding author upon reasonable request. Competing interests The authors declared that they have no known competing interests. Funding Not applicable. Authors contributions KCMP drafted the final research manuscript. KCMP and WNDP were assigned to screen studies and extract data. HTCSA helped to prepare the study protocol and assigned as a third review author to resolve the conflicts of screening and bias assessment. All three authors read and approved the final manuscript. Acknowledgement This systematic review and meta-analysis was conducted under the supervision of Associate Professor Susan Jordan, The School of Public Health, University of Queensland.The guidance to prepare the search strategy for systematic review and meta-analysis was provided by Marcos Riba, a librarian at the University of Queensland. We are grateful to the School of Public Health at the University of Queensland, the Post Graduate Institute of Medicine, the University of Colombo and the Ministry of Health, Sri Lanka. Author's information Corresponding author: Dr KCM Perera, Consultant Community Physician, Visiting Research Fellow, The School of Public Health, University of Queensland, Australia, Family Health Bureau, Ministry of Health, Sri Lanka [email protected] Dr WND Perera, Consultant Community Physician, Visiting Research Fellow, The School of Public Health, University of Queensland, Australia, National Institute of Health Science, Ministry of Health, Sri Lanka [email protected] , Prof. Chrishantha Abeysena, Senior Professor in Community Medicine, University of Kelaniya [email protected] References Hosseininasab-Nodoushan SA, Ghazvini K, Jamialahmadi T, Keikha M, Sahebkar A. Association of Chlamydia and Mycoplasma infections with susceptibility to ovarian cancer: A systematic review and meta-analysis. Semin Cancer Biol. 2022;86(Pt 2):923–8. Webb PM, Jordan SJ. Epidemiology of epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol. 2017;41:3–14. Peres LC, Cushing-Haugen KL, Anglesio M, Wicklund K, Bentley R, Berchuck A, et al. Histotype classification of ovarian carcinoma: A comparison of approaches. Gynecol Oncol. 2018;151(1):53–60. Susan J, Jordan JEF, Anne E, Nelson HM, Zorbas KA, Luxford, Penelope M, Webb. Pathways to the diagnosis of epithelial ovarian cancer in Australia. MJA. 2010. Jori S, Carter LSDJ. Ovarian Cancer Tests and Treatment. 2011. Gifkins DM. Antioxidants and Cancer of The Endometrium and Ovary. A Dissertation submitted to the Graduate School-New Brunswick Rutgers, The State University of New Jersey. 2011. Torun M, Aldemir H, Yardim S. Serum Selenium levels in various cancer types. 1995. Cai X, Wang C, Yu W, Fan W, Wang S, Shen N, et al. Selenium Exposure and Cancer Risk: an Updated Meta-analysis and Meta-regression. Sci Rep. 2016;6:19213. Terry PD, Qin B, Camacho F, Moorman PG, Alberg AJ, Barnholtz-Sloan JS, et al. Supplemental Selenium May Decrease Ovarian Cancer Risk in African-American Women. J Nutr. 2017;147(4):621–7. Huzarski T, TB, JG, EbK, SaZc BG et al. A Lowering of Breast and Ovarian Cancer Risk in Women with a BRCA1 Mutation by Selenium Supplementation of Diet Hereditary Cancer in Clinical Practice. 2006. Fleischauer AT, Olson SH, Mignone L, Simonsen N, Caputo TA, Harlap S. Dietary antioxidants, supplements, and risk of epithelial ovarian cancer. Nutr Cancer. 2001;40(2):92–8. Tung KWL, Wu AH, McDuffie K, Hankin JH, Nomura AMYKL, Goodman MT. Association of Dietary Vitamin A, Carotenoids, and Other Antioxidants with the Risk of Ovarian Cancer. Cancer Epidemiol Biomarkers Prev. 2005;14(Cancer Epidemiol Biomarkers Prev). Thomson CA, Neuhouser ML, Shikany JM, Caan BJ, Monk BJ, Mossavar-Rahmani Y, et al. The role of antioxidants and vitamin A in ovarian cancer: results from the Women's Health Initiative. Nutr Cancer. 2008;60(6):710–9. Helzlsouer KJAA, Norkus EP, Morris JS, Hoffman SC, Comstock GW. Prospective Study of Serum Micronutrients and Ovarian Cancer. J Natl Cancer Inst. 1996. Knekt P, Aromaa A, Alfthan G, Maatela J, Hakama M, Hakulinen T et al. Prospective Study of Serum Micronutrients and Ovarian Cancer. J Natl Cancer Inst, 1996. Guo Y, Lu Y, Jin H. Appraising the role of circulating concentrations of micro-nutrients in epithelial ovarian cancer risk: A Mendelian randomization analysis. Sci Rep. 2020;10(1):7356. Lubinski L, Marciniac W, Derkacz R, Baszuk P, Muszyńska M, Kuświk M et al. Read-Gene SA -DP. Increased Risk of Cancers Among B. Garland M, Morris JS, Stampfer MJCG, Spate VL, Baskett CK, Rosner B et al. Prospective Study of Toenail Selenium Levels and Cancer Among Women, 1995. Gifkins DM. Antioxidants and Cancer of The Endometrium and Ovary. A Dissertation submitted to the Graduate School-New Brunswick Rutgers, The State University of New Jersey, 2011. Thomson CA, Neuhouser ML, Shikany JM, Caan BJ, Monk BJ, Mossavar-Rahmani Y, et al. The role of antioxidants and vitamin A in ovarian cancer: results from the Women's Health Initiative. Nutr Cancer. 2008;60(6):710–9. Tables Table 1: Some important characteristics of the included studies Title of the study Year Study setting Study design Ovarian cancer case group(n) Control group (n) Intervention OR 95% CI P value Conclusion Garland(1995 1995 USA Prospective Cohort 58 503 Amount of Selenium that has been consumed in the diet by toenail selenium level from the members of the cohort 1.22 0.44-3.38 0.52 Toenail selenium was not inversely associated with ovarian cancer in this study Helzlsouer(1996) 1996 Washington County Nested case-control 35 67 Measurement of serum concentration of selenium 0.58 0.2-1.7 0.33 Serum Se was associated with a decreased risk of ovarian cancer only among case participants diagnosed 4 or more years after blood collections Measurement of serum concentration of selenium- Cases found after 4 years of blood collection 0.23 0.1-0.9 0.02 Tung(2005) 2005 Hawaii and Los Angeles Case-control 558 607 Amount of Selenium that has been consumed in the diet by FFQ-Mucinous tumours 0.78 0.27-2.21 0.18 No evidence of a dose-response relation between Se and Ovarian Cancer Amount of Selenium that has been consumed in the diet by FFQ-Non mucinous tumours 1.03 0.6-1.8 0.98 Huzarski(2006) 2006 Poland Non-randomized clinical trial 100 100 Oral Selenium supplementation/administration 0.49 0.35-0.69 0.04 BRCA1-associated tumours were 2 times lower in women who supplemented their diet with selenium as compared to women without supplement Thomson(2008) 2008 USA Clinical Trial and Prospective Cohort 451 133163 Amount of Selenium consumed as a dietary supplement by interviewer-administered dietary supplement questionnaire 1.16 0.91-1.48 0.11 Intake of dietary antioxidants is not associated with a reduction in ovarian cancer risk Fleischauer(2009) 2009 USA Case-control 168 251 Amount of selenium that has been consumed as a food supplement by FFQ-cases vs. community controls 0.78 0.46-1.34 0.36 No evidence of a dose-response relation between Se and Ovarian Cancer Amount of selenium that has been consumed as a food supplement by FFQ-cases vs. total controls 0.9 0.56-1.45 0.64 Gifkins(2012) 2012 USA Case-control 205 309 Amount of Selenium that has been consumed from food in the diet by FFQ 0.41 0.2-0.85 0.04 The strong inverse association between selenium from food sources and EOC Amount of Selenium that has been consumed as a supplement in the diet by FFQ 1.64 1.05-2.56 0.02 Se suppl. users had a significantly increased risk of EOC after further adjustment of smoking and physical activity status. Amount of Selenium that has been consumed as food and dietary supplement by FFQ 0.75 0.39-1.43 0.3 No statistically significant increased risk was observed for the combined intake of food and supplements Lubinski (2017) 2017 Poland Nested case-control 48 92 Measurement of Selenium concentration in the blood 0.32 0.1-0.85 0.033 Blood Se level <110µĝ/l had a higher than 3-fold increased risk of cancer Terry(2017) 2017 USA Case-control 406 632 Amount of Selenium that has been consumed in the diet by FFQ 0.66 0.31-1.37 0.1 No association with dietary selenium Amount of Selenium that has been consumed as a food supplement by FFQ 0.67 0.46-0.97 0.035 The highest intakes of supplemental selenium had a lower risk of ovarian cancer than those with no supplemental intake Amount of selenium that has been consumed overall as a diet and food supplement by FFQ 0.67 0.39-1.14 0.1 No association between overall diet and food supplements Amount of selenium that has been consumed as a food supplement by FFQ-In current smokers 0.13 0.04-0.46 0.001 The inverse association was stronger in current smokers Additional Declarations No competing interests reported. Supplementary Files Annexure102.05.2026.pdf Annexure202.05.2026.docx Annexure302.05.2026.docx PRISMAPchecklistBMCCancer02.05.2026.docx AdditionalFiles.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9660701","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":637956009,"identity":"845a61e2-3e72-460d-9f8b-7b3d4376a6e3","order_by":0,"name":"KCM Perera","email":"data:image/png;base64,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","orcid":"","institution":"Family Health Bureau","correspondingAuthor":true,"prefix":"","firstName":"KCM","middleName":"","lastName":"Perera","suffix":""},{"id":637956010,"identity":"47480d80-8be7-4c26-9e7a-6cb8e66e69e2","order_by":1,"name":"WND Perera","email":"","orcid":"","institution":"National Institute of Health Science","correspondingAuthor":false,"prefix":"","firstName":"WND","middleName":"","lastName":"Perera","suffix":""},{"id":637956011,"identity":"3b4cc6f6-8eb8-4af2-8cda-4002602f87e2","order_by":2,"name":"HTCS Abeysena","email":"","orcid":"","institution":"University of Kelania","correspondingAuthor":false,"prefix":"","firstName":"HTCS","middleName":"","lastName":"Abeysena","suffix":""}],"badges":[],"createdAt":"2026-05-09 07:09:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9660701/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9660701/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109043086,"identity":"ae7fb502-40b9-4409-a381-3eafb541556c","added_by":"auto","created_at":"2026-05-12 04:37:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":129356,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe PRISMA Flowchart of study selection\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/7a83b71a94b28291617b7111.png"},{"id":109043089,"identity":"33f99a09-db7f-4d03-bfa8-dcb74e2cb9f9","added_by":"auto","created_at":"2026-05-12 04:37:44","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":12056,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe possible relationship between Se from food sources and EOC\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/01329d5f15811206548e2fcc.jpg"},{"id":109043088,"identity":"77e916e6-5d13-489d-b176-e9fb66d8ca1d","added_by":"auto","created_at":"2026-05-12 04:37:44","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":13383,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plot for estimation of publication bias of studies with Se from food sources and EOC among women\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/ebad70b2af681ec479ce0def.jpg"},{"id":109043095,"identity":"b64fcfb7-d730-42d6-8b29-adbaea145413","added_by":"auto","created_at":"2026-05-12 04:37:44","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":16495,"visible":true,"origin":"","legend":"\u003cp\u003eThe possible relationship between Se from food supplements and EOC\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/6f0d739a1ead89d3b8482edc.jpg"},{"id":109068040,"identity":"ca0b75b8-cab2-4a26-b2c5-12c0435f42fa","added_by":"auto","created_at":"2026-05-12 10:03:10","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":12303,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plot for estimation of publication bias of studies with Se from food supplements and EOC among women\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/24e620b67775729ba58ec4b2.jpg"},{"id":109068217,"identity":"de3e2b4e-f862-4045-9a12-579d995dc0a5","added_by":"auto","created_at":"2026-05-12 10:04:43","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":13666,"visible":true,"origin":"","legend":"\u003cp\u003eThe possible relationship between Se from biological samples and EOC\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/e6268ef81f436f521c5db19b.jpg"},{"id":109068147,"identity":"b938200a-50c4-4911-8eb6-f61b755ff0eb","added_by":"auto","created_at":"2026-05-12 10:04:03","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":13902,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plot for estimation of publication bias of studies with Se from biological samples and EOC among women\u003c/p\u003e","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/3ebccfadc527e7158acf171d.jpg"},{"id":109068283,"identity":"6c58d4f2-259d-4cc7-af21-96dc47c1b7db","added_by":"auto","created_at":"2026-05-12 10:05:19","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":11628,"visible":true,"origin":"","legend":"\u003cp\u003eThe possible relationship between Se from diet and food supplements and EOC\u003c/p\u003e","description":"","filename":"8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/1a77137234b6eca992577571.jpg"},{"id":109081091,"identity":"92bb5e1e-faad-4784-9678-286fa17976d0","added_by":"auto","created_at":"2026-05-12 11:57:18","extension":"jpg","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":13491,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plot for estimation of publication bias of studies with Se from diet and supplements and EOC among women\u003c/p\u003e","description":"","filename":"9.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/f76601de06cc9d0f1a90df08.jpg"},{"id":109082598,"identity":"a189871b-74ee-4d83-8ef4-2a03cc85bdb6","added_by":"auto","created_at":"2026-05-12 12:41:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":515696,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/2ec4fe53-ed63-4afe-a91d-45b871ff21fa.pdf"},{"id":109043087,"identity":"59f1c3dc-8f6e-4ff8-8ffb-54c51e05fceb","added_by":"auto","created_at":"2026-05-12 04:37:44","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":249247,"visible":true,"origin":"","legend":"","description":"","filename":"Annexure102.05.2026.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/c0fc01689e6996890fecf808.pdf"},{"id":109043093,"identity":"cd939078-c667-4514-b450-89c04c1a269b","added_by":"auto","created_at":"2026-05-12 04:37:44","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":31660,"visible":true,"origin":"","legend":"","description":"","filename":"Annexure202.05.2026.docx","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/c211d2b644d6792900ff6ccd.docx"},{"id":109043094,"identity":"0f95b42a-858f-4486-9def-d10ddb576b0f","added_by":"auto","created_at":"2026-05-12 04:37:44","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":24515,"visible":true,"origin":"","legend":"","description":"","filename":"Annexure302.05.2026.docx","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/efa73b5219ff34398cbd2b72.docx"},{"id":109043091,"identity":"725ce4f0-2ba5-4701-900e-ac6ba722e446","added_by":"auto","created_at":"2026-05-12 04:37:44","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":34109,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMAPchecklistBMCCancer02.05.2026.docx","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/9778b132a918bd522ab580ef.docx"},{"id":109067702,"identity":"1927ff21-35ac-491a-ae6d-6886d9e1ee74","added_by":"auto","created_at":"2026-05-12 10:00:06","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":40614,"visible":true,"origin":"","legend":"","description":"","filename":"AdditionalFiles.docx","url":"https://assets-eu.researchsquare.com/files/rs-9660701/v1/246c9ae26d46be26e54f524e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The association between Selenium and Epithelial Ovarian Cancer among women: A systematic review and meta-analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eOvarian cancer is ranked as one of the sixth most prevalent and fatal cancers among women, and the 5-year survival rate is less than 40%. Around 165,000 new ovarian cancer cases and 100,000 deaths are diagnosed annually(1). Even though age-standardised incidence rates (ASR) are stable or falling in most of the developed countries, they are still rising in low and middle-income countries. In addition, due to the higher life expectancy of women now, the detection rate of ovarian cancer is high (2).\u003c/p\u003e\n\u003cp\u003eMore than 90% of ovarian cancers occurring in women over 40 years are epithelial. High-grade serous, low-grade serous, endometrioid, clear cell and mucinous carcinoma are the main 5 different histotypes of ovarian cancer in women (3). Even if it is classified as ovarian, a high proportion of high-grade serous cancers are now thought to originate from the fallopian tube (2). Lack of symptoms in the early-stages of ovarian cancer leads to a high mortality rate overall among women.\u0026nbsp;In Australia,\u0026nbsp;66% of ovarian cancers were diagnosed within 1 month of the initial presentation, but for around 12 % of women, the diagnostic process took longer than 6 months, and this was more likely for those with lower incomes, those presenting with non-specific symptoms, or with more than one symptom (4).\u003c/p\u003e\n\u003cp\u003eTransvaginal ultrasound and serum CA-125 testing can be effectively used at present to evaluate symptomatic women for ovarian cancer, but the United States Preventive Services Task Force (USPSTF) does not recommend routine screening for ovarian cancer using any method (5). Therefore, protective measures play a vital role in reducing ovarian cancer burden worldwide.\u003c/p\u003e\n\u003cp\u003eIn the ovaries, during the process of ovulation and luteinisation, free radicals are produced in excess and surrounding cells are exposed to excessive reactive oxidants. Antioxidants work by tracking down free radicals and neutralising their harmful effects. For proper physiological function, there should be a balance between free radicals and antioxidants. If an imbalance with excess free radicals overwhelms the body\u0026apos;s ability to regulate them, a condition known as oxidative stress, ensues, which damages healthy cells and becomes cancerous(6). Therefore, limiting oxidative stress to the ovarian tissues could be \u0026nbsp;considered a protective measure against ovarian cancer.\u003c/p\u003e\n\u003cp\u003eSelenium (Se) is an essential dietary component and a powerful antioxidant for humans that fights against oxidative stress. The concentration of malondialdehyde (MDA), a lipid peroxidation product, was high in carcinomatous tissues. The basic function of Se in the organism is to be the cofactor of the enzyme Glutathion Peroxidase (GSH-Px), which protects the cells from the destruction caused by peroxides as it reduces already formed hydroperoxides to less reactive alcohol(7). Selenium is regarded as a protective agent against some selected cancers i.e., breast, lung, oesophagal, gastric, and prostate, but there was no such relationship with some other cancers, i.e. colorectal, bladder, and skin cancers(8).\u003c/p\u003e\n\u003cp\u003eSeveral observational studies and some non-randomised clinical trials have assessed the relationship between selenium as an etiological factor and Epithelial Ovarian Cancer (EOC) risk among women. An inverse association for EOC was observed for the highest compared to the lowest tertile of Se intake from food sources (6, 8). In addition, women with the highest intakes of supplemental Se had an inverse association for EOC with no supplemental intake (9, 10). In contrast, some other studies have concluded that there is no inverse association between Se from food sources (11, 12), supplements (13) and serum concentration (14) with the incidence of ovarian\u0026nbsp;cancer.\u003c/p\u003e\n\u003cp\u003eSo far, no published systematic reviews or meta-analyses have assessed the association between Se as an etiological factor and EOC risk. Epidemiological studies have shown some inconsistent results on the pre-mentioned association. Therefore, the objective of this systematic review and meta-analysis was to assess whether there is an inverse relationship between Se and EOC among women who have not had an oophorectomy, as such a relationship would have an impact on future preventive measures for ovarian cancer.\u003c/p\u003e"},{"header":"Methodology","content":"\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eSearch strategy\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eA search strategy was developed for PubMed and Medline, EMBASE, Scopus, Proquest, and Web of Science databases.\u0026nbsp;A librarian of the University of Queensland was involved to develop the search strategy.\u0026nbsp;Medical Subject Heading Terms (MeSH) and keywords were used in various combinations to develop search strategies. Search strategies were reviewed by all authors. A comprehensive electronic search was undertaken from the starting date of the databases up to the 30\u003csup\u003eth\u003c/sup\u003e of September 2022, according to the prepared search strategies, without limitations related to the language and publication status, and the study protocol was registered at the PROSPERO(Annexure-1). Studies will be retrieved from the mentioned databases using the following search strategy, and the completed search strategy was attached as\u0026nbsp;Annexure-2.\u003c/p\u003e\n\u003cp\u003e(Selenium) AND ((((((((Epithelial Ovarian Cancer) OR (Ovarian Cancer)) OR (Gynaecological Malignancies)) OR (Ovarian Carcinoma)) OR (Ovarian tumour)) OR (Ovarian tumor)) OR (ovarian malignancy)) OR \u0026nbsp;(female malignancies)) Sort by: Publication Date\u003c/p\u003e\n\u003cp\u003eIn addition, references of review articles, systematic reviews, meta-analyses, commentaries, editorials, meeting abstracts, and references of the included studies were evaluated for additional articles. Further, books related to gynaecological malignancies and hand searches of journals were done. And also searched for grey literature such as conference abstracts/proceedings, published lists of thesis and dissertations, and other literature outside of the main journal literature, where possible. Searched for unpublished outcomes and studies by searching informal sources, including meeting abstracts and Ph.D. theses, and contacting authors of included studies.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eInclusion and Exclusion Criteria:\u003c/strong\u003e\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eWe selected all observational studies (prospective/retrospective, case-control, and nested case-control) with provided adjusted risk estimates or provided data allowing the calculation of the risk estimates and 95% Confidence Interval (CI) for the association between Se and EOC, ecological studies, cross-sectional analytical studies, randomised control studies (RCTs) and non-randomised clinical trials. Studies published across all dates, times, and countries were included in the review. Studies published in other languages were translated into English by Google Translate.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eExclusion criteria:\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eDescriptive studies (i.e. case reports, case series, editorials, and opinion pieces) and animal studies were excluded from the review.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eStudy selection\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eTwo review authors independently screened studies using COVIDENCE software for systematic reviews under the University of Queensland multiple systematic review license to identify the eligible studies according to the following procedure;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eRetrieved studies using the COVIDENCE software and removed duplicates\u003c/li\u003e\n \u003cli\u003eAssessed the title and abstract of all studies and removed irrelevant ones\u003c/li\u003e\n \u003cli\u003eAssessed the full text of all studies identified as possibly relevant\u003c/li\u003e\n \u003cli\u003eSelected studies for the systematic review and meta-analysis \u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eAny inconsistencies between the two review authors over the eligibility of particular studies were resolved through discussion with a third reviewer.\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eQuality assessment\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eTwo review authors independently used the New Castle Ottawa scale of quality assessment for observational studies and the ROBINS-1 tool of quality assessment for the non-clinical randomised study. Disagreements between the two review authors over the risk of bias in particular studies were resolved by discussion, with the involvement of the third review author where necessary.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eData extraction\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eTwo review authors independently retrieved the following general study information, where available, from all included studies: author, publication year, study design, study setting; study population, participant demographics and baseline characteristics, details of the intervention and control conditions, recruitment and study completion rates, outcomes\u0026nbsp;with risk estimates and 95%CIs, adjusted/matched factors for individual studies\u0026nbsp;and times of outcome measurement, and information for the assessment of the risk of bias. Discrepancies were identified and resolved through discussion with the third author where necessary. As per the PRISMA-P expanded checklist 2020, We had cited studies that appeared to meet the inclusion, but which were excluded, and explained why they were excluded\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eSynthesis of the findings\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eOne review author had abstracted data into standard evidence tables; the second review author checked them for accuracy. The findings were synthesised via a narrative description in the first place. Quantitative synthesis for the pooling of data was done by meta-analysis.\u003c/p\u003e\n\u003cp\u003eHeterogeneity between the studies in effect measures was assessed by using the \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e statistic and Cochran\u0026rdquo;s Q test. The random effect inverse-variance model was used in the meta-analysis by STATA-17 with DerSimonian-Laird estimate of tau\u0026sup2; and four meta-analyses were conducted between; Se from food sources, supplements, biological samples and diet and supplement and EOC among women. A subgroup analysis was conducted by reducing each study to substantial heterogeneity.\u003c/p\u003e\n\u003cp\u003eThe results were displayed via forest plots of log OR against log lower and log upper CIs. The existence of\u0026nbsp; publication bias was also considered using the asymmetry of funnel plots, Egger̓s p-value and, Begg̓s p-value. All analyses were conducted using STATA-17.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOut of the 652 articles retrieved and selected from the electronic databases, 145 studies were excluded due to duplication. In the next step, titles and abstracts of studies were screened and 405 irrelevant studies were removed; 102 studies were included in the full-text review and 29 studies were selected for data extraction. However, only 9 studies were considered eligible for the systematic review and meta-analysis. Performed a narrative synthesis and 4 separate meta-analyses were conducted based on selenium from food sources, supplements, biological samples and overall diet and supplements \u003cstrong\u003e(Figure 1)\u003c/strong\u003e. As per the PRISMA-P expanded checklist 2020, studies that had appeared to meet the inclusion criteria, but were excluded (n=20), were cited \u003cstrong\u003e(Annexure- 3)\u003c/strong\u003e and explained why they were excluded.\u003c/p\u003e\n\u003cp\u003eEligible studies were published from the starting date of the relevant database up to the 30\u003csup\u003eth\u003c/sup\u003e of September 2022 in Washington country (n=1), Hawai and Los Angeles (n=1), Poland (n=2), and the USA (n=5) (Table 1). In these studies, data from 108,872 individuals (1930 subjects with ovarian cancers and 106942 control subjects) were reviewed.\u003c/p\u003e\n\u003cp\u003eAll data were synthesised based on the following research question:\u0026nbsp;Is there an inverse relationship between Se (food sources, supplements, and measures of selenium in blood, serum, toenails, and other biological samples) and EOC risk among women who have not had an oophorectomy. Data were synthesised based on the study design, the intervention, and the association of Se and EOC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe study design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were 7 observational studies, including 2 nested case-control studies, 4 case-control studies, and 1 prospective cohort study, that presented the association between exposure and an outcome (Odds Ratio). One study of observational (prospective cohort) combined with an experimental trial presented the association between exposure and an outcome over time (Hazard Ratio). One study of a non-randomized clinical trial presented the ratio of the probability of an adverse outcome in an exposure group to the probability of an adverse outcome in an unexposed group (Relative risk).\u003c/p\u003e\n\u003cp\u003eTwo nested case-control studies were from Washington Country and Poland. Four case-control studies were from the USA, and Los Angeles, and Hawaii. One prospective cohort study was from the USA, and the study of a prospective cohort combined with an experimental trial was also from the USA. One study of a non-randomized clinical trial was from Poland.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe intervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn case-control studies, cohort studies, and cohort studies combined with the clinical trial, the\u0026nbsp;amount of Se that has been consumed in the diet or food supplement by the Food Frequency Questionnaire (FFQ) was the intervention, and the measurement of blood/serum concentration of Se was the intervention in nested case-control studies. An oral Se supplementation was the intervention for the non-randomised clinical trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe association of Se and EOC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGarland et al (1995) revealed that there is no association between the amount of Se that has been consumed in the diet and toenail selenium level among the members of the cohort and EOC among women (OR; 1.22, 95%CI; 0.44-3.88, p; 0.52).\u003c/p\u003e\n\u003cp\u003eHelzlsouer et al (1996) was given an inverse association between the measurement of serum concentration of Se and the EOC diagnosed only after 4 years of blood collection (OR;0.23, 95%CI; 0.1-0.9, p;0.02) but there was no overall association between measurement of serum concentration of Se and the EOC (OR;0.58, 95%CI; 0.2-1.7, p;0.33).\u003c/p\u003e\n\u003cp\u003eThere was no association between the amount of Se that was consumed in the diet by FFQ in mucinous (OR; 0.78, 95%CI; 0.27-2.21, p; 0.18) and non-mucinous EOC (OR; 1.03, 95%CI;\u0026nbsp;0.6-1.8, p; 0.98) according to the study carried out by Tung et al (2005).\u003c/p\u003e\n\u003cp\u003eThe study carried out by Huzarski et al (2006) indicated that there is an inverse association between the amount of oral Se supplement and EOC (OR; 0.49, 95%CI; 0.35-0.69, p; 0.04).\u003c/p\u003e\n\u003cp\u003eThomson et al (2008) indicated that there is no association between the amount of Se consumed as a dietary supplement by interviewer-administered dietary supplement questionnaire and EOC (HR; 1.16, 95%CI; 0.91-1.48, p; 0.11).\u003c/p\u003e\n\u003cp\u003eFleischauer et al (2009) found no association between the amount of Se that has been consumed as a food supplement by FFQ between EOC cases and community controls (OR; 0.78, 95%CI; 0.46-1.34, p; 0.36) and total controls (OR; 0.9, 95%CI; 0.56-1.45, p; 0.64) as well.\u003c/p\u003e\n\u003cp\u003eGifkins et al. (2012) found an inverse association between the amount of Se that has been consumed from food in the diet by FFQ and EOC (OR; 0.41, 95%CI; 0.2-0.85, p; 0. 0.04) but there was a risk association of Se that has been consumed as a supplement in the diet by FFQ and EOC and it was reached to a significant level only after further adjusting smoking and physical activity (OR; 1.64, 95%CI;\u0026nbsp;1.05-2.56, p; 0.02).\u0026nbsp;No association between Se has been consumed as food and dietary supplement by FFQ and EOC (OR; 0.75, 95%CI; 0.39-1.43, p; 0.3).\u003c/p\u003e\n\u003cp\u003eLubinski et al. (2017) found a significant inverse association between the measurement of Se concentration in the blood ≥110µĝ/l and EOC among women (OR; 0.32, 95%CI; 0.1-0.85, p; 0.033).\u003c/p\u003e\n\u003cp\u003eTerry et al (2017) was given an inverse association between the amount of Se that has been consumed as a food supplement by FFQ and EOC (OR; 0.67, 95%CI; 0.46-0.97, p; 0.035).\u0026nbsp;This inverse association was stronger in current smokers\u0026nbsp;(OR; 0.13, 95%CI; 0.04-0.46, p; 0.001). In contrast, there was no association between the amount of Se that has been consumed in the diet by FFQ and EOC (OR; 0.66, 95%CI; 0.31-1.37, p; 0.1) and the amount of Se that has been consumed overall as a diet and food supplement by FFQ and EOC (OR; 0.67, 95%CI; 0.39-1.14, p; 0.1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMeta-analysis\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003e\u003cstrong\u003eSelenium from food sources and EOC\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eBased on the meta-analysis conducted on Se from food sources and EOC among women, there was no significant association between Se from food sources and EOC (OR: 0.68; 95%CI: 0.39-1.17; p-value:0.167; I²:50.1%; Q value:4.01; p-value:0.135) (Figure 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr clear=\"all\"\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs there was a mild substantial heterogeneity, subgroup analysis was conducted by reducing each study to see the changes in heterogeneity.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eSubgroup analysis 1;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eMeta-analysis between Tung (2005) and Gifkins (2012) increased heterogeneity further (I²:74.7%; p-value: 0.047).\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eSubgroup analysis 2;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eMeta-analysis between Tung (2005) and Terry (2017) had reached 0 heterogeneity (I²:0.0%; p-value: 0.345).\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eSubgroup analysis 3\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eMeta-analysis between Gifkins (2012) and Terry (2017) also reached 0 heterogeneity (I²:0.0%; p-value: 0.368).\u003c/p\u003e\n\u003cp\u003ePublication bias was estimated using Begg̓s p-value (p≥0.05) and Egger̓s p-value (p≥0.05) and a funnel plot (Figure 3). Our findings revealed that there was no publication bias.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Selenium from food supplements and EOC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on the meta-analysis conducted on Se from food supplements and EOC among women, there was no significant association between Se from food supplements and EOC (OR:0.83; 95%CI:0.56-1.24; p-value:0.37; I²:80.8%; Q value:20.78; p-value:0.000)\u0026nbsp;(Figure 4).\u003c/p\u003e\n\u003cp\u003eAs there was substantial heterogeneity, subgroup analysis was conducted by reducing each study to see the changes in heterogeneity.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eSubgroup analysis 1\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eMeta-analysis between Fleischauer (2009), Terry (2017), Huzarski (2006), and Thomson (2008) decreased heterogeneity (I²:67.9%; p-value: 0.025).\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eSubgroup analysis 2\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eMeta-analysis between Fleischauer (2009), Gifkins (2012), Huzarski (2006), and Thomson (2008) increased heterogeneity (I²:84.7%; p-value: 0.000).\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eSubgroup analysis 3\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eMeta-analysis between Fleischauer (2009), Gifkins (2012), Terry (2017), and Thomson (2008) decreased heterogeneity (I²:69.3%; p-value: 0.021).\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eSubgroup analysis 4\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eMeta-analysis between Fleischauer (2009), Gifkins (2012), Terry (2017), and Huzarski (2006) further increased heterogeneity (I²:83.5%; p-value: 0.000).\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eSubgroup analysis 5\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eMeta-analysis between Gifkins (2012), Terry (2017), Huzarski (2006), and Thomson (2008) also further increased heterogeneity (I²:85.6%; p-value: 0.000).\u003c/p\u003e\n\u003cp\u003ePublication bias was estimated using Begg̓ s p-value (p≥0.05) and Egger̓ s p-value (p≥0.05) and a funnel plot\u0026nbsp;(Figure 5).\u0026nbsp;Our findings revealed that there was no publication bias.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Selenium from biological samples and EOC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on the meta-analysis conducted on Se from biological samples and EOC among women, there was no significant association between Se from biological samples and EOC (OR: 0.62; 95%CI:0.29-1.33; p-value:0.218; I²:37%; Q value:3.18; p-value:0.204)\u0026nbsp;(Figure 6).\u003c/p\u003e\n\u003cp\u003ePublication bias was estimated using Begg̓s p-value (p≥0.05) and Egger̓s p-value (p≥0.05) and a funnel plot\u0026nbsp;(Figure 7).\u0026nbsp;Our findings revealed that there was no publication bias.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Selenium from diet and food supplements and EOC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on the meta-analysis conducted on Se from diet and food supplement and EOC among women, there was no significant association between Se from diet and food supplement and EOC (OR:0.7; 95%CI:0.46-1.06; p-value:0.093; I²:0%; Q value:0.07; p-value:0.793)\u0026nbsp;(Figure 8).\u003c/p\u003e\n\u003cp\u003ePublication bias was estimated using Begg̓s p-value (p≥0.05) and Egger̓s p-value (p≥0.05) and a funnel plot\u0026nbsp;(Figure 9).\u0026nbsp;Our findings revealed that there was no publication bias.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eOvarian cancer is the most fatal of all gynecologic cancers (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). It usually detects at advanced stages, and treatment is unlikely to be curative, survival is poor. The majority of ovarian cancers had been diagnosed with metastasis as the symptoms of ovarian cancers are often non-specific (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Due to the lack of recommended screening tools for ovarian cancer by the United States Preventive Services Task Force (USPTF), the identification of modifiable risk factors and preventive tools is essential to reduce ovarian cancer mortality and morbidity (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSelenium is a micronutrient and powerful antioxidant, it reduces oxidative stress and ultimately prevents cell damage (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). There is some evidence that Se has a protective effect against some cancers (i.e. colon, prostate, lung, stomach and oesophagus) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) but epidemiological studies have yielded inconsistent results on the association between Se and EOC risk. Some studies have given the inverse relationship between Se from food sources and EOC (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) while, some other studies found no association (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Some were given an inverse relationship between Se from supplements (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) and EOC. In contrast, some other studies were given no association (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Upon searching the literature, there were no systematic reviews and meta-analysis conducted so far on the association between Se and EOC risk.\u003c/p\u003e \u003cp\u003eThough blood/serum levels of Se (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) and toenail levels of Se (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) were considered as proxy measures of Se intake from food sources and supplements when we assess the association of Se as an etiological factor for EOC, blood/serum levels or tissue levels of Se of diagnosed ovarian cancer cases in case-control studies were not suitable to include in the systematic review and meta-analysis and therefore they were excluded from the review.\u003c/p\u003e \u003cp\u003eOnly 9 studies were included in the final systematic review and meta-analysis. At first, a narrative synthesis was made. In the narrative synthesis, it was visible that some studies had given an inverse relationship between Se and EOC (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). In addition, a few more studies showed an inverse relationship in narrative synthesis between Se and EOC with some special adjustments (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFour separate meta-analyses were conducted between Se from food sources, supplements, biological samples and diet and supplements and EOC, but none of them showed a significant inverse relationship. Two meta-analyses reported substantial heterogeneity.\u003c/p\u003e \u003cp\u003eMeta-analysis between Se from food sources and EOC was given mild substantial heterogeneity (I\u0026sup2;\u003cem\u003e=\u003c/em\u003e50.1%, p\u0026thinsp;=\u0026thinsp;0.135). It was reduced, when we removed Gifkin et al (2012) and conducted a meta-analysis between Tung et al (2005) and Terry et al (2017) (I\u0026sup2;= 0.0%, p\u0026thinsp;=\u0026thinsp;0.345) and when we removed Tung et al (2005) and conducted meta-analysis between Gifkin et al (2012) and Terry et al (2017)(I\u0026sup2;= 0.0%, p\u0026thinsp;=\u0026thinsp;0.368).\u003c/p\u003e \u003cp\u003eMeta-analysis between Se from supplements and EOC was given severe substantial heterogeneity (I\u0026sup2;\u003cem\u003e=\u003c/em\u003e80.8%, p\u0026thinsp;=\u0026thinsp;0.000). It was reduced, when we removed Gifkin et al (2012) and conducted a meta-analysis between Fleischauer et al (2009), Terry et al (2017), Huzarski et al (2006) and Thomson et al (2008) (I\u0026sup2;= 67.9%, p\u0026thinsp;=\u0026thinsp;0.025) and when we removed Huzarski et al (2006) and conducted meta-analysis between Fleischauer et al (2009), Gifkin et al (2012), Terry et al (2017), and Thomson et al (2008) (I\u0026sup2;= 69.3%, p\u0026thinsp;=\u0026thinsp;0.021).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e\u0026not; Limitations\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe major limitation of the study is the confounding bias of the studies selected for the systematic review and meta-analysis for the association between Se and EOC. It was not uniformly controlled in all selected studies for the review, which may have a significant impact on the results.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e\u0026not; Strengths\u003c/h2\u003e \u003cp\u003eThe search strategy for electronic databases was created with the assistance of an expert librarian at the University of Queensland. To minimise the bias, two independent reviewers screened the title and abstracts of uploaded articles, screened the full text of selected articles, did the data extraction, assessed the risk of bias of included studies, and data synthesis and conflicts were resolved by the third review author were the strengths of this study. No limitations related to the language and publication status.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThough there was no true inverse relationship between Se and EOC in meta-analysis, there is strong evidence of a protective effect between Se and EOC in narrative synthesis. Confounding bias will play an important role in the true relationship between Se and EOC, and if the confounding bias were uniformly controlled in studies selected for the review, then the relationship between Se and EOC would have been different.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSe\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSelenium\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEOC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEpithelial Ovarian Cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMeSH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMedical Subject Heading Terms\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eASR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAge- Standardized Rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUSPSTF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eUnited States Preventive Service Task Force\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEMBASE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eExcerpta Medica data BASE\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePRISMA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePreferred Reporting Items for Systematic Reviews and Meta-analysis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSTATA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStatistics and Data\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFFQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFood Frequency Questionnaire\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConfidence Interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOdds ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRelative risk\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe need for ethical approval and consent was waived as the systematic review and meta-analysis are based on ethically approved\u0026nbsp;and conducted studies only.\u0026nbsp;It was not appropriate or possible to involve patients or the public in the design, conduct, reporting, or dissemination plans of our research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used to analyze this systematic review and meta-analysis are available at the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declared that they have no known competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKCMP drafted the final research manuscript. KCMP and WNDP were assigned to screen studies and extract data. HTCSA helped to prepare the study protocol and assigned as a third review author to resolve the conflicts of screening and bias assessment. All three authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis systematic review and meta-analysis was conducted under the supervision of Associate Professor Susan Jordan, The School of Public Health, University of Queensland.The guidance to prepare the search strategy for systematic review and meta-analysis was provided by Marcos Riba, a librarian at the University of Queensland. We are grateful to the School of Public Health at the University of Queensland, the Post Graduate Institute of Medicine, the University of Colombo and the Ministry of Health, Sri Lanka.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor's information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorresponding author:\u003c/p\u003e\n\u003cp\u003eDr KCM Perera, Consultant Community Physician, Visiting Research Fellow, The School of Public Health, University of Queensland, Australia, Family Health Bureau, Ministry of Health, Sri Lanka\u003c/p\u003e\n\u003cp\[email protected] \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDr WND Perera, Consultant Community Physician, Visiting Research Fellow, The School of Public Health, University of Queensland, Australia, National Institute of Health Science, Ministry of Health, Sri Lanka\u003c/p\u003e\n\u003cp\[email protected]\u003cu\u003e,\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eProf. Chrishantha Abeysena, Senior\u0026nbsp;Professor in Community Medicine, University of Kelaniya\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;[email protected]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHosseininasab-Nodoushan SA, Ghazvini K, Jamialahmadi T, Keikha M, Sahebkar A. Association of Chlamydia and Mycoplasma infections with susceptibility to ovarian cancer: A systematic review and meta-analysis. Semin Cancer Biol. 2022;86(Pt 2):923\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWebb PM, Jordan SJ. Epidemiology of epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol. 2017;41:3\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeres LC, Cushing-Haugen KL, Anglesio M, Wicklund K, Bentley R, Berchuck A, et al. Histotype classification of ovarian carcinoma: A comparison of approaches. Gynecol Oncol. 2018;151(1):53\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSusan J, Jordan JEF, Anne E, Nelson HM, Zorbas KA, Luxford, Penelope M, Webb. Pathways to the diagnosis of epithelial ovarian cancer in Australia. MJA. 2010.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJori S, Carter LSDJ. Ovarian Cancer Tests and Treatment. 2011.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGifkins DM. Antioxidants and Cancer of The Endometrium and Ovary. A Dissertation submitted to the Graduate School-New Brunswick Rutgers, The State University of New Jersey. 2011.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTorun M, Aldemir H, Yardim S. Serum Selenium levels in various cancer types. 1995.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCai X, Wang C, Yu W, Fan W, Wang S, Shen N, et al. Selenium Exposure and Cancer Risk: an Updated Meta-analysis and Meta-regression. Sci Rep. 2016;6:19213.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTerry PD, Qin B, Camacho F, Moorman PG, Alberg AJ, Barnholtz-Sloan JS, et al. Supplemental Selenium May Decrease Ovarian Cancer Risk in African-American Women. J Nutr. 2017;147(4):621\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuzarski T, TB, JG, EbK, SaZc BG et al. A Lowering of Breast and Ovarian Cancer Risk in Women with a BRCA1 Mutation by Selenium Supplementation of Diet Hereditary Cancer in Clinical Practice. 2006.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFleischauer AT, Olson SH, Mignone L, Simonsen N, Caputo TA, Harlap S. Dietary antioxidants, supplements, and risk of epithelial ovarian cancer. Nutr Cancer. 2001;40(2):92\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTung KWL, Wu AH, McDuffie K, Hankin JH, Nomura AMYKL, Goodman MT. Association of Dietary Vitamin A, Carotenoids, and Other Antioxidants with the Risk of Ovarian Cancer. Cancer Epidemiol Biomarkers Prev. 2005;14(Cancer Epidemiol Biomarkers Prev).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThomson CA, Neuhouser ML, Shikany JM, Caan BJ, Monk BJ, Mossavar-Rahmani Y, et al. The role of antioxidants and vitamin A in ovarian cancer: results from the Women's Health Initiative. Nutr Cancer. 2008;60(6):710\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHelzlsouer KJAA, Norkus EP, Morris JS, Hoffman SC, Comstock GW. Prospective Study of Serum Micronutrients and Ovarian Cancer. J Natl Cancer Inst. 1996.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKnekt P, Aromaa A, Alfthan G, Maatela J, Hakama M, Hakulinen T et al. Prospective Study of Serum Micronutrients and Ovarian Cancer. J Natl Cancer Inst, 1996.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo Y, Lu Y, Jin H. Appraising the role of circulating concentrations of micro-nutrients in epithelial ovarian cancer risk: A Mendelian randomization analysis. Sci Rep. 2020;10(1):7356.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLubinski L, Marciniac W, Derkacz R, Baszuk P, Muszyńska M, Kuświk M et al. Read-Gene SA -DP. Increased Risk of Cancers Among B.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarland M, Morris JS, Stampfer MJCG, Spate VL, Baskett CK, Rosner B et al. Prospective Study of Toenail Selenium Levels and Cancer Among Women, 1995.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGifkins DM. Antioxidants and Cancer of The Endometrium and Ovary. A Dissertation submitted to the Graduate School-New Brunswick Rutgers, The State University of New Jersey, 2011.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThomson CA, Neuhouser ML, Shikany JM, Caan BJ, Monk BJ, Mossavar-Rahmani Y, et al. The role of antioxidants and vitamin A in ovarian cancer: results from the Women's Health Initiative. Nutr Cancer. 2008;60(6):710\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Some important characteristics of the included studies\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTitle of the study\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eYear\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy setting\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOvarian cancer case group(n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl group (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003eGarland(1995\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e1995\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eProspective Cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e503\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eAmount of Selenium that has been consumed in the diet by toenail selenium level from the members of the cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e1.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.44-3.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eToenail selenium was not inversely associated with ovarian cancer in this study\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003eHelzlsouer(1996)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e1996\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003eWashington County\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNested case-control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eMeasurement of serum concentration of selenium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.2-1.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eSerum Se was associated with a decreased risk of ovarian cancer only among case participants diagnosed 4 or more years after blood collections\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMeasurement of serum concentration of selenium- Cases found after 4 years of blood collection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.1-0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003eTung(2005)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e2005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003eHawaii and Los Angeles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eCase-control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e558\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e607\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eAmount of Selenium that has been consumed in the diet by FFQ-Mucinous tumours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.27-2.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNo evidence of a dose-response relation between Se and \u0026nbsp;Ovarian Cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eAmount of Selenium that has been consumed in the diet by FFQ-Non mucinous tumours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.6-1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003eHuzarski(2006)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e2006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003ePoland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNon-randomized clinical trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eOral Selenium supplementation/administration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.35-0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eBRCA1-associated tumours were 2 times lower in women who supplemented their diet with selenium as compared to women without supplement\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003eThomson(2008)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e2008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eClinical Trial and Prospective Cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e451\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e133163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eAmount of Selenium consumed as a dietary supplement by interviewer-administered dietary supplement questionnaire\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e1.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.91-1.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIntake of dietary antioxidants is not associated with a reduction in ovarian cancer risk\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003eFleischauer(2009)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eCase-control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e168\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e251\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eAmount of selenium that has been consumed as a food supplement by FFQ-cases vs. community controls\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.46-1.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNo evidence of a dose-response relation between Se and \u0026nbsp;Ovarian Cancer\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eAmount of selenium that has been consumed as a food supplement by FFQ-cases vs. total controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.56-1.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003eGifkins(2012)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eCase-control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e205\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e309\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eAmount of Selenium that has been consumed from food in the diet by FFQ\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.2-0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eThe strong inverse association between selenium from food sources and EOC\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eAmount of Selenium that has been consumed as a supplement in the diet by FFQ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e1.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e1.05-2.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eSe suppl. users had a significantly increased risk of EOC after further adjustment of smoking and physical activity status.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eAmount of Selenium that has been consumed as food and dietary supplement by FFQ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.39-1.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo statistically significant increased risk was observed for the combined intake of food and supplements\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003eLubinski (2017)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003ePoland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNested case-control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eMeasurement of Selenium concentration \u0026nbsp;in the blood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.1-0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eBlood Se level \u0026lt;110\u0026micro;ĝ/l had a higher than 3-fold increased risk of cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003eTerry(2017)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eCase-control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e406\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e632\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eAmount of Selenium that has been consumed in the diet by FFQ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.31-1.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNo association with dietary selenium\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eAmount of Selenium that has been consumed as a food supplement by FFQ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.46-0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eThe highest intakes of supplemental selenium had a lower risk of ovarian cancer than those with no supplemental intake\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eAmount of\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;selenium that has been consumed overall as a diet and food supplement \u0026nbsp;by FFQ\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.39-1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo association between overall diet and food supplements\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 52px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 153px;\"\u003e\n \u003cp\u003eAmount of selenium that has been consumed as a \u0026nbsp;food supplement \u0026nbsp;by FFQ-In current smokers\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.04-0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 42px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eThe inverse association was stronger in current smokers\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Cancer, ovarian, epithelial, association, aetiology, selenium","lastPublishedDoi":"10.21203/rs.3.rs-9660701/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9660701/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eOvarian cancer is the sixth most prevalent and fatal cancer among females worldwide.\u003c/p\u003e\n\u003cp\u003eAntioxidants have been shown to have some proven anti-cancerous effects by limiting oxidative stress. Selenium is a powerful antioxidant, it also protects the cells from the destruction caused by peroxides. This study aimed to determine the association between Selenium and Epithelial Ovarian Cancer among women who have not had an oophorectomy.\u003c/p\u003e\n\u003cp\u003e\u003cimg width=\"68\" height=\"19\" src=\"file:///C:/Users/khan07/AppData/Local/Temp/msohtmlclip1/01/clip_image001.gif\"/\u003e\u003cstrong\u003eMethods and analysis: \u003c/strong\u003eA comprehensive electronic search was carried out according to the prepared search strategy from the starting date of the PubMed/Medline, EMBASE, Scopus, Proquest, and Web of Science databases up to the 30\u003csup\u003eth\u003c/sup\u003e of September 2022 without limitations related to language and publication status. All observational studies, cross-sectional analytical studies, ecological studies, randomised control studies, and non-randomised clinical trials were included in the systematic review. Studies were screened by COVIDENCE. The exposure of interest was high selenium intake from either food sources, supplements, or high selenium measures in blood and toenails. Data extraction was done. New Castle Ottawa Scale and the ROBINS-1 tool were used to assess the bias of selected studies. The narrative synthesis and meta-analysis were conducted. Results were displayed via forest plots. All analyses were conducted using STATA-17.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eNine studies (n=9) comprising 108,872 women were evaluated in the systematic review and meta-analysis. In narrative synthesis, there was a significant inverse association between Se and EOC, with high serum Se (n=2), diet by FFQ (n=2), food supplements (n=1), and oral supplements (n=1). There was no association between toenail Se and EOC. Based on four meta-analyses there was no significant association between Selenium from food sources(OR:0.68; 95%CI:0.39-1.17; p-value:0.167; I²:50.1%; Q value:4.01; p-value:0.135), food supplements (OR:0.83; 95%CI:0.56-1.24; p-value:0.37; I²:80.8%; Q value:20.78; p-value:0.000), biological samples (OR: 0.62; 95%CI:0.29-1.33; p-value:0.218; I²:37%; Q value:3.18; p-value:0.204), and diet and food supplement (OR:0.7; 95%CI:0.46-1.06; p-value:0.093; I²:0%; Q value:0.07; p-value:0.793) and Epithelial Ovarian Cancer.\u0026nbsp; There was no publication bias in all four meta-analyses according to the funnel plots, Egger’s p-value (p≥0.05), and Begg’s p-value (p≥0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion \u003c/strong\u003eUniformity of controlling confounding bias among studies is a must to obtain the real association between Selenium and Epithelial Ovarian Cancer in this meta-analysis.\u003c/p\u003e","manuscriptTitle":"The association between Selenium and Epithelial Ovarian Cancer among women: A systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-12 04:37:38","doi":"10.21203/rs.3.rs-9660701/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4f046ef6-a366-49ef-83ca-1dedf0e1b89b","owner":[],"postedDate":"May 12th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-05-12T10:34:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-12T04:40:52+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-12T04:40:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2026-05-09T07:01:43+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-12T11:09:59+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-12 04:37:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9660701","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9660701","identity":"rs-9660701","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}