Hysterectomy and risk of epithelial ovarian cancer by histologic type, endometriosis, and menopausal hormone therapy

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Methods From the Danish Cancer Registry, all women registered with epithelial ovarian cancer during 1998‒2016 were identified (n = 6,738). Each case was sex- and age-matched to 15 population controls using risk-set sampling. Information on previous hysterectomy on benign indication and potential confounders was retrieved from nationwide registers. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between hysterectomy and ovarian cancer according to histology, endometriosis, and use of MHT. Results Hysterectomy was not associated with risk of epithelial ovarian cancer overall (OR = 0.97; 95% CI 0.88‒1.06) but was associated with reduced risk of clear cell ovarian cancer (OR = 0.47; 95% CI 0.28‒0.78). In stratified analyses, decreased ORs associated with hysterectomy were seen in women with endometriosis (OR = 0.73; 95% CI 0.50‒1.09) and in non-users of MHT (OR = 0.87; 95% CI 0.76‒1.00). Conclusion Hysterectomy was not associated with epithelial ovarian cancer overall but with reduced risk of clear cell ovarian cancer. Our findings may suggest a reduced risk of ovarian cancer after hysterectomy in women with endometriosis and in MHT non-users, but the statistical precision of our results did not allow firm conclusions. Epithelial ovarian cancer hysterectomy histological type endometriosis menopausal hormone therapy what Does This Study Adds To The Clinical Work We found an inverse association between hysterectomy and the risk of clear cell ovarian cancer, and a potential protection against ovarian cancer in women with endometriosis and in non-users of menopausal hormone-therapy. Introduction Worldwide, ovarian cancer is the eighth most common cancer in women with an age-standardized incidence rate of 6.6 cases per 100,000 person-years [ 1 ]. Approximately 95% of ovarian cancers are of epithelial origin and are primarily classified into five main types; high- and low-grade serous, endometrioid, clear cell, and mucinous ovarian cancer [ 2 ]. High-grade serous carcinoma is the most common histological type accounting for approximately 70% of ovarian carcinomas [ 2 ]. It has been suggested that hysterectomy protects against ovarian cancer by blocking transfer of carcinogenic agents, and retrograde menstruation or endometriosis travelling through the female genital tract [ 3 – 5 ]. A number of studies have investigated the association between hysterectomy and risk of ovarian cancer with inconsistent findings [ 4 – 15 ]. A meta-analysis observed a time-dependent trend in findings and pointed out that one explanation could be changes over time in use of menopausal hormone therapy (MHT) [ 13 ]. MHT is known to increase the risk of ovarian cancer moderately [ 16 , 17 ], and is more commonly used among hysterectomized women [ 18 ], which might explain why a few recent observational studies have reported that the association between hysterectomy and ovarian cancer risk differs by use of MHT [ 8 – 10 ]. Other studies have reported that the association between hysterectomy and ovarian cancer varies by tumor histology [ 5 , 6 , 9 , 12 ], and history of endometriosis [ 6 , 10 , 14 ]. Concomitant removal of the fallopian tubes and/or ovaries at time of hysterectomy are also important factors to consider. Recent research has revealed that the precursor lesion of high-grade serous carcinoma originates in the fallopian tube as serous tubal intraepithelial carcinoma lesions [ 19 ], and that bilateral salpingectomy therefore reduces the risk of ovarian cancer [ 3 , 7 ]. Clarification of the impact of hysterectomy on the risk of ovarian cancer may elucidate the pathogenesis of the disease but it is also important from a clinical point of view to determine whether the procedure protects against ovarian cancer, and identify potential target groups who benefit the most. The aim of this nationwide register-based case-control study is to evaluate the association between hysterectomy on benign indication and the risk of ovarian cancer. Our analyses are stratified by histologic subtype of ovarian cancer and investigate whether endometriosis and MHT may be effect modifiers for the association between hysterectomy and the risk of ovarian cancer. Methods This nationwide, register-based case-control study has previously been described in detail [ 3 ], and has since been updated with four additional years. In Denmark, the Civil Registration System assigns all Danish citizens a personal identification number, which enables accurate linkage between the different registers. The register also contains information on dates of death, and migration to and from Denmark [ 20 ]. Study population Cases were identified in the Danish Cancer Registry, which contains information on cancer diagnoses in Denmark since 1943 and with mandatory reporting of new cancer cases since 1987 [ 21 ]. Since 2004, cancer cases have been registered using the 10th revision of the International Classification of Diseases (ICD-10) and the 3rd revision of the International Classification of Diseases for Oncology (ICD-O-3), and codes for cancer cases registered during 1978‒2003 have been converted to ICD-10 and ICD-O-3. Cases were identified in the Cancer Registry by ICD-10 DC56. We required that cases were aged 40‒79 years at the index date, defined as the date of diagnosis, without previous cancer, and with a first diagnosis of histologically verified epithelial ovarian cancer during 1998‒2016. Ovarian cancer cases were classified according to the ICD-O-3 morphology code into serous, endometrioid, clear cell, mucinous and other (Supplementary Table S1). Information on grade was not available. Each case was matched by month and year of birth to 15 control women identified in the Civil Registration System using risk set sampling. Controls were not allowed to have a history of bilateral oophorectomy/salpingo-oophorectomy or cancer (except non-melanoma skin cancer) at the time the corresponding case was diagnosed, i.e., index date. Women were eligible as controls before becoming cases. Information on exposure Information on hysterectomy up until one year prior to index date was retrieved from the Danish National Patient Register, which has registered all diagnoses and surgical procedures performed during hospitalizations since 1977, and during outpatient visits since 1995 [ 22 ]. From 1977 to 1993, all diagnoses are coded according to ICD-8, and from 1994 diagnoses are coded according to ICD-10. All surgical procedures are classified according to the Danish Classification of Surgical Procedures up until the end of 1995, and afterwards according to the Nordic Classification of Surgical Procedures. Information on covariates Information on use of oral contraceptives and MHT was obtained from the Danish National Prescription Registry, where individual-level information on all prescription drugs dispensed at pharmacies in Denmark since 1995 are registered [ 23 ], and classified by the Anatomical Therapeutic Chemical Index [ 24 ]. From the Danish National Patient Register, information since 1977 on endometriosis, tubal ligation, and other gynecological surgical procedures including salpingectomies and oophorectomies up until one year prior to index date was obtained. Parity was derived from the Danish Fertility Database, which contains information on reproductive variables for all women aged 13‒49 years in Denmark from 1980 and onwards [ 25 ]. Statistical analyses We used conditional logistic regression to calculate age-matched and multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between hysterectomy and risk of epithelial ovarian cancer overall and stratified according to histologic subtype. Potential confounders were selected a priori based on evidence of risk factors for ovarian cancer and availability in the registers. The model was adjusted for age (by design), parity, endometriosis, tubal ligation, other gynecological surgical procedures (tubal ligation, unilateral/bilateral salpingectomy, unilateral oophorectomy, and unilateral salpingo-oophorectomy), and use of oral contraceptives and MHT. To investigate effect modification by endometriosis and MHT use, we performed stratified analysis using logistic regression without the matching, but with adjustment for the matching factors (age and calendar year). All analyses were performed using the statistical software R version 4.1.0. Use of register data for this study was approved by the Danish National Board of Health Data (FSEID-4295). In agreement with the General Data Protection Regulation, the present study is registered in the Danish Cancer Society’s internal list of projects dealing with personalized data (journal number: 2019-DCRC-0054). All data related to the study are stored at the Danish Cancer Society Research Center’s project database at Statistics Denmark (project number 704327), and the Danish Cancer Society is responsible for the data stored at this project database. The data that support the information of this manuscript were accessed remotely on a secure platform at Statistics Denmark ( www.dst.dk ). According to Danish laws and regulations, individual-level sensitive data can only be made available for researchers who fulfil legal requirements for accessing personal sensitive data. Results The study population included 6,738 women with epithelial ovarian cancer and 101,070 matching controls. The majority of cases were 60‒79 years old at diagnosis and the most common histologic type of tumor was serous (58.7%) (Table 1 ). Hysterectomy was reported in 588 (8.7%) cases and in 9,289 (9.2%) controls. Cases (18.1%) were more likely to be nulliparous compared with controls (12.7%). Endometriosis was diagnosed in 130 (1.9%) cases and in 1,665 (1.6%) controls. Finally, ever use of MHT was slightly more common among cases (35.6%) compared with controls (33.2%). Table 1 Characteristics of women with epithelial ovarian cancer and matching controls Cases Controls (n = 101,070) (n = 6,738) Characteristics n % n % Histology Serous 3,953 (58.7) — Mucinous 565 (8.4) — Endometrioid 596 (8.8) — Clear cell 328 (4.9) — Other 1,296 (19.2) — Age at diagnosis / index date (years) 40–49 794 (11.8) 11,910 (11.8) 50–59 1,707 (25.3) 25,605 (25.3) 60–69 2,270 (33.7) 34,050 (33.7) 70–79 1,967 (29.2) 29,505 (29.2) Hysterectomy No 6,150 (91.3) 91,781 (90.8) Yes 588 (8.7) 9,289 (9.2) Age at hysterectomy (years) No hysterectomy 6,150 (91.3) 91,781 (90.8) <50 459 (6.8) 7,036 (7.0) ≥50 129 (1.9) 2,253 (2.2) Parity Nulliparous 1,218 (18.1) 12,866 (12.7) One 1,311 (19.5) 17,047 (16.9) Two 2,631 (39.0) 42,629 (42.2) Three or more 1,578 (23.4) 28,528 (28.2) Endometriosis No 6,608 (98.1) 99,405 (98.4) Yes 130 (1.9) 1,665 (1.6) Oral contraceptives No 6,309 (93.6) 90,667 (89.7) Yes 429 (6.4) 10,403 (10.3) Menopausal hormone therapy No ( 2 prescriptions) 2,396 (35.6) 33,603 (33.2) Tubal ligation No 6,411 (95.1) 94,775 (93.8) Yes 327 (4.9) 6,295 (6.2) Other gynecological surgical procedures a No 6,563 (97.4) 96,969 (95.9) Yes 175 (2.6) 4,101 (4.1) Hysterectomy was not associated with the overall risk of epithelial ovarian cancer (OR = 0.97; 95% CI 0.88‒1.06) (Table 2 ). When the analysis was stratified according to tumor histology, we observed a significantly reduced risk of clear cell ovarian cancer after hysterectomy (OR = 0.47; 95% CI 0.28‒0.78). The OR for mucinous ovarian cancer was decreased (OR = 0.80; 95% CI 0.56‒1.14), whereas an elevated OR was observed for endometrioid ovarian cancer (OR = 1.29; 95% CI 0.97‒1.72). Finally, hysterectomy was associated with neutral ORs for serous (OR = 1.00; 95% CI 0.89‒1.13) and other epithelial ovarian cancers (OR = 0.96; 95% CI 0.76‒1.20). Table 2 Hysterectomy and risk of epithelial ovarian cancer stratified according to histologic subtype Cases Controls Age-adjusted Adjusted a Histologic subtype N (%) N (%) OR 95% CI OR 95% CI All epithelial No hysterectomy 6,150 (91.3) 91,781 (90.8) Ref. Ref. Hysterectomy 588 (8.7) 9,289 (9.2) 0.94 (0.86‒1.03) 0.97 (0.88‒1.06) Serous No hysterectomy 3,585 (90.7) 53,677 (90.5) Ref. Ref. Hysterectomy 368 (9.3) 5,618 (9.5) 0.98 (0.88‒1.10) 1.00 (0.89‒1.13) Mucinous No hysterectomy 529 (93.6) 7,715 (91.0) Ref. Ref. Hysterectomy 36 (6.4) 760 (9.0) 0.69 (0.49‒0.97) 0.80 (0.56‒1.14) Endometrioid No hysterectomy 531 (89.1) 8,156 (91.2) Ref. Ref. Hysterectomy 65 (10.9) 784 (8.8) 1.28 (0.98‒1.67) 1.29 (0.97‒1.72) Clear cell No hysterectomy 309 (94.2) 4,466 (90.8) Ref. Ref. Hysterectomy 19 (5.8) 454 (9.2) 0.60 (0.37‒0.97) 0.47 (0.28‒0.78) Other No hysterectomy 1,196 (92.3) 17,767 (91.4) Ref. Ref. Hysterectomy 100 (7.7) 1,673 (8.6) 0.89 (0.72‒1.10) 0.96 (0.76‒1.20) Abbreviations: OR, Odds ratio; CI, Confidence interval; Ref., Reference a Adjusted for age (by design), calendar year (by design), parity (categorical), tubal ligation, endometriosis, other gynaecological surgical procedures, oral contraceptive use, and use of menopausal hormone therapy. Table 3 presents the analysis stratified according to occurrence of endometriosis. In women with a previous diagnosis of endometriosis, hysterectomy was associated with a reduced OR for ovarian cancer (OR = 0.73; 95% CI 0.50‒1.09), whereas the association between hysterectomy and ovarian cancer in patients without a diagnosis of endometriosis was close to unity (OR = 0.99; 95% CI 0.90‒1.08). Table 3 Hysterectomy and risk of epithelial ovarian cancer by history of endometriosis Age-adjusted OR (95% CI) Adjusted a OR (95% CI) No endometriosis No hysterectomy Ref. Ref. Hysterectomy 1.04 (0.94‒1.14) 0.99 (0.90‒1.08) Endometriosis No hysterectomy Ref. Ref. Hysterectomy 0.75 (0.51‒1.12) 0.73 (0.50‒1.09) Abbreviations: OR, Odds ratio; CI, Confidence interval; Ref., Reference a Adjusted for age, calendar year, parity (categorical), tubal ligation, other gynaecological surgical procedures, oral contraceptive use and use of menopausal hormone therapy. Finally, we examined the effect of hysterectomy stratified according to use of MHT. The ORs for the association between hysterectomy and ovarian cancer were 0.87 (95% CI 0.76‒1.00) in women who never used MHT and 1.05 (95% CI 0.93‒1.19) in women who had redeemed minimum two prescriptions of MHT before index date (Table 4 ). Table 4 Hysterectomy and risk of epithelial ovarian cancer by ever use of menopausal hormone therapy (MHT) Age-adjusted OR (95% CI) Adjusted a OR (95% CI) Non-use of MHT No hysterectomy Ref. Ref. Hysterectomy 0.90 (0.78‒1.03) 0.87 (0.76‒1.00) Ever-use of MHT No hysterectomy Ref. Ref. Hysterectomy 1.08 (0.95‒1.22) 1.05 (0.93‒1.19) OR: Odds ratio; CI: Confidence interval; Ref.: Reference a Adjusted for age, calendar year, parity (categorical), tubal ligation, other gynaecological surgical procedures, and use of oral contraceptives. Discussion In this study hysterectomy was not associated with the risk of epithelial ovarian cancer overall but seemed to reduce risk of the clear cell type. In women with endometriosis and in women not using MHT, reduced odds for ovarian cancer after hysterectomy were observed. In line with our findings, recent studies have found no association between hysterectomy and risk of ovarian cancer overall [ 6 , 10 , 15 ], and a meta-analysis reported a pooled OR of 0.97 (95% CI: 0.83–1.12) based on data from 18 case-control studies published between 2000 and 2017 [ 5 ]. In contrast, data from two earlier meta-analyses published in 2012 [ 4 ], and 2013 [ 13 ], respectively, suggested that hysterectomy was associated with a lower risk of ovarian cancer. Both meta-analyses reported significant heterogeneity between the included studies primarily explained by median year of ovarian cancer diagnosis, where studies published before 2000 indicated a lower risk of ovarian cancer following hysterectomy, whereas studies published after 2000 did not. The authors speculated that the temporal change in the association between hysterectomy and ovarian cancer risk could in part be attributed to increasing use of MHT over calendar time in hysterectomized women [ 13 ]. MHT is more commonly prescribed to hysterectomized women than to non-hysterectomized women [ 18 ], and is associated with a moderately increased ovarian cancer risk [ 16 , 17 ]. In accordance, a recent study from the Ovarian Cancer Association Consortium (OCAC) found that adjustment for duration of MHT use affected the association between hysterectomy and ovarian cancer risk markedly [ 10 ]. A case-control study including 614 African-American women with ovarian cancer reported that hysterectomy decreased the risk of epithelial ovarian cancer (OR = 0.65, 95% CI: 0.46‒0.92) in never users of estrogen-only MHT, whereas increased odds was observed among users [ 8 ]. Moreover, data from the Nurses’ Health Study also showed that hysterectomy was associated with decreased odds for ovarian cancer only in women who had never used MHT (hazard ratio (HR) = 0.81, 95% CI: 0.54‒1.20) [ 9 ], which is in line with our findings. Ovarian cancer is a heterogeneous disease and the etiology of the different subtypes may differ. Therefore, it is also suggested that the association between hysterectomy and ovarian cancer may vary according to the histological types of epithelial ovarian cancer [ 5 , 6 , 9 ]. Endometrioid and clear cell types are strongly associated with endometriosis [ 26 ]. By preventing menstruation or endometriosis from retrograde transport through the female genital tract, hysterectomy may protect primarily against those types of ovarian cancer. A meta-analysis pooling data from four case-control studies with information on tumor histology reported that hysterectomy was associated with a statistically significant risk reduction for endometrioid/clear cell ovarian cancer (OR = 0.70, 95% CI: 0.51‒0.94) [ 5 ]. The OR for mucinous ovarian cancer was reduced but statistically not significant and there was no association between hysterectomy and serous ovarian cancer [ 5 ]. Other studies not included in the meta-analysis by Huo et al. [ 5 ] have also reported that hysterectomy protected against clear cell ovarian cancer [ 12 ] or that risk estimates for endometrioid and/or clear cell ovarian cancer pointed in the protective direction without statistical significance [ 6 , 9 , 12 ]. Risk estimates for mucinous ovarian cancer are also reported statistically non-significantly decreased in several studies [ 6 , 9 , 12 ], whereas a null-association with serous ovarian cancer is most often observed [ 6 , 9 , 12 ]. Our results are consistent with the majority of previous recent studies, as we also found that hysterectomy was not associated with serous ovarian cancer but protected against clear cell ovarian cancer. However, our data showed increased odds for endometrioid ovarian cancer after hysterectomy. We have no definite explanation for this finding but misclassification may have played a role. Cases in our study go back to 1998 and some of the tumors that were diagnosed as endometrioid ovarian cancers may have been classified as high-grade serous carcinomas today based on their immunoprofile [ 27 ]. The association between hysterectomy and endometrioid ovarian cancer may also be affected by unmeasured confounding. Although our study was based on high-quality nationwide registers, registration of potential confounders such as endometriosis may not be complete. Our findings in stratified analysis showing reduced odds for ovarian cancer after hysterectomy in women with endometriosis is compatible with reports from previous studies [ 6 , 10 , 14 ]. One study with pooled information from four US population-based case-control studies reported that hysterectomy was associated with statistically non-significantly decreased odds for ovarian cancer (OR = 0.69, 95% CI: 0.38‒1.24) in women with endometriosis, whereas this was not found in women without endometriosis (OR = 1.02, 95% CI: 0.86‒1.23) [ 14 ]. In addition, an Australian register-based cohort study reported substantially decreased risk of ovarian cancer (HR = 0.17, 95% CI: 0.12‒0.24) after hysterectomy in women with endometriosis [ 6 ], and OCAC data also showed that hysterectomy statistically significantly reduced the risk of ovarian cancer in women with endometriosis (OR = 0.69, 95% CI 0.48‒0.99) [ 10 ]. Although hysterectomy, as previously discussed, may prevent retrograde transport of endometriosis, the observed protective effect of hysterectomy on ovarian cancer risk among women with endometriosis may also be explained by removal of endometriotic lesions at the time of hysterectomy. One of the main strengths of our study is the large sample size including more than 6,700 women with ovarian cancer, making it possible to investigate associations with histologic subtypes of ovarian cancer. Data were derived from nationwide registers with no risk of selection or recall bias. The registers contain virtually complete and continuously updated data on surgical procedures, diagnoses, and drug use. The register-based design of our study thereby enabled us to ensure that all control women had at least one intact ovary and provided us with information on important potential confounding factors such as MHT use and endometriosis. Our study also has some limitations. Although all of our cases were histologically verified, we did not perform a central pathology review of the ovarian tumors, and there may therefore be some degree of misclassification, especially affecting those cancers diagnosed in the early part of our study period. Moreover, we did not have information on tumor grade which precluded us from differentiating between low and high-grade serous carcinomas. Finally, left truncation of prescription data may have led to misclassification of MHT use among those women who initiated MHT before 1995, and although the Danish National Patient Register was established earlier (1977), information on hysterectomy and endometriosis may be incomplete. It is important to know whether to recommend hysterectomy or not when it comes to the risk of ovarian cancer, and due to the shift in findings over time, new studies are required to clarify this. In our study, hysterectomy does not protect against ovarian cancer overall, but a potentially decreased risk is observed in women with endometriosis and in non-users of MHT. In this nationwide, register-based case-control study there was no association between hysterectomy and risk of ovarian cancer overall, but the analysis by histologic subtype revealed a reduced risk of clear cell ovarian cancer. Data also showed reduced odds for ovarian cancer after hysterectomy in women with endometriosis and in women not using MHT, albeit not statistically significant. The statistical precision of our results do not allow firm conclusions but combined with findings from other recent studies, they suggest that hysterectomy may be protective against ovarian cancer in these groups of women. Declarations Author contribution L.L. Ring: Protocol/project development, data analysis, manuscript writing/editing L. Baandrup: Protocol/project development, data analysis, manuscript writing/editing M. Gottschau: Protocol/project development, data analysis, manuscript writing/editing C. Dehlendorff: Data collection or management, data analysis, manuscript writing/editing L. Mellemkjær: Protocol/project development, data analysis, manuscript writing/editing S.K. Kjaer: Protocol/project development, data analysis, manuscript writing/editing Funding This work was supported by the Mermaid project [Mermaid 3]. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Competing Interests Lene Mellemkjær has an immediate family member employed at Novo Nordisk, and has an immediate family member who owns stocks in Novo Nordisk. All other authors declare no conflicts of interest. 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J Oncol 2010:740968. https://doi.org/10.1155/2010/740968 Supplementary Files SupplementaryMaterial.docx Cite Share Download PDF Status: Published Journal Publication published 31 May, 2023 Read the published version in Cancer Epidemiology → 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-2173859","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":147529896,"identity":"5e858e4f-8e80-4785-9050-ce34f3ec26e3","order_by":0,"name":"Linea Landgrebe Ring","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAo0lEQVRIiWNgGAWjYBACPmbmBoYPMB7PASK0sDEzNjDOIE0LA2MDMw9pWtgZ2z7b1Njl8bf3PmB4c4Y4hzXPzjmWXCxx5rgB45wbRGphzm1gTtwgkcbAzPOBsA6IFsuG+sQN8s9I0cLYcBhoCxtQC7EOY+w5djxxxpk0hoNziPE+P//hwww/aqoT+9uPMT54c4wILSjgAKkaRsEoGAWjYBTgAADLRS+73J2HrAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-7149-8908","institution":"Danish Cancer Society: Kraeftens Bekaempelse","correspondingAuthor":true,"prefix":"","firstName":"Linea","middleName":"Landgrebe","lastName":"Ring","suffix":""},{"id":147529897,"identity":"d7d49d3b-00ad-49b1-b729-e4f146eb1502","order_by":1,"name":"Louise Baandrup","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Louise","middleName":"","lastName":"Baandrup","suffix":""},{"id":147529898,"identity":"4989df63-b734-4ea6-8869-84e9b61583de","order_by":2,"name":"Mathilde Gottschau","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Mathilde","middleName":"","lastName":"Gottschau","suffix":""},{"id":147529899,"identity":"a41ddb71-930a-479c-8b06-5e39eee6990b","order_by":3,"name":"Christian Dehlendorff","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Dehlendorff","suffix":""},{"id":147529900,"identity":"1a0fab48-7262-479a-bdac-a944dfe9884c","order_by":4,"name":"Lene Mellemkjær","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Lene","middleName":"","lastName":"Mellemkjær","suffix":""},{"id":147529901,"identity":"cd9e7138-c92c-4a61-9cf2-3907e5a404dd","order_by":5,"name":"Susanne K. Kjaer","email":"","orcid":"https://orcid.org/0000-0002-8347-1398","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Susanne","middleName":"K.","lastName":"Kjaer","suffix":""}],"badges":[],"createdAt":"2022-10-17 08:25:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2173859/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2173859/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1016/j.canep.2023.102359","type":"published","date":"2023-06-01T02:43:50+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":57383389,"identity":"9e0e6187-1053-4e65-b35d-21f6cf1c7514","added_by":"auto","created_at":"2024-05-30 02:43:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":741626,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2173859/v1/187ae731-b86e-4f97-be32-609e4c5d0c5d.pdf"},{"id":28532774,"identity":"c6426e7c-337c-4c04-9ffd-c3f8e5c0f57c","added_by":"auto","created_at":"2022-11-01 19:47:52","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13119,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-2173859/v1/3cb6d6a97d76ca16f282b6fa.docx"}],"financialInterests":"","formattedTitle":"Hysterectomy and risk of epithelial ovarian cancer by histologic type, endometriosis, and menopausal hormone therapy","fulltext":[{"header":"what Does This Study Adds To The Clinical Work","content":"\u003cp\u003eWe found an inverse association between hysterectomy and the risk of clear cell ovarian cancer, and a potential protection against ovarian cancer in women with endometriosis and in non-users of menopausal hormone-therapy.\u0026nbsp;\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eWorldwide, ovarian cancer is the eighth most common cancer in women with an age-standardized incidence rate of 6.6 cases per 100,000 person-years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Approximately 95% of ovarian cancers are of epithelial origin and are primarily classified into five main types; high- and low-grade serous, endometrioid, clear cell, and mucinous ovarian cancer [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. High-grade serous carcinoma is the most common histological type accounting for approximately 70% of ovarian carcinomas [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt has been suggested that hysterectomy protects against ovarian cancer by blocking transfer of carcinogenic agents, and retrograde menstruation or endometriosis travelling through the female genital tract [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. A number of studies have investigated the association between hysterectomy and risk of ovarian cancer with inconsistent findings [\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A meta-analysis observed a time-dependent trend in findings and pointed out that one explanation could be changes over time in use of menopausal hormone therapy (MHT) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. MHT is known to increase the risk of ovarian cancer moderately [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], and is more commonly used among hysterectomized women [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], which might explain why a few recent observational studies have reported that the association between hysterectomy and ovarian cancer risk differs by use of MHT [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Other studies have reported that the association between hysterectomy and ovarian cancer varies by tumor histology [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and history of endometriosis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Concomitant removal of the fallopian tubes and/or ovaries at time of hysterectomy are also important factors to consider. Recent research has revealed that the precursor lesion of high-grade serous carcinoma originates in the fallopian tube as serous tubal intraepithelial carcinoma lesions [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], and that bilateral salpingectomy therefore reduces the risk of ovarian cancer [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClarification of the impact of hysterectomy on the risk of ovarian cancer may elucidate the pathogenesis of the disease but it is also important from a clinical point of view to determine whether the procedure protects against ovarian cancer, and identify potential target groups who benefit the most.\u003c/p\u003e \u003cp\u003eThe aim of this nationwide register-based case-control study is to evaluate the association between hysterectomy on benign indication and the risk of ovarian cancer. Our analyses are stratified by histologic subtype of ovarian cancer and investigate whether endometriosis and MHT may be effect modifiers for the association between hysterectomy and the risk of ovarian cancer.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis nationwide, register-based case-control study has previously been described in detail [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and has since been updated with four additional years. In Denmark, the Civil Registration System assigns all Danish citizens a personal identification number, which enables accurate linkage between the different registers. The register also contains information on dates of death, and migration to and from Denmark [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eCases were identified in the Danish Cancer Registry, which contains information on cancer diagnoses in Denmark since 1943 and with mandatory reporting of new cancer cases since 1987 [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Since 2004, cancer cases have been registered using the 10th revision of the International Classification of Diseases (ICD-10) and the 3rd revision of the International Classification of Diseases for Oncology (ICD-O-3), and codes for cancer cases registered during 1978‒2003 have been converted to ICD-10 and ICD-O-3. Cases were identified in the Cancer Registry by ICD-10 DC56. We required that cases were aged 40‒79 years at the index date, defined as the date of diagnosis, without previous cancer, and with a first diagnosis of histologically verified epithelial ovarian cancer during 1998‒2016. Ovarian cancer cases were classified according to the ICD-O-3 morphology code into serous, endometrioid, clear cell, mucinous and other (Supplementary Table S1). Information on grade was not available.\u003c/p\u003e \u003cp\u003eEach case was matched by month and year of birth to 15 control women identified in the Civil Registration System using risk set sampling. Controls were not allowed to have a history of bilateral oophorectomy/salpingo-oophorectomy or cancer (except non-melanoma skin cancer) at the time the corresponding case was diagnosed, i.e., index date. Women were eligible as controls before becoming cases.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eInformation on exposure\u003c/h2\u003e \u003cp\u003eInformation on hysterectomy up until one year prior to index date was retrieved from the Danish National Patient Register, which has registered all diagnoses and surgical procedures performed during hospitalizations since 1977, and during outpatient visits since 1995 [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. From 1977 to 1993, all diagnoses are coded according to ICD-8, and from 1994 diagnoses are coded according to ICD-10. All surgical procedures are classified according to the Danish Classification of Surgical Procedures up until the end of 1995, and afterwards according to the Nordic Classification of Surgical Procedures.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInformation on covariates\u003c/h2\u003e \u003cp\u003eInformation on use of oral contraceptives and MHT was obtained from the Danish National Prescription Registry, where individual-level information on all prescription drugs dispensed at pharmacies in Denmark since 1995 are registered [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], and classified by the Anatomical Therapeutic Chemical Index [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. From the Danish National Patient Register, information since 1977 on endometriosis, tubal ligation, and other gynecological surgical procedures including salpingectomies and oophorectomies up until one year prior to index date was obtained. Parity was derived from the Danish Fertility Database, which contains information on reproductive variables for all women aged 13‒49 years in Denmark from 1980 and onwards [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eWe used conditional logistic regression to calculate age-matched and multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between hysterectomy and risk of epithelial ovarian cancer overall and stratified according to histologic subtype. Potential confounders were selected a priori based on evidence of risk factors for ovarian cancer and availability in the registers. The model was adjusted for age (by design), parity, endometriosis, tubal ligation, other gynecological surgical procedures (tubal ligation, unilateral/bilateral salpingectomy, unilateral oophorectomy, and unilateral salpingo-oophorectomy), and use of oral contraceptives and MHT.\u003c/p\u003e \u003cp\u003eTo investigate effect modification by endometriosis and MHT use, we performed stratified analysis using logistic regression without the matching, but with adjustment for the matching factors (age and calendar year). All analyses were performed using the statistical software R version 4.1.0.\u003c/p\u003e \u003cp\u003eUse of register data for this study was approved by the Danish National Board of Health Data (FSEID-4295). In agreement with the General Data Protection Regulation, the present study is registered in the Danish Cancer Society\u0026rsquo;s internal list of projects dealing with personalized data (journal number: 2019-DCRC-0054). All data related to the study are stored at the Danish Cancer Society Research Center\u0026rsquo;s project database at Statistics Denmark (project number 704327), and the Danish Cancer Society is responsible for the data stored at this project database. The data that support the information of this manuscript were accessed remotely on a secure platform at Statistics Denmark (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.dst.dk\" target=\"_blank\"\u003ewww.dst.dk\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.dst.dk\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). According to Danish laws and regulations, individual-level sensitive data can only be made available for researchers who fulfil legal requirements for accessing personal sensitive data.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe study population included 6,738 women with epithelial ovarian cancer and 101,070 matching controls. The majority of cases were 60‒79 years old at diagnosis and the most common histologic type of tumor was serous (58.7%) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Hysterectomy was reported in 588 (8.7%) cases and in 9,289 (9.2%) controls. Cases (18.1%) were more likely to be nulliparous compared with controls (12.7%). Endometriosis was diagnosed in 130 (1.9%) cases and in 1,665 (1.6%) controls. Finally, ever use of MHT was slightly more common among cases (35.6%) compared with controls (33.2%).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u0026nbsp;Characteristics of women with epithelial ovarian cancer and matching controls\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eCases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c5\" namest=\"c4\" rowspan=\"2\"\u003e \u003cp\u003eControls \u003c/p\u003e \u003cp\u003e (n\u0026thinsp;=\u0026thinsp;101,070)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;6,738)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistology\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3,953\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(58.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucinous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e565\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(8.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrioid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e596\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(8.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClear cell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e328\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,296\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(19.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge at diagnosis / index date (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40\u0026ndash;49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e794\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(11.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11,910\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(11.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50\u0026ndash;59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,707\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(25.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25,605\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(25.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e60\u0026ndash;69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2,270\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(33.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34,050\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(33.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e70\u0026ndash;79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,967\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(29.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29,505\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(29.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHysterectomy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6,150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(91.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91,781\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(90.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e588\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9,289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(9.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge at hysterectomy (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo hysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6,150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(91.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91,781\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(90.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e459\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7,036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(7.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2,253\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(2.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eParity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNulliparous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,218\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(18.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12,866\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(12.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOne\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,311\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(19.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17,047\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(16.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2,631\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(39.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42,629\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(42.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThree or more\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,578\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(23.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28,528\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(28.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEndometriosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6,608\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(98.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99,405\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(98.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,665\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOral contraceptives\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6,309\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(93.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90,667\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(89.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e429\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(6.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10,403\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(10.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMenopausal hormone therapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo (\u0026lt;\u0026thinsp;2 prescriptions)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4,342\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(64.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67,467\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(66.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes (\u0026gt;\u0026thinsp;2 prescriptions)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2,396\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(35.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33,603\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(33.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTubal ligation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6,411\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(95.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e94,775\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(93.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e327\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6,295\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(6.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOther gynecological surgical procedures\u003c/b\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6,563\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(97.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e96,969\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(95.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e175\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4,101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(4.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHysterectomy was not associated with the overall risk of epithelial ovarian cancer (OR\u0026thinsp;=\u0026thinsp;0.97; 95% CI 0.88‒1.06) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). When the analysis was stratified according to tumor histology, we observed a significantly reduced risk of clear cell ovarian cancer after hysterectomy (OR\u0026thinsp;=\u0026thinsp;0.47; 95% CI 0.28‒0.78). The OR for mucinous ovarian cancer was decreased (OR\u0026thinsp;=\u0026thinsp;0.80; 95% CI 0.56‒1.14), whereas an elevated OR was observed for endometrioid ovarian cancer (OR\u0026thinsp;=\u0026thinsp;1.29; 95% CI 0.97‒1.72). Finally, hysterectomy was associated with neutral ORs for serous (OR\u0026thinsp;=\u0026thinsp;1.00; 95% CI 0.89‒1.13) and other epithelial ovarian cancers (OR\u0026thinsp;=\u0026thinsp;0.96; 95% CI 0.76‒1.20).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHysterectomy and risk of epithelial ovarian cancer stratified according to histologic subtype\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eCases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eControls\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eAge-adjusted\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003eAdjusted\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistologic subtype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAll epithelial\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo hysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6,150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(91.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e91,781\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(90.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e588\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9,289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(0.86‒1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0.88‒1.06)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSerous\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo hysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3,585\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(90.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e53,677\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(90.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e368\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5,618\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(0.88‒1.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0.89‒1.13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMucinous\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo hysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e529\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(93.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7,715\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(91.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(6.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e760\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(9.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(0.49‒0.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0.56‒1.14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEndometrioid\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo hysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e531\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(89.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8,156\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(91.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(10.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e784\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(8.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(0.98‒1.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0.97‒1.72)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClear cell\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo hysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e309\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(94.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4,466\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(90.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(5.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e454\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(0.37‒0.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0.28‒0.78)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOther\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo hysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(92.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17,767\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(91.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1,673\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(0.72‒1.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0.76‒1.20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"12\" nameend=\"c12\" namest=\"c1\"\u003e \u003cp\u003eAbbreviations: OR, Odds ratio; CI, Confidence interval; Ref., Reference\u003c/p\u003e \u003cp\u003e\u003csup\u003ea\u003c/sup\u003eAdjusted for age (by design), calendar year (by design), parity (categorical), tubal ligation, endometriosis, other gynaecological surgical procedures, oral contraceptive use, and use of menopausal hormone therapy.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the analysis stratified according to occurrence of endometriosis. In women with a previous diagnosis of endometriosis, hysterectomy was associated with a reduced OR for ovarian cancer (OR\u0026thinsp;=\u0026thinsp;0.73; 95% CI 0.50‒1.09), whereas the association between hysterectomy and ovarian cancer in patients without a diagnosis of endometriosis was close to unity (OR\u0026thinsp;=\u0026thinsp;0.99; 95% CI 0.90‒1.08).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHysterectomy and risk of epithelial ovarian cancer by history of endometriosis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge-adjusted\u003c/p\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdjusted\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo endometriosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo hysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.04 (0.94‒1.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.99 (0.90‒1.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEndometriosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo hysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.75 (0.51‒1.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.73 (0.50‒1.09)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eAbbreviations: OR, Odds ratio; CI, Confidence interval; Ref., Reference\u003c/p\u003e \u003cp\u003e\u003csup\u003ea\u003c/sup\u003eAdjusted for age, calendar year, parity (categorical), tubal ligation, other gynaecological surgical procedures, oral contraceptive use and use of menopausal hormone therapy.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFinally, we examined the effect of hysterectomy stratified according to use of MHT. The ORs for the association between hysterectomy and ovarian cancer were 0.87 (95% CI 0.76‒1.00) in women who never used MHT and 1.05 (95% CI 0.93‒1.19) in women who had redeemed minimum two prescriptions of MHT before index date (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHysterectomy and risk of epithelial ovarian cancer by ever use of menopausal hormone therapy (MHT)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge-adjusted\u003c/p\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdjusted\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNon-use of MHT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo hysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.90 (0.78‒1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.87 (0.76‒1.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEver-use of MHT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo hysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHysterectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.08 (0.95‒1.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.05 (0.93‒1.19)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eOR: Odds ratio; CI: Confidence interval; Ref.: Reference\u003c/p\u003e \u003cp\u003e\u003csup\u003ea\u003c/sup\u003eAdjusted for age, calendar year, parity (categorical), tubal ligation, other gynaecological surgical procedures, and use of oral contraceptives.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study hysterectomy was not associated with the risk of epithelial ovarian cancer overall but seemed to reduce risk of the clear cell type. In women with endometriosis and in women not using MHT, reduced odds for ovarian cancer after hysterectomy were observed.\u003c/p\u003e \u003cp\u003eIn line with our findings, recent studies have found no association between hysterectomy and risk of ovarian cancer overall [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and a meta-analysis reported a pooled OR of 0.97 (95% CI: 0.83\u0026ndash;1.12) based on data from 18 case-control studies published between 2000 and 2017 [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In contrast, data from two earlier meta-analyses published in 2012 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], and 2013 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], respectively, suggested that hysterectomy was associated with a lower risk of ovarian cancer. Both meta-analyses reported significant heterogeneity between the included studies primarily explained by median year of ovarian cancer diagnosis, where studies published before 2000 indicated a lower risk of ovarian cancer following hysterectomy, whereas studies published after 2000 did not. The authors speculated that the temporal change in the association between hysterectomy and ovarian cancer risk could in part be attributed to increasing use of MHT over calendar time in hysterectomized women [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMHT is more commonly prescribed to hysterectomized women than to non-hysterectomized women [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], and is associated with a moderately increased ovarian cancer risk [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In accordance, a recent study from the Ovarian Cancer Association Consortium (OCAC) found that adjustment for duration of MHT use affected the association between hysterectomy and ovarian cancer risk markedly [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A case-control study including 614 African-American women with ovarian cancer reported that hysterectomy decreased the risk of epithelial ovarian cancer (OR\u0026thinsp;=\u0026thinsp;0.65, 95% CI: 0.46‒0.92) in never users of estrogen-only MHT, whereas increased odds was observed among users [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Moreover, data from the Nurses\u0026rsquo; Health Study also showed that hysterectomy was associated with decreased odds for ovarian cancer only in women who had never used MHT (hazard ratio (HR)\u0026thinsp;=\u0026thinsp;0.81, 95% CI: 0.54‒1.20) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], which is in line with our findings.\u003c/p\u003e \u003cp\u003eOvarian cancer is a heterogeneous disease and the etiology of the different subtypes may differ. Therefore, it is also suggested that the association between hysterectomy and ovarian cancer may vary according to the histological types of epithelial ovarian cancer [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Endometrioid and clear cell types are strongly associated with endometriosis [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. By preventing menstruation or endometriosis from retrograde transport through the female genital tract, hysterectomy may protect primarily against those types of ovarian cancer. A meta-analysis pooling data from four case-control studies with information on tumor histology reported that hysterectomy was associated with a statistically significant risk reduction for endometrioid/clear cell ovarian cancer (OR\u0026thinsp;=\u0026thinsp;0.70, 95% CI: 0.51‒0.94) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The OR for mucinous ovarian cancer was reduced but statistically not significant and there was no association between hysterectomy and serous ovarian cancer [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Other studies not included in the meta-analysis by Huo et al. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] have also reported that hysterectomy protected against clear cell ovarian cancer [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] or that risk estimates for endometrioid and/or clear cell ovarian cancer pointed in the protective direction without statistical significance [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Risk estimates for mucinous ovarian cancer are also reported statistically non-significantly decreased in several studies [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], whereas a null-association with serous ovarian cancer is most often observed [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Our results are consistent with the majority of previous recent studies, as we also found that hysterectomy was not associated with serous ovarian cancer but protected against clear cell ovarian cancer. However, our data showed increased odds for endometrioid ovarian cancer after hysterectomy. We have no definite explanation for this finding but misclassification may have played a role. Cases in our study go back to 1998 and some of the tumors that were diagnosed as endometrioid ovarian cancers may have been classified as high-grade serous carcinomas today based on their immunoprofile [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The association between hysterectomy and endometrioid ovarian cancer may also be affected by unmeasured confounding. Although our study was based on high-quality nationwide registers, registration of potential confounders such as endometriosis may not be complete.\u003c/p\u003e \u003cp\u003eOur findings in stratified analysis showing reduced odds for ovarian cancer after hysterectomy in women with endometriosis is compatible with reports from previous studies [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. One study with pooled information from four US population-based case-control studies reported that hysterectomy was associated with statistically non-significantly decreased odds for ovarian cancer (OR\u0026thinsp;=\u0026thinsp;0.69, 95% CI: 0.38‒1.24) in women with endometriosis, whereas this was not found in women without endometriosis (OR\u0026thinsp;=\u0026thinsp;1.02, 95% CI: 0.86‒1.23) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In addition, an Australian register-based cohort study reported substantially decreased risk of ovarian cancer (HR\u0026thinsp;=\u0026thinsp;0.17, 95% CI: 0.12‒0.24) after hysterectomy in women with endometriosis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and OCAC data also showed that hysterectomy statistically significantly reduced the risk of ovarian cancer in women with endometriosis (OR\u0026thinsp;=\u0026thinsp;0.69, 95% CI 0.48‒0.99) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Although hysterectomy, as previously discussed, may prevent retrograde transport of endometriosis, the observed protective effect of hysterectomy on ovarian cancer risk among women with endometriosis may also be explained by removal of endometriotic lesions at the time of hysterectomy.\u003c/p\u003e \u003cp\u003eOne of the main strengths of our study is the large sample size including more than 6,700 women with ovarian cancer, making it possible to investigate associations with histologic subtypes of ovarian cancer. Data were derived from nationwide registers with no risk of selection or recall bias. The registers contain virtually complete and continuously updated data on surgical procedures, diagnoses, and drug use. The register-based design of our study thereby enabled us to ensure that all control women had at least one intact ovary and provided us with information on important potential confounding factors such as MHT use and endometriosis.\u003c/p\u003e \u003cp\u003eOur study also has some limitations. Although all of our cases were histologically verified, we did not perform a central pathology review of the ovarian tumors, and there may therefore be some degree of misclassification, especially affecting those cancers diagnosed in the early part of our study period. Moreover, we did not have information on tumor grade which precluded us from differentiating between low and high-grade serous carcinomas. Finally, left truncation of prescription data may have led to misclassification of MHT use among those women who initiated MHT before 1995, and although the Danish National Patient Register was established earlier (1977), information on hysterectomy and endometriosis may be incomplete.\u003c/p\u003e \u003cp\u003eIt is important to know whether to recommend hysterectomy or not when it comes to the risk of ovarian cancer, and due to the shift in findings over time, new studies are required to clarify this. In our study, hysterectomy does not protect against ovarian cancer overall, but a potentially decreased risk is observed in women with endometriosis and in non-users of MHT.\u003c/p\u003e \u003cp\u003eIn this nationwide, register-based case-control study there was no association between hysterectomy and risk of ovarian cancer overall, but the analysis by histologic subtype revealed a reduced risk of clear cell ovarian cancer. Data also showed reduced odds for ovarian cancer after hysterectomy in women with endometriosis and in women not using MHT, albeit not statistically significant. The statistical precision of our results do not allow firm conclusions but combined with findings from other recent studies, they suggest that hysterectomy may be protective against ovarian cancer in these groups of women.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthor contribution\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eL.L. Ring: Protocol/project development, data analysis, manuscript writing/editing\u003c/p\u003e\n\u003cp\u003eL. Baandrup: Protocol/project development, data analysis, manuscript writing/editing\u003c/p\u003e\n\u003cp\u003eM. Gottschau: Protocol/project development, data analysis, manuscript writing/editing\u003c/p\u003e\n\u003cp\u003eC. Dehlendorff: Data collection or management, data analysis, manuscript writing/editing\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eL. Mellemkj\u0026aelig;r: Protocol/project development, data analysis, manuscript writing/editing\u003c/p\u003e\n\u003cp\u003eS.K. Kjaer: Protocol/project development, data analysis, manuscript writing/editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Mermaid project [Mermaid 3].\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting Interests\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLene Mellemkj\u0026aelig;r has an immediate family member employed at Novo Nordisk, and has an immediate family member who owns stocks in Novo Nordisk. All other authors declare no conflicts of interest.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71:209\u0026ndash;249. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3322/caac.21660\u003c/span\u003e\u003cspan address=\"10.3322/caac.21660\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrat J, D'Angelo E, Espinosa I (2018) Ovarian carcinomas: at least five different diseases with distinct histological features and molecular genetics. 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Scand J Public Health 39(7 Suppl):79\u0026ndash;82. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/1403494811399957\u003c/span\u003e\u003cspan address=\"10.1177/1403494811399957\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKurman RJ, Shih Ie M (2016) The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded. Am J Pathol. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ajpath.2015.11.011\u003c/span\u003e\u003cspan address=\"10.1016/j.ajpath.2015.11.011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. 186:733 \u0026ndash; 47\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGilks CB(2010) Molecular abnormalities in ovarian cancer subtypes other than high-grade serous carcinoma. J Oncol 2010:740968. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1155/2010/740968\u003c/span\u003e\u003cspan address=\"10.1155/2010/740968\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"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":"Epithelial ovarian cancer, hysterectomy, histological type, endometriosis, menopausal hormone therapy ","lastPublishedDoi":"10.21203/rs.3.rs-2173859/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2173859/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThis nationwide, register-based case-control study investigated the association between hysterectomy and risk of epithelial ovarian cancer according to histology and by history of endometriosis and MHT use.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eFrom the Danish Cancer Registry, all women registered with epithelial ovarian cancer during 1998‒2016 were identified (n\u0026thinsp;=\u0026thinsp;6,738). Each case was sex- and age-matched to 15 population controls using risk-set sampling. Information on previous hysterectomy on benign indication and potential confounders was retrieved from nationwide registers. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between hysterectomy and ovarian cancer according to histology, endometriosis, and use of MHT.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eHysterectomy was not associated with risk of epithelial ovarian cancer overall (OR\u0026thinsp;=\u0026thinsp;0.97; 95% CI 0.88‒1.06) but was associated with reduced risk of clear cell ovarian cancer (OR\u0026thinsp;=\u0026thinsp;0.47; 95% CI 0.28‒0.78). In stratified analyses, decreased ORs associated with hysterectomy were seen in women with endometriosis (OR\u0026thinsp;=\u0026thinsp;0.73; 95% CI 0.50‒1.09) and in non-users of MHT (OR\u0026thinsp;=\u0026thinsp;0.87; 95% CI 0.76‒1.00).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eHysterectomy was not associated with epithelial ovarian cancer overall but with reduced risk of clear cell ovarian cancer. Our findings may suggest a reduced risk of ovarian cancer after hysterectomy in women with endometriosis and in MHT non-users, but the statistical precision of our results did not allow firm conclusions.\u003c/p\u003e","manuscriptTitle":"Hysterectomy and risk of epithelial ovarian cancer by histologic type, endometriosis, and menopausal hormone therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-11-01 19:47:51","doi":"10.21203/rs.3.rs-2173859/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":"4caae4f6-357a-40a2-9c8d-56dcad87c415","owner":[],"postedDate":"November 1st, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-05-30T02:43:50+00:00","versionOfRecord":{"articleIdentity":"rs-2173859","link":"https://doi.org/10.1016/j.canep.2023.102359","journal":{"identity":"cancer-epidemiology","isVorOnly":true,"title":"Cancer Epidemiology"},"publishedOn":"2023-06-01 02:43:50","publishedOnDateReadable":"June 1st, 2023"},"versionCreatedAt":"2022-11-01 19:47:51","video":"","vorDoi":"10.1016/j.canep.2023.102359","vorDoiUrl":"https://doi.org/10.1016/j.canep.2023.102359","workflowStages":[]},"version":"v1","identity":"rs-2173859","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2173859","identity":"rs-2173859","version":["v1"]},"buildId":"0U-iFTyB6qxOgVj8rjrZV","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}