Effects of medical and surgical treatment on the risk of major adverse cardiovascular and cerebrovascular events in Asian women with endometriosis

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Chiang, Fu-Tsai Kung, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.15783/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Background: Endometriosis is linked to major adverse cardiovascular and cerebrovascular events (MACCE). However, whether this finding can be applied to the Asian population remained unanswered. Additionally, results are still inconsistent for the impact of endometriosis treatment on incidental MACCE. Thus, we intended to investigate the association between endometriosis and MACCE, and study the effect of endometriosis therapies on the risk of MACCE among Asian women. Methods: The Taiwan National Health Insurance Research Database was used for this retrospective population-based cohort study from 1997 to 2013. A total of 17 543 patients with endometriosis aged between 18 and 50 years were identified from a general population of 1 million after excluding diagnoses of major cardiovascular disease (CVD) and cerebrovascular accident (CVA) prior to endometriosis. The comparison group (n = 70 172) without endometriosis was selected by matching the study cohort with age, sex, and income and urbanization levels in a 4:1 ratio. Demographic data and the frequency of comorbidities between groups were compared using the independent t test and chi-square test. The incidence and risk of MACCE were analyzed using the log-rank test and a multivariate Cox proportional hazards model. Results: During a median follow-up period of 9.2 years, Asian women with endometriosis had a significantly higher frequency of comorbidities, medical and surgical treatment, and MACCE than did their non-endometriosis counterparts (2.76% vs 2.18%, P < .001). After adjustment for comorbidities, patients with endometriosis had an approximately 1.2-fold increased risk of MACCE (95% CI 1.05-1.29; P = .005) and a higher cumulative incidence of MACCE compared with the normal population. Among women with endometriosis, neither medical nor surgical treatment increased the risk of MACCE, including major CVD and CVA. Furthermore, medical treatment for endometriosis appeared to be protective against MACCE in the endometriosis females. Conclusion: Asian women with endometriosis not only had a higher frequency of comorbidities but also an increased risk of MACCE compared with the general population. In addition, the safety concern about medical or surgical treatment of endometriosis on the risk of MACCE was not evident in this study. Preventive Medicine Endometriosis Major adverse cardiovascular and cerebrovascular events Population-based cohort study Medical and surgical treatment Figures Figure 1 Figure 2 Figure 3 Background Endometriosis, characterized by extrauterine endometrial-like lesions, is a worldwide concern affecting many women of childbearing age. Approximately 10% of the general female population has endometriosis, and nearly 50% of women with infertility are affected by it [1,2]. endometriosis is strongly associated with systemic inflammation, neovascularization, and tissue remodeling [3]. Additionally, a recent study reported that endothelial dysfunction (ED) plays a crucial role in one of the pathological mechanisms underlying endometriosis [4]. The development of atherosclerotic cerebrovascular or cardiovascular disease (CVD), such as vascular dementia, coronary artery disease (CAD), and peripheral vascular disease, is closely related to systemic inflammation and ED [5,6]. Therefore, considering the common pathological pathways of inflammation and ED, the phenomenon that women under emotional stress or with low level of anti-Müllerian hormone (AMH) are associated with higher risk of CVD has been observed by several studies [7,8]. Recently, data from the US Health Study II registry indicated that the risk of CAD is not only linked to endometriosis but also higher in patients with endometriosis who underwent hysterectomy or oophorectomy [9]. The unfavorable effect of surgical treatment for endometriosis on the risk of CVD raised clinical safety concerns among operators, health care providers, and patients. Furthermore, hormonal treatment strategies for endometriosis [10,11], including gonadotropin-releasing hormone (GnRH) analogs, oral contraceptives, progesterone, and danazol, potentially or controversially increase the cardiovascular risk and yield inconsistent results [7,8,12]. However, whether the aforementioned findings derived from Western countries can be generally applied to the Asian population and whether women with endometriosis receiving medical, surgical, or combined treatment have increased risks of major adverse cardiovascular and cerebrovascular events (MACCE) remain unanswered. Using the Taiwan National Health Insurance Research Database (NHIRD), we studied (1) the risk of MACCE and (2) the impact of endometriosis therapy on MACCE in Asian women with endometriosis. Methods Introduction of the Taiwan NHIRD The Taiwan National Health Insurance program provides health care to 99% of the population of 24 million and is linked to 97% of hospitals and clinics in Taiwan ( http://nhird.nhri.org.tw/en/ ) [13]. The NHIRD is a considerable source of information on medical facilities, inpatient and outpatient order details, dental services, drug prescriptions, patient care, and other paramedical registration files (eg, payment, regions, and catastrophic illness), but it does not include laboratory data. Diagnoses are entered based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The NHIRD longitudinal data collection started in 2000, and 1 000 000 beneficiaries were randomly sampled. The database contains the entire original claims data from 1997 to 2013. The study design and protocol were approved by the Institutional Review Board of Chang Gung Memorial Hospital (No. 201800664B1). Study population We selected female patients with endometriosis (ICD-9-CM code 617) from 1 million individuals in the NHIRD between January 01, 1997 and December 31, 2013 to conduct a retrospective nationwide population-based cohort study. Women aged between 18 and 50 with a record of at least 3 medical visits or 1 admission for endometriosis were included in the study. To confirm the diagnosis of endometriosis, we linked the relevant clinical information with the corresponding vaginal ultrasound, surgical findings, and medications. Those patients with clinically suspicious diagnosis of endometriosis without image- or procedure-proven evidence were not included. We excluded patients aged 50 years, male patients, patients experiencing menopause (627), patients with missing or incomplete baseline characteristics data, and patients with a follow-up duration of less than 1 year. For the first purpose of the study, that is, the incidental MACCE in women with endometriosis, patients with diagnoses of acute myocardial infarction (AMI; 410-411), heart failure (HF; 428), or cerebrovascular accident (CVA; 430-436) in the beginning or prior to endometriosis were excluded. Thus, we identified a total of 17 543 women with endometriosis (EM group) at the beginning of the study. A comparison cohort of 70 172 non-endometriosis (non-EM) women was selected from January 01, 1997 and December 31, 2013 after matching the study cohort at a 4:1 ratio with age and socioeconomic background, including income and urbanization level (Fig. 1). Urbanization was categorized into 4 levels, from level 1 indicating the least urbanized level (country) to level 4 indicating the most urbanized level (city). The insurance taxable income level was stratified into 4 categories based on the monthly insurance payment of each insured participant (ie, level 1: none; level 2: 1-15 840; level 3: 15 841-25 000; and level 4: > 25 000 New Taiwan dollars per month). Definition The MACCE were divided into 2 disease entities, namely CVD and CVA. Major CVD involved AMI or HF. CVA encompassed acute ischemic (433-436) or hemorrhagic stroke (430-432). Moreover, information on medications was acquired based on the World Health Organization Anatomical Therapeutic Chemical classification (WHO ATC codes) system. Medical treatment for endometriosis comprised danazol, gestrinone, oral contraceptives, and GnRH agonists. Patients with prescriptions exceeding a month were considered medication users. By contrast, we considered patients with a regimen duration of less than a month as nonusers, because drugs might have been prescribed temporarily for symptomatic relief, diagnostic test, or purposes other than standard treatment for endometriosis. Surgical treatment for endometriosis mainly consisted of therapeutic laparotomy and laparoscopy (ICD-9-CM procedure codes 541 and 542). The time frame of medical and surgical treatment was from the diagnosis of endometriosis to the end of follow-up. Identification of symptoms, comorbidities, location, and outcomes We conducted a retrospective longitudinal study. The date of initial diagnosis of endometriosis was defined as the index date. To clarify the association between MACCE and endometriosis, potential risk factors for MACCE and possible confounders were retrieved for further analysis. We assessed gynecological presentations and relevant comorbidities for each patient during the follow-up period (from the diagnosis of endometriosis to the end of study), including dysmenorrhea (ICD-9-CM code 625.3), amenorrhea (ICD-9-CM code 626.0), infertility (ICD-9-CM code 628), ovarian cancer (ICD-9-CM code 183), hypertension (ICD-9-CM codes 401-405), diabetes (ICD-9-CM code 250), dyslipidemia (ICD-9-CM code 272), gout (ICD-9-CM code 274), chronic ischemic heart disease (ICD-9-CM codes 412-414 and 429.2), peripheral vascular disease (ICD-9-CM codes 440, 443.9, 444.0, 444.2, 444.8, 444.9, 447.8, 447.9, 445.0, and 445.02), atrial fibrillation (ICD-9-CM code 427.31), and chronic kidney disease (ICD-9-CM code 585). Endometriosis was further divided into ovarian and extraovarian groups according to its occurrence location. With respect to study outcomes, the day of the first event occurrence was defined as the event date. The diagnosis of MACCE, including AMI, HF, and CVA, was confirmed by 3 consecutive records of outpatient visits or a one-time diagnosis on admission with the corresponding standard treatment during the whole study period. Endpoints between the 2 groups were censored, whereas clinical events were identified by ICD-9-CM codes and the event date. We investigated the frequency and incidence of MACCE in both EM and non-EM Asian groups. Additionally, we analyzed whether the risk of MACCE was higher in the EM group than in the normal population in Asian women. Furthermore, we studied the differences in the risk of MACCE among diseased population according to none, surgical alone, medical alone, or combination treatment for endometriosis. Statistical analysis The ratios of demographic data and comorbidities between the study cohort (EM group) and the matched control cohort (non-EM group) were compared using the independent t test and chi-square test, as appropriate. The incidence rates and 95% CIs of MACCE were calculated for the entire follow-up period. We also examined the outcomes of MACCE and stratified them by subgroups according to age, amenorrhea diagnosis, and comorbidities. Additionally, the Kaplan–Meier method was used to estimate the cumulative incidences, and a log-rank test was performed to examine differences between disease and non-disease groups. Using Cox proportional hazards regression models, we analyzed hazard ratios (HRs) and corresponding 95% CIs after adjusting for age, medications, surgery types, and associated comorbidities. To further understand the effect of surgical or medical treatment for endometriosis, a multivariate Cox regression model was used to examine the adjusted HRs of endometriosis for the occurrence of MACCE in the subgroups. A two-tailed P value of <.05 was considered statistically significant. All analyses were conducted using the SAS statistical software program (Version 9.4; SAS Institute, Cary, NC, USA). Results Demographic data and outcomes in women with and without endometriosis (Table 1) Over the 17-year dataset period, there were a total of 17 543 and 70 172 eligible patients in the EM and non-EM group, respectively. More than 60% of women with endometriosis were aged between 35 and 50 years with a median age of 38 years. The frequencies of irregular menstruation, infertility, and ovarian cancer were higher in the EM group than in the non-EM group. Approximately 13% of endometriosis cases were detected in the ovaries alone. A majority of women in the EM group had endometriosis in both ovarian and extraovarian locations. Approximately 1 in 5 patients with endometriosis received regular medical or standard surgical treatment for endometriosis. The EM group had a significantly higher prevalence of comorbidities compared with its non-EM counterpart, except for atrial fibrillation and chronic kidney disease. The mean follow-up duration was 9.3 years. At the end of the study, the frequency of MACCE in patients with endometriosis and without endometriosis was 2.76% and 2.18%, respectively. Therefore, the frequency of MACCE, including major CVD and CVA, was significantly higher in the EM group than in the non-EM group (all P values < .002). However, the all-cause mortality rate was approximately 1% and did not significantly differ between groups. Incidence and risk of MACCE in women with endometriosis and without endometriosis (Table 2 and Fig. 2) The incidence rate of MACCE in patients with and without endometriosis was 300.0 and 235.5 per 100,000 person-years, respectively, amounting to an incidence rate ratio of MACCE in the EM group to MACCE in the non-EM group of 1.27 (95% CI 1.15-1.41; P < .001). After adjustment for age, socioeconomic background, and associated comorbidities, women with endometriosis had a 1.17-fold increased risk of MACCE compared to women without (95% CI = 1.05-1.29; P = .005). Additionally, the Kaplan–Meier curve demonstrated that the EM group had a higher cumulative incidence of MACCE compared with the non-EM group ( P < .001 in the log-rank test). Looking deeply, the cumulative incidence of major CVD and CVA between groups displayed a similar pattern to that of MACCE (Fig. 2). The findings of the stratified analysis revealed that the adjusted HRs of MACCE in the endometriosis cohort to the non-endometriosis cohort were significantly higher in the subgroups of patients aged 35 to 50 years and without conventional atherosclerotic risk factors (ie, hypertension, diabetes, dyslipidemia, and gout). Nevertheless, the adjusted HRs did not change significantly for patients with amenorrhea and those experiencing premature menopause, which suggested that the risk of MACCE might be higher for those relatively healthy middle-aged Asian women with endometriosis, regardless of their menstrual presentation. Association between MACCE and endometriosis (Table 3) Using a multivariate Cox regression model with adjustment for age, urbanization/income, and conventional atherosclerotic risk factors, we observed that apart from endometriosis, age between 35 and 50 years, higher urbanization and income levels, hypertension, and diabetes were significantly associated with MACCE. Moreover, endometriosis was identified to be related to both major CVD and CVA. Effects of medical and surgical treatment on clinical outcomes (Fig. 3 and Table 4) Approximately 20% of patients with endometriosis received medical or surgical therapy. To clarify the effect of various endometriosis treatment strategies on the occurrence of MACCE, we divided the EM group into 4 subgroups according to whether they received surgical or medical treatment. Fig. 3 indicates that the cumulative incidence of MACCE was the highest in the endometriosis subgroup without any treatment and significantly lower in the subgroups of patients who received medical, surgical, or combined treatment ( P < .001 in the log-rank test). However, there was no significant difference in MACCE among the aforementioned 3 subgroups. We further adjusted for procedures and medications apart from the aforementioned potential confounders in a multivariate analysis of these women with endometriosis. Findings indicated that women who were aged ≥35 years and had a higher urbanization level, hypertension, and diabetes were closely associated with MACCE in endometriosis as expected. In addition, there was no safety concern regarding the increase of the risk of MACCE in surgical treatment of endometriosis. Medical treatment alone appeared to be associated with a significantly decreased MACCE risk. The occurrence of MACCE in combined medical and surgical treatment for endometriosis did not further increase compared with that in conservative therapy, i.e., no treatment or only pain killer for symptomatic relief of endometriosis. Discussion The present study that used the Taiwan NHIRD to investigate the association between EM and MACCE and the effect of endometriosis treatment on the risk of MACCE in the Asian population yielded several relevant clinical findings. First, the risk of MACCE, including AMI, HF, and CVA, was found higher in the Asian women with endometriosis than in those without. Second, after multivariate adjustment, endometriosis women had an approximately 1.2-time increased risk of MACCE throughout their early life. Third, surgical and medical treatment for endometriosis did not present a risk of increased MACCE incidence. Furthermore, Asian endometriosis women treated only with medication appeared to have a lower risk of MACCE compared with those who received surgical or combined treatment. This large-scale nationwide population-based cohort study identified the association between endometriosis and MACCE as well as the influence of endometriosis-associated medical/surgical therapies on cardiovascular events in the Asian population. The increased risk of MACCE after surgical treatment of endometriosis reported in a previous publication [9] was not observed in our study. Asian women with endometriosis could be considered with medical treatment first and then with surgical intervention or combination therapy later, because we did not find an increased risk of MACCE in the subgroups of medical or surgical therapy as compared with that in the no-treatment subgroup. Our findings, therefore, suggested a safer management strategy not only for endometriosis per se but also for preventing future occurrence of MACCE in these relatively young and healthy women. The link between systemic inflammation and ED has been well documented for several decades [4,14]. Furthermore, abundant evidence has supported the relationship among ED, arterial atherosclerosis, and acute arterial occlusive diseases (eg, acute stroke, AMI, and critical limb ischemia) [15-18]. Although the causal relationship between ED and CVD is complex, they are undoubtedly linked with an unfavorable prognostic outcome [5]. Similarly, the underlying mechanisms of endometriosis have been proposed to be multifactorial and multifaceted and to include genetic and environmental factors, stem cell theory, vasculogenesis, neurohormonal dysregulation, and autoimmune dysfunction [19-21]. Recently, increasing data have demonstrated that the strong association between endometriosis and ED can be attributed to abnormal vasculogenesis from endothelial progenitor cells to the microvascular endothelium of ectopic endometrial tissue rather than to the normal angiogenesis process [20]. Additionally, endometriosis is recognized as a disabling disease owing to chronic pelvic pain, dysmenorrhea, dyspareunia, and dysuria, thus severely affecting quality of life [22]. Patients with intractable endometriosis experience painful symptoms or psychological and emotional stress, which further increases the risk of future CVD [7]. Therefore, these findings [15-21] raised the hypothesis that endometriosis and MACCE share a common pathological pathway and disease mechanism of inflammation, ED, and emotional or physical stress from frequent dysmenorrhea. In the present study, not only were the frequency and incidence of MACCE higher in Asian women with endometriosis than in those without, but endometriosis also appeared to be independently associated with major CVD and CVA. The aforementioned hypotheses were verified by the present real-world analytic results. In addition to age between 35 and 50 years and conventional atherosclerotic (or CAD) risk factors, endometriosis might be considered as another risk factor for MACCE. Santoro et al addressed a similar issue regarding the relationship between endometriosis and atherosclerosis [23]. Verit et al also reported that the risk of CVD may increase in women with unexplained infertility [24]. Furthermore, the causes of female infertility include polycystic ovarian syndrome, obesity, thyroid function, and endometriosis [25,26], and all these factors strongly influence CVD outcomes [27-29]. Therefore, our finding regarding MACCE in endometriosis is not only consistent with previous clinical observations but also compatible with their pathological hypotheses. However, the causal relationship between endometriosis and CVD through the possible mechanism of inflammation and ED as well as associated mediators deserves further investigation. de Kat et al [8] demonstrated the negative correlation of the AMH level with an increased CVD risk. The level of AMH, an indicator of ovarian preservation, remarkably decreased after surgical or laparoscopic treatment for endometriosis [30,31]. Therefore, the aforementioned phenomena could, at least in part, explain why the CVD risk notably increased after surgery for endometriosis in a recent observational study [3]. Unfortunately, the level of AMH was unavailable in the present study; therefore, we could not analyze the association among AMH, endometriosis surgery, and CVD risk. Data from the present study based on the Asian population revealed that endometriosis patients treated with surgery or combined therapy did not have a higher risk of MACCE than those who did not receive treatment. Therefore, the effect of endometriosis surgery on the risk of MACCE might not be a cause for concern. Our finding was supported by results reported by Santoro et al [32] according to which surgical treatment of endometriosis can lead to the regression of ED, and an improved cardiovascular outcome from surgery is predictable. Taken together, the results of the current study suggested that surgical intervention for endometriosis might adversely affect the ovarian function but may not be considered as a risk factor for MACCE. Based on the results of the current study, which demonstrated lower MACCE risks in endometriosis patients receiving medications only, medical treatment followed by surgical management might be a therapeutic option of endometriosis. Limitations Our study has several limitations. First, the detailed personal history and lifestyle of patients, such as smoking or alcohol abuse, body mass index, and functional capacity, were not provided in the Taiwan NHIRD. This weakness was overcome by matching the socioeconomic level at baseline. Second, all diagnoses and management of endometriosis in the present study were retrieved according to registered ICD-9-CM codes; therefore, the staging or severity of endometriosis and procedural details are lacking. Third, laboratory data including the AMH level or other inflammatory biomarkers are not available in the NHIRD. Fourth, compared with the therapeutic rate of over 50% for endometriosis in a UK-based population [33], data from the current study Asian cohort revealed a surgical or medical treatment rate for endometriosis of 20% only. This is because Taiwanese endometriosis women usually do not like to seek medical aid or receive relevant treatment until the relevant symptoms become more severe. Therefore, we are unsure whether the results of this Taiwanese population-based study can be applied to the clinical practice worldwide and vice versa. Thus, the effect of endometriosis treatment on the incidence of MACCE deserves further investigation through a well-designed prospective study. Finally, the type of medication used for cardiovascular protection (eg, antihypertensive medicine and antidiabetic or lipid-lowering agents) could not be obtained from the NHIRD. Therefore, the effect of medications beyond standard treatment for endometriosis on the occurrence of MACCE was not fully investigated. Exploring the medications with potential benefit to reduce CVD risks paves the way for future studies. Conclusions Asian endometriosis women had a higher prevalence of comorbidities than the matched general population and might increase the risk of MACCE, especially for those aged between 35 and 50 years and relatively healthy. In addition, endometriosis can be safely treated with surgery alone or a combined medical and surgical therapy because no safety concern was raised regarding a further increase in the MACCE risk. Abbreviations EM: endometriosis; MACCE: major adverse cardiovascular and cerebrovascular events; CVD: cardiovascular disease; CAD: coronary artery disease; CVA: cerebrovascular accident; AMI: acute myocardial infarction; HF: heart failure; NHIRD: National Health Insurance Research Database. Declarations Acknowledgments We thank the Institute of Occupational Medicine and Industrial Hygiene of the College of Public Health at the National Taiwan University for the data acquisition. We are also grateful to the Health Information and Epidemiology Laboratory of the Chang Gung Memorial Hospital (Chia-yi Branch) for the comments and assistance in data analysis. In addition, this study was supported by a grant from the Chang Gung Memorial Hospital (Chia-yi Branch) (CLRPG6G0041) and based on the NHIRD provided by the Bureau of National Health Insurance, Department of Health, Taiwan. The retrieved data were analyzed and interpreted for academic purposes; therefore, the viewpoint presented in this study is not representative of the Bureau of National Health Insurance, Department of Health, or National Health Research Institutes. Authors’ contributions PHS and HJC participated in the study design, data acquisition and analysis, as well as manuscript drafting. FTK, FJH, YJL, and YTS were responsible for the data acquisition and troubleshooting. YHY and JYC participated in the data analysis and interpretation. KCL conceived the study and coordinated all research efforts. All authors read and approved the final manuscript. Funding none. Availability of data and materials The datasets used and/or analyzed during the current study are provided by the corresponding author on a reasonable request. Ethics approval and informed consent The study design and protocol were approved by the Institutional Review Board of Chang Gung Memorial Hospital (No. 201800664B1). The informed consent was waived due to delinked database. Consent for publication Not applicable Competing interests All authors report no conflict of interest. References Bulletti C, Coccia ME, Battistoni S, Borini A. Endometriosis and infertility. J Assist Reprod Genet. 2010;27(8):441-447. Culley L, Law C, Hudson N, Denny E, Mitchell H, Baumgarten M, Raine-Fenning N. 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Thyroid hormones and cardiovascular disease. Nat Rev Cardiol. 2017;14(1):39-55. Mostaejeran F, Hamoush Z, Rouholamin S. Evaluation of antimullerian hormone levels before and after laparoscopic management of endometriosis. Adv Biomed Res. 2015;4:182. Streuli I, de Ziegler D, Gayet V, Santulli P, Bijaoui G, de Mouzon J, Chapron C. In women with endometriosis anti-Mullerian hormone levels are decreased only in those with previous endometrioma surgery. Hum Reprod. 2012;27(11):3294-3303. Santoro L, D'Onofrio F, Campo S, Ferraro PM, Flex A, Angelini F, Forni F, Nicolardi E, Campo V, Mascilini F et al . Regression of endothelial dysfunction in patients with endometriosis after surgical treatment: a 2-year follow-up study. Hum Reprod. 2014;29(6):1205-1210. Cea Soriano L, López-Garcia E, Schulze-Rath R, Garcia Rodríguez LA. Incidence, treatment and recurrence of endometriosis in a UK-based population analysis using data from The Health Improvement Network and the Hospital Episode Statistics database. The European Journal of Contraception & Reproductive Health Care. 2017;22(5):334-343. Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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-6444","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":260230,"identity":"ffa464f0-c1bf-4603-a3e1-33ea66ef79fc","order_by":1,"name":"Hsin-Ju Chiang","email":"","orcid":"","institution":"Chang Gung Memorial Hospital Kaohsiung Branch","correspondingAuthor":false,"prefix":"","firstName":"Hsin-Ju","middleName":"","lastName":"Chiang","suffix":""},{"id":260231,"identity":"907e8cc8-5957-4aea-8df8-caaf021eaa91","order_by":2,"name":"Kuo-Chung Lan","email":"","orcid":"","institution":"Chang Gung Memorial Hospital Kaohsiung Branch","correspondingAuthor":false,"prefix":"","firstName":"Kuo-Chung","middleName":"","lastName":"Lan","suffix":""},{"id":260232,"identity":"f77dd667-51ec-40b9-bd9c-7d468672094c","order_by":3,"name":"Yao-Hsu Yang","email":"","orcid":"","institution":"Chiayi Chang Gung Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yao-Hsu","middleName":"","lastName":"Yang","suffix":""},{"id":260233,"identity":"17cec038-97fd-4431-a2ee-cbf2740e611d","order_by":4,"name":"John Y. Chiang","email":"","orcid":"","institution":"Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"Y.","lastName":"Chiang","suffix":""},{"id":260234,"identity":"e827593b-aa12-40ce-aaa4-04ec61564aaf","order_by":5,"name":"Fu-Tsai Kung","email":"","orcid":"","institution":"Chang Gung Memorial Hospital Kaohsiung Branch","correspondingAuthor":false,"prefix":"","firstName":"Fu-Tsai","middleName":"","lastName":"Kung","suffix":""},{"id":260235,"identity":"7e90b29c-56ce-4626-9edd-248d6bf066f0","order_by":6,"name":"Fu-Jen Huang","email":"","orcid":"","institution":"Chang Gung Memorial Hospital Kaohsiung Branch","correspondingAuthor":false,"prefix":"","firstName":"Fu-Jen","middleName":"","lastName":"Huang","suffix":""},{"id":260236,"identity":"cb73e59e-925f-46ef-a7f9-c330fc552856","order_by":7,"name":"Yu-Ju Lin","email":"","orcid":"","institution":"Chang Gung Memorial Hospital Kaohsiung Branch","correspondingAuthor":false,"prefix":"","firstName":"Yu-Ju","middleName":"","lastName":"Lin","suffix":""},{"id":260237,"identity":"2245fa5a-6f76-4770-a75b-e6ea327dfe4e","order_by":8,"name":"Yu-Ting Su","email":"","orcid":"","institution":"Chang Gung Memorial Hospital Kaohsiung Branch","correspondingAuthor":false,"prefix":"","firstName":"Yu-Ting","middleName":"","lastName":"Su","suffix":""},{"id":260238,"identity":"1fd0b0f1-426e-4e54-b81b-55c33edb1006","order_by":9,"name":"Pei-Hsun Sung","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2klEQVRIie3SsQrCMBCA4SsBuxx0VQrmFS6Lk+hbOEcEpyI+gIrgKrgG+hK6O6QEdFIfoIOdnOOkg4Oli1tbN8H8HCRDPrghAC7XL8ZYklnq5jesS/zGSKjp+EOqZYCdEK35ggQMqKXowvngpOG+n0O/KctJawWSLKVil06kp25HwCpCBvRQUSpFHBFDfQAMK0jfeEuDdP6CEGPeCklLHhZkVk2apsE8RSOxzUmitEa8ZuUk2FweT/vqcR5HIrN60fbXupx8Nswf5mNq/wEAviyORX3hcrlcf9MbfipB5gLG0C4AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-1989-9752","institution":"Chang Gung Memorial Hospital Kaohsiung Branch","correspondingAuthor":true,"prefix":"","firstName":"Pei-Hsun","middleName":"","lastName":"Sung","suffix":""}],"badges":[],"createdAt":"2019-10-02 20:37:43","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.2.15783/v2","doiUrl":"https://doi.org/10.21203/rs.2.15783/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":280789,"identity":"e9b56e87-c23e-4b9f-9120-14017d34d205","added_by":"auto","created_at":"2019-12-19 11:41:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":500598,"visible":true,"origin":"","legend":"Flowchart of patient screening, enrollment, and assignment for the EM and matched non-EM groups. The non-EM group was selected by matching the EM group with age and socioeconomic background in a 4:1 ratio after excluding major CVD and CVA before the diagnosis of endometriosis and patients aged \u003c 18 or \u003e 50. Abbreviations: EM, endometriosis; CVD, cardiovascular disease; CVA, cerebrovascular accident.","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/0d9a5939-24e9-4766-b853-4842d69f05f0/v2/Figure 1.jpg"},{"id":280790,"identity":"c6d7869f-7f24-4cab-9f4a-f2d589823b4a","added_by":"auto","created_at":"2019-12-19 11:41:37","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":583232,"visible":true,"origin":"","legend":"Cumulative incidence of MACCE (2A), major CVD (2B), and CVA (2C) in the EM versus non-EM groups. Abbreviations: EM, endometriosis; MACCE, major adverse cardiovascular and cerebrovascular events; CVD, cardiovascular disease; CVA, cerebrovascular accident.","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/0d9a5939-24e9-4766-b853-4842d69f05f0/v2/Figure 2.jpg"},{"id":280791,"identity":"1d6ab5ad-3f37-444d-91ec-953a4b8825b0","added_by":"auto","created_at":"2019-12-19 11:41:37","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":221718,"visible":true,"origin":"","legend":"Cumulative incidence of MACCE in the endometriosis subgroups, namely the no treatment, medical treatment, surgical treatment, or combined treatment groups. Abbreviations: EM, endometriosis; MACCE, major adverse cardiovascular and cerebrovascular events.","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/0d9a5939-24e9-4766-b853-4842d69f05f0/v2/Figure 3.jpg"},{"id":13482638,"identity":"73d9bb49-55a0-4472-a9bb-8fa5a2e00111","added_by":"auto","created_at":"2021-09-16 21:51:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":582389,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6444/v2/8246d83e-85c9-4fcf-9b55-cfeaef2da619.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eEffects of medical and surgical treatment on the risk of major adverse cardiovascular and cerebrovascular events in Asian women with endometriosis\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eEndometriosis, characterized by extrauterine endometrial-like lesions, is a worldwide concern affecting many women of childbearing age. Approximately 10% of the general female population has endometriosis, and nearly 50% of women with infertility are affected by it [1,2]. endometriosis is strongly associated with systemic inflammation, neovascularization, and tissue remodeling [3]. Additionally, a recent study reported that endothelial dysfunction (ED) plays a crucial role in one of the pathological mechanisms underlying endometriosis [4].\u003c/p\u003e\n\u003cp\u003eThe development of atherosclerotic cerebrovascular or cardiovascular disease (CVD), such as vascular dementia, coronary artery disease (CAD), and peripheral vascular disease, is closely related to systemic inflammation and ED [5,6]. Therefore, considering the common pathological pathways of inflammation and ED, the phenomenon that women under emotional stress or with low level of anti-M\u0026uuml;llerian hormone (AMH) are associated with higher risk of CVD has been observed by several studies [7,8]. Recently, data from the US Health Study II registry indicated that the risk of CAD is not only linked to endometriosis but also higher in patients with endometriosis who underwent hysterectomy or oophorectomy [9]. The unfavorable effect of surgical treatment for endometriosis on the risk of CVD raised clinical safety concerns among operators, health care providers, and patients. Furthermore, hormonal treatment strategies for endometriosis [10,11], including gonadotropin-releasing hormone (GnRH) analogs, oral contraceptives, progesterone, and danazol, potentially or controversially increase the cardiovascular risk and yield inconsistent results [7,8,12]. However, whether the aforementioned findings derived from Western countries can be generally applied to the Asian population and whether women with endometriosis receiving medical, surgical, or combined treatment have increased risks of major adverse cardiovascular and cerebrovascular events (MACCE) remain unanswered. Using the Taiwan National Health Insurance Research Database (NHIRD), we studied (1) the risk of MACCE and (2) the impact of endometriosis therapy on MACCE in Asian women with endometriosis.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eIntroduction of the Taiwan NHIRD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Taiwan National Health Insurance program provides health care to 99% of the population of 24 million and is linked to 97% of hospitals and clinics in Taiwan (\u003ca href=\"http://nhird.nhri.org.tw/en/\"\u003ehttp://nhird.nhri.org.tw/en/\u003c/a\u003e) [13]. The NHIRD is a considerable source of information on medical facilities, inpatient and outpatient order details, dental services, drug prescriptions, patient care, and other paramedical registration files (eg, payment, regions, and catastrophic illness), but it does not include laboratory data. Diagnoses are entered based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The NHIRD longitudinal data collection started in 2000, and 1\u0026thinsp;000\u0026thinsp;000 beneficiaries were randomly sampled. The database contains the entire original claims data from 1997 to 2013. The study design and protocol were approved by the Institutional Review Board of Chang Gung Memorial Hospital (No. 201800664B1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe selected female patients with endometriosis (ICD-9-CM code 617) from 1 million individuals in the NHIRD between January 01, 1997 and December 31, 2013 to conduct a retrospective nationwide population-based cohort study. Women aged between 18 and 50 with a record of at least 3 medical visits or 1 admission for endometriosis were included in the study. To confirm the diagnosis of endometriosis, we linked the relevant clinical information with the corresponding vaginal ultrasound, surgical findings, and medications. Those patients with clinically suspicious diagnosis of endometriosis without image- or procedure-proven evidence were not included. We excluded patients aged \u0026lt;18 or \u0026gt;50 years, male patients, patients experiencing menopause (627), patients with missing or incomplete baseline characteristics data, and patients with a follow-up duration of less than 1 year. For the first purpose of the study, that is, the incidental MACCE in women with endometriosis, patients with diagnoses of acute myocardial infarction (AMI; 410-411), heart failure (HF; 428), or cerebrovascular accident (CVA; 430-436) in the beginning or prior to endometriosis were excluded. Thus, we identified a total of 17\u0026thinsp;543 women with endometriosis (EM group) at the beginning of the study.\u003c/p\u003e\n\u003cp\u003eA comparison cohort of 70\u0026thinsp;172 non-endometriosis (non-EM) women was selected from January 01, 1997 and December 31, 2013 after matching the study cohort at a 4:1 ratio with age and socioeconomic background, including income and urbanization level (Fig. 1). Urbanization was categorized into 4 levels, from level 1 indicating the least urbanized level (country) to level 4 indicating the most urbanized level (city). The insurance taxable income level was stratified into 4 categories based on the monthly insurance payment of each insured participant (ie, level 1: none; level 2: 1-15 840; level 3: 15 841-25\u0026thinsp;000; and level 4: \u0026gt; 25\u0026thinsp;000 New Taiwan dollars per month).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinition\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe MACCE were divided into 2 disease entities, namely CVD and CVA. Major CVD involved AMI or HF. CVA encompassed acute ischemic (433-436) or hemorrhagic stroke (430-432). Moreover, information on medications was acquired based on the World Health Organization Anatomical Therapeutic Chemical classification (WHO ATC codes) system. Medical treatment for endometriosis comprised danazol, gestrinone, oral contraceptives, and GnRH agonists. Patients with prescriptions exceeding a month were considered medication users. By contrast, we considered patients with a regimen duration of less than a month as nonusers, because drugs might have been prescribed temporarily for symptomatic relief, diagnostic test, or purposes other than standard treatment for endometriosis. Surgical treatment for endometriosis mainly consisted of therapeutic laparotomy and laparoscopy (ICD-9-CM procedure codes 541 and 542). The time frame of medical and surgical treatment was from the diagnosis of endometriosis to the end of follow-up.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIdentification of symptoms, comorbidities, location, and outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a retrospective longitudinal study. The date of initial diagnosis of endometriosis was defined as the index date. To clarify the association between MACCE and endometriosis, potential risk factors for MACCE and possible confounders were retrieved for further analysis. We assessed gynecological presentations and relevant comorbidities for each patient during the follow-up period (from the diagnosis of endometriosis to the end of study), including dysmenorrhea (ICD-9-CM code 625.3), amenorrhea (ICD-9-CM code 626.0), infertility (ICD-9-CM code 628), ovarian cancer (ICD-9-CM code 183), hypertension (ICD-9-CM codes 401-405), diabetes (ICD-9-CM code 250), dyslipidemia (ICD-9-CM code 272), gout (ICD-9-CM code 274), chronic ischemic heart disease (ICD-9-CM codes 412-414 and 429.2), peripheral vascular disease (ICD-9-CM codes 440, 443.9, 444.0, 444.2, 444.8, 444.9, 447.8, 447.9, 445.0, and 445.02), atrial fibrillation (ICD-9-CM code 427.31), and chronic kidney disease (ICD-9-CM code 585). Endometriosis was further divided into ovarian and extraovarian groups according to its occurrence location.\u003c/p\u003e\n\u003cp\u003eWith respect to study outcomes, the day of the first event occurrence was defined as the event date. The diagnosis of MACCE, including AMI, HF, and CVA, was confirmed by 3 consecutive records of outpatient visits or a one-time diagnosis on admission with the corresponding standard treatment during the whole study period. Endpoints between the 2 groups were censored, whereas clinical events were identified by ICD-9-CM codes and the event date. We investigated the frequency and incidence of MACCE in both EM and non-EM Asian groups. Additionally, we analyzed whether the risk of MACCE was higher in the EM group than in the normal population in Asian women. Furthermore, we studied the differences in the risk of MACCE among diseased population according to none, surgical alone, medical alone, or combination treatment for endometriosis.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ratios of demographic data and comorbidities between the study cohort (EM group) and the matched control cohort (non-EM group) were compared using the independent \u003cem\u003et\u003c/em\u003e test and chi-square test, as appropriate. The incidence rates and 95% CIs of MACCE were calculated for the entire follow-up period. We also examined the outcomes of MACCE and stratified them by subgroups according to age, amenorrhea diagnosis, and comorbidities. Additionally, the Kaplan\u0026ndash;Meier method was used to estimate the cumulative incidences, and a log-rank test was performed to examine differences between disease and non-disease groups. Using Cox proportional hazards regression models, we analyzed hazard ratios (HRs) and corresponding 95% CIs after adjusting for age, medications, surgery types, and associated comorbidities. To further understand the effect of surgical or medical treatment for endometriosis, a multivariate Cox regression model was used to examine the adjusted HRs of endometriosis for the occurrence of MACCE in the subgroups. A two-tailed \u003cem\u003eP\u003c/em\u003e value of \u0026lt;.05 was considered statistically significant. All analyses were conducted using the SAS statistical software program (Version 9.4; SAS Institute, Cary, NC, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eDemographic data and outcomes in women with and without \u003c/strong\u003e\u003cstrong\u003eendometriosis (Table 1)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOver the 17-year dataset period, there were a total of 17 543 and 70 172 eligible patients in the EM and non-EM group, respectively. More than 60% of women with endometriosis were aged between 35 and 50 years with a median age of 38 years. The frequencies of irregular menstruation, infertility, and ovarian cancer were higher in the EM group than in the non-EM group. Approximately 13% of endometriosis cases were detected in the ovaries alone. A majority of women in the EM group had endometriosis in both ovarian and extraovarian locations. Approximately 1 in 5 patients with endometriosis received regular medical or standard surgical treatment for endometriosis. The EM group had a significantly higher prevalence of comorbidities compared with its non-EM counterpart, except for atrial fibrillation and chronic kidney disease.\u003c/p\u003e\n\u003cp\u003eThe mean follow-up duration was 9.3 years. At the end of the study, the frequency of MACCE in patients with endometriosis and without endometriosis was 2.76% and 2.18%, respectively. Therefore, the frequency of MACCE, including major CVD and CVA, was significantly higher in the EM group than in the non-EM group (all \u003cem\u003eP\u003c/em\u003e values \u0026lt; .002). However, the all-cause mortality rate was approximately 1% and did not significantly differ between groups.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIncidence and risk of MACCE in women with \u003c/strong\u003e\u003cstrong\u003eendometriosis and without endometriosis (Table 2 and Fig. 2)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe incidence rate of MACCE in patients with and without endometriosis was 300.0 and 235.5 per 100,000 person-years, respectively, amounting to an incidence rate ratio of MACCE in the EM group to MACCE in the non-EM group of 1.27 (95% CI 1.15-1.41; \u003cem\u003eP\u003c/em\u003e \u0026lt; .001). After adjustment for age, socioeconomic background, and associated comorbidities, women with endometriosis had a 1.17-fold increased risk of MACCE compared to women without (95% CI = 1.05-1.29; \u003cem\u003eP\u003c/em\u003e = .005). Additionally, the Kaplan\u0026ndash;Meier curve demonstrated that the EM group had a higher cumulative incidence of MACCE compared with the non-EM group (\u003cem\u003eP\u003c/em\u003e \u0026lt; .001 in the log-rank test). Looking deeply, the cumulative incidence of major CVD and CVA between groups displayed a similar pattern to that of MACCE (Fig. 2).\u003c/p\u003e\n\u003cp\u003eThe findings of the stratified analysis revealed that the adjusted HRs of MACCE in the endometriosis cohort to the non-endometriosis cohort were significantly higher in the subgroups of patients aged 35 to 50 years and without conventional atherosclerotic risk factors (ie, hypertension, diabetes, dyslipidemia, and gout). Nevertheless, the adjusted HRs did not change significantly for patients with amenorrhea and those experiencing premature menopause, which suggested that the risk of MACCE might be higher for those relatively healthy middle-aged Asian women with endometriosis, regardless of their menstrual presentation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssociation between MACCE and \u003c/strong\u003e\u003cstrong\u003eendometriosis (Table 3)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUsing a multivariate Cox regression model with adjustment for age, urbanization/income, and conventional atherosclerotic risk factors, we observed that apart from endometriosis, age between 35 and 50 years, higher urbanization and income levels, hypertension, and diabetes were significantly associated with MACCE. Moreover, endometriosis was identified to be related to both major CVD and CVA.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEffects of medical and surgical treatment on clinical outcomes (Fig. 3 and Table 4)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproximately 20% of patients with endometriosis received medical or surgical therapy. To clarify the effect of various endometriosis treatment strategies on the occurrence of MACCE, we divided the EM group into 4 subgroups according to whether they received surgical or medical treatment. Fig. 3 indicates that the cumulative incidence of MACCE was the highest in the endometriosis subgroup without any treatment and significantly lower in the subgroups of patients who received medical, surgical, or combined treatment (\u003cem\u003eP\u003c/em\u003e \u0026lt; .001 in the log-rank test). However, there was no significant difference in MACCE among the aforementioned 3 subgroups.\u003c/p\u003e\n\u003cp\u003eWe further adjusted for procedures and medications apart from the aforementioned potential confounders in a multivariate analysis of these women with endometriosis. Findings indicated that women who were aged \u0026ge;35 years and had a higher urbanization level, hypertension, and diabetes were closely associated with MACCE in endometriosis as expected. In addition, there was no safety concern regarding the increase of the risk of MACCE in surgical treatment of endometriosis. Medical treatment alone appeared to be associated with a significantly decreased MACCE risk. The occurrence of MACCE in combined medical and surgical treatment for endometriosis did not further increase compared with that in conservative therapy, i.e., no treatment or only pain killer for symptomatic relief of endometriosis.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study that used the Taiwan NHIRD to investigate the association between EM and MACCE and the effect of endometriosis treatment on the risk of MACCE in the Asian population yielded several relevant clinical findings. First, the risk of MACCE, including AMI, HF, and CVA, was found higher in the Asian women with endometriosis than in those without. Second, after multivariate adjustment, endometriosis women had an approximately 1.2-time increased risk of MACCE throughout their early life. Third, surgical and medical treatment for endometriosis did not present a risk of increased MACCE incidence. Furthermore, Asian endometriosis women treated only with medication appeared to have a lower risk of MACCE compared with those who received surgical or combined treatment.\u003c/p\u003e\n\u003cp\u003eThis large-scale nationwide population-based cohort study identified the association between endometriosis and MACCE as well as the influence of endometriosis-associated medical/surgical therapies on cardiovascular events in the Asian population. The increased risk of MACCE after surgical treatment of endometriosis reported in a previous publication [9] was not observed in our study. Asian women with endometriosis could be considered with medical treatment first and then with surgical intervention or combination therapy later, because we did not find an increased risk of MACCE in the subgroups of medical or surgical therapy as compared with that in the no-treatment subgroup. Our findings, therefore, suggested a safer management strategy not only for endometriosis per se but also for preventing future occurrence of MACCE in these relatively young and healthy women.\u003c/p\u003e\n\u003cp\u003eThe link between systemic inflammation and ED has been well documented for several decades [4,14]. Furthermore, abundant evidence has supported the relationship among ED, arterial atherosclerosis, and acute arterial occlusive diseases (eg, acute stroke, AMI, and critical limb ischemia) [15-18]. Although the causal relationship between ED and CVD is complex, they are undoubtedly linked with an unfavorable prognostic outcome [5]. Similarly, the underlying mechanisms of endometriosis have been proposed to be multifactorial and multifaceted and to include genetic and environmental factors, stem cell theory, vasculogenesis, neurohormonal dysregulation, and autoimmune dysfunction [19-21]. Recently, increasing data have demonstrated that the strong association between endometriosis and ED can be attributed to abnormal vasculogenesis from endothelial progenitor cells to the microvascular endothelium of ectopic endometrial tissue rather than to the normal angiogenesis process [20]. Additionally, endometriosis is recognized as a disabling disease owing to chronic pelvic pain, dysmenorrhea, dyspareunia, and dysuria, thus severely affecting quality of life [22]. Patients with intractable endometriosis experience painful symptoms or psychological and emotional stress, which further increases the risk of future CVD [7]. Therefore, these findings [15-21] raised the hypothesis that endometriosis and MACCE share a common pathological pathway and disease mechanism of inflammation, ED, and emotional or physical stress from frequent dysmenorrhea. In the present study, not only were the frequency and incidence of MACCE higher in Asian women with endometriosis than in those without, but endometriosis also appeared to be independently associated with major CVD and CVA. The aforementioned hypotheses were verified by the present real-world analytic results. In addition to age between 35 and 50 years and conventional atherosclerotic (or CAD) risk factors, endometriosis might be considered as another risk factor for MACCE.\u003c/p\u003e\n\u003cp\u003eSantoro et al addressed a similar issue regarding the relationship between endometriosis and atherosclerosis [23]. Verit et al also reported that the risk of CVD may increase in women with unexplained infertility [24]. Furthermore, the causes of female infertility include polycystic ovarian syndrome, obesity, thyroid function, and endometriosis [25,26], and all these factors strongly influence CVD outcomes [27-29]. Therefore, our finding regarding MACCE in endometriosis is not only consistent with previous clinical observations but also compatible with their pathological hypotheses. However, the causal relationship between endometriosis and CVD through the possible mechanism of inflammation and ED as well as associated mediators deserves further investigation. de Kat et al [8] demonstrated the negative correlation of the AMH level with an increased CVD risk. The level of AMH, an indicator of ovarian preservation, remarkably decreased after surgical or laparoscopic treatment for endometriosis [30,31]. Therefore, the aforementioned phenomena could, at least in part, explain why the CVD risk notably increased after surgery for endometriosis in a recent observational study [3]. Unfortunately, the level of AMH was unavailable in the present study; therefore, we could not analyze the association among AMH, endometriosis surgery, and CVD risk. Data from the present study based on the Asian population revealed that endometriosis patients treated with surgery or combined therapy did not have a higher risk of MACCE than those who did not receive treatment. Therefore, the effect of endometriosis surgery on the risk of MACCE might not be a cause for concern. Our finding was supported by results reported by Santoro et al [32] according to which surgical treatment of endometriosis can lead to the regression of ED, and an improved cardiovascular outcome from surgery is predictable. Taken together, the results of the current study suggested that surgical intervention for endometriosis might adversely affect the ovarian function but may not be considered as a risk factor for MACCE. Based on the results of the current study, which demonstrated lower MACCE risks in endometriosis patients receiving medications only, medical treatment followed by surgical management might be a therapeutic option of endometriosis.\u003c/p\u003e"},{"header":"Limitations","content":"\u003cp\u003eOur study has several limitations. First, the detailed personal history and lifestyle of patients, such as smoking or alcohol abuse, body mass index, and functional capacity, were not provided in the Taiwan NHIRD. This weakness was overcome by matching the socioeconomic level at baseline. Second, all diagnoses and management of endometriosis in the present study were retrieved according to registered ICD-9-CM codes; therefore, the staging or severity of endometriosis and procedural details are lacking. Third, laboratory data including the AMH level or other inflammatory biomarkers are not available in the NHIRD. Fourth, compared with the therapeutic rate of over 50% for endometriosis in a UK-based population [33], data from the current study Asian cohort revealed a surgical or medical treatment rate for endometriosis of 20% only. This is because Taiwanese endometriosis women usually do not like to seek medical aid or receive relevant treatment until the relevant symptoms become more severe. Therefore, we are unsure whether the results of this Taiwanese population-based study can be applied to the clinical practice worldwide and vice versa. Thus, the effect of endometriosis treatment on the incidence of MACCE deserves further investigation through a well-designed prospective study. Finally, the type of medication used for cardiovascular protection (eg, antihypertensive medicine and antidiabetic or lipid-lowering agents) could not be obtained from the NHIRD. Therefore, the effect of medications beyond standard treatment for endometriosis on the occurrence of MACCE was not fully investigated. Exploring the medications with potential benefit to reduce CVD risks paves the way for future studies.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAsian endometriosis women had a higher prevalence of comorbidities than the matched general population and might increase the risk of MACCE, especially for those aged between 35 and 50 years and relatively healthy. In addition, endometriosis can be safely treated with surgery alone or a combined medical and surgical therapy because no safety concern was raised regarding a further increase in the MACCE risk.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eEM: endometriosis; MACCE: major adverse cardiovascular and cerebrovascular events; CVD: cardiovascular disease; CAD: coronary artery disease; CVA: cerebrovascular accident; AMI: acute myocardial infarction; HF: heart failure; NHIRD: National Health Insurance Research Database.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the Institute of Occupational Medicine and Industrial Hygiene of the College of Public Health at the National Taiwan University for the data acquisition. We are also grateful to the Health Information and Epidemiology Laboratory of the Chang Gung Memorial Hospital (Chia-yi Branch) for the comments and assistance in data analysis. In addition, this study was supported by a grant from the Chang Gung Memorial Hospital (Chia-yi Branch) (CLRPG6G0041) and based on the NHIRD provided by the Bureau of National Health Insurance, Department of Health, Taiwan. The retrieved data were analyzed and interpreted for academic purposes; therefore, the viewpoint presented in this study is not representative of the Bureau of National Health Insurance, Department of Health, or National Health Research Institutes.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePHS and HJC participated in the study design, data acquisition and analysis, as well as manuscript drafting. FTK, FJH, YJL, and YTS were responsible for the data acquisition and troubleshooting. YHY and JYC participated in the data analysis and interpretation. KCL conceived the study and coordinated all research efforts. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003enone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are provided by the corresponding author on a reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and informed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study design and protocol were approved by the Institutional Review Board of Chang Gung Memorial Hospital (No. 201800664B1). The informed consent was waived due to delinked database.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors report no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBulletti C, Coccia ME, Battistoni S, Borini A. Endometriosis and infertility. J Assist Reprod Genet. 2010;27(8):441-447.\u003c/li\u003e\n\u003cli\u003eCulley L, Law C, Hudson N, Denny E, Mitchell H, Baumgarten M, Raine-Fenning N. The social and psychological impact of endometriosis on women's lives: a critical narrative review. Hum Reprod Update. 2013;19(6):625-639.\u003c/li\u003e\n\u003cli\u003eWu M-H, Hsiao K-Y, Tsai S-J. Endometriosis and possible inflammation markers. 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Anti-M\u0026uuml;llerian hormone trajectories are associated with cardiovascular disease in women: results from the Doetinchem cohort study. Circulation. 2017;135(6):556-565.\u003c/li\u003e\n\u003cli\u003eMu F, Rich-Edwards J, Rimm EB, Spiegelman D, Missmer SA. Endometriosis and Risk of Coronary Heart Disease. Circ Cardiovasc Qual Outcomes. 2016;9(3):257-264.\u003c/li\u003e\n\u003cli\u003ePatel B, Elguero S, Thakore S, Dahoud W, Bedaiwy M, Mesiano S. Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Hum Reprod Update. 2015;21(2):155-173.\u003c/li\u003e\n\u003cli\u003eWellbery C. Diagnosis and treatment of endometriosis. Am Fam Physician. 1999;60(6):1753-1762, 1767-1758.\u003c/li\u003e\n\u003cli\u003eFarley TM, Meirik O, Collins J. Cardiovascular disease and combined oral contraceptives: reviewing the evidence and balancing the risks. Hum Reprod Update. 1999;5(6):721-735.\u003c/li\u003e\n\u003cli\u003eCheng T-M. 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Adv Biomed Res. 2015;4:182.\u003c/li\u003e\n\u003cli\u003eStreuli I, de Ziegler D, Gayet V, Santulli P, Bijaoui G, de Mouzon J, Chapron C. In women with endometriosis anti-Mullerian hormone levels are decreased only in those with previous endometrioma surgery. Hum Reprod. 2012;27(11):3294-3303.\u003c/li\u003e\n\u003cli\u003eSantoro L, D'Onofrio F, Campo S, Ferraro PM, Flex A, Angelini F, Forni F, Nicolardi E, Campo V, Mascilini F\u003cem\u003e et al\u003c/em\u003e. Regression of endothelial dysfunction in patients with endometriosis after surgical treatment: a 2-year follow-up study. Hum Reprod. 2014;29(6):1205-1210.\u003c/li\u003e\n\u003cli\u003eCea Soriano L, L\u0026oacute;pez-Garcia E, Schulze-Rath R, Garcia Rodr\u0026iacute;guez LA. Incidence, treatment and recurrence of endometriosis in a UK-based population analysis using data from The Health Improvement Network and the Hospital Episode Statistics database. The European Journal of Contraception \u0026amp; Reproductive Health Care. 2017;22(5):334-343.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Endometriosis, Major adverse cardiovascular and cerebrovascular events, Population-based cohort study, Medical and surgical treatment","lastPublishedDoi":"10.21203/rs.2.15783/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.15783/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background: Endometriosis is linked to major adverse cardiovascular and cerebrovascular events (MACCE). However, whether this finding can be applied to the Asian population remained unanswered. Additionally, results are still inconsistent for the impact of endometriosis treatment on incidental MACCE. Thus, we intended to investigate the association between endometriosis and MACCE, and study the effect of endometriosis therapies on the risk of MACCE among Asian women.\nMethods: The Taiwan National Health Insurance Research Database was used for this retrospective population-based cohort study from 1997 to 2013. A total of 17 543 patients with endometriosis aged between 18 and 50 years were identified from a general population of 1 million after excluding diagnoses of major cardiovascular disease (CVD) and cerebrovascular accident (CVA) prior to endometriosis. The comparison group (n = 70 172) without endometriosis was selected by matching the study cohort with age, sex, and income and urbanization levels in a 4:1 ratio. Demographic data and the frequency of comorbidities between groups were compared using the independent t test and chi-square test. The incidence and risk of MACCE were analyzed using the log-rank test and a multivariate Cox proportional hazards model.\nResults: During a median follow-up period of 9.2 years, Asian women with endometriosis had a significantly higher frequency of comorbidities, medical and surgical treatment, and MACCE than did their non-endometriosis counterparts (2.76% vs 2.18%, P \u003c .001). After adjustment for comorbidities, patients with endometriosis had an approximately 1.2-fold increased risk of MACCE (95% CI 1.05-1.29; P = .005) and a higher cumulative incidence of MACCE compared with the normal population. Among women with endometriosis, neither medical nor surgical treatment increased the risk of MACCE, including major CVD and CVA. Furthermore, medical treatment for endometriosis appeared to be protective against MACCE in the endometriosis females.\nConclusion: Asian women with endometriosis not only had a higher frequency of comorbidities but also an increased risk of MACCE compared with the general population. In addition, the safety concern about medical or surgical treatment of endometriosis on the risk of MACCE was not evident in this study.","manuscriptTitle":"Effects of medical and surgical treatment on the risk of major adverse cardiovascular and cerebrovascular events in Asian women with endometriosis","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2019-12-19 11:41:36","doi":"10.21203/rs.2.15783/v2","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}},{"code":1,"date":"2019-10-09 21:59:32","doi":"10.21203/rs.2.15783/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":"da4311ed-0ac7-4ac8-9263-0e79df98fca4","owner":[],"postedDate":"December 19th, 2019","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":30823,"name":"Preventive Medicine"}],"tags":[],"updatedAt":"","versionOfRecord":[],"versionCreatedAt":"2019-12-19 11:41:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-6444","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-6444","version":["v2"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}