Risk of cardiovascular disease and mortality among women with endometriosis: A systematic review and meta-analysis

All authors contributed to the conception or the design of the work. Iphigénie Cavadias and Geneviève Plu‐Bureau: Data extraction, methodology, statistical analyses and Iphigénie Cavadias: Write the original draft. Lorraine Maitrot‐Mantelet, Sandrine Perol, Mathilde Bourdon, Pietro Santulli, Louis Marcellin and Charles Chapron: Critically revised the manuscript. Iphigénie Cavadias and Geneviève Plu‐Bureau: Drafted the final version. All authors gave final approval and agreed to be accountable for all aspects of the work ensuring integrity and accuracy.

The systematic retrieval process to identify eligible studies is summarized in Figure  1 . A total of 1417 references were identified. Of these, 228 duplicates were removed, and 1189 were excluded after review of the titles and abstracts, leaving 31 articles for full‐text screening. After full‐text assessment, 12 articles were included in this review. All 12 were cohort studies. 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 Flowchart of eligible studies. In total, 12 studies were included in this review. Four studies were conducted in the United States, 23 , 29 , 30 , 33 one in Finland, 24 three in Taiwan, 25 , 27 , 28 one in the United Kingdom, 26 two in Canada, 31 , 34 and one in Denmark. 32 Five studies analyzed stroke, 25 , 26 , 29 , 32 , 34 four analyzed all‐cause mortality, 24 , 26 , 32 , 33 and two analyzed specific cardiovascular mortality. 24 , 33 Six studies analyzed coronary heart disease 23 , 26 , 27 , 28 , 30 , 32 but two of them analyzed the same database (Taiwan National Health Insurance Research Database) during the same period (2000–2012) and with the same outcome (coronary heart disease), 27 , 28 and two others analyzed the same database (Nurses' Health Study II) during almost the same period and with the same outcome (coronary heart disease). 23 , 30 For coronary heart disease outcome, data were chosen from Wei et al. 27 instead of Li et al. 28 and from Mu et al. 23 instead of Powell et al. 30 because models were adjusted on more variables. Four analyzed composite cardiovascular disease, one of them, including acute myocardial infarction, heart failure, ischemic, or hemorrhagic stroke 25 ; one of them, including ischemic heart disease, heart failure, and cerebrovascular disease 26 ; one of them, including hospital admission for acute myocardial infarction, stroke, congestive heart failure, percutaneous coronary intervention, coronary artery bypass graft surgery, ischemic heart disease, or cerebrovascular disease, 31 and one of them, including acute myocardial infarction and ischemic stroke. 32 Endometriosis was laparoscopically confirmed in five studies, 23 , 24 , 29 , 30 , 33 radiologically or laparoscopically confirmed in three studies, 25 , 27 , 28 and laparoscopically or based on clinical suspicion in three studies. 26 , 31 , 34 Two studies analyzed the same database (Nurses' Health Study II) but within different periods and different outcomes. 23 , 29 Two studies analyzed the same database (administrative health data from the Ontario Health Insurance Plan) but different outcomes. 31 , 34 All studies performed outcome adjustments, but adjustments were different. All studies were adjusted for age and most of them adjusted for cardiovascular risk factors but the confounding factors taken into account were not the same. More details about the characteristics of the studies are presented in Table  2 . Characteristics of the studies assessing the risk of cardiovascular diseases or mortality in patients diagnosed with endometriosis and risks (95% CI). Saavalainen, 2019 24 Age, income and conventional atherosclerotic risk factors (hypertension, diabetes, dyslipidemia, and gout) Registers Population‐based cohort study, The Health Improvement Network database Abbreviations: BMI, body mass index; HR, hazard ratio; NA, not applicable; NSAID, non‐steroidal anti‐inflammatory drugs; PCOS, polycystic ovary syndrome; RR, relative risk. Five studies reported data about the risk of stroke. 25 , 26 , 29 , 32 , 34 The pooled estimated OR for stroke risk associated with endometriosis was 1.18 (95% CI [1.13–1.22]). The test for heterogeneity was not significant ( p  = 0.64, I 2 = 0%) (Figure  2 ). Forest plot for the risk of stroke and coronary heart disease (odds ratio [ORs] and 95% confidence intervals) associated with endometriosis. Four studies reported data about the risk of coronary heart disease. 23 , 26 , 27 , 32 The pooled estimated OR for coronary heart disease risk associated with endometriosis was 1.36 (95% CI [1.32–1.40]). The test for heterogeneity was not significant ( p  = 0.55, I 2 = 0%) (Figure  2 ). Four studies reported data about the risk of composite cardiovascular disease. 25 , 26 , 31 , 32 The pooled estimated OR for composite cardiovascular disease risk associated with endometriosis was 1.16 (95% CI [1.12–1.20]). The test for heterogeneity was not significant ( p  = 0.49, I 2 = 0%) (Figure  3 ). Forest plot for the risk of composite cardiovascular disease (odds ratio [ORs] and 95% confidence intervals) associated with endometriosis. Four studies reported data about the risk of all‐cause mortality. 24 , 26 , 32 , 33 The pooled estimated OR for all‐cause mortality risk associated with endometriosis was 0.88 (95% CI [0.65–1.18]). Although data were very heterogeneous ( I 2 = 97.8%) (Figure  4 ) because three studies reported that endometriosis was associated with decreased all‐cause mortality 24 , 26 , 32 and the most recent study reported that endometriosis was associated with increased all‐cause mortality. 33 Forest plot for the risk of all‐cause mortality (odds ratio [ORs] and 95% confidence intervals) associated with endometriosis. Only two studies reported data about the risk of specific cardiovascular mortality. 24 , 33 The pooled estimated OR for specific cardiovascular mortality risk associated with endometriosis was 0.78 (95% CI [0.40–1.51]). Data were also very heterogeneous ( I 2 = 91%) because one study reported a non‐significantly increased risk of cardiovascular mortality with endometriosis at 1.12 (95% CI [0.77–1.63]), 33 and one study reported a decreased risk of cardiovascular mortality at 0.57 (95% CI [0.50–0.65]). 24 The adjustments for cardiovascular risk factors differ across studies. Including only studies adjusted for high blood pressure, diabetes, and dyslipidemia and/or BMI, three studies reported data about the risk of stroke with a pooled risk of 1.15 (95% CI [1.08–1.23]), 25 , 26 , 34 two studies reported data about the risk of coronary heart disease with a pooled risk of 1.44 (95% CI [1.28–1.61]), 26 , 27 three studies reported data about the risk of composite cardiovascular disease with a pooled risk of 1.18 (95% CI [1.12–1.24]), 25 , 26 , 31 and only one study reported data about the risk of all‐cause mortality with a risk of 0.66 (95% CI [0.59–0.74]). 26 In sensitivity analyses excluding studies with non‐surgical diagnoses, only one study assessed an increased risk of stroke in women monitored for endometriosis at 1.34 (95% CI 1.10–1.62). 29 Regarding the risk of coronary heart disease, only two studies included women with laparoscopic diagnosis of endometriosis, and both studies analyzed the same database (Nurses' Health Study II) during almost the same period, with risks of 1.52 (95% CI 1.17–1.98) and 1.45 (95% CI 1.27–1.65). 23 , 30 Regarding cardiovascular mortality risks, the two studies presented included only women with laparoscopic diagnosis of endometriosis. 24 , 33 Regarding bias evaluation through the Newcastle‐Ottawa Scale, detailed information can be found in Table  1 . The risk of bias was medium in nine cohort studies. 23 , 25 , 26 , 27 , 28 , 29 , 30 , 32 , 33 Four cohorts were classified as fair‐quality because they lacked representativeness of the exposed cohort (only included registered nurses). 23 , 29 , 30 , 33 Three cohorts accepted the ascertainment of the exposure as based on clinical suspicion. 26 , 31 , 34 In two cohorts, the control for major confounders did not meet the established criteria. 24 , 33 Three cohorts 24 , 31 , 34 were classified as poor quality for the reasons explained above. The small number of studies for each outcome failed to provide enough information to distinguish chance from real asymmetry/publication bias. The asymmetry in the funnel plot on all‐cause mortality means that these results should be interpreted with caution. The funnel plots are shown at Figure  5 . Funnel plots for stroke (A), coronary heart disease (B), composite cardiovascular disease (C), and all‐cause mortality (D) (odds ratio [ORs] and 95% confidence intervals).

Our meta‐analysis shows that endometriosis is associated with an increased risk of stroke and myocardial infarction. The association between endometriosis and cardiovascular diseases appears to be linked to a chronic inflammatory state that promotes endothelial dysfunction. A recent study focusing on arterial stiffness in women with endometriosis and healthy control women showed that women with endometriosis had impaired endothelial function and higher advanced glycation end‐products skin accumulation, markers of arterial stiffness, and thus an increased cardiovascular risk. 35 Two previous studies had already suggested that endometriosis was linked to increased arterial stiffness in non‐menopausal women. 36 , 37 It seems that endothelial dysfunction is one of the earliest measurable markers of vessel wall deterioration in atherosclerosis, even in the absence of traditional cardiovascular risk factors. Various inflammatory factors, markers of oxidative stress and lipids have been shown to be elevated in women with endometriosis compared with controls. 38 Interestingly, one study has shown that endothelial dysfunction through evaluation of flow‐mediated dilation, regresses after surgical treatment of endometriosis. 39 Previous studies had looked at the association between endometriosis and other cardiovascular risk factors. A prospective cohort study showed an increased risk of high blood pressure and hypercholesterolemia in women followed for endometriosis. 40 Other studies had shown a change in the lipid profile in women followed for endometriosis, including a higher risk of hypertriglyceridemia. 41 , 42 , 43 Endometriosis was also associated with a higher risk of metabolic syndrome. 41 However, no association was found between endometriosis and type 2 diabetes. 44 , 45 Endometriosis was also associated with an increased risk of hypertensive disorders of pregnancy, including preeclampsia, 46 , 47 , 48 in women who conceived spontaneously. 49 The data regarding the association with gestational diabetes are contradictory, with some studies finding an increased risk of gestational diabetes in cases of endometriosis 46 , 47 and some finding no significant association. 50 Women followed for endometriosis also seem to have a higher risk of early menopause, 51 which is also a risk factor for cardiovascular disease. 6 The risk of cardiovascular disease increases progressively with the age of menopause. A study involving 203 767 postmenopausal women from 10 observational studies found that, using a menopausal age of 50–54 as a reference, women who experienced menopause at younger ages had significantly higher risks of cardiovascular disease. Specifically, postmenopausal women aged 40–44 had an increased risk of cardiovascular disease of 1.32 (95% CI 1. 24–1.41), those aged 35–39 had an increased risk of 1.51 (95% CI 1.33–1.72). and women under 35 had an increased risk of 1.59 (95% CI 1.23–2.05). 52 In addition, women who underwent surgical menopause faced an increased risk of cardiovascular disease compared with those who experienced natural menopause, with this risk being higher the earlier the surgical menopause. 52 Women diagnosed with endometriosis are more likely to undergo bilateral salpingo‐oophorectomy, with or without hysterectomy, especially at a young age, leading to an increased risk of early or premature menopause 53 for which absence of hormone replacement therapy is associated with higher cardiovascular risk. Women with endometriosis may also sometimes receive medical treatment, such as gonadotrophin‐releasing hormone analogs (GnRHa). 54 GnRHa suppress ovarian function and alter the endometrium as well as the endometriosis tissue, which in turn often results in amenorrhea and relief of endometriosis‐related pain symptoms. However, this suppression of ovarian function reduces estrogen levels, inducing a hypothalamic amenorrhea that can increase cardiovascular risk in the long term. 55 Recently, a study analyzing genetically determined endometriosis using genetic variants showed that the relationship between endometriosis and stroke was attributable to site‐specific and comorbidity‐related disease subtypes. Significantly increased ischemic stroke risks were found for endometriosis subtypes of the ovary, pelvic peritoneum, recto‐vaginal septum, and vagina, and occurring infertility. 56 While studies agree that endometriosis is associated with an increased risk of stroke and myocardial infarction, contradictory results have been found regarding mortality, particularly cardiovascular mortality. A previous study from 2019 had shown a decreased risk of cardiovascular mortality in women followed for laparoscopically confirmed endometriosis. 24 The authors then hypothesized that women followed for endometriosis benefited from increased medical attention, but a recent study involving more than 110 000 women from the Nurses' Health Study II showed an increased risk of cardiovascular mortality in women followed for laparoscopically confirmed endometriosis, although not significant. 33 Some differences in population characteristics (e.g., parity and professions) and their access to medical care and therapeutic resources may also lead to inconsistent findings between studies. Results may also be influenced by follow‐up durations and study methodologies. Unlike other studies, the study by Wang et al. 33 is based on prospective data and focuses specifically on premature mortality (before the age of 70) with a longer follow‐up period (27 years per person in Wang et al. 33 vs. median follow‐up of 17 years in Saavalainen et al. 24 ). Further research is required concerning the association between mortality and endometriosis. The results of our study are consistent with previous data from the literature. This systematic review presents limitations inherent to the included studies as well as limitations related to the meta‐analysis. As with any systematic review, it is possible that publication bias, measured or not, limits our general conclusions. Indeed, it is possible that data showing no association between endometriosis and cardiovascular diseases did not lead to publication. Moreover, the included studies were limited by their design and methodology: all studies were observational in nature and therefore likely to be biased; the diagnosis of endometriosis was sometimes confirmed surgically and sometimes merely suspected clinically involving misclassification bias; the adjustment factors were different depending on the studies and some studies were not adjusted for known and major cardiovascular risk factors, such as high blood pressure, diabetes, and dyslipidemia. With regard to diagnosis based on clinical suspicion, it is possible that a diagnosis of endometriosis may have been made in cases of severe dysmenorrhea without any underlying endometriosis. With regard to only radiological diagnosis, it is possible that superficial endometriosis lesions may not be visible on imaging, leading to underdiagnosis of endometriosis. Furthermore, given the improvement in radiological diagnosis of endometriosis and the decrease in the number of laparoscopies performed to diagnose endometriosis, there are fewer studies based solely on laparoscopic confirmation of endometriosis. The fact that three studies on 12 are considered of poor quality is what most affects the quality of our results. Other high‐quality prospective cohort studies are needed, assessing the risk of cardiovascular events related to the presence of endometriosis while taking into account all known cardiovascular risk factors to date, including emerging factors specific to women.

Endometriosis appears to be associated with an increased risk of cardiovascular disease. More studies are needed to confirm these results and to explain the association between endometriosis and mortality. However, these results highlight the importance of considering primary cardiovascular prevention strategies for women, especially for women with endometriosis. Endometriosis is an emerging cardiovascular risk factor specific to women. Women with endometriosis should undergo a cardiovascular risk assessment, including hypertension screening, presence of migraine with aura, lipid and diabetes screening, BMI assessment, and investigation of family history of early cardiovascular disease. This cardiovascular risk assessment should be repeated during the follow‐up of women. Further research is needed to confirm whether endometriosis should be integrated into cardiovascular risk prediction models. Modern endometriosis management must not be limited to pain and infertility treatments, but must also offer individualized, multimodal and interdisciplinary patient‐centered care considering the patient's “endometriosis life.”

Cardiovascular diseases (CVD) stand as the foremost cause of death globally. The World Health Organization reports that in 2019, CVDs claimed 17.9 million lives, accounting for 32% of all deaths worldwide. A significant 85% of these deaths stemmed from coronary heart diseases and strokes. 1 Recent years have seen a notable decline in avoidable mortality from cardiovascular diseases within European Union nations, with men experiencing a more substantial decrease in preventable deaths than women. 2 There is growing evidence indicating that the risk of coronary heart disease in women is often underestimated, which leads to underdiagnosis and undertreatment. 3 Beyond traditional risk factors for cardiovascular disease—such as hypertension, diabetes, dyslipidemia, early familial arterial disease, obesity, smoking, a sedentary lifestyle, and a suboptimal diet—recent studies have pinpointed risk factors unique to women. 4 Notably, women undergoing premature or early menopause are at an elevated risk for cardiovascular disease and related mortality. 5 , 6 Additionally, migraines—a common symptom in women—are linked to significant cardiovascular events, including myocardial infarction, stroke, and cardiovascular death. 7 Other female‐specific cardiovascular risk factors include polycystic ovary syndrome, 8 infertility, the use of assisted reproductive technologies, and adverse pregnancy outcomes like maternal hypertension, preeclampsia, or gestational diabetes. 9 , 10 , 11 Furthermore, recent research suggests that hot flashes might also be a cardiovascular risk factor, potentially increasing the incidence of coronary heart disease and cardiovascular ailments. 12 , 13 Endometriosis seems to be another women‐specific risk factor. 14 Endometriosis is a chronic hormone‐dependent inflammatory disease, defined by the presence of endometrial tissue outside the uterus, which can cause pelvic pain and infertility. 15 Endometriosis affects around 10% of women of reproductive age worldwide, about 190 million people according to the World Health Organization. 16 Management of endometriosis must offer interdisciplinary patient‐centered care considering the patient's “endometriosis life.” 15 The association between endometriosis and cardiovascular disease appears to be linked to a chronic inflammatory state. The aim of the present systematic review was to provide a meta‐analysis of the association between endometriosis and cardiovascular diseases (ischemic heart disease and stroke) and mortality.

The authors declare that there is no conflict of interest regarding the publication of this article. The manuscript has been read and approved for submission by all authors.

This article follows the PRISMA reporting guideline. 17 This review was not registered. An extensive literature search of articles was conducted in MEDLINE and EMBASE databases from the earliest record to 31 March 2025. The following MESH terms were searched: “stroke,” “cerebrovascular disease,” “cardiovascular disease,” “coronary heart disease,” “ischemic heart disease,” “mortality,” and “endometriosis.” Only studies published in English were retrieved. All identified articles were screened based on their abstracts. Original articles were also identified through back references from reviews. Publications that were not related to the topic or biological studies were excluded. The selected articles were reviewed, and reviews and case reports were excluded. Two investigators (I.C. and G.P.B.) in consensus selected all relevant articles. All prospective and retrospective cohort studies reporting cardiovascular outcomes as coronary heart disease, stroke, composite cardiovascular outcome or mortality in both women with endometriosis and women without endometriosis were considered eligible. All types of strokes, ischemic and hemorrhagic, were included in the meta‐analysis. Endometriosis was diagnosed clinically, radiologically, or laparoscopically. The controls had to be women without endometriosis. Reviews and case reports were excluded. Two reviewers meticulously screened the titles and abstracts retrieved from the electronic search. They independently extracted critical data, including the authors, publication year, study design, follow‐up period, and population specifics. In cases where multiple studies utilized the same database to evaluate similar outcomes, preference was given to the study that incorporated the most adjustments for outcomes. Bias within each study was rigorously evaluated employing the validated Newcastle‐Ottawa scale, a semi‐quantitative instrument specifically designed to assess the quality of non‐randomized studies. 18 The quality assessment was predicated on stringent selection criteria for participants, comparability between cases and controls, and meticulous evaluation of exposure and outcome measures. Studies awarded a nine‐star rating were considered to exhibit a low risk of bias. Conversely, studies receiving seven or eight stars were regarded as having a medium risk, while those with six or fewer stars were categorized as having a high risk of bias. Detailed documentation concerning the evaluation of study quality and the determination of bias risk is delineated in Table  1 . Quality of the included studies. For each study, the most adjusted hazard ratio (HR) or relative risk (RR) with their 95% confidence interval (CI) was used. Random‐effects meta‐analysis was performed by weighting by the inverse‐variance method to estimate pooled risk (expressed as odds ratio [OR]) and 95% CI as recommended by DerSimonian and Fleiss. 19 , 20 Homogeneity between studies was tested using I 2 statistics. Publication bias was assessed through visual inspection of funnel plots' asymmetry and also by the Egger test. 21 , 22 Subgroup analysis of studies with comparable adjustments of cardiovascular risk factors was performed. Sensitivity analyses taking into account only studies using the same methods for diagnosing endometriosis were performed. The R statistical software package version R 4.2.2 was used for all analyses.