Key message
Currently available evidence suggests that women with endometriosis are at higher lifetime risk of developing atherosclerotic
Endometriosis is a poorly understood chronic medical condition that poses a diagnostic dilemma for physicians. Through a combination of genetic predisposition, hormone dysregulation and immunologic susceptibility, hormonally active endometrial tissue has the capacity to spread and subsist outside the uterine cavity in affected individuals (Giudice and Kao, 2004). Although epidemiological studies are lacking, it is estimated that endometriosis affects up to 10% of reproductive age women. Manifestations of endometriosis are varied in both extent and severity, but typically include some combination of pelvic, gastrointestinal and genitourinary symptoms, dyspareunia and infertility. Endometriosis is asymptomatic in one-third of cases, but it has been shown to significantly reduce quality of life in the majority of affected women (de Ziegler et al., 2010). Despite its wide prevalence and significant morbidity burden, few epidemiological studies have elucidated the pathophysiology and natural history of the disease.
Endometriosis has been implicated in multiple immune-mediated processes related to systemic inflammation, increased oxidative stress and an atherogenic lipid profile (de Ziegler et al., 2010; Santanam et al., 2002). Most likely through a combination of factors involving dysregulated hormone receptors and activation of inflammatory genes, the levels of markers for each of these processes have been shown to be elevated in peritoneal fluid and serum of women with endometriosis compared with controls (Akoaum et al., 2008; Bedaiwy and Falcone, 2003, Bedaiwy et al., 2002). Indeed, these markers of oxidative stress and reactive oxygen species have also been implicated in the disease processes of autoimmune conditions such as systemic lupus erythematosus and rheumatoid arthritis that manifest with both rheumatological symptoms and severe systematic comorbidities (Van Langendonckt et al., 2002). Due to a similar process, it has been suggested that endometriosis could induce, or at least be associated with, similar adverse effects on other body systems. This could lead to long-term systemic comorbidities that may negatively affect the lifelong health of women (Hughes et al., 2015; Sinaii et al., 2002; Taskin et al., 2019). Given the widely accepted association between subclinical systemic inflammation and endometriosis (Agic et al., 2006; Berkes et al., 2014; Jaeger-Lansky et al., 2018; Kobayashi et al., 2014; Yun et al., 2018), there is emerging evidence that endometriosis may predispose these patients to a spectrum of disorders later in life, including multiple cancers, inflammatory bowel disease, endocrine disorders and atherosclerosis (Hughes et al., 2015).
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality for women globally. The population-adjusted risk of cardiovascular mortality is greater for women than men (20.9% versus 14.9%), despite numerous improvements in evidence-based treatments for established ASCVD and increased awareness of ASCVD risk factors (McSweeney et al., 2016; Yusuf et al., 2004). Traditional ASCVD risk factors include diabetes, hypertension, dyslipidaemia, smoking, obesity and physical inactivity (Brown et al., 2018; McSweeney et al., 2016; Mosca et al., 2011). However, ASCVD risk in women also encompasses numerous non-traditional ASCVD risk factors such as hypertensive disorders of pregnancy, a history of preterm labour, gestational diabetes, breast cancer treatment, autoimmune diseases and depression (Agic et al., 2006; Giudice and Kao, 2004). Furthermore, a potential influence of immunologic and sex-related disorders associated with chronic inflammation on lifetime ASCVD risk is a subject of ongoing research.
Recent epidemiological studies have reported a similar potential association between endometriosis and ASCVD, citing similar pathogenic mechanisms such as systemic chronic inflammation, increased oxidative stress, coronary microvascular dysfunction, endothelial dysfunction and atherogenic lipid profile (Kinugasa et al., 2011; Melo et al., 2010; Pretta et al., 2007; Santoro et al., 2012, 2014). Moreover, Shen et al. (2008) demonstrated that chromosome 9p21 confers a higher risk for the development of acute myocardial infarction and endothelial dysfunction, while Uno et al. (2010) reported a similar association between endometriosis and several CDKN2CBAS genetic variants on chromosome 9p21. Ultimately, this association and plausible mechanistic similarities suggest that women with endometriosis may represent a high-risk population for the development of ASCVD and severe cardiovascular complications due to longstanding states of chronic inflammation and early onset progression of atherosclerosis (Hughes et al., 2015; Santanam et al., 2002).
Clear identification of a link between endometriosis and lifelong cardiovascular disease would necessitate a radical shift in public health management. Beyond treatments for infertility and chronic pelvic pain, it would signal the need for targeted prevention and early detection guidelines for chronic and life-threatening diseases for which women with endometriosis would be at greater risk. This systematic review considers the evidence for associations between endometriosis and cardiovascular disease, including markers of atherogenic dyslipidaemia, endothelial dysfunction and subclinical atherosclerosis; such associations would reflect an increased predisposition to cardiovascular disease as a clinical endpoint independent of other known ASCVD risk factors.
This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Liberati et al., 2009).
The electronic databases Embase, PubMed, MEDLINE, Cochrane Register of Trials and ClinicalTrials.gov were systematically searched from inception to May 2018. The following search terms were used: ‘endometriosis’, ‘atherosclerosis’, ‘cardiovascular disease’, ‘lipids’, ‘endometrial dysfunction’, ‘dyslipidemia’, ‘oxidative stress’ and ‘chronic inflammation’. A summary of the search strategy performed through Embase and MEDLINE is included in Supplementary Table 1.
All original research articles, including cohort studies, randomized and non-randomized controlled trials published up to 1 May 2018 were analysed. Included studies reported cardiovascular disease outcomes among women with endometriosis as measured by either direct incidence of cardiovascular events, imaging assessment of subclinical disease, or assessment of markers of endothelial dysfunction and abnormal lipid profiling. Additional studies were extracted from the references in the full-text articles. Only articles published in English were included; published abstracts from conferences were also considered.
Studies were assigned to one of three groups: (i) epidemiological studies that assessed the relative risk of direct ASCVD outcomes among women with endometriosis; (ii) studies that investigated the association between endometriosis and serum markers of dyslipidaemia (serum paraoxonase 1 [PON-1], polyunsaturated fatty acids [PFA], eicosapentaenoic acid [EPA], total cholesterol, low-density lipoprotein cholesterol [LDL], high-density lipoprotein cholesterol [HDL], triglycerides, lipoprotein a [Lp(a)]); and (iii) studies pertaining to the prevalence of serum and instrumental markers as indirect measures of future ASCVD risk and subclinical atherosclerosis among women with endometriosis. Pertinent serum markers included serum inflammatory markers (SIM), asymmetric dimethylarginine (ADMA), serum amyloid A (SAA), endothelial activation parameters (EAP), interleukin-6 (IL-6), TNF-alpha, vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), E-selectin, ristocetin cofactor and von Willebrand factor (vWF). Instrumental markers of subclinical atherosclerosis included carotid artery intima media thickness (ccIMT), distensibility coefficient, flow mediated dilation (FMD), brachial-ankle pulse wave velocity (baPWV) and uterine artery pulsatility/resistance index and diameter (UtA PI/RI/d).
The primary outcome measure was ASCVD risk, defined as dyslipidaemia, increase in SIM or increases in EAP. Secondary markers measured were the effects of surgical and/or medical therapy on endothelial function and ASCVD risk. Two authors (OT and MI) independently searched and reviewed the retrieved articles and results were compared. Any disagreement was resolved by discussion and included studies were evaluated according to the Newcastle–Ottawa Quality Assessment Scale (Supplementary Table 2) (Wells et al., 2013).
Figure 1 is a flow chart of the studies included. Unfortunately, no randomized controlled trials and only one comparative follow-up study were identified in the search. Most of the included articles were cross-sectional and case-controlled studies. An initial search of studies that described endometriosis and cardiovascular risk resulted in identification of 598 articles, reduced to 580 after removal of duplicates. After review of title and abstracts, 39 articles were deemed relevant to the
There are many ways to evaluate the association between endometriosis and cardiovascular disease. Large population-based studies provide the most direct evidence by assessing the relative incidence of various cardiovascular endpoints such as myocardial infarction, hypertension and hypercholesterolemia among women with laparoscopically-confirmed endometriosis compared with women without the disease. Because a diagnosis of endometriosis is typically made at a younger premenopausal age due to
Justin Tan is an Obstetrics and Gynecology Resident at The University of British Columbia. He received his Bachelors in Engineering from the Massachusetts Institute of Technology (MIT), followed by a Masters in Public Health and Biostatistics from the University of Cambridge, and most recently his medical degree from McGill University. Key message Currently available evidence suggests that women with endometriosis are at higher lifetime risk of developing atherosclerotic
Justin Tan is an Obstetrics and Gynecology Resident at The University of British Columbia. He received his Bachelors in Engineering from the Massachusetts Institute of Technology (MIT), followed by a Masters in Public Health and Biostatistics from the University of Cambridge, and most recently his medical degree from McGill University. Key message Currently available evidence suggests that women with endometriosis are at higher lifetime risk of developing atherosclerotic cardiovascular disease (ASCVD) than women without endometriosis. However, robust evidence is still severely lacking and future studies are needed to more definitively evaluate a possible causal association between ASCVD risk and endometriosis.