The possible association between endometriosis and atherosclerosis represents an emerging topic in the field of women’s health. In this Clinical Opinion paper, we analyze this theme focusing on the pathogenetic mechanisms of both diseases, deeply discussing about what is already known about this association and producing starting points about what we consider suitable to research in the near future with regard to cardiovascular involvement in women affected by endometriosis. We have identified 5 reports specifically carried out to investigate the relationship between atherosclerosis and endometriosis; these studies show the presence of subclinical atherosclerosis in women affected by endometriosis, susceptible of regression after surgical removal of endometriosis, with a possible prognostic relevance for variations of cardiovascular risk in these women. However, to date, no studies in literature have been carried out to investigate the real incidence of cardiovascular events in women with endometriosis.
Endometriosis is a very common, chronic benign gynecological disease characterized by the presence of endometrium-like tissue outside the uterine cavity. In the last few years, a growing interest regarding this pathology has arisen because more often it has been reported in association with other pathologies. In particular, starting from common pathogenetic features, recent studies have investigated the possible coexistence of cardiovascular (CV) disorders in patients with endometriosis.
Although endometriosis was first acknowledged more than 100 years ago, the pathogenesis underlying the development and maintenance of this disorder remains far from being definitively understood. The theory of retrograde menstruation of Sampson remains the most generally accepted; however, several additional alterations in key biological processes must occur to allow a successful implantation and development of displaced endometrial tissue in ectopic sites, mainly consisting in the developing of a more immunotolerant peritoneal environment.
Endometriosis is currently considered as a multifactorial disorder caused by a combination of genetic, hormonal, environmental, immunological, and anatomical factors ; in particular, over the years, a number of studies have been carried out about the immunological/inflammatory features of endometriosis that have been referred to favor the key processes, like adhesion of endometrial cells to the peritoneum, invasion of the mesothelial lining, degradation of the underlying extracellular matrix, proliferation, resistance to apoptosis, and neoangiogenesis.
In this context, peritoneal macrophages have been identified among the main players in the initiation, maintenance, and progression of endometriosis, being the main source of cytokines and growth factors that can promote the ectopic growth of endometrial tissue fragments survived to phagocytosis, also considering the decreased phagocytic capacity and uptake of debris of macrophages themselves. Several of these mediators promote the recruitment of additional inflammatory immune cells, such as neutrophils, type 17 T-helper cells, and regulatory T-cells, which may further exacerbate an excessive inflammatory microenvironment.
It has been becoming more and more clear that these dysfunctions are not restricted only to the peritoneal cavity because endometriosis may be associated with a state of systemic subclinical inflammation, as evidenced by an increase of serum cytokines and biomarkers, like C-reactive protein and carbohydrate antigen 125. On the basis of these reports, endometriosis is now considered a chronic systemic inflammatory disease, with local inflammation considered as an essential cause of pelvic pain and infertility.
An increased oxidative stress has been widely described as a major constituent of endometriosis-associated inflammation. Retrograde menstruation is likely to carry into the peritoneal cavity a number of well-known inducers of oxidative stress, such as erythrocytes, apoptotic endometrial tissue, and cell debris in addition to pelvic macrophages. In particular, hemoglobin and its toxic products heme and iron are prooxidant and proinflammatory substances. Peritoneal production of reactive oxygen species may be involved in endometriosis-associated inflammation and also by regulating the expression of numerous inflammatory genes.
Finally, the role of a genetic predisposition for development of endometriosis has been recently described in the literature. It is known that endometriosis shows a polygenic inheritance, with a prevalence of 4-9% in first-degree relatives of patients. Moreover, several polymorphisms of genes encoding for various factors (such as estrogen receptors, cytokines or immunomodulating proteins, detoxification, and extracellular matrix remodeling enzymes) have been reported, with some of these variants that could confer a worse prognosis and an increased risk of endometriosis recurrence.
Atherosclerosis pathogenesis
Most of the previously discussed mechanisms implicated in the pathogenesis of endometriosis (ie, systemic chronic inflammation and increased oxidative stress) have been widely described also to be involved in atherosclerosis development, as emerging factors. In fact, usually atherosclerosis etiopathogenesis has been linked to a variety of traditional CV risk factors, such as increased local shear stress from hypertension, elevated plasma concentrations of low-density lipoprotein cholesterol, low serum levels of high-density lipoprotein cholesterol, insulin resistance, glycosylated end product formation in diabetes mellitus, and chemical toxins in cigarette smoke. The role of these traditional CV risk factors has been widely described, and predictive models of the CV risk, such as the Framingham 10-year risk score, have been elaborated.
Moreover, a number of population-based studies have shown that a family history of CV diseases is an independent risk factor for future CV events. In particular, in the last several years, genome-wide association studies have discovered the first genetic risk variant for coronary artery disease, located on the short arm (p) of chromosome 9, commonly referred as 9p21. Subsequently, more than 50 genetic risk variants of genome-wide significance have been identified.
However, the absence of these factors does not completely protect from the disease because up to 60% of patients with coronary heart disease have been shown to have only one or none of these risk factors.
In the last decades, several studies have widely described the role of endothelium as primary actor in the whole process of atherosclerosis, with a condition of endothelium dysfunction representing the key factor of all steps of atherosclerosis development. First of all, dysfunctional endothelium reduces production of several substances, including nitric oxide, the most important regulator of vascular tone, with a consequent imbalance of vasoconstriction properties; in this period of time, this altered endothelial function represents the earliest measurable marker of deterioration of vessel wall, preceding morphological atherosclerotic changes. Moreover, nitric oxide release reduction alters vascular wall homeostasis by stimulating inflammation, cellular proliferation, and thrombosis throughout a proinflammatory pathway.
Atherosclerosis represents the main pathogenetic substrate of most acute CV events, as unstable angina pectoris, myocardial infarction, ischemic stroke, and sudden cardiac death. Currently these events still represent the first cause of death in most industrialized countries. Nevertheless, an advance of atherosclerosis leading to premature CV disease, named accelerated atherosclerosis, has been reported in several pathologies, such as systemic vasculitis and autoimmune rheumatic disorders. It seems that in these diseases the role of the traditional CV risk factors can be marginal in advancing the clinical expression of atherosclerosis, with chronic inflammation observed in all these conditions as crucial.
In the last few years, several lines of research have focused their attention on the possibility of a specific CV involvement in women affected by endometriosis, documenting the presence of markers of subclinical atherosclerosis in these subjects.
Literature search
We performed a comprehensive literature review about the possible association of atherosclerosis and endometriosis, using PubMed, ClinicalTrials.gov , and other medical available databases. The search included all English-language papers investigating one or more parameters suggestive for atherosclerosis in women affected by endometriosis; the final search was performed on Dec. 30, 2014.
Five studies about the presence of one or more parameters suggestive for atherosclerosis in women affected by endometriosis were identified. Four studies were observational; one study was prospective ( Tables 1-4 ). No metaanalyses and systematic studies about this topic were available.
| Study authors, country | Population | Parameter | Main results |
|---|---|---|---|
| Pretta et al, Italy | 66 patients, 66 centers | ccIMT, DC, SIP | Women with endometriosis do not have more subclinical atherosclerosis than the general population. |
| Kinugasa et al, Japan | 41 patients, 28 centers | FMD, ADMA, SIP | Increased plasma ADMA levels and enhanced inflammation are associated with inhibited function in women with endometriosis. |
| Santoro et al, Italy | 37 patients, 31 centers | ccIMT, FMD, SIP, EAP | Women with endometriosis have more subclinical atherosclerosis with respect to controls, as documented by endothelial function impairment and inflammation, in absence of structural atherosclerotic changes. |
| Santoro et al, Italy | 22 patients, 10 centers | ccIMT, FMD, SIP, EAP | Surgical treatment of endometriosis is associated with a regression of endothelial dysfunction in these patients. |
| Tani et al, Japan | 28 patients, 21 centers | PWV, SIP, EAP | Women with endometriosis show significantly increased arterial stiffness with respect to general population. |
| ccIMT Distensibility coefficient FMD PWV |
| C-reactive protein Carbohydrate antigen 125 Asymmetric dimethylarginine Tumor necrosis factor-α. |
| ICAM-1 VCAM-1 VEGF E-selectin vWF Ristocetinic cofactor |
Markers of atherosclerosis in women with endometriosis
In the last few years, a possible development of accelerated atherosclerosis in patients with endometriosis has been hypothesized on the basis of common mechanisms, mainly represented by systemic chronic inflammation and increased oxidative stress; in fact, as described in previous text, in women with endometriosis, chronic inflammation and oxidative stress are not restricted only to the peritoneal cavity, insomuch as endometriosis is characterized by a state of systemic subclinical inflammation. Moreover, several studies have documented the presence of a proatherogenic lipid profile in women with endometriosis.
Based on these assumptions, some recent studies have been carried out to assess the markers of subclinical atherosclerosis in women with endometriosis. In the first study, the authors, assessing common carotid intima-media thickness (ccIMT), have concluded that women with endometriosis do not have more subclinical atherosclerosis compared with control subjects. In our opinion, these findings were due mainly to the fact that in this study, involving young women, it was evaluated to be a morphological parameter in which the alterations take years to realize. Indeed, the authors themselves have concluded the suggestion to confirm their preliminary observations with further studies including patients aged older than 50 years.
So, further studies have evaluated earlier, functional parameters, just considering the average age of the enrolled patients, very young for CV risk. In particular, Kinugasa et al have reported that for Japanese women with endometriosis, an inhibition of endothelial function evaluated by flow-mediated dilation (FMD), in association with an increase of inflammatory markers and plasma asymmetric dimethylarginine levels, an inhibitor of endogenous nitric oxide synthase. Their results enforce the concept of a link between the impairment of vascular reactivity and enhanced systemic inflammation, which may promote the development of atherosclerosis in endometriosis. However, a comprehensive evaluation of the whole early atherosclerotic process was not performed in any of these 2 studies. In fact, regarding the first, the measurement of ccIMT allows the detection of only morphological atherosclerotic changes of the vascular wall that appear in a more advanced phase of atherosclerosis, without providing data about the impairment of endothelial function that, as known, occurs before ccIMT thickening. On the other hand, the second study evaluated levels of serum cytokines as an expression of systemic inflammation and FMD as a marker of endothelial function, without exploring the structural parameters of subclinical atherosclerosis.
In attempting to overcome these limitations, our group has first investigated both structural (ie, ccIMT) and functional (ie, FMD) parameters of subclinical atherosclerosis. In particular, we have performed an evaluation of brachial artery FMD, which is the most common test for the assessment of endothelial function. FMD assessed with this technique measures the nitric oxide–mediated vasodilation produced by an increased flow after a period of ischemia (endothelium-dependent vasodilation). The methodology is indicated in the actual guidelines.
An impaired FMD response is an expression of endothelial dysfunction. Because endothelial dysfunction is a systemic process and a correlation between responses in the coronary circulation and in the forearm has been demonstrated, testing of FMD of the peripheral arteries is an index of the functional status of the whole circulatory system. Clinical studies reported that FMD strongly predicts CV events in patients with established CV disease, providing independent prognostic information, which may exceed the predictive value of CV traditional risk factors so that its evaluation has been proposed as a noninvasive and inexpensive tool to investigate the cumulative CV burden and the responsiveness to therapies.
Persistent endothelial dysfunction predisposes to organic damage of the arterial wall that, in a preclinical stage before overt disease, can be detectable through an assessment of ccIMT at B-mode ultrasonography. In fact, an increase of ccIMT has been reported to precede the development of overt atherosclerotic lesions by at least 1-2 decades. Moreover, ccIMT has been shown to correlate significantly with the presence of coronary artery disease and to predict fatal and nonfatal cerebrovascular and CV events. All these findings highlight the importance of recognizing and managing the early stages of atherosclerosis for an effective CV prevention.
In the study mentioned in the previous text, we have found that in young women with endometriosis, even if a structural alteration is confirmed to be absent, functional endothelial damage has already occurred. These results were consistent with the fact that, in young people, an increase in ccIMT reflects a structural vascular damage requiring a longer time to realize. Moreover, the patients showed increased serum levels of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), and ristocetin cofactor, reflecting a systemic inflammatory state and the activation of endothelial cells as an early step of the atherosclerotic process. Interestingly, these results were independent of the presence of potential confounding factors as diseases impairing endothelial function and other factors known to play a role in atherosclerosis development.
In our successive follow-up study, it was found that laparoscopic surgical treatment of endometriosis leads to the improvement of endothelial function, as expressed by a significant increase of FMD in these patients with respect to baseline values, becoming similar to that of control subjects, associated with no significant differences of serological markers of endothelial activation (ICAM-1, VCAM-1, E-selectin, VEGF, vWF, and ristocetinic cofactor) between patients and controls, as opposed in baseline evaluations.
These new findings are very important just considering the characteristic of reversibility of endothelial dysfunction; this dynamic nature supports the possibility of choosing a treat-to-target approach, in which FMD can be monitored as a functional marker, with the goal of normalizing or enhancing vascular health. It has been found that an improvement in FMD identifies those patients with a more favorable prognosis, whereas a persistent impairment, despite therapeutic interventions, is a significant independent predictor of adverse events. In particular, a recent metaanalysis has provided clear evidence for a prognostic relevance of FMD, showing a 13% (95% confidence interval, 9–17%) decrease in the future risk of CV events for every 1% increase in FMD.
Finally, very recently Tani et al have confirmed the presence of subclinical atherosclerosis in women with endometriosis by evaluating arterial stiffness together with laboratory markers of inflammation and oxidative stress. In particular, they have measured brachial-ankle pulse wave velocity (PWV), evidencing that this marker of arterial stiffness was significantly higher in 28 women affected by endometriosis with respect to 21 control subjects. PWV, defined as the speed of a pressure wave traveling along an artery length over a certain time, reflects a complex process including several adverse alterations of vascular function and structure and is well known to be a useful marker of vascular damage.
It reflects a different aspect of vascular damage than that reflected by FMD or ccIMT so that this study gives further support to the observations that young women with endometriosis need to be cautious of the future onset of atherosclerosis. Moreover, it is conceivable that the presence of increased arterial stiffness in these women could have a role in the onset of hypertension, preeclampsia, and intrauterine growth restriction during pregnancy.
Another aspect to take into account when considering the CV risk of women affected by endometriosis is the recurrent use of a variety of medications, including nonsteroidal antiinflammatory drugs (NSAIDs) and contraceptive steroids. Although there are no data about the effects of these drugs on the CV risk in women affected by endometriosis, some considerations can be made. First of all, it is known that the chronic administration of NSAIDs can theoretically increase CV risk; this finding, first strengthened especially for some NSAIDs (ie, cyclooxygenase-2 selective inhibitors), seems now to be applicable for all NSAIDs. On the other hand, other studies have documented a protective role of naproxen.
With regard to oral contraceptives, the effect of this therapy on the CV system is unclear. Data about chronic treatment in premenopausal women are lacking; on the other hand, the effect of hormone replacement therapy on CV risk in menopausal women has been widely described. In these subjects, the so-called critical timing hypothesis postulates that there is a critical time in the development of CV disease when the introduction of hormone replacement therapy is atheroprotective, following which there is greater harm than benefit because of the beginning of an underlying clinical or subclinical CV disease.
Finally, with regard to hormone analogs (gonadotropin-releasing hormone analog), no data are present about their specific relationship with atherosclerosis. On the other hand, it can be hypothesized that this medical treatment could have a protective effect on endothelial function by reducing associated inflammation.
Conclusions
A condition of accelerated atherosclerosis is a very important entity, especially considering the possible risk to develop CV events in patients affected by diseases known to be associated with this condition. With regard to the higher rates of CV, morbidity and mortality, mainly caused by accelerated atherosclerosis, have been reported in autoimmune rheumatic disorders, in particular systemic lupus erythematosus and rheumatoid arthritis.
In the last few years, some authors have confirmed the concept of endometriosis as a condition that may favor subclinical atherosclerosis; moreover, it has been reported a regression of endothelial dysfunction after the surgical removal of endometriosis, which could have a prognostic relevance for variations of CV risk in these subjects.
In addition to these studies involving only the presence of atherosclerosis, to date no studies in literature have been carried out to investigate the real incidence of CV events as clinical consequences of atherosclerosis. So we consider it suitable to conduct large, long-term longitudinal studies that follow up women over decades to support the prognostic significance of atherosclerosis presence in women affected by endometriosis. In this context, also studies reporting hospital discharge data about CV diseases in women with a history of endometriosis would be very useful.
Moreover, considering the role of genetic predisposition in the etiopathogenesis of both pathologies, it is reasonable to predict that, in the future, further genetic studies could better clarify the role of endometriosis as a risk factor for atherosclerosis and CV diseases.
Another aspect to consider about the possible coexistence of endometriosis and CV diseases is represented by diagnostic difficulties/heterogeneity; more and more, endometriosis is found in patients without typical clinical signs and symptoms, represented by severe dysmenorrhea, deep dyspareunia, menorrhagia, metrorrhagia, recurrent chronic pelvic pain, and infertility, that lead women to refer to gynecological attention. Rather, the clinical picture of endometriosis cannot be specific and widely heterogeneous, with atypical signs and symptoms, such as gastrointestinal, respiratory, CV, and neurological disorders. As a consequence, patients are frequently referred to other medical specialists than a gynecologist, with frequent delay of several years before the correct diagnosis.
All these clinical manifestations are explained by unexpected localizations of endometriosis in other sites, like the colon, small intestine, bladder, appendix, umbilical scar, and, very rarely, outside the abdominal cavity (ie. in pericardium, pleura, and brain), making the diagnosis more difficult to reach.
It could hypothesize that, in the near future, clinical pictures secondary to accelerated atherosclerosis also will be observed as a cause of searching medical attention in women with endometriosis.
The authors report no conflict of interest.
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