Endometriosis and co-morbidities

BY MARINA KVASKOFF PhD

In a recent comprehensive review we suggest that endometriosis may be associated with a higher risk of several chronic diseases.

While the underlying mechanisms of endometriosis are not yet understood, the available data to date suggest that endometriosis may have important long-term health consequences, which – if confirmed in future well-conducted studies – will have important implications in the management and care of women with endometriosis.

Endometriosis and associated diseases

Over recent decades, endometriosis has been associated with the risk of several chronic diseases, such as cancer, autoimmune diseases, asthma or allergic manifestations, and cardiovascular diseases.

Because the underlying mechanisms for these relations are not known, a deeper understanding is needed as it may lead to novel discoveries on the causes or consequences of endometriosis.

Our research group, led by Dr Stacey Missmer at Harvard University, examined the existing scientific literature to summarise the current evidence on chronic disease risk in women with endometriosis [1].

We also explored the potential explanations for these associations and formulated methodological recommendations for future studies.

Endometriosis and the risk of cancer

While endometriosis has a benign nature, some evidence suggests a potential association between endometriosis and the risk of some cancers. The disease has even been suggested to share some characteristics with malignant tumours, such as invasion of local and distant organs, abnormal tissue growth, dysfunction of target organs, and genetic damage [2].

This review suggests that women with endometriosis are generally at higher risk of ovarian cancer, breast cancer, and skin melanoma, but that they are at decreased risk of cervical cancer.

NOTE:

In reviewing available evidence both the European Society of Human Reproduction and Embryology Guidelines [3] and the World Endometriosis Society Montpellier Consortium Consensus [4] do not call for routine screening of women with endometriosis for cancer.

All women should be vigilant of any changes in their bodies, and should seek medical help if they have suggestive symptoms.

Ovarian cancer

The association with ovarian cancer was the most consistent across studies: out of the 21 studies reviewed, 20 reported an association [5-24]. The available data suggest that the relation is restricted to the endometrioid and clear-cell subtypes of ovarian cancer [20, 22] – rare types of ovarian cancer. It must be emphasised that the overall risk is low.

Breast cancer

Among other gynaecological cancers, 14 studies were reviewed on endometriosis and breast cancer: while six of them reported a modest increase in breast cancer risk in women with endometriosis [7, 8, 15, 16, 25, 26], four others reported no association [24, 27-29], and four even reported a decreased breast cancer risk associated with endometriosis [10, 13, 30, 31]. Overall this is inconclusive, based on current evidence.

Endometrial and cervical cancer

Results for endometrial cancer were conflicting; however, it is important to note the low numbers of cases in the eight studies reviewed [7, 8, 10, 15, 16, 24, 32]. Despite even lower numbers for cervical cancer, however, the four studies that evaluated this association all reported a decreased risk in women with endometriosis [7, 8, 15, 16]. It is possible that this is due to women with endometriosis being vigilant about regular examinations by their gynaecologist.

Melanoma skin cancer

Among non-gynaecological cancers, melanoma skin cancer has been the most studied in relation to a history of endometriosis. Out of the 12 studies that explored this topic, seven suggested a positive association [10, 13, 15, 16, 33-35], while five studies reported no clear relation between endometriosis and melanoma risk [8, 28, 36-38], so the evidence is mostly inconclusive.

Other cancers

Explorations of associations with other cancers have been sparse; consequently, no firm conclusions can be drawn to date as to the subsequent risk of other malignant tumours in women with endometriosis.

Endometriosis and autoimmune diseases

An autoimmune disease is a disorder that occurs when the body’s immune system attacks and damages its own tissue. This type of condition may affect one or more organs or tissue types, and it has been shown to more frequently affect women than men [39].

While endometriosis is not itself an autoimmune disease, our review found nine studies that suggest that women with endometriosis may be at higher risk of several autoimmune diseases, including systemic lupus erythematosus [40, 41], Sjögren’s syndrome [40, 41], multiple sclerosis [40, 41], rheumatoid arthritis [40], inflammatory bowel diseases (such as Crohn’s disease and ulcerative colitis) [42], and coeliac disease [43].

Endometriosis and asthma and allergic manifestations

Based on the review of six studies on the topic [40, 44-48], the available evidence suggests that women with endometriosis may be more susceptible to allergic manifestations (eg. eczema, hay fever, food sensitivities, allergies to medication) and to allergy-related conditions such as asthma.

Endometriosis and cardiovascular diseases

Among the four studies that investigated a possible relation between endometriosis and cardiovascular diseases, two reported significantly lower flow-mediation dilation (ie. lower ability of the artery to dilate in response to a shear stress) in women with endometriosis as compared with controls [49, 50], while another study found no evidence of a significant difference in carotid intima-media thickness (ie. the thickness of the innermost two layers of the carotid artery’s wall) [51].

However, the only large-scale epidemiological study on the topic, conducted in the Nurses’ Health Study II cohort, showed increased risks of myocardial infarction, angina, and surgical treatment of the coronary artery in women with endometriosis [52].

Potential explanations for these associations

While the exact mechanisms underlying these associations are unknown, the co-occurrence of endometriosis and other disease outcomes may reflect at least four potential explanations:

1: Previous studies may have reported spurious associations due to methodological bias

First, the exploration of the subsequent risk of chronic diseases in women with endometriosis carries a number of methodological complexities, which, if not tackled appropriately, may lead to biased conclusions.

For instance, the difficulty to characterise endometriosis and some chronic diseases (e.g. autoimmune diseases) accurately in large-scale population-based studies, or recall bias from women in studies relying on self-reported diagnosis, could lead to systematic errors in the definition of the disease status of study subjects, which in turn may alter the results in an unpredictable direction.

2: Endometriosis may induce physiological changes that increase the risk of some chronic diseases

However, it is possible that some consequences of endometriosis (such as infertility , chronic inflammation, aberrant hormonal and immunologic responses, or lifestyle changes associated with disease diagnosis) influence the long-term risk of other diseases.

For example, chronic inflammation in the pelvic cavity may influence a woman’s risk of ovarian cancer. However, deeper research is needed in order to investigate the physiological pathways that may link endometriosis consequences to chronic disease risk.

3: Endometriosis may share common risk factors with some chronic diseases

Another possibility is that endometriosis and the studied chronic diseases share common risk factors, whether they are already known or not. All or part of the observed associations could thus simply reflect a correlation of factors.

In this case, this research may allow the discovery of novel risk factors for endometriosis and/or the studied chronic disease. For example, the investigation of an association between endometriosis and melanoma skin cancer helped to discover a novel risk profile for women with endometriosis, who were shown to be more likely to have moles [36, 53-56] and/or a sun-sensitive pigmentary profile (i.e. poor tanning ability [54-56], red hair [34, 57, 58], fair eyes [56, 59], or freckling [55, 56]) than women without endometriosis.

4: Treatment for endometriosis could be associated with some chronic diseases

Finally, it is also possible that these associations reflect an underlying relation between treatment(s) for endometriosis and the risk of these chronic diseases.

However, little of the research reviewed accounted for this possibility in the analyses.

Endometriosis and potential co-morbidities

In conclusion, the available data to date suggest that women with endometriosis may represent a high-risk group for a number of chronic diseases.

However, given the methodological complexities associated with this research and a general lack of detailed data on endometriosis in previous studies, further research is needed in order to increase our understanding of this disease, for which the causes are largely unknown to date.

If relationships between endometriosis and chronic diseases are confirmed, these findings will have important implications in the management and care of women with endometriosis.

See also

References