MARCH 21, 2022
The Link Between Endometriosis and Chronic Diseases:
Empowering Clinicians to Screen More Effectively
By Conor Bradley
Executive Director’s Note: Despite a high prevalence of endometriosis in the general population, its cause remains poorly understood. Through his summary of a research review, “Endometriosis: a high-risk population for major chronic diseases?” by Marina Kvaskoff et al.[1], Conor Bradley teaches us a great deal about this condition and the links between endometriosis and chronic diseases. He also highlights how fertility awareness-based methods can improve the quality of data collection and its relevance in future research, information he gained through his participation in the FACTS elective.
Introduction
This article published in 2015 by Kvaskoff et al [1] reviewed all the research prior to May 2014 that linked endometriosis to other chronic medical diseases. Because the underlying cause of endometriosis is not well understood, studying the links of endometriosis to other conditions, such as cancers, autoimmune diseases, cardiovascular disease, and allergic diseases may prove fruitful to understanding how endometriosis arises. Additionally, recognizing these links means endometriosis could serve as a warning or risk factor for other conditions, empowering clinicians to screen more effectively.
Methodology
The researchers conducted a comprehensive search of online medical journal databases using key words and manually reviewing the referenced articles within the papers generated from their search. Key words included many types of cancers, autoimmune diseases, cardiovascular disease, and allergic/atopic disease. They summarized the literature and generated hypotheses about underlying links, while also noting possible places for error.
Results
Cancer
Existing research has suggested that endometriosis and cancer share certain characteristics such as the presence of local/distant invasion, abnormal tissue growth, dysfunction of the target organ, and genetic damage. Sixteen of the twenty-one studies looking at the link between ovarian cancer and endometriosis found a statistically significant positive correlation between the two. In one study that looked at large samples of women with endometriosis or ovarian cancer, the authors found that the link between the two conditions occurred between 1.2 and 2.5 times more, on average, compared with other women without those conditions. Interestingly, though, having ovarian cancer and endometriosis was associated with better overall survival and earlier-stage, lower-grade cancer. Only three of the fourteen studies looking at the link between breast cancer and endometriosis yielded significant positive correlation, although most studies suggested a non-significant positive correlation.
Most of the eight studies looking at the link between endometrial cancer and endometriosis showed no association. All studies about the link between cervical cancer and endometriosis showed a significant negative correlation between the two conditions, meaning higher incidence of endometriosis was linked with lower incidence of cervical cancer. Other cancers like cutaneous melanoma, non-Hodgkin’s lymphoma, endocrine, brain, kidney, thyroid, and other non-melanomatous skin cancers were shown in some studies to have no association with endometriosis and in other studies to have non-statistically significant positive association with endometriosis.
Autoimmune disease
Studies have found autoimmune diseases to be more prevalent in women, leading to the hypothesis that female hormones play a role in the development of these conditions. Research also has shown that estrogen and prolactin are immune stimulants, while androgens are immune suppressors. Women with endometriosis have been found to have lower cell-mediated immunity and higher humoral (antibody-mediated) immunity, which is similar to what is found in autoimmune diseases.
The largest study reviewed by Kvaskoff et al showed significant increased risk of systemic lupus erythematosus (SLE), Sjogren’s syndrome (SS), and multiple sclerosis (MS). Additionally, significantly increased risk of having inflammatory bowel diseases such as ulcerative colitis or Crohn’s disease was also linked to endometriosis in the same study. Associations between celiac disease and endometriosis in three studies were significant or non-statistically significant but still positive. No significant association was found between autoimmune thyroid disease and endometriosis.
Allergy/Atopy
It has been suggested that, in a mechanism similar to autoimmunity, the aberrant immunologic response and heightened inflammation in allergies could be related to endometriosis pathophysiology. Six studies examined allergies and endometriosis. Five studies found statistically significant positive associations between endometriosis and allergies/asthma. One study found additional significant associations between endometriosis and asthma, allergic rhinitis, medication allergy, and first-degree relatives with allergic disease.
Cardiovascular disease
Prior research has suggested that endometriosis could play a role in increasing risk for cardiovascular disease because it has been associated with increased inflammation, oxidative stress (a marker of cellular damage), and low-density lipoprotein levels (LDL cholesterol). The most important study in this review showed that endometriosis was significantly associated with increased risks of myocardial infarction, angina, and the need for procedures to fix blocked coronary arteries such as grafting or stents. Notably, some of the association could be attributed to treatments for endometriosis such as surgical removal of the uterus/ovaries, since the resulting hormone changes are known risk factors for heart disease.
The most important study in this review showed that endometriosis was significantly associated with increased risks of myocardial infarction, angina, and the need for procedures to fix blocked coronary arteries such as grafting or stents.
Discussion
The authors identified four different ways to think about the associations noted above. First, endometriosis could have a common risk factor or a common exposure to the diseases studied; additionally, risk factors themselves need to be analyzed to understand whether they are causal or not. Second, endometriosis could induce a systemic change that is associated with these conditions. Third, the treatment for endometriosis could be the reason for the association. Finally, the linked associations could be found due to bias.
Several factors could bias the studies included in the review. Most are retrospective, which limits the causal relationships that can be drawn. Prospective studies are more useful. Diagnosis of endometriosis is considerably delayed, a factor that affects patient reporting. Self-reporting health conditions carries its own bias for data collection. Having laparoscopic diagnosis of endometriosis can help remove reporting bias, but it also introduces its own bias of time and variability, since it often takes time from symptom onset to surgical diagnosis, which can affect reporting of onset of other diseases of interest.
Women with endometriosis are also more likely than control subjects to be high users of the healthcare system, which may lead to more diagnoses of other health problems compared with controls. A relevant comparison group is also difficult, as the control group may contain a certain percentage of women with asymptomatic endometriosis. Study size is also a limiting factor, as many studies these authors reviewed were too small to have sufficient power. Finally, one limitation of this research is that comorbid disease links may vary by endometriosis staging, but insufficient studies on staging are available.
The authors suggest the best future studies will be forward-looking with a cohort of patients, large sample size, surgically diagnosed endometriosis, and medically confirmed disease outcomes. The combination of these factors will allow future investigators to assess timing and confounding associations.
The pertinence of fertility awareness-based methods (FABMs) to this study is that widespread implementation of FABMs may lead to more robust, clinically useful research. The FACTS elective highlights how women can regularly track their symptoms and overall health alongside their cycles. Implementation of FABMs may provide researchers with precise and detailed data as patients can track clinical symptoms in real time and collect data less prone to recall bias. Overall, researchers could also have more relevant temporal information involving comorbid conditions due to earlier diagnosis of endometriosis.
References
[1] Kvaskoff M, Mu F, Terry KL, Harris HR, Poole EM, Farland L, & Missmer SA (2015). Endometriosis: a high-risk population for major chronic diseases?. Hum Reprod Update, 21(4), 500–516. https://doi.org/10.1093/humupd/dmv013
About the Author
Conor Bradley
Conor Bradley is a fourth-year medical student at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, PA, his home city. He attended the University of Notre Dame and graduated in 2017. Conor has applied for residency in family medicine, and his interests include FABMs, sports medicine, and primary care. He hopes one day to create a culture within health care where “charting cycles for women’s health is as standardized as exercise is for musculoskeletal health!”
