Pathways, mediation by treatment, and long-term effects of endometriosis

From the Harris Group, Public Health Sciences Division

Endometriosis is a common, chronic disease in women defined by endometrial-like tissue outside of the uterine cavity. This condition affects 10% of reproductive-age women and is associated with high healthcare costs and morbidity. Pain is the most common symptom experience by women with endometriosis. Inflammation has been hypothesized to play a significant role in the development of endometriosis. The increased production of inflammatory hormones (prostaglandins) and proteins, (cytokines, chemokines, metalloproteinases) from endometrial scarring on the peritoneal surface along with immune dysregulation can contribute to disease progression. 

Women with endometriosis have been noted to be at an increased risk of some chronic diseases. However, past research has been convoluted by methodological issues including temporality, overlap of disease onset and diagnosis, confounding factors, definition of endometriosis, biases, and others.  The Harris Group, from the Division of Public Sciences, stated, "Despite its significant impact on quality of life, there has been limited research into why women with endometriosis are at higher risk for some other chronic conditions and how treatments for endometriosis may impact their long-term health." In this study, the researchers reviewed recent literature on endometriosis and the risk of chronic diseases, explained the potential pathophysiology of endometriosis to other diseases' progression, and shed light on how treatments for endometriosis can increase the risk of chronic diseases later in life. The review is published in Current Obstetrics and Gynecology Reports. 

The Harris group highlighted three potential pathways of association between endometriosis and chronic diseases (Figure 1). The pathways include altered milieu/aberrant environment, shared risk factors, and treatments for endometriosis. The majority of studies have shown a consistent association between endometriosis and epithelial ovarian cancer. The Ovarian Cancer Cohort Consortium (OC3) conducted an international pooled analysis and reported hazard ratios of 2.32 (95% CI: 1.36-3.95) and 2.87 (95% CI:1.53-5.39) for the association between endometriosis and the endometroid and clear cell cancer histotypes, respectively. Although multiple ovarian cancer studies have reported significant relationships with endometriosis, the absolute risk of ovarian cancer among women with endometriosis (1.8%) is considered low but still higher than the general population. Importantly, there is limited research on endometriosis treatments that may influence the risk of ovarian cancer. 

Graphical Representation of Potential pathways of association between endometriosis and chronic diseases
Potential pathways of association between endometriosis and chronic diseases Image from Dr. Holly Harris

Although the pathophysiology between endometriosis and skin cancer is not confirmed, hormonal exposures from treatments (oral contraceptives, hormonal replacement therapy) and hormonal factors (age at menarche, menstrual regularity) may be associated with melanomas. Several studies examining endometriosis and breast cancer have reported varying associations (increased, decreased, and null). Because of the overlapping risk factors, the biology of breast cancer subtypes, menopausal status, and hormone receptor status, it is difficult to establish causality. However, progesterone-dominant treatments for endometriosis may contribute to an increased risk of breast cancer. Endometrial cancer case-control studies have reported a significant association, while cohort studies reported null or slightly positive associations between endometriosis and endometrial cancer. The case-control studies may exhibit a greater effect estimate due to recall bias. High hysterectomy rates and progesterone-dominant treatments for endometriosis could also impact the association if not controlled for in the analysis. 

Women with endometriosis may be more likely to experience various comorbid autoimmune conditions. Past literature has shown the difficulties in establishing whether autoimmune diseases and endometriosis are associated because of common immunological abnormalities, hormonal factors, or impacts of endometriosis treatments. Those with endometriosis have a higher risk of hypertension, hypercholesterolemia, and subclinical atherosclerosis, leading to cardiovascular disease later in life. Surgical treatments and hormonal medications that directly or indirectly cause weight gain and alter lipid profiles may play a role in developing cardiovascular disease.  

Few high-quality studies with limited bias exist to determine the relationship between endometriosis and chronic diseases. However, it's still important to understand the long-term impact of health on women with endometriosis. Dr. Harris summarized the paper, "This review identified gaps in our knowledge of the long-term health impacts of an endometriosis diagnosis. This will help us focus our future work on areas of greatest need with the ultimate goal of improving the quality of life of all women with endometriosis."

This research was supported by the National Cancer Institute, National Institute of Health.

Fred Hutch/UW Cancer Consortium member Holly Harris contributed to this work.

Farland LV, Harris HR. Long-Term Health Consequences of Endometriosis—Pathways and Mediation by Treatment. Current Obstetrics and Gynecology Reports. 2020 Sep;9:79-88.