© Center for Endometriosis Care/Ken Sinervo MD, MSc, FRCSC. All rights reserved. No reproduction permitted without written permission. Revised since original publication and current as of 2024. No external funding was utilized in the creation of this material. The Center for Endometriosis Care neither endorses nor has affiliation with any resources cited herein. The following material is for informational purposes only and does not constitute medical advice.

Is Endometriosis An Autoimmune Disease?

Endometriosis is, by definition, a systemic inflammatory disease characterized by the presence of endometrial-like tissue outside the uterus. While the evidence-based literature has demonstrated a universally acknowledged potential for increased prevalence of and coexistence with endometriosis/autoimmune disease(s), no data supports formal re-classification of endometriosis from inflammatory disease to autoimmune. Specifically: though endometriosis shares some similarities and an increased association with some autoimmune disorders (e.g., elevated cytokines, decreased apoptosis, cell-mediated abnormalities), in accordance with the most current evidence-based studies, it does not meet the criteria for classification as a true autoimmune condition.

Disease pathogenesis remains under constant debate and is far from clarified; however, it is generally agreed that endometriosis is a multifactorial disorder with marked chronic inflammation, increased oxidative stress, overproduction of metalloproteinases, prostaglandins, IL-6, TNF-alpha and more. The evidence-based literature has long demonstrated that endometriosis patients are at higher risk of several other chronic diseases, including some of those from the autoimmune realm (see also: endometriosis.org). However, while there is a long-recognized association between endometriosis and other conditions including a potentially higher prevalence of AI disorders in those with the disease, this does not mean that endometriosis itself is an autoimmune disease; hence it is not classified as one, but rather, as ‘an inflammatory disease with multi-organ effects.’

Correlation, causation, and comorbidity are concepts used in different contexts, each with a distinct and different meaning. For example, correlation refers to a statistical measure that describes the degree to which two variables change together. It measures the strength and direction of a relationship between the two variables. Correlation does not imply causation. Causation refers to the relationship between two variables in which one variable (cause) directly influences the other (effect). Establishing causation requires rigorous, reproducible experimental design and control to demonstrate that the changes in one variable directly cause changes in the other. It is essential to differentiate between correlation and causation because again, correlation alone cannot establish causation. Comorbidity refers to the presence of two or more chronic conditions or diseases in a patient at the same time, which arise due to shared risk factors, common biological pathways, genetic predispositions, environmental influences, and more. While the overlapping conditions/comorbidities may - but not always - influence the other's management and outcomes, one does not always cause the other. Correlation between endometriosis and comorbidities, including AI conditions, does not indicate causation.

The proposition of endometriosis as an autoimmune disease was raised by Gleicher et al. about 40 years ago based on their small study, in which the authors found that endometriosis fulfilled some but not all criteria for autoimmune classification in a handful of their study subjects. Nothnick et al. later clarified (as have others) this notion through their own larger study. Moreover, several subsequent investigations over the years into the use of immunomodulators for treatment have not supported the successful role of such drugs in endometriosis management. Still others have even gone as far as to state, "the association between endometriosis and autoimmune diseases is still being argued with little and conflicting evidence" (Chao et al., 2022). Clearly, there is still much more to be learned about the connection between endometriosis, autoimmune and/or other diseases and conditions.

Classification notwithstanding, endometriosis impacts every single life domain of those affected, from physical to sexual to financial to emotional overall health/well-being (and more). It is widely agreed that the known coexistence of endometriosis and autoimmune diseases when either is diagnosed remains an important association clinicians should be aware of in patients, as well as the impact on chances of pregnancy in the presence of autoimmune comorbidities when counseling infertile individuals with the disease. Fortunately, there is an ongoing research effort underway to better understand the disease model, e.g., how hormones, cytokines and the immune system influence one another, including the potential recent connection drawn between endometriosis and possible immune mechanism dysfunction and/or autoimmune regulation. Some other limited data has also illustrated possible association of concomitant autoimmunity with more severe forms of endometriosis, which remains to be expanded on. Nevertheless, the disease remains a true public health crisis which deserves increased funding for research focused on further clarifying disease mechanisms; better identifying endometriosis subtypes; elucidating the connection between endometriosis, inflammatory, autoimmune, malignant and/or other comorbid conditions; advancing personalized medicine approaches vis a vis genomics, transcriptomics, proteomics, etc.; and providing far better insights to disease persistence and progression.

Citations
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