the chronicOften called a 'disease of theories,' the definitive cause(s) of endometriosis remain under debate, though a demonstrated association with a number of hereditary, environmental, epigenetic, and menstrual characteristics exist. No single researcher has found 'the' answer.
The etiology of endometriosis is complex and not completely understood. There are general theories on the causes of the disease but each has its limitations. No theory is adequate in describing the many factors that contribute to endometriosis’s manifestation and behaviors. No theory can explain endometriosis in all patients, especially cis men and in extrapelvic manifestations.
A possible explanation is that individuals are born with multiple mechanisms that combine over time to create the perfect environment for triggering the disease. It’s also possible that the pain and symptoms are due to a variety of comorbid conditions such as autoimmune diseases, allergies, and environmental sensitivities.
No single theory explains endometriosis in all patients. Likely, we are born with mechanisms which, when later combined, 'the perfect storm' trigger the disease.
Since there are many theories in circulation, this article examines several of the current ones for a better understanding of the possible causes of endometriosis.
Retrograde Menstruation
The century-old theory of retrograde menstruation remains one of the most popular theories despite its proven flaws. In the 1920's, Dr. Sampson proposed the disease resulted from a reversal in menstruation in which the endometrium is deposited and implanted outside of the uterus. The endometrium is not the same as endometriosis lesions so this does not offer an explanation. Also, retrograde menstruation is very common and does not cause endometriosis in a majority of those who menstruate. Multiple studies have demonstrated that retrograde menstruation does not account for pathogenesis, or disease development. Sadly this myth rules much of modern thinking and delays further disease management efforts.
Sampson’s theory has guided thought on endometriosis for too long and patients are being physically harmed by its continued acceptance, since repeated surgeries and rounds of medical therapy are the unfortunate hallmarks of modern therapy.-A Critical Review of the Development of Sampson's Theory of Origin of Endometriosis
Immunologic Dysfunction
It’s thought that a dysfunctional immune system may allow for implantation of endometriosis lesions. However, this does not sufficiently explain the initial disease process. Endometriosis shares similarities with several autoimmune diseases including elevated levels of cytokines, decreased apoptosis, and cell-mediated abnormalities. Research is still needed to determine whether it is an autoimmune disease. There is also a belief that it may share an underlying pathology with several autoimmune disorders.
Stem Cells
The stem cell theory suggests that specific stem cells play a large part in the development of endometriosis and regeneration of the endometrium. Stem cells may spread to regions outside the uterus where they regenerate and spread further. Even in the absence of menstruation, stem cells have been shown to populate lesions, or areas of endometriosis tissue. This might explain the rare cases of cis male endometriosis but more research is needed to fully understand.
Genetics
Genetics may play a role in developing endometriosis. There is a 7 to 10 fold risk in those whose mother or relative have disease. While studies suggest that familial clustering is a component of the disease, the mechanism of inheritance is not yet known. Likely, endometriosis is a complex gene trait that results from an interaction of multiple genes and the environment.
Environmental Toxins
Environmental pollutants or toxins are hypothesized to cause changes to cells that alter cytokines, the immune system, the endocrine system, and growth factors which could promote endometriosis. Chemicals like dioxins and polychlorinated biphenyls (PCBs) have been considered to increase this risk but further research is needed to be certain. Research studies have shown that animals develop endometriosis when exposed to high levels of dioxin but this has not been proven in humans.
Halban’s Theory of Lymphatic Spread
Halban’s Theory hypothesizes that endometriosis travels throughout the lymphatic or vascular systems. This theory explains rare endometriotic lesions in the brain or lung, but does not explain why endometriosis most commonly occurs in the gravitationally dependent parts of the pelvis.
Meyer’s Theory of Metaplasia
Meyer’s Theory suggests that metaplasia, or the abnormal change in the nature of a tissue, may explain endometriosis. Metaplasia commonly occurs as a response to inflammation. The process allows for cells to alter themselves to better adapt to their environment. This may explain the appearance of endometriosis on the lungs and skin and in patients with no womb. While this theory seems logical, it has been difficult to support scientifically.
Theory of Mulleriosis And Embryonic Origin
According to the theory of Mulleriosis, the development of the uterus is thought to play a key role in the cause of endometriosis. Homeobox genes, or HOX genes, play a fundamental role in the shaping of the organism during embryonic development. HOX gene mutations cause alterations to the normal gene expression patterns which leads to developmental abnormalities in the reproductive tract. Studies have shown abnormal HOX gene expression in patients with endometriosis. This dysfunctional expression may result in abnormal cell behavior that causes the disease later on. Dr. David Redwine, a leading endometriosis researcher and excision specialist, suggested an embryologic origin some 30 years ago due to the presence of endometriosis in fetuses.
The theory of Mulleriosis proposes that the cause of endometriosis lies in developmental abnormalities in the female reproductive system. It proposes that endometriosis occurs due to abnormal differentiation or migration of any component of the mullerian duct system. This system is a channel in the early embryo that goes on to develop into the fallopian tubes, uterus, and cervix.
Additional Theories
In conclusion, there is no single theory that is entirely adequate in describing the disease origin, process, locations, and behaviors of endometriosis. Additional theories are discussed on Endopaedia and in Molecular and Cellular Pathogenesis of Endometriosis. Researchers and specialists speculate that it likely takes a variety of factors described in each theory to cause endometriosis.
Without question, there are various additional factors that contribute to disease pathophysiology and pathogenesis. Propagation of outdated myths and misinformation, and the continued research positioning of endometriosis as normal endometrium, keeps the disease mired in outdated concepts, hysterectomy, failed drug therapy, and incomplete treatment.
For the next article in the Endometriosis Series, see How Endometriosis Is Diagnosed