What Causes Endometriosis

What Causes Endometriosis?

At this point in time we do not know the cause of endometriosis. When considering the origin and manifestation of a disease we need to consider the factors that determine whether a woman develops the condition or not and, of those women who do develop the disease, the factors that determine how severe her disease ultimately is (how symptomatic, how aggressive, how invasive and how extensive).

Until now several theories of the origin and disease manifestation of endometriosis have been proposed. The aim of a theory of origin is to present an explanation that adequately accommodates all that we know about the disease. Generally the best-fit theory is adopted and used to guide and predict treatments and outcomes. Over time if new information becomes available the best-fit theory may be surpassed or replaced by another competing theory or alternatively may be adapted in order to accommodate the new findings.

Perhaps one of the most popular and enduring theories of origin is that of retrograde menstruation, transportation and implantation. This is the belief that endometriosis occurs through a process of endometrial tissue flowing back through the fallopian tubes during menstruation, entering the pelvic cavity and implanting and invading the surfaces of the pelvic structures.

Retrograde menstruation, however, is a common phenomenon that occurs in 90% of women yet only 10% of women develop endometriosis and the refluxed material only contains minimal deposits of endometrial tissue. Furthermore, endometriosis consists of tissue that is similar but not identical to the native endometrium that lines the uterus, suggesting that it is not a mere autotransplant. Other phenomena about the disease that cannot be adequately explained by this theory include the presence of endometriosis in stillborn female fetuses, in women without a functional uterus and in a small number of men undergoing treatment for prostate cancer. The theory of retrograde menstruation predicts that the disease will recur after surgery and worsen over time with each menstrual flow, yet surgical excision of endometriosis has been found to effectively remove the disease in most patients with true disease recurrence being rare. Studies examining the extent of disease across different age groups of patients have failed to find an increase in disease with age.

Research reveals that women with endometriosis are at increased risk of also having various autoimmune disorders, including allergies, systemic lupus erythematosus, Sjögren’s Syndrome, rheumatoid arthritis, and multiple sclerosis. Based on this finding a hybrid theory was developed that extends upon Sampson’s theory of retrograde menstruation. As mentioned above, retrograde menstruation occurs in around 90% of women yet only a minority ever develop endometriosis. It has been hypothesized that an underlying immune dysfunction interferes with the body’s natural ability to clear up this refluxed tissue from the pelvis and therefore the tissue is allowed to establish itself and proliferate, resulting in endometriosis. This line of argument suffers many of the same limitations as the original theory of retrograde menstruation. While autoimmune disorders are more common in women with endometriosis, many women with endometriosis do not have any such disorders. Another important question is whether immune dysfunction truly precedes the onset of endometriosis or rather is it a result of the disease process itself. Endometriosis triggers an ongoing immune response, which over time could moderate or disrupt immune function, altering an individual’s propensity to developing autoimmune disorders.

The theory of Mülleriosis is the notion that endometriosis is already laid down during embryonic development and remains dormant until later in life when changes in hormones (such as during puberty or pregnancy) trigger the disease to become active and symptomatic. During embryonic development tissue is laid down and differentiated into the various pelvic organs and structures that form the pelvis, including the reproductive organs. In women with endometriosis, something goes awry during this process and tissue that would ordinarily be restricted to the inside of the uterus ends up developing in locations outside the uterus. A helpful analogy is that of a chef who is following a recipe for a full course dinner. He has all of the right ingredients but the recipe contains mistakes and some of the ingredients that should belong in the starter end up in the desert and some ingredients intended for the dessert end up in the main course. In the development of the reproductive organs HOX genes determine which tissue develops where. It is possible that abnormalities in these genes, whether spontaneous or inherited, result in coding errors that in turn result in the presence of aberrant endometriotic tissue outside the uterus (endometriosis). This theory can explain why the disease has been observed in infants and prepubescent girls, as well as the presence of other types of aberrant tissue that may co-occur with endometriosis, such as endocervicosis (tissue similar to the cervix found outside the uterus) and endosalpingiosis (tissue similar to the lining of the fallopian tubes present outside the tubes). It could also help explain the unique patterning of the disease i.e. why it occurs more commonly in some locations than others. Interestingly, there is a pattern of abnormalities and anomalies, such as urinary tract and uterine anomalies, adenomyosis, fibroids, and peritoneal pockets that are significantly more common in patients with endometriosis. This syndrome of conditions could be explained by a common underlying pattern of “coding errors” that manifest during embryonic development.

The embryonic rest theory proposes that cells of Müllerian origin can persist within the peritoneal cavity and under certain circumstances induce the formation of endometriotic tissue. An embryonic rest is a remnant of embryonic tissue that has persisted beyond the embryonic phase of development. Cells of Müllerian origin are the embryonic cells that originally comprised the Müllerian duct, a structure that subsequently differentiated into the female reproductive organs (specifically the fallopian tubes, the uterus and part of the vagina). It is unknown, however, whether these cells really can persist beyond early life.

A recent theory is that endometriosis arises from endometrial stem cells located outside the uterus. Stem cells are undifferentiated cells that harbor the potential to regenerate and produce more differentiated “daughter” cells. It is proposed that stem cells located in the pelvis outside the uterus bring about the regeneration and differentiation of endometriotic lesions. These same cells play a role in the monthly regeneration of endometrial tissue inside the uterus after each menstrual flow.

In very rare cases a patient will present with endometriosis in far away places, such as the lung, the brain or even the eye. One explanation for these occurrences is that small amounts of endometrial tissue can spread throughout the body via the lymphatic and vascular system. It is unclear, however, how this process would occur and perhaps a more plausible explanation is that the disease presents in these distant sites due to a process of coelomic metaplasia (the transformation of cells or tissue from one type to another).

Coelomic metaplasia rests on the notion that any cell in the body has the potential to become any other cell. All cells have the same basic genetic code but are differentiated by the different ways in which their basic genetic code is expressed. The expression of any given cell’s genetic code may be influenced by any manner of factors (such as inflammation, exposure to toxins, and wound healing). In the case of endometriosis the theory of coelomic metaplasia predicts that the genetic material in a cell or a group of cells (tissue) becomes expressed differently causing the tissue to transform into endometriosis. This theory could explain the occurrence of disease in distant sites in the body, scar endometriosis, and the presence of disease in men undergoing treatment for prostate cancer.

It has been found that endometriosis runs in families. A woman’s risk of developing the disease is significantly increased if her mother or sister also also has the disease. These findings point to a genetic origin of the disease. What we do know is that no individual gene is responsible for endometriosis and the pattern of inheritance is complex. Most likely a complex array of genes are involved in the familial transmission and expression of this disease and these genes may interact with environmental factors to determine disease extent and severity.

With an increase in exposure to toxins in the surrounding environment (air pollutants, toxic chemicals in household products and in the food chain) as well as increasing exposure to estrogens in the foods we consume it has been hypothesized that more women may develop endometriosis than previously or that the severity of endometriosis may be exacerbated by exposure to certain chemicals. There are two potential mechanisms through which environmental factors may play a role. Firstly there is the potential for dioxin exposure in vitro to result in genetic mutation, which in turn could cause the disease to occur, and secondly exposure to certain chemicals over the lifespan could enhance disease activity or even result in an underlying “latent” susceptibility to the disease becoming expressed. If an area of tissue harbors the potential to become endometriosis through metaplasia, an environmental factor could be the catalyst that triggers this change to occur. This brings up the role of epigenetics, which is when external factors alter the expression of a person’s genes. Alterations in gene expression can in turn result in changes in the behavior of cells in the body. It is important to note, however, that endometriosis has existed for millennia.

As you can see, various theories have been proposed to explain the origin and presentation of endometriosis. The question of what causes this disease and why some women present with more advanced and aggressive disease than others is far from simple. At this point in time we do not have all the answers. Most likely a complex interplay between several of the above described theories ultimately holds the key to fully unraveling the cause and in turn the cure of this enigmatic disease.

 

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