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Causes of Endometriosis: Several Proposed Theories

by Tamer Seckin, MD | Posted on June 10, 2020


While science can't point to a singular cause of endometriosis, a multitude of highly supported theories exist, from the classic Sampson’s theory of retrograde menstruation to more modern beliefs of endometrial stem cells. However, the idea that there is a singular cause for endometriosis is much less likely than the idea that the true underlying cause results from a combination of these well-researched theories.

Sampson’s Theory of Retrograde Menstruation
The stem cell hypothesis, combined with Sampson’s theory of retrograde menstruation, are proposed theories for the formation of endometriosis lesions.

What is the cause of endometriosis?

Endometriosis is a disease of ectopic endometrial-like tissue found outside the uterus. Lesions are characterized as estrogen-dependent, benign, inflammatory, stem-cell driven, and at times progressive with diffuse fibrosis, deep infiltration, and resistance to apoptosis and progesterone. While the cause of endometriosis is unknown, multiple plausible theories have been proposed. These include retrograde menstruation, implantation, spontaneous development of ectopic endometrial tissue (mülleriosis), peritoneal metaplasia (abnormal change in tissue), differentiation of mesenchymal cells (development issues), or an uncharacterized combination of these potential causes. While there are multiple theories behind the cause of endometriosis, there is no known direct singular mechanism. In the end, the true cause of endometriosis most likely lies in a combination of these factors, as opposed to just one.

What is the stem cell hypothesis of endometriosis?

Normal human endometrial lining is subject to numerous cycles of growth and differentiation as the endometrium (uterine lining) sheds and regenerates during a normal menstrual cycle. Its regenerative capacity is believed to come from resident mesenchymal stem/stromal cells that potentially have the classic properties of bone marrow mesenchymal stem cells. These stem cells are known for their multipotency (ability to generate into several forms of cells) and their potential for self-renewal and reconstitution in ectopic locations. This ability to self renew in ectopic regions is one theory as to how these stem cells can lead to endometriosis. Genetics can also play a potential role in this process and disease development.

Hox gene
The transcription and translation of the Hox gene, specifically the HoxA 10 gene, has been shown to have a significant impact on the development of the uterus, and thus its role in endometriosis.

What possible role do genetics play in endometriosis development?

Genealogical databases have shown a familial connection between first and second degree relatives affected by endometriosis, suggesting a genetic component of the disease. In addition, alterations in the HOX gene expression cause uterine structural abnormalities and abnormal endometrial development. Gene expression profiling has shown differences in the endometrium with a higher susceptibility for causing endometriosis. The molecular composition of the endometrial tissue influences whether ectopic endometrium will have the ability to interact with a receptive peritoneum (lining of the abdominal cavity) and become functional, thereby leading to disease. For example, decreased expression of HOXA10 in eutopic endometrium is seen in animal models of endometriosis as well as in women with endometriosis. This means there is a possible epigenetic phenomena in endometriosis that could play secondary to other causes.

A genetic predisposition to the disease could account for the discrepancy between those who develop endometriosis lesions or symptoms and those who do not following an inciting event. For instance, many women experience retrograde menstruation, as evidenced by blood in the pelvis at entry during laparoscopy, but most are asymptomatic or have no pathologic evidence of endometriosis.

Retrograde menstruation lead to worsening endometriosis
Sampson’s theory of retrograde menstruation, a proposed cause of endometriosis, is rooted in retrograde bleeding and reflux of menstrual debris.

What is the theory of retrograde menstruation in endometriosis development?

During normal menstruation, the female body naturally sheds the endometrium, or the lining of the uterus, which is the tissue that grows every month to prepare for the implantation of a fertilized egg. While many women experience retrograde menstruation (the backward flow of menstrual debris) there is speculation that this mechanism may in fact play a role in endometriosis development. Sampson’s theory of retrograde menstruation is based on endometrial cells being transported through the fallopian tubes into the peritoneal cavity (lining of the abdomen) at the time of menstruation, leading to ectopic endometrial tissue and the development of endometriosis.

As a woman’s hormones change during her menstrual cycle, these endometriosis implants (also referred to as lesions or nodules) caused by retrograde menstruation, ovarian development, and leakage respond to hormonal fluctuations. The lesions grow, menstruate, and shed along with the normal lining of the uterus, causing endometriosis to spread. Unfortunately, unlike normal endometrium that naturally leaves the body, when these implants shed there is no way for the material to exit the body as the lesions are implanted in ectopic regions much deeper in the pelvic and abdominal cavity.

Retrograde menstruation brings blood into the ovaries through the fallopian tubes, which then accumulates in other parts of the body. Here, you can see the blood both flow out to other areas of the abdominal/pelvic cavity, as well as form an ovarian endometrioma that also leaks into other areas of the body.

How do uterine structural anomalies play a role in endometriosis development?

Multiple studies have also noted an association between uterine anomalies and endometriosis, a relationship that may in fact be causal. Structural defects of the uterus likely contribute to dysfunctional uterine contractions and abnormal blood flow during menstruation, i.e. retrograde menstruation. Both obstructive and nonobstructive uterine anomalies can lead to increased retrograde menstruation. However, persistence of endometriosis symptoms after the correction of an outflow obstruction challenges the theory that an outflow obstruction must be present to cause abnormal menstruation. Nevertheless, an outflow obstruction could contribute to an increased volume of blood directed through the fallopian tubes into the peritoneal cavity (retrograde menstruation). Correction of a structural abnormality has been shown to improve endometriosis symptoms, and could potentially improve a common sequelae of both uterine anomalies and endometriosis: infertility.

How does abnormal uterine peristalsis play a role in endometriosis development?

A distinct but interrelated issue to uterine structure abnormalities is dysfunctional uterine peristalsis (movement) and the distribution of ectopic endometrial tissue. Uterine peristalsis occurs in the endometrium (lining of the uterus) and subendometrial myometrium (beneath the lining). Women with laparoscopically-proven endometriosis show enhancement of the subendometrial myometrium on transvaginal ultrasound. Functional MRI studies demonstrate similar findings of a dysfunctional peristalsis, suggesting that the origin of endometriosis could be in the structure and function of the uterus. With a structural anomaly, the uterus will be at an increased risk of dysfunctional uterine peristalsis. The combination of dysperistalsis and retrograde menstruation with a receptive peritoneum to this menstrual debris serves as a plausible explanation for how ectopic endometrial tissue can anchor and become functional, thus causing endometriosis.

What symptoms can these theories cause in forming endometriosis?

Endometriosis causes internal bleeding, inflammation, and expression of irritating enzymes. It can implant in the bowel, bladder, intestines, and other areas of the pelvic cavity, causing severe pain, the formation of scar tissue, and adhesions (fibrous bands of dense tissue). It can also cause the growth of new blood vessels (angiogenesis) and root to existing nerves. This can lead to chronic pelvic pain, severe cramping, bowel or urinary disorders, painful intercourse, and even infertility.

If you find yourself experiencing these symptoms, it could be due to a high rate of retrograde menstruation, which means that endometriosis may be either forming or has already developed. The most important step towards treating your symptoms is through overcoming the taboo that surrounds the menstrual cycle and in turn a disease such as endometriosis.

Medically reviewed by Tamer Seckin, MD on June 10, 2020

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