What are the requirements of a theory of origin of endometriosis?

If we were to try to construct a theory of origin, there would be many requirements based on modern understanding of the disease.

Although everyone has believed for 70 years that endometriosis is exactly like the endometrium lining the inside of the uterus, we know that is not true. It has low and varying levels of hormone receptors compared to native endometrium, causing it to respond somewhat unpredictably to ovarian or man-made hormones.

Although a lot of people have believed that endometriosis bleeds with each menstrual flow, it has been shown that endometriosis bleeds unpredictably, non-cyclically, or not at all. This causes endometriosis to have many different visual appearances which can differ from the classic typical "black powder burn" lesion. In fact, most patients have lesions with an "atypical" visual appearance.

Younger patients can have very subtle, colorless lesions which can change in visual appearance over time and become more obvious with age.

We know that endometriosis can occur in many areas of the body, although it is most commonly found in the posterior pelvis and can even occur in males. Students of the distribution of pelvic endometriosis are struck by the fact that the disease is consistently found in the same types of patterns in the pelvis. Although Sampson's theory predicts that the pelvis should fill up like a rain barrel with endometriosis by the time a patient is in her thirties, pelvic mapping studies have not found an age-related increase in the number of pelvic areas involved, surface area involved, or disease stage.

Sampson's theory also predicts a 100% rate of recurrence after surgical destruction of disease, although many patients have no disease at re-operation, even without postoperative medical therapy.

The disease can be invasive or superficial, but superficial disease does not necessarily become invasive disease. A patient can have both superficial and invasive disease side by side in the pelvis.

Adenomyosis of the uterus and fibroid tumors of the uterus seem to develop more commonly later in life in endometriosis patients, and mitral valve prolapse may be more common as well.

Studies of the immune systems of endometriosis patients have found slight differences such as impairment of natural killer cells. Although this has been postulated to facilitate implantation of refluxed endometrial cells via Sampson's theory, endometriosis patients do not seem to have a higher rate of cancer or opportunistic infections (except questionably minor yeast infections) which should accompany a decrepit immune system. Also, no one has shown evidence of the competent, robust immunologic warfare which should be occurring in the peritoneum of patients without endometriosis as their normal immune mechanisms function.

Wow, that's a lot for a theory to cover, and I've even left out speculation about endometriosis-associated infertility. While many researchers throw up their hands at this point and say that it is probable that multiple theories of origin are operating, it would be nice if one theory could explain everything. In trying to combine all of the above requirements into one theory, most rational theorists are inevitably drawn to the embryo. There is obviously something different about patients with endometriosis beyond the fact that they have pelvic disease which causes pain. It is too much to ask that all of these differences suddenly appear out of the blue after puberty, and it is more likely that we are dealing with inborn differences. How can this all be combined? I'll give it my best shot below.

EPM - Embryologically Patterned Metaplasia: Genetic wild cards

At the moment of conception, the egg and sperm combine to form a new mass of DNA destined to become a human being. There is a system controlling development of the embryo. This system is able to differentiate one type of cell from another. It controls the differentiation and migration of cells to their proper locations.

This embryonic control system has features similar to those found in an immune system: the ability to distinguish between types of cells and the ability to control and operate on these cells in certain ways.

The DNA of patients destined to develop endometriosis has variable genetic codes which deal several wild cards to the endo-patient-to-be. The most important wild card results in a mild defect in the embryonic immune system which controls the differentiation and development of organs. It is this card which determines whether a patient will develop endometriosis or not.

With this wild card, the fetal immunologic controlling system has slight difficulty in directing the proper cells into the pelvis to form the uterus.

Differentiation and migration of the female internal genitalia normally occur across the back surface of the pelvis. In endometriosis patients, certain tracts of tissue are laid down across the rear surface of the pelvis which are not yet endometriosis, but which can change into endometriosis later in life with the proper stimulus.

This explains why endometriosis is most commonly found in the cul-de-sac, uterosacral ligaments, and broad ligaments. (It is not due to the effects of gravity as Sampson's theory postulates). These tracts of tissue primarily involve the peritoneum, but can also involve deeper tissue layers.

Other wild cards are dealt. One results in a more widespread distribution of these embryonic tracts in areas remote from the pelvis, such as the diaphragm, intestinal tract, or brain. Another wild card controls how biologically active an area of endometriosis will be: biologically active areas are more likely to become scarred and involved with invasive disease, which is more likely to cause pain.

Still other wild cards determine whether the patient will develop mitral valve prolapse, rheumatoid arthritis, adenomyosis or fibroid tumors of the uterus.

At puberty, the ovaries begin to produce estrogen. Metaplasia (the changing of one type of tissue into another) is occurring as a normal process on the cervix and elsewhere in the female genital system as a result of estrogenic stimulation as the woman within blossoms. However, estrogen is also acting on the wayward tracts of tissue which were laid down in embryonic life. These tracts of tissue begin to change into endometriosis, with varying degrees of geographic distribution, biologic activity and invasiveness which have been predetermined genetically by the various wild cards dealt at the moment of conception.

At first, the tissue is colorless, but the passage of time can bring surrounding fibrosis and scarring which can give a yellow or white color. In addition, endometriosis secretes an unidentified substance which destabilizes surrounding capillaries, resulting in a red or blackish color. This substance also brings white blood cells to the region which can release irritating substances.

This estrogenic stimulation can be increased by environmental estrogen mimics, such as dioxin. Higher levels of estrogen can induce more estrogen receptors in the metaplastic tracts, resulting in the full expression of predetermined disease strength.

Blood studies in adult women with endometriosis may identify abnormalities of the immune system which are left over from the mild abnormalities of the fetal immune system responsible for the spectrum of developmental abnormalities associated with endometriosis. These immune system abnormalities are an echo of the "Big Bang" of conception, however, not a facilitating factor allowing the occurrence of endometriosis in the adult by virtue of reflux menstruation.

Women with pelvic endometriosis may begin to develop various types of pelvic pain. Those with intestinal or diaphragmatic endometriosis begin to develop intestinal symptoms or chest and shoulder pain. When endometriosis is excised surgically, the tracts of tissue which can undergo metaplasia may be removed completely, in which case endometriosis will not recur in that area. If deeper substrate tissues are involved by metaplastic tracts, recurrence is possible if these tracts have not been completely removed.

However, recurrence is much lower than the 100% predicted by Sampson's theory, and when endometriosis is found, it is usually much less than present previously. Despite surgical cure of endometriosis by excision, some patients may go on to develop adenomyosis or fibroid tumors which may eventually require hysterectomy for treatment.

Another reason Sampson's theory doesn't make sense is that in some elderly males with prostate cancer, one treatment is to remove the testicles and start the patient on estrogen. In some patients, this has resulted in the diagnosis of endometriosis in the male bladder or prostate. This occurs because at 6 to 8 weeks of embryonic life, the male and female internal genital systems exist in all humans. In genetic males, the female system is supposed to regress, and in genetic females, the male system is supposed to regress. This does not always happen perfectly, however.

Well, there you have it. This picture of endometriosis is certainly more complex than that proposed by Sampson. But a picture is all that there is at this point. Effective medical therapy for endometriosis is more than light years away if attention is still directed toward reflux menstruation as a cause. Until then, aggressive excision of endometriosis remains the best way to eradicate the disease.