The histogenesis of endometriosis remains controversial. It is thought that no one theory can explain all cases. Because of new basic knowledge, we must continuously scrutinize conventional wisdom related to the disease. Modern studies and reinterpretation of historic evidence lead inevitably to a single model of the origin of endometriosis that is an expansion of the embryonic rest theory. The term mülleriosis is suggested for this model since the term endometriosis is too limiting. This model of disease origin suggests its own proof.
Discussions of the origin of endometriosis are of more than just academic interest because rational treatment of the disease could be devised if its origin were known. However, discussions in the literature have changed very little in the last 60 years, with proponents of various origin theories presenting and re-presenting circumstantial evidence to support their biases.
Modern study techniques, using near-contact laparoscopy [2, 2], pelvic mapping , vigorous peritoneal biopsies [1, 2, 3] and astute clinical associations , have resulted in new basic and clinical information on the disease not available to earlier theorists.
It is now apparent that many of the visual manifestations characterized by the color [2, 3] and size  of lesions are so subtle that they have been overlooked, no doubt, by past and many present investigators. That is likely because most older papers speak of "black" or "powder-burn" lesions or of other dark manifestations resulting from hemorrhage adjacent to endometriotic glands and stroma. We now know that the black lesion constitutes only a third of the visual spectrum of the disease  and that lesions as small as 100 µm have been detected. When the entire spectrum of manifestations is considered, it becomes apparent that pain is the most common symptom and that infertility is a presenting complaint in less than one-third of patients.
Because of the above observations, it is likely that conventional wisdom regarding the origin of endometriosis is skewed by a significant selection bias on two levels: adherence to an inaccurate clinical profile for patient selection and failure to identify the disease at surgery.
Endometriosis actually is a disease of predominantly fertile women of any age suffering from predominantly non-menstrual pelvic pain caused by lesions that are predominantly non-black and easily missed and that do not spread progressively throughout the pelvis with advancing age. Infertility and dysmenorrhea are less common symptoms and frequently are not due to endometriosis. Anatomic and physiologic derangements frequently accompany but are not necessarily the result of endometriosis.
As long as the origin remains unknown, anyone caring for endometriosis patients is obligated to consider his own model of disease origin in order to select treatment. There are many treatments because there are many theories of origin. It would be immensely satisfying if one theory could explain all that we know about the disease.
Mülleriosis, my current best-fit model of the origin of endometriosis, refers to a developmental defect in the differentiation or migration of any cellular component of the müllerian duct system, whether endometrial, myometrial, tubal or cervical, or of the coelomic epithelial anlage of the adult peritoneum, from which both the müllerian ducts and peritoneum arise. The concept of mülleriosis is a broadened view of the embryonic rest theory advanced by Russell  and others. It is different from Sampson's Müllerianosis, a term referring only to ectopic endometrial elements and that he considered and then discarded .
The non-spreading nature of endometriosis  and its low recurrence rate after conservative surgery [8, 9, 10, 11, 12] would be a natural consequence of a developmental birth defect. Since the pathways of müllerian differentiation and migration are caudally down the dorsal coelomic epithelium [13, 14], it is not surprising that the most common pelvic sites are the pathway of the posterior pelvis, particularly the cul-de-sac and uterosacral ligaments . Once a defect in differentiation or migration is proposed, occurrence of the disease anywhere in the female body is explainable [15, 16, 17, 18, 19, 20]. Occurrence in the arm or thorax can be explained by the fact that the genital ridges from which the müllerian ducts spring are located quite high, near the thorax and arm buds of the embryo [21, 22].
Endometriosis of the male bladder  and prostate  is explainable by incomplete dedifferentiation of the müllerian ducts in embryonic life. Occurrence with other müllerian structural defects, such as cervical atresia , diethylstilbestrol syndrome [26, 27] and Rokitansky-Kuster-Hauser syndrome , probably represents an ontologic relationship: whatever was operating in embryonic life to result in a mesenchymal structural defect also induced aberrant differentiation or migration of endometrial cells. The dictum "endometriosis does not develop in the absence of endometrium" is not absolute [28, 29] and does not rule out an ontologic relationship of the endometrium to endometriosis.
The positive association with peritoneal pockets [4, 19, 20, 30] probably represents another ontologic relationship, a simultaneous defect in the formation of the pelvic peritoneum associated with aberrant differentiation or migration of endometrial-tissue-to-be.
The occurrence of the other ectopic müllerian tissue, such as cervical, myometrial and tubal (Figure 1) , simply means that any müllerian cellular component is at risk of aberrant differentiation or migration. Endometrial-tissue-to-be is by far the most common and symptomatic.
Fimbria-like structure removed from the left uterosacral ligament.
The various degrees of histologic differentiation that occur intralesionally and interlesionally (Figures 2 and 3) may result from incomplete maturation during embryogenesis or from the varying and low levels of estrogen and progesterone receptors in the lesions [32, 33, 34]; they themselves may be the result of incomplete maturation. A pathologic diagnosis of "mesothelial glandular rest" may represent either an endometrial gland sectioned away from stroma or a forme fruste of endometriosis.
Some of the glandular and stromal elements are more differentiated than others in the microscopic field.
Intralesional variation in differentiation is possible with endometriosis. The well-differentiated gland and stroma (left) are in sharp contrast to the sparse appearance of another part of the same gland (right). The dark area at the bottom represents a fold of tissue created during sectioning. If a section had been taken only through the material on the right, the diagnosis of the endometriosis would not have been made. The diagnosis might have been mesothelial inclusion cyst.
Several studies have found a majority of parous patients among those with endometriosis, thus weakening the association between endometriosis and infertility [1, 4, 35, 36, 37, 38, 39, 40]; no evidence exists of a beneficial effect of pregnancy on endometriosis [41, 42, 43]. Since endometriosis is not always the unequivocal cause of infertility, an alternative explanation for infertility from embryonic life could lie with subtle structural defects of the fallopian tubes that lead to tubal dysfunction or problems anywhere in the pelvis at the molecular level. Are the ovulatory problems [44, 45, 46, 47] that have been identified in patients with endometriosis secondary to the disease, or might they be a manifestation of a primary defect in embryogenesis? The same questions apply to the recently described alterations in the immune system in these patients [48, 49]. Visible structural tubal defects, such as accessory fimbriae and hydatids, seem more common in patients with endometriosis and may even have a positive ipsilateral relationship with the disease in the pelvis.
The facts and speculations described above weaken several legs of Sampson's theory. The idea that rare obstructions to menstrual outflow, such as cervical stenosis, predispose to endometriosis by enhancing reflux menstruation is unproven and less plausible than the possibility that both the rare obstructive element and the endometriosis share a common developmental etiology. No longer can it be said that the ovaries are the most common site of disease because they are closest to the source of reflux menstruation. The occurrence of the disease deep in the pelvis due to gravity is no longer the only plausible explanation of the disease in that location. The twin notions of progressive spread of disease throughout the pelvis and an inevitably high recurrence rate after conservative surgery are false. The notion is inaccurate that pregnancy provides protection against the disease, and no one has ever proven that pregnancy has a toxic effect on it. The idea that endometriosis menstruates and sheds in the peritoneal cavity has never been demonstrated microscopically, and it is difficult to believe that it would ever occur since no-one has ever defined functional layers of endometriosis similar to those of the endometrium. Additionally, endometriosis does not respond like native endometrium because of low and varying populations of hormone receptors.
In addition to the above arguments countering Sampson's theory, one fact speaks most strongly against it: no one has ever demonstrated convincing microscopic evidence of early peritoneal attachment and implantation of endometriosis. Considering the millions of patients who have been diagnosed as having the disease and the millions of biopsies that have been performed, surely someone should have found the "golden slide" demonstrating this supposedly most common and most important mode of origin. In fact, microscopic study of clear papules, which are among the earliest manifestations of the disease reported , has shown no convincing evidence that these cells have attached recently (Figure 4). Recent studies [50, 51] finding bloody peritoneal fluid at menses have proven neither reflux menstruation nor implantation of viable endometrium, and patients with endometriosis do not have preferential tubal regurgitation of endometrium [52, 53]. Since Sampson's theory has been advanced purely on the strength of circumstantial evidence, this absence of proof must be counted as strong circumstantial evidence against it.
Low-power photomicrograph of a clear endometriosis papule on the peritoneal surface. There is nothing to suggest recent or remote implantation.
If endometriosis is viewed as a developmental abnormality that is ontologically related to numerous other anatomic and physiologic developmental defects, then it follows that evidence for this concept could be found by examining the female pelvic peritoneum before puberty.
Report of a study
Materials and methods
Since a pelvic mapping study in women showed that the cul-de-sac was the most common site of endometriosis in women , I decided to examine peritoneal biopsies from the cul-de-sac of female infants who died of sudden infant death syndrome (SIDS). The Oregon medical examiner's office is responsible for investigating suspect deaths and routinely performs autopsies on SIDS victims. Specimens were obtained consisting of the posterior cervix, cul-de-sac and part of the rectum bound by the uterosacral ligaments. Eight specimens were obtained from the medical examiner, while one was obtained from a deputy examiner working in the community.
A magnifying glass was used to examine the peritoneum of the cul-de-sac in all cases. In one case a tiny, whitish plaque, approximately 200µm in diameter, was identified. It was excised, fixed in formalin and stained with hematoxylin and eosin for light microscopy.
The microscopic findings associated with the plaque from the cul-de-sac of a 2 month-old infant showed a flattened, glandular structure with well-defined epithelium surrounded by questionable stroma (Figure 5).
High-power photomicrograph of a glandular lesion from the cul-de-sac of a 2 month-old female infant.
Modern study and reinterpretation of the endometriosis literature led to a model of disease origin that predicted that it would be present at birth and most probably would be found in the cul-de-sac. The above evidence supports this concept. Previous investigators found no such evidence in the fetus [21, 22, 54], although it is not clear how closely or how often the cul-de-sac was examined. No one knows what endometriosis is supposed to look like microscopically in an infant. Although fetuses are exposed transplacentally to maternal estrogen, that exposure may not be sufficient to cause stromal cells to attain identifiable characteristics. Additionally, there is no information on hormone receptor populations in this area in infants. Therefore, the tissue found in this study may or may not represent endometriosis. However, the thought is provocative and suggests the need for further study of the posterior pelvic peritoneum of premenarchal females, whether at autopsy or at laparotomy for surgical indications. Until that is done, there will be a continuing controversy over the origin of endometriosis.
Although the finding of glandular elements suggestive of endometriosis in an infant lends support to the concept of an embryonic rest source, metaplasia still could be invoked to explain the origin of endometriosis, although with specific requirements: certain predetermined areas of the pelvis must somehow be selected to undergo metaplasia, and the relative extents of these areas must be similar and fairly constant in frequency in all age groups
Although evidence of possible metaplasia in a patient has been offered , the presumed ongoing differentiation illustrated could as well represent an arrest of embryonic differentiation, and the invaginations of the ovarian surface illustrated may represent simply one of the many morphologies of endometriosis rather than a way station of metaplasia.
A Millipore filter chamber packed with minced endometrium and implanted autologously in rabbits resulted in induction of glandular elements across the filter material . That finding cannot be accepted as proof of peritoneal metaplasia to endometriosis since it is not clear where the chambers illustrated were implanted (either the cul-de-sac, broad ligament or anterior abdominal wall) or that the glandular elements truly represented endometriosis.
The concept of mülleriosis does not try to explain surgical implantation of endometriosis [56, 57, 58]. Such cases do not prove implantation on the peritoneum or anywhere other than the surgical site since a fresh surgical scar differs fundamentally from the peritoneum.
Evidence of early implantation has not been presented in the literature. To be convincing, such evidence should demonstrate obvious microscopic evidence of the adherence of endometrial fragments to the peritoneal surface without penetration. The nature of the adhesive action, whether fibrous or otherwise, might be elucidated by electron microscopy. Beyond adherence, evidence of early penetration remains to be demonstrated. Without such evidence, the implantation theory will remain a gynecologic windmill before which successive generations of theorists will joust.
This paper was originally published in November, 1988. Now, nearly a quarter of a century later, a pertinent question is whether subsequent research has provided new evidence in support of the theory of Mülleriosis as the best-fit origin of endometriosis.
One suggestion made in this paper was the need for further investigation of the posterior pelvic peritoneum in premenarchal girls either during abdominal surgery or at autopsy. While no such studies have been conducted to date, Ebert and colleagues  describe a case of histologically confirmed endometriosis of the right portion of the cul-de-sac and right uterosacral ligament in a premenarchal 9-year-old girl, presenting with unexplained cyclic pelvic pain. Furthermore, findings in the original series of biopsied specimens from 9 autopsied female infants have since been supported in a subsequent series of 101 autopsied human female fetuses, in which 9 cases of endometriosis were confirmed . Just as in the original series, the location and patterning of endometriosis as well as the rate of occurrence closely mirror that of the disease manifest in adolescent girls and women.
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