Endometriosis is the presence outside the uterus of tissue which somewhat resembles endometrium from the uterine lining. It affects approximately 10% of the female population in their reproductive years and may cause non-menstrual or menstrual pain as well as infertility. The most widely held theory of origin is Sampson's theory of reflux menstruation. Sampson's final version of his theory [1] proposed that endometriosis occurs as a result of the reflux of menstrual blood out through the end of the fallopian tubes, this blood carrying with it viable cells from the endometrial lining which could attach to peritoneal surfaces, proliferate, invade, and become the disease known as endometriosis.

This theory has undergone successive mutations by Sampson and others to accommodate new information. It is helpful to read Sampson's earlier papers with one of his last papers as a guide to understand fully the thought processes which resulted in this theory [2].

Sampson burst on the endometriosis scene in 1921, [3] with a study of 23 cases of ovarian chocolate cysts, although endometriosis was confirmed histologically in only 9 cases. This focus on the ovaries convinced him that the ovaries were the most common site of disease and he proposed that endometriosis appeared on or within the ovaries as a result of metaplasia or embryonic rests. He noted that ovaries involved by endometriosis were frequently adherent to the pelvic sidewall or uterus, in which locations endometriosis could also be found. He surmised that the endometriosis on these contiguous pelvic surfaces was the result of direct extension or seeding from menstrual bleeding from ovarian endometriotic cysts or from superficial disease of the ovarian cortex. Like Cullen, [4, 5, 6, 7] Stevens, [8] and Lockyer [9] before him, he described thick adhesions in the cul-de-sac between the rectum and uterus which could accompany ovarian endometriomas and proposed that such adhesions were the result of repeated irritation of the peritoneum by monthly leakage of blood from the ovarian cysts. Although he recognized that endometriosis could be present in an 'adenomyomatous' form beneath the visible adhesions with involvement of both the rectal wall and the cervical stroma, his focus on this morphologic feature (which now is commonly referred to as obliteration of the cul-de-sac) revolved around an adhesive process rather than an endometriotic process. Observing that only 9 of 16 married women had been pregnant in an era when the normal pregnancy rate was thought to approach 100%, Sampson introduced the notion that pregnancy protected against endometriosis or that infertility promoted it. This was before tubal, ovulatory or male factors were commonly recognized as possible contributors to infertility, and certainly well before the current knowledge that pain (not infertility) is the most common and most specific symptom of the disease. In that day, the term 'adenomyoma' was used to reflect the histologic appearance of what is now commonly called invasive or deep endometriosis, where glands and stroma of endometriosis are surrounded by dense fibromuscular metaplasia somewhat resembling tissue which can be seen in a uterine leiomyoma.

With increasing experience and reading of the older literature, Sampson shifted his thoughts by 1922, although not necessarily toward greater clarity [10]. He noted that Russel in 1899 had referred to earlier works by Nagel and Waldeyer who had found that the germinal epithelium of the posterior fetal pelvis was the origin of all Müllerian structures. In fact, evidence existed that the germinal epithelium of the mature ovary itself could give rise to endometriosis since germinal epithelium could be traced in serial sections of ovarian cortex and seen to transform into tubular structures containing glandular structures resembling endometrium. While this seemed to solidify the concept of an embryonic origin of endometriosis, Sampson headed in another direction based on speculation and specious concepts which must have seemed correct to him at the time:

1. He observed that the surface of the ovary could contain ciliated epithelium resembling the epithelial lining of the Fallopian tube, bringing to mind the possibility that Müllerian epithelium of the Fallopian tube could slough and shed out of the end of the tube and attach and implant on the ovary.
2. He concluded that the ovarian tubules of Nagel and Waldeyer must be the result of implantation of epithelium from the Fallopian tube or endometrium on the ovary with secondary formation of tubules.
3. He concluded that these tubules were the origin of ovarian endometriosis and that the ovaries are the most common site of disease in part because they are so near the ostia of the Fallopian tubes.
4. He concluded that endometriosis formed later in life, usually after the age of 30, because he had only seen two patients younger than 30, so endometriosis could not possibly be a congenital or developmental process, otherwise it could be seen shortly after menarche.
5. By a method of study which is unclear, he noted that ovarian and peritoneal endometriosis appeared to be of the same chronological age, so they must have a common source and time of origin such as retrograde menstruation.
6. Observing obliteration of the cul-de-sac, uterine leiomyomas and endometrial polyps in some, but not all patients, he concluded that these pathologies might result in retrograde passage of menstrual blood out of the Fallopian tubes, which always appeared to be open, thus facilitating development of endometriosis.
7. He noted that the ovarian adhesions associated with endometriosis were similar in location to adhesion resulting from salpingitis spreading out from the end of the tubes so they must have a similar transtubal origin, such as reflux menstruation.
8. He noted that some patients could have adenomyomatous endometriosis without coexisting ovarian endometrioma cysts, indicating that infrequently peritoneal endometriosis might exist without ovarian disease.

In his final version [1] of the theory of reflux menstruation, he had concluded that the ovaries are not as commonly involved by endometriosis as he had once thought. Peritoneal disease could occur in the absence of ovarian disease and actually seemed more common and clinically more important than ovarian disease, a position he later affirmed [2]. Since he had seen menstrual blood exiting the tubal ostia during surgery performed during menses, and since some Fallopian tubes removed at hysterectomy had endometrial fragments within them, he concluded that refluxed endometrium was likely the source of ovarian and pelvic endometriosis, and that rupture or bleeding of ovarian endometrioma cysts could result in peritoneal disease by secondary implantation. It is clear in his writings that the mode of spread of ovarian cancer weighed heavily in his conclusions about the spread of endometriosis. It is also clear that he considered endometriosis to be identical to endometrium and that the tubes were usually open. Among 293 cases of endometriosis surgically diagnosed by that time in his career, six had bilateral tubal blockage and he concluded that reflux menstruation must have occurred before blockage of the tubes. Much of the rest of his career was spent defending his theory against attacks by Emil Novak, one of the pre-eminent gynecologists of the first half of the 20th century. Dr Novak was highly skeptical of the evidence supporting reflux menstruation as the origin of endometriosis and favored coelomic metaplasia instead [11].

Where to begin? How could an initial study with such small numbers in which most patients did not have histologic confirmation of ovarian endometrioma cysts be accepted as a seminal paper on the disease? Sampson's intimation of a cause and effect between endometriosis and infertility seems unsupportable since other fertility factors were not considered, and the notion that normal fertility approaches 100% seems unreasonable today. Sampson could have easily argued that since most of his married patients with endometriosis had been pregnant, that pregnancy or fertility causes endometriosis. There was no evidence whatsoever that tubal epithelium sloughs, attaches to the ovary and grows into the ovarian tubules of Nagel and Waldeyer. Sampson also took evidence which had previously been interpreted by those who developed it as showing development of ovarian cortical epithelium into glandular tissue (from the 'inside out') and turned it on its head, now introducing an interpretation whereby glandular elements alight upon the ovary and begin to penetrate it (from the 'outside in'). Again, there was no real evidence to support this usurpation of intellectual primacy. The youngest patient with endometriosis was noted to be 10.5 years, [12] and an entire literature on the visual appearance of endometriosis shows that teenagers can, indeed, have endometriosis which is often not identified because it is so subtle. Sampson's incorrect conclusion that endometriosis forms only in later years was clearly the result of selection bias since he was concentrating on disease which was apparently easily and more frequently diagnosed because of the presence of ovarian endometrioma cysts, which occur more commonly in older age groups. His conclusion that endometriosis could not be congenital was unsustainable since it arose from incorrect data, so another of the initial pillars supporting his belief in his theory topples. Regarding the notion that uterine structural or positional abnormalities might encourage reflux menstruation and development of endometriosis, he apparently did not consider the likelihood that endometriosis might have been present before the development of fibroids or uterine retroversion related to obliteration of the cul-de-sac, thus rendering moot the notion of facilitation of menstrual reflux by these conditions. The conclusion that adhesions of endometriosis must have a tubal origin since they are similar to adhesions resulting from salpingitis is obviously comparing apples to oranges. The most common site of involvement by disease began to shift in Sampson's mind from the ovaries to the peritoneum, especially the cul-de-sac, a process thought to be facilitated by the effects of gravity, although a plausible alternate explanation based on fetal pelvic organogenesis across the posterior coelomic cavity exists [13]. The notion that endometriosis is identical to endometrium has been thoroughly dispelled by modern data [14].

Most of Sampson's theory was promulgated on the basis of speculation, errors of interpretation or leaps of faith, aided and abetted by Berkson's fallacy and skewed by the very small number of cases seen in his career. Additionally, Sampson obviously had a personal bias toward supporting this theory and was its greatest champion for over two decades. If his theory is misleading and incorrect, he can be forgiven since he was doing the best with the evidence at hand. But what of modern support for this theory? We have much more evidence than did Sampson. How have we used it? Sadly, not well. In Sampson's absence, generations of authors have become apologists for this theory. What has been written in the distant past has often been repeated without thought or consideration of more recent available evidence. Circumstantial evidence is sometimes grotesquely twisted in an effort to support the theory. There are several examples of this which are readily identifiable to modern clinicians.

Continuing errors of interpretation

It is still possible to read that the ovaries are the most common site of disease. This notion was on its way out in 1927 by Sampson's own evidence and has no place in rational discussion of endometriosis. Modern studies of endometriosis in all its morphologic forms clearly indicate that the cul-de-sac is the most common area of pelvic involvement [15]. Even if the frequency of involvement of the right ovary were added to that of the left and the total taken as one area, the frequency of involvement of the ovaries would still trail the cul-de-sac, left broad ligament, left uterosacral ligament, right broad ligament and right uterosacral ligament.

One of the consequences predicted by Sampson's theory is that more of the pelvis should be involved by endometriosis with the passing of time. If monthly seedings of menstrual endometrium were occurring, the pelvis should fill up with endometriosis like a pasture filling up with dandelions. Older age groups should have more disease than younger age groups, and most untreated patients should develop more extensive disease over time. Such a progressively spreading character of endometriosis is a widely held belief among clinicians. But what is the evidence that this occurs? Actually none at all. Older age groups do not have more disease than younger age groups regardless of whether disease extent is measured by the number of pelvic areas involved, [16] the revised American Fertility Society (rAFS) classification system, [17] or by the square centimeters of peritoneum involved by disease [18]. Most untreated patients do not have disease progression between surgical investigations [19, 20, 21, 22].

Another of the consequences predicted by Sampson's theory is that it should be impossible to cure endometriosis since the pelvis will only be re-seeded by monthly reflux menstruation. Actually, it has been known for over half a century that endometriosis can be cured by conservative surgery, [23] and recurrence rates following conservative surgery are surprisingly low [24, 25, 26, 27, 28, 29, 30, 31]. And cure rates of over 50% following one conservative surgery in 'resistant' or difficult cases have been confirmed by modern studies at laparoscopy [32] or laparotomy [33].

The mysterious circulation within the peritoneal cavity

A slight increased frequency of involvement of the left side of the pelvis has been explained by an especially strained mutation of Sampson's theory. An alleged intraperitoneal circulation of fluid from the left upper quadrant down across the cul-de-sac and ascending to the right upper quadrant is thought by some to alter the pelvic microenvironment. Thus, eddies of this circulation caused by the protective effect of the sigmoid colon's physiologic attachment to the left pelvic brim supposedly predispose to the deposition of regurgitant cells in the left side of the pelvis which is more protected by the sigmoid. The 'proof' of existence of such a circulation is dubious. In one experiment on stillborn infants, artificial perforations were created in intestines, and barium was injected continuously over 3 hours and x-rays were taken to follow the course of the barium [34]. Depending on where the perforation was created, barium could literally disperse in any direction. In one stillborn female infant, the uterus was perforated and barium was injected at a pressure of 100 mmHg and was seen to travel into the right upper quadrant! In another study, [35] a catheter was passed through the right subcostal margin of the abdominal wall of rhesus monkeys and led down to the right iliac fossa. Another catheter was placed into the left upper quadrant of the peritoneal cavity and not advanced. Radioactive albumen was injected through the second catheter and was found to eventually track up the path of the first catheter, which is unsurprising. It is astounding that such evidence is offered to support the theory of reflux menstruation.

The immune system arm of Sampson's theory

One persistent question about reflux menstruation is why all women do not develop endometriosis. It has been found that between 80% [36] and 90% [37] of women with patent Fallopian tubes have bloody peritoneal fluid during menses, while only 15% of women with tubal blockage have bloody fluid during menses [37]. This suggests that the actual rate of bloody peritoneal fluid due to reflux menstruation may be about 75-80% of women rather than 100% as is often stated. In any event, it seems safe to say that a great majority of women have reflux menstruation but most do not develop endometriosis. While one possible conclusion that comes quickly to mind would be that reflux menstruation has nothing to do with development of endometriosis, supporters of Sampson's theory have provided yet another mutation to explain this on an immune basis.

The immune arm of Sampson's theory alleges that women with endometriosis have decrepit immune systems which cannot identify and destroy refluxed menstrual endometrium and so these cells are allowed to attach to peritoneal surfaces and to proliferate and invade to become the disease known as endometriosis. In women with normal immune systems, the refluxed cells are supposedly attacked and digested before attachment can occur. Since the immune system functions in part to identify 'non-self', one immediate objection to this notion is that the immune system should not be expected to attack refluxed endometrial cells in the first place since they are 'self'.

If all women destined to develop endometriosis have decrepit immune systems, then there should be an extraordinarily high rate of immune system diseases, cancers, and opportunistic infections perhaps approaching 100% in women with endometriosis. However, a large questionnaire survey of women with surgically proved endometriosis found that most women with endometriosis did not have endocrinological disease, autoimmune inflammatory diseases, or chronic pain and fatigue, with the prevalence of these conditions ranging between 0.5% and 9.6%. Nonetheless, these prevalence rates were increased by between 0.9 times and 180.5 times over the prevalence of historical population controls [38]. A population-based study in Sweden found a slight increase of ovarian, breast and hematopoietic cancers among patients with endometriosis, but it was clear that most women with endometriosis will not develop cancer, [39] and no one has documented a high rate of opportunistic infections in women with endometriosis. Another problem with this concept is that no one has produced evidence of the immunological warfare which is alleged to occur in the pelvis of women with normal immune systems who do not develop endometriosis. Presumably, there should be easily obtained photomicrographic evidence of macrophage destruction of refluxed endometrium since this must be occurring in billions of instances.

Decreased natural killer (NK) cell activity against autologous endometrium has been identified as due to both a defect in NK activity as well as resistance of the endometrium to NK activity, [40] and this defect is more pronounced with increasing stage of disease [41]. This defect persists after excision of endometriosis, indicating that it apparently is not a result of the effect of endometriosis but a primary defect originating elsewhere in the body [42]. The NK defect may be secondary to an unknown effect of the uterus or ovarian endometriomas since removal of these organs results in an improvement of NK activity [43]. Thus, the evidence suggests that NK activity is not directly related to endometriosis and seems unlikely related to its origin in the manner postulated.

The immune system can be activated in patients with endometriosis, with increased macrophage activity found both within the peritoneal fluid itself, [44] as well as within the endometriotic lesion itself [45].

It is clear that most women with endometriosis do not have immune system problems but that their immune systems are dynamic and active, producing an appropriate inflammatory response to the effects of the disease. Some, but not all, may have accompanying abnormalities of the immune system but it would be incorrect to conclude that these abnormalities have anything at all to do with facilitating attachment of refluxed endometrial cells.

Where is the evidence?

Despite almost 100 years of research, Sampson's theory remains a theory supported only by circumstantial evidence. The simplest evidence to prove Sampson's theory would be to display photomicrographs of the steps that are missing: (1) Initial attachment of endometrial fragments to peritoneal surfaces. (2) Secondary proliferation and invasion of the attached cells. These two steps occur by the billions during the course of any year so it would be simple to photograph one or both of these steps and our textbooks should be filled with clear photographic evidence of hundreds or thousands of examples of initial attachment. Despite the ease of such proof, no convincing photomicrographs exist as such proof. Researchers examining the concept of microscopic endometriosis found no evidence of initial attachment in hundreds of biopsies of normal peritoneum in patients with endometriosis [46, 47, 48, 49, 50, 51].

The dangers of Sampson's theory

While it is difficult to say anything positive about the theory of reflux menstruation as the origin of endometriosis, the story worsens. Sampson's theory of reflux menstruation is stifling progress in research and treatment of endometriosis. Because all treatment failures can be explained away by this theory, a clinician does not have to worry about whether the treatment used has efficacy since 'everybody knows that the disease comes back because of reflux menstruation'. Thus, medical therapists may beat their chests and exult that pain is decreased during ovarian suppression with the thought that the disease might be eradicated or 'dried up'. When pain returns after the return of ovarian function, the patient can be told that the reason was not failure of the medicine to eradicate the disease, but because it is the nature of the disease to recur. Similarly, when endometriosis is treated by shining a light at it or by spraying electrons at its surface, Sampson's theory can be used to explain any treatment failures. Endometriosis is thought to be an incurable, chronic, enigmatic, recurrent, progressively spreading disease which can only be treated by removal of the uterus, tubes and ovaries (which are uncommonly involved by endometriosis) with retention of the disease. This pessimistic view seems to be the result of several generations of clinicians observing the results of ineffective medical therapy or less effective surgical therapy, blaming treatment failures on Sampson's theory and ignoring the possibility of cure by removal of all disease from the body.

Research on endometriosis is hampered by Sampson's theory because so many dollars and minds are devoted to chasing this theory and various intellectual spinoffs which have led nowhere. It would be much cheaper and more productive for effort to be spent in trying to obtain photomicrographs of initial attachment. If initial attachment does not occur, then it would be unnecessary to waste more time on the theory of reflux menstruation and real progress could then be made.

The new endometriosis paradigm: what is old is new again

In the vacuum left by revocation of the reflux menstruation theory of origin of endometriosis, coelomic metaplasia as championed by Novak, [11] Moench, [52] and Gruenwald [53] rises to the top of the short list of possible causes of the disease, with certain modern alterations and insights: polygenic and/or environmental factors present at the moment of conception result in estrogen-responsive target mesenchymal substrate being laid down during embryogenesis in tracts or fields which roughly follow the pathways of fetal pelvic organogenesis caudally across the posterior coelomic epithelium. The distribution of these tracts may vary from female to female, and the inherent potential biologic activity of these tracts may also vary even at different sites in the same pelvis. For example, tracts laid down in parenchymal structures, such as the uterosacral ligaments, or within the muscularis of bowel or bladder have the potential of undergoing fibromuscular metaplasia which is not seen with simple peritoneal or ovarian endometriosis. Undifferentiated substrate tracts in girls or young women have no distinctive morphology that would allow them to be identified at surgery. During puberty, rising estrogen production by the ovaries causes these tracts to begin to undergo metaplasia into various preordained forms of endometriosis or endosalpingiosis with the many possible differences in histology, morphology and function that have been observed. In a metaplastic process similar in timing to squamous metaplasia of the cervix, by their mid-twenties women have developed essentially all of the sites of endometriosis they will have. Those sites destined to develop fibromuscular hyperplasia or adenomyotic changes may continue to do so until the mid-thirties. This model of embryologically patterned metaplasia, a derivation of the concept of Mülleriosis, [13] predicts the surgical results that have been observed following conservative excisional surgery [32, 33]. If surgery is performed and if all endometriosis and all underlying substrate which is destined to form endometriosis are removed, then endometriosis can be cured by a single conservative surgery. If all existing endometriosis is removed but not all underlying or adjacent undifferentiated estrogen-targeted substrate is removed, then recurrence of new disease is possible. However, such recurrent disease will almost always be much less than the initial amount of disease, [32] since the majority of substrate will have already changed into endometriosis. If the uterus, tubes and ovaries are removed but endometriosis is left untreated, patients are at risk for continuing symptoms, especially if they have deep disease or intestinal involvement [54]. Local growth factors associated with the metaplasia of healing can induce formation of only small amounts of superficial endometriosis within or at the margin of the surgical site. Some patients can have endometriosis-associated Müllerian disorders of the uterus, such as adenomyosis or fibroids, which may necessitate surgery later. Gruenwald pointed out that this model can explain the occurrence of endometriosis anywhere in the body or in males, [55, 56, 57] since between 6 and 8 weeks of fetal development, all fetuses contain both Müllerian and Wolffian tracts.

The high probability that reflux menstruation is not the origin of any form of endometriosis is one of the main reasons to learn about aggressive excision of the disease, for cure of endometriosis is within the grasp of gifted surgeons around the world. The other reason to learn about excision is that patients are truly helped by the process and excision of endometriosis becomes a life-changing experience for both patient and surgeon.

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