A critical review of the development of Sampson's theory of origin of endometriosis


The origin of any disease is important to know as precisely as possible, because rational, effective treatment can then be developed. The origin of endometriosis continues to be debated against a background of confusion. This suggests that some fundamental concepts about the disease might be wrong. For example, two decades ago it was learned that most visual manifestations of endometriosis had long been overlooked, which should have led to re-evaluation or disposal of existing concepts about endometriosis, including its origin. Instead, this new information was patched onto existing thought, which only amplified confusion about the disease.

Could Sampson have been wrong? A critical appraisal of the development of his theory of origin of endometriosis might illuminate errors of thought which persist to this day, allowing us to discard what is wrong so that we may see what is correct.

Certain steps must occur during the development of a theory of origin of a disease, from the first descriptions to a robust, profound understanding of origin and effective therapy (table 1).

Table 1. Steps in developing a theory of disease origin
  1. Accurate initial observations
  2. Confirmation and expansion of observations
  3. Development of a theory of origin
  4. Comparing theory with old and new facts
  5. Adjusting or discarding theory to accommodate all facts and observations
  6. Emergence of the correct pathogenesis

The efficiency with which these necessary repetitive steps of observation and introspection are taken may vary with the scientific era: initial observations in a technologically unsophisticated era may result in a slower and less efficient development and dissemination of knowledge than first descriptions in a modern era with the advantages of advanced technology and instant communication of thoughts. However, modern instantaneous electronic communications of incorrect thoughts may do harm more quickly. Repeated and robust confirmation of initial observations is important since anecdotal reports or small series may not be representative of the entire spectrum of a disease.

The rate of development of valid information about a disease is also important in defining a theory of origin. Intellectual voids left by slowly developing knowledge will be filled with myths, nonsense, or "herd wisdom", a consensus whereby physician-scientists act on their mutually supported beliefs rather than on science. Near-truths or outright mistakes, if repeated by the "herd" often enough, will seem to masquerade as scientific fact, although the supporting evidence can never quite be pinned down. Progress in identifying a correct theory of origin will be delayed, and the resultant persistent ignorance will result in frustrating confusion, especially among patients. More importantly, an incorrect theory of origin necessarily results in misdirected treatment which may harm patients and waste resources.

Eliminating scientific confusion about the origin of endometriosis does not necessarily require a laboratory but can be combated by examining how closely the steps in table 1 were followed. If the steps were not followed rigorously, errors of thought will occur, and confusion will continue. The history of endometriosis is littered with unfortunate examples of departures from the required steps of developing a correct theory of origin, which perfectly explains the confusion so prevalent today. A portion of this history will be discussed by examining the original works of Dr. Sampson.

...the history of endometriosis is littered with unfortunate examples of departures from the required steps of developing a correct theory of origin, which perfectly explains the confusion so prevalent today...

Development of Sampson's theory of the origin of endometriosis

As an historical note regarding nomenclature, the term "endometriosis" did not exist when Sampson began writing about the disease. Severe manifestations of a disease are frequently the first to be described, since they are more clinically obvious, and this was true with endometriosis. Reports by Lockyer in 1913 [1]. Cullen in 1914 [2] and then Sampson focused on what would today be described as severe or deeply invasive disease, usually with ovarian chocolate cysts and frequently with complete cul-de-sac obliteration with rectal and vaginal involvement. The histology of these deeply invasive lesions of the uterosacral ligaments and other pelvic sites was characterized by small deposits of glands and stroma resembling eutopic endometrium, surrounded by fibromuscular metaplasia. Since this resembled adenomyosis of the uterus, these invasive pelvic lesions located away from the uterus were called "adenomyomas" and could involve nodules of the rectovaginal septum, uterosacral ligaments, inguinal canal and bowel wall. Sampson often referred to invasive disease of the pelvic floor as "implantation adenomyoma of endometrial type" or "implantation adenomas". He also recognized that early, superficial peritoneal lesions also existed and these were also called "implantation adenomas". He often referred to ovarian chocolate cysts as "cysts of endometrial type".

Sampson began his publishing career in a radiological lab, [3] performing transcervical injections of gelatinized bismuth or barium into surgically removed uteri which were then x-rayed. He noted that if the endometrium were intact, no injected medium would flow out of the stumps of the uterine arteries or veins. If menstruation was occurring at the time of hysterectomy, or if the endometrium had been disrupted by curettage, the study medium could flow out of the open vascular stumps along each side of the uterus, since receiving veins underneath the endometrium were exposed. He also noted that the study material would flow out the fallopian tubes. Although not directed at the question of endometriosis, this paper clearly was important in focusing his attention on the consequences of retrograde flow out the fallopian tubes, as he warned that ascending pelvic infections might occur from intrauterine injections. Although not mentioned in the paper, he later noted [4] that this study taught him that the diameter of the fallopian tubes in resected uteri could be variable, and that this might facilitate retrograde tubal flow of menstruum or material injected transcervically . Although one might wonder if evidence collected on resected surgical specimens would transfer seamlessly to other clinical interpretations, Sampson had no such difficulty. In 1925 [5] he borrowed these findings to infer that in menstruating women, endometrium sloughing into uterine veins could cause adenomyosis and disease beyond the pelvis.

In an often-cited paper, [6] Sampson in 1921 wrote of 23 patients with chocolate ovarian cysts, only 9 of whom had histologically proved ovarian cysts of "endometrial type". Other cysts had flat, cuboidal linings while others appeared to be corpora lutea. His extremely detailed observations led him to believe that endometrial cysts formed by downgrowth of endometrium from the ovarian cortex into a ruptured ovarian cyst, including follicle and corpus luteum cysts. Since many of these patients had what today would be called deeply invasive endometriosis of pelvic surfaces, by the fourth page of the paper he postulated that chocolate fluid leaking out of these ruptured cysts would carry endometrial cells which implanted on the pelvic surfaces, eventually becoming implantation adenomas, in a process resembling spread of ovarian cancer. He tentatively began thinking that some endometrial cells might reflux out of the fallopian tubes to cause the peritoneal disease he occasionally saw in women without ovarian involvement. On the basis of only his beliefs, he specifically rejected reactive metaplasia due to irritation of refluxed menstrual blood as the origin of peritoneal disease. He had only operated on two women under 30 years of age with such cysts, while the oldest was 47. Seven of 16 (44%) married patients had been pregnant, in an era when the "normal" pregnancy rate was believed to approach 100% and knowledge of other factors contributing to infertility was scant. He thus initiated the thought that pregnancy was protective against endometriosis. Succeeding generations of readers have assumed that this was a seminal paper on endometriosis, but the accuracy of this initial paper with respect to ovarian endometrioma cysts was manifestly low if most of the patients did not have cysts of endometrial type. We see in this paper the origins of several long-held beliefs regarding endometriosis. To Sampson, it appeared to be a disease of older women with reduced fertility; it appeared to spread throughout the pelvis by mechanical dispersion of sloughed endometrial fragments, similar to the presumed mode of spread of ovarian cancer or transtubal infection. It appeared to be a disease which usually involved the ovary as perhaps the most common site of occurrence. Yet we also see in this paper departures from the requisite steps toward the truth: even in modern tertiary referral centers dealing with endometriosis, most women do not have the severe disease described in this early paper, so Sampson's observations were obviously skewed by selection bias. Therefore, any demographic conclusions or theory of origin cannot necessarily be applied to all women with the disease. While this paper is illustrated with a multitude of excellent illustrations and photomicrographs, no photomicrograph was offered of either initial attachment of endometrial cells or tissue fragments to peritoneal surfaces or secondary proliferation and invasion of tissue by those cells. Immediately out of the gate, he presented a partially-evolved theory as a proven fact without supporting scientific evidence. This is most clearly illustrated by one of his conclusions: "The fact that material escaping from the ovarian hematomas may give rise to ... adenomas of endometrial type ... is further proof that these hematomas contain endometrial tissue." He presented no supporting evidence for this statement and this proactive mixing of "factual" statements supported only by adverbs or subjunctive verb forms was to become a foundation for "proof" of his theory in subsequent publications as he sought to expand and defend it.

In 1922, in an example [7] of what today would be regarded as duplicate publication, he republished the information and many of the line drawings of his 1921 paper [6]. He continued to focus on seeding of the ovary by endometrial cells refluxing out of the adjacent fallopian tubes (which he found always to be patent), with superficial lesions or deeper-lying ovarian chocolate cysts forming. He believed that rupture of these cysts would later seed further disease throughout the pelvis, reinforcing a concept of geographic disease spread. One figure illustrated an endometrial polyp in a lymph vessel. No photomicrograph of initial attachment or secondary proliferation and invasion is shown.

The first sentence of a paper published in 1922 [8] states that reflux menstruation is the cause of implantation adenomas (endometriosis). Thus, in just over 1 year, observations in a few dozen patients, many without proven endometriosis, had transformed into a theory which he now pronounced correct. Heavily illustrated like his previous articles, this paper made much of pelvic microanatomy: differences of fallopian tube lengths of just a few millimeters was taken as evidence to explain why superficial ovarian implants were found on the lateral or mesial side of the ovary. This began to introduce the concept of regulation of flow of reflux menstruation by the pelvic environment. He continued to champion the ovary as a site of common occurrence of disease since it lay adjacent to the fimbriae. Sampson was not particular about where endometrial-like tissue might come from, stating that it might have "escaped either from the tubes ... or from the perforating hematoma of the ovary, or probably from both. " Since his earlier thoughts had convinced him that the ovaries were key in the development of "implantation adenomas", he was reluctant to drop the ovaries from the original equation. He believed that ovarian cysts of endometrial type and implantation adenomas were simply misplaced tissue which originally came from the eutopic endometrium. Once this tissue fell on suitable "soil", it could attach, multiply and invade, and subsequently respond by menstruating like eutopic endometrium. In the ovary, he postulated that if the entire cyst lining sloughed and shed, the cyst would regress completely, although he thought it was more common for incomplete shedding to occur, with resultant persistence of such a cyst. In the audience discussion, it is apparent that his hard work and enthusiasm had won devoted adherents. Dr. J. W. Williams said "I do not hesitate to tell you that I believe that everything Dr. Sampson has said is entirely justified ... I have no hesitation in endorsing everything Dr. Sampson has said ... "

By the autumn of 1922, [9] Sampson's experience with hemorrhagic ovarian cysts was up to 49 patients. He had begun to understand that implantation adenomas could exist on pelvic surfaces without ovarian disease as an intermediary. To account for the occurrence of superficial or deeply invasive peritoneal disease in some women without ovarian endometrial cysts, he postulated that endometrial and tubal epithelium refluxing out the fimbriated end of the fallopian tube might attach and implant on peritoneal surfaces without having to attach to the ovary first, especially in the cul-de-sac where he envisioned gravity directing the refluxed tissue. Without supporting evidence, he again stated that peritoneal implantations arose from perforation and leakage of ovarian hematomas. His evidence consisted of numerous line drawings, photomicrographs of established superficial disease resembling eutopic endometrium, as well as tangential cuts across uterine adenomyosis and arrangement of the resulting pictures to make it appear that the disease began on the uterine serosa and then invaded the muscularis. Once again there were no photomicrographs of initial attachment of endometrial cells or tissue fragments to peritoneal or ovarian surfaces, nor were there photomicrographs of secondary proliferation and invasion of these cells. Using a scientific argument supported only by adverbs, he noted implantation adenomas on the sigmoid, rectum, terminal ileum and appendix and observed that these sites were in close proximity to the ipsilateral ovary, from which the intestinal disease "usually (possibly always)" came. Pathoconsortive relationships observed at surgery were thus taken literally as cause-and-effect relationships. He dismissed the possibility of a developmental origin because he had only once seen ovarian hematomas of endometrial type in women younger than 30 and thought that this manifestation of endometriosis should be present in the early teenage years if it were developmental. This was another example of conclusions reached from a small number of observations skewed toward older age groups and women with severe disease. Unbeknownst to Sampson, an entire unidentified reservoir of other disease morphologies was present, but by focusing on the minority of patients with severe disease and by repeating observations as causal fact, errors in understanding were simply reinforced. Severe disease does not just appear overnight but must have early, subtle morphologies.

In 1924, [10] Sampson discussed benign implantation adenomas and peritoneal metastases of endometrial cancer to illustrate his belief that both conditions could arise from reflux of endometrial tissue from the fallopian tubes. The ovarian tumors described are benign endometrial cysts and are included in the paper somewhat tangentially since he had focused previously on the ovaries as the initial site of implantation adenomas. Soon thereafter, [11] he united the concept of reflux menstruation and ovarian endometrioid carcinoma, which no doubt pleased him greatly since it reinforced his belief that the mode of spread of cancer was identical to the mode of spread of endometriosis. Sampson's belief that refluxed endometrial cancer cells could mimic implantation adenomas arising from reflux menstruation caused him to recommend ligation of the fallopian tubes before hysterectomy for endometrial carcinoma. He also wondered whether vigorous bimanual examination might force malignant cells out of the uterus and postulated that uterine retroversion, polyps, or fibroid tumors might augment reflux menstruation. Sampson stated that most evidence that he and others had provided for reflux menstruation as the cause of implantation adenomas has been only circumstantial. He indicated that the one solid proof that endometrium could implant and grow ectopically was that of endometriosis of a surgical scar. He did not consider the profound difference between intact peritoneum and an open incision, instead borrowing scar endometriosis as further proof of reflux menstruation as the cause of pelvic endometriosis. He also did not consider that Iwanoff's serosal theory of peritoneal totipotentiality might be too restrictive but could extend to totipotentiality of more far-ranging areas of the body, including the lower anterior abdominal wall in the path of surgical incisions. In such areas, substrate tissue might exist which could be susceptible to metaplasia into endometriosis, aided and abetted by the growth factors of wound healing. By this time Sampson had more experience with the varied morphologies that could be displayed by implantation adenomas, using terms such as "red/purple raspberry" and "blueberry", which would delight a later generation of morphologists.

In 1925, [12] Sampson first introduced the term "endometriosis", although he was not quite comfortable with discarding the term "implantation adenomyoma", which he occasionally used as well. Also notable are depictions of lesions of various colors, including white. Photomicrographs of superficial endometriosis of the uterus and ovarian cortex are supplied, but none of initial attachment of endometrial cells or tissue fragments to pelvic surfaces, or of secondary proliferation and invasion.

Sampson stated [13] that during menstruation, pregnancy and menopause, endometriosis was identical in structure and function to eutopic endometrium, a notion that was finally discarded in the 21st century when the dozens of differences noted between endometriosis and native endometrium [14] multiplied into hundreds [15]. He asserted without biochemical evidence that refluxed menstrual blood was far more irritating to the pelvis than normal blood, and this was what led to the formation of significant adhesions in some patients. The possibility never crossed his mind that endometrial glands are biologically active and might secrete some paracrine substance which is the actual cause of inflammation, hemorrhage and adhesions. He continued to offer as evidence for his theory that if surgery were done during menstruation, blood could occasionally be seen coming from the fimbriated ends of the tubes, although Novak commented that in all the surgeries that he had done during menstruation, he had never seen blood exiting the fimbriae. Further "evidence" of repeated monthly seedings was the observation that in an individual patient, different morphologies could be seen. To him, this indicated different stages of development resulting from different episodes of implantation. He did not consider that different areas of endometriosis in the same pelvis might have innately different potentials for both biologic activity and virulence which could result in different morphologies. Scar endometriosis following surgeries where the uterus was not opened was explained by unseen refluxed endometrial cells which were present in the peritoneal cavity and which implanted in the fresh surgical incision, again not considering the possibility that tissue near the pelvis might have some potential for Müllerian metaplasia promoted by growth factors of healing. On the basis of his radiological work published in 1918, [3] he postulated that adenomyosis of the uterus was caused by venous emboli of endometrium.

Sampson firmly believed that endometriosis presents the same structural variations as eutopic endometrium and is often governed by the same hormonal events regardless of location [16]. He continued to cobble together circumstantial evidence to define menstruum as a never-dying super-tissue: experimental autotransplantation of endometrium in non-menstruating animals mirrored the finding of post-Cesarean section scar endometriosis; endometrium had occasionally been observed in the lumen of the fallopian tube during menses and might escape from the fimbriated end; menstrual blood possibly could cause reactive peritoneal metaplasia into endometriosis; monkey endometrium scattered in the peritoneal cavity could result in implantation; endometrium can be found in lymphatics and venous channels.

In a nascent mixing of two competing theories of origin, (reflux menstruation and coelomic metaplasia), he stated that menstrual blood might, "in some magical and mysterious way" convert the peritoneum into endometriosis. He postulates a solid element in refluxed menstrual blood acting as a specific irritant, or "there are scattered throughout the pelvic peritoneum areas of potential mullerian tissue which under the specific action of menstrual blood develop into endometrial tissue."

He postulated gravity as the reason for the most common areas of involvement by virtue of reflux menstruation, ignoring the pathways of fetal organogenesis across the posterior coelomic cavity which might lay down the tracts of potential mullerian tissue which he had previously rejected as a possible cause of endometriosis.

Without any proof whatsoever, he stated that "Menstrual blood undoubtedly irritates the peritoneum causing inflammatory exudation, granulation tissue, adhesions and peritoneal inclusions ... the very conditions which would favor the retention and growth of any epithelium or other tissue present in this blood, just as similar peritoneal reactions make possible the retention and growth of fragments of cancer escaping into the peritoneal cavity. While menstrual blood may be very injurious to the mesothelium the fragments of uterine tissue in it might remain alive for a longer time, being more accustomed to its presence." This fanciful notion of reflux menstruation inciting such florid peritoneal reaction is belied, of course, by the rather bland morphologies and clear peritoneal fluid which can commonly be seen with early stage disease. Again, his focus on severe disease led him to "borrow" findings in that uncommon morphology as an explanation for the origin of the disease.

Having experience with only 101 patients with ovarian endometriosis[17] by 1929 he continued to be heavily dependent on qualifying verb forms to support his argument rather than hard science, including "might, suggested, could have, probably, may, at least suggest, it is natural to assume,... " as well as definitive unsupported adverbial statements such as "undoubtedly,..." He also was quick to come to scientific conclusions without supporting evidence, such as peritonitis due to refluxed menstrual blood allowing enhanced attachment of endometrium to peritoneal surfaces.

In 1932, [18] Sampson studied peritoneal spread of ovarian cancer, implying that evidence of possible metastases could be borrowed to explain peritoneal endometriosis (figure 1).

Figure 1. Peritoneal implant of metastatic ovarian carcinoma [18]. Such lesions were used as ancillary "proof" of Sampson's theory.

By 1932 [19] Sampson must have been feeling pressure from objections to his theory of reflux menstruation. He reluctantly agreed that peritoneal metaplasia might cause some cases of peritoneal endometriosis, especially when there was no ovarian endometriosis to blame for spread to the peritoneum. However, since most patients with endometriosis had patent tubes, he was unwilling to let go of a possible contribution of reflux menstruation as a specific irritant to the peritoneum which might result in reactive metaplasia of peritoneum into endometriosis. Straining ever-more-mightily to protect his theory, he stated (without direct evidence) that irritative cellular detritus (menstruum) or perhaps nuclei extruded from secretory endometrial cells escaping the fimbriated ends of the fallopian tubes incited irritative reactive metaplasia of the peritoneum into endometriosis just like cellular detritus escaping the tubes during pregnancy incited decidual reaction in similar locations of the pelvic peritoneum. Progesterone as a cause of decidual reaction was apparently unknown to him. He thought some type of cellular or nuclear debris was important because he had never seen endometriosis in women who had a previous ruptured tubal pregnancy, his thought being that tubal pregnancy would 'soil' the peritoneum with pure blood rather than any cellular debris. The validity of this thought is questionable given that with a ruptured tubal pregnancy, embryonic, fetal and placental tissue could conceivably provide cellular detritus to the peritoneum. Giving his power of free association unfettered but somewhat confusing reign, and without direct evidence, he posed that if Müllerian epithelial tissue could stimulate mesenchymal tissue into Müllerian stroma, then why couldn't Müllerian tissue stimulate epithelial tissue into epithelial stroma? He went on to show in elegant photomicrographs that tubal endometriosis could arise de novo beneath the normal tubal epithelium (independent of reflux menstruation), and posited that preceding inflammation and repair of the tube had resulted in metaplasia into endometriosis, similar to the process by which endosalpingiosis can affect tubal stumps[20]. He then suggested that these deposits of new endometriosis would undergo sloughing due to menstruation (no photomicrographic evidence was ever shown), and implant in the pelvis causing peritoneal or ovarian endometriosis. Sampson repeatedly asks scientific questions and supplies his own answers based on rhetorical logic. It is clear that he depended on rote repetition of what he had stated in previous publications, reinforced by copious photomicrographs illustrating his thoughts only up to a point, but never delivered robust photomicrograph proof of menstruating endometriosis, attachment of endometrial tissue to peritoneal surfaces, or secondary proliferation and invasion.

In a summation of his career, [21] he focused on peritoneal disease, stating that endometriosis occurred because of reflux menstruation and that peritoneal implants would menstruate and thus create new implants, causing the disease to spread, similar to ovarian cancer. He admitted that there was no positive proof that endometrial tissue from ovarian cysts is shed and becomes implanted on the peritoneum to become endometriosis, but he suggested that the evidence was very strong. In a preternatural defense of his theory, he stated "If bits of Müllerian mucosa carried by menstrual blood escaping into the peritoneal cavity are always dead, the implantation theory ... also is dead and should be buried and forgotten. If some of these bits are even occasionally alive, the implantation theory also is alive."

Sampson's great strengths as a researcher included his unbounded curiosity and enthusiasm for studying endometriosis, as well as an active imagination which continually sought to mold clinical observations to his fervently-held theory instead of the opposite way around. His papers were long, averaging over 35 pages with the longest being 88 pages. His works were copiously and elegantly illustrated with surgical photographs, line drawings, and photomicrographs, all of which would be very impressive to any reader and which would lend an air of supreme authority to his work which would be difficult to question.

Much of Sampson's work would be found unsuitable for publication today.

In retrospect, the weaknesses of his arguments outnumbered the strengths. His papers included numbing repetition of the same thoughts, supported by very detailed speculations and by frequent use of qualifying words such as "might", "probably", "possibly", "could", etc. His beliefs were little altered by the passage of time or new findings such as discovery of more subtle disease morphologies which might shed a new perspective on the origin of disease. He tried to characterize objections or exceptions to his theory as uncommon outliers which really had no effect on the veracity of his beliefs, instead of attempting to modify his theory to explain all instances of observations. There seemed to be few of his peers who were willing to challenge his strongly held convictions, and this allowed his thoughts to reign unchecked over several generations of gynecologists. His clinical experience with endometriosis appears to have been limited only to perhaps a few hundred patients, skewed toward the minority of patients with advanced disease. This inexperience would necessarily result in his having an incomplete view of the disease which would make incorrect conclusions more likely in that era. How could he possibly have come up with the correct theory of origin with all of these limitations?

His strong conviction that he was correct, combined with illustrations and scholarly repetition, served as proxies for what was lacking: he never published a photomicrograph of endometriosis menstruating, and published only one photomicrograph of alleged initial attachment [16, figure 7] and none of secondary proliferation and invasion of endometrial cells or tissue fragments. Since he did not do serial sections of the rare examples of alleged initial attachment to peritoneal surfaces of what he assumed was refluxed endometrium we don't know whether there might have been evidence that such tissue might have originated in the peritoneum without the need for reflux menstruation. He never discussed the origin of the fibromuscular metaplasia surrounding deeply invasive disease. Perhaps he considered that reconciling this finding with reflux menstruation would require either postulating that myometrium also sloughs and sheds by reflux menstruation or that the theory of reflux menstruation was not the origin of implantation adenomyomas, in which case he never would have proposed the theory in the first place.

Reflux menstruation as the origin of endometriosis requires that endometriosis be a surgically incurable, progressively spreading, autotransplant disease. Yet all of these features have been disproved [22]. The high prevalence of endometriosis and the frequency of surgical diagnosis should have resulted in robust photomicrographic confirmation of Sampson's allegations of initial attachment of refluxed tissue, as well as of proliferation and invasion, yet investigators looking for this have never found it. Initial attachment and secondary proliferation and invasion remain unexplained miracles.

...reflux menstruation as the origin of endometriosis requires that endometriosis be a surgically incurable, progressively spreading, autotransplant disease. Yet all of these features have been disproved. The high prevalence of endometriosis and the frequency of surgical diagnosis should have resulted in robust photomicrographic confirmation of Sampson's allegations of initial attachment of refluxed tissue, as well as of proliferation and invasion, yet investigators looking for this have never found it. Initial attachment and secondary proliferation and invasion remain unexplained miracles...

Despite these fatal flaws, some authors still make efforts to support this theory, the latest being the peritoneal circulation modification of Sampson's theory [23]. This inventive model attempts to explain the slightly increased frequency of involvement of the ovary and uterosacral ligament on the left side of the pelvis compared to their twins on the right. Supporters of this modification propose that there is a natural clockwise (as one views the patient) circulation of the peritoneal fluid, but that the pelvic portion of the sigmoid colon diverts the circulation toward the midline and away from the left pelvic region. This "protected" area on the left side of the pelvis theoretically allows refluxed endometrial tissue from the left tube to lie alongside the peritoneum longer, thus facilitating attachment compared to the right side of the pelvis, where the peritoneal current sweeps refluxed cells away from the pelvis. Lacking their own supporting evidence, the authors relied entirely on work published by Meyers in 1970, [24] in which radiological dye was injected into the peritoneal cavity of male and female adults suffering from peritoneal cancer, effusions, abscesses, and adhesions. The position of the patients was altered on a tilt table, and radiographs taken during position changes. A schematic diagram was published (figure 2), indicating that dye could travel virtually anywhere in the abdominal cavity depending on the tilt of the table. Beyond the obvious objection that such work is unphysiologic and unrelated to the question of reflux menstruation lies a more serious concern. To support their argument, the authors took the figure published by Meyers and altered it to fit their arguments, erasing or adding arrows to fabricate supportive "evidence" for the circulation they propose. (figure 3). By further alteration, Meyers' original figure could also be shown to "prove" that only a counter- clockwise circulation exists (figure 4).

Figures 2-4 (left to right): Figure 2. The original figure published by Meyers [24]. Notice there are strong arrows running up and down the right colonic gutter with flow toward Morrison's pouch, and a weak arrow going past the right hepatic margin, with another strong arrow from Morrison's pouch to the subphrenic space. Figure 3. Hypothetical alteration of Meyers' figure. All arrows which depict a clockwise path have been deleted, and a strong arrow added around the spleen, giving the impression of a counter-clockwise peritoneal circulation, thus "proof" that a clockwise circulation does not exist. Figure 4. Alteration of Meyers' figure by Bricou and colleagues [23]. Notice Meyers' strong arrow going caudad down the right colonic gutter has been deleted and his weak arrow shaft going past the right hepatic margin has been replaced by a strong arrow which is continuous with the pelvis. Meyers' strong arrow from Morrison's pouch to the right subphrenic space has been deleted. Bricou and colleagues don't discuss the effects on the distribution of endometriosis of the weak arrow ascending the left colonic gutter - there should be frequent deposition of disease near the spleen (although disease in this area is extremely rare or unreported).


Sampon's theory and ineffective medical or superficial surgical treatment of endometriosis have an unholy symbiosis. Sampson's theory predicts failure of all treatment modalities while ineffective treatments provide that failure. Physicians don't have to blame ineffective treatment for therapeutic failures, because "it's the nature of the disease. It always comes back." Sampson's theory has guided thought on endometriosis for too long and women are being physically harmed by its continued acceptance, since repeated surgeries and rounds of medical therapy are the unfortunate hallmarks of modern therapy. Supporters of this theory have failed to address its fatal flaws and now are creating "evidence" out of thin air. If Sampson's theory is finally discarded, we will be free to imagine another, possibly more correct theory of origin which will be helpful both to science and to patients.

Sampson's theory has guided thought on endometriosis for too long and women are being physically harmed by its continued acceptance, since repeated surgeries and rounds of medical therapy are the unfortunate hallmarks of modern therapy... if Sampson's theory is finally discarded, we will be free to imagine another, possibly more correct theory of origin which will be helpful both to science and to patients.


  1. Lockyer C, Proc Roy Soc Med 1913:6.
  2. Cullen TS. Adenomyoma of the rectovaginal septum. JAMA 1914;14:835.
  3. Sampson JA. The escape of foreign material from the uterine cavity into the uterine veins. Am J Obstet August, 1918;78:161-175.
  4. Sampson JA. Benign and malignant endometrial implants in the peritoneal cavity, and their relation to certain ovarian tumors. Surg Gynecol Obstet March, 1924;38:286-311.
  5. Sampson JA. Heterotopic or misplaced endometrial tissue. Am J Obstet Gynecol 1925;10:649-664.
  6. Sampson JA. Perforating hemorrhagic (chocolate) cysts of the ovary. Arch Surg Sept 1921;3:245-323.
  7. Sampson JA. Ovarian hematomas of endometrial type (perforating hemorrhagic cysts of the ovary) and implantation adenomas of endometrial type. Boston Med Surg J April, 1922;180;445-456.
  8. Sampson JA. The life history of ovarian hematomas (hemorrhagic cysts) of endometrial (Mullerian) type. Am J Obstet Gynecol November, 1922; 4:451-512. (Discussion pp. 561-563)
  9. Sampson JA. Intestinal adenomas of endometrial type. Arch Surg Sept 1922;5:217-280.
  10. Sampson JA. Benign and malignant endometrial implants in the peritoneal cavity, and their relation to certain ovarian tumors. Surg Gynecol Obstet March, 1924;38:286-311.
  11. Sampson JA. Endometrial carcinoma of the ovary, a rising in endometrial tissue in that organ. Arch Surg January, 1925;10:1-72.
  12. Sampson JA. Inguinal endometriosis (often reported as endmetrial tissue in the groin, adeomyoma in the groin, and adenomyoma of the round ligament). Am J Obstet Gynecol, 1925;10:462-503.
  13. Sampson JA. Heterotopic or misplaced endometrial tissue. Am J Obstet Gynecol 1925;10:649-664.
  14. Redwine DB. Was Sampson wrong? Fertil Steril 2002;78:686-93.
  15. Eyster KM, Klinkova O, Kennedy V, Hansen KA. Whole genome deoxyribonucleic acid microarray analysis of gene expression in ectopic versus eutopic endometrium. Fertil Steril 2007;88(6):1505-33.
  16. Sampson JA. Endometriosis of the sac of a right inguinal hernia, associated with a pelvic peritoneal endometriosis and an endometrial cyst of the ovary. Am J Obstet Gynecol 1926:459-83.
  17. Sampson JA. Infected endometrial cysts of the ovaries. Am J Obstet Gynecol 1929;18:1 - 16.Sampson JA. Endometriosis of the sac of a right inguinal hernia, associated with a pelvic peritoneal endometriosis and an endometrial cyst of the ovary. Am J Obstet Gynecol 1926:459-83.
  18. Sampson JA. Implantation peritoneal carcinomatosis of ovarian origin. Am J Path 1931; 7(5):423-44.
  19. Sampson JA. Pelvic endometriosis and tubal fimbriae Am J Obstet Gynecol 1932;24:497-542.
  20. Sampson JA. Endometriosis following salpingectomy. Am J Obstet Gynecol 1928;16:461-499.
  21. Sampson JA. The development of the implantation theory for the origin of peritoneal endometriosis. Am J Obstet Gynecol 1940;40:549-557.
  22. Redwine DB. Was Sampson wrong? In: Redwine DB, ed. Surgical Management of Endometriosis. New York, Martin Dunitz, Taylor and Francis Group, 2004.
  23. Bricou A, Batt RE, Chapron C. Peritoneal fluid flow influences anatomical distribution of endometriotic lesions: why Sampson seems to be right. Eur J Obstet Gynecol Reprod Biol 2008; 138:127-34.
  24. Meyers MA. The spread and localization of acute intraperitoneal effusions. Radiology 1970 95:547-54.