© Center for Endometriosis Care/Ken Sinervo MD, MSc, FRCSC. All rights reserved. No reproduction permitted without written permission. Revised since original publication (2013) and current as of 2023. No external funding was utilized in the creation of this material. The Center for Endometriosis Care neither endorses nor has affiliation with any resources cited herein. The following material is for informational purposes only and does not constitute medical advice.

“‘While Sampson’s work was essential in advancing endometriosis research, some experts today worry that it doesn’t hold up to more modern and robust research. “Retrograde flow is common, occurring in most people who menstruate, so this theory wouldn’t explain why just 1 in 10 menstruators would develop endometriosis,” says Ken Sinervo, MD, the Medical Director of the Center for Endometriosis Care. The theory of retrograde menstruation is further challenged by research showing critical histological differences between the type of tissue found in the endometrium and that found in endometriosis lesions. Because endometriosis has been found in organs far from the pelvis and even in neonates and cisgender men, retrograde flow cannot explain all cases of the disease.”-In: Why Can’t Women Get Diagnosed with Endometriosis? by Aria Vyas for Neo.Life, Mar 31, 2022

Dr John Sampson (August 17, 1873- December 23, 1946)
President, American Gynecological Society, 1923

John A. Sampson, MD was an eminent gynecologist from upstate NY, renowned for his seminal works on endometriosis. It is undeniable that his persistent search for answers over the course of his career were pivotal across the endometriosis landscape. Taken in the context of his time and era, Sampson was indeed a pioneer who contributed to the framework of disease understanding and early applications of technology. Still, much debate and contention continue to encompass his Theory of Retrograde Menstruation as the singular cause of the disease.

Initially, Dr. Sampson assumed that endometriosis resulted from “seedlings” from the ovaries. His beliefs evolved until he concluded that the disease arises “as the result of retrograde flow of menstrual discharge from the uterus through the fallopian tubes, with spill of endometrial cells onto the ovary and other sites in the pelvis.” He maintained that “[f]ragments of endometrial tissue, at times, are disseminated into the venous circulation during menstruation, from the mucosa lining the uterine cavity and also from ectopic endometrial foci; [that] metastatic or embolic endometriosis arises from the implantation of these emboli in nearby veins; [and that] endometrial tissue set free by menstruation, therefore, is sometimes not only alive – but may actually continue to grow if transferred to situations favorable to its existence.”1

As for why his works became quickly - and are still - so prominent in endometriosis, Dastur et al. may have stated it best: “At the 1927 meeting of the American Gynecological Society, he presented his findings and the theory of retrograde menstruation as the etiology of endometriosis. The theory was well received especially because the disease process had never been studied in great detail. It was also anatomically and practically a feasible explanation to the problem.”2 Subsequently, it became readily accepted that endometriosis, then, was the result of so-called ‘normal’ endometrium transported via backflow menstruation. Yet context is often missing from the broader generalizations of Sampson’s works.

In fact, Sampson himself repeatedly acknowledged that the lesions he was seeing were not always identical to the native endometrium, even as he promoted the idea of retrograde menses – though this is often left out of the conversations surrounding his work. Writing in 1925, he stated: "From a diagnostic standpoint, misplaced endometrium-like tissue may be divided into three groups. The histologic structure and associated conditions of that found in the first group are such as to enable one to make a definite diagnosis of endometrial tissue. In the second group, it can be ascertained that the tissue is not endometrial. Its structure is atypical and the gland-like spaces have obviously been derived from inclusions of the peritoneal mesothelium, or their relation to known remnants of the wolffian body may be such as to indicate their origin from these. In the third group, the diagnosis is uncertain due to the small amount of tissue for microscopic study, its atypical structure, and indefinite associations...”3 He stated in similar works that ‘misplaced endometrial-type tissue may be divided into 2 groups: true endometrial or Müllerian tissue, which is derived from the uterine and tubal mucosa; and secondly pseudo-endometrial tissue, possibly arising from Wolffian remnants, metaplasia of peritoneal serosa, or other sources.’4  To that end, various studies have further detailed the variances in the native endometrium of those with endometriosis vs. those without the disease that Sampson acknowledged throughout his works, along with elucidating the fundamental invasive, adhesive, proliferative, and biochemical differences in lesions vs. ‘normal’ endometrial tissue.5,6,7, 8

To be sure, his concepts were not without enduring support. For example, in 1961, Ridley conducted an experiment submitted as evidence of Sampson's theory as a valid cause of endometriosis via the surgical implantation of shed (human) endometrium at a site where gross and microscopic observation could be subsequently made. Of note, while 85 participants were found to qualify, only 15 patients were ultimately enrolled in this study. Of those, only 2 cases showed gross and microscopic evidence of endometriosis at the sites of implantation. This experiment was a continuation by the author of previous work in 1950-3, in which only 1 of those 8 cases developed endometriosis. Despite these limited results, the author and his peer reviewers boldly proclaimed "Sampson's theory is now a fact" - on the basis of a mere 3/23 total patients developing the disease via experimental surgical implantation.9

Still, despite widespread acceptance, Sampson’s works were also subject to harsh criticisms as well, even early on, as his theory failed to, at least, “account for primary lesions in the umbilicus and in remote areas such as chest and limbs."10 He was not without the collegial spirit of debate, however, and routinely welcomed - even encouraged - questions about his evolving theories. Sampson responded frequently to the ongoing objections (some rather strenuous) voiced to his concept that ‘bits of endometrial tissue are carried by menstrual blood escaping through the tubes and become implanted on the visceral and parietal peritoneum,‘ including those expressed by Novak11 and others who asserted that:

“1. Menstrual blood rarely, if ever, escapes from the uterine cavity into the tubes.
2. The lumen of the interstitial portion of the tube is too small for bits of endometrial tissue to pass through it.
3. Endometrial tissue, set free by menstruation, is dead or dying and therefore incapable of implantation. Several days must be required for endometrial tissue to be carried from the uterine cavity through the tubes, and, therefore, there is little chance that 'such degenerative tissue' after 'probably many days of continuing degeneration and autolysis should grow where it falls'.”

In response, Sampson wrote, "I fully realize that the implantation theory does not account for all instances of ectopic endometrium-like tissue in the pelvis and that menstruation is only one means of disseminating that tissue. Even if peritoneal endometriosis arises from the implantation of endometrial and tubal tissue on the surface of the peritoneum, as I believe it does, this does not prove that all instances of endometrium-like tissue involving the peritoneum arise from this source."12

In earlier works, he also clarified - importantly - that “[t]he implantation theory was presented only for the explanation of the origin of peritoneal lesions and the conditions resulting from them. The metastatic origin of extraperitoneal lesions was not only considered by me, but reasons given for believing that it might occur. More than one channel is employed in the dissemination of cancer and the same might apply to the dissemination of endometrial tissue."13 In the near-century to follow, of course, many other aspects of the disease - importantly, alternative explanations and theories ‘based on immunology, extrapelvic sites of endometriosis and its association with genetics’ - would become well known.

As stated by critics of Sampson even a century ago, ‘backflow periods’ simply cannot explain all endometriosis in all those affected by the disease. If his theory were singularly correct, endometriosis could not possibly occur until someone’s first period – yet there is evidence disproving this. It also fails to account for the presence of the disease in uncommon cis men and individuals who have never menstruated. Further, when we review a patient’s videos of multiple previous surgeries, we rarely see disease in new areas. For example, if bladder disease is present at Surgery A, it may persist through subsequent operations. On the other hand, if bladder disease is not present at Surgery A, it does not just suddenly appear at surgeries B, C, D, etc. According to Sampson’s Theory, it would be reasonable to expect to see abundant, brand-new endometriosis in previously unaffected areas all the time, growing in every patient with each menstrual cycle. Yet, in our experiences across over 10,000 patients for three decades and tens of thousands of procedures, this is not the case. It has also been our personal experience that if all endometriosis is excised at surgery, the individual has a lower chance of true recurrence (which can occur) or persistence. Such evidence, then, would favor a metaplastic or congenital theory, which suggests endometriosis is a finite disease. Additionally, because most of the menstrual flow involves the vagina and vulva, a logical extension of Sampson’s Theory would predict a high incidence of endometriosis in those locations – yet vaginal and vulvar endometriosis are actually less common.

Retrograde menses does occur. There has also been research revisiting the role of reflux menses in the neonate. No definitive conclusions have been drawn from this ongoing area of study as yet; nevertheless, we have long known that retrograde menstruation is a common phenomenon among menstruators – yet not all will develop endometriosis.14 See also David Redwine, MD’s article: Is endometriosis an autotransplant? (http://endopaedia.info/origin36.html). However, while Sampson was quite ahead of his time in terms of endometriosis research, particularly in the context of the limited knowledge available to him then, it simply cannot be the case for every patient of just merely ‘normal endometrium showered backwards into their pelvis.’

Nearing the end of his lifetime career in treating and studying endometriosis, Dr Sampson reflected upon his body of work. On his Theory of Retrograde Menstruation specifically, he wrote:

“The viability of this theory is of secondary importance to me as compared with the pleasure and the increased knowledge of this and kindred subjects which I have gained in these studies and the resulting more intelligent treatment of patients who have peritoneal endometriosis. There are many other interesting unsolved problems associated with the pathogenesis and life history of endometriosis of all types…If bits of Müllerian mucosa carried by menstrual blood escaping into the peritoneal cavity are always dead, the implantation theory, as presented by me, also is dead and should be buried and forgotten. If some of these bits are even occasionally alive, the implantation theory also is alive."15

Sampson was indeed a medical visionary, and his ‘backflow’ theory may play a role in endometriosis – a theory which undoubtedly would have evolved much further as more research became available to him. However, the scope of this mechanism’s role in the disease still remains unclear. The enduring notion of retrograde periods as the sole cause of endometriosis is problematic, particularly without acknowledgment of the specific distinctions in Sampson’s own works. The over-simplification of his disease concepts - despite modern scholarship and access to far better disease data now than he could have likely ever envisioned - relegates endometriosis to ‘just a bad period’ only impacting menstruation and factors directly into the way it is ‘treated’ (e.g., menstrual cessation, hysterectomy as mythical cures, etc.).

Countless other theories of origin have emerged over the past century, each singularly failing to account for all forms of endometriosis in all those affected. Researchers do agree that endometriosis is polygenic and multifactorial, though the exact pathogenic mechanism(s) are still yet unclear. However, without question: there are many factors contributing to disease pathophysiology and pathogenesis in addition to and apart from Sampson’s ‘backflow’ premise, and although his work in endometriosis was critically important, his early assertions are not the lone guiding concepts by which today’s care and treatments should be rendered.

Perhaps it was Kleinsasser who framed endometriosis best of all in May of 1936 when he wrote, "In conclusion, it may be said that the probability is that no one theory can explain all sites of endometriosis and that more than one theory will be invoked to explain the various sites of involvement. It may be true that, while one theory is the correct explanation for one site of involvement, another theory may account for a second site of involvement."16

Indeed.

Additional reading of interest:

"The Sampson theory is no longer valid to explain the etiology of endometriosis since it is not compatible with all observations of endometriosis such as endometriosis in man, and the clonal aspect of endometriosis. In 1927 Sampson suggested that cells from retrograde menstruation could implant and develop. Since this could not explain all forms of endometriosis, the metaplasia theory was proposed, and later the hematogenic and lymphangenic spread."-Philippe R. Koninckx and Anastasia Ussia, Leuven and Gruppo Italo Belga, Rome Italy, Gynsurgery.

"Endometriosis is dissimilar to eutopic endometrium and therefore lacks characteristics of an autotransplant. Sampson's theory of origin of endometriosis is not supported by the results of this study. Studies of experimental endometriosis that have not used menstrual endometrium may be misleading."-Redwine DB. Was Sampson wrong? Fertil Steril. 2002 Oct;78(4):686-93.

"...results show that the ultrastructure of endometriosis eutopic endometrium is different from that of normal endometrium...Medvedev et al. are divided into 3 groups according to the expression of study markers in glands (ER, PGR, Ki-67, BCL-2, and MMP-9) and matrix (ER, PGR, and Ki-67). ER, PGR, and MMP-9 markers established a statistically significant difference between the normal endometrium and the ectopic and ectopic endometrium." Jiao L, Wang J, Zhu L. A Comparative Study of Endometriosis and Normal Endometrium Based on Ultrasound Observation. Appl Bionics Biomech. 2022 Apr 30;2022:7934690.

"Ectopic endometriotic tissue exhibits decelerated DNAm age, similar to that observed in teratomas composed of multipotent tissue, but distinct from eutopic tissue. The migration process does not change DNAm age and eutopic endometrium is concordant with chronological age regardless of disease status. We conclude that DNAm age of ectopic lesions suggests a distinct developmental origin for a subset of lesions...Since cell migration, such as retrograde menstruation, does not explain the substantial DNAm age deceleration of ectopic tissue, we explored the possibility that ectopic tissue had been deposited during development and might share a similar DNAm age to tissues of developmental origin...We show that epigenetic age estimators (e.g. the pan tissue epigenetic clock by Horvath) lend themselves to addressing vexing problems surrounding the etiology of endometriosis. Using human tissue samples, we demonstrate a) that DNAm age strongly correlates with chronological age in the endometrium, b) that ectopic tissue is substantially younger than eutopic tissue according to the epigenetic clock, c) that tissue migration through metastasis does not change DNAm age, and d) that ectopic endometriotic lesions and teratomas share age deceleration that is not as young as pluripotent embryonic or induced pluripotent cells according to the epigenetic clock." Leap K, Yotova I, Horvath S, Martinez-Agosto JA. Epigenetic age provides insight into tissue origin in endometriosis. Sci Rep. 2022 Dec 8;12(1):21281.

"Later Sampson suggested retrograde menstruation with the tubal transport of endometrial cells as etiology. When retrograde menstruations was found in almost all women, speculation started why not all women developed endometriosis. It remains debated whether these lesions should be considered either as initial lesions after implantation or as ‘‘a physiologic’’ phenomenon occurring intermittently in all women...Endometriosis, including the rare premenarcheal endometriosis that presents the same phenotype with angiogenic peritoneal implants and the formation of OMA as adolescent endometriosis, is unexplained by Sampson's hypothesis."-Gordts S, Koninckx P, Brosens I. Pathogenesis of deep endometriosis. Fertil Steril. 2017 Dec;108(6):872-885.e1.

"Physicians later realized, however, that most women actually experience retrograde menstruation, while very few develop symptoms or evidence of endometriosis. The cause of endometriosis could not have been due simply to the presence of uterine cells that had migrated outside the uterus. As explained by endometriosis.org, endometriosis has also been found in women who have had a hysterectomy and very rarely in men who have been treated with estrogen therapy."-Karen Brown for GE Healthcare, "Retrograde Menstruation and Endometriosis: Cause or Factor?" [caveat: there are other publications demonstrating endometriosis in cis males who were not on estrogen therapy.]

”Retrograde menstruation theory is the oldest principle explaining the aetiology of endometriosis. This theory proposes that endometriosis occurs due to the retrograde flow of sloughed endometrial cells/debris via the fallopian tubes into the pelvic cavity during menstruation. However, retrograde menstruation occurs in 76%–90% of women with patent fallopian tubes and not all of these women have endometriosis...this theory has been disputed in the past since it cannot explain the occurrence of endometriosis in pre-pubertal girls, newborns, or males."-Sourial S, Tempest N, Hapangama DK. Theories on the pathogenesis of endometriosis. Int J Reprod Med. 2014;2014:179515.

"However, although retrograde menstruation is widely reported among fertile women, endometriosis is only diagnosed in 10% of them. Despite the widespread acceptance of this theory, it is unable to justify the occurrence of this disease in extra-abdominal districts as well as the occurrence of male endometriosis...The case presented supports the hypothesis that endometriosis is a disease not at all related to the phenomenon of retrograde menstruation but is a consequence of some alterations in the morphogenesis of the female genital system and therefore it could be found in any mammal."-Baldi A, Lanza A, Menicagli F, Signorile PG, Spugnini EP. Histological and Immunohistochemical Characterization of a Case of Endometriosis in a Guinea Pig (Cavia tschudii). Case Rep Vet Med. 2017 May 8;2017:4594510.

"The theory of retrograde menstruation as aetiopathogenesis of endometriosis formulated by John Sampson in 1927 shows clear shortcomings: this does not explain why retrograde menstruation is a physiological process that affects 90% of women, while endometriosis occurs in only 10% of cases; it also does not explain the endometriotic foci distant from the pelvis, nor explains the cases of endometriosis in male patients."-Laganà AS, Vitale SG, Salmeri FM, Triolo O, Ban Frangež H, Vrtačnik-Bokal E, Stojanovska L, Apostolopoulos V, Granese R, Sofo V. Unus pro omnibus, omnes pro uno: A novel, evidence-based, unifying theory for the pathogenesis of endometriosis. Med Hypotheses. 2017 Jun;103:10-20.

"Endometriosis and its associated infertility have been the object of continuous research for over a century. To understand the molecular mechanisms underlying the disease, it has become necessary to determine the aspects of its etiology that are not explained by the retrograde menstruation theory. This could in turn elucidate how various clinical and surgical treatments might affect the evolution and remission of the disease. Multiple lines of evidence suggest that the actions of the homeobox A10 (Hoxa10/HOXA10) gene could account for some aspects of endometriosis."-Zanatta A, Rocha AM, Carvalho FM, Pereira RM, Taylor HS, Motta EL, Baracat EC, Serafini PC. The role of the Hoxa10/HOXA10 gene in the etiology of endometriosis and its related infertility: a review. J Assist Reprod Genet. 2010 Dec;27(12):701-10.

"In this manuscript we describe four new cases of fetal endometriosis found among a series of 52 female fetuses analyzed at autopsy. The anatomical localization of this ectopic endometrium, and its histological and immunohistochemical characteristics are depicted. We suggest that endometriosis is caused by dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis."-Signorile PG, Baldi F, Bussani R, Viceconte R, Bulzomi P, D'Armiento M, D'Avino A, Baldi A. Embryologic origin of endometriosis: analysis of 101 human female fetuses. J Cell Physiol. 2012 Apr;227(4):1653-6.

"Our findings revealed a possible involvement of the PTEN-PI3K/Akt-Bad axis in the pathogenesis of endometriosis, which may facilitate the discovery of suitable pathway inhibitors for disease treatment."-Govatati S, Kodati VL, Deenadayal M, Chakravarty B, Shivaji S, Bhanoori M. Mutations in the PTEN tumor gene and risk of endometriosis: a case-control study. Hum Reprod. 2014 Feb;29(2):324-36.

"The disease is likely to be polygenic and multifactorial, but the exact pathogenic mechanisms are still not entirely clear. Recently, adult stem cells have been identified in several tissues, including the endometrium. These cells are probably involved in the regenerative ability of the endometrial cycle, and also in the pathogenesis of proliferative gynaecological diseases, such as endometriosis. The identification of stem cells in animal and human tissues is very complex and the putative stem cells are supposed to be found through several assays such as clonogenicity, label-retaining cells, "side-population" cells, undifferentiation markers, and cellular differentiation. Bone marrow-derived stem cells transplanted into humans and animals have also been identified in eutopic endometrium and endometriotic implants. This review evaluates the available evidence regarding stem/progenitor cells in the human endometrium and explores the possible involvement of these cells in the etiology of endometriosis."-Oliveira FR, Dela Cruz C, Del Puerto HL, Vilamil QT, Reis FM, Camargos AF. Stem cells: are they the answer to the puzzling etiology of endometriosis? Histol Histopathol. 2012 Jan;27(1):23-9.

"The prevalence of PF samples containing endometrial epithelial and stromal cells was not higher in patients with endometriosis than in controls without endometriosis during menstruation. Our findings question the relevance of endometrial cells in PF for the pathogenesis of endometriosis and support the importance of other mechanisms such as immune dysfunction and/or endometrial stem cells."-O DF, Roskams T, Van den Eynde K, Vanhie A, Peterse DP, Meuleman C, Tomassetti C, Peeraer K, D'Hooghe TM, Fassbender A. The Presence of Endometrial Cells in Peritoneal Fluid of Women With and Without Endometriosis. Reprod Sci. 2017 Feb;24(2):242-251.

”Since endometrial cells are rarely present in PF, since there is no evidence that these endometrial cells from PF can implant and invade the pelvic peritoneum, and since microscopic endometriosis is also rare, the validity of the Sampson theory can be questioned."-D'Hooghe TM. Invisible microscopic endometriosis: how wrong is the sampson hypothesis of retrograde menstruation to explain the pathogenesis of endometriosis? Gynecol Obstet Invest. 2003;55(2):61-2.

"Proposed hypothetical causes of endometriosis include retrograde menstruation, lymphatic and vascular metastasis, iatrogenic direct implantation, coelomic metaplasia, embryonic rest, and mesenchymal cell differentiation (induction). Each theory, individually, fails to account for all types of endometriotic lesions, thereby implicating combined and/or type-specific mechanisms. Recent evidence supports the presence of endometrial stem/progenitor cells and their possible involvement in eutopic endometrial regeneration and differentiation."-Maruyama T, Yoshimura Y. Stem cell theory for the pathogenesis of endometriosis. Front Biosci (Elite Ed). 2012 Jun 1;4(8):2754-63.

"Sampson's theory is supported by the observation of the anatomical distribution of endometriotic lesions, which is asymmetric in a way that would be expected after retrograde menstrual flow. This theory cannot explain, however, the appearance of endometriosis in patients with nonfunctioning uteruses...In this case report, we present endometriosis in a patient with Mayer-Rokitansky-Küster-Hauser syndrome, without a functioning uterus. This case reinforces the theory of coelomic metaplasia as having a complementary role in the genesis of endometriosis rather than Sampson's retrograde menstruation theory alone."-Troncon JK, Zani AC, Vieira AD, Poli-Neto OB, Nogueira AA, Rosa-E-Silva JC. Endometriosis in a patient with mayer-rokitansky-küster-hauser syndrome. Case Rep Obstet Gynecol. 2014;2014:376231.

"Since retrograde menstruation is a very common phenomenon among women of reproductive age, there must be other factors that may contribute to the pathophysiology and/or pathogenesis of endometriosis. Genetic predisposition, environmental factors, and alterations in immune and endocrine functions are believed to play significant roles in the establishment and maintenance of endometriosis. Although the eutopic endometriums of women with and without endometriosis are histologically similar, studies revealed that there are many fundamental differences between these two tissues. Invasive properties, decreased apoptosis, alterations in expression of specific gene and proteins, and increased steroid and cytokine production have been identified in eutopic endometrium of women with endometriosis. Furthermore, significant biochemical differences exist even between ectopic and autologous eutopic endometrium."-Ulukus M, Cakmak H, Arici A. The role of endometrium in endometriosis. J Soc Gynecol Investig. 2006 Oct;13(7):467-76.

"The metaplasia theory or induction theory was necessary, since the implantation theory cannot explain all localisations and manifestations of endometriosis, such as endometriosis in men or in women without retrograde menstruation."-Koninckx PR, Barlow D, Kennedy S. Implantation versus infiltration: the Sampson versus the endometriotic disease theory. Gynecol Obstet Invest. 1999;47 Suppl 1:3-9; discussion 9-10.

"The histogenesis of pelvic endometriosis cannot be sufficiently accounted for by a single theory. Thus it may be necessary to pressure plural theories for the explanation of their histogenesis."-Sekine T, Tsukahara T, Asano H, Yokoyama S, Ohsone S, Ito H, Hosokawa T. Study on histogenesis of pelvic endometriosis. Nihon Sanka Fujinka Gakkai Zasshi. 1980 Jan;32(1):123-8.

“However, the transplantation theories are unable to explain endometriosis in women with Mayer–Rokitansky–Küster–Hauser syndrome, in adolescents before or shortly after menarche, and in males. Moreover, available evidence suggests that endometriosis is not simply a transplanted normal endometrium. Numerous differences in hormone receptor levels, as well as histological, morphological, and biological characteristics, were reported when comparing endometriosis with eutopic endometrium, with only limited similarities. Although Sampson recognized that endometriosis was different from endometrium "both in structure and in function” and noted a transition from one to the other, his 1920s observations of a transition do not include all of the inflammatory, chemical, immunologic, epigenetic and genetic changes that have been discovered the last 40 years. Those changes require additional understanding of the transformation of any Müllerian (endometrial or rest) or non-Müllerian cell to endometriosis. Furthermore, eutopic endometrium of affected women is reported to have similar alterations of endometriotic lesions, that are not found in the eutopic endometrium of healthy women…the gap between the incidence of refluxed menstruation and the incidence of endometriosis highlights the presence of further mechanisms.”-Laganà AS, Garzon S, Götte M, Viganò P, Franchi M, Ghezzi F, Martin DC. The Pathogenesis of Endometriosis: Molecular and Cell Biology Insights. Int J Mol Sci. 2019 Nov 10;20(22):5615.

“The present and previously published cases of endometriosis in males may provide insight into the true origin of endometriosis. This presiding clinical evidence discredits the leading theory of retrograde menstruation as the dominant origin of endometriosis and points more towards an embryologic origin as the mechanism of this disease process.”-Rei et al. Endometriosis in a Man as a Rare Source of Abdominal Pain: A Case Report and Review of the Literature. Case Reports in Obstetrics & Gynecology, vol. 2018, Article ID 2083121.

“Endometriosis is a “mysterious” disease and its exact cause has not yet been established. Among the etiological factors, congenital, environmental, epigenetic, autoimmune and allergic factors are listed. It is believed that the primary mechanism of the formation of endometriosis foci is retrograde menstruation, i.e., the passage of menstrual blood through the fallopian tubes into the peritoneal cavity and implantation of exfoliated endometrial cells. However, since this mechanism is also observed in healthy women, other factors must also be involved in the formation of endometriosis foci.”-Smolarz B, Szyłło K, Romanowicz H. Endometriosis: Epidemiology, Classification, Pathogenesis, Treatment and Genetics (Review of Literature). Int J Mol Sci. 2021 Sep 29;22(19):10554.

“Endometriosis of the sciatic nerve is a very particular pathology because it induces a completely new aspect on the pathogenesis of endometriosis: all hypothesis of implanted endometrial cells following retrograde menstruation, angiogenic spread, lymphogenic spread or the metaplasia theory cannot explain the pathogenesis of this disease.” - Possover M. Laparoscopic morphological aspects and tentative explanation of the aetiopathogenesis of isolated endometriosis of the sciatic nerve: a review based on 267 patients. Facts Views Vis Obgyn. 2021 Dec;13(4):369-375.

“The results of the present study demonstrated that retrograde menstruation alone does not account for the pathogenesis of endometriosis as eutopic and ectopic counterparts of ESCs from patients with endometriosis exhibit differential invasive, adhesive, and proliferative behavior.”-Delbandi AA, Mahmoudi M, Shervin A, Akbari E, Jeddi-Tehrani M, Sankian M, Kazemnejad S, Zarnani AH. Eutopic and ectopic stromal cells from patients with endometriosis exhibit differential invasive, adhesive, and proliferative behavior. Fertil Steril. 2013 Sep;100(3):761-9.

“…retrograde menstruation is common (perhaps universal among menstruating women) while endometriosis is much less common. Therefore, other factors, such as hormonal, inflammatory, or immunologic milieu may determine whether lesions deposited in the pelvic cavity implant and persist. Alternatively, endometriosis lesions may arise from Müllerian remnants that did not properly differentiate or migrate during fetal development or from circulating blood cells that transdifferentiate into endometriosis. Similarly, the characteristics of the local environment would influence the maintenance of these endometriotic lesions. When considering these etiologic hypotheses, it is important to recognize that endometriotic lesions are antigenically similar to eutopic endometrium but are not necessarily endometrium.” - Parasar P, Ozcan P, Terry KL. Endometriosis: Epidemiology, Diagnosis and Clinical Management. Curr Obstet Gynecol Rep. 2017;6(1):34-41.

“However, because most women experience retrograde menstrual flow, while only approximately 10% suffer from endometriosis, there is more to endometriosis than retrograde menstrual flow, which is what led to the proposal of the stem cell theory.” - Alimi Y, Iwanaga J, Loukas M, Tubbs RS. The Clinical Anatomy of Endometriosis: A Review. Cureus. 2018;10(9):e3361.

“If retrograde menstruation is the mechanism, one must assume that the menstrual endometrium containing both epithelial and stromal cells can enter into angiolymphatic circulation without disruption and has the ability to co-invade and undergo extravasation from the vessels in order to reside within the muscular layers of organs. However, there is no evidence that menstrual endometrium arising from benign endometrium is able to accomplish these demanding cancer-like tasks. Furthermore, the retrograde menstruation model cannot explain endometriosis found outside the abdominal cavity, such as in the thoracic cavity or brain, and at other sites. Thus, the long-held model of retrograde menstruation faces a crisis, and such a crisis leads to changes in models and changes in paradigms. The stem cell theory of endometriosis represents one of the new paradigms.” - Wang Y, Nicholes K, Shih IM. The Origin and Pathogenesis of Endometriosis. Annu Rev Pathol. 2020 Jan 24;15:71-95.

References:

1. Sampson JA. Metastatic or Embolic Endometriosis, due to the Menstrual Dissemination of Endometrial Tissue into the Venous Circulation. Am J Pathol. 1927 Mar;3(2):93-110.43.

2. Dastur AE, Tank PD. John A Sampson and the origins of Endometriosis. J Obstet Gynaecol India. 2010 Aug;60(4):299–300.

3. Sampson JA. Inguinal endometriosis (often reported as endometrial tissue in the groin, adenomyoma in the groin, and adenomyoma of the round ligament). American Journal of Obstetrics & Gynecology, 1925;10(4), 462–503.

4. Yovich JL (2020) Understanding Endometriosis: Clarifying Sampson’s Theories with a Personal Perspective. Med J Obstet Gynecol 8(1): 1130.

5. Aghajanova L, Giudice LC. Molecular evidence for differences in endometrium in severe versus mild endometriosis. Reprod Sci. 2011;18(3):229-251.

6. Brosens I, Benagiano G. Endometriosis, a modern syndrome. Indian J Med Res. 2011;133(6):581-593.

7. Delbandi AA, Mahmoudi M, Shervin A, Akbari E, Jeddi-Tehrani M, Sankian M, Kazemnejad S, Zarnani AH. Eutopic and ectopic stromal cells from patients with endometriosis exhibit differential invasive, adhesive, and proliferative behavior. Fertil Steril. 2013 Sep;100(3):761-9.

8. Freger S, Leonardi M, Foster WG. Exosomes and their cargo are important regulators of cell function in endometriosis. Reprod Biomed Online. 2021 Sep;43(3):370-378.

9. Ridley JH. The validity of Sampson's theory of endometriosis. Am J Obstet Gynecol. 1961 Oct;82:777-82.

10. Mathew AG. A Case Exemplifying Sampson’s Theory of the Aetiology of Endometriosis. Aust N Z J Obstet Gynaecol. 1963 Dec;3(4):159-61.

11. Novak, E. The significance of uterine mucosa in the Fallopian Tube, with a discussion of the Origin of aberrant endometrium, Am.J.Ob. & Gyn.,12:484-525,1926.

12. Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. American Journal of Obstetrics and Gynecology, 1927;14(4), 422–469.

13. Sampson JA. Inguinal endometriosis (often reported as endometrial tissue in the groin, adenomyoma in the groin, and adenomyoma of the round ligament). American Journal of Obstetrics & Gynecology, 1925;10(4), 462–503.

14. Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. 1984 Aug;64(2):151-4.

15. Sampson JA. The development of the implantation theory for the origin of peritoneal endometriosis. American Journal of Obstetrics and Gynecology, 1940;40(4), 549–557.

16. Kleinsasser LJ. The etiology of endometriosis (1936). MD Theses. Online: https://digitalcommons.unmc.edu/mdtheses/445. Last accessed August 16, 2022.