Is endometriosis an autotransplant?

Abstract

Objective: Sampson's theory of reflux menstruation suggests that endometriosis is one form of a condition known as an autotransplant. This study seeks to characterize autotransplants as they are described in the literature and to determine whether endometriosis resembles an autotransplant.

Design: Literature review of published studies containing the following types of information: (1) characterization of the histologic features, immunohistochemistry, or structural function of autotransplants; and (2) comparisons of endometriosis with endometrium.

Main Outcome Measure(s): Characteristics of multiple types of autotransplants were noted. Similarity or dissimilarity of endometriosis and endometrium was tabulated to judge qualitatively whether the bulk of the evidence supports the notion that endometriosis is an autotransplant.

Result(s): Autotransplants remain very similar or identical to eutopic tissues of origin, regardless of the length of time following autotransplantation. Endometriosis differs in many profound and fundamental ways from eutopic endometrium, including clonality of origin, enzymatic activity, protein expression, and histologic and morphologic characteristics. A minority of studies has found similarities between endometriosis and eutopic endometrium.

Conclusion(s): 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.

Introduction

Endometriosis affects approximately 10% of the female population in their reproductive years [1] and represents one of the most common human diseases. The most widely accepted theory of origin [2] is Sampson's theory of reflux menstruation. Sampson's final version of his theory [3] proposed that endometriosis occurs as a result of the reflux of menstrual blood out through the fimbriated 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. Generations of gynecologists have been taught that endometriosis is simply misplaced normal endometrium that is identical to eutopic endometrium and responds normally and predictably to the ovarian hormonal cycle.

Endometriosis would therefore represent an autotransplant, in which tissue is transplanted to an ectopic location in an organism. The notion that endometriosis is an autotransplant brings up the question "What is the nature of autotransplants?" The relevant literature on autotransplants was reviewed to identify the nature of autotransplants. Studies comparing endometriosis to eutopic endometrium were reviewed to help answer the important follow-up question "Is endometriosis an autotransplant?"

Materials and methods

A MEDLINE search for English language literature from 1966 forward was conducted using keywords such as autograft, autotransplant, endometrium + endometriosis, histology, Sampson's theory, reflux menstruation, endometriosis + graft, or microscopic endometriosis. Additionally, monthly abstracts of the endometriosis literature provided by a medical library were searched for likely articles from 1988 to the present time. Finally, the reference lists of retrieved articles were reviewed for further papers of interest.

Over 200 papers from autotransplant and gynecology literature were read for this study. Papers from the autotransplant literature were included if they contained functional, morphologic, histologic, or other biological comparisons of the autotransplanted tissue with tissue in its native location. The intent was to determine how closely an autotransplant resembles the eutopic tissue of origin. Gynecologic papers were included for analysis if they clearly identified a comparative study between endometriosis and eutopic endometrium either from the same patient or from a normal endometrium control group. Such comparative studies would indicate how closely endometriosis resembles endometrium. No institutional review board approval was sought for this literature review.

Results

What is the nature of an autotransplant?
An autotransplant is tissue transplanted from one site to another site in the same organism, either due to a pathologic process or surgical intervention. Autotransplants do not require immunosuppression for existence. Although a reasonable assumption could be made that autotransplants should remain essentially identical to eutopic tissue, such transplants could conceivably be affected by the passage of time, disruption of normal blood supply, unavailability of biochemical precursors, infection, immune system attack, or unknown factors that could alter their immunohistochemistry or change them morphologically, histologically, or biochemically. Alternatively, such tissue might remain unchanged in its new location, unaffected by any of the above factors. Autotransplants exist as disease states, as modes of therapy, and as experimental animal models of endometriosis.

...an autotransplant is tissue transplanted from one site to another site in the same organism, either due to a pathologic process or surgical intervention...

Autotransplants as human disease states
Ovarian remnant syndrome [ORS] is a late complication of difficult oophorectomy [4] in the presence of periovarian adhesions, in which shreds of ovarian cortex remain behind and can be stimulated by pituitary hormones. Despite lacking a normal vascular supply, ORS autotransplants can be normally responsive to pituitary hormones [5, 6, 7], retaining the ability to produce sufficient estradiol to inhibit menopausal symptoms [8] and to form functional cysts that can be symptomatic [9, 10] Microscopic examination of the tissue causing ORS reveals entirely normal ovarian structures, including corpora lutea, follicle cysts, and oocytes [11, 12, 13], which can persist in humans for up to 5 [11] to 10 years [12].

Splenosis refers to macroscopic particles of splenic tissue that attach most commonly to abdominal or thoracic surfaces following traumatic rupture of the spleen. Pelvic splenosis can be a cause of pelvic pain, and can be confused with endometriosis [14, 15]. The histologic features of such splenic autotransplants have been noted as normal, regardless of the site of autotransplantation [16, 17, 18, 19, 20, 21, 22] which can include the pelvis [14, 15, 23, 24, 25, 26]. The histologic features can remain normal for decades after traumatic autotransplantation [16], although occasional variations in the macroarchitecture are described, including poorly developed white pulp [27] and trabeculae. Regeneration of normal splenic tissue from small splenic fragments [28] may be responsible for the normal anti-infective immunobiologic response that can be found in some [29, 30] but not all [31] patients with splenosis.

Autotransplants as human therapeutics
Therapeutic autotransplants depend on an autotransplant retaining all or most of its intrinsic features and functions. External autotransplants such as skin grafts, hair transplants, and digit substitution after amputation will not be discussed, as it is intuitively clear that the autotransplanted tissue remains identical to eutopically located tissue. Examples of internal therapeutic autotransplants include adrenal medullary transplants into the brain for Parkinson's disease, transplantation of the pulmonary valve for treatment of aortic valvular disease, and transplantation of strips of ovarian cortex into the forearm.

Autotransplantation of adrenal chromaffin cells into the brain has been performed for treatment of advanced Parkinson's disease. Immunohistochemical study of the transplanted tissue at autopsy 4 months after surgery has shown that the transplanted cells retain the intrinsic ability to express glial fibrillary acidic protein, chromogranin A, and neurofilament subunits, although not the capacity to produce tyrosine hydroxylase [32]. The investigators speculated that the lack of expression of tyrosine hydroxylase might be due to disruption of normal paracrine regulatory feedback that exists in the intact adrenal gland.

Substitution of the aortic valve by an autotransplanted pulmonary valve has been performed since 1967 for the treatment of severe aortic valve disease [33]. Patient survival is good [34] and depends on maintenance of normal valvular morphology and function, which can be taken as evidence of normal anatomy and histologic features. A good rate of patient survival for over 26 years after surgery has been documented. Late explanted pulmonary autotransplants showed remarkable preservation of cellular viability and tissue architecture, both macroscopically and histologically [35].

Strips of human ovarian cortex have been autotransplanted to the forearm in women scheduled to undergo pelvic radiation for cancer or castration because of adhesions. Such autotransplants have been found to function normally, despite the absence of a normal vascular supply [36], in a manner similar to ORS.

Experimental endometriosis in animals as an autotransplant model of a disease state
Experimental autotransplants as well as human-to-mouse xenografts have been used in animal models to study endometriosis and its medical and surgical treatment. Such autotransplants are typically made by taking minced eutopic endometrium and autologously injecting it intraperitoneally, or surgically implanting it retroperitoneally, somewhere in the abdominal cavity. This results in experimental endometriosis, which has been described as similar to native endometrium with normal histologic features and normal hormonal response [37]. The creation of such autotransplants as experimental models of endometriosis is the strongest manifestation of the belief that endometriosis is identical to native endometrium. Experimental endometriosis has been induced in humans, lesser primates, rabbits, rats, and mice.

In a human model of experimental endometriosis, menstrual blood was injected autologously into the subcutaneous fat of the lower abdominal wall of eight women [38], resulting in typical histologic findings of glands and stroma in one woman. The endometriosis in this patient was not characterized in detail. In a case report [39], iatrogenic endometriosis in a human female was described following an Estes procedure for infertility due to blocked fallopian tubes. In the Estes procedure, a portion of uterine wall is removed, creating a window into which an ovary is sutured to allow intrauterine ovulation to occur. The window would not necessarily be considered watertight, and in this case endometriosis was seen around the uterine incision at reoperation, but not in the cul-de-sac. However, it is not clear whether a small deposit seen on a round ligament was noted at the time of the initial surgery.

Primates other than humans have been the subject of several studies of experimental endometriosis. Autologous endometrium inserted into the anterior chamber of the eyes of 41 rhesus monkeys [40] was noted to remain viable if a vascular supply became established within 24 hours. The ectopic endometrium was noted to respond normally to endogenous and exogenous hormones. Although intraocular shedding of endometrium was observed thousands of times in the 432 menstrual cycles observed, shed endometrium never became implanted into the eye in another location.

Experimental endometriosis in monkeys induced by injecting minced eutopic endometrium into intraabdominal retroperitoneal locations showed typical glands and stroma, with no significant variation of glandular columnar cell height [41]. Autotransplanted nonmenstrual native endometrium survived for longer than 26 days in six of seven rhesus monkeys [42] with typical glands and stroma and glandular epithelium of consistent height on intralesional comparison, although gland sizes varied somewhat.

Ten monkeys were subjected to a famous experiment [42] in which the uterine fundus was separated from the cervix, and the uterus was rotated 180 degrees so that the top of the fundus could be sutured to the cervix or vagina to hold the uterus in its new, upside-down position. This allowed menstrual blood to exit directly into the mid-abdominal portion of the peritoneal cavity, coming into initial contact with loops of bowel. At interval reoperations over several years, five monkeys had developed massive adhesions of bowel to the stump of the inverted fundus, and endometriosis was found within the adhesions and fibrosis. Only one of these animals had endometriosis noted away from the surgical site, and the histologic features of one lesion from the right peritoneal sidewall were interpreted as normal, with glandular elements of consistent size and columnar cells of consistent height. Five other monkeys developed no endometriosis, and no endometriosis was described in the most dependent portion of the pelvis of any animal.

Experimental endometriosis in rabbits created by implantation of fragments of endometrial tissue has been found to be histologically similar to eutopic endometrium [43, 44, 45] with well-developed glandular columnar epithelium that shows consistent glandular height [46] and proteins similar to those found in eutopic endometrium [47]. Use of relatively large tissue fragments was thought by some to be too identical to the eutopic endometrium of rabbit [48] or rats [49], although variability in the histologic characteristics of glandular elements of experimental endometriosis in chinchilla rabbits had occasionally been observed [50]. Because of this concern and also because tissue fragments did not morphologically resemble menstrual endometrium, suspensions of dispersed endometrial cells were injected intraperitoneally in rabbits [48] and were found to produce lesions demonstrating characteristic glandular changes.

Experimental endometriosis induced in rats either by suturing native endometrium to peritoneal surfaces or mesentery [51] or by insertion under the renal capsule [52] remains normal histologically when compared with eutopic endometrium and retains its ability to respond histologically normally to circulating estrogen levels [53]. In another rat model, experimentally induced endometriosis was not mentioned to differ histologically from native endometrium [54].

Investigators have also induced experimental endometriosis in a mouse xenograft model most frequently by injecting human non-menstrual endometrium into the peritoneal cavities of severely combined immunodeficient [SCID] mice. Experimental endometriosis in SCID mice retains the specific histologic, hormonal, and functional responses as well as biochemical properties of native eutopic endometrium [55, 56]; however, in one study, all explants reverted to a proliferative pattern regardless of the original cycle pattern of the xenografts, including menstrual endometrium [57]. Peritoneal lesions of experimental endometriosis have been visible to the naked eye in such SCID mice within only a few days of insertion [57, 58], with a histologic appearance and immunohistochemical characteristics similar to eutopic endometrium. Other investigators reported difficulty seeing small lesions unless they were tagged with fluorescent dye [59].

From the above observations, it seems that autotransplants in humans or animals typically remain normal in structure, function, morphology, histology, and hormone response. The continued normal function of this tissue is frequently a benefit to the patient in the case of therapeutic autotransplants. Autotransplants do not seem to be attacked in their new location by any identified humoral or local factor, nor do they seem to be changed in any profound way. Autotransplants may remain similar or identical to eutopic tissue for decades.

...autotransplants in humans or animals typically remain normal in structure, function, morphology, histology, and hormone response...

Is endometriosis an autotransplant?
If endometriosis is an autotransplant, one would expect that it should be very similar or identical to menstrual endometrium - or at least to native eutopic endometrium - because that is the nature of an autotransplant. There have been many studies comparing endometriosis with endometrium from the same patient or with endometrium from normal controls. These studies have compared hormone receptor levels, and the histologic, morphologic, and biologic nature of endometriosis at increasingly sophisticated levels. These studies, which are too numerous to detail, are summarized in Table 1 [60 - 107].

Table 1. Differences between endometriosis and eutopic endometrium in humans

Characteristic compared: first author (reference) Endometriosis Endometrium
Cyclicity of estrogen receptors; Gould [60] Absent Present
Secretory phase estrogen binding by stroma; Gould [60] Present Absent
Sex hormone receptors; Tamaya [61], Janne [62], Bergqvist [63], Lessey [64], Nisolle [65], Bergqvist [66] Low-variable Normal
Sex hormone receptors; Jones [67] High Normal
Postmenopausal hormone receptor levels; Toki [68] Higher Lower
Normal cyclic histology; Metzger [69] Absent Present
Cyclic differentiation; Metzger [69] Absent Present
Patient-specific endometrial phase tissue synchronicity; Metzger [69] Variable Phase-specific
Intralesional glandular or stromal variation; Redwine [70] Present Absent
Fibromuscular metaplasia, deep disease; Cullen [71, 72, 73, 74], Sampson [75], Fallon [76], Nisolle [77] Present Absent
Cystic morphology; Sampson [78], Nezhat [79] Possible in ovary Absent
Loss of heterozygosity; Jiang [80], Jimbo [81] Present Absent
Cyclic tenascin expression; Harrington [82] Absent Present
Fibronectin receptors; Beliard [83] Present Absent
Integrin alpha 3; Regidor [84] Increased Absent
Integrin alpha 3; Rai [85] Positive Negative
Integrin alpha 6; Rai [85] Negative Positive
E-cadherin, alpha/beta-catenin mRNAs; Fujimoto [86] Abnormal, low Normal
Apoptosis of eutopic endometrium; Gebel [87] Lower Normal
Apoptosis in patients with endometriosis; Dmowski [88] Lower Normal
Expression of aromatase; Leyendecker [89], Kitawaki [90] Present Absent
Stromal cell proliferation due to interleukin 6; Yoshioka [91] Not inhibited Inhibited
Interleukin 6 secretion; Tseng [92] Strongly present Present
Interleukin 1 receptor antagonist in glands; Sahakian [93] Always absent Usually present
Granulated lymphocytes; Jones [94] Absent Present
Activated T-cells; Witz [95] Increased Normal
Expression of interferon gamma; Klein [96] Increased Normal
17-OH steroid dehydrogenase; Zeitoun [97] Absent Normal
Gelatinase A production; Wenzl [98] Increased Normal
Cathepsin D proteolytic enzyme; Bergqvist [99] Increased Normal
Perimenstrual matrix metalloproteinase-1; Kokorine [100] Present Absent
Matrix metalloproteinase-7, protein-stimulated invasion; Rodgers [101] Present Absent
Urokinase-type plasminogen activator; Bruse [102] Increased Normal
Vascular endothelial growth factor in black lesions; Donnez [103] Reduced Normal
Transcripts of CYP1A1 gene; Starzinski-Powitz [104] Elevated 8.7 times Normal
Endometriosis protein-I (ENDO-I); Piva [105] Increased Normal
Bcl-2 expression; Watanabe [106] Noncyclic Cyclic
Stromal cell DNA and protein synthesis response to endothelial growth factor; Mellor [107] Increased Greatly increased

Relatively few studies have found similarities between endometriosis and endometrium (Table 2). Some of these studies have examined very sophisticated parameters that may reach beyond comparisons of endometriosis to endometrium, and may simply approach the essential nature of all living tissues. As laboratory investigations of a disease become increasingly minutely focused, the results may not apply to the entire spectrum of that disease due to selection bias.

Table 2. Similarities between endometriosis and eutopic endometrium in humans

Characteristic compared: first author (reference) Endometriosis Endometrium
Vascular endothelial growth factor in red lesions; Donnez [103] Present Present
Dioxin-related activating factors, target genes; Bulun [108] Present Present
Collagen types I, III, IV; Stovall [109] Present Present
Vascular tissue complement components; D'Cruz [110] Present Present
Acidic and basic fibroblast growth factors; Ferriani [111] Present Present
Keratins 5,7,8,14,18,19; Kruitwagen [113] Present Present
Cell adhesion molecule expression; Bridges [114] Present Present
Invisible "microscopic" disease with magnification; Redwine [115] Absent Absent

Discussion

Some degree of caution was necessary in interpretation of the literature reviewed here. For example, the literature on ORS and splenosis autotransplants might not be complete if a possible population of "silent" cases were not described; they may not have been diagnosed due to lack of symptoms, and their condition may have differed profoundly from eutopic tissue. Such an undiagnosed population might theoretically differ significantly from the picture that emerges from this literature review of autotransplants as disease states. However, existence of such a population of silent cases is speculative, and the weight of available evidence indicates that autotransplant disease states remain largely similar or identical to eutopic tissue.

Additionally, menstrual endometrium was not used in most studies of experimental endometriosis in animals, in part because many of the species studied do not have a menstrual cycle. Accordingly, it could be argued that all animal studies of experimental endometriosis that do not involve menstrual endometrium are irrelevant because they do not duplicate the putative causal event thought to occur in humans: that is, menstrual endometrium refluxing out of the fimbriated end of the fallopian tubes and attaching to peritoneal surfaces, proliferating, invading, and becoming the disease known as endometriosis. It seems either that researchers have considered the use of menstrual endometrium to be impertinent to the study of experimental endometriosis, or that most researchers have not considered its pertinence at all. In either case, the evidence presented seems to be the only evidence available, and so it must be accepted for face value.

Given the caveats stated above, the answer to the question "Is endometriosis an autotransplant?" arguably could be no. An autotransplant is very similar or identical to tissue in its native location and can remain normal in structure and function for decades. In contrast, there are multiple, profound differences between endometriosis and native endometrium. Studies showing similarities between these two tissues are in the distinct minority. The balance of the evidence suggests that endometriosis is not simply displaced normal endometrium as would be expected in an autotransplant disease. There are only two possible explanations for such incongruence. Either normal native endometrium is profoundly damaged sometime between its eutopic origin and the eventual establishment of disease, or endometriosis does not originate from native endometrium in the first place, but rather has a different provenance.

...the balance of the evidence suggests that endometriosis is not simply displaced normal endometrium as would be expected in an autotransplant disease. There are only two possible explanations for such incongruence. Either normal native endometrium is profoundly damaged sometime between its eutopic origin and the eventual establishment of disease, or endometriosis does not originate from native endometrium in the first place...

Regarding the first possibility of tissue damage en route to the peritoneal cavity, it is theoretically possible that the biologic action of menstruation damages normal endometrium in multiple profound ways (see Table 1). However, it is difficult to conceive that the mere casting off of tissue that was once "normal" would cause it to be so "abnormal," and such an occurrence is only speculation. Such differences require an explanation of their origin. Indeed, in studies of experimental endometriosis using menstrual endometrium, the resulting grafted tissue has been characterized as normal [38, 57]. Thus, the available evidence suggests that menstruation is not the damaging event.

Could tissue damage en route be caused by some other agent? There is no reason to suspect that normal or menstrual endometrium should be damaged during its retrograde journey to attach to the pelvic surfaces, or after proliferation and invasion allegedly occur. No putative mechanism seems to exist to explain why such tissue damage should occur during the retrograde passage of these cells. Indeed, one modern arm of the theory of reflux menstruation holds that women destined to develop endometriosis have deficient immune systems that cannot identify or defend against refluxed endometrium in the first place [116, 117, 118]. Such a deficient immune system would seem unlikely to damage endometrial cells and change them in all the ways that have been identified, but an alternate system to produce such damage is difficult to nominate. Such profound obligatory damage by an unidentified process to native endometrium during transit through the fallopian tube with resultant wide-ranging toxic effects would represent a strained convolution of Sampson's theory, and would also have profound ramifications for embryotoxicity.

...there is no reason to suspect that normal or menstrual endometrium should be damaged during its retrograde journey to attach to the pelvic surfaces, or after proliferation and invasion allegedly occur...

Evidence-based medicine is gaining sway, as well it should. We in the modern era have intellectual and scientific advantages that have resulted in the compilation of scientific evidence regarding endometriosis that was unavailable to previous generations of clinicians, researchers, and proponents of theories of origin. How will we use this evidence? It is clear that endometriosis cannot be considered to be merely displaced normal endometrium. This idea, categorically accepted as one of the mainstays of Sampson's theory of origin, must be discarded.

...it is clear that endometriosis cannot be considered to be merely displaced normal endometrium. This idea, categorically accepted as one of the mainstays of Sampson's theory of origin, must be discarded...

Given the differences between endometriosis and endometrium, the continued acceptance of Sampson's theory as the origin of endometriosis must be questioned. Proponents of Sampson's theory have observed these multiple and profound differences but have not explained them. The simplest proof of Sampson's theory would be to provide abundant photomicrographic evidence in humans of in vivo initial attachment of menstrual endometrium to peritoneal surfaces, with further demonstration of secondary proliferation and invasion. This still has not been done, despite the belief that attachment, proliferation, and invasion occur in billions of instances around the world. Regardless of how long endometrium allegedly remains attached to the peritoneum before invasion, enough peritoneal biopsies have been obtained over the years for this event to have been conclusively proven, as well as the equally unproven events of peritoneal invasion and retroperitoneal proliferation. Abundant photomicrographic evidence exists of established endometriosis, but no satisfactory explanation has been advanced for why the steps preceding it cannot be photographed in humans. Now Sampson's theory must also provide an explanation of why the alleged autotransplant known as endometriosis differs so profoundly from native endometrium and from other autotransplants. Our profession and women with endometriosis cannot wait much longer for these answers.

...Sampson's theory must provide an explanation of why the alleged autotransplant known as endometriosis differs so profoundly from native endometrium and from other autotransplants. Our profession and women with endometriosis cannot wait much longer for these answers...

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