{"paper_id":"76be273a-8748-44cb-befd-d60dc9b120a8","body_text":"Summary\nThe major authors of the last century described en-\ndometriosis as ectopic endometrial lesions occurring\nboth in the uterus and in the peritoneal cavity, and the\nlesions were considered as variants of the same disease\nprocess. In the 1920s a theory had been put forward\nthat, although severely and chronically challenged, re-\nsulted in the clear cut separation of the two entities. A\nnew understanding of the disease process, however,\nenables to reunify these two disease entities and to in-\ntegrate them into a new nosological concept. Circum-\nstantial evidence suggests that endometriosis and ade-\nnomyosis share a similar pathophysiology and are\ncaused by trauma. In the spontaneously developing\ndisease, chronic uterine peristaltic activity or phases of\nhyperperistalsis induce, at the endometrial-myometri-\nal interface near the fundo-cornual raphe, microtrau-\nmata with the activation of the basal and general\nmechanism of “tissue injury and repair” (TIAR). This\nresults in the local production of estrogens. With on-\ngoing peristaltic activity, such sites will accumulate\nand the increasingly produced estrogens interfere via\nparacrine mode of action with the endocrine ovarian\ncontrol over uterine peristaltic activity, resulting in\npermanent hyperperistalsis and a self-perpetuation of\nthe disease process. Overt auto-traumatization of the\nuterus, with dislocation of fragments of basal en-\ndometrium into the peritoneal cavity and infiltration\nof basal endometrium into the depth of the myometri-\nal wall, ensues. In most cases of endometriosis/adeno-\nmyosis, a causal event early in the reproductive period\nof life must be postulated leading to uterine hyperperi-\nstalsis. In late premenopausal adenomyosis such overt\nevent might not have occurred. However, as indicated\nby the high prevalence of the disease, it appears to be\nunavoidable that, with time, chronic normoperistalsis\nthroughout the reproductive period of life may result\nin events that accumulate to the same extent of micro-\ntraumatizations. With the activation of the TIAR\nmechanism, followed by infiltrative growth and\nchronic inflammation, endometriosis/adenomyosis of\nthe younger woman and premenopausal adenomyosis\nshare in principal the same pathophysiology. In con-\nclusion, endometriosis and adenomyosis result from\nthe physiological mechanism of ‘tissue injury and re-\npair’ (TIAR) involving local estrogen production in an\nestrogen-sensitive environment normally controlled by\nthe ovary. It appears that many of the altered endome-\ntrial molecular markers described in the context of en-\ndometriosis are the consequence rather than the\ncause(s) of the disease.\nIntroduction\nEndometriosis is a disease that affects women pre-\ndominantly during the reproductive period of life.\nWith the cardinal symptoms, pelvic pain, bleeding dis-\norders, and infertility, the disease has a tremendous\nimpact on women’s health. In most of the women af-\nfected the first symptoms can be traced back to adoles-\ncence [1]. Many women, however, remain free of\nsymptoms or exhibit only minor complaints. More-\nover, in cases with the development of the disease after\nchildbearing, the condition may remain undiagnosed.\nNot infrequently, at laparoscopy for tubal sterilisation\n[2] and hysterectomy for fibroids and adenomyosis,\nendometriotic implants and scars, respectively, can be\nobserved. Thus, the current estimates of prevalence are\nprobably too low. The syndrome of dislocated basal\nendometrium (SDBE), a term that comprises the\n1 Kinderwunschzentrum (Fertility Center) Darmstadt, Germany\n2 University Clinic of Gynecological Endocrinology and Reproductive Medicine,\nDepartment of Obstetrics and Gynecology, Medical University Innsbruck,\nAustria\n3 Institute of Pathology, Klinikum Darmstadt, Academic Teaching Hospital to the\nUniversities of Frankfurt and Heidelberg, Germany\nKeynote lecture\n4th International Congress on Endometriosis – Rome May 28-30, 2009\n© Copyright 2010, CIC  Edizioni Internazionali, Roma\nEndometriosis and adenomyosis – a shared pathophysiology\nLEYENDECKER G.1, WILDT L.2, MALL G.3\nGiorn. It. Ost. Gin. Vol. XXXII - n. 5\nSettembre-Ottobre 2010\n259\nrassegne\n© CIC Edizioni Internazionali\n\npathophysiological continuum of endometriosis, en-\ndometriosis in association with adenomyosis and pre-\nmenopausal adenomyosis, thus appears to be a very\ncommon phenomenon [3]. We had, therefore, a\ndecade ago, suggested that its cause or causes may be\nunspectacular and closely related to the physiologic\nprocess of reproduction. T rauma followed by tissue\nspecific hyper reactive inflammatory response and re-\npair involving specific, albeit physiological cellular,\nbiochemical, and molecular mechanisms may be con-\nsidered the major events in the development of the dis-\nease [4]. \nRecently we could extend our previous views and\nelaborate a comprehensive model of the pathophysiol-\nogy of endometriosis and adenomyosis [5]. This en-\ndeavour was undertaken with the premise that all phe-\nnotypes of endometriosis share in principal the same\npathophysiology and that no parallel and separate\nmechanisms of their development do exist. This does,\nhowever, not exclude various and different etiologies at\nthe very onset of the disease process including iatro-\ngenic [6], exogenous [7, 8], and hereditary [9] factors.\nWith respect to hereditary factors, they might be re-\nmote from the genuine disease process and thus not\neasily to disclose.\nHistorical remarks\nThe aetiology and pathogenesis of endometriosis,\nwhich is the ectopic occurrence of endometrial tissue,\nhas been enigmatic from its first description until to-\nday. The theory of dissemination of endometrial tissue\nby retrograde menstruation, proposed by Sampson in\n1927, has remained the presently prevailing patho-\nphysiological concept [10]. However, since retrograde\nmenstruation has later been considered to be a physi-\nological phenomenon, other factors, such as menstru-\nal outflow obstruction or pelvic peritoneum immuno-\nlogical defects have been additionally proposed to re-\nfine Sampson’s theory (for review: [4]). Also the recent\nadvances in the understanding of the molecular biolo-\ngy of endometriosis, both on the endometriotic lesions\nand the eutopic endometrium in affected women, did\nnot result in a principal revision of Sampson’s concept.\nIt is suggested that in women with endometriosis frag-\nments of inherently or epigenetically altered en-\ndometrium are shed during menstruation and dissem-\ninated within the peritoneal cavity [11, 12].\nSampson’s theory was continuously challenged.\nWhile in monkey experience endometrial tissue from\ncyclic endometrium could readily grow as autotrans-\nplants or in culture, this was not the case with men-\nstrual debris. Even experimentally produced utero-\nperitoneal fistulae did not result in peritoneal en-\ndometriosis. In contrast, with and much to the surprise\nof the investigators, following surgery for retroflexio\nuteri (by a thread of silk positioned into the fundal\npart of the uterus) severe uterine adenomyosis ensued\nand penetrated along the thread into the peritoneal\ncavity to form endometriotic lesions (for review:\n[13]). Philipp and Huber speculated that retrogradely\ntransported menstrual debris would only cause en-\ndometriosis in those rare cases when the necrotic ma-\nterial was mixed with vital tissue fragments detached\nfrom the deeper basal layer [13]. \nFor the first time we provided strong circumstan-\ntial evidence that, in the human, endometriosis results,\nin fact, from the dislocation of fragments of basal op-\nposed to functional endometrium [14]. This was at\nharmony with findings in the baboon model that in-\noculation of bioptic material taken from menstrual en-\ndometrium was more likely to result in endometriotic\nlesions than that obtained from secretory endometri-\num [15]. It is possible that the higher implantation\nrate with biopsies from menstrual endometrium was\nowed to fragments of basal endometrium, that could\nhave been more easily obtained from menstrual than\nfrom secretory endometrium. Nevertheless, for the in-\nduction of experimental endometriosis in the baboon\nmodel, it is now strongly recommended to use materi-\nal that results from “vigorous” biopsies during the\nmenstrual period [16, 17]. According to our view,\nsuch biopsies have a high probability to contain basal\nendometrium.\nIn critically analyzing Sampson’s data and the\navailable clinical and experimental literature, Philipp\nand Huber in 1939 appreciated Sampson’s observa-\ntion that in nearly all of his patients the tubes were\npatent, a finding that they thought should be kept in\nmind and incorporated into a future comprehensive\nmodel of the pathophysiology of the disease. They\nstressed, however, that retrograde menstruation would\nbe, for various reasons, an insufficient model to de-\nscribe the pathophysiology of a disease that did com-\nprise, in their opinion and that of other authorities at\nthat time, more than just a disease of the pelvic peri-\ntoneum [13]. \nIn fact, the major authors of the last century de-\nscribed ectopic endometrial lesions occurring both in\nthe uterus and in the peritoneal cavity, and the lesions\nwere considered as variants of the same disease\nprocess. Robert Meyer, favouring the concept of meta-\nplasia, was the first to hint at the chronic inflammato-\nry character of the lesions both in, the extra- and in-\ntrauterine sites [18]. Also Sampson, who introduced\nthe term ‘endometriosis’, described “primary en-\ndometriosis” as the uterine variant of the disease [10].\nHis scientific interest, however, was nearly exclusively\ndirected towards the development of the peritoneal\n260\nLeyendecker G. e Coll.\n© CIC Edizioni Internazionali\n\nvariety. This, and his view of uterine adenomyosis to\nresult from vascular transmission, were probably the\nreasons why he did not report on the parallel presen-\ntation of “primary endometriosis” in his cases of peri-\ntoneal endometriosis [19]. In fact, it was his theory\nthat laid the basis for considering uterine adenomyosis\nand external endometriosis as different disease entities\n[20]. This was later on enforced by the fact that en-\ndometriosis was mostly diagnosed by laparoscopy in a\nsterility work-up and for obvious reasons the uterus\nevades histological, structural, and morphological ex-\namination in such cases. Pelvic endometriosis became\na topic of research, while the clinical and scientific in-\nterest in uterine adenomyosis nearly completely van-\nished. The definition of endometriosis that is current-\nly in use and propagated by influential societies such\nas the ASRM and the ESHRE is reflecting this strict\nseparation and present confinement to the peritoneal\nvariety [21, 22]. Much of the research work per-\nformed during the last two decades originated from\nthis concept [23-29].\nYet, the issue of endometriosis and adenomyosis\nwhether or not representing distinct disease entities is\nfar from being resolved. A search in PubMed reveals\nthat under the headings of endometriosis and adeno-\nmyosis, respectively, rather the same items are dis-\nplayed. In addition, the recent resurrection of the\nterm ‘adenomyoma’ does, in our opinion, not con-\ntribute to the clarification of the issue. In an attempt\nto prove the distinctiveness of endometriosis and ade-\nnomyosis, respectively, hospital records of surgery\nwere analyzed [30, 31]. Given the fact that pre-\nmenopausal adenomyosis represents the slowly and\nendometriosis with and without associated adeno-\nmyosis the more rapidly developing form of the dis-\nease, respectively, it was to be expected that the former\nwomen, given also the fact they represented a study\npopulation with a reproductive pattern of attempting\nearly pregnancies, would more likely be parous than\nthe latter. Moreover, it is unlikely, that during routine\nhysterectomy, the same meticulous search for en-\ndometriosis is performed as in work-up for infertility.\nIn our opinion, these studies do not take into account\nthe pleiomorphic character of endometriosis and ade-\nnomyosis. \nWhen we, for the first time, recognized again the\nfrequent association of endometriosis with adeno-\nmyosis [32-34], seemingly challenging Sampson’s\nview, we earned pure disbelief. Fortunately, our Ger-\nman colleagues in contrast to those in other coun-\ntries, are entitled to perform ultrasound in their own\noffices. Thus, it took only a few weeks after they had\nseen enough cases on their own and had also per-\nformed some MRI scans, until the discussion\nwhether or not endometriosis may be associated with\nadenomyosis was terminated. Also other groups that\nincorporated imaging techniques in their set up con-\nfirmed in principal the frequent association [35].\nMeticulously performed ultrasound usually reveals in\ncases of endometriosis characteristic signs of uterine\nadenomyosis (“abnormal patterns” of the uterus;\nMargit Dueholm, personal communication) such as\nabnormal shapes and sizes of the uterus if fibroids are\nexcluded, asymmetry with respect to the anterior and\nposterior walls, irregularities of the lining of the en-\ndometrium, an unusual texture of the myometrium,\nand of course a broadened, focally destroyed or com-\npletely absent ‘halo’. MRI usually confirms these\nfindings [3] (Figs 1 and 2). Cullen and some of the\nscientific giants around the turn of the last century\nwere rapidly back [36]. Of course, Sampson was not\nproven wrong, in a strict sense, in that tubal dissem-\nination constitutes, without doubt, an important as-\npect in the disease process. This aspect, however, has\nto be more precisely defined in a consistent and com-\nprehensive concept of the pathophysiology of en-\ndometriosis and adenomyosis (vide infra). In any\nevent, the focus of studying the pathogenesis of en-\ndometriosis shifted from the pelvic peritoneum to\nthe archimetra, which is the Müllerian part of the\nuterus [4]. It became evident that the peritoneal en-\ndometriotic lesion merely constitutes one of the\npleiomorphic phenomena rather than the genuine\ndisease itself.\n261\nEndometriosis and adenomyosis – a shared pathophysiology\nFig. 1 - Transvaginal sonography (TVS) and magnetic resonance im-\naging (MRI) of the uterus of a 29 years old woman unaffected with en-\ndometriosis and adenomyosis. Sagittal scans of the uterine midline\nare shown. The myometrial-endometrial lining is sharp and smooth;\nthe “halo” in TVS and the “junctional zone” in MRI are unaltered;\nthere is symmetry with respect to the anterior and posterior myome-\ntrial walls and the texture of the myometrium in TVS appears to be ho-\nmogenous.\n© CIC Edizioni Internazionali\n\nThe role of the uterus in the disease\nprocess\nIn the understanding of the pathophysiology of en-\ndometriosis and adenomyosis a re-analysis of both\nstructure and function of the non-pregnant uterus\nturned out to be of utmost importance [4, 37-39].\nWith uterine peristalsis and directed sperm transport a\nnovel uterine function has been discovered [40-47]. It\nbecame evident that the non-pregnant uterus is con-\nstantly active throughout the reproductive period of\nlife and thereby, like other mechanically active organs\nof the body such as the skeletal and the cardiovascular\nsystems, respectively, rather inevitably subjected to\nmechanical strain. Research performed over the last\nyears has demonstrated a crucial role of mechanical\nstrain in normal and pathological function of various\ntissues. Moreover, it became apparent that the molec-\nular mechanisms associated with mechanical strain, in-\njury, and repair displays a pattern that is quite similar\nin different tissues and involves the expression of the\nP450 aromatase and the local production of estrogen\n[48]. The sequels of tissue injury and repair, however,\nmay become very specific depending on structure and\nfunctions of the tissues and organs involved such as\ntendons and cartilage in the skeletal and the intima in\nthe cardiovascular system, respectively. This is of par-\nticular importance, when the tissue, as it is the case\nwith the uterus, is physiologically highly estrogen sen-\nsitive and when injury is chronic in character. \nThere are several lines of evidence for the notion\nthat dysfunctions of the uterus play a crucial role in\nthe pathophysiology of endometriosis. \n1. Fragments of basal endometrium were found in\nthe menstrual effluent with a higher prevalence\nin women with endometriosis than in controls.\nOn the basis of these and other findings it was\nsuggested that pelvic endometriosis results from\nthe transtubal dislocation of fragments of basal\nendometrium [14]. \n2. There is a significant association of pelvic en-\ndometriosis with uterine adenomyosis in\nwomen and in the baboon with life-long infer-\ntility. In women, the reported prevalence, how-\never, differs according to the study population\nchosen and to the criteria applied to the inter-\npretation of MRI findings [4, 32, 34, 49, 50].\n3. The uterine function of rapid and directed sperm\ntransport into the ‘dominant tube’ is dysfunc-\ntional in women with endometriosis and is char-\nacterized by hyper- and dysperistalsis [51-56].\nIt was suggested that this uterine dysfunction in\nwomen with endometriosis and adenomyosis is a re-\nsult of archimetral hyperestrogenism [3, 4, 53, 57].\nThere are several lines of evidence that support this\nnotion.\n1. In comparison to normal controls and in con-\ntrast to peripheral blood, estradiol levels are el-\nevated in menstrual blood of women with en-\ndometriosis and adenomyosis [58]. \n2. The expression of the P450 aromatase is in-\ncreased in adenomyotic tissue and in the ec-\n262\nLeyendecker G. e Coll.\nFig. 2 - Pleiomorphic appearance of focal and diffuse adenomyosis in women with moderate to severe endometriosis (27 to 31 year s of age; a-\nc). In patient (d) (37 years of age) because of low sperm count of the husband no laparoscopy was performed. She had a curettag e at an age\nof 22. The TVS was apparently normal. Meticulous analysis, however, showed asymmetry of the uterine walls and no “halo” could be demon-\nstrated. MRI revealed focal to diffuse adenomyosis of the anterior wall and beginning adenomyosis of the posterior wall of the uterus. Sagittal\nscans of the uterine midline are shown.\n© CIC Edizioni Internazionali\n\ntopic and eutopic endometrium of women with\nendometriosis [11, 12, 59-63].\n3. A highly estrogen-dependent gene, Cyr61, is\nup-regulated in eutopic endometrium in\nwomen with endometriosis and also in ectopic\nlesions as well as in experimental endometriosis\n[64, 65].\n4. The peristaltic activity of the subendometrial\nmyometrium can be dramatically increased by\nelevated peripheral levels of estradiol as they are\nobserved during controlled ovarian hyperstimu-\nlation. The intensity of uterine peristaltic activ-\nity in women with endometriosis resembles that\nof women during controlled ovarian hyperstim-\nulation although the peripheral estradiol levels\nare within the normal range [4, 53, 66]. \nOn the basis of the data presented above, we had\nsuggested that auto-traumatisation of the uterus would\nconstitute the critical factor in the development of en-\ndometriosis and adenomyosis [3, 4, 57]. Hyperperistal-\nsis induced by the local production of estrogens would\nconstitute a mechanical trauma resulting in an in-\ncreased desquamation of fragments of basal endometri-\num and [14], in combination with an increased retro-\ngrade uterine transport capacity [53], in enhanced\ntranstubal dissemination of these fragments. Hyper-\nperistalsis and increased intrauterine pressure would re-\nsult, with time, in myometrial dehiscences that are in-\nfiltrated by basal endometrium with the secondary de-\nvelopment of peristromal muscular tissue. Diffuse or\nfocal adenomyosis of various extent ensues. Adenomy-\notic foci are usually localized in the anterior and/or pos-\nterior wall, with preference of the posterior, but only\nrarely in the lateral walls of the uterine corpus. Early le-\nsions usually present close to the “fundo-cornual raphe”\nof the archimyometrium [3, 33, 34] (Figs 3 and 4). \nThe enigma of archimetral\nhyperestrogenism\nUndoubtedly the local production of estrogens\nboth on the level of the eutopic endometrium in\nwomen with endometriosis and of the ectopic lesions\nis central to the understanding of the pathophysiology\nof the disease. However the etiology of this increased\nestrogen-producing “glandular” potential of these tis-\nsues, however, is still enigmatic. It was recently sug-\ngested that the susceptibility of developing the disease,\n263\nEndometriosis and adenomyosis – a shared pathophysiology\nFig. 4 - Examples of uterine adenomyosis in six patients as presented by magnetic resonance imaging (MRI). Representative sagittal and coro-\nnary scans are shown. In the infertile, non-parous women (a-e) (30-32 years of age) pelvic endometriosis of grade I-IV was demonstrated by la-\nparoscopy. In the parous woman (f) (40 years of age) no laparoscopy was performed. In all scans preponderance of the adenomyotic lesions\n(expanded junctional zone) in the midline close to the fundo-cornual raphe of the archimyometrium can be demonstrated. In the f irst three\nscans (a-c) the diagnosis of adenomyosis would not meet the established radiologic criteria for MRI. In a scientific context, however, the irreg-\nularities of the junctional zone are characteristic of beginning adenomyosis.\nFig. 3 - Modified original drawing from Werth and Grusdew [9] show-\ning the architecture of the subendometrial myometrium (archimy-\nometrium) in a human fetal uterus. The specific orientation of the cir-\ncular fibers of the archimyometrium results from the fusion of the two\nparamesonephric ducts forming a fundo-cornual raphe in the midline\n(dashed rectangle). The peristaltic pump of the uterus, which is con-\ntinuously active during the menstrual cycle, is driven by coordinated\ncontractions of these muscular fibers. Directed sperm transport into\nthe dominant tube is made possible by differential activation of these\nfibers. The fundo-cornual raphe constitutes a region of increased me-\nchanical strain and tissue injury followed by local estrogen produc-\ntion (TIAR). \n© CIC Edizioni Internazionali\n\nwith the potential to locally produce estrogens within\nthe eutopic endometrium, would be acquired during\nprenatal life by an epigenetic mechanisms that would\nbecome manifest not until after puberty [12]. Other\nauthors suggest that the endometrium in women with\nendometriosis is inherently altered [11]. Clinical and\nexperimental evidence do not supports these views. If\nprimary alterations of the endometrium were a prereq-\nuisite of the development of the disease, it is impossi-\nble, in the primate model, to induce peritoneal en-\ndometriosis by inoculation of endometrial fragments\nobtained from endometrial biopsies of healthy animals\n[15-17, 65]. Moreover, following caesarean section ab-\ndominal wall endometriosis develops in presumably\nprimarily healthy subjects. \nTissue injury and repair (TIAR)\nRecent studies have increasingly shown that estra-\ndiol is of utmost importance in the process of wound\nhealing [67-69]. This action appears to be mainly me-\ndiated by the estrogen receptor-beta (ER2). Animal\nexperiments with chemotoxic and mechanic stress to\nastroglia [48, 70, 71] and urinary bladder tissue, as\nwell as studies with isolated connective tissue such as\nfibroblasts and cartilage [72-74], have revealed that tis-\nsue injury and inflammation with subsequent healing\nis associated with a specific physiological process that\ninvolves the local production of estrogen from its pre-\ncursors. Interleukin-1 induced activation of the cy-\nclooxygenase-2 enzyme (COX-2) results in the pro-\nduction of prostaglandin E2 (PGE2), which in turn\nactivates STAR (steroidogenic acute regulatory pro-\ntein) and P450 aromatase. Thus, with the increased\ntransport of cholesterole to the inner mitochondrial\nmembrane, testosterone can be formed and aroma-\ntized into estradiol that exerts its proliferative and\nhealing effects via the ER2. In studies with fibroblast\nit was surprising that the first steps of this cascade\ncould be activated by seemingly minor biophysical\nstrain [72]. Following termination of unphysiological\nstrain and healing this process is down-regulated and\nthe local production of estrogen or up-regulation of es-\ntrogen-dependent genes ceases [72, 75]. This cascade\ncan even be activated in tissue that normally does not\nexpress P450 aromatase, indicating the basic physio-\nlogical significance of the local production of estrogen\nin tissue injury and repair (TIAR) [76]. The similar-\nity of the molecular biology of TIAR in various tis-\nsues with that described in endometriosis [11, 12,\n63-65, 77-80] strongly suggests that this represents\nthe common underlying mechanisms of both\nprocesses (Fig. 5).\nMechanism of disease: uterine auto-\ntraumatisation\nStructure and function of the subendometrial my-\nometrium and the endocrine control of directed sperm\ntransport have been described elsewhere [33, 37, 43,\n66, 81, 82]. It is comprehensible that the myometrial\nfibers and the fibroblats at the endometrial-myometri-\nal interface, near the fundo-cornual raphe, are subject-\ned to increased mechanical strain during midcycle, be-\ncause not only is the ovarian estradiol secretion at its\npeak at that time, but also additional mechanical\nstrain is imposed on these cells due to estradiol that\nreaches the uterus via the utero-ovarian counter-cur-\nrent system and controls the direction of the upward\ntransport [81]. Directed sperm transport begins dur-\ning the mid-follicular phase of the cycle when the\ndominant follicle becomes visible [43]. The fundo-\ncornual raphe as a site of predilection of mechanical\nstrain is documented by the observation that early ade-\nnomyosis usually evolves in the sagittal midline of the\nmid-corporal and fundal parts of the uterus (Fig. 4).\nEven in more advanced cases of adenomyosis the ex-\npansion of the junctional zone in MRI often shows\npreponderance at these locations [3]. \nFirst step injury: microtraumatization \nExperiments with cultivated fibroblasts have\nshown that within certain limits mechanical strain is\nphysiological to such cells. However, even minor in-\ncrements in mechanical strain resulted the activation\nof COX-2 and the production of PGE2, the basic bio-\nchemical mechanisms underlying tissue injury [72],\nand also in the production of interleukin-8 [83]. Thus,\nwith respect to the subendometrial myometrium, de-\n264\nLeyendecker G. e Coll.\nFig. 5 - The basic aspects of the molecular biology of the physiologi-\ncal mechanism of ‘tissue injury and repair’ (TIAR) as demostrated in\nmesenchymal tissue such as astrocytes, tendons and cartilage.\nTissue Injury and Repair (TIAR)\nCOX-2\nPGE2STAR\nER-betaEstradiol-17βTestosterone\nCholesterole\nInterleukin-1β\nP450arom\n© CIC Edizioni Internazionali\n\nviations from the normal cyclic endocrine pattern,\nwith increases or prolongations of estradiol stimula-\ntion of uterine peristalsis, could impose supraphysio-\nlogical mechanical strain on the cells near the fundo-\ncornual raphe. It has been attempted to relate irregu-\nlarities of the menstrual cycle to the development of\nendometriosis without clear-cut evidence [84]. The ir-\nregularities under discussion, however, are not easily\ndisclosed and might escape self-observation and\nrecording of patient history. It is tempting to speculate\nthat events, such as prolonged follicular phases, anovu-\nlatory cycles or periods of follicular persistency and al-\nso the presence of large antral follicles in both ovaries\nbefore definite selection of the dominant follicle,\nwould impose, by increased or prolonged estrogenic\nstimulation, stronger mechanical strain to the muscu-\nlar fibers and fibroblasts. A prolonged period of estro-\ngenic stimulation might promote the development of\nendometriosis as documented in a study on the hered-\nitary component of endometriosis in colonized rhesus\nmonkeys. Only a history of application of estrogen\npatches (in addition to a history of trauma by hystero-\ntomy) showed a significant association with en-\ndometriosis [85]. The cyclic irregularities discussed\nabove, that might have also a hereditary background,\noccur frequently during the early period of reproduc-\ntive life. This concurs with an early onset of en-\ndometriosis in most cases. But also other factors that\nmight increase the susceptibility to mechanical strain\nand tissue injury should be taken into consideration.\nIn any event, repeated and sustained overstretching\nand injury of the myocytes and\nfibroblasts at the endometrial-\nmyometrial interface close to the\nfundo-cornual raphe would acti-\nvate focally the TIAR system\nwith increased local production\nof estradiol. This process starts\non a microscopical level and\ncomplete healing might be pos-\nsible, particularly if the mechan-\nical strain with subsequent tissue\ninjury happened to be only a\nsingular event or followed by a\nlonger phase of uterine quies-\ncence such as during pregnancy\nand breastfeeding. \nDuring such a singular phase\nof ‘first step’ injury, transtubal\ndislocation of fragments of basal\nendometrium might occur. In\naddition to the very low proba-\nbility of transtubal seeding of\nfragments of basal endometrium\nin normal women, such single\nevents could contribute to the development of asymp-\ntomatic pelvic endometriosis [2, 3, 14]. In case of ac-\ncidental implantation at an unfavorable site, such as\nthe ovaries, severe intraperitoneal endometriosis could\ndevelop without further involvement of the uterus in\nthe disease process, as indicated by a completely nor-\nmal junctional zone in MRI.\nWith continuing hyperperistaltic activity and sus-\ntained injury, however, healing at the fundo-cornual\nraphe will not ensue and an increasing number of foci\nare involved in this process of chronic injury, prolifer-\nation, and inflammation. The expansion or accumula-\ntion of such sites with activated TIAR system renders\nlocal areas of the basal endometrium to function as an\nendocrine gland that produces estradiol (Fig. 6). \nSecond step injury: auto-traumatization\nby hyperperistalsis\nFocal estrogen production might reach a tissue lev-\nel that acts in a paracrine fashion, upon the archimy-\nometrium and increases uterine peristaltic activity,\npresumably mediated by endometrial oxytocin and its\nreceptor [66, 86, 87]. Hyperperistalsis constitutes a\nmechanical trauma resulting in an increased desqua-\nmation of fragments of basal endometrium and, in\ncombination with an increased retrograde uterine\ntransport capacity, in enhanced transtubal dissemina-\ntion of these vital fragments [14, 53]. The develop-\nment of peritoneal endometriotic lesions from frag-\nments of basal endometrium is in fact a process of\n265\nEndometriosis and adenomyosis – a shared pathophysiology\nFig. 6 - Model of ‘tissue injury and repair (TIAR) on the level of the endometrial-myometrial inter-\nface at the fundo-cornual raphe. The mechanisms of first and second step injury are depicted.\nPersistent uterine peristaltic activity and hyperperistalsis are responsible for perpetuation of in-\njury with permanently increased paracrine estrogen action.\nCOX-2 PGE2\nSTAR\nP450arom\nER-beta\nEstradiol-17β\nOT\nER-alpha\nTissue Injury and Repair\n(TIAR) in abnormal fibroblasts\nAugmented Injury by\nHyperperistalsis\nSecond Step Injury\nInitial Focus of Injury\nclose to the fundo-cornual raphe\nFirst Step Injury\nAngiogenesis\nProliferation\n© CIC Edizioni Internazionali\n\ntransplantation and represents to a certain extent\nSampson’s aspect of the disease development [10]. \nThe development of uterine adenomyosis is a con-\ntinuation of the process that is initiated by the ‘first\nstep injury’. With the extension or accumulation of\nthe sites of injury and with the ensuing hyperperistal-\nsis following paracrine estrogen effects this inflamma-\ntory process of tissue injury and repair is reinforced\nand perpetuated resulting in the proliferation of con-\nnective tissue with the inherent potential of smooth\nmuscle metaplasia. That is why adenomyotic lesions,\nin contrast to superficial endometriotic lesions, display\na more fibro-muscular character. While even short\ntime transtubal seeding might result in peritoneal le-\nsions such as in experimental endometriosis with inoc-\nulation of endometrial material in the peritoneal cavi-\nty, the development of adenomyosis is a more pro-\nlonged process. In any event, the initiation of the\nTIAR mechanism in the depth of the endometrial\nstroma and its possible perpetuation constitute the ini-\ntial events in the development of both, endometriosis\nand adenomyosis. \nPremenarcheal endometriosis\nPelvic endometriosis has been described in adoles-\ncent girls prior to menarche and coelomic metaplasia\nhad been suggested as the underlying mechanism [88].\nIt has, however to be taken into consideration that with\nthe progression of puberty there is an increasing noctur-\nnal hypothalamo-pituitary activity with secretory bursts\nof LH and FSH [89]. Such as in low grade hypothala-\nmic amenorrhea large antral follicles are observed in the\novaries of premenarcheal girls that, following the noc-\nturnal gonadotropic stimulation, intermittently secrete\nestradiol during the morning hours that presumably in\nturn stimulates uterine peristalsis [90-92]. Thus, in\nthese girls detachment and upward transport of frag-\nments of basal endometrium from the more or less un-\nstimulated endometrium has to be considered as well. \nIn this respect, the significance of menstruation in\nthe disease process [10] should be more precisely de-\nfined. It is not the menstruation per se but rather the\nfact that the basal endometrium is, following the de-\ntachment of the functionalis, maximally exposed. This\nfacilitates, in the presence of hyperperistalsis, both the\ndetachment of fragments of basal endometrium and\ntheir upward transport [14, 53, 56]. \nIatrogenic injury\nIatrogenic trauma to the uterus are considered to in-\ncrease the risk for the development of endometriosis\nand adenomyosis [93]. A history of hysterotomy in col-\nonized Rhesus monkeys showed a significant associa-\ntion with the later development of endometriosis in\nthese animals [85]. The underlying mechanism of in-\nduction of endometriosis by iatrogenic trauma, such as\ncurettage and other ablative techniques, appears to be\nvery similar to those described above. Such surgical in-\nterventions might result in extended lesions with an en-\nhanced TIAR reaction. The rapidly increasing local es-\ntrogen levels during the process of healing interfere with\nthe ovarian control over uterine peristaltic activity, lead-\ning rapidly to second step injury with ensuing auto-\ntraumatisation and perpetuation of the disease process.\nThus, within the context of our model, iatrogenic le-\nsions that result in the development of endometriosis\nand adenomyosis can be viewed as strong one-time\n‘first-step’ injuries. In the baboon model experimental\nendometriosis was induced by inoculation of endome-\ntrial fragments that were obtained by endometrial biop-\nsies during the menstrual phase of the animals. In the\nendometriotic lesions Cyr61, a highly estrogen-depend-\nent gene, was soon up-regulated [65]. Surprisingly,\nCyr61 started to be up-regulated also in the eutopic en-\ndometrium of these primarily healthy animals. Proba-\nbly, the activation of Cyr61 in the eutopic endometri-\num resulted from the activation of the TIAR system,\nwith local production of estrogen, following tissue in-\njury caused by the biopsy rather than from a ‘cross-talk’\nbetween the endometriotic lesions and the eutopic en-\ndometrium, as suggested by the authors. \nThe eutopic endometrium \nin endometriosis and \nthe endometriotic lesions\nIn both, the endometriotic lesions and in the eu-\ntopic endometrium of women with endometriosis, the\ncellular and molecular components of the regulatory\nsystems that enable the tissue to produce estradiol have\nbeen demonstrated to be expressed. While this has\nbeen convincingly shown for peritoneal lesions, data\nconcerning the eutopic endometrium of women with\nendometriosis are unequivocal in this respect. \nThe ectopic lesions. Fragments of basal endometri-\num constitute injured tissue. The expression of acute\nand inflammatory cytokines, such as interleukin-1ß\nand interleukin 6 and also interleukin-8 [83, 94] facil-\nitate implantation. As auto-transplants, however, the\nfragments should implant without inflammatory se-\nquels. The endometriotic lesions are, however, as the\neutopic endometrium, subjected to cyclic endocrine\nstimuli and immunological phenomena but devoid\nthe potential of desquamation and externalization of\ncellular debris. Presumably due to this cyclic strain im-\nposed upon the peritoneal endometriotic lesions the\n266\nLeyendecker G. e Coll.\n© CIC Edizioni Internazionali\n\nTIAR system is repeatedly and chronically activated.\nImmunhistochemistry has demonstrated also a dra-\nmatic up-regulation of the estradiol receptor alpha\n[14]. The recent finding of nerve fibers in ectopic le-\nsions and also in the eutopic endometrium of affected\nwomen and their regression following gestagen admin-\nistration is at harmony with the view that chronic\nstrain and healing sustains an inflammatory process\n[95-99].\nSuperficial lesions usually display the glandular\ncharacter of the parent tissue and are surrounded by\nmuscular fibers [14, 100] that result from the inherent\npotential of the basal mesenchym to form muscular\ntissue [14]. They have, therefore, been described as\n‘microuteri’ or ‘microarchimetras’ [14]. The un-\nfavourable environment, however, does in most cases\nnot allow for an even truncated simulation of the\ncyclic events seen in the parent tissue such as prolifer-\nation and secretory transformation. Therefore, the\nglandular epithelium and the stroma of the lesions dis-\nplay the immunohistochemical character of the basalis\nlayer of the eutopic endometrium [14].\nIn superficial lesions this chronic inflammatory\nprocess might calm down and healing might be pos-\nsible [101]. Deeply infiltrating lesions develop at sites\nthat are in addition subjected to chronic mechanical\nirritation such as the recto-sigmoid fixed to the pelvic\nwall or uterus, the sacro-uterine ligaments, the uri-\nnary bladder, ovaries fixed to the pelvic wall, the rec-\nto-vaginal septum as well as the abdominal wall. It ap-\npears that chronic trauma to the\nectopic lesions maintains the in-\nflammatory process and results\nin the same tissue response as\nseen in uterine adenomyosis [3].\nThese are in fact the extra-uter-\nine sites of adenomyoma de-\nscribed by Cullen [36]. The\nperistromal fibromuscular tissue\nof endometriotic lesions is ho-\nmologous to the respective tis-\nsue within the archimetra [14].\nand probably in the same way\nsusceptible to mechanical strain.\nChronic mechanical strain re-\nsults in proliferation and pre-\nponderance of fibromuscular\ntissue, both characteristic of\ndeeply infiltrating endometrio-\nsis and uterine adenomyosis\n[102]. Deeply infiltrating le-\nsions tend to persist, while su-\nperficial lesions might heal.\nThat is why long lasting en-\ndometriosis usually presents\nwith deeply infiltrating lesions [101] and also uterine\nadenomyosis [3, 32, 34].\nThe eutopic endometrium. As delineated above, the\ndisease process starts focally in the depth of the basal\nendometrium. Thus, endometrial biopsies might miss\nthe focus with an activated TIAR system. With the\nprogression of the disease the area of alteration might\nbe expanded. This is in keeping with the observation\nthat the molecular markers associated with en-\ndometriosis could be more consistently demonstrated\nin more advanced stages of the disease [11]. \nWith respect to the molecular biology of the eu-\ntopic endometrium in endometriosis it has to be tak-\nen into consideration that the endometrium is com-\nposed morphologically and functionally of at least two\ndistinct layers, the basalis and the functionalis layers,\nrespectively [14, 103-105]. This is not sufficiently tak-\nen into account when studies on molecular biology are\nperformed with material taken from more or less ran-\ndom endometrial biopsies [11, 12, 63, 106]. The basal\nendometrium in women with endometriosis is twice as\nthick as in healthy women [14, 57]. Moreover, while\nin healthy women the endometrial-myometrial lining\nis smooth and regular it is irregular and sometimes\npolypoid in affected women [14, 107]. Thus, endome-\ntrial biopsies taken from women with endometriosis\nmight, to a variable and unknown extent, be ‘contam-\ninated’ with basal endometrium. They may even con-\ntain basal endometrial stroma of the fundo-cornual re-\n267\nEndometriosis and adenomyosis – a shared pathophysiology\nFig. 7 - Model of the pathophysiology of endometriosis and adenomyosis.Tissue injury in the\ndepth of the endometrium and the activation of the TIAR system constitute the primum movens\nin the disease development. This pertains to spontaneously developing andometriosis/adeno-\nmyosis as well as to that induced by iatrogenic trauma. The dashed rectangle depicts the extra\nuterine sites of the disease process.\nEstradiol-17β E2\nTIARTIAR\nTIAR\nEndometriotic lesion Adenomyotic lesion\nIatrogenic trauma\nAuto-traumatization\nHyperperistalsis\n2nd step injury\nDeeply infiltrating\nendometriosis\n1st step injury Infiltration of basal endometrium\ninto the myometrium\nDesquamation of fragments\nof basal endometrium\nDirect dislocation of\nfragments of basal endometrium\nArchimoymetrium\nTranstubal\ndislocation\n© CIC Edizioni Internazionali\n\ngion that is altered by the TIAR process, because en-\ndometrial biopsies are, for obvious anatomical reasons,\nmostly taken from the midline of the anterior and pos-\nterior walls of the uterine cavity. This might explain at\nleast in part the finding of ‘progesterone resistance’ or\n‘attenuated progesterone response’ [11, 108, 109] and\nan impaired estradiol metabolism in the endometrium\nof women with endometriosis [11, 106]. Using im-\nmunohistochemistry of estradiol receptor alpha and\nprogesterone receptor no progesterone resistance could\nbe observed in the late secretory phase of the function-\nal endometrium of affected women. As in healthy\nwomen, with the progression of the secretory phase,\nthe ER and PR expression declined in the functionalis\nand steadily rose in the basalis as well as in the en-\ndometriotic lesions [14]. The latter findings suggest\nphysiological progesterone resistance in the basal en-\ndometrium and also in the endometriotic lesions as\nthey are derived from implanted fragments of basal en-\ndometrium. Moreover, clinical studies with oocyte do-\nnation do not support a generally impeded implanta-\ntion in women with endometriosis [110]. With respect\nto the expression of the 17ßHSD type 2 no data are\navailable that distinguish between functionalis and\nbasalis as well as endometrial tissue subjected to the\nchronic TIAR process [111]. In any event, en-\ndometriosis and adenomyosis result from the physio-\nlogical mechanism of ‘tissue injury and repair’ (TIAR)\ninvolving local estrogen production in an estrogen-\nsensitive environment normally controlled by the\novary. It appears that many of the altered endometrial\nmolecular markers described in the context of en-\ndometriosis are the consequence rather than the\ncause(s) of the disease.\nConclusions\nEndometriosis and adenomyosis may now be inte-\ngrated into the pyhsiological mechanism and new\nnosological concept of “tissue injury and repair”\n(TIAR) and in this context, may just represent the ex-\ntreme of a basically physiological, estrogen-related\nmechanism, that is pathologically exaggerated in an\nextremely estrogen- sensitive, reproductive organ. \nCircumstantial evidence suggests that en-\ndometriosis and adenomyosis are caused by trauma.\nIn the spontaneously developing disease, chronic\nuterine peristaltic activity or phases of hyperperistal-\nsis induce, at the endometrial-myometrial interface\nnear the fundo-cornual raphe, microtraumatizations\nwith the activation of the TIAR mechanism. This re-\nsults in the local production of estrogens. With on-\ngoing peristaltic activity such sites might accumulate\nand the increasingly produced estrogens interfere in a\nparacrine fashion with the ovarian control over uter-\nine peristaltic activity resulting in permanent hyper-\nperistalsis and self- perpetuation of the disease\nprocess. Overt auto-traumatization of the uterus,\nwith dislocation of fragments of basal endometrium\ninto the peritoneal cavity and infiltration of basal en-\ndometrium into the depth of the myometrial wall,\nensues. In most cases of endometriosis/adenomyosis\na causal event early in the reproductive period of life\nmust be postulated leading rapidly to uterine hyper-\nperistalsis. In late premenopausal adenomyosis, such\nan event might not have occurred. However, as indi-\ncated by the high prevalence of the disease, it appears\nto be unavoidable that, with time, chronic nor-\nmoperistalsis throughout the reproductive period of\nlife leads to the same kind of microtraumatizations.\nWith the activation of the TIAR mechanism, fol-\nlowed by chronic inflammation [18] and infiltrative\ngrowth endometriosis/adenomyosis of the younger\nwoman and premenopausal adenomyosis share in\nprincipal the same pathophysiology. In conclusion,\nendometriosis and adenomyosis result from the exag-\ngeration of the basically physiological mechanism of\n‘tissue injury and repair’ (TIAR) involving local es-\ntrogen production. This is magnified in an estrogen-\nsensitive environment normally controlled by the\novary. \n268\nLeyendecker G. e Coll.\n1. Greene R, Stratton P , Cleary SD, Ballweg ML, Sinaii N.\n(2009). Diagnostic experience among 4,334 women repor-\nting surgically diagnosed endometriosis. 1: Fertil Steril.\n91:32-39.\n2. 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