Endometriosis and adenomyosis – a shared pathophysiology

in the local production of estrogens. With on- going peristaltic activity, such sites will accumulate and the increasingly produced estrogens interfere via paracrine mode of action with the endocrine ovarian control over uterine peristaltic activity, resulting in permanent hyperperistalsis and a self-perpetuation of the disease process. Overt auto-traumatization of the uterus, with dislocation of fragments of basal en- dometrium into the peritoneal cavity and infiltration of basal endometrium into the depth of the myometri- al wall, ensues. In most cases of endometriosis/adeno- myosis, a causal event early in the reproductive period of life must be postulated leading to uterine hyperperi- stalsis. In late premenopausal adenomyosis such overt event might not have occurred. However, as indicated by the high prevalence of the disease, it appears to be unavoidable that, with time, chronic normoperistalsis throughout the reproductive period of life may result in events that accumulate to the same extent of micro- traumatizations. With the activation of the TIAR mechanism, followed by infiltrative growth and chronic inflammation, endometriosis/adenomyosis of the younger woman and premenopausal adenomyosis share in principal the same pathophysiology. In con- clusion, endometriosis and adenomyosis result from the physiological mechanism of ‘tissue injury and re- pair’ (TIAR) involving local estrogen production in an estrogen-sensitive environment normally controlled by the ovary. It appears that many of the altered endome- trial molecular markers described in the context of en- dometriosis are the consequence rather than the cause(s) of the disease.

Endometriosis is a disease that affects women pre- dominantly during the reproductive period of life. With the cardinal symptoms, pelvic pain, bleeding dis- orders, and infertility, the disease has a tremendous impact on women’s health. In most of the women af- fected the first symptoms can be traced back to adoles- cence [1]. Many women, however, remain free of symptoms or exhibit only minor complaints. More- over, in cases with the development of the disease after childbearing, the condition may remain undiagnosed. Not infrequently, at laparoscopy for tubal sterilisation [2] and hysterectomy for fibroids and adenomyosis, endometriotic implants and scars, respectively, can be observed. Thus, the current estimates of prevalence are probably too low. The syndrome of dislocated basal endometrium (SDBE), a term that comprises the 1 Kinderwunschzentrum (Fertility Center) Darmstadt, Germany 2 University Clinic of Gynecological Endocrinology and Reproductive Medicine, Department of Obstetrics and Gynecology, Medical University Innsbruck, Austria 3 Institute of Pathology, Klinikum Darmstadt, Academic Teaching Hospital to the Universities of Frankfurt and Heidelberg, Germany Keynote lecture 4th International Congress on Endometriosis – Rome May 28-30, 2009 © Copyright 2010, CIC Edizioni Internazionali, Roma Endometriosis and adenomyosis – a shared pathophysiology LEYENDECKER G.1, WILDT L.2, MALL G.3 Giorn. It. Ost. Gin. Vol. XXXII - n. 5 Settembre-Ottobre 2010 259 rassegne © CIC Edizioni Internazionali pathophysiological continuum of endometriosis, en- dometriosis in association with adenomyosis and pre- menopausal adenomyosis, thus appears to be a very common phenomenon [3]. We had, therefore, a decade ago, suggested that its cause or causes may be unspectacular and closely related to the physiologic process of reproduction. T rauma followed by tissue specific hyper reactive inflammatory response and re- pair involving specific, albeit physiological cellular, biochemical, and molecular mechanisms may be con- sidered the major events in the development of the dis- ease [4]. Recently we could extend our previous views and elaborate a comprehensive model of the pathophysiol- ogy of endometriosis and adenomyosis [5]. This en- deavour was undertaken with the premise that all phe- notypes of endometriosis share in principal the same pathophysiology and that no parallel and separate mechanisms of their development do exist. This does, however, not exclude various and different etiologies at the very onset of the disease process including iatro- genic [6], exogenous [7, 8], and hereditary [9] factors. With respect to hereditary factors, they might be re- mote from the genuine disease process and thus not easily to disclose. Historical remarks The aetiology and pathogenesis of endometriosis, which is the ectopic occurrence of endometrial tissue, has been enigmatic from its first description until to- day. The theory of dissemination of endometrial tissue by retrograde menstruation, proposed by Sampson in 1927, has remained the presently prevailing patho- physiological concept [10]. However, since retrograde menstruation has later been considered to be a physi- ological phenomenon, other factors, such as menstru- al outflow obstruction or pelvic peritoneum immuno- logical defects have been additionally proposed to re- fine Sampson’s theory (for review: [4]). Also the recent advances in the understanding of the molecular biolo- gy of endometriosis, both on the endometriotic lesions and the eutopic endometrium in affected women, did not result in a principal revision of Sampson’s concept. It is suggested that in women with endometriosis frag- ments of inherently or epigenetically altered en- dometrium are shed during menstruation and dissem- inated within the peritoneal cavity [11, 12]. Sampson’s theory was continuously challenged. While in monkey experience endometrial tissue from cyclic endometrium could readily grow as autotrans- plants or in culture, this was not the case with men- strual debris. Even experimentally produced utero- peritoneal fistulae did not result in peritoneal en- dometriosis. In contrast, with and much to the surprise of the investigators, following surgery for retroflexio uteri (by a thread of silk positioned into the fundal part of the uterus) severe uterine adenomyosis ensued and penetrated along the thread into the peritoneal cavity to form endometriotic lesions (for review: [13]). Philipp and Huber speculated that retrogradely transported menstrual debris would only cause en- dometriosis in those rare cases when the necrotic ma- terial was mixed with vital tissue fragments detached from the deeper basal layer [13]. For the first time we provided strong circumstan- tial evidence that, in the human, endometriosis results, in fact, from the dislocation of fragments of basal op- posed to functional endometrium [14]. This was at harmony with findings in the baboon model that in- oculation of bioptic material taken from menstrual en- dometrium was more likely to result in endometriotic lesions than that obtained from secretory endometri- um [15]. It is possible that the higher implantation rate with biopsies from menstrual endometrium was owed to fragments of basal endometrium, that could have been more easily obtained from menstrual than from secretory endometrium. Nevertheless, for the in- duction of experimental endometriosis in the baboon model, it is now strongly recommended to use materi- al that results from “vigorous” biopsies during the menstrual period [16, 17]. According to our view, such biopsies have a high probability to contain basal endometrium. In critically analyzing Sampson’s data and the available clinical and experimental literature, Philipp and Huber in 1939 appreciated Sampson’s observa- tion that in nearly all of his patients the tubes were patent, a finding that they thought should be kept in mind and incorporated into a future comprehensive model of the pathophysiology of the disease. They stressed, however, that retrograde menstruation would be, for various reasons, an insufficient model to de- scribe the pathophysiology of a disease that did com- prise, in their opinion and that of other authorities at that time, more than just a disease of the pelvic peri- toneum [13]. In fact, the major authors of the last century de- scribed ectopic endometrial lesions occurring both in the uterus and in the peritoneal cavity, and the lesions were considered as variants of the same disease process. Robert Meyer, favouring the concept of meta- plasia, was the first to hint at the chronic inflammato- ry character of the lesions both in, the extra- and in- trauterine sites [18]. Also Sampson, who introduced the term ‘endometriosis’, described “primary en- dometriosis” as the uterine variant of the disease [10]. His scientific interest, however, was nearly exclusively directed towards the development of the peritoneal 260 Leyendecker G. e Coll. © CIC Edizioni Internazionali variety. This, and his view of uterine adenomyosis to

from vascular transmission, were probably the reasons why he did not report on the parallel presen- tation of “primary endometriosis” in his cases of peri- toneal endometriosis [19]. In fact, it was his theory that laid the basis for considering uterine adenomyosis and external endometriosis as different disease entities [20]. This was later on enforced by the fact that en- dometriosis was mostly diagnosed by laparoscopy in a sterility work-up and for obvious reasons the uterus evades histological, structural, and morphological ex- amination in such cases. Pelvic endometriosis became a topic of research, while the clinical and scientific in- terest in uterine adenomyosis nearly completely van- ished. The definition of endometriosis that is current- ly in use and propagated by influential societies such as the ASRM and the ESHRE is reflecting this strict separation and present confinement to the peritoneal variety [21, 22]. Much of the research work per- formed during the last two decades originated from this concept [23-29]. Yet, the issue of endometriosis and adenomyosis whether or not representing distinct disease entities is far from being resolved. A search in PubMed reveals that under the headings of endometriosis and adeno- myosis, respectively, rather the same items are dis- played. In addition, the recent resurrection of the term ‘adenomyoma’ does, in our opinion, not con- tribute to the clarification of the issue. In an attempt to prove the distinctiveness of endometriosis and ade- nomyosis, respectively, hospital records of surgery were analyzed [30, 31]. Given the fact that pre- menopausal adenomyosis represents the slowly and endometriosis with and without associated adeno- myosis the more rapidly developing form of the dis- ease, respectively, it was to be expected that the former women, given also the fact they represented a study population with a reproductive pattern of attempting early pregnancies, would more likely be parous than the latter. Moreover, it is unlikely, that during routine hysterectomy, the same meticulous search for en- dometriosis is performed as in work-up for infertility. In our opinion, these studies do not take into account the pleiomorphic character of endometriosis and ade- nomyosis. When we, for the first time, recognized again the frequent association of endometriosis with adeno- myosis [32-34], seemingly challenging Sampson’s view, we earned pure disbelief. Fortunately, our Ger- man colleagues in contrast to those in other coun- tries, are entitled to perform ultrasound in their own offices. Thus, it took only a few weeks after they had seen enough cases on their own and had also per- formed some MRI scans, until the discussion whether or not endometriosis may be associated with adenomyosis was terminated. Also other groups that incorporated imaging techniques in their set up con- firmed in principal the frequent association [35]. Meticulously performed ultrasound usually reveals in cases of endometriosis characteristic signs of uterine adenomyosis (“abnormal patterns” of the uterus; Margit Dueholm, personal communication) such as abnormal shapes and sizes of the uterus if fibroids are excluded, asymmetry with respect to the anterior and posterior walls, irregularities of the lining of the en- dometrium, an unusual texture of the myometrium, and of course a broadened, focally destroyed or com- pletely absent ‘halo’. MRI usually confirms these findings [3] (Figs 1 and 2). Cullen and some of the scientific giants around the turn of the last century were rapidly back [36]. Of course, Sampson was not proven wrong, in a strict sense, in that tubal dissem- ination constitutes, without doubt, an important as- pect in the disease process. This aspect, however, has to be more precisely defined in a consistent and com- prehensive concept of the pathophysiology of en- dometriosis and adenomyosis (vide infra). In any event, the focus of studying the pathogenesis of en- dometriosis shifted from the pelvic peritoneum to the archimetra, which is the Müllerian part of the uterus [4]. It became evident that the peritoneal en- dometriotic lesion merely constitutes one of the pleiomorphic phenomena rather than the genuine disease itself. 261 Endometriosis and adenomyosis – a shared pathophysiology Fig. 1 - Transvaginal sonography (TVS) and magnetic resonance im- aging (MRI) of the uterus of a 29 years old woman unaffected with en- dometriosis and adenomyosis. Sagittal scans of the uterine midline are shown. The myometrial-endometrial lining is sharp and smooth; the “halo” in TVS and the “junctional zone” in MRI are unaltered; there is symmetry with respect to the anterior and posterior myome- trial walls and the texture of the myometrium in TVS appears to be ho- mogenous. © CIC Edizioni Internazionali The role of the uterus in the disease process In the understanding of the pathophysiology of en- dometriosis and adenomyosis a re-analysis of both structure and function of the non-pregnant uterus turned out to be of utmost importance [4, 37-39]. With uterine peristalsis and directed sperm transport a novel uterine function has been discovered [40-47]. It became evident that the non-pregnant uterus is con- stantly active throughout the reproductive period of life and thereby, like other mechanically active organs of the body such as the skeletal and the cardiovascular systems, respectively, rather inevitably subjected to mechanical strain. Research performed over the last years has demonstrated a crucial role of mechanical strain in normal and pathological function of various tissues. Moreover, it became apparent that the molec- ular mechanisms associated with mechanical strain, in- jury, and repair displays a pattern that is quite similar in different tissues and involves the expression of the P450 aromatase and the local production of estrogen [48]. The sequels of tissue injury and repair, however, may become very specific depending on structure and functions of the tissues and organs involved such as tendons and cartilage in the skeletal and the intima in the cardiovascular system, respectively. This is of par- ticular importance, when the tissue, as it is the case with the uterus, is physiologically highly estrogen sen- sitive and when injury is chronic in character. There are several lines of evidence for the notion that dysfunctions of the uterus play a crucial role in the pathophysiology of endometriosis. 1. Fragments of basal endometrium were found in the menstrual effluent with a higher prevalence in women with endometriosis than in controls. On the basis of these and other findings it was suggested that pelvic endometriosis results from the transtubal dislocation of fragments of basal endometrium [14]. 2. There is a significant association of pelvic en- dometriosis with uterine adenomyosis in women and in the baboon with life-long infer- tility. In women, the reported prevalence, how- ever, differs according to the study population chosen and to the criteria applied to the inter- pretation of MRI findings [4, 32, 34, 49, 50]. 3. The uterine function of rapid and directed sperm transport into the ‘dominant tube’ is dysfunc- tional in women with endometriosis and is char- acterized by hyper- and dysperistalsis [51-56]. It was suggested that this uterine dysfunction in women with endometriosis and adenomyosis is a re- sult of archimetral hyperestrogenism [3, 4, 53, 57]. There are several lines of evidence that support this notion. 1. In comparison to normal controls and in con- trast to peripheral blood, estradiol levels are el- evated in menstrual blood of women with en- dometriosis and adenomyosis [58]. 2. The expression of the P450 aromatase is in- creased in adenomyotic tissue and in the ec- 262 Leyendecker G. e Coll. Fig. 2 - Pleiomorphic appearance of focal and diffuse adenomyosis in women with moderate to severe endometriosis (27 to 31 year s of age; a- c). 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 of 22. The TVS was apparently normal. Meticulous analysis, however, showed asymmetry of the uterine walls and no “halo” could be demon- strated. MRI revealed focal to diffuse adenomyosis of the anterior wall and beginning adenomyosis of the posterior wall of the uterus. Sagittal scans of the uterine midline are shown. © CIC Edizioni Internazionali topic and eutopic endometrium of women with endometriosis [11, 12, 59-63]. 3. A highly estrogen-dependent gene, Cyr61, is up-regulated in eutopic endometrium in women with endometriosis and also in ectopic lesions as well as in experimental endometriosis [64, 65]. 4. The peristaltic activity of the subendometrial myometrium can be dramatically increased by elevated peripheral levels of estradiol as they are observed during controlled ovarian hyperstimu- lation. The intensity of uterine peristaltic activ- ity in women with endometriosis resembles that of women during controlled ovarian hyperstim- ulation although the peripheral estradiol levels are within the normal range [4, 53, 66]. On the basis of the data presented above, we had suggested that auto-traumatisation of the uterus would constitute the critical factor in the development of en- dometriosis and adenomyosis [3, 4, 57]. Hyperperistal- sis induced by the local production of estrogens would constitute a mechanical trauma resulting in an in- creased desquamation of fragments of basal endometri- um and [14], in combination with an increased retro- grade uterine transport capacity [53], in enhanced transtubal dissemination of these fragments. Hyper- peristalsis and increased intrauterine pressure would re- sult, with time, in myometrial dehiscences that are in- filtrated by basal endometrium with the secondary de- velopment of peristromal muscular tissue. Diffuse or focal adenomyosis of various extent ensues. Adenomy- otic foci are usually localized in the anterior and/or pos- terior wall, with preference of the posterior, but only rarely in the lateral walls of the uterine corpus. Early le- sions usually present close to the “fundo-cornual raphe” of the archimyometrium [3, 33, 34] (Figs 3 and 4). The enigma of archimetral hyperestrogenism Undoubtedly the local production of estrogens both on the level of the eutopic endometrium in women with endometriosis and of the ectopic lesions is central to the understanding of the pathophysiology of the disease. However the etiology of this increased estrogen-producing “glandular” potential of these tis- sues, however, is still enigmatic. It was recently sug- gested that the susceptibility of developing the disease, 263 Endometriosis and adenomyosis – a shared pathophysiology Fig. 4 - Examples of uterine adenomyosis in six patients as presented by magnetic resonance imaging (MRI). Representative sagittal and coro- nary 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- paroscopy. In the parous woman (f) (40 years of age) no laparoscopy was performed. In all scans preponderance of the adenomyotic lesions (expanded junctional zone) in the midline close to the fundo-cornual raphe of the archimyometrium can be demonstrated. In the f irst three scans (a-c) the diagnosis of adenomyosis would not meet the established radiologic criteria for MRI. In a scientific context, however, the irreg- ularities of the junctional zone are characteristic of beginning adenomyosis. Fig. 3 - Modified original drawing from Werth and Grusdew [9] show- ing the architecture of the subendometrial myometrium (archimy- ometrium) in a human fetal uterus. The specific orientation of the cir- cular fibers of the archimyometrium results from the fusion of the two paramesonephric ducts forming a fundo-cornual raphe in the midline (dashed rectangle). The peristaltic pump of the uterus, which is con- tinuously active during the menstrual cycle, is driven by coordinated contractions of these muscular fibers. Directed sperm transport into the dominant tube is made possible by differential activation of these fibers. The fundo-cornual raphe constitutes a region of increased me- chanical strain and tissue injury followed by local estrogen produc- tion (TIAR). © CIC Edizioni Internazionali with the potential to locally produce estrogens within the eutopic endometrium, would be acquired during prenatal life by an epigenetic mechanisms that would become manifest not until after puberty [12]. Other authors suggest that the endometrium in women with endometriosis is inherently altered [11]. Clinical and experimental evidence do not supports these views. If primary alterations of the endometrium were a prereq- uisite of the development of the disease, it is impossi- ble, in the primate model, to induce peritoneal en- dometriosis by inoculation of endometrial fragments obtained from endometrial biopsies of healthy animals [15-17, 65]. Moreover, following caesarean section ab- dominal wall endometriosis develops in presumably primarily healthy subjects. Tissue injury and repair (TIAR) Recent studies have increasingly shown that estra- diol is of utmost importance in the process of wound healing [67-69]. This action appears to be mainly me- diated by the estrogen receptor-beta (ER2). Animal experiments with chemotoxic and mechanic stress to astroglia [48, 70, 71] and urinary bladder tissue, as well as studies with isolated connective tissue such as fibroblasts and cartilage [72-74], have revealed that tis- sue injury and inflammation with subsequent healing is associated with a specific physiological process that involves the local production of estrogen from its pre- cursors. Interleukin-1 induced activation of the cy- clooxygenase-2 enzyme (COX-2) results in the pro- duction of prostaglandin E2 (PGE2), which in turn activates STAR (steroidogenic acute regulatory pro- tein) and P450 aromatase. Thus, with the increased transport of cholesterole to the inner mitochondrial membrane, testosterone can be formed and aroma- tized into estradiol that exerts its proliferative and healing effects via the ER2. In studies with fibroblast it was surprising that the first steps of this cascade could be activated by seemingly minor biophysical strain [72]. Following termination of unphysiological strain and healing this process is down-regulated and the local production of estrogen or up-regulation of es- trogen-dependent genes ceases [72, 75]. This cascade can even be activated in tissue that normally does not express P450 aromatase, indicating the basic physio- logical significance of the local production of estrogen in tissue injury and repair (TIAR) [76]. The similar- ity of the molecular biology of TIAR in various tis- sues with that described in endometriosis [11, 12, 63-65, 77-80] strongly suggests that this represents the common underlying mechanisms of both processes (Fig. 5). Mechanism of disease: uterine auto- traumatisation Structure and function of the subendometrial my- ometrium and the endocrine control of directed sperm transport have been described elsewhere [33, 37, 43, 66, 81, 82]. It is comprehensible that the myometrial fibers and the fibroblats at the endometrial-myometri- al interface, near the fundo-cornual raphe, are subject- ed to increased mechanical strain during midcycle, be- cause not only is the ovarian estradiol secretion at its peak at that time, but also additional mechanical strain is imposed on these cells due to estradiol that reaches the uterus via the utero-ovarian counter-cur- rent system and controls the direction of the upward transport [81]. Directed sperm transport begins dur- ing the mid-follicular phase of the cycle when the dominant follicle becomes visible [43]. The fundo- cornual raphe as a site of predilection of mechanical strain is documented by the observation that early ade- nomyosis usually evolves in the sagittal midline of the mid-corporal and fundal parts of the uterus (Fig. 4). Even in more advanced cases of adenomyosis the ex- pansion of the junctional zone in MRI often shows preponderance at these locations [3]. First step injury: microtraumatization Experiments with cultivated fibroblasts have shown that within certain limits mechanical strain is physiological to such cells. However, even minor in- crements in mechanical strain resulted the activation of COX-2 and the production of PGE2, the basic bio- chemical mechanisms underlying tissue injury [72], and also in the production of interleukin-8 [83]. Thus, with respect to the subendometrial myometrium, de- 264 Leyendecker G. e Coll. Fig. 5 - The basic aspects of the molecular biology of the physiologi- cal mechanism of ‘tissue injury and repair’ (TIAR) as demostrated in mesenchymal tissue such as astrocytes, tendons and cartilage. Tissue Injury and Repair (TIAR) COX-2 PGE2STAR ER-betaEstradiol-17βTestosterone Cholesterole Interleukin-1β P450arom © CIC Edizioni Internazionali viations from the normal cyclic endocrine pattern, with increases or prolongations of estradiol stimula- tion of uterine peristalsis, could impose supraphysio- logical mechanical strain on the cells near the fundo- cornual raphe. It has been attempted to relate irregu- larities of the menstrual cycle to the development of endometriosis without clear-cut evidence [84]. The ir- regularities under discussion, however, are not easily disclosed and might escape self-observation and recording of patient history. It is tempting to speculate that events, such as prolonged follicular phases, anovu- latory cycles or periods of follicular persistency and al- so the presence of large antral follicles in both ovaries before definite selection of the dominant follicle, would impose, by increased or prolonged estrogenic stimulation, stronger mechanical strain to the muscu- lar fibers and fibroblasts. A prolonged period of estro- genic stimulation might promote the development of endometriosis as documented in a study on the hered- itary component of endometriosis in colonized rhesus monkeys. Only a history of application of estrogen patches (in addition to a history of trauma by hystero- tomy) showed a significant association with en- dometriosis [85]. The cyclic irregularities discussed above, that might have also a hereditary background, occur frequently during the early period of reproduc- tive life. This concurs with an early onset of en- dometriosis in most cases. But also other factors that might increase the susceptibility to mechanical strain and tissue injury should be taken into consideration. In any event, repeated and sustained overstretching and injury of the myocytes and fibroblasts at the endometrial- myometrial interface close to the fundo-cornual raphe would acti- vate focally the TIAR system with increased local production of estradiol. This process starts on a microscopical level and complete healing might be pos- sible, particularly if the mechan- ical strain with subsequent tissue injury happened to be only a singular event or followed by a longer phase of uterine quies- cence such as during pregnancy and breastfeeding. During such a singular phase of ‘first step’ injury, transtubal dislocation of fragments of basal endometrium might occur. In addition to the very low proba- bility of transtubal seeding of fragments of basal endometrium in normal women, such single events could contribute to the development of asymp- tomatic pelvic endometriosis [2, 3, 14]. In case of ac- cidental implantation at an unfavorable site, such as the ovaries, severe intraperitoneal endometriosis could develop without further involvement of the uterus in the disease process, as indicated by a completely nor- mal junctional zone in MRI. With continuing hyperperistaltic activity and sus- tained injury, however, healing at the fundo-cornual raphe will not ensue and an increasing number of foci are involved in this process of chronic injury, prolifer- ation, and inflammation. The expansion or accumula- tion of such sites with activated TIAR system renders local areas of the basal endometrium to function as an endocrine gland that produces estradiol (Fig. 6). Second step injury: auto-traumatization by hyperperistalsis Focal estrogen production might reach a tissue lev- el that acts in a paracrine fashion, upon the archimy- ometrium and increases uterine peristaltic activity, presumably mediated by endometrial oxytocin and its receptor [66, 86, 87]. Hyperperistalsis constitutes a mechanical trauma resulting in an increased desqua- mation of fragments of basal endometrium and, in combination with an increased retrograde uterine transport capacity, in enhanced transtubal dissemina- tion of these vital fragments [14, 53]. The develop- ment of peritoneal endometriotic lesions from frag- ments of basal endometrium is in fact a process of 265 Endometriosis and adenomyosis – a shared pathophysiology Fig. 6 - Model of ‘tissue injury and repair (TIAR) on the level of the endometrial-myometrial inter- face at the fundo-cornual raphe. The mechanisms of first and second step injury are depicted. Persistent uterine peristaltic activity and hyperperistalsis are responsible for perpetuation of in- jury with permanently increased paracrine estrogen action. COX-2 PGE2 STAR P450arom ER-beta Estradiol-17β OT ER-alpha Tissue Injury and Repair (TIAR) in abnormal fibroblasts Augmented Injury by Hyperperistalsis Second Step Injury Initial Focus of Injury close to the fundo-cornual raphe First Step Injury Angiogenesis Proliferation © CIC Edizioni Internazionali transplantation and represents to a certain extent Sampson’s aspect of the disease development [10]. The development of uterine adenomyosis is a con- tinuation of the process that is initiated by the ‘first step injury’. With the extension or accumulation of the sites of injury and with the ensuing hyperperistal- sis following paracrine estrogen effects this inflamma- tory process of tissue injury and repair is reinforced and perpetuated resulting in the proliferation of con- nective tissue with the inherent potential of smooth muscle metaplasia. That is why adenomyotic lesions, in contrast to superficial endometriotic lesions, display a more fibro-muscular character. While even short time transtubal seeding might result in peritoneal le- sions such as in experimental endometriosis with inoc- ulation of endometrial material in the peritoneal cavi- ty, the development of adenomyosis is a more pro- longed process. In any event, the initiation of the TIAR mechanism in the depth of the endometrial stroma and its possible perpetuation constitute the ini- tial events in the development of both, endometriosis and adenomyosis. Premenarcheal endometriosis Pelvic endometriosis has been described in adoles- cent girls prior to menarche and coelomic metaplasia had been suggested as the underlying mechanism [88]. It has, however to be taken into consideration that with the progression of puberty there is an increasing noctur- nal hypothalamo-pituitary activity with secretory bursts of LH and FSH [89]. Such as in low grade hypothala- mic amenorrhea large antral follicles are observed in the ovaries of premenarcheal girls that, following the noc- turnal gonadotropic stimulation, intermittently secrete estradiol during the morning hours that presumably in turn stimulates uterine peristalsis [90-92]. Thus, in these girls detachment and upward transport of frag- ments of basal endometrium from the more or less un- stimulated endometrium has to be considered as well. In this respect, the significance of menstruation in the disease process [10] should be more precisely de- fined. It is not the menstruation per se but rather the fact that the basal endometrium is, following the de- tachment of the functionalis, maximally exposed. This facilitates, in the presence of hyperperistalsis, both the detachment of fragments of basal endometrium and their upward transport [14, 53, 56]. Iatrogenic injury Iatrogenic trauma to the uterus are considered to in- crease the risk for the development of endometriosis and adenomyosis [93]. A history of hysterotomy in col- onized Rhesus monkeys showed a significant associa- tion with the later development of endometriosis in these animals [85]. The underlying mechanism of in- duction of endometriosis by iatrogenic trauma, such as curettage and other ablative techniques, appears to be very similar to those described above. Such surgical in- terventions might result in extended lesions with an en- hanced TIAR reaction. The rapidly increasing local es- trogen levels during the process of healing interfere with the ovarian control over uterine peristaltic activity, lead- ing rapidly to second step injury with ensuing auto- traumatisation and perpetuation of the disease process. Thus, within the context of our model, iatrogenic le- sions that result in the development of endometriosis and adenomyosis can be viewed as strong one-time ‘first-step’ injuries. In the baboon model experimental endometriosis was induced by inoculation of endome- trial fragments that were obtained by endometrial biop- sies during the menstrual phase of the animals. In the endometriotic lesions Cyr61, a highly estrogen-depend- ent gene, was soon up-regulated [65]. Surprisingly, Cyr61 started to be up-regulated also in the eutopic en- dometrium of these primarily healthy animals. Proba- bly, the activation of Cyr61 in the eutopic endometri- um resulted from the activation of the TIAR system, with local production of estrogen, following tissue in- jury caused by the biopsy rather than from a ‘cross-talk’ between the endometriotic lesions and the eutopic en- dometrium, as suggested by the authors. The eutopic endometrium in endometriosis and the endometriotic lesions In both, the endometriotic lesions and in the eu- topic endometrium of women with endometriosis, the cellular and molecular components of the regulatory systems that enable the tissue to produce estradiol have been demonstrated to be expressed. While this has been convincingly shown for peritoneal lesions, data concerning the eutopic endometrium of women with endometriosis are unequivocal in this respect. The ectopic lesions. Fragments of basal endometri- um constitute injured tissue. The expression of acute and inflammatory cytokines, such as interleukin-1ß and interleukin 6 and also interleukin-8 [83, 94] facil- itate implantation. As auto-transplants, however, the fragments should implant without inflammatory se- quels. The endometriotic lesions are, however, as the eutopic endometrium, subjected to cyclic endocrine stimuli and immunological phenomena but devoid the potential of desquamation and externalization of cellular debris. Presumably due to this cyclic strain im- posed upon the peritoneal endometriotic lesions the 266 Leyendecker G. e Coll. © CIC Edizioni Internazionali TIAR system is repeatedly and chronically activated. Immunhistochemistry has demonstrated also a dra- matic up-regulation of the estradiol receptor alpha [14]. The recent finding of nerve fibers in ectopic le- sions and also in the eutopic endometrium of affected women and their regression following gestagen admin- istration is at harmony with the view that chronic strain and healing sustains an inflammatory process [95-99]. Superficial lesions usually display the glandular character of the parent tissue and are surrounded by muscular fibers [14, 100] that result from the inherent potential of the basal mesenchym to form muscular tissue [14]. They have, therefore, been described as ‘microuteri’ or ‘microarchimetras’ [14]. The un- favourable environment, however, does in most cases not allow for an even truncated simulation of the cyclic events seen in the parent tissue such as prolifer- ation and secretory transformation. Therefore, the glandular epithelium and the stroma of the lesions dis- play the immunohistochemical character of the basalis layer of the eutopic endometrium [14]. In superficial lesions this chronic inflammatory process might calm down and healing might be pos- sible [101]. Deeply infiltrating lesions develop at sites that are in addition subjected to chronic mechanical irritation such as the recto-sigmoid fixed to the pelvic wall or uterus, the sacro-uterine ligaments, the uri- nary bladder, ovaries fixed to the pelvic wall, the rec- to-vaginal septum as well as the abdominal wall. It ap- pears that chronic trauma to the ectopic lesions maintains the in- flammatory process and results in the same tissue response as seen in uterine adenomyosis [3]. These are in fact the extra-uter- ine sites of adenomyoma de- scribed by Cullen [36]. The peristromal fibromuscular tissue of endometriotic lesions is ho- mologous to the respective tis- sue within the archimetra [14]. and probably in the same way susceptible to mechanical strain. Chronic mechanical strain re- sults in proliferation and pre- ponderance of fibromuscular tissue, both characteristic of deeply infiltrating endometrio- sis and uterine adenomyosis [102]. Deeply infiltrating le- sions tend to persist, while su- perficial lesions might heal. That is why long lasting en- dometriosis usually presents with deeply infiltrating lesions [101] and also uterine adenomyosis [3, 32, 34]. The eutopic endometrium. As delineated above, the disease process starts focally in the depth of the basal endometrium. Thus, endometrial biopsies might miss the focus with an activated TIAR system. With the progression of the disease the area of alteration might be expanded. This is in keeping with the observation that the molecular markers associated with en- dometriosis could be more consistently demonstrated in more advanced stages of the disease [11]. With respect to the molecular biology of the eu- topic endometrium in endometriosis it has to be tak- en into consideration that the endometrium is com- posed morphologically and functionally of at least two distinct layers, the basalis and the functionalis layers, respectively [14, 103-105]. This is not sufficiently tak- en into account when studies on molecular biology are performed with material taken from more or less ran- dom endometrial biopsies [11, 12, 63, 106]. The basal endometrium in women with endometriosis is twice as thick as in healthy women [14, 57]. Moreover, while in healthy women the endometrial-myometrial lining is smooth and regular it is irregular and sometimes polypoid in affected women [14, 107]. Thus, endome- trial biopsies taken from women with endometriosis might, to a variable and unknown extent, be ‘contam- inated’ with basal endometrium. They may even con- tain basal endometrial stroma of the fundo-cornual re- 267 Endometriosis and adenomyosis – a shared pathophysiology Fig. 7 - Model of the pathophysiology of endometriosis and adenomyosis.Tissue injury in the depth of the endometrium and the activation of the TIAR system constitute the primum movens in the disease development. This pertains to spontaneously developing andometriosis/adeno- myosis as well as to that induced by iatrogenic trauma. The dashed rectangle depicts the extra uterine sites of the disease process. Estradiol-17β E2 TIARTIAR TIAR Endometriotic lesion Adenomyotic lesion Iatrogenic trauma Auto-traumatization Hyperperistalsis 2nd step injury Deeply infiltrating endometriosis 1st step injury Infiltration of basal endometrium into the myometrium Desquamation of fragments of basal endometrium Direct dislocation of fragments of basal endometrium Archimoymetrium Transtubal dislocation © CIC Edizioni Internazionali gion that is altered by the TIAR process, because en- dometrial biopsies are, for obvious anatomical reasons, mostly taken from the midline of the anterior and pos- terior walls of the uterine cavity. This might explain at least in part the finding of ‘progesterone resistance’ or ‘attenuated progesterone response’ [11, 108, 109] and an impaired estradiol metabolism in the endometrium of women with endometriosis [11, 106]. Using im- munohistochemistry of estradiol receptor alpha and progesterone receptor no progesterone resistance could be observed in the late secretory phase of the function- al endometrium of affected women. As in healthy women, with the progression of the secretory phase, the ER and PR expression declined in the functionalis and steadily rose in the basalis as well as in the en- dometriotic lesions [14]. The latter findings suggest physiological progesterone resistance in the basal en- dometrium and also in the endometriotic lesions as they are derived from implanted fragments of basal en- dometrium. Moreover, clinical studies with oocyte do- nation do not support a generally impeded implanta- tion in women with endometriosis [110]. With respect to the expression of the 17ßHSD type 2 no data are available that distinguish between functionalis and basalis as well as endometrial tissue subjected to the chronic TIAR process [111]. In any event, en- dometriosis and adenomyosis result from the physio- logical mechanism of ‘tissue injury and repair’ (TIAR) involving local estrogen production in an estrogen- sensitive environment normally controlled by the ovary. It appears that many of the altered endometrial molecular markers described in the context of en- dometriosis are the consequence rather than the cause(s) of the disease.

Endometriosis and adenomyosis may now be inte- grated into the pyhsiological mechanism and new nosological concept of “tissue injury and repair” (TIAR) and in this context, may just represent the ex- treme of a basically physiological, estrogen-related mechanism, that is pathologically exaggerated in an extremely estrogen- sensitive, reproductive organ. Circumstantial evidence suggests that en- dometriosis and adenomyosis are caused by trauma. In the spontaneously developing disease, chronic uterine peristaltic activity or phases of hyperperistal- sis induce, at the endometrial-myometrial interface near the fundo-cornual raphe, microtraumatizations with the activation of the TIAR mechanism. This re- sults in the local production of estrogens. With on- going peristaltic activity such sites might accumulate and the increasingly produced estrogens interfere in a paracrine fashion with the ovarian control over uter- ine peristaltic activity resulting in permanent hyper- peristalsis and self- perpetuation of the disease process. Overt auto-traumatization of the uterus, with dislocation of fragments of basal endometrium into the peritoneal cavity and infiltration of basal en- dometrium into the depth of the myometrial wall, ensues. In most cases of endometriosis/adenomyosis a causal event early in the reproductive period of life must be postulated leading rapidly to uterine hyper- peristalsis. In late premenopausal adenomyosis, such an event might not have occurred. However, as indi- cated by the high prevalence of the disease, it appears to be unavoidable that, with time, chronic nor- moperistalsis throughout the reproductive period of life leads to the same kind of microtraumatizations. 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