Cássia G. T. Silveira1, Admir Agic2, Geraldine O. Canny3 and Daniela Hornung1, 2
Department of Gynecology and Obstetrics, University of Lübeck, Lübeck, Germany
Department of Gynecology and Obstetrics, Diakonissenkrankenhaus Karlsruhe Rüppurr, Diakonissenstr. 28, 76199 Karlsruhe, Germany
Geneva Foundation for Medical Education and Research, Versoix, Switzerland
As it has been presented thus far, the pathogenesis of endometriosis is complex and multifactorial. The intrinsic endometrial abnormalities thought to be associated with endometriosis include abnormal gene expression, altered endometrial responses to hormones such as progesterone, impaired immunological response, increased nerve density, and oxidative stress. Also interesting is the fact that such biological alterations have also been observed in the eutopic endometrium of patients with endometriosis, which strongly indicates their critical role in the pathophysiology of the disease. Indeed, it has been suggested that the evaluation of eutopic endometrium is an important line of investigation which may help to achieve a fuller understanding of endometriosis pathogenesis. Hence, we present herein a literature review and a comprehensive evaluation of the involvement of the eutopic endometrium in endometriosis. The biological characteristics of both eutopic and ectopic endometrial tissues as well as their clinical correlations with the disease are highlighted, with the primary objective of understanding the role of the eutopic endometrium in this enigmatic gynecological disorder.
17.1.1 The Biology of Eutopic and Ectopic Endometria
The endometrium is a highly specialized tissue composed of a surface epithelium and associated glands surrounded by a cell-rich connective tissue stroma containing a rich supply of blood vessels. Within the endometrium, two distinct layers can be clearly distinguished: the first layer is the transient superficial functionalis, which comprises the upper-two-thirds of the endometrium and which includes loose stroma and differentiating glands; it is constantly regulated by sequential changes in circulating sex steroid hormones through the menstrual cycle and is shed during menstruation; the second layer is the basalis (germinal layer), which comprises undifferentiated glands embedded in stroma and which is responsible for producing a new functionalis in the subsequent cycle; it is relatively insensitive to hormonal changes persisting from cycle to cycle [1–4].
Remarkably, the human endometrium is a dynamic tissue that undergoes cycles of regeneration (proliferative phase), differentiation (secretory phase), and shedding (menstrual phase) over the reproductive life of women. These successive events of cellular proliferation and differentiation are finely orchestrated by sequential changes in circulating sex steroid hormones across the menstrual cycle, which is also accompanied by significant variations in histological and gene expression profiles  and by immune mediators .
Prior to ovulation, increasing levels of ovarian estrogens produced in response to follicle-stimulating hormone promotes the reepithelialization of the luminal edge and growth of stromal and glandular components, preparing the tissue for the subsequent secretory transformation of the glands triggered by the post-ovulation production of progesterone. In addition to glandular cell differentiation, progesterone also mediates growth and coiling of spiral arteries, influx of distinct immune cells, and pre-decidualization of stromal compartments. Subsequently, in the absence of implantation and upon steroid hormone withdrawal, the stromal compartment signals the activation of matrix-degrading enzymes to mediate tissue desquamation and endometrial bleeding .
The actions of estrogen and progesterone are mediated by specific intracellular and membrane bound receptor proteins in stromal and epithelial endometrial cells . In particular, estrogen-related effects on endometrial cell proliferation and survival are predominantly mediated via estrogen receptor α (ER1) , while its isoform β (ER2), expressed at low levels in the endometrium, promotes epithelial differentiation through negative regulation of ER1-mediated responses . In the secretory phase, the antiproliferative effect of progesterone on the endometrial epithelium is mediated via progesterone receptor A (PR-A) .
During the menstrual cycle, locally produced growth factors also participate in endometrial regeneration exerting mitogenic effects of estrogen and differentiating effects of progesterone through autocrine and/or paracrine interactions between epithelial and stromal cells. For instance, the synthesis and secretion of transforming growth factor β (TGFβ), epidermal growth factor (EGF) and EGF receptors, as well as insulin-like growth factor-1 (IGF-1) in response to estrogen were shown and associated with endometrial cell proliferation and decidualization. Interestingly, these growth factors are also believed to modulate the effects of estrogen or progesterone or each other by altering growth factor receptor or binding protein expression [12–14].
Indeed, the architecture and function of the endometrium are maintained by the dynamic relationship between epithelial and stromal cells and the complex microenvironment that includes the extracellular matrix (ECM), diffusible growth factors, cytokines, and other paracrine messengers, as well as a variety of other cell types such as endothelial cells, lymphocytes, and macrophages [15, 16]. Thus, it has become evident that the abnormal interactions between these cellular components and their microenvironments may disrupt tissue homeostasis and precede the development of several endometrial pathologies, including endometriosis. So far, numerous studies have pointed out that the onset and progression of endometriosis are potentially supported by the interruption of this well-balanced cellular equilibrium [15, 17–21] potentially resulting from genetic  and epigenetic changes .
Similar to intrauterine endometrium, ectopic endometrial tissue consists of endometrial-like epithelial and stromal cells although cases of only stromal endometriosis have also been reported . In ectopic loci, such as the peritoneum and ovary, both endometriotic epithelial and stromal cells are functional and respond actively to steroid hormones during the menstrual cycle. On the other hand, endometriotic tissue displays a distinct production of cytokines and prostaglandins, diverse estrogen biosynthesis and metabolic pathways, as well as an altered response to progesterone, e.g., progesterone resistance , that seem to favor ectopic endometrial growth and maintenance.
In addition to altered steroid content and metabolism, ectopic endometrium also retains other peculiar characteristics that contribute to disease development. Although peritoneal, ovarian, and rectovaginal endometriotic lesions are considered distinct entities with a different pathogenesis [26–28], a general consensus exists regarding the critical role of the cross talk between endometriotic cells, host peritoneum and infiltrating leukocytes, endothelial cells, and fibroblasts. This all appears to support the development of the disease .
17.1.2 Eutopic Endometrium in Endometriosis: Villain or Victim?
Although a number of studies have been focused on elucidating the etiology of endometriosis, a unifying theory regarding its origin has remained elusive. Instead, several theories have emerged to account for the disparate observations regarding the pathogenesis, and these can generally be categorized as those suggesting that implants originate from uterine endometrium and those proposing that implants arise from tissues or cells other than the uterus. Intrinsic to these theories are inciting factors (i.e., immune, endocrine, and environmental factors) and genetic susceptibilities whose roles are beginning to be delineated, although they are still insufficient to fully explain the cause and development of disease. For instance, acquired genomic alterations and several physiological changes were shown to represent a potential source for a conferred proliferation and survival advantage to endometriotic implants .
In this context, the potential involvement of eutopic endometrium seems to be particularly critical in the pathogenesis of endometriosis, evinced by Sampson’s retrograde menstruation theory in 1921 , the most widely accepted hypothesis, which nonetheless does not fully explain the etiology. In accordance with this theory, it is presumed that the establishment of endometrial cells from refluxed menses in ectopic sites is supported by the following characteristics: (a) the endometrial debris, including both epithelial and stromal cells, must exist in the reflux menses; (b) these two cellular components must be viable and able to evade immune attack within the pelvic cavity; (c) both epithelial and stromal cells must have the potential ability to attach and implant into the pelvic mesothelium; and (d) ultimately, once implanted at an ectopic location, endometriotic cells must be able to survive and develop a neovascular system . Indeed, the link between altered eutopic endometrium and the risk for developing endometriosis may possibly justify the morbidity of the disease in only 10–15 % of the women with menstrual reflux [32, 33] and at least partially explain the high rate of recurrence after medical and/or surgical treatment .
In fact, important functional and biochemical differences between eutopic endometrium of women with and without endometriosis have been reported in the literature [35, 36]. In particular, a large number of differentially expressed gene transcripts, miRNAs, and proteins have been detected and they appear to mostly encode molecular signals mediating cross talk between epithelial and stromal cells, cell proliferation, differentiation and survival, as well as endometrial receptivity [37–43]. For instance, aberrant production of cytokines, growth and angiogenic factors, different steroid receptor expression and signaling, and abnormal expression of specific cancer-related genes presented in eutopic endometrial cells are thought to predispose to growth and survival of endometrial foci outside the uterus and to produce disease-related symptoms such as reduced fertility and implantation failures.
The role of the eutopic endometrium as a major and active contributor for the development of endometriotic lesions has also been supported by the accumulating evidence implying the involvement of stem cells. Stem cells are rare undifferentiated cells characterized by high proliferative, self-renewal, and differentiation potential that are present in virtually all adult tissues and organs . The presence of aberrant stem cells has been associated with the pathogenesis of several tumors and proliferative disorders in female reproductive organs . As thoroughly addressed in Chap. 4, endometrium-derived stem/progenitor cells residing in the basalis and/or functionalis have been suggested to reach the peritoneal cavity via menstrual reflux or lymphovascular dissemination and establish endometriotic implants [46, 47].
Bearing in mind that the eutopic endometrium of women with endometriosis shows a wide variety of anomalies both in the tissue architecture and biochemistry and this tissue being a potential source of endometrial stem cells, it is plausible that the primary defect in endometriosis may be the eutopic endometrium [48–50]. Nevertheless, it is becoming increasingly apparent that interplay between eutopic endometrium and endometriotic lesions is more complex than abnormal eutopic endometrium resulting in establishment of endometriotic lesions . In addition to critical interactions between shed endometrial fragments and peritoneum (i.e., peritoneal mesothelium and environment) during lesion establishment [16, 52], it is likely that the biology of eutopic endometrium is altered in response to the presence of endometriotic lesions as it has currently been demonstrated in in vivo models of endometriosis .
So far, the abnormalities described in endometriotic endometrium and suggested to predispose to endometriosis were in fact identified when the disease was already present, thus making it difficult to define whether these endometrial changes are a cause or an effect of endometriosis. Alternatively, by using mouse and non-primate models with no previous history of disease, it was possible to evaluate the endometrium before and after induction of endometriosis and to obtain strong evidence that the presence of endometriotic lesions directly influences the endometrial environment.
In particular, data obtained from baboon models of experimentally induced endometriosis indicate that a complex series of changes in endometrial gene and protein expression occurs at different time points during disease progression [53, 54], potentially as a result of epigenetic modifications triggered in the presence of ectopic lesions . Similar to anomalies in eutopic endometrium of women with endometriosis, collective findings in this model show a local increase in proliferation and angiogenesis and a significant alteration in steroid hormone receptor distribution and signaling with an evident progesterone resistance [53, 54, 56–60]. Moreover, it has recently been demonstrated in a mouse model of endometriosis that cells from endometriotic lesions can migrate to and preferentially populate the endometrial basal layer, thus further supporting the bidirectional interaction between eutopic and ectopic endometrial tissue .
In women with endometriosis, the effects of ectopic lesions on eutopic endometrium remain uncertain, and due to a range of reasons (mainly ethics-related issues), this relationship is extremely difficult to study. However, the interaction between lesions and eutopic endometrium is likely to occur and contribute to both endometriosis establishment and progression. From animal model data, it is speculated that the interconnecting roles of the vascular, lymphatic, and nervous systems in both the uterine and peritoneal environments with concurrent participation of eutopic endometrium, ovarian steroids, and inflammatory mediators may favor the development of endometriosis and its associated symptoms. A hypothesized pathway has been suggested .
17.2 Eutopic and Ectopic Endometria: Similarities and Dissimilarities
As addressed above, eutopic endometrium of endometriosis patients retains several abnormalities that in fact resemble the biological characteristics found in ectopic endometrial tissues such as augmented proliferation, aromatase activity, unusual cytokine expression, decreased apoptosis, as well as altered local hormone metabolism [62, 63].
Although the morphological appearance of endometriotic implants may reflect that of eutopic endometrium, these similarities are often only limited. Indeed, a variety of investigations have also revealed important differences between eutopic and ectopic endometria involving cell structure, gene expression, and responsiveness of various proteins [16, 63–68].
Morphologically, both endometriotic glandular and stromal cells retain ultrastructural features that are recognizably different from those of eutopic endometrium of patients with endometriosis. In contrast to eutopic tissue, endometriotic tissue was shown to encompass a wide range of morphological development from poorly to highly differentiated glands . Interestingly, such variations were detected not only from gland to gland but also within the same gland. Moreover, while complete proliferative development has been detected in some endometriosis patients, full secretory transformation seems to frequently be absent in ectopic implants . Additionally, the comparative observations of Yu et al.  of eutopic and ectopic endometrial cells cultured in vitro described an enlarged nucleus and manifold chromatin in endometriotic glandular cells, whereas endometriotic stromal cells appeared to be smaller and characterized by many tiny villi and protuberances on the plasma membrane.
Apart from morphological features, the dissimilarities between endometriotic lesions and eutopic endometrium are even more evident at the molecular level. With the advent of microarray-based technologies, several investigators were able to explore the distinct pattern of gene expression in eutopic and ectopic endometrium. Large-scale transcriptional profiling analyses using microarrays are widely employed for analyzing the expression of thousands of genes simultaneously in a single experiment supported by the availability of the complete nucleotide sequence of the human genome. Microarray studies provide extremely important information enabling a better understanding of the etiology and pathophysiology of a variety of diseases and the development of new diagnostic and therapeutic strategies [71, 72].
To date, a considerable number of studies comparing the global expression profiles of paired eutopic endometrium and endometriosis specimens have been published although the data available in the public domain is still restricted and occasionally divergent. In fact, it is important to note that some discrepancies may be a result of the potential impact of one or more factors such as demographic characteristics, site of endometriosis, fertility history, severity of stages, and phases of the menstrual cycle that were not fully considered in most studies despite their well-known influences on gene expression in eutopic and ectopic tissues [73–75].
In spite of these limitations, significant and interesting findings have been provided by microarray-based analyses of eutopic and ectopic endometrium which have been confirmed by subsequent investigations using other conventional and sophisticated methodologies. Collectively, these published data highlight differences in the expression of gene-encoding proteins involved in multiple biological process and hypothesized to be responsible for the establishment of ectopic endometrial implants, including cell adhesion, extracellular matrix remodeling, migration, proliferation, apoptosis, immune system regulation, inflammatory pathways, sex hormone-related signaling and neuroangiogenesis [16, 64–68, 75] that will be thoroughly addressed in the following sections.
Also noteworthy are the observations on the differential expression pattern of microRNAs (miRNAs) in ectopic versus eutopic endometrium [76, 77]. miRNAs are small noncoding RNA molecules that have a critical role in posttranscriptional regulation of gene expression by repression of target mRNA translation. A relatively recent microarray-based investigation in paired eutopic and ectopic endometria has identified more than 80 differentially expressed miRNAs. Interestingly, most of them are predicted to regulate a large fraction of protein-coding genes associated with genetic (i.e., cancer) and immunological disorders and involved in cellular growth and proliferation, apoptosis, cellular movement, cell-mediated immune response, cell-to-cell signaling and interaction, as well as gene expression regulation .
Evidence for molecular abnormalities in eutopic and ectopic endometria has also been revealed through proteomic approaches. In particular, large-scale proteomic studies including mass spectrometry and protein microarray-based technologies have enabled the simultaneous evaluation of several hundred proteins in eutopic and ectopic endometrium as well as biological fluids and provided valuable information regarding their expression pattern, functions, localization, posttranslational modifications, and interactions . Investigations focusing on the comparative proteomic analysis of paired eutopic and ectopic endometrial tissues are still limited although they are currently gaining more attention. For instance, a recent study combining two-dimensional electrophoresis and mass spectrometry demonstrated a remarkable difference in the protein repertoire of endometriotic lesions compared with its uterine counterpart . Interestingly, significant differences comprised proteins primarily involved in cellular spreading and attachment, cell homeostasis and survival, mRNA processing and transport, immune response, and protein trafficking .
In addition to differences between eutopic and ectopic endometrium, increasing evidence in the literature has also suggested that the biological characteristics of endometriotic cells might differ between different forms of endometriosis [28, 81]. These findings may possibly account for the high heterogeneity observed in endometriosis pathogenesis and disease-related symptoms and imply that a single universal treatment is perhaps not effective for all forms of endometriosis.
17.3 Endometrial Cell Proliferation, Survival, and Invasion
Endometriosis could result from increased cellular proliferation or decreased apoptosis in response to appropriate stimuli. Eutopic endometrium from women with endometriosis has several differences compared with normal endometrium of women without endometriosis. These differences may contribute to the survival of retrograded endometrial cells into the peritoneal cavity and thus to the development of endometriosis.
Nearly all women of reproductive age exhibit some degree of endometrial debris reflux . Menstrual effluent retrogradely shed into the peritoneal cavity was observed to contain viable endometrial cells [83–87]. Summarizing previous knowledge of the disease, Vinatier et al.  presented two theories to explain why only some patients develop the disease. The first theory is based on disorders of the ectopic endometrial tissue whereby it resists normal peritoneal “cleaning.” The second suggests that the disease is secondary to abnormalities of cellular and humoral immunity, which induces excessive receptivity of the peritoneal mesothelium, hyperactivated macrophages, and NK cell abnormalities. Mediators in the peritoneal environment may alter a genetically predisposed endometrium which then exhibits increased invasion. It is also possible that an excess of refluxed endometrium or altered endometrium has the potential to contribute to the development of a proinflammatory environment favorable to disease establishment .
17.3.1 Apoptosis in Endometriosis
Accumulating evidence suggests that endometrial cells from women with and without endometriosis exhibit fundamental differences in their apoptotic capacity. Endometrial cells from women with endometriosis have enhanced proliferation and an increased ability to implant and survive in ectopic locations. Impaired sensitivity of endometrial tissue to spontaneous apoptosis contributes to the abnormal implantation and growth of endometrium at ectopic sites.
The inability of endometrial cells to transmit a “death” signal or their ability to avoid cell death is associated with increased expression of anti-apoptotic factors (Bcl-2) and decreased expression of pre-apoptotic factors (BAX) . However, it remains unclear whether abnormal apoptosis in the eutopic endometrium from patients with endometriosis is a primary or a secondary process after establishment of the pelvic endometriosis process. This could be attributed to the fact that at the time of clinical presentation and diagnosis, most women already have established disease and, therefore, it is difficult to investigate the early developmental stages of endometriosis.
Reflux of endometrial fragments during menstruation into the peritoneal cavity is a common phenomenon. Under normal conditions, cells which do not adhere to their extracellular matrix enter apoptosis as they receive different signals from their adhesion receptors . However, in women with endometriosis, these cells have the ability to adhere to mesothelial cells of the peritoneum, proliferate, and induce neoangiogenesis resulting in the development of active endometriotic implants. The effect of MMPs on apoptotic factors and their regulation by steroid hormones may provide a link between endometrial turnover and the invasive process necessary for the development of disease.
Recent studies from González-Ramos et al. [91, 92] showed constitutive NF-κB activation in peritoneal endometriosis. They reported that the NF-κB pathway is implicated in the development of endometriotic lesions in vivo and that NF-κB inhibition reduces intracellular adhesion molecule-1 expression and cell proliferation, but increases apoptosis of endometriotic lesions, diminishing the initial development of endometriosis in an animal model. This and other observations support the notion that endometriosis is characterized by persistent inflammation and proliferation.
Murk et al.  described extracellular signal-regulated kinase (ERK1/2) activity in human endometrium. ERK1/2 plays key intracellular roles in activating cellular survival and differentiation processes. The authors found that ERK1/2-mediated steroid inhibition in endometrial stromal cells reduced proliferation and increased apoptosis. They suggested that abnormally high levels of ERK1/2 activity may be involved in endometriosis, possibly by stimulating endometrial cell survival.
Some studies have suggested that genetic factors are likely to influence individual susceptibility to endometriosis. Genetic alterations in somatic chromosomes  and DNA deletions that inactivate some tumor suppressor genes (e.g. PTEN) are likely to be involved in the initiation, persistence, and progression of endometriosis [95, 96].
cDNA microarray analysis provided an interesting insight into altered gene expression profiles in endometriosis patients. Using this method, Arimoto et al.  found 97 upregulated and 337 downregulated genes in women with endometriosis. Genes related to apoptosis (GADD34, GADD45A, GADD45B, PIG11) and the tumor suppressor TP53 gene were downregulated in endometriotic tissues. On the other hand, Eyster et al.  found that only a few genes in apoptosis resistance pathways were differentially expressed in endometriosis cells compared to normal endometrial cells. They suggested that the presence of ligands to activate the apoptotic pathway or the apoptosis resistance pathways may be more important than whether specific members of the pathway are over- or underexpressed.
Braun et al.  demonstrated that the transcript abundance ratio of anti-apoptotic to pro-apoptotic isoforms of the Bcl-X gene favors survival in eutopic and ectopic endometrial cells from women with endometriosis, but not control endometrial cells. This was found throughout the menstrual cycle for ectopic endometrial cells. Eutopic but not ectopic endometrial cells also expressed increased transcript abundance of the anti-apoptotic DAD-1 gene in endometriosis. Eutopic and ectopic endometrial cells from women with endometriosis expressed decreased transcript abundance of p53 and caspase-1 compared to endometrial cells from women without endometriosis. Dysregulation of pro- and anti-apoptotic regulatory gene expression characterized eutopic and ectopic endometrial cells from women with endometriosis, consistent with apoptotic resistance and enhanced survival of endometrial cells in endometriosis. This data should provide useful information for finding candidate genes whose products might regulate the apoptotic machinery in endometriosis and, additionally, could serve as molecular targets for diagnosis or treatment of endometriosis.
Othman et al.  reported that mutants of estrogen receptor genes delivered to endometriotic cells via an adenovirus vector (Ad-DNER) decreased cell proliferation, induced apoptosis, and decreased cytokine production. The authors suggested that adenovirus-mediated gene therapy may represent a potential therapeutic option for endometriosis in the future.
17.3.2 Invasion in Endometriosis
Endometriosis is a benign and frequently progressive disease with a high prevalence in the female population of reproductive age. Nevertheless, endometriosis shows behavior similar to malignant tumors. Deep invasion in different tissues such as the peritoneum, ovary, and intestines is presumably occurs as a result of migrating epithelial and stromal cells of modified endometrium adhering to distant tissues . Endometriotic cells are capable of attaching to the peritoneal mesothelium, breaking the peritoneal lining, and destroying ECM, thereby invading surrounding tissue.
Endometriosis is associated with an increased risk for several types of malignant diseases [100, 101]. Especially the endometrioid subtype of ovarian cancer has a high probability for developing on the basis of existing endometriosis [102–105]. Like malignancy, endometriosis displays features of atypia, adherence, invasion, and metastases. The risk of direct malignant transformation of ovarian endometriosis has been estimated as 0.7–1.6 % over an average of 8 years.
Among several investigated potential invasion markers, two proteins, YB-1 and L1CAM, seem to have very important roles in the progression of endometriosis.
22.214.171.124 Cold Shock Domain Family Member YB-1 Expression in Endometrium and Endometriosis
The Y-box binding protein YB-1, an evolutionarily conserved 48 kDa protein, belongs to the superfamily of cold shock domain proteins with pleiotropic biological functions. Eukaryotic YB proteins are involved in the regulation of DNA transcription and repair, in translational control of protein synthesis, as well as in cellular responses to a wide variety of stressors [106–108].
The YB-1 protein is highly expressed in a number of malignant diseases, and it seems to promote tumor growth and multidrug resistance  through the induction of specific growth factors [110–113].
Based on multiple biological functions of YB-1 and its close association with tumorigenesis, YB-1 expression in human endometrium, ovarian endometriosis, and peritoneal macrophages was investigated . YB-1 gene and protein expression was significantly higher in ovarian lesions, eutopic endometrium, and peritoneal macrophages of patients with endometriosis in comparison to the control group. Interestingly, the strongest YB-1 expression was observed in the epithelial compartment of endometrial tissues. In the 12Z endometriotic epithelial cell line, YB-1 knockdown resulted in significant cell growth inhibitory effects including reduced cell proliferation and increased spontaneous and TNFα-induced apoptosis rate. Significantly higher RANTES (regulated upon activation, normal T cell expressed and secreted chemokine) expression and decreased cell invasion in vitro were also associated with YB-1 inactivation. Elevated YB-1 expression seems to have an impact on the development and progression of endometriosis .
126.96.36.199 L1 Cell Adhesion Molecule (L1CAM) as a Pathogenic Factor in Endometriosis
L1 cell adhesion molecule (L1CAM, CD171) is a type I transmembrane glycoprotein (200–220 kDa) which belongs to the immunoglobulin superfamily . Initial studies showed that L1CAM plays an important role in the development of the nervous system [115–117] and have implicated L1CAM also in the ontogeny of human tumors including melanomas, neural tumors, renal carcinomas, colon carcinoma, and endometrial and ovarian carcinomas [118–121]. The expression of L1CAM in carcinomas augments dissemination of tumor cells by enabling cell migration and invasion [122–124].
Given the role of L1 in endometrial and ovarian carcinomas, L1CAM was also investigated as a pathogenetic factor in endometriosis .
L1CAM was found present in endometriotic tissue of women with endometriosis and increased at gene and protein levels using short-term cultures of endometriosis lesions. A significantly higher expression of L1CAM Significantly higher L1CAM expression in the epithelial cell fraction in rAFS stages III and IV (AFS 1997) of endometriosis was found. The nerve growth-promoting activity of the conditioned medium of endometrial epithelial cell cultures from women with endometriosis was studied using a chicken ganglion assay. The conditioned medium of endometrial epithelial cell cultures from patients with endometriosis stimulated strong neurite growth which was blocked by co-incubation with anti-L1-mAb in a dose-dependent fashion .
17.4 Estrogen-Related Signaling and Progesterone Resistance in Endometrium and Endometriotic Lesions
It is well known that endometriosis is a hormone-responsive disease and that disease progression is inhibited by an antiestrogenic environment. In postmenopausal women undergoing in vitro fertilization with donor eggs, the exogenous administration of only estradiol (E2) and progesterone is sufficient to prepare the endometrium for implantation in the absence of ovarian function. This observation underscores the essential roles of these steroids in uterine physiology. Indeed, both E2 and progesterone are master regulators of endometrial tissue . Each hormone is estimated to regulate expression of hundreds of genes during various phases of the menstrual cycle . Endometriotic and eutopic endometrial tissues respond to E2 and progesterone with apparently similar histological changes, and both tissues contain immunoreactive ERs and PRs. The eutopic endometrium predictably becomes atrophic in response to prolonged progestin therapy or oral contraceptives that contain progestins. Treatment with these agents, however, does not predictably suppress endometriotic tissue growth. Endometriotic tissue in ectopic locations, such as the peritoneum or ovary, is fundamentally different from eutopic endometrium within the uterus in terms of production of cytokine and prostaglandin production, estrogen biosynthesis and metabolism, and clinical response to progestins [127–129].
17.4.1 Estrogen Action in the Endometrium and Endometriosis
Both circumstantial and laboratory evidence strongly supports the notion that estrogen is an extremely strong mitogen for endometriotic tissue. The biologically active estrogen 17 beta estradiol (E2), which is secreted by the ovary or locally produced by in endometriotic tissue, acts as a classical steroid hormone to regulate growth of endometrial or endometriotic tissue. E2 enters cells and binds to the ER in estrogen-responsive cells. ER subtypes α and β are proteins with high affinity for E2 and are encoded by separate genes. The classical human ERα was cloned in 1986, and a second estrogen receptor, ERβ, was cloned from rat prostate and human testis in 1996 [130–132]. Although both ERα and ERβ are present in the endometrium, ERα seems to be the primary mediator of estrogenic action in this tissue . Studies using ERα-deficient mice have revealed the central role of this receptor in reproductive function, at all levels of the hypothalamic–pituitary–gonadal axis . Despite its sensitivity to estrogen, endometriosis appears to have an altered steroid hormone receptor profile compared with that of its normal tissue counterpart, the eutopic endometrium. For example, several investigators reported markedly higher levels of ERβ and lower levels of ERα in human endometriotic tissues and primary stromal cells compared with eutopic endometrial tissues and cells [56, 135, 136]. Moreover, the levels of both isoforms of PR, particularly PR-B, are significantly lower in endometriosis compared with eutopic endometrium [137, 138].
The E2-receptor complex acts as a transcription factor that becomes associated with the promoters of E2-responsive genes via direct DNA binding or binding to other docking transcription factors at basal promoter regions . This interaction brings about ER-specific initiation of gene transcription, which promotes the synthesis of specific mRNAs and proteins . PR is one of many E2-responsive genes, and E2 acts in eutopic endometrial tissues and stromal cells to promote endometrial responsiveness to progesterone . In contrast, PR mRNA and protein levels are not elevated in biopsied endometriotic tissues exposed to high E2 levels during late proliferative phase or in endometriotic cells treated with E2, indicating that E2 induction of PR expression in endometriosis is markedly blunted .
17.4.2 Progesterone Resistance in Eutopic Endometrium and Endometriotic Lesions
E2 is the best-defined mitogen for growth and inflammation processes in ectopic endometriotic tissue that commonly resides on pelvic organs. Progesterone and progestins may relieve pain by limiting growth and inflammation in endometriosis, but some patients with pelvic pain do not respond to treatment with progestins. Moreover, progesterone-induced molecular changes in eutopic endometrial tissue of women with endometriosis are either blunted or undetectable. These in vivo observations are indicative of resistance to progesterone action in endometriosis. The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in levels of progesterone receptors (PRs) and the lack of the PR isoform progesterone receptor B (PR-B). In normal endometrium, progesterone acts on stromal cells to induce secretion of paracrine factor(s). These unknown factor(s) act on neighboring epithelial cells to induce the expression of the enzyme 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD-2), which metabolizes E2 to the less active estrone (E1). In endometriotic tissue, progesterone does not induce epithelial 17β-HSD-2 expression due to a stromal cell defect. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that stimulate 17β-HSD-2 may be due to the lack of PR-B and very low levels of progesterone receptor A (PR-A) observed in vivo in endometriotic tissue. The end result is deficient E2 metabolism in endometriosis giving rise to high local concentrations of this mitogen .
Other mechanisms proposed to explain progesterone resistance are altered expression or function of chaperone proteins like FKBP52  and co-regulators such as HIC-5/ARA55 .
PR is a target gene of ERα in several cell types including breast cancer epithelial cells. ERα mediates E2-induced PR expression. It has been reported that two distinct E2-regulated promoters generate transcripts encoding two functionally different human PR isoforms, PR-A and PR-B . Previous studies have demonstrated that maximal PR mRNA and protein levels are reached after human breast cancer cells have been exposed to E2 for 3 days [144–146]. Two major transcriptional start sites have been identified. The upstream transcription start site gives rise to a full-length mRNA species that encodes the PR-B protein. Another mRNA species with a further downstream transcription initiation site gives rise to the truncated PR-A form. Despite the fact that both proposed PR promoter sequences are E2 responsive, neither contains a classical palindromic ERE sequence . Several nonclassic regulatory elements (e.g., AP1, Sp1) in the human PR promoter have been reported. These sites have been shown to bind ERα and on one occasion ERβ [140, 147–155]. Bulun et al. speculate that a critical level of ERα may be necessary for E2-dependent induction of PR in endometrial stromal cells. The occupancy of the PR promoter regions with varying ratios of ERα to ERβ may be critical in determining the effect of E2 on PR expression. A strikingly lower ERα-to-ERβ ratio in endometriotic stromal cells may be responsible for a shift from E2 stimulation to E2 inhibition of PR expression in endometriotic stromal cells .
17.5 The Inflammatory Response in Eutopic and Ectopic Endometria
The immune status has been suggested to play an important role in both initiation and progression of endometriosis. T and B lymphocytes and natural killer cells seem to play essential roles in determining if endometrial and endometriotic cells accept or reject survival, implantation, and proliferation [156, 157]. Several studies have shown a reduced activity of cytotoxic T cells and NK cells, cytokine secretion by helper T cells, and autoantibody production by B lymphocytes in women with endometriosis [156–158]. As alluded to in a previous section, NF-κB transcriptional activity modulates inflammatory key cell processes contributing to the initiation and progression of endometriosis . It has further been shown that immune–endocrine interactions are likely to be involved in the pathogenesis of endometriosis.
Endometriosis is associated with an increased inflammatory activity, as seen by elevated serum levels of inflammatory markers such as CA-125  and C-reactive protein . Changes in peritoneal fluid inflammatory markers of peritoneal fluid have also been observed in women with endometriosis . The generalized inflammatory activity may lead to more generalized clinical effects where some women with endometriosis suffer from fever and a general feeling of sickness, especially AT times when they experience more pain.
17.6 Neurogenesis in Endometrial and Endometriotic Tissue
Recent evidence indicates that ectopic endometriotic implants recruit their own unique neural and vascular supplies through neuroangiogenesis. It is believed that these nascent nerve fibers in endometriotic implants influence dorsal root neurons within the central nervous system, increasing pain perception in patients .
Several studies have suggested that endometrial biopsies with the detection of nerve fibers provide a reliability of diagnosing endometriosis [164, 165]. Newer studies however were not able to demonstrate any differences in the amount of nerve fibers or neuronal markers in endometrium of women with endometriosis compared to women without endometriosis. The neuronal markers, PGP9.5, NGFp75, and VR1, are expressed in the endometrium at levels that do not differ between women with and without endometriosis .
Endometrial functional layer nerve fibers were identified in 22 % of biopsies overall including 19 % of cases with histologically confirmed peritoneal endometriosis and 29 % of cases without endometriosis. There was no correlation between the presence of functional layer nerve fibers and the presenting symptoms, endometrial histology, or current hormonal therapy. Endometrial functional layer nerve fibers assessment performed using standard immunohistochemical techniques on routine biopsy specimens proved neither sensitive nor specific for the diagnosis of endometriosis . In conclusion, much rigorous research to better understanding this complex pathology and to find specific and sensitive biomarkers remains to be done.
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