Women with Endometriosis-Who Is at Risk for Complications Associated with Pregnancy and Childbirth? A Retrospective Case-Control Study.

Women with endometriosis (EM), particularly the manifestations of adenomyosis (AM) and deep infiltrating endometriosis (DIE), suffer from pain and sterility. DIE also appears with several specific obstetric complications. To determine the risk profile, we designed a retrospective case-control study. Primary outcomes were defined as the risk of preterm birth and caesarean delivery (CD). Primiparous singleton pregnancies in women with DIE were compared with controls without EM. We matched for mode of conception and maternal age. A total of 41 women diagnosed with DIE and 164 controls were recruited. A total of 92.7% of the cases were also diagnosed with AM. Preterm birth occurred in 12.2% of cases and in 6.7% of controls. The difference was not statistically significant (OR: 1.932; 95% CI: 0.632-5.907). The rate of CD was similar in both groups. Remarkably, placental implantation disorders in the form of placenta praevia were eight times more frequent in women with DIE (9.8%) than in controls (1.2%, OR: 8.757; 95% CI: 1.545-49.614). Neonatal outcome was similar in both groups. Four out of fourteen cases reported abdominal wall endometriosis after CD. Women with DIE/AM and with placenta praevia are at risk of bleeding complications. After CD, they can develop abdominal wall EM. We therefore suggest evaluating the birth mode in each woman with DIE/AM.

Multicenter evaluation of blood-based biomarkers for the detection of endometriosis and adenomyosis: A prospective non-interventional study.

OBJECTIVE: To evaluate blood-based biomarkers to detect endometriosis and/or adenomyosis across nine European centers (June 2014-April 2018). METHODS: This prospective, non-interventional study assessed the diagnostic accuracy of 54 blood-based biomarker immunoassays in samples from 919 women (aged 18-45 years) with suspicion of endometriosis and/or adenomyosis versus symptomatic controls. Endometriosis was stratified by revised American Society for Reproductive Medicine stage. Symptomatic controls were "pathologic symptomatic controls" or "pathology-free symptomatic controls". The main outcome measure was receiver operating characteristic-area under the curve (ROC-AUC) and Wilcoxon P values corrected for multiple testing (q values). RESULTS: CA-125 performed best in "all endometriosis cases" versus "all symptomatic controls" (AUC 0.645, 95% confidence interval [CI] 0.600-0.690, q < 0.001) and increased (P < 0.001) with disease stage. In "all endometriosis cases" versus "pathology-free symptomatic controls", S100-A12 performed best (AUC 0.692, 95% CI 0.614-0.769, q = 0.001) followed by CA-125 (AUC 0.649, 95% CI 0.569-0.729, q = 0.021). In "adenomyosis only cases" versus "symptomatic controls" or "pathology-free symptomatic controls", respectively, the top-performing biomarkers were sFRP-4 (AUC 0.615, 95% CI 0.551-0.678, q = 0.045) and S100-A12 (AUC 0.701, 95% CI 0.611-0.792, q = 0.004). CONCLUSION: This study concluded that no biomarkers tested could diagnose or rule out endometriosis/adenomyosis with high certainty.

Shedding Light on the Interaction Between Rif1 and Telomeres in Ovarian Cancer.

Ovarian cancer, more precisely high-grade serous ovarian cancer, is one of the most lethal age-independent gynecologic malignancies in women worldwide, regardless of age. There is mounting evidence that there is a link between telomeres and the RIF1 protein and the proliferation of cancer cells. Telomeres are hexameric (TTAGGG) tandem repeats at the tip of chromosomes that shorten as somatic cells divide, limiting cell proliferation and serving as an important barrier in preventing cancer. RIF1 (Replication Time Regulation Factor 1) plays, among other factors, an important role in the regulation of telomere length. Interestingly, RIF1 appears to influence the DNA double-strand break (DSB) repair pathway. However, detailed knowledge regarding the interplay between RIF1 and telomeres and their degree of engagement in epithelial ovarian cancer (EOC) is still elusive, despite the fact that such knowledge could be of relevance in clinical practice to find novel biomarkers. In this review, we provide an update of recent literature to elucidate the relation between telomere biology and the RIF1 protein during the development of ovarian cancer in women.

Rare Clinical Presentation of Postmenopausal Endometriosis: A New Perspective.

Endometriosis affects 2-5 % of postmenopausal women with menopause hormone therapy and is less common in women without treatment with exogenous estrogen or tamoxifen. Postmenopausal endometriosis has more unknown aspects in its pathogenesis and clinical manifestation than in the case of premenopausal patients. The aim of this review was to summarize the clinical presentation of rare cases of endometriosis, including deep infiltrating (DIE) and extragenital endometriosis, in women. The symptoms of endometriosis in the post-reproductive age are more heterogeneous than in women of childbearing age, often resembling symptoms of gastrointestinal tumors or urinary tract diseases. We summarize cases of endometriosis of the intestines, liver, pancreas, and stomach, as well as endometriosis of the urinary tract and skin, with non-gynecological manifestations. We also describe the pathogenesis of endometrial tissue activity in the context of reduced estrogen levels after menopause, which is also not clear, and demands more molecular and genetic studies. NAD+-dependent deacetylases called Sirtuins are metabolic sensors for maintaining body homeostasis. In the context of endometriosis, Sirtuins are being studied for their potential role in modulating inflammation, cell proliferation, and sex hormone sensitivity, but their role in postmenopausal endometriosis is not well researched. Treatment in postmenopausal women includes mostly for now surgery, depending on the location of the lesion, and aromatase inhibitors. The complete genetic and epigenetic profile in women post-reproductive age is needed to propose target therapy, especially in severe cases such as endometriosis that is deeply infiltrating and located outside the pelvis.

ARID1a Gene as a Potential Early Marker to Tackle Endometriosis-Associated Ovarian Cancer.

The worries of women with endometriosis - a chronic gynecological disease affecting approximately 10% of women of childbearing age - about the increased risk of ovarian cancer are present worldwide. Endometriosis is a common, often painful, but benign gynecological disease that affects women. However, the pathogenesis remains elusive but is certainly multifactorial. Interestingly, endometriosis shares similarities with cancer. Therefore, women suffering from endometriosis fear an increased risk of ovarian cancer. In addition, these patients suffer from anxiety and depression. Previous studies have provided evidence that epithelial mutations in endometriosis or in the endometrium include certain inactivating mutations responsible for ovarian cancer, such as in the ARID1A gene.

Sox-2 positive cells identified in lymph nodes from endometriosis patients may play a role in the disease pathogenesis.

OBJECTIVE: This study aimed to characterize Sox-2 in sentinel lymph nodes and randomly obtained lymph nodes from endometriosis (EM) patients for the first time. STUDY DESIGN: This prospective study analyzed tissue samples from surgical specimens collected from May until December 2007 in the Endometriosis Center Charité, Berlin. Lymph node samples from 38 women aged between 22 and 49 years who underwent laparoscopy due to symptomatic EM were analyzed. The material was obtained either randomly or, in the case of deep infiltrating endometriosis, detected using 4 cc Patent Blue®, labeled intraoperatively, which made the sentinel lymph nodes available for histological examination. Together with hematoxylin and eosin staining, the sections were evaluated by immunohistochemistry with antibodies against estrogen and progesterone receptors and Sox-2. Using double-immunofluorescence microscopy, the colocalization of Sox-2 and estrogen receptors were evaluated. RESULTS: Sox-2-positive cells were identified in the lymph nodes' cortical and medullary zones, with a higher expression in the medullary layer. Occasionally, Sox-2 positive stained cell groups, called cell nests, could also be detected. The number of Sox-2 positive cells in the sentinel lymph nodes was almost three times higher than in the random lymph nodes (p = 0.031). A significant five-fold increase (p = 0.0013) in Sox-2 expression was seen in the estrogen and progesterone receptor (ER/PR) positive patient group compared to the progesterone receptor positive group or hormone receptor negative patients. Identical hormone-related Sox-2 expression was also detected separately for the sentinel lymph node group (p = 0.0174). Sox-2 showed pronounced colocalisation with estrogen receptors. CONCLUSION: The lymphatic involvement in EM is evidence of a systemic disease manifestation and provides evidence of an immune system failure. In recent years, many theories have been studied, but there is no single theory that could explain all aspects of EM. The future concept of EM is likely to incorporate the elements from all the pathogenetic theories already described. Through this study, stem cells and lymphatic metastasis theories were incorporated.

Endometriosis, an Ongoing Pain-Step-by-Step Treatment.

Endometriosis is a disease that is becoming more and more challenging for the medical community. The current therapeutic concepts (surgical therapy and/or hormonal therapies) often do not lead to sufficient pain control, and late diagnosis and high recurrence rates mean that women affected by the disease can suffer for decades before receiving proper treatment. Although the introduction of certified endometriosis centers has created contact points for surgical therapies performed by endometriosis experts, these centers are not sufficient to offer the affected patients the all-encompassing long-term support they need. In recent years, new findings regarding the pathogenesis and correlations of the pain phenomena caused by endometriosis have shown that conventional therapy strategies are not adequate and individual long-term concepts must be developed. Not only can endometriosis cause nociceptive pain, but it can also lead to a nociplastic reaction with central sensitization. Hence, aside from the classic cyclic complaints, patients increasingly suffer from atypical pain. Due to the high number of affected patients who are treated inadequately, it is necessary for gynecologists in private practices to become familiar with multimodal treatment concepts since they are the central point of contact of their patients. The following article will provide an overview of treatment strategies for chronic symptomatic endometriosis.

Neurogenic Inflammation in the Context of Endometriosis-What Do We Know?

Endometriosis (EM) is an estrogen-dependent disease characterized by the presence of epithelial, stromal, and smooth muscle cells outside the uterine cavity. It is a chronic and debilitating condition affecting ~10% of women. EM is characterized by infertility and pain, such as dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, and dyschezia. Although EM was first described in 1860, its aetiology and pathogenesis remain uncertain. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with EM but also contribute to a growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. Here we review the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the role of this system, as well as its interactions with immune cells, will unearth novel disease-relevant pathways and targets, providing new therapeutics and better-tailored treatment options.

Pathogenesis of Endometriosis: The Origin of Pain and Subfertility.

Endometriosis (EM) and adenomyosis (AM) are common conditions with pain and infertility as the principal symptoms. The pathophysiology of pain in EM and AM comprises sensory and somatoform pain mechanisms. Over time, these may aggravate and lead to individual complex disease patterns if not diagnosed and treated. Despite the known facts, several years often pass between the onset of symptoms and diagnosis. Chronic pain disorders with changes on a neuronal level frequently arise and are linked to depressive disorders, with the process becoming a vicious cycle. Additionally, women with EM and AM suffer from sub- and infertility. Low fecundity rates are caused by anatomical changes in combination with behavioral changes in the sexual activity of women with chronic pain as well as local proinflammatory factors that not only decrease implantation rates but also promote early abortions.

Functional changes of immune cells: signal of immune tolerance of the ectopic lesions in endometriosis?

RESEARCH QUESTION: What is the potential role of immune cells and their inflammatory cytokines in the pathogenesis, development and establishment of endometriosis? DESIGN: Peritoneal fluid from 59 women (43 with endometriosis and 16 controls) who had undergone laparoscopic surgery was analysed. Changes in the population of innate and adaptive immune cells, cytokines, chemokines and growth factor expression were measured by flow cytometry, Luminex Technology and enzyme-linked immunosorbent assay. RESULTS: No differences were found in the frequencies of the innate and adaptive immune cells between women with and without endometriosis. In the peritoneal fluid of women with endometriosis, IL-1ß, IL-1RN, IL-2, IL-4, IL-8, IL-10, IL-12 (p70), IL-17α, FGF2, G-CSF, MCP-1, MIP-1α and TNF-α were significantly increased compared with controls. A correlation between IL-2, MCP-1, MIP-1α, TNF-α and the severity of endometriosis was observed. The concentration of neopterin, a possible biomarker for this disease, was increased in women with endometriosis compared with controls. CONCLUSIONS: The functional activity of immune cells seemed to be reduced despite their numbers remaining unchanged. The data indicate that a shift of TH cytokine profile occurs, which increases the TH1-TH2 ratio. This is driven by the increased levels of the cytokines (TNF-α and IL-2) in women with severe endometriosis.

[Management of endometriosis pain : Stage-based treatment strategies and clinical experience]. / Endometrioseschmerz beherrschen : Stufenschema und klinische Erfahrungen.

BACKGROUND: Endometriosis is associated with various types of intense pain. In addition to nociceptive pain, there is also a nociplastic reaction with central sensitization. Atypical symptoms such as acyclic lower abdominal pain, radiating pain, non-specific bladder and intestinal complaints or even depression are frequent as are classic cyclical complaints such as severe dysmenorrhea, cyclical lower abdominal pain, dyspareunia, dysuria and dyschezia. In cases of a diverse range of symptoms, patients often consult not just gynecologists but specialists from other disciplines (e.g., internal medicine, gastroenterology, orthopedics, pain therapy, psychology). AIMS: Overview about the pathophysiology and complexity of the disease and the resulting treatment options. A multimodal interdisciplinary concept might be able to take into consideration all aspects of the complex disease. METHODS: Interdisciplinary concepts should be involved in the treatment of endometriosis patients along with hormonal and surgical therapy, which are generally under the supervision of a gynecologist. Pain management, dietary changes, psychological support, as well as physiotherapy should be included. The present article is intended to provide an overview of possible treatment strategies for chronic, symptomatic endometriosis. CONCLUSION: The use of multimodal treatment strategies regarding the complex pathophysiological aspects of this disease might be helpful in significantly improving the quality of life of endometriosis patients.

Deep Infiltrating Endometriosis and Adenomyosis: Implications on Pregnancy and Outcome.

Endometriosis (EM), especially deep infiltrating endometriosis (DIE) and adenomyosis (AM), are known to cause pain and sterility in young women. More recently, they have also been described as risk factors for obstetric complications. While the pathophysiology is not yet completely understood, they seem to share a common origin: archimetrosis. Methods: A systematic literature review was conducted to summarize the existing evidence on DIE and AM as risk factors for obstetric complications. Results: Preterm birth, caesarean section delivery (CS) and placental abnormalities are associated with the diagnosis of DIE and AM. Women with AM seem to experience more often hypertensive pregnancy disorders, premature rupture of membranes and their children are born with lower birth weights than in the control groups. However, many of the studies tried to evaluate AM, EM and DIE as separate risk factors. Moreover, often they did not adjust for important confounders such as multiple pregnancies, parity, mode of conception and maternal age. Therefore, prospective studies with larger numbers of cases and appropriate adjustment for confounders are needed to explore the pathophysiology and to prove causality.

Post-operative management and follow-up of surgical treatment in the case of rectovaginal and retrocervical endometriosis.

INTRODUCTION: Deep infiltrating endometriosis (DIE) affects between 3.8% and 37% of all endometriosis patients, mostly affecting rectovaginal septum or retrocervical space and characterized by the severe endometriosis-related complaints. Nowadays, generally managed with surgery. However, this is associated with a risk of postoperative complications. To better evaluate intra- and postoperative complications and outcomes for rectovaginal (RVE) and retrocervical endometriosis (RCE), the preoperative management should be accurately described and compared. METHODOLOGY: This is a cohort retrospective study performed at the Endometriosis Centre of Charité-University Clinic, Berlin. 34 patients were investigated in their reproductive age, n = 19 with RVE and n = 15 RCE, operated between 2011 and 2015. The surgical approach was divergent in both groups. Single laparoscopy was performed in RCE patients (RCEP) and vaginal assisted laparoscopy in RVE patients (RVEP). Long-term postoperative outcome included complications, fertility rate and recurrence rate. RESULTS: The median follow-up time was three years (y). Symptom-free status was revealed in n = 12 RVEP and n = 9 RCEP. Postoperatively, endometriosis-related complaints were presented in n = 7 RVEP and n = 6 RCEP, but with significant pain relief. From n = 8 RVE patients seeking fertility, pregnancy occurred in n = 7 and from n = 9 RCEP pregnancy appeared in n = 5 patients in the meantime of 6 months. Postoperative complications were reported in n = 1 RVEP with early postoperative bleeding, after ureter leakage and n = 1 RCEP with postoperative anastomotic insufficiency. The postoperative recurrence rate was equivalent to zero. CONCLUSION: The appropriate surgical approach for each group, preserving anatomy and functionality of the organs, seems to be very essential and efficient.

Possible Role of the Posterior Compartment Peritonectomy, as a Part of the Complex Surgery, Regarding Recurrence Rate, Improvement of Symptoms and Fertility Rate in Patients with Endometriosis, Long-Term Follow-Up.

STUDY OBJECTIVE: Beside the pain, there are 2 further problems in the management of endometriosis: the high recurrence rate (10% per year) and the high rate of impaired fertility. The objective of this study was to investigate the pathogenesis of these 2 factors. DESIGN: This is a retrospective cohort study, and the aim is to evaluate the complete excision of endometriotic lesions, including the posterior compartment of the peritoneum, with regard to postoperative outcome, focusing on relieving pain, increasing fertility rate, and decreasing recurrence rate. SETTING: Charité-University Clinic, Department of Gynaecology, Endometriosis research Centre. PATIENTS: Fifty-four patients were enrolled in this study, with severe deep infiltrating endometriosis (scored by ENZIAN) and superficial endometriosis, as well as endometriomas (revised American Society for Reproductive Medicine [rASRM] I = 3; II = 15; III = 10; and IV = 26). INTERVENTIONS: Posterior compartment peritonectomy (visible endometriotic lesions and inflamed altered peritoneum) was performed in all patients as part of a complex surgery: complete excision of endometriosis. MEASUREMENTS AND MAIN RESULTS: Postoperative outcomes were evaluated, based on the postoperative follow-up (up to 5 years) of 54 investigated patients. In 36 women (66%) preoperative complaints were eliminated. Furthermore, of 28 women seeking improved fertility, pregnancy was reported in 13 cases (46%). In 7 (54%) cases pregnancy occurred spontaneously, and in the remainder with assisted fertilization. In addition, long-term follow-up demonstrated a recurrence rate in 1.8% of patients. CONCLUSION: Overall, the number of complaints was significantly reduced. Only in the case of reproductive-aged women with ongoing postoperative complaints was it important to preserve the uterus. Although this pilot study on systematic posterior peritonectomy showed improvement in recurrence and fertility rate, the main question remains: will this surgical technique achieve better results and outcomes in the future? This has to be addressed in a prospective randomized study.

Arrangement of myofibroblastic and smooth muscle-like cells in superficial peritoneal endometriosis and a possible role of transforming growth factor beta 1 (TGFß1) in myofibroblastic metaplasia.

PURPOSE: Superficial peritoneal endometriotic (pEM) lesions are composed of endometrial glands and stroma, in addition to a third component-myofibroblasts and smooth muscles (SM)-like cells. The latter develops secondary to a metaplasia. In this study, we characterised the third component cells in pEM according to differentiation markers in different micro-compartments. Furthermore, a possible effect of TGFß1 on myofibroblastic metaplasia in endometriotic epithelial cells was studied. METHODS: Seventy-six premenopausal patients were included. Peritoneal biopsies were excised from EM patients (n = 23), unaffected peritoneum (peritoneum from EM patients but without EM components, n = 5/23) and non-EM patients (n = 10). All peritoneal biopsies were immunolabeled for ASMA, calponin, collagen I, desmin, TGFß receptor 1 (R1), R2 and R3 in addition to ultrastructure examination by transmission electron microscopy (TEM) (n = 1). TGFß1 level was measured in peritoneal fluid (PF) (EM, n = 19 and non-EM, n = 13) collected during laparoscopy. Furthermore, TGFß1 effect on myofibroblastic metaplasia was studied in vitro. RESULTS: At the centre of pEM lesions, calponin immunolabeling outweighs the collagen I while in the periphery the reverse occurs. SM-like cells expressing desmin predominate at the periphery, while ASMA immunolabeling was detectable in all micro-compartments. Both indicate an abundance of myofibroblasts at the centre of pEM lesions and SM-like cells in the periphery. Although activated TGFß1 in PF did not differ between EM and non-EM, it inhibited the cell proliferation of the endometriotic epithelial cells and induced an upregulation in ASMA and collagen IA2 expression as well. CONCLUSION: The abundance of the myofibroblasts and SM-like cells points to a myofibroblastic metaplasia in pEM. Both cells are differentially arranged in the different micro-compartments of pEM lesions, with increasing cell maturity towards the periphery of the lesion. Furthermore, TGFß1 may play a role in the myofibroblastic metaplasia of the endometriotic epithelial cells. These findings provide a better insight in the micro-milieu in EM lesions, where most of the disease dynamics occur.

Laparoscopic Neuronavigation for Deep Lateral Pelvic Endometriosis: Clinical and Surgical Implications.

STUDY OBJECTIVE: To evaluate the clinical presentation and surgical outcome in patients with deep lateral pelvic endometriosis (dLPE). DESIGN: A retrospective multicentric study (Canadian Task Force classification II-2). SETTING: University tertiary referral centers. PATIENTS: One hundred forty-eight women with deep infiltrating endometriosis (DIE). INTERVENTIONS: Laparoscopic excision of DIE. Disease distribution was classified as follows: central pelvic endometriosis (CPE) when DIE involved 1 of the following anatomic sites: cervix, vagina, uterosacral ligaments, rectum, bladder, or pelvic peritoneum; superficial lateral pelvic endometriosis when parametria, ureters, or hypogastric plexus were involved; and dLPE in the presence of sacral plexus and/or sciatic nerve infiltration. MEASUREMENTS AND MAIN RESULTS: All patients showed CPE. LPE was detected in 116 cases (78.4%); among these, we observed dLPE in 41 patients (35.3%). dLPE occurred in 40% of women with CPE and in 72.7% of patients with hypogastric plexus involvement. Thirty women with dLPE (73.2%) received gastrointestinal or urologic resection in addition to gynecologic procedures compared with 40 patients (57.1%) without dLPE (p = .001). No differences were observed in terms of perioperative complications according to the presence of dLPE. According to univariate/multivariate analysis, chronic pelvic pain was the only predictor of dLPE (odds ratio = 3.041, p = .003). The median preoperative visual analog scale for dysmenorrhea (median = 8, range, 0-10) and dyspareunia (median = 5; range, 0-10) dropped to 0 after surgery. The median follow-up was 36 months (range, 6-66 months) with a recurrence rate of 8.8%. CONCLUSIONS: dLPE is not a rare event in women with DIE. Complete laparoscopic removal of endometriosis seems to ensure benefit in terms of recurrence rate without increased surgical morbidities.

Pain Mechanisms in Peritoneal Diseases Might Be Partially Regulated by Estrogen.

To identify factors influencing the differential pain pathogenesis in peritoneal endometriosis (pEM) and peritoneal carcinomatosis in ovarian cancer (pOC), we undertook an experimental study. Tissue samples of 18 patients with pEM, 15 patients with pOC, and 15 unaffected peritoneums as controls were collected during laparoscopy or laparotomy. Immunohistochemical stainings were conducted to identify nerve fibers and neurotrophins in the tissue samples. Additionally, 23 pEM fluids, 25 pOC ascites fluids, and 20 peritoneal fluids of patients with myoma uteri as controls were collected. In these fluids, the expression of neurotrophins was evaluated. The effects of peritoneal fluids and ascites on the neurite outgrowth of chicken sensory ganglia were estimated by using a neuronal growth assay. An electrochemiluminescence immunoassay was carried out to determine the expression of estrogen in the peritoneal fluids and ascites. The total and sensory nerve fiber density was significantly higher in pEM than in pOC ( P < .001 and P < .01). All neurotrophins tested were present in tissue and fluid samples of pEM and pOC. Furthermore, the neurotrophic properties of pEM and pOC fluids were demonstrated, leading to sensory nerve fiber outgrowth. Estrogen concentration in the peritoneal fluids of pEM was significantly higher compared to ascites of pOC ( P < .001). The total and sensory nerve fiber density in the tissue samples as well as the estrogen expression in the peritoneal fluid of pEM was considerably higher than that in pOC, representing the most notable difference found in both diseases. This might explain the differential pain perception in pEM and pOC. Therefore, estrogen might be a key factor in influencing the genesis of pain in endometriosis.

Myofibroblasts Are Evidence of Chronic Tissue Microtrauma at the Endometrial-Myometrial Junctional Zone in Uteri With Adenomyosis.

BACKGROUND: Adenomyosis (AM) uteri exhibit hyperperistalsis. The latter causes a chronic tissue trauma at the endometrial-myometrial junctional zone (EMJZ). Upon tissue trauma, microdehiscences in the myometrium facilitate the translocation of basal endometrial fragments into the myometrium. There, a metaplasia (mediated by transforming growth factor ß1 [TGFß1] and connective tissue growth factor [CTGF]) occurs and AM lesions develop. The abundance of myofibroblasts in a tissue hallmarks metaplasia and points to a tissue microtrauma. MATERIALS AND METHODS: To study if myofibroblasts-as an evidence of tissue microtrauma-are more abundant at EMJZ in AM-uteri, a case-control experimental study was carried out at Charité University Hospital-Endometriosis Research Centre. In all, 18 uteri with AM and 14 uteri without AM were obtained during laparoscopy-assisted vaginal hysterectomy. The immunolabeling of myofibroblastic metaplasia (alpha smooth muscle actin [ASMA] and collagen I), differentiated smooth muscle marker (desmin) and metaplasia mediators (TGF-ß receptors 1, 2, 3 and CTGF) was investigated. The ultrastructure of myofibroblasts at EMJZ of AM uterus was characterized by transmission electron microscopy, in addition to an in vitro study to characterize myofibroblasts in the endometrium of non-AM uterus. RESULTS: Immunolabeling of ASMA and collagen I was significantly higher at EMJZ of AM uteri versus non-AM uteri. Furthermore, myofibroblasts were ultrastructurally characterized at EMJZ of AM. Endometrium of non-AM uterus exhibited 5% to 8% of its cells, expressing ASMA and collagen I. No difference was noted regarding metaplasia mediators immunolabeling between both the groups. CONCLUSION: The abundant and persistent myofibroblasts (expressing ASMA/collagen I) at EMJZ in AM uteri are ultra-/microscopic evidence of chronic tissue trauma. They are of nonmyometrial origin, as they lack desmin immunolabeling.

Abdominal Wall Endometriosis: Myofibroblasts as a Possible Evidence of Metaplasia: A Case Report.

In this study, we report about a patient with extra-uterine endometriosis (EM) in the abdominal wall muscle with evident metaplasia based on the abundant alpha smooth muscle actin (ASMA)-expressing myofibroblasts. Laparotomy excision of the abdominal wall EM was done following ultrasonographic evidence of a hypodense swelling in the right rectus abdominis, which was confirmed by MRI. Immunohistochemistry staining for ASMA and collagen I was done, with the results confirming that endometriotic stromal cells expressed both. Anterior abdominal wall endometriosis was suspected because of the patient's history of recurrent EM combined with the cyclic nature of symptoms. MRI is useful in determining the extent of the disease. In case of persisting symptoms even under hormonal treatment, surgical excision is mandatory. The expression of both ASMA and collagen I in and around EM lesions supports the notion of the metaplastic process in the course of disease development.

Reduced Sympathetic Innervation in Endometriosis is Associated to Semaphorin 3C and 3F Expression.

Endometriosis is a chronic inflammatory disease and one of the most common causes of pelvic pain. The mechanisms underlying pain emergence or chronic inflammation during endometriosis remain unknown. Several chronic inflammatory diseases including endometriosis show reduced amounts of noradrenergic nerve fibers. The source of the affected innervation is still unclear. Semaphorins represent potential elicitors, due to their known role as axonal guidance cues, and are suggested as nerve repellent factors in different chronic inflammatory diseases. Therefore, semaphorins might influence the progress of neuroinflammatory mechanisms during endometriosis. Here, we analyzed the noradrenergic innervation and the expression of the specific semaphorins and receptors possibly involved in the neuroimmunomodulation in endometriosis. Our studies revealed an affected innervation and a significant increase of semaphorins and their receptors in peritoneal endometriotic tissue. Thereby, the expression of the receptors was identified on the membrane of noradrenergic nerve fibers and vessels. Macrophages and activated fibroblasts were found in higher density levels and additionally express semaphorins in peritoneal endometriotic tissue. Inflammation leads to an increased release of immune cells, which secrete a variety of inflammatory factors capable of affecting innervation. Therefore, our data suggests that the chronic inflammatory condition in endometriosis might contribute to the increase of semaphorins, which could possibly affect the innervation in peritoneal endometriosis.