Endometriosis Research Center Charite

Berlin, Germany

Endometriosis Research Center Charite

Berlin, Germany
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Chiantera V.,Endometriosis Research Center Charite | Chiantera V.,University of Palermo | Abesadze E.,Endometriosis Research Center Charite | Mechsner S.,Endometriosis Research Center Charite
Journal of Endometriosis and Pelvic Pain Disorders | Year: 2017

Pain is the most important symptom in patients with endometriosis, and its management is truly challenging. Due to the different localization of the endometriotic lesions in the pelvis, patients suffer from visceral and somatic pain or both at the same time. There are specific and unspecific symptoms characterized by endometriosis. Specific symptoms include dysmenorrhea, cyclic and acyclic pelvic pain, dyschezia, dysuria and dyspareunia. There is also a wide range of unspecific symptoms, such as unspecific bowel and bladder complaints, the emission of pain in the legs, vegetative concomitants like vomiting, emesis, gastric disorders, headaches, dizziness, painful ovulation, irregular pelvic pain, lower back pain, chronic fatigue. These symptoms can be both cyclic and acyclic, and in most cases, they are permanent. Visceral and somatic pain are completely different pain subtypes and can therefore be an explanation for the wide variety of symptoms. The close interaction between visceral sensory nerve fibers and the autonomic ganglia explain the high rate of concomitant vegetative reactions, such as vomiting and orthostatic dysregulation. In general, pain generation is a complex interplay of peripheral and central sensitization mechanisms. Accordingly, the pain produced in endometriotic lesions is the result of mediating substances, nerve fibers, cytokine-releasing immune cells and macrophages synthesis. These interactions seem to stimulate the neurogenic inflammatory process and sensitization of the peripheral nerves. Furthermore, the disruption of the input on the level of the spinal cord and the recognition of the pain in the brain may lead to exaggerated responses known as central hyperalgesia. Hormones and psychological factors influence the pain sensation and make the status of each patient very individual. Consequently, the involvement of professional pain management along with an implementation of pain-coping strategies in the patient’s everyday life are obligatory in chronic pain situations. An additional osteopathic treatment with a manual resolve of muscle blockades to avoid secondary “pain intensifying” changes of the pelvic floor (tension) or malposition through relieving posture, is also recommended. Pain management in patients with endometriosis is very complex and requires an individual treatment strategy for each patient to avoid unnecessary surgical procedures. This information proves that it is hard to break the cycle of pain when chronic pain syndrome is already apparent. © 2017 Wichtig Publishing.


Barcena De Arellano M.L.,Endometriosis Research Center Charite | Wagner M.F.,Endometriosis Research Center Charite | Oldeweme J.,Endometriosis Research Center Charite | Arnold J.,Endometriosis Research Center Charite | And 4 more authors.
Journal of Molecular Neuroscience | Year: 2012

To investigate the involvement of neurotrophins and nerve fibres in the pathogenesis of adenomyosis, we performed a retrospective, clinical study. Hysterectomy specimens from 40 patients with histologically proven adenomyosis and from 20 patients without adenomyosis or endometriosis were used for immunohistochemical analysis. In order to investigate neurotrophic properties in adenomyosis, the antibodies against nerve growth factor (NGF), neurotrophin 3 (NT-3), the high-affinity NGF receptor (TrkA), the low-affinity neurotrophin receptor (p75NTR), the neuronal marker S100 (for myelinated nerve fibres) and protein gene product 9.5 (PGP9.5; for intact nerve fibres) were used. There was no significant difference in the NGF, NT-3 and p75 NTRexpression in the myometrium or endometrium between the adenomyosis and the control group. The nerve fibre density (S100, PGP9.5 and p75NTR) did not significantly differ between the adenomyosis and control group, the nerve fibre density of the adenomyosis group was tendentially decreased when compared with the nonporous control group. The present study suggests that endometrial and uterine neurotrophin expression and endometrial innervation are not altered in adenomyosis; however, women with adenomyosis or with adenomyosis/endometriosis tendentially had less myometrial nerve fibres than the control group. © Springer Science+Business Media, LLC 2012.


Barcena De Arellano M.L.,Endometriosis Research Center Charite | Oldeweme J.,Endometriosis Research Center Charite | Oldeweme J.,Institute for Dental | Arnold J.,Endometriosis Research Center Charite | And 3 more authors.
Fertility and Sterility | Year: 2013

Objective: To investigate neuronal remodeling processes in the uterine innervation, particularly a remodeling of sympathetic nerve fibers, as well as the role of estrogen in this modulation in adenomyosis. Design: Retrospective case-control study. Setting: University hospital endometriosis center. Patient(s): Forty-two patients with histologically proven adenomyosis and 19 patients without adenomyosis. Intervention(s): Endometrial and myometrial tissue were immunohistochemically analyzed to further characterize the uterine innervation. Main Outcome Measure(s): Immunohistochemical analysis was used to identify PGP 9.5-, substance P-, and tyrosine hydroxylase-positive nerve fibers. The expression of the aromatase cytochrome P450 was evaluated in uterine tissue, and the expression of the estrogen receptor (ER) -α and ERβ in uterine nerve fibers was analyzed. Result(s): Adenomyotic lesions are not innervated. The density of sympathetic nerve fibers in the myometrium of women with adenomyosis is reduced when compared with the nonadenomyosis group. The aromatase expression in the myometrium of women with adenomyosis was increased when compared with the control group. The ERα/ERβ ratio is in trend shifted to the ERα side in the myometrial tyrosine hydroxylase-positive nerve fibers in adenomyosis compared to the controls. Conclusion(s): The disruption of the modulation of the uterine sympathetic innervation seems to be an important aspect in the pathogenesis of adenomyosis. Estrogen and its receptors seem to play a crucial role in the depletion of myometrial sympathetic nerve fibers. © 2013 by American Society for Reproductive Medicine.


Mechsner S.,Endometriosis Research Center Charite | Grum B.,Endometriosis Research Center Charite | Gericke C.,Charité - Medical University of Berlin | Loddenkemper C.,Institute of Pathology | And 2 more authors.
Fertility and Sterility | Year: 2010

Objective: To investigate the expression of oxytocin (OTR) and/or vasopressin (VP1αR) receptor in patients with and without adenomyosis uteri. Design: Retrospective nonrandomized study. Setting: University hospital endometriosis research center. Patient(s): Forty patients with histologically proven adenomyosis and 40 patients without adenomyosis who had undergone hysterectomy for dysmenorrhea, bleeding disorders, and fibroids. Intervention(s): Immunohistochemical examination of both OTR and VP1αR expression in endometrium, myometrium, and adenomyotic lesions, and identification of smooth muscle cells using antibodies against OTR, VP1αR, and smooth muscle actin (sm-actin). Main Outcome Measure(s): The immunoreactive score (IRS) was used for expression of OTR, VP1αR, and sm-actin. Result(s): Expression of OTR in epithelial cells of adenomyotic lesions and surrounding myometrial cells was detectable. VP1αR was expressed only in myometrial cells and blood vessels. Using a specific anti-sm-actin antibody, another spindle cell population was characterized to represent smooth muscle cells which are in direct contact with the adenomyotic stroma. Compared with the unaffected myometrium, the surrounding adenomyosis-associated myometrium overexpressed OTR and showed changes in morphology. In the uteri of patients with adenomyosis, the junctional zone was often seen to be quite fissured. Conclusion(s): In addition to the specific expression of VP1αR, OTR expression and morphologic changes in the myometrial architecture of uteri having adenomyosis support the hypothesis that dysperistalsis plays an essential role in the development of endometriosis and dysmenorrhea. In the near future, specific inhibition of this receptor might yield a promising treatment for therapy. Copyright © 2010 American Society for Reproductive Medicine, Published by Elsevier Inc.


Barcena De Arellano M.L.,Endometriosis Research Center Charite | Arnold J.,Endometriosis Research Center Charite | Vercellino G.F.,Endometriosis Research Center Charite | Chiantera V.,Endometriosis Research Center Charite | And 3 more authors.
Reproductive Sciences | Year: 2011

To investigate the role of the nerve growth factor (NGF) in the development of dysmenorrhea/pelvic pain in patients with endometriosis, we performed a prospective, clinical, blind study. Peritoneal fluids (PFs) were obtained from patients with histologically proven endometriosis. Patients with endometriosis were divided into 7 different groups depending on their preoperative pain score and symptomatology: patients with no pain, patients with minimal pain (dysmenorrhea, pelvic pain, or both), and patients with severe pain (dysmenorrhea, pelvic pain, or both) and were used for the neuronal growth assay with cultured chicken dorsal root ganglia (DRG) and for Western blot analyses. Dorsal root ganglia were stained with anti-calcitonin gene-related peptide (CGRP) and anti-growth-associated protein 43 (GAP 43). Peritoneal fluids from patients with endometriosis induce neurite outgrowth. There was no significant difference in the outgrowth between the 7 pain groups. Western blot analyses showed a moderate NGF expression in the PFs from patients with endometriosis, without significant differences in the 7 pain groups. The present study suggests that the neurotrophic properties of endometriotic tissues are endometriosis- and not pain-associated. © Society for Gynecologic Investigation 2011.


Barcena de Arellano M.L.,Endometriosis Research Center Charite | Arnold J.,Endometriosis Research Center Charite | Arnold J.,Free University of Berlin | Sacher F.,Bayer AG | And 7 more authors.
Journal of Neuroimmunology | Year: 2012

The role of neurotrophins in eutopic endometrium from endometriosis-patients was investigated in a prospective study using immunofluorescence-staining, Western blot and a neuronal growth assay. The nerve growth factor is expressed in primary endometrial cell culture from women with and without endometriosis. Western blot analysis of endometrial biopsies or uterine fluid from patients with and without endometriosis shows no difference in the neurotrophin expression. We could not find a difference between patients with and without endometriosis with regards to the neurite outgrowth of sensory ganglia when treated with conditioned cultured medium or uterine fluid. This result refutes the assumed neurotrophic properties of eutopic endometrium of patients with endometriosis. © 2012 Elsevier B.V.


Reichelt U.,University Hospital | Keichel S.,Endometriosis Research Center Charite | De Arellano M.L.B.,Endometriosis Research Center Charite | Chiantera V.,Endometriosis Research Center Charite | And 2 more authors.
Reproductive Sciences | Year: 2012

To investigate the occurrence of lymph vessels and lymphangiogenic growth factors in peritoneal lesions, we performed immunohistochemical staining of peritoneal lesions of 37 patients with antibodies against podoplanin (D2-40), lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), prospero homeobox protein 1 (Prox-1), vascular epithelial growth factor (VEGF)-C/VEGF-D. Overall, 10 lesions were double stained against D2-40 and von Willebrand factor. The lymph vessel density in peritoneal lesion was significantly higher in comparison with healthy peritoneum. All lymph vessel makers could be detected, whereby the lymph vessel density of LYVE-1- and Prox-1-positive lymph vessels was significantly higher than the lymph vessel density of D2-40-positive lymph vessels. Endometriotic epithelial cells and stromal cells (SCs) showed a moderate-to-strong VEGF-C/VEGF-D expression. The VEGF-C-/VEGF-D-positive macrophages in endometriotic SCs could be observed. The lymphatic vasculature seems to form a further component of peritoneal lesions and could be involved in the inflammatory process. These data demonstrated a further step in the clarification of the pathogenesis of endometriosis. © The Author(s) 2012.


Barcena De Arellano M.L.,Endometriosis Research Center Charite | Arnold J.,Endometriosis Research Center Charite | Vercellino F.,Endometriosis Research Center Charite | Chiantera V.,Endometriosis Research Center Charite | And 2 more authors.
Fertility and Sterility | Year: 2011

To investigate the role of the nerve growth factor (NGF) in the endometriosis-associated innervation in the development of endometriosis- associated symptoms, 41 peritoneal fluid samples (PF) from patients with surgically and histologically proven endometriosis and 20 PF from patients with other gynecologic conditions were analyzed with Western blot and a novel in vitro model using dorsal root ganglia (DRG) to show neuronal outgrowth; endometrial cells also were analyzed. The results suggest that the PF of endometriosis patients and endometriotic lesions have neurotropic properties, because the Western blot analysis and the cell culture stainings showed NGF expression, and the neurite outgrowth of DRG treated with PF of patients with endometriosis was significantly higher than when treated with PF of patients without endometriosis. Furthermore, blocking NGF with both anti-NGF and K252a leads to a significant decrease in neurite outgrowth. ©2011 by American Society for Reproductive Medicine.


Barcena de Arellano M.L.,Endometriosis Research Center Charite | Arnold J.,Endometriosis Research Center Charite | Arnold J.,Free University of Berlin | Lang H.,Endometriosis Research Center Charite | And 4 more authors.
Cytokine | Year: 2013

To investigate the neurotrophic properties of endometriosis, as well as the involvement of neurotrophic factors in the development of chronic pelvic pain in patients with endometriosis, we performed a prospective clinical study. The presence of neurotrophins was investigated in the peritoneal fluid (PF) of patients with peritoneal endometriotic lesions or adenomyosis, as well as from women with non-endometriotic adhesions and from women without endometriosis/adenomyosis/adhesions. The PF from patients with peritoneal endometriotic lesions was divided in three groups: asymptomatic endometriosis, minimal pain and severe pain. PF from patients with adenomyosis or with non-endometriotic adhesions and the control group were divided in patients without pain and with pain. Neurotrophin expression in PF was analyzed using Elisa and the neuronal growth assay with cultured chicken sensory ganglia (dorsal-root-ganglia, DRG) and sympathetic ganglia. PF from women with peritoneal endometriotic lesions overexpress nerve growth factor (NGF) and neurotrophin-3 (NT-3), but not brain derived neurotrophic factor (BDNF), whereas the PF of women with adenomyosis or adhesions seems to express normal amounts of these factors. Neurotrophin expression did not differ among the pain groups. Furthermore, the PF from patients with peritoneal endometriotic lesions induced a strong sensory and a marginal sympathetic neurite outgrowth, while the PF from women with adenomyosis and non-endometriotic adhesions induced an outgrowth similar to the control group. The induced neurite outgrowth could only be inhibited in DRG incubated with peritoneal endometriotic lesions. Interestingly, the outgrowth of sympathetic ganglia was inhibited in all studied groups.The present study suggests that only peritoneal endometriotic lesions lead to an increased release of NGF and NT-3 into the PF and that NGF modulates the nerve fiber growth in endometriosis. © 2013 Elsevier Ltd.


Mechsner S.,Endometriosis Research Center Charite | Weichbrodt M.,Endometriosis Research Center Charite | Riedlinger W.F.J.,Institute of Pathology | Kaufmann A.M.,Endometriosis Research Center Charite | And 2 more authors.
Fertility and Sterility | Year: 2010

Objective: To investigate the frequency of endometriotic lesions and disseminated endometriotic-like cells in a series of incidentally removed lymph nodes (LNs) in patients with endometriosis. Design: Retrospective study. Setting: University hospital endometriosis center. Patient(s): Premenopausal patients underwent surgery because of endometriosis-associated symptoms. Intervention(s): Retrospective analysis of 108 coincidentally resected LNs of 24 patients with endometriosis. To identify endometriotic cells, immunohistochemical analysis of estrogen and progestogen receptor (ER-PR), CD10, and cytokeratin was performed. Mean Outcome Measure(s): The occurrence of endometriotic lesions (ER-PR, CD10, and cytokeratin positive) and disseminated endometriotic-like ER-PR-positive cells in LNs. Result(s): Deep infiltrating endometriosis was diagnosed in 23 of the 24 patients with incidentally removed LNs. In 8 of 24 (33.3%) patients with incidentally removed LNs, typical endometriotic lesions were detected. Disseminated ER-PR-positive cells were found in 17 of 24 patients (70.8%). Lymph node involvement correlated directly with the deep infiltrating endometriosis lesional size. Conclusion(s): Estrogen receptor-progestogen receptor-positive endometriotic lesions and disseminated endometriotic-like cells frequently are detected in LNs of patients with deep infiltrating endometriosis and, therefore, might reflect "nonlocalized" disease. If clinical significance of such lesions were provided, adjuvant hormonal treatment could be considered as a possible additional mode of therapy. © 2010 American Society for Reproductive Medicine.

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