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Endocannabinoids and their receptors modulate endometriosis pathogenesis and immune response. eLife Endometriosis (EM), characterized by the presence of endometrial-like tissue outside the uterus, is the leading cause of chronic pelvic pain and infertility in females of reproductive age. Despite its high prevalence, the molecular mechanisms underlying EM pathogenesis remain poorly understood. The endocannabinoid system (ECS) is known to influence several cardinal features of this complex disease including pain, vascularization, and overall lesion survival, but the exact mechanisms are not known. Utilizing CNR1 knockout (k/o), CNR2 k/o, and wild-type (WT) mouse models of EM, we reveal contributions of ECS and these receptors in disease initiation, progression, and immune modulation. Particularly, we identified EM-specific T cell dysfunction in the CNR2 k/o mouse model of EM. We also demonstrate the impact of decidualization-induced changes on ECS components, and the unique disease-associated transcriptional landscape of ECS components in EM. Imaging mass cytometry (IMC) analysis revealed distinct features of the microenvironment between CNR1, CNR2, and WT genotypes in the presence or absence of decidualization. This study, for the first time, provides an in-depth analysis of the involvement of the ECS in EM pathogenesis and lays the foundation for the development of novel therapeutic interventions to alleviate the burden of this debilitating condition. 10.7554/eLife.96523
Pelvic plexus block is more effective than periprostatic nerve block for pain control during office transrectal ultrasound guided prostate biopsy: a single center, prospective, randomized, double arm study. Cantiello Francesco,Cicione Antonio,Autorino Riccardo,Cosentino Carlo,Amato Francesco,Damiano Rocco The Journal of urology PURPOSE:We compared intrarectal local anesthesia plus pelvic plexus block vs intrarectal local anesthesia plus periprostatic nerve block during transrectal ultrasound guided prostate biopsy. MATERIALS AND METHODS:Patients were randomized 1:1 by a computer generated schedule into group 1-90 who received intrarectal local anesthesia (lidocaine 1.5%-nifedipine 0.3% cream) plus pelvic plexus block (2.5 ml lidocaine 1% plus naropine 0.75% injected on each side into the pelvic neurovascular plexus lateral to the seminal vesicle tip) and group 2-90 who received intrarectal local anesthesia plus periprostatic nerve block (2.5 ml of the same mixture injected on each side into the neurovascular bundles at the prostate-bladder-seminal vesicle angle) before transrectal ultrasound guided prostate biopsy. After the procedure patients were instructed to rate the level of pain/discomfort from 0 to 10 on the visual analog scale at certain time points, including during the introduction and presence of the probe in the rectum, during pelvic plexus block or periprostatic nerve block, during biopsy and 30 minutes after biopsy. RESULTS:The 2 groups were similar in age, serum prostate specific antigen and total prostate volume. There was no difference in pain perception during probe introduction and pelvic plexus or periprostatic nerve block. Pain during prostate biopsy was significantly lower in group 1 than in group 2 (p <0.001). The same trend was recorded for pain perception 30 minutes after biopsy (p = 0.001). There were no major complications. CONCLUSIONS:Pelvic plexus block under Doppler ultrasound guidance provides better analgesia than periprostatic nerve block during office based transrectal ultrasound guided prostate biopsy. 10.1016/j.juro.2012.04.003
Topical Lidocaine for Chronic Pain Treatment. Voute Marion,Morel Véronique,Pickering Gisèle Drug design, development and therapy Topical lidocaine is widely used in current practice for a variety of pain conditions. This literature review shows that its limited absorption and relative lack of systemic adverse events are an attractive analgesic option for a number of vulnerable patients. Topical lidocaine has been approved by health authorities for the treatment of post-herpetic neuralgia in a number of countries, and studies present some degree of evidence of its efficacy and safety in postsurgical pain, diabetic peripheral neuropathy, carpal tunnel syndrome, chronic lower back pain and osteoarthritis. Topical lidocaine may be a great alternative alone or in addition to systemic drugs and non-pharmacological approaches for an optimized pain management and in multimodal analgesia. 10.2147/DDDT.S328228
Disease modifying actions of interleukin-6 blockade in a rat model of bone cancer pain. Pain Metastasis of cancer to the skeleton represents a debilitating turning point in the lives of patients. Skeletal metastasis leads to moderate to severe ongoing pain along with bone remodeling that can result in fracture, events that dramatically diminish quality of life. Interleukin-6 (IL-6) levels are elevated in patients with metastatic breast cancer and are associated with a lower survival rate. We therefore determined the consequences of inhibition of IL-6 signaling using a novel small molecule antagonist, TB-2-081, on bone integrity, tumor progression, and pain in a rodent model of breast cancer. Rat MAT B III mammary adenocarcinoma cells were injected and sealed within the tibia of female Fischer rats. Growth of these cells within the rat tibia elicited increased IL-6 levels both within the bone exudate and in the plasma, produced ongoing pain and evoked hypersensitivity, and bone fracture that was observed by approximately day 12. Systemic TB-2-081 delivered by subcutaneous osmotic minipumps starting at tumor implantation prevented tumor-induced ongoing bone pain and evoked hypersensitivity without altering tumor growth. Remarkably, TB-2-081 infusion significantly reduced osteolytic and osteoblastic bone remodeling and time to fracture likely by decreasing osteoclastogenesis and associated increase in bone resorption. These findings indicate that blockade of IL-6 signaling may represent a viable, disease-modifying strategy to prevent tumor-induced bone remodeling allowing for stabilization of bone and decreased fractures as well as diminished ongoing pain that may improve quality of life of patients with skeletal metastases. Notably, anti-IL-6 antibodies are clinically available allowing for rapid testing of these possibilities in humans. 10.1097/j.pain.0000000000001139
Ultrasound-guided erector spinae nerve block for relief of endometriosis pain in the emergency department. The American journal of emergency medicine Endometriosis is a debilitating chronic condition often accompanied by severe pelvic pain and infertility issues. When outpatient medical management is not adequate, controlling pain can be challenging for providers in the acute setting. We report the case of a 23-year-old female with a past medical history of endometriosis who presented to a freestanding emergency department with a chief complaint of 10/10 pelvic pain on a numeric rating scale. She had tried non-steroidal inflammatory medications and heat with no success. The patient had medication intolerances to opioid analgesics and was given ketorolac intramuscularly with no relief of her pain. The emergency physician discussed and offered to perform an erector spinae plane nerve block (ESPB) for pain relief. Ultrasonography was utilized for visualization of landmarks with a curvilinear transducer; a 20-gauge Pajunk® Sonoplex needle was used to inject a total of 100 mg bupivacaine 0.25% without epinephrine along with dexamethasone 10 mg under the bilateral erector spinae fascial planes at the T9 level. Post-procedure, the patient had significant improvement in pain and rated it a 2/10. Utilizing nerve blocks for endometriosis and other chronic pelvic pain in the acute care setting can serve as an effective alternative to opioids. In patients with multiple medication intolerances and for providers navigating pain control in the setting of a nationwide opioid crisis, ESPB blocks can help alleviate acute pain or exacerbations of chronic pain. This case demonstrates the first known use of an ESPB to relieve endometriosis pain in the emergency department. 10.1016/j.ajem.2024.03.001
A Novel, Non-opioid Treatment for Chronic Pelvic Pain in Women with Previously Treated Endometriosis Utilizing Pelvic-Floor Musculature Trigger-Point Injections and Peripheral Nerve Hydrodissection. Plavnik Kathy,Tenaglia Amy,Hill Charity,Ahmed Tayyaba,Shrikhande Allyson PM & R : the journal of injury, function, and rehabilitation BACKGROUND:Endometriosis is the abnormal growth of uterine tissue outside the uterine cavity that can cause chronic pain, dysmenorrhea, and dyspareunia. Although the disease is common and nonmalignant in nature, the symptoms can severely impact function and quality of life. Treatment options for endometriosis are limited and not well understood despite a growing need. OBJECTIVE:To determine the effectiveness of pelvic-floor musculature trigger-point injections and peripheral nerve hydrodissection in treating endometriosis symptoms, associated pain, and pelvic functionality. DESIGN:Retrospective longitudinal study case series. SETTING:Private practice. PATIENTS:Sixteen female patients with biopsy-confirmed endometriosis. INTERVENTIONS:Ultrasound-guided pelvic-floor trigger-point injections and peripheral nerve hydrodissection performed once a week for 6 weeks. MAIN OUTCOME MEASUREMENTS:Pelvic pain intensity as measured pretreatment and posttreatment by the 0 to 10 Visual Analogue Scale (VAS) and the Functional Pelvic Pain Scale (FPPS). RESULTS:Pretreatment, the mean VAS score was 6.0 (standard deviation [SD] 2.7), and posttreatment the mean VAS score was 2.9 (SD 2.6); P < .05, 95% confidence interval (CI) 1.16 to 4.97. The mean total FPPS score before treatment was 14.4 (SD 5.2) and posttreatment it was 9.1 (SD 5.8); P < .05, 95% CI 1.34 to 9.28. Analysis of the subcategories within the FPPS indicated that the improvement was statistically significant in the categories of intercourse, sleeping, and working. In the category of intercourse, the mean change in score after treatment was 1.3 (P < .05, 95% CI 0.26-2.31). In the category of sleeping, the mean change in score after treatment was 1.2 (P < .05, 95% CI 0.32-1.99). In the category of working, the mean change in score after treatment was 0.9 (P < .05, 95% CI 0.18-1.53). CONCLUSIONS:Analysis suggests that the treatment was effective at relieving pain related to endometriosis; it also reflected promise in improving overall pelvic function, particularly in relation to intercourse, working, and sleeping. 10.1002/pmrj.12258
High density of small nerve fibres in the functional layer of the endometrium in women with endometriosis. Tokushige N,Markham R,Russell P,Fraser I S Human reproduction (Oxford, England) BACKGROUND:Endometriosis is a common gynaecological disease and is frequently associated with recurrent and serious pelvic pain such as dysmenorrhoea and dyspareunia, but the mechanisms by which these symptoms are generated are not well understood. METHODS:Histological sections of endometrial tissue were prepared from endometrial curettings and hysterectomies performed on women with endometriosis (n=25 and n=10, respectively) and without endometriosis (n=47 and n=35, respectively). These were stained immunohistochemically for the highly specific polyclonal rabbit anti-protein gene product 9.5 (PGP9.5) and monoclonal mouse anti-neurofilament protein (NF) to demonstrate both myelinated and unmyelinated nerve fibres. RESULTS:Small nerve fibres were identified throughout the basal and functional layers of the endometrium in all endometriosis patients, but were not seen in the functional layer of the endometrium in any of the women without endometriosis (P<0.001). NF-immunoreactive nerve fibres were present in the basal layer in all endometriosis patients but not in non-endometriosis patients, with one exception (P<0.001). CONCLUSIONS:Small nerve fibres detected in the functional layer in all women with endometriosis may have important implications for understanding the generation of pain in these patients. The presence of nerve fibres in an endometrial biopsy may be a novel surrogate marker of clinical endometriosis. 10.1093/humrep/dei368
Neurotrophins and Their Receptors, Novel Therapeutic Targets for Pelvic Pain in Endometriosis, Are Coordinately Regulated by IL-1β via the JNK Signaling Pathway. The American journal of pathology Pelvic pain in women with endometriosis is attributed to neuroinflammation and afferent nociceptor nerves in ectopic and eutopic endometrium. The hypothesis that uterine nociception is activated by IL-1β, a prominent cytokine in endometriosis, was tested herein. Immunofluorescence histochemistry confirmed the presence of neurons in human endometrial tissue. Expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and their receptors in endometrial tissue and cells was validated by immunohistochemistry and Western blotting. Isolated endometrial stromal cells (ESCs) were subjected to dose-response and time-course experiments with IL-1β and kinase inhibitors to characterize in vitro biomarkers. Neural biomarkers were co-localized in endometrial nerve fibers. NGF, BDNF, and their receptors tropomyosin receptor kinase (Trk) A, TrkB, and p75 neurotrophin receptor were all expressed in primary ESCs. IL-1β stimulated higher TrkA/B expression in ESCs derived from endometriosis cases (2.8- ± 0.2-fold) than cells from controls (1.5- ± 0.3-fold, t-test, P < 0.01), effects that were mediated via the c-Jun N-terminal kinase (JNK) pathway. BDNF concentrations trended higher in peritoneal fluid of endometriosis cases but were not statistically different from controls (P = 0.16). The results support the hypothesis that NGF and BDNF and their corresponding receptors orchestrate innervation of the endometrium, which is augmented by IL-1β. We postulate that JNK inhibitors, such as SP600125, have the potential to reduce neuroinflammation in women with endometriosis. 10.1016/j.ajpath.2023.04.007
Overexpression of nerve growth factor in peritoneal fluid from women with endometriosis may promote neurite outgrowth in endometriotic lesions. Barcena de Arellano Maria Luisa,Arnold Julia,Vercellino Filiberto,Chiantera Vito,Schneider Achim,Mechsner Sylvia Fertility and sterility 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. 10.1016/j.fertnstert.2010.10.023
Possible involvement of nerve growth factor in dysmenorrhea and dyspareunia associated with endometriosis. Kajitani Takashi,Maruyama Tetsuo,Asada Hironori,Uchida Hiroshi,Oda Hideyuki,Uchida Sayaka,Miyazaki Kaoru,Arase Toru,Ono Masanori,Yoshimura Yasunori Endocrine journal Nerve growth factor (NGF) has been recently proposed as one of the key factors responsible not only for promotion of nerve fiber growth but also for the onset and maintenance of pain in a variety of diseases. The aim of this study was to investigate the role of NGF in the pelvic pain associated with endometriosis. Tissue and peritoneal fluid samples were collected from 95 women with laparoscopically and histopathologically confirmed endometriosis and 59 control women without endometriosis. Expression levels of NGF mRNA and protein were examined using real-time RT-PCR and immunohistochemistry, respectively. Concentration of NGF in the peritoneal fluid (PF-NGF) was measured using ELISA. The degree of dyspareunia and dysmenorrhea was evaluated using a verbal rating scale. Real-time RT-PCR analysis revealed that NGF mRNA was significantly more abundant in the ovarian endometriomas and peritoneal endometriosis than in the normal control endometrium. Immunohistochemical analyses demonstrated that NGF was prominently expressed and preferentially localized to the glands of the ovarian endometriomas and peritoneal endometriosis, whereas it was only weakly detectable in the normal endometrium. Although PF-NGF was undetectable in some normal subjects and endometriosis patients, elevated PF-NGF in the peritoneal fluid was more frequently observed in endometriosis patients with severe pain than in those with less severe pain. Our results suggest that NGF produced locally in the peritoneal cavity may be involved in the generation of endometriosis-associated pelvic pain.
Effect of antiangiogenic treatment on peritoneal endometriosis-associated nerve fibers. Novella-Maestre Edurne,Herraiz Sonia,Vila-Vives José María,Carda Carmen,Ruiz-Sauri Amparo,Pellicer Antonio Fertility and sterility OBJECTIVE:To investigate the effect of antiangiogenic treatment on experimental endometriotic lesion nerve fibers. DESIGN:Heterologous mouse model of endometriosis. SETTING:University Institute IVI, University Hospital La Fe. ANIMAL(S):Ovariectomized nude mice (n = 16) receiving human endometrial fragments from oocyte donors (n = 4). INTERVENTION(S):Endometrium fragments stuck in the peritoneum of 5-week-old female nude mice treated with vehicle (n = 8) and antiangiogenic agent cabergoline (n = 8; Cb(2,) 0.05 mg/kg/day) for 14 days. MAIN OUTCOME MEASURE(S):Immunofluorescence analysis of von-Willebrand factor (vWF) and vascular smooth muscle cells (αSMA) for evaluating the number of immature blood vessels (IBV) and microvascular density (MVD); immunochemical analysis of protein-gene product 9.5 (PGP 9.5) to assess nerve fibers density (NFD), and blue toluidine staining to confirm presence of mast cells and macrophages in endometriotic lesions. RESULT(S):All the results were quantified by morphometric techniques. The IBV, NFD, and number of macrophages and mast cells were statistically significantly decreased in the Cb2-treated group when compared with controls. CONCLUSION(S):Antiangiogenic treatment statistically significantly diminishes new blood vessel formation after macrophage, mast cell, and nerve fiber reduction, providing a rationale to test antiangiogenic agents as a novel therapeutic approach to severe pelvic pain associated with human peritoneal endometriosis. 10.1016/j.fertnstert.2012.07.1103
Nerve fibers and endometriotic lesions: partners in crime in inflicting pains in women with endometriosis. Yan Dingmin,Liu Xishi,Guo Sun-Wei European journal of obstetrics, gynecology, and reproductive biology One of major objectives in treating endometriosis is to alleviate pain since dysmenorrhea and other types of pain top the list of complaints from women with endometriosis who seek medical attention. Indeed, endometriosis-associated pain (EAP) is the most debilitating of the disease that negatively impacts on the quality of life in affected women, contributing significantly to the burden of disease and adding to the substantial personal and societal costs. Unfortunately, the mechanisms underlying the EAP are still poorly understood. In the last two decades, one active research field in endometriosis is the investigation on the distribution and genesis of nerve fibers in eutopic and ectopic endometrium, and the attempt to use endometrial nerve fiber density for diagnostic purpose. Since EAP presumably starts with the terminal sensory nerves, in or around endometriotic lesions, that transduce noxious mediators to the central nervous system (CNS) which ultimately perceives pain, this field of research holds the promise to elucidate the molecular mechanisms underlying the EAP, thus opening new avenues for novel diagnostics and therapeutics. In this review, we shall first briefly provide some basic facts on nerve fibers, and then provide an overview of some major findings in this filed while also note some conflicting results and expose areas in need of further research. We point out that since recently accumulated evidence suggests that endometriotic lesions are wounds undergoing repeated tissue injury and repair, the relationship between endometriotic lesions and nerve fibers is not simply unidirectional, i.e. lesions promote hyperinnervations. Rather, it is bidirectional, i.e. endometriotic lesions and nerve fibers engage active cross-talks, resulting in the development of endometriosis and pain. That is, nerve fibers and endometriotic lesions are actually partners in crime in inflicting pains in women with endometriosis, aided and abetted possibly by other culprits, some yet to be identified. We provide a list of possible perpetrators likely to be involved in this crime. Finally, we discuss possible implications when viewing the relationship from this vista. 10.1016/j.ejogrb.2016.06.017
Nerve fibers and histopathology of endometriosis-harboring peritoneum. Tulandi T,Felemban A,Chen M F The Journal of the American Association of Gynecologic Laparoscopists STUDY OBJECTIVE:To evaluate the presence of nerve fibers and histopathology of normal peritoneum and endometriosis-harboring peritoneum. DESIGN:Prospective, nonrandomized study (Canadian Task Force classification II-1). SETTING:University hospital. MATERIALS:Peritoneal specimen from 40 women with laparoscopic findings of endometriosis (24 confirmed histopathologically, group H, 16 diagnosed by laparoscopy, group L) and from 9 women with no endometriosis (controls). INTERVENTION:Histopathologic examination of peritoneal specimens with nerve fibers identified by immunocytochemistry staining with an antibody to neurofilament. MEASUREMENTS AND MAIN RESULTS:No differences in mean nerve score were seen among the three groups. Degrees of lymphocytic infiltration and mesothelial hyperplasia were higher in group H than in the other two groups (p <0.01 and <0.05, respectively). The degree of lymphocytic infiltration was significantly higher in group L than in the control group (p <0.05). There were no differences in all measurements between women in group H who experienced chronic pelvic pain and those who did not. CONCLUSION:The presence of nerve fibers in peritoneum is not related to endometriosis. Endometriosis-harboring peritoneum contains more lymphocytic infiltration than normal peritoneum. (J Am Assoc Gynecol Laparosc 8(1):95-98, 2001)
Nerve Bundle Density and Expression of NGF and IL-1β Are Intra-Individually Heterogenous in Subtypes of Endometriosis. Biomolecules Endometriosis is a gynecological disorder associated with local inflammation and neuroproliferation. Increased nerve bundle density has been attributed to increased expression of nerve growth factor (NGF) and interleukin-1β (IL-1β). Immunohistochemical analysis was carried out on 12 patients presenting with all three anatomic subtypes of endometriosis (deep, superficial peritoneal, endometrioma) at surgery, with at least two surgically excised subtypes available for analysis. Immunolocalization for nerve bundle density around endometriosis using protein gene product 9.5 (PGP9.5), as well as NGF and IL-1β histoscores in endometriosis epithelium/stroma, was performed to evaluate differences in scores between lesions and anatomic subtypes per patient. Intra-individual heterogeneity in scores across lesions was assessed using the coefficient of variation (CV). The degree of score variability between subtypes was evaluated using the percentage difference between mean scores from one subtype to another subtype for each marker. PGP9.5 nerve bundle density was heterogenous across multiple subtypes of endometriosis, ranging from 50.0% to 173.2%, where most patients (8/12) showed CV ≥ 100%. The percentage difference in scores showed that PGP9.5 nerve bundle density and NGF and IL-1β expression were heterogenous between anatomic subtypes within the same patient. Based on these observations of intra-individual heterogeneity, we conclude that markers of neuroproliferation in endometriosis should be stratified by anatomic subtype in future studies of clinical correlation. 10.3390/biom14050583
Efficacy of niclosamide on the intra-abdominal inflammatory environment in endometriosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology Endometriosis, a common gynecological disease, causes chronic pelvic pain and infertility in women of reproductive age. Due to the limited efficacy of current therapies, a critical need exists to develop new treatments for endometriosis. Inflammatory dysfunction, instigated by abnormal macrophage (MΦ) function, contributes to disease development and progression. However, the fundamental role of the heterogeneous population of peritoneal MΦ and their potential druggable functions is uncertain. Here we report that GATA6-expressing large peritoneal MΦ (LPM) were increased in the peritoneal cavity following lesion induction. This was associated with increased cytokine and chemokine secretion in the peritoneal fluid (PF), as well as MΦ infiltration, vascularization and innervation in endometriosis-like lesions (ELL). Niclosamide, an FDA-approved anti-helminthic drug, was effective in reducing LPM number, but not small peritoneal MΦ (SPM), in the PF. Niclosamide also inhibits aberrant inflammation in the PF, ELL, pelvic organs (uterus and vagina) and dorsal root ganglion (DRG), as well as MΦ infiltration, vascularization and innervation in the ELL. PF from ELL mice stimulated DRG outgrowth in vitro, whereas the PF from niclosamide-treated ELL mice lacked the strong stimulatory nerve growth response. These results suggest LPM induce aberrant inflammation in endometriosis promoting lesion progression and establishment of the inflammatory environment that sensitizes peripheral nociceptors in the lesions and other pelvic organs, leading to increased hyperalgesia. Our findings provide the rationale for targeting LPM and their functions with niclosamide and its efficacy in endometriosis as a new non-hormonal therapy to reduce aberrant inflammation which may ultimately diminish associated pain. 10.1096/fj.202002541RRR
Influence of nerve growth factor in endometriosis-associated symptoms. Barcena de Arellano Maria L,Arnold Julia,Vercellino Giuseppe F,Chiantera Vito,Ebert Andreas D,Schneider Achim,Mechsner Sylvia Reproductive sciences (Thousand Oaks, Calif.) 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. 10.1177/1933719111410711
Role of interleukin-1β in nerve growth factor expression, neurogenesis and deep dyspareunia in endometriosis. Human reproduction (Oxford, England) STUDY QUESTION:Does interleukin-1β (IL-1β) play a role in promoting nerve growth factor expression, neurogenesis and deep dyspareunia in endometriosis? SUMMARY ANSWER:IL-1β directly stimulates nerve growth factor (NGF) expression in endometriosis and is associated with local neurogenesis around endometriosis and more severe deep dyspareunia. WHAT IS KNOWN ALREADY:Local nerve density around endometriosis (using the pan-neuronal marker PGP9.5) is associated with deep dyspareunia in endometriosis, mediated in part by NGF expression. STUDY DESIGN, SIZE, DURATION:This in vitro study included endometriotic tissue samples from 45 patients. PARTICIPANTS/MATERIALS, SETTING, METHODS:This study was conducted in a university hospital affiliated research institute and included 45 women with surgically excised deep uterosacral/rectovaginal endometriosis (DIE, n = 12), ovarian endometriomas (OMA, n = 14) or superficial peritoneal uterosacral/cul-de-sac endometriosis (SUP, n = 19). Immunolocalisation of IL-1β, IL-1 receptor type 1 (IL-1R1), NGF and PGP9.5 in endometriotic tissues was examined by immunohistochemistry (IHC), and the intensity of IHC staining in the endometriotic epithelium and stroma was semi-quantitatively evaluated using the Histoscore method (H-score). For each case, deep dyspareunia was pre-operatively rated by the patient on an 11-point numeric rating scale (0-10). In addition, primary endometriosis stromal cells were isolated and cultured from surgically excised endometriosis. These cells were treated with IL-1β alone or in combination of Anakinra (an inhibitor of IL-1R1), small inference RNA (siRNA) against IL-1R1, siRNA against c-FOS or NGF neutralising antibody. The mRNA and protein levels of target genes (NGF and c-FOS) were assessed by reverse-transcription qPCR and western blot/ELISA, respectively. Furthermore, immunofluorescent microscopy was used to examine the neurite growth of rat pheochromocytoma PC-12 cells, as an in vitro model of neurogenesis. MAIN RESULTS AND THE ROLE OF CHANCE:For IHC, IL-1β expression in the endometriosis epithelium was significantly associated with more severe deep dyspareunia (r = 0.37, P = 0.02), higher nerve fibre bundle density around endometriosis (r = 0.42, P = 0.01) and greater NGF expression by the endometriosis epithelium (r = 0.42, P = 0.01) and stroma (r = 0.45, P = 0.01). In primary endometriosis stromal cells, treatment with exogenous IL-1β significantly increased the mRNA and protein levels of NGF and c-FOS. Pre-treatment with Anakinra, siRNA against IL-1R1, or siRNA against c-FOS, each attenuated IL-1 β-induced increases of NGF expression. In addition, supernatants from IL-1β treated endometriosis stromal cells significantly stimulated PC-12 neurite growth compared to controls, and these effects could be attenuated by pre-treatment with NGF neutralising antibody or Anakinra. LARGE-SCALE DATA:N/A. LIMITATIONS, REASONS FOR CAUTION:We did not have data from cultures of endometriosis glandular epithelium, due to the known difficulties with primary cultures of this cell type. WIDER IMPLICATIONS OF THE FINDINGS:Our study revealed a mechanism for deep dyspareunia in endometriosis, whereby IL-1β stimulates NGF expression, promoting local neurogenesis around endometriosis, which in turn leads to tender pelvic anatomic sites and thus deep-hitting dyspareunia. There may also be potential for drug targeting of IL-1β and/or NGF in the management of endometriosis-associated pain. STUDY FUNDING/COMPETING INTEREST(S):This study was funded by grants from the Canadian Institutes of Health Research (MOP-142273 and PJT-156084). P.Y. is also supported by a Health Professional Investigator Award from the Michael Smith Foundation for Health Research. MB has financial affiliations with Abbvie and Allergan. Otherwise, there are no conflicts of interest to declare. 10.1093/humrep/deaa017
Diagnosis of endometrial nerve fibers in women with endometriosis. Aghaey Meibody Fatemeh,Mehdizadeh Kashi Abolfazl,Zare Mirzaie Ali,Ghajarie Bani Amam Marjan,Shariati Behbahani Afsane,Zolali Bita,Najafi Laily Archives of gynecology and obstetrics PURPOSE:Recent studies indicated that there is a high density of small nerve fibers in the functional layer of the endometrium in women with endometriosis and that it can be used as a marker to detect endometriosis. In this study, the efficacy assessment of small nerve fibers' density as a diagnostic marker was compared in patients with and without endometriosis. METHODS:In this study, women with history of pelvic pain and/or infertility who were candidates for laparoscopy or laparotomy in Rassoul hospital (2007-2009) were enrolled. Histological sections of endometrial tissue were prepared from endometrial biopsy from women with endometriosis (n = 12) (1) and without endometriosis (n = 15) (2). Protein gene product 9.5 and neurofilament were evaluated as marker from endometrial biopsies by immunohistochemical methods. RESULTS:There was no statistically significant difference between two groups according to age, body mass index. Nerve fibers were detected in all endometrial biopsies from all women with endometriosis but detected only in three women without endometriosis. The mean density of nerve fibers was 2.2 ± 4.7 mm(-2) in group without endometriosis and) 13.1 ± 3.3 (in group with endometriosis (p < 0.001). Women with endometriosis had significantly higher nerve fiber density in comparison with women without endometriosis. CONCLUSIONS:Our findings indicated that endometrial biopsy for detecting density of nerve fibers by usage of protein gene product 9.5, provided a reliable marker for diagnosis of endometriosis. 10.1007/s00404-010-1806-5
Estradiol is a critical mediator of macrophage-nerve cross talk in peritoneal endometriosis. Greaves Erin,Temp Julia,Esnal-Zufiurre Arantza,Mechsner Sylvia,Horne Andrew W,Saunders Philippa T K The American journal of pathology Endometriosis occurs in approximately 10% of women and is associated with persistent pelvic pain. It is defined by the presence of endometrial tissue (lesions) outside the uterus, most commonly on the peritoneum. Peripheral neuroinflammation, a process characterized by the infiltration of nerve fibers and macrophages into lesions, plays a pivotal role in endometriosis-associated pain. Our objective was to determine the role of estradiol (E2) in regulating the interaction between macrophages and nerves in peritoneal endometriosis. By using human tissues and a mouse model of endometriosis, we demonstrate that macrophages in lesions recovered from women and mice are immunopositive for estrogen receptor β, with up to 20% being estrogen receptor α positive. In mice, treatment with E2 increased the number of macrophages in lesions as well as concentrations of mRNAs encoded by Csf1, Nt3, and the tyrosine kinase neurotrophin receptor, TrkB. By using in vitro models, we determined that the treatment of rat dorsal root ganglia neurons with E2 increased mRNA concentrations of the chemokine C-C motif ligand 2 that stimulated migration of colony-stimulating factor 1-differentiated macrophages. Conversely, incubation of colony-stimulating factor 1 macrophages with E2 increased concentrations of brain-derived neurotrophic factor and neurotrophin 3, which stimulated neurite outgrowth from ganglia explants. In summary, we demonstrate a key role for E2 in stimulating macrophage-nerve interactions, providing novel evidence that endometriosis is an estrogen-dependent neuroinflammatory disorder. 10.1016/j.ajpath.2015.04.012
Endometriosis-associated nerve fibers and pain. Medina Melissa G,Lebovic Dan I Acta obstetricia et gynecologica Scandinavica The assessment and diagnosis of endometriosis remain elusive targets. Patient and medical-related factors add to delays in the detection and treatment. Recently, investigators have revealed specific nerve fibers present in endometriotic tissue, with existing parallels between density and pain severity. The aim of this review is to compile a comprehensive review of existing literature on endometriosis-related nerve fiber detection, and the effects of medical therapy on these neural fibers. We performed a systematic literature-based review using Medline and PubMed of nerve fibers detected in eutopic endometrium, endometriotic lesions, and the peritoneum. Various arrangements of significant medical terms and phrases consisting of endometriosis, pelvic pain, nerve fiber detection/density in endometriosis, and diagnoses methodology, including treatment and detection were applied in the search. Subsequent references used were cross-matched with existing sources to compile all additional similar reports. Similar nerve fibers were detected within lesions, endometrium, and myometrium, though at varying degrees of density. Hormonal therapy is widely used to treat endometriosis and was shown to be related to a reduction in fiber density. A direct result of specific nerve fiber detection within eutopic endometrial layers points to the use of a minimally invasive endometrial biopsy technique in reducing delay in diagnosis and subsequent possible preservation of fertility. 10.1080/00016340903176826
Evidence for asymmetric distribution of sciatic nerve endometriosis. Vercellini Paolo,Chapron Charles,Fedele Luigi,Frontino Giada,Zaina Barbara,Crosignani Pier Giorgio Obstetrics and gynecology OBJECTIVE:To investigate if a lateral asymmetry exists in the distribution of endometriotic lesions of the sciatic nerve. DATA SOURCES:All articles on sciatic nerve endometriosis identified by MEDLINE and EMBASE database searches were retrieved, and additional reports were collected by systematically reviewing all references. Monographs on endometriosis published in the last 15 years were consulted. METHODS OF STUDY SELECTION:We considered articles in which the presence of an endometriotic lesion of the sciatic nerve and the affected side were assessed. We also included reports lacking histological examination of sciatic nerve specimens but with a surgical diagnosis of pelvic endometriosis. Two authors abstracted data independently on standardized forms. The number of women and the side of the lesion were obtained from individual studies, and the combined frequency of left- and right-side sciatic nerve endometriosis in published reports was computed. TABULATION, INTEGRATION, AND RESULTS:Thirty-two reports including 63 subjects were selected. Endometriosis of the sciatic nerve was on the right side in 41 patients, on the left in 20, and bilateral in two. Considering only patients with unilateral sciatic nerve endometriosis, the observed proportion of right-side lesions (41 of 61 [67.2%]; 95% confidence interval 54.0%, 78.7%) significantly differed from the expected proportion of 50% (chi(2)(1) 7.23, P =.007). Among the 16 cases of histological demonstration of endometriosis infiltrating sciatic nerve roots or fibers, ten had it on the right side (62.5%) and six on the left. Twenty-six of the 38 subjects (68.4%) with surgical demonstration of pelvic endometriosis but without histopathologic evidence of direct sciatic nerve involvement were affected by right cyclic sciatica. CONCLUSION:The finding that two thirds of patients with sciatic nerve endometriosis had right-side lesions constitutes further evidence against the coelomic metaplasia theory. The interposition of the sigmoid colon between the regurgitated endometrial cells implanted on the left posterolateral pelvic peritoneum seems to protect the left lumbosacral plexus and sciatic nerve.
Surgical interruption of pelvic nerve pathways in dysmenorrhea: a systematic review of effectiveness. Latthe P M,Proctor M L,Farquhar C M,Johnson N,Khan K S Acta obstetricia et gynecologica Scandinavica OBJECTIVES:To assess the effectiveness of surgical interruption of pelvic nerve pathways in primary and secondary dysmenorrhea. Data sources. The Cochrane Menstrual Disorders and Subfertility Group Trials Register (9 June 2004), CENTRAL (The Cochrane Library, Issue 2, 2004), MEDLINE (1966 to Nov. 2003), EMBASE (1980 to Nov. 2003), CINAHL (1982 to Oct. 2003), MetaRegister of Controlled Trials, the citation lists of review articles and included trials, and contact with the corresponding author of each included trial. REVIEW METHODS:The inclusion criteria were randomized controlled trials of uterosacral nerve ablation or presacral neurectomy (both open and laparoscopic procedures) for the treatment of dysmenorrhea. The main outcome measures were pain relief and adverse effects. Two reviewers extracted data on characteristics of the study quality and the population, intervention, and outcome independently. RESULTS:Nine randomized controlled trials were included in the systematic review. There were two trials with open presacral neurectomy; all other trials used laparoscopic techniques. For the treatment of primary dysmenorrhea, laparoscopic uterosacral nerve ablation at 12 months was better when compared to a control or no treatment (OR 6.12; 95% CI 1.78-21.03). The comparison of laparoscopic uterosacral nerve ablation with presacral neurectomy for primary dysmenorrhea showed that at 12 months follow-up, presacral neurectomy was more effective (OR 0.10; 95% CI 0.03-0.32). In secondary dysmenorrhea, along with laparoscopic surgical treatment of endometriosis, the addition of laparoscopic uterosacral nerve ablation did not improve the pain relief (OR 0.77; 95% CI 0.43-1.39), while presacral neurectomy did (OR 3.14; 95% CI 1.59-6.21). Adverse events were more common for presacral neurectomy than procedures without presacral neurectomy (OR 14.6; 95% CI 5-42.5). CONCLUSION:The evidence for nerve interruption in the management of dysmenorrhea is limited. Methodologically sound and sufficiently powered randomized controlled trials are needed. 10.1080/00016340600753117
Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Fauconnier A,Chapron C Human reproduction update The relationship between chronic pelvic pain symptoms and endometriosis is unclear because painful symptoms are frequent in women without this pathology, and because asymptomatic forms of endometriosis exist. Our comprehensive review attempts to clarify the links between the characteristics of lesions and the semiology of chronic pelvic pain symptoms. Based on randomized trials against placebo, endometriosis appears to be responsible for chronic pelvic pain symptoms in more than half of confirmed cases. A causal association between severe dysmenorrhoea and endometriosis is very probable. This association is independent of the macroscopic type of the lesions or their anatomical locations and may be related to recurrent cyclic micro-bleeding in the implants. Endometriosis-related adhesions may also cause severe dysmenorrhoea. There are histological and physiopathological arguments for the responsibility of deeply infiltrating endometriosis (DIE) in severe chronic pelvic pain symptoms. DIE-related pain may be in relation with compression or infiltration of nerves in the sub-peritoneal pelvic space by the implants. The painful symptoms caused by DIE present particular characteristics, being specific to involvement of precise anatomical locations (severe deep dyspareunia, painful defecation) or organs (functional urinary tract signs, bowel signs). They can thus be described as location indicating pain. A precise semiological analysis of the chronic pelvic pain symptoms characteristics is useful for the diagnosis and therapeutic management of endometriosis in a context of pain. 10.1093/humupd/dmi029
Detection of nerve fibers in the eutopic endometrium of women with endometriosis, uterine fibroids and adenomyosis. Yadav Garima,Rao Meenakshi,Gothwal Meenakshi,Singh Pratibha,Kathuria Priyanka,Sharma Prem Prakash Obstetrics & gynecology science OBJECTIVE:The primary objective of this study was to establish the presence of nerve fibers in the eutopic endometrium of women with endometriosis and to determine whether these nerve fibers are exclusive to endometriosis or are also found in other pelvic pathologies associated with dysmenorrhea. METHODS:Endometrial tissue was obtained by aspiration (Pipelle), endometrial curettage, or following hysterectomy in women with endometriosis confirmed through histopathological examination, leiomyomas, and adenomyosis. The eutopic endometrium was subjected to immunohistochemical staining to detect PGP 9.5, which is a highly specific pan-neuronal marker. The nerve fiber density was correlated with the patient's pain score, as indicated by the Visual Analog Scale. A control group was formed by staining the endometrium of women presenting with dysmenorrhea but without the above-mentioned disorders. RESULTS:Nerve fibers were observed in sections of the endo-myometrium (in the deep endometrium) in 68% of patients with endometriosis who underwent hysterectomy or a deep endometrial biopsy. Nerve fibers were not observed in the aspirated endometrium of women with endometriosis. Only 13.7% of women with adenomyosis and 3.3% of women with fibroids had nerve fibers in their endometrium. Nerve fiber density was correlated with pain score in women with endometriosis. CONCLUSION:Nerve fibers were found in the functional layer of eutopic endometrium in women with endometriosis; hence, we concluded that the presence of nerve fibers in the eutopic endometrium could diagnose endometriosis with a fairly good specificity of 92.7%. However, the absence of nerve fibers does not always exclude the disease. 10.5468/ogs.21114
Managing the neuroinflammatory pain of endometriosis in light of chronic pelvic pain. Expert opinion on pharmacotherapy INTRODUCTION:Endometriosis affects 5% to 10% of reproductive age women and may be associated with severely painful and debilitating symptoms as well as infertility. Endometriosis involves hormonal fluctuations, angiogenesis, neurogenesis, vascular changes and neuroinflammatory processes. The neuroinflammatory component of endometriosis makes it a systemic disorder, similar to other chronic epithelial inflammatory conditions. AREAS COVERED:Inflammatory mediators, mast cells, macrophages, and glial cells play a role in endometriosis which can result in peripheral sensitization and central sensitization. There is overlap between chronic pelvic pain and endometriosis, but the two conditions are distinct. Effective treatment is based on a personalized approach using a variety of pharmacologic and other treatment options. EXPERT OPINION:Hormonal therapies are a first-line approach, but endometriosis is a challenging condition to manage. 'Add-back' hormonal therapy has been effective. Painful symptoms are likely caused by the interplay of multiple factors and there may be a neuropathic component. Analgesics and anticonvulsants may be appropriate. A holistic approach and multimodal treatments are likely to be most effective. In addition to pharmacologic treatment, there are surgical and alternative medicine options. Endometriosis may also have a psychological component. 10.1080/14656566.2024.2425727
Endometriosis: the role of neuroangiogenesis. Asante Albert,Taylor Robert N Annual review of physiology Endometriosis is a common cause of pelvic pain and infertility, affecting ∼10% of reproductive-age women. Annual costs for medical and surgical care in the United States exceed $20 billion. The disorder is characterized by implants of endometrial tissue outside the uterine cavity. Endometriotic lesions induce a state of chronic peritoneal inflammation, accompanied by elevated prostaglandin, cytokine, and growth factor concentrations. The current therapy is surgical ablation of ectopic implants and hormones that block the hypothalamic-pituitary-ovarian axis, but these approaches are expensive, carry perioperative risks, or have unpleasant side effects of hypoestrogenism. 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 endometriosis implants influence dorsal root neurons within the central nervous system, increasing pain perception in patients. We consider the mechanisms and therapeutic implications of neuroangiogenesis in these lesions and propose potential treatments for the control or elimination of endometriosis-associated pain. 10.1146/annurev-physiol-012110-142158
Neurogenic Inflammation in the Context of Endometriosis-What Do We Know? Velho Renata Voltolini,Taube Eliane,Sehouli Jalid,Mechsner Sylvia International journal of molecular sciences 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. 10.3390/ijms222313102
Endometriosis Resection Using Nerve Sparing Versus Non-nerve Sparing Surgical Techniques. Journal of obstetrics and gynaecology of India Introduction:Endometriosis is the condition in which there are ectopic endometrial tissues outside the uterine cavity. The use of nerve sparing technique has been well established in the field of oncology, leading to better quality of life following radical oncologic procedures without compromising on the long-term survival. The objective of this study is to compare the quality of life in terms of sexual function and urinary function in women undergoing nerve sparing surgeries for endometriosis and those undergoing non-nerve sparing surgeries. Material and Methods:Data of 51 patients operated for endometriosis at Galaxy Care Laparoscopic Institute, Pune, India between 1st January 2020 till 31st December 2020 were collected and analysed. We included patients in age group between 38 and 44 years in monogamous relationship, with moderate to severe endometriosis (Revised American Society of Reproductive Medicine r-ASRM score of 16 and above 5), being operated for hysterectomy along with ureterolysis and/or bowel resection (including shaving of rectal endometriosis, discoid resection, segmental resection), and excision of large ovarian endometriomas (> 3 cm size) with cul-de-sac obliteration. Results:The patients were evaluated for the following factors: age, parity, nature of surgery done, immediate intraoperative complications (bowel injury, bladder injury, ureteric injury), operative time in minutes, average blood loss, length of hospital stay, days to removal of foley's catheter and postoperative urinary and sexual function which were assessed on follow up visit and a 1-year follow up interview. We found that the urinary and sexual function in the group undergoing nerve sparing surgeries was significantly better than the patients undergoing non-nerve sparing surgeries. Conclusion:Laparoscopic nerve sparing approach for clearance of endometriosis has allowed better quality of life post surgery. Proper understanding and demonstration of pelvic neuroanatomy has made this approach feasible and achievable in carefully selected patients. 10.1007/s13224-023-01794-4
Hormonal treatment isolated versus hormonal treatment associated with electrotherapy for pelvic pain control in deep endometriosis: Randomized clinical trial. European journal of obstetrics, gynecology, and reproductive biology OBJECTIVE:The aim of the study was to evaluate the clinical effectiveness of complementary treatment using self-applied electrotherapy treatment for pain control over the standard hormonal treatment alone for deep infiltrative endometriosis (DIE). STUDY DESIGN:Multicentre randomized clinical trial. We included a hundred-one participants with DIE in electrotherapy (n = 53) (hormonal treatment + electrotherapy) or control group (n = 48) (only hormonal treatment) by 8 weeks of follow-up. The primary measurement was chronic pelvic pain (CPP) using a visual analogue scale (VAS) and deep dyspareunia. The secondary outcomes were the quality of life by endometriosis health profile (EHP-30) and sexual function by female sexual function index (FSFI). RESULTS:CPP relief was observed only in the electrotherapy group (pre:7.11 ± 2.40, post:4.55 ± 3.08, p < 0.001). In terms of deep dyspareunia, improvements were observed for both groups (electrotherapy pre:2.02 ± 0.54-1.36 ± 0.96, p < 0.001; control pre:1.95 ± 0.86-1.68 ± 0.82, p = 0.006). Considering the secondary outcomes, a higher total score post-treatment for the EHP-30 was noted in both groups. Regarding sexual function, there was a statistically significant improvement in the FSFI score for the electrotherapy group (p < 0.001), with an increase in the scores for lubrication and pain domains (p = 0.013 and p < 0.001). CONCLUSIONS:Electrotherapy treatment using transcutaneous electrical nerve stimulation proved to be a good complementary option for pain control, showing benefits in the reduction of CPP and deep dyspareunia and improving patient's quality of life and sexual function. 10.1016/j.ejogrb.2020.10.018
The pains of endometriosis. Berkley Karen J,Rapkin Andrea J,Papka Raymond E Science (New York, N.Y.) Endometriosis is a disease defined by the presence of endometrial tissue outside of the uterus. Severe pelvic pain is often associated with endometriosis, and this pain can be diminished with therapies that suppress estrogen production. Many women with endometriosis also suffer from other chronic pain conditions. Recent studies suggest that mechanisms underlying these pains and sensitivity to estrogen involve the growth into the ectopic endometrial tissue of a nerve supply, which could have a varied and widespread influence on the activity of neurons throughout the central nervous system. 10.1126/science.1111445
Unveil the pain of endometriosis: from the perspective of the nervous system. Expert reviews in molecular medicine Endometriosis is a chronic inflammatory disease with pelvic pain and uncharacteristic accompanying symptoms. Endometriosis-associated pain often persists despite treatment of the disease, thus it brings a deleterious impact on their personal lives as well as imposing a substantial economic burden on them. At present, mechanisms underlie endometriosis-associated pain including inflammatory reaction, injury, aberrant blood vessels and the morphological and functional anomaly of the peripheral and central nervous systems. The nerve endings are influenced by the physical and chemical factors surrounding the lesion, via afferent nerve to the posterior root of the spinal nerve, then to the specific cerebral cortex involved in nociception. However, our understanding of the aetiology and mechanism of this complex pain process caused by endometriosis remains incomplete. Identifying the pathogenesis of endometriosis is crucial to disease management, offering proper treatment, and helping patients to seek novel targets for the maintenance and contributors of chronic pain. The main aim of this review is to focus on every possible mechanism of pain related to endometriosis in both peripheral and central nervous systems, and to present related mechanisms of action from the interaction between peripheral lesions and nerves to the changes in transmission of pain, resulting in hyperalgesia and the corresponding alterations in cerebral cortex and brain metabolism. 10.1017/erm.2022.26
Pain in Endometriosis. Frontiers in cellular neuroscience Endometriosis is a chronic and debilitating condition affecting ∼10% of women. Endometriosis is characterized by infertility and chronic pelvic pain, yet treatment options remain limited. In many respects this is related to an underlying lack of knowledge of the etiology and mechanisms contributing to endometriosis-induced pain. Whilst many studies focus on retrograde menstruation, and the formation and development of lesions in the pathogenesis of endometriosis, the mechanisms underlying the associated pain remain poorly described. Here we review the recent clinical and experimental evidence of the mechanisms contributing to chronic pain in endometriosis. This includes the roles of inflammation, neurogenic inflammation, neuroangiogenesis, peripheral sensitization and central sensitization. As endometriosis patients are also known to have co-morbidities such as irritable bowel syndrome and overactive bladder syndrome, we highlight how common nerve pathways innervating the colon, bladder and female reproductive tract can contribute to co-morbidity via cross-organ sensitization. 10.3389/fncel.2020.590823
The importance of pelvic nerve fibers in endometriosis. Miller Emily J,Fraser Ian S Women's health (London, England) Several lines of recent evidence suggest that pelvic innervation is altered in endometriosis-affected women, and there is a strong presumption that nerve fibers demonstrated in eutopic endometrium (of women with endometriosis) and in endometriotic lesions play roles in the generation of chronic pelvic pain. The recent observation of sensory C, sensory A-delta, sympathetic and parasympathetic nerve fibers in the functional layer of endometrium of most women affected by endometriosis, but not demonstrated in most women who do not have endometriosis, was a surprise. Nerve fiber densities were also greatly increased in myometrium of women with endometriosis and in endometriotic lesions compared with normal peritoneum. Chronic pelvic pain is complex, and endometriosis is only one condition which contributes to this pain. The relationship between the presence of certain nerve fibers and the potential for local pain generation requires much future research. This paper reviews current knowledge concerning nerve fibers in endometrium, myometrium and endometriotic lesions, and discusses avenues of research that may improve our knowledge and lead to enriched understanding and management of endometriotic pain symptoms. 10.2217/whe.15.47
Endometriosis-Related Chronic Pelvic Pain. Biomedicines Endometriosis, which is the presence of endometrial stroma and glands outside the uterus, is one of the most frequently diagnosed gynecologic diseases in reproductive women. Patients with endometriosis suffer from various pain symptoms such as dysmenorrhea, dyspareunia, and chronic pelvic pain. The pathophysiology for chronic pain in patients with endometriosis has not been fully understood. Altered inflammatory responses have been shown to contribute to pain symptoms. Increased secretion of cytokines, angiogenic factors, and nerve growth factors has been suggested to increase pain. Also, altered distribution of nerve fibers may also contribute to chronic pain. Aside from local contributing factors, sensitization of the nervous system is also important in understanding persistent pain in endometriosis. Peripheral sensitization as well as central sensitization have been identified in patients with endometriosis. These sensitizations of the nervous system can also explain increased incidence of comorbidities related to pain such as irritable bowel disease, bladder pain syndrome, and vulvodynia in patients with endometriosis. In conclusion, there are various possible mechanisms behind pain in patients with endometriosis, and understanding these mechanisms can help clinicians understand the nature of the pain symptoms and decide on treatments for endometriosis-related pain symptoms. 10.3390/biomedicines11102868
[Sympathetic nerve block in the management of chronic pelvic and perineal pain]. Rigaud J,Delavierre D,Sibert L,Labat J-J Progres en urologie : journal de l'Association francaise d'urologie et de la Societe francaise d'urologie INTRODUCTION:The autonomic sympathetic nervous system conveys nociceptive messages from the viscera to the brain. The purpose of this article is to review the place of autonomic nerve blocks in the management of chronic pelvic and perineal pain. MATERIAL AND METHODS:A comprehensive review of the literature was performed by searching PubMed for articles on autonomic nerve blocks and related procedures in the management of chronic pelvic and perineal pain. RESULTS:Intervention on the sympathetic nervous system for the management of chronic pelvic and perineal pain has been proposed at main three levels: ganglion Impar, hypogastric plexus and L2 lumbar sympathetic blocks. Infiltration of the sympathetic nervous system with local anaesthetic constitutes a diagnostic test by providing pain relief for the duration of action of the local anaesthetic in two third of patients. Specific procedures have been performed such as alcohol nerve block, radiofrequency ablation, surgical section or botulinum toxin infiltration at these various sites to achieve more lasting results. CONCLUSION:A sympathetic nervous system test block plays a diagnostic role in the management of chronic pelvic and perineal pain by guiding more specific global pain management procedures. 10.1016/j.purol.2010.08.047
Laparoscopic nerve-sparing transperitoneal approach for endometriosis infiltrating the pelvic wall and somatic nerves: anatomical considerations and surgical technique. Ceccaroni Marcello,Clarizia Roberto,Alboni Carlo,Ruffo Giacomo,Bruni Francesco,Roviglione Giovanni,Scioscia Marco,Peters Inge,De Placido Giuseppe,Minelli Luca Surgical and radiologic anatomy : SRA PURPOSE:Endometriotic or fibrotic involvement of sacral plexus and pudendal and sciatic nerves may be quite frequently the endopelvic cause of ano-genital and pelvic pain. Feasibility of a laparoscopic transperitoneal approach to the somatic nerves of the pelvis was determined and showed by Possover et al. for diagnosis and treatment of ano-genital pain caused by pudendal and/or sacral nerve roots lesions and adopted at our institution. In this paper we report our experience and anatomo-surgical consideration regarding this technique. METHODS:Confidence with this technique was obtained after several laparoscopic and laparotomic dissections on fresh, embalmed and formalin-fixed female cadavers and is now routinely performed at our institution in all cases of extensive endometriosis of the pelvic wall, involving the somatic nerves. RESULTS:We describe two different laparoscopic transperitoneal approaches to the lateral pelvic wall in case of: (A) deep pelvic endometriosis with rectal and/or parametrial involvement extending to pelvic wall and somatic nerves; (B) isolated endometriosis of pelvic wall and somatic nerves. CONCLUSIONS:Laparoscopic transperitoneal retroperitoneal nerve-sparing approach to the pelvic wall proved to be a feasible and useful procedure even if limited to referred laparoscopic centers and anatomically experienced and skilled surgeons. 10.1007/s00276-010-0624-6
[Somatic nerve block in the management of chronic pelvic and perineal pain]. Rigaud J,Riant T,Delavierre D,Sibert L,Labat J-J Progres en urologie : journal de l'Association francaise d'urologie et de la Societe francaise d'urologie INTRODUCTION:Chronic pelvic and perineal pain can be related to a nerve lesion caused by direct or indirect trauma or by an entrapment syndrome, which must then be demonstrated by a test block. The purpose of this article is to review the techniques and modalities of somatic nerve block in the management of chronic pelvic and perineal pain. MATERIAL AND METHODS:A review of the literature was performed by searching PubMed for articles on somatic nerve infiltrations in the management of chronic pelvic and perineal pain. RESULTS:Nerves involved in pelvic and perineal pain are: thoracolumbar nerves (obturator, ilioinguinal, iliohypogastric and genitofemoral) and sacral nerves (pudendal and inferior cluneal branches of the posterior cutaneous nerve of the thigh). Infiltration has a dual objective: to confirm the diagnostic hypothesis by anaesthetic block and to try to relieve pain. Evaluation of the severity and site of the pain before and immediately after the test block is essential for interpretation of the block. The various infiltration techniques for each nerve are described together with their respective advantages, disadvantages and risk of complications. CONCLUSION:Somatic nerve blocks are an integral part of the management of chronic pelvic and perineal pain and are predominantly performed under CT guidance in order to be as selective as possible. Once the diagnosis and the level of the nerve lesion have been defined, more specific therapeutic procedures can then be proposed. 10.1016/j.purol.2010.08.053
Surgical interruption of pelvic nerve pathways for primary and secondary dysmenorrhoea. Wilson M L,Farquhar C M,Sinclair O J,Johnson N P The Cochrane database of systematic reviews BACKGROUND:Dysmenorrhoea is the occurrence of painful menstrual cramps of uterine origin and is a very common gynaecological complaint. Medical therapy for dysmenorrhoea includes oral contraceptive pills (OCP) and nonsteroidal anti-inflammatory drugs (NSAIDS) which both act by suppressing prostaglandin levels. While these treatments are very successful there is still a 20-25% failure rate and surgery has been an option for cases of dysmenorrhoea that fail to respond to medical therapy. Uterine nerve ablation (UNA) and presacral neurectomy (PSN) are two surgical treatments that have become increasingly utilised in recent years. These procedures both interrupt the majority of the cervical sensory nerve fibres, thus diminishing uterine pain. Uncontrolled studies have supported the use of these procedures for primary dysmenorrhoea however both operations only partially interrupt some of the cervical sensory nerve fibres in the pelvic area; therefore dysmenorrhoea associated with additional pelvic pathology may not always benefit from this type of surgery. OBJECTIVES:To assess the effectiveness of surgical interruption of pelvic nerve pathways as treatment for primary and secondary dysmenorrhoea, and to determine the most effective surgical treatment. SEARCH STRATEGY:Electronic searches of the Cochrane Menstrual Disorders and Subfertility Group Register of controlled trials, MEDLINE, and EMBASE were performed to identify relevant randomised controlled trials (RCTs). Attempts were also made to identify trials from citation lists of review articles and handsearching. In most cases, the first or corresponding author of each included trial was contacted for additional information. SELECTION CRITERIA:The inclusion criteria were randomised comparisons of surgical techniques of interruption of the pelvic nerve pathways (both open and laparoscopic procedures) for the treatment of primary and secondary dysmenorrhoea. The main outcome measures were pain relief and adverse effects. DATA COLLECTION AND ANALYSIS:Seven RCTs were identified that fulfilled the inclusion criteria for this review. One trial (Sutton 1994) was excluded because another treatment was given in combination with destruction of pelvic nerve pathways and the effects of these two treatments could not be separated. Of the remaining six trials, three were included in the meta-analysis (Chen 1996, Candiani 1992, Lichten 1987). The results of the other three trials (Dover 1999, Tjaden 1990, Vercellini 1997) were included in the text of the review for discussion because the data were not available in a form that allowed them to be combined in a meta-analysis. MAIN RESULTS:For the treatment of primary dysmenorrhoea there is some evidence of the effectiveness of uterine nerve ablation (UNA) when compared to a control of no treatment. The comparison between UNA with presacral neurectomy (PSN) for primary dysmenorrhoea showed no significant difference in pain relief in the short term, however long term PSN was shown to be significantly more effective. For the treatment of secondary dysmenorrhoea the identified RCTs addressed only endometriosis. The treatment of UNA combined with surgical treatment of endometrial implants versus surgical treatment of endometriosis alone showed that the addition of UNA did not aid pain relief. For PSN combined with endometriosis treatment versus endometriosis treatment alone there was also no overall difference in pain relief, although the data suggests a significant difference in relief of midline abdominal pain. Adverse events were significantly more common for presacral neurectomy, however the majority were complications such as constipation, which may spontaneously improve. REVIEWER'S CONCLUSIONS:There is insufficient evidence to recommend the use of nerve interruption in the management of dysmenorrhoea, regardless of cause. Future RCTs should be undertaken. 10.1002/14651858.CD001896
MRI Features of Pelvic Nerve Involvement in Endometriosis. Radiographics : a review publication of the Radiological Society of North America, Inc Endometriosis is a common condition that mostly affects people assigned as female at birth. The most common clinical symptom of endometriosis is pain. Although the mechanism for this pain is poorly understood, in some cases, the nerves are directly involved in endometriosis. Endometriosis is a multifocal disease, and the pelvis is the most common location involved. Nerves in the pelvis can become entrapped and involved in endometriosis. Pelvic nerves are visible at pelvic MRI, especially when imaging planes and sequences are tailored for neural evaluation. In particular, high-spatial-resolution anatomic imaging including three-dimensional isotropic imaging and contrast-enhanced three-dimensional short inversion time inversion-recovery (STIR) fast spin-echo sequences are useful for nerve imaging. The most commonly involved nerves are the sciatic, obturator, femoral, pudendal, and inferior hypogastric nerves and the inferior hypogastric and lumbosacral plexuses. Although it is thought to be rare, the true incidence of nerve involvement in endometriosis is not known. Symptoms of neural involvement include pain, weakness, numbness, incontinence, and paraplegia and may be constant or cyclic (catamenial). Early diagnosis of neural involvement in endometriosis is important to prevent irreversible nerve damage and chronic sensorimotor neuropathy. Evidence of irreversible damage can also be seen at MRI, and radiologists should evaluate pelvic nerves that are commonly involved in endometriosis in their search pattern and report template to ensure that this information is incorporated into treatment planning. 10.1148/rg.230106
The Role of Interventional Pain Management Strategies for Neuropathic Pelvic Pain in Endometriosis. Pain physician BACKGROUND:Endometriosis is a chronic common condition affecting 10% of reproductive-aged women globally. It is caused by the growth of endometrial-like tissue outside the uterine cavity and leads to chronic pelvic pain, affecting various aspects of a woman's physical, mental, emotional, and social well-being. This highlights the importance of an understanding of the potential involvement of the nervous system and involved nerves as well as an effective multidisciplinary pain management. OBJECTIVES:Our aim was to assess the current understanding of pain mechanisms in endometriosis and the effectiveness of different interventional pain management strategies. STUDY DESIGN:Literature review. METHODS:A search was conducted using multiple databases, including Google Scholar, MEDLINE (Ovid), PubMed, and Embase. We used keywords such as "endometriosis," "pain," pelvic pain, "management," and "anaesthesia" along with Boolean operators and MeSH terms. The search was limited to English language articles published in the last 15 years. RESULTS:Nerve involvement is a well-established mechanism for pain generation in patients with endometriosis, through direct invasion, irritation, neuroangiogenesis, peripheral and central sensitization, and scar tissue formation. Endometriosis may also affect nerve fibers in the pelvic region, causing chronic pelvic pain, including sciatic neuropathy and compression of other pelvic nerves. Endometriosis can cause sciatica, often misdiagnosed due to atypical symptoms. Interventional pain management techniques such as superior hypogastric plexus block, impar ganglion block, S3 pulsed radiofrequency, myofascial pain trigger point release, peripheral nerve hydrodissection, and neuromodulation have been used to manage persistent and intractable pain with positive patient outcomes and improved quality of life. LIMITATIONS:The complex and diverse clinical presentations of endometriosis make it challenging to compare the effectiveness of different pain management techniques. CONCLUSION:Endometriosis is a complex condition causing various forms of pain including nerve involvement, scar tissue formation, and bowel/bladder symptoms. Interventional pain management techniques are effective for managing endometriosis-related pain. KEY WORDS:Endometriosis, chronic pain, therapeutic interventions, interventional techniques, pain injections, visceral pain, peripheral pain.
Vulvodynia: a neuroinflammatory pain syndrome originating in pelvic visceral nerve plexuses due to mechanical factors. Archives of gynecology and obstetrics This short opinion aimed to present the evidence to support our hypothesis that vulvodynia is a neuroinflammatory pain syndrome originating in the pelvic visceral nerve plexuses caused by the failure of weakened uterosacral ligaments (USLs) to support the pelvic visceral nerve plexuses, i.e., T11-L2 sympathetic and S2-4 parasympathetic plexuses. These are supported by the USLs, 2 cm from their insertion to the cervix. They innervate the pelvic organs, glands, and muscles. If the USLs are weak or lax, gravitational force or even the muscles may distort and stimulate the unsupported plexuses. Inappropriate afferent signals could then be interpreted as originating from an end-organ site. Activation of sensory visceral nerves causes a neuro-inflammatory response in the affected tissues, leading to neuroproliferation of small peripheral sensory nerve fibers, which may cause hyperalgesia and allodynia in the territory of the damaged innervation. Repair of the primary abnormality of USL laxity, responsible for mechanical stimulation of the pelvic sensory plexus, may lead to resolution of the pain syndrome. 10.1007/s00404-022-06424-4
Is the detection of endometrial nerve fibers useful in the diagnosis of endometriosis? Leslie Connull,Ma Tony,McElhinney Bernadette,Leake Robyn,Stewart Colin J R International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists Laparoscopy is currently considered to be the gold standard investigation in patients suspected to have endometriosis, but this is an invasive and relatively costly procedure and there may be significant delays in diagnosis. As the eutopic endometrium is recognized to be abnormal in patients with endometriosis, it has been suggested that endometrial sampling could provide an indirect diagnostic approach. In particular, recent reports have suggested that the presence of nerve fibers within the endometrial functional layer could represent a specific and sensitive marker of concurrent peritoneal endometriosis. However, such studies have been performed in select patient groups and using novel sampling and analytic techniques that are not used routinely in clinical pathology laboratories. The present study was performed upon conventional endometrial biopsies from 68 patients who underwent laparoscopy for suspected endometriosis. The biopsies were stained immunohistochemically for the neural marker PGP 9.5 and examined in a blinded manner. Endometrial functional layer nerve fibers were identified in 15 (22%) biopsies overall including 9/47 (19%) cases with histologically confirmed peritoneal endometriosis and 6/21 (29% 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. In our experience, 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. Pathologists and gynecologists considering this diagnostic approach should carefully consider the methodological factors that may influence its reliability. 10.1097/PGP.0b013e31825b0585