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Importance: Approximately 60% of women develop a uterine niche after a cesarean delivery (CD). A niche is associated with various gynecological symptoms including abnormal uterine bleeding, pain, and infertility, but there is little consensus in the literature on the distinction between the sonographic finding of a niche and the constellation of associated symptoms., Objective: To achieve consensus on defining the clinical condition that constitutes a symptomatic uterine niche and agree upon diagnostic criteria and uniform nomenclature for this condition., Design, Setting, and Participants: A consensus based modified electronic Delphi (eDelphi) study, with a predefined Rate of Agreement (RoA) of 70% or higher. Experts were selected according to their expertise with niche-related consultations, publications, and participation in expert groups and received online questionnaires between November 2021 and May 2022., Main Outcomes and Measures: Definition, nomenclature, symptoms, conditions to exclude, and diagnostic criteria of an illness caused by a symptomatic uterine niche., Results: In total, 31 of the 60 invited experts (51.7%) participated, of whom the majority worked in university-affiliated hospitals (28 of 31 [90.3%]), specialized in benign gynecology (20 of 31 [64.5%]), and worked in Europe (24 of 31 [77.4%]). Three rounds were required to achieve consensus on all items. All participants underlined the relevance of a new term for a condition caused by a symptomatic niche and its differentiation from a sonographic finding only. Experts agreed to name this condition cesarean scar disorder, defined as a uterine niche in combination with at least 1 primary or 2 secondary symptoms (RoA, 77.8%). Defined primary symptoms were postmenstrual spotting, pain during uterine bleeding, technical issues with catheter insertion during embryo transfer, and secondary unexplained infertility combined with intrauterine fluid. Secondary symptoms were dyspareunia, abnormal vaginal discharge, chronic pelvic pain, avoiding sexual intercourse, odor associated with abnormal blood loss, secondary unexplained infertility, secondary infertility despite assisted reproductive technology, negative self-image, and discomfort during participation in leisure activities. Consensus was also achieved on certain criteria that should be met and conditions that should be excluded before making the diagnosis., Conclusions and Relevance: In this modified Delphi study, a panel of 31 international niche experts reached consensus for the constellation of symptoms secondary to a uterine niche and named it cesarean scar disorder.

In Brief: Traditionally viewed as enigmatic and elusive, adenomyosis is a fairly common gynecological disease but is under-recognized and under-researched. This review summarizes the latest development on the pathogenesis and pathophysiology of adenomyosis, which have important implications for imaging diagnosis of the disease and for the development of non-hormonal therapeutics., Abstract: Traditionally considered as an enigmatic disease, adenomyosis is a uterine disease that affects many women of reproductive age and is a contributing factor for pelvic pain, heavy menstrual bleeding (HMB), and subfertility. In this review, the new development in the pathogenesis and pathophysiology of adenomyosis has been summarized, along with their clinical implications. After reviewing the progress in our understanding of the pathogenesis and describing the prevailing theories, in conjunction with their deficiencies, a new hypothesis, called endometrial-myometrial interface disruption (EMID), which is backed by extensive epidemiologic data and demonstrated by a mouse model, is reviewed, along with recent data implicating the role of Schwann cells in the EMI area in the genesis of adenomyosis. Additionally, the natural history of adenomyotic lesions is elaborated and underscores that, in essence, adenomyotic lesions are fundamentally wounds undergoing repeated tissue injury and repair (ReTIAR), which progress to fibrosis through epithelial-mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, and smooth muscle metaplasia. Increasing lesional fibrosis propagates into the neighboring EMI and endometrium. The increased endometrial fibrosis, with ensuing greater tissue stiffness, results in attenuated prostaglandin E2, hypoxia signaling and glycolysis, impairing endometrial repair and causing HMB. Compared with adenomyosis-associated HMB, the mechanisms underlying adenomyosis-associated pain are less understood but presumably involve increased uterine contractility, hyperinnervation, increased lesional production of pain mediators, and central sensitization. Viewed through the prism of ReTIAR, a new imaging technique can be used to diagnose adenomyosis more accurately and informatively and possibly help to choose the best treatment modality.

Background: Microbiota play essential roles in the pathogenesis of prostatitis and depression. However, the changes in prostate microbiota have not yet been explored in rats with prostatitis/depression. This study aimed to investigate the changes of prostate microbiota in rats with prostatitis/depression., Methods: Rats with experimental autoimmune prostatitis (EAP) complicated with depression were constructed through injection of rat prostate antigen with immunoadjuvants followed by application of chronic unpredictable mild stress (CUMS). The rats were subjected to inflammatory factor detection and behavioral testing to confirm the establishment of the model. Subsequently, the prostate microbiota was assayed in the rats and compared by 16S rRNA gene sequencing., Results: A rat model of EAP complicated with depression was established and confirmed by increases in IL-1β, IL-6, and TNF-α as well as the occurrence of depressive-like behaviors. EAP/CUMS significantly altered the richness, evenness, and composition of prostate microbiota. Forty-six taxonomic biomarkers for prostate microbiota were enriched in rats with EAP/depression and exhibited statistically significant and biologically consistent differences. Metabolomics profiling revealed that EAP/depression was associated with reductive acetyl coenzyme A pathway, L-lysine fermentation to acetate and butanoate, protein N-glycosylation and purine nucleobases degradation I, which is regulated by DCE29, Nocardioes, Helicobacter and Dorea ., Conclusion: Findings from the study demonstrate the existence of abnormal prostate microbiota in EAP complicated with depression and may be helpful in the treatment of comorbid diseases of prostatitis and depression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Xu, Wang and Wu.)

CD44 partcipates in multiple inflammatory reactions. Here, we aimed to investigate the role of CD44 and the ligand, hyaluronan (HA), on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) pathogenesis. We found that CD44 was universally expressed in CD4 + lymphocytes in the peripheral blood of CP/CPPS patients. After silencing CD44 expression or delivering 4-methylumbelliferone (4-MU), the pain severity and prostatic inflammation were significantly relieved. In vitro assay found that HA/CD44 was able to regulate T helper 1 (Th1) cells differentiation, the deficiency of which diminished experimental autoimmune prostatitis (EAP) susceptibility. Bioinformatic analysis suggested that after HA or 4-MU treatment, mTOR signaling was significantly altered, and these results were confirmed by subsequent Western blotting assay. Besides, mass spectrometry and co-immunoprecipitation assays found that CD44 was able to interact with Annexin A1 (ANX A1), and this kind of interaction stabilized ANX A1 protein and maintained the activation of Akt/mTOR pathway. Meanwhile, HA-treatment-enhanced prostatic inflammation, Th1 cell differentiation, and Akt/mTOR pathway activation were reversed after silencing the expression of ANX A1 using shANX A1-lentivirus. The present study systematically investigates the functional role of HA/CD44 in CP/CPPS and identifies novel mechanisms for HA/CD44 promoting Th1 cell differentiation. Targeting the HA/CD44/ANX A1/Akt/mTOR signaling represents novel potential therapeutic strategies for patients with CP/CPPS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Meng, Li, Li, Liu, Jin, Zhang, Hao, Chen, Zhang and Liang.)

Endometriosis is a gynaecological disease defined by the growth of endometrium-like tissue outside the uterus. The disease is present in approximately 5-10% of women of reproductive age and causes pelvic pain and infertility. The pathophysiology is not completely understood, but retrograde menstruation and deficiency in natural killer (NK) cells that clear endometriotic cells in the peritoneal cavity play an important role. Nowadays, hormonal therapy and surgery to remove endometriosis lesions are used as treatment. However, these therapies do not work for all patients, and hormonal therapy prevents patients from getting pregnant. Therefore, new treatment strategies should be developed. Since the cytotoxicity of NK cells is decreased in endometriosis, we performed a literature search into the possibility of NK cell therapy. Available treatment options include the inhibition of receptor-ligand interaction for KIR2DL1, NKG2A, LILRB1/2, and PD-1/PD-L1; inhibition of TGF-β; stimulation of NK cells with IL-2; and mycobacterial treatment with BCG. In preclinical work, these therapies show promising results but unfortunately have side effects, which have not specifically been studied in endometriosis patients. Before NK cell treatment can be used in the clinic, more research is needed.

We investigated the therapeutic effects of superoxide dismutase (SOD) from thermophilic bacterium HB27 on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and its underlying mechanisms. A Sprague-Dawley rat model of CP/CPPS was prepared and then administered saline or Thermus thermophilic (Tt)-SOD intragastrically for 4 weeks. Prostate inflammation and fibrosis were analyzed by hematoxylin and eosin staining, and Masson staining. Alanine transaminase (ALT), aspartate transaminase (AST), serum creatinine (CR), and blood urea nitrogen (BUN) levels were assayed for all animals. Enzyme-linked immunosorbent assays (ELISA) were performed to analyze serum cytokine concentrations and tissue levels of malondialdehyde, nitric oxide, SOD, catalase, and glutathione peroxidase. Reactive oxygen species levels were detected using dichlorofluorescein diacetate. The messenger ribonucleic acid (mRNA) expression of tissue cytokines was analyzed by reverse transcription polymerase chain reaction (RT-PCR), and infiltrating inflammatory cells were examined using immunohistochemistry. Nuclear factor-κB (NF-κB) P65, P38, and inhibitor of nuclear factor-κBα (I-κBα) protein levels were determined using western blot. Tt-SOD significantly improved histopathological changes in CP/CPPS, reduced inflammatory cell infiltration and fibrosis, increased pain threshold, and reduced the prostate index. Tt-SOD treatment showed no significant effect on ALT, AST, CR, or BUN levels. Furthermore, Tt-SOD reduced inflammatory cytokine expression in prostate tissue and increased antioxidant capacity. This anti-inflammatory activity correlated with decreases in the abundance of cluster of differentiation 3 (CD3), cluster of differentiation 45 (CD45), and macrophage inflammatory protein 1α (MIP1α) cells. Tt-SOD alleviated inflammation and oxidative stress by reducing NF-κB P65 and P38 protein levels and increasing I-κBα protein levels. These findings support Tt-SOD as a potential drug for CP/CPPS., Competing Interests: None

Interstitial cystitis (IC) is a chronic inflammatory disease characterized by bladder pain and increased urinary frequency. Although the C57BL/6J (B6) and FVB/NJ (FVB) mouse strains are commonly used as animal models for studies involving the urinary system, few reports have compared their lower urinary tract anatomy, despite the importance of such data. Our study aimed to characterize bladder function changes in FVB and B6 mouse strains with lipopolysaccharide (LPS)-induced IC, to understand mouse model-based bladder research. The bladder function parameters were measured by cystometrogram. Histological assay was examined by hematoxylin and eosin stain, Masson's trichrome stain, and immunofluorescence staining. Results indicated that the two strains in the control group exhibited different bladder structures and functions, with significant anatomical differences, including a larger bladder size in the FVB than in the B6 strain. Furthermore, cystometry tests revealed differences in bladder function pressure. LPS-treated B6 mice presented significant changes in peak pressure, with decreased intercontraction intervals; these results were similar to symptoms of IC in humans. Each strain displayed distinct characteristics, emphasizing the care required in choosing the appropriate strain for bladder-model studies. The results suggested that the B6 mouse strain is more suitable for IC models.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is not only a chronic urinary bladder pain syndrome but is also associated with multifactorial etiology. Our study aimed to test the hypothesis that IC/BPS is associated with subsequent increased risks of outpatient visits and hospitalizations. Using nationwide database, the diagnoses were based on the International Classification Codes (ICD-9-CM) (595.1) of at least three outpatient services during 2002-2008, (n = 27,990) and cystoscopic finding Hunner type and/or glomerulation with pre-audit criteria. All recruited cases monitored for subsequent outpatient visits and hospitalizations for 2 years, including all-cause and specialty-specific departments, were classified according to medical specialty and age group (<40, 40-60, ≥60 years of age). IC/BPS patients have more overall outpatient department (OPD) visits and an overall adjusted incidence rate ratio (IRR) of 1.64. As for specialty, IRRs were higher in psychiatry (2.75), Chinese medicine (2.01), and emergency medicine (2.00), besides urology and gynecology. The IRRs decreased as age advanced (2.01, 1.71, and 1.44, respectively), except for gynecology (2.42, 2.52, and 2.81). A similar phenomenon happens in hospitalization with IRR of 1.69. Due to claim data characteristics, whether ulcer type IC/BPS findings can be deductive to non-ulcer type remains inclusive. Current results indicate the impacts of healthcare burden in broad spectrum about IC/PBS patients. IC/BPS has been suggested to be associated with lower threshold of healthcare visits and some coexisting disease and is comprised of systemic dysregulation, and is beyond the scope of local bladder-urethra disease. Adequate recognition of associated or comorbid factors and possible recommendation or referral for IC/BPS patients can help provide better healthcare quality., Competing Interests: The authors have declared that no competing interests exist.

Background: As one of the most common conditions in urological outpatients, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) puzzles many individuals because of its unclear etiology and lack of effective treatment. Recently, immunological alterations underpinning CP/CPPS have been extensively investigated., Methods: The PubMed, Web of Science, Cochrane library, and EMBASE databases were used to search original articles on immune mediators in patients with CP/CPPS and in experimental autoimmune prostatitis (EAP) models through April 10, 2020. Standardized mean differences (SMD) were calculated to summarize the differences in immune mediator levels between groups. Funnel plot, Begg's funnel plot, Egger's regression test, and the sensitivity analysis were applied to determine and visualize the stability of our findings., Results: A total of 34 original studies were included in the meta-analysis, including 24 studies on patients with CP/CPPS and 10 studies on EAP models. We found that TNF-α, IL-1β, IL-6, and IL-8 were the four immune mediators that elevated in most of the samples derived from patients with CP/CPPS and the EAP models. The adjusted publication bias analysis indicated that publication bias was not existed, and the sensitivity analyses showed that the results were stable., Conclusions: Immune responses play significant roles during the pathogenesis of CP/CPPS by promoting intraprostatic inflammation. Our findings provide potential diagnostic and therapeutic targets for CP/CPPS patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: We sought to assess hernia characteristics and classification through comprehensive review of the literature involving broad ligament herniation., Methods: A literature search via MEDLINE and Embase databases was conducted to identify and select broad ligament herniation studies published between January 1, 2000 and September 30, 2020. Extracted data included previous surgical history, previous obstetric history, diagnostic imaging, herniated organ, hernia classification, and repair performed. The reported data has been compared to a unique case of broad ligament herniation that presented to our institution., Results: A total of 44 articles with 49 cases were identified for the study. Eighteen (36.7%) patients had a history of previous abdominal surgery while 29 (59.2%) had a history of previous childbirth. Type I (51.0%) and Type II (18.4%) defects were most commonly reported with most patients reporting only one defect (85.7%) using the Cilley classification. Twenty-nine patients underwent primary laparoscopic repair of the defect while 19 patients underwent exploratory laparotomy., Conclusions: The analysis of previously reported cases adds to the limited literature on broad ligament hernias and highlights the surgical management of this uncommon pathology. It also highlights the need for a broad differential diagnosis when female patients present with pelvic pain or symptoms of small bowel obstruction. The broad ligament should be fully inspected when mesenteric defects are suspected as multiple defects can be present as evidenced by the attached case study., Competing Interests: Conflict of interests: none., (© 2021 by SLS, Society of Laparoscopic & Robotic Surgeons.)

To evaluate the characteristics of the spinopelvic parameters on radiography in patients with sacroiliac joint pain (SIJP). Two hundred fifty patients were included and divided into the SIJP group (those diagnosed with SIJP based on physical findings and response to analgesic periarticular injections; n = 53) and the non-SIJP group (those with low back pain [LBP] because of other reasons; n = 197). We compared their demographic characteristics and spinopelvic parameters using radiography. All differences found in the patients' demographic characteristics and spinopelvic parameters were analyzed. More female participants experienced SIJP than male participants (P = 0.0179). Univariate analyses revealed significant differences in pelvic incidence (PI) (P = 0.0122), sacral slope (SS) (P = 0.0034), and lumbar lordosis (LL) (P = 0.0078) between the groups. The detection powers for PI, SS, and LL were 0.71, 0.84, and 0.66, respectively. Logistic regression analyses, after adjustment for age and sex, revealed significant differences in PI (P = 0.0308) and SS (P = 0.0153) between the groups, with odds ratios of 1.03 and 1.05, respectively. More female participants experienced SIJP than male participants. Higher PI and SS values were related to SIJP among LBP patients.

Recent evidence revealed that Hunner-type interstitial cystitis (HIC) is a robust inflammatory disease potentially associated with enhanced immune responses and histologically characterized by epithelial denudation and lymphoplasmacytic infiltration with frequent clonal expansion of infiltrating B cells. To date, few animal models that reproduce the histological and clinical correlates of HIC have yet been established. In the present study, we aimed to develop a novel animal model for HIC via autoimmunity to the bladder urothelium using the transgenic mouse model (URO-OVA) that expresses the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the bladder urothelium. OVA-specific lymphocytes (splenocytes) were generated by immunization of C57BL/6 mice with OVA protein and injected intravenously into URO-OVA mice. The splenocytes from OVA-immunized C57BL/6 mice showed increased interferon (IFN)-γ production in response to OVA stimulation in vitro. URO-OVA mice adoptively transferred with OVA-primed splenocytes developed cystitis exhibiting histological chronic inflammatory changes such as remarkable mononuclear cell infiltration predominantly composed of T and B lymphocytes, increased vascularity, and mucosal hyperemia in the bladder at days 7 - 28 with a peak at day 21 tested. No systemic inflammation was found in cystitis-induced URO-OVA mice, nor was any inflammation found in wild-type C57BL/6 mice adoptively transferred with OVA-primed splenocytes. Along with bladder inflammation, URO-OVA mice demonstrated significantly increased pelvic nociceptive responses, voiding dysfunction, and upregulated mRNA expression levels for IFN-γ, tumor necrosis factor-α (TNF-α), and substance P precursor in the bladder. This model reproduces the histological and clinical features of human HIC, providing a novel model for HIC research.

Objectives: To describe the clinical and ultrasound characteristics of adnexal torsion., Methods: This was a retrospective study. From the operative records of the eight participating gynecological ultrasound centers, we identified patients with a surgically confirmed diagnosis of adnexal torsion, defined as surgical evidence of ovarian pedicle, paraovarian cyst and/or Fallopian tube twisted on its own axis, who had undergone preoperative ultrasound examination by an experienced examiner, between 2008 and 2018. Only cases with at least two available ultrasound images and/or videoclips (one grayscale and one with Doppler evaluation) were included. Clinical, ultrasound, surgical and histological information was retrieved from each patient's medical record and entered into an Excel file by the principal investigator at each center. In addition, two authors reviewed all available ultrasound images and videoclips of the twisted adnexa, with regard to the presence of four predefined ultrasound features reported to be characteristic of adnexal torsion: (1) ovarian stromal edema with or without peripherally displaced antral follicles, (2) the follicular ring sign, (3) the whirlpool sign and (4) absence of vascularization in the twisted organ., Results: A total of 315 cases of adnexal torsion were identified. The median age of the patients was 30 (range, 1-88) years. Most patients were premenopausal (284/314; 90.4%) and presented with acute or subacute pelvic pain (305/315; 96.8%). The surgical approach was laparoscopic in 239/312 (76.6%) patients and conservative surgery (untwisting with or without excision of a lesion) was performed in 149/315 (47.3%) cases. According to the original ultrasound reports, the median largest diameter of the twisted organ was 83 (range, 30-349) mm. Free fluid in the pouch of Douglas was detected in 196/275 (71.3%) patients. Ovarian stromal edema with or without peripherally displaced antral follicles was reported in the original ultrasound report in 167/241 (69.3%) patients, the whirlpool sign in 178/226 (78.8%) patients, absent color Doppler signals in the twisted organ in 119/269 (44.2%) patients and the follicular ring sign in 51/134 (38.1%) patients. On retrospective review of images and videoclips, ovarian stromal edema with or without peripherally displaced antral follicles (201/254; 79.1%) and the whirlpool sign (139/153; 90.8%) were the most commonly detected features of adnexal torsion., Conclusion: Most patients with surgically confirmed adnexal torsion are of reproductive age and present with acute or subacute pain. Common ultrasound signs are an enlarged adnexa, the whirlpool sign, ovarian stromal edema with or without peripherally displaced antral follicles and free fluid in the pelvis. The follicular ring sign and absence of Doppler signals in the twisted organ are slightly less common signs. Recognizing ultrasound signs of adnexal torsion is important so that the correct treatment, i.e. surgery without delay, can be offered. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.)

Competing Interests: The authors have no conflicts of interest to declare.

Cowper's syringoceles are uncommon, usually described in children and most commonly limited to the ducts. We describe more complex variants in an adult population affecting with varying degrees of severity, the glands themselves, and the complications they may lead to. One hundred consecutive urethrograms of patients with unreconstructed strictures were reviewed. Twenty-six patients (mean age: 41.1 years) with Cowper's syringoceles who were managed between 2009 and 2016 were subsequently evaluated. Presentation, radiological appearance, treatment (when indicated), and outcomes were assessed. Of 100 urethrograms in patients with strictures, 33.0% demonstrated filling of Cowper's ducts or glands, occurring predominantly in patients with bulbar strictures. Only 1 of 26 patients with non-bulbar strictures had a visible duct/gland. Of 26 symptomatic patients, 15 presented with poor flow. In four patients, a grossly dilated Cowper's duct obstructed the urethra. In the remaining 11 patients, a bulbar stricture caused the symptoms and the syringocele was identified incidentally. Eight patients presented with perineal pain. In six of them, fluoroscopy and magnetic resonance imaging (MRI) revealed complex multicystic lesions within the bulbourethral glands. Four patients developed perineoscrotal abscesses. In the 11 patients with strictures, the syringocele was no longer visible after urethroplasty. In three of four patients with urethral obstruction secondary to a dilated Cowper's duct, this resolved after transperineal excision (n = 2) and endoscopic deroofing (n = 1). Five of six patients with complex syringoceles involving Cowper's glands were excised surgically with symptomatic relief in all. In conclusion, Cowper's syringocele in adults is more common than previously thought and may cause lower urinary tract symptoms or be associated with serious complications which usually require surgical treatment., Competing Interests: None

Endometriosis is a complex, heterogeneous, chronic inflammatory condition impacting ~176 million women worldwide. It is associated with chronic pelvic pain, infertility, and fatigue, and has a substantial impact on health-related quality of life. Endometriosis is defined by the growth of endometrial-like tissue outside the uterus, typically on the lining of the pelvic cavity and ovaries (known as "lesions"). Macrophages are complex cells at the center of this enigmatic condition; they are critical for the growth, development, vascularization, and innervation of lesions as well as generation of pain symptoms. In health, tissue-resident macrophages are seeded during early embryonic life are vital for development and homeostasis of tissues. In the adult, under inflammatory challenge, monocytes are recruited from the blood and differentiate into macrophages in tissues where they fulfill functions, such as fighting infection and repairing wounds. The interplay between tissue-resident and recruited macrophages is now at the forefront of macrophage research due to their differential roles in inflammatory disorders. In some cancers, tumor-associated macrophages (TAMs) are comprised of tissue-resident macrophages and recruited inflammatory monocytes that differentiate into macrophages within the tumor. These macrophages of different origins play differential roles in disease progression. Herein, we review the complexities of macrophage dynamics in health and disease and explore the paradigm that under disease-modified conditions, macrophages that normally maintain homeostasis become modified such that they promote disease. We also interrogate the evidence to support the existence of multiple phenotypic populations and origins of macrophages in endometriosis and how this could be exploited for therapy., (Copyright © 2020 Hogg, Horne and Greaves.)

Aims: To assess the efficacy of a micronized-palmitoylethanolamide-polydatin (m-PEA-Pol) based product on chronic pelvic pain and severity of other symptoms in interstitial cystitis/bladder pain syndrome (IC/BPS) patients refractory to conventional therapies., Methods: A pilot, open-label bicentric study was carried out involving 32 IC/BPS patients. Chronic, oral m-PEA-Pol treatment lasted 6 months. Bladder pain was evaluated using the visual analog scale, while changes from baseline in other urinary symptoms were evaluated by means of the O'Leary-Sant Interstitial Cystitis Symptom and Problem Index and the Pelvic Pain and Urgency/Frequency (PUF) symptom scale questionnaires. The generalized linear mixed model was used to evaluate significant mean changes across time., Results: A significant and progressive reduction of pain intensity was observed during m-PEA-Pol treatment ( p < 0.0001 for reduction over time). The effect was associated with a reduction in severity of patients' symptoms evaluated with the O'Leary-Sant questionnaire ( p =0.0110 and p =0.0014 for cystitis symptoms and problem mean scores, respectively) and the PUF scale ( p =0.0163 and p =0.0005 for symptom and bother mean scores, respectively). m-PEA-Pol therapy elicited a significant reduction over time in the urinary frequency evaluated with voiding diary ( p =0.0005) and a small but not significant improvement of bladder capacity., Conclusions: These data highlight the potential benefit of m-PEA-Pol in patients with rare pathology such as IC/BPS and confirm the good safety profile of micronized PEA-based products., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 M. Cervigni et al.)

Objective: To evaluate the efficacy of elagolix, an oral GnRH antagonist, for the reduction of fatigue in women with moderate or severe endometriosis-associated pain., Design: Randomized, double-blind, multicenter, placebo-controlled phase III trial., Setting: Clinics., Patient(s): A total of 860 women treated with elagolix or placebo., Intervention(s): Women received either elagolix at 150 mg daily (QD) orally, elagolix at 200 mg twice daily (BID) orally, or placebo., Main Outcome Measure(s): Change from baseline to month 1, 3, and 6 visits, in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 6a questionnaire T-scores., Results(s): At baseline, 54%-74% of women with moderate to severe pain associated with endometriosis reported having fatigue-related issues "quite a bit" or "very much," depending on the question asked. Fatigue extent was reduced to 29%-43% and 14%-29% for women treated with elagolix at 150 mg QD and 200 mg BID, respectively, at 6 months, compared with 35%-50% with placebo. The resultant decrease in fatigue T-scores was significant after elagolix treatment compared with placebo at 6 months, with changes of -2.21 and -5.90 with elagolix at 150 mg QD and 200 mg BID, respectively. Significant reduction in fatigue scores were observed among patients reporting clinically meaningful response "reduction" in dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia (-7.31, -6.62, and -4.31, respectively) compared with nonresponders., Conclusion(s): In women with moderate to severe endometriosis related pain, elagolix significantly reduces fatigue levels., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The objective is to study the significance of altered interleukin levels in endometriosis-related infertility or pelvic pain. The present systematic review and meta-analysis includes a discussion on the roles of interleukin in the physiopathology of endometriosis-associated infertility and/or pelvic pain. We included all studies in which interleukins in peritoneal fluid, follicular fluid or serum from patients were measured and that correlated the findings with either peritoneal or deep endometriosis-associated infertility or pelvic pain. For the meta-analysis, we selected studies on the following cytokines: interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8). Endometriosis is a chronic inflammatory disease. Inflammatory processes clearly participate in the etiology of endometriosis. Cytokines are mediators of inflammation, and increase in their concentration in plasma or other body fluids signals the presence and extent of tissue lesions. A number of studies have reported on the association between higher cytokine levels and progression or maintenance of endometriosis and coexisting infertility or pelvic pain. The results of the analyses support that an association exists between elevated serum IL-6 and/or IL-8 concentrations and the occurrence of endometriosis-associated infertility. Such association was not found for endometriosis-associated pain. In spite of accumulated evidence on the association of pro-inflammatory cytokines and endometriosis, it still is not clear if and how these mediators participate in the physiopathology of endometriosis-associated infertility or pelvic pain, in part due to poor quality of the evidence established in the vast majority of interleukins and challenges in endometriosis research reproducibility. In summary, the results of the analyses support that an association exists between elevated serum IL-6 and/or IL-8 concentrations and the occurrence of endometriosis-associated infertility.

Objective: To demonstrate the prevalence of small fiber polyneuropathy (SFPN) in patients with refractory chronic pelvic pain (CPP)., Design: Retrospective study of prospective database., Subjects: Participants were complex CPP patients recruited from subspecity referral clinics defined as those who were refractory to initial treatment and/or exhibited comorbid pain syndromes at initial presentation., Methods: Comprehensive treatment history for CPP was obtained, and participants referred as above; 3-mm punch biopsies were obtained of the lower extremity and sent to diagnostic reference labs to evaluate for SFPN. The reported lab sensitivity and specificity for SFPN are 78-92% and 65-90%, respectively., Results: Twenty-five of 39 patients (64%) were positive for SFPN. Comorbid conditions noted in our population included gastroesophageal reflux disease (46%), migraine (38%), irritable bowel syndrome (33%), lower back pain (33%), fibromyalgia (38%), endometriosis (15%), interstitial cystitis (18%), vulvodynia (5%), and other chronic pain syndromes (36%)., Conclusions: The prevalence of SFPN in our specialty referral patients with complex CPP is remarkably high vs published general population prevalence data (53/100,000). Identification of SFPN in this complex population shifts the focus from undefined syndromes to symptom complexes with linked potentially treatable mechanisms (e.g., SFPN, central sensitization). Most CPP patients with SFPN are undiagnosed. Considering the diagnosis may expand treatment options beyond conventional or so-called adjuvant analgesics. Treatment may expand to therapies such as IV lidocaine, IVIG, or other immunomodulatory options. In addition, the value to the patient of receiving a diagnosis for a multisystem or refractory pain syndrome, often attributed to negative psychologic factors, cannot be underestimated. Identifying SFPN should be contemplated in CPP patients who present with multisystem pain or who have not responded to initial evaluation and management., (© 2018 American Academy of Pain Medicine. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Provoked vestibulodynia (PVD) is a chronic pelvic pain disorder affecting 16% of the female population. Neuroimaging studies have highlighted central abnormalities in PVD, similar to other chronic pelvic pain disorders, including brain regions involved in sensory processing and modulation of pain. The aim of the study was to determine alterations in the subvoxel, microstructural organization within tissues in PVD compared with healthy control participants (HCs) and a disease control group (irritable bowel syndrome [IBS]). Diffusion tensor imaging magnetic resonance imaging was conducted in 87 age-matched premenopausal women (29 PVD, 29 HCs, 29 IBS). Statistical parameter mapping of fractional anisotropy (FA) and mean diffusivity (MD) maps were used to identify microstructural difference in the brain specific to PVD or shared with IBS. PVD alterations in microstructural organization of the brain were predominantly observed in fibers associated with sensorimotor integration and pain processing that relay information between the thalamus, basal ganglia, sensorimotor, and insular cortex. PVD, compared with HCs, showed extensive increases in the FA of somatosensory and basal ganglia regions. In contrast, PVD and IBS subjects did not show any FA-related group differences. PVD subjects showed greater MD in the basal ganglia compared with HCs (higher MD in the internal capsule and pallidum) and IBS (higher MD in the putamen and pallidum). Increases in MD were associated with increased vaginal muscle tenderness and vulvar pain. The current findings highlight possible shared mechanisms between 2 different pelvic pain disorders, but also highlight the widespread alterations observed specifically in PVD compared with HCs., Perspective: Alterations in microstructure in PVD were observed in fibers associated with sensorimotor integration and pain processing, which were also associated with increased vaginal muscle tenderness and vulvar pain. These alterations may be contributing to increased pain sensitivity and tenderness, highlighting the need for new therapies targeting the central nervous system., (Copyright © 2018 The American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objective: To explore how pain intensity and pain cognition are related to health-related quality of life (HRQoL) in women with endometriosis., Design: Cross-sectional questionnaire-based survey., Setting: Multidisciplinary referral center., Patient(s): Women with laparoscopically and/or magnetic resonance imaging-proven endometriosis (n = 50) and healthy control women (n = 42)., Intervention(s): For HRQoL, two questionnaires: the generic Short Form Health Survey (SF-36) and the Endometriosis Health Profile 30 (EHP-30). For pain cognition, three questionnaires: the Pain Catastrophizing Scale (PCS), the Pain Vigilance and Awareness Questionnaire (PVAQ), and the Pain Anxiety Symptoms Scale (PASS). For pain intensity, the verbal Numeric Rating Scale (NRS)., Main Outcome Measure(s): Association between pain intensity and pain cognition with HRQoL in women with endometriosis, and the differences in HRQoL and pain cognition between women with endometriosis and healthy controls., Result(s): Health-related quality of life was statistically significantly impaired in women with endometriosis as compared with healthy control women. The variables of pain intensity and pain cognition were independent factors influencing the HRQoL of women with endometriosis. Patients with endometriosis had statistically significantly more negative pain cognition as compared with controls. They reported more pain anxiety and catastrophizing, and they were hypervigilant toward pain., Conclusion(s): Pain cognition is independently associated with the HRQoL in endometriosis patients. Clinicians should be aware of this phenomenon and may consider treating pain symptoms in a multidimensional, individualized way in which the psychological aspects are taken into account. In international guidelines on management of women with endometriosis more attention should be paid to the psychological aspects of care., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to explore the neural mechanism in Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) using resting-state functional magnetic resonance imaging. The functional magnetic resonance imaging was performed on 31 male CP/CPPS-patients and 31 age and education matched male healthy controls on a 3-T magnetic resonance imaging unit. A two-sample t-test was adopted to reveal the regional homogeneity between the patients and healthy controls. The mean regional homogeneity values in the alerted brain regions of patients were correlated with the clinical measurements by using Pearson's correlation analyses. The CP/CPPS-patients had significantly decreased regional homogeneity in the bilateral anterior cingulate cortices, insular cortices and right medial prefrontal cortex, while significantly increased regional homogeneity in the brainstem and right thalamus compared with the healthy controls. In the CP/CPPS-patients, the mean regional homogeneity value in the left anterior cingulate cortex, bilateral insular cortices and brainstem were respectively correlated with the National Institutes of Health Chronic Prostatitis Symptom Index total score and pain subscale. These brain regions are important in the pain modulation process. Therefore, an impaired pain modulatory system, either by decreased descending pain inhibition or enhanced pain facilitation, may explain the pain symptoms in CP/CPPS.

Purpose: Chronic prostatitis (CP)/chronic pelvic pain syndrome (CPPS) has been studied mainly in adults; reports in adolescents are rare. We compared the clinical characteristics of adolescent CP/CPPS patients with those of young adults., Materials and Methods: We retrospectively analyzed 20 adolescents with CP/CPPS aged <20 years who visited our outpatient department from August 2005 to April 2012. The control group comprised 120 young adult CP/CPPS patients. A complete medical history, physical examination, the national institute of health-chronic prostatitis symptoms index (NIH-CPSI) questionnaire, urinalysis, expressed prostatic secretion (EPS) or semen analysis, transrectal prostate ultrasonography, and prostate-specific antigen (PSA) were performed. Based on the EPS or semen analysis, patients were divided into category III-A or III-B., Results: The mean age was 16.5±2.0 and 32.8±5.0 years in the adolescent and control groups, respectively. A sexual activity history was seen in 2 patients; 9 and 11 patients were in category III-A and III-B, respectively. The PSA was 0.65±0.39 and 1.22±0.48 ng/mL in the adolescent and control groups, respectively. The prostate size was 12.4±4.4 and 21.0±4.9 g in the adolescent and control groups, respectively. The NIH-CPSI scores in the adolescent group were 9.2±5.2, 5.5±3.5, 7.5±3.2, and 22.2±8.1 for pain, voiding, quality of life (QoL) domains, and total scores, respectively. The adolescent group showed a tendency to exhibit high voiding symptom scores., Conclusions: CPPS has an equally severe impact on QoL in adults and adolescents. Apart from high voiding symptom scores in adolescents, no difference was found in terms of urologic clinical parameters., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic voiding disorder that presents with pain in the urinary bladder and surrounding pelvic region. A growing body of evidence suggests that an increase in the permeability of the urothelium, the epithelial barrier that lines the interior of the bladder, contributes to the symptoms of IC/BPS. To examine the consequence of increased urothelial permeability on pelvic pain and afferent excitability, we overexpressed in the urothelium claudin 2 (Cldn2), a tight junction (TJ)-associated protein whose message is significantly upregulated in biopsies of IC/BPS patients. Consistent with the presence of bladder-derived pain, rats overexpressing Cldn2 showed hypersensitivity to von Frey filaments applied to the pelvic region. Overexpression of Cldn2 increased the expression of c-Fos and promoted the activation of ERK1/2 in spinal cord segments receiving bladder input, which we conceive is the result of noxious stimulation of afferent pathways. To determine whether the mechanical allodynia observed in rats with reduced urothelial barrier function results from altered afferent activity, we examined the firing of acutely isolated bladder sensory neurons. In patch-clamp recordings, about 30% of the bladder sensory neurons from rats transduced with Cldn2, but not controls transduced with GFP, displayed spontaneous activity. Furthermore, bladder sensory neurons with tetrodotoxin-sensitive (TTX-S) action potentials from rats transduced with Cldn2 showed hyperexcitability in response to suprathreshold electrical stimulation. These findings suggest that as a result of a leaky urothelium, the diffusion of urinary solutes through the urothelial barrier sensitizes bladders afferents, promoting voiding at low filling volumes and pain.

Aim: To test whether plasma BDNF levels are useful to predict the presence of endometriosis in women with pelvic pain., Patients & Methods: Prospective cross-sectional study including 67 consecutive women aged 24-49 years, scheduled for laparoscopy due to chronic pelvic pain. Preoperative plasma samples were assayed for BDNF using a commercial enzyme immunoassay., Results: Women with ovarian endometrioma had higher preoperative plasma BDNF (1063 ± 157 pg/ml) compared with women with other benign ovarian tumors (537 ± 131 pg/ml, F = 2.53; p = 0.02). However, plasma BDNF levels were not helpful to indicate the presence of peritoneal or deep infiltrating endometriosis. Plasma BDNF levels were positively correlated with the severity of pelvic pain (r = 0.489; p < 0.0001)., Conclusion: Plasma BDNF might be a biomarker of ovarian endometrioma but not a useful diagnostic marker to detect other forms of endometriosis in women with painful symptoms.

Background: Patients with groin, hip and pelvic pain but normal findings on MRI and minimal changes on x-ray can be a diagnostic problem. This paper looks at the arthroscopic findings of patients who have had hip pain and a positive response to an intra-articular anaesthetic but have non-contributory imaging. We hypothesized that standard MRI's were missing significant pathology and if there was a response to intra-articular local anaesthesia, pathology found during arthroscopy was likely., Methods: A retrospective review of all hip arthroscopies performed from March 2011 to January 2015 by two orthopaedic surgeons specializing in hip arthroscopy was conducted to identify patients with clinically suspected intra-articular hip pathology despite a normal MRI report and X-ray. Clinical suspicion of intra-articular hip pathology was confirmed with a positive response to a fluoroscopically guided intra-articular injection of local anaesthetic and corticosteroid. Pathologic findings were collated from the standardised operative notes., Results: Fifty-three hip arthroscopies performed in 51 patients met the inclusion criteria from a total of 1348 hip arthroscopies performed over a 46-month period. All but one of the 53 (98%) hips had arthroscopically confirmed pathology. Mean patient age was 32.5 years [15 to 67 years] with 40 (78%) females and 11 (22%) males. 92.5% of the hips (49/53) were FADIR (flexion, adduction and internal rotation) positive on clinical examination, giving this test a positive predictive value of 98% (95% CI: 89.31 to 99.67%) for intra-articular pathology., Conclusions: In patients with a normal MRI without contrast and a positive response (relief of pain) to an intra-articular injection that failed conservative management, there is a 98% chance of intra-articular hip pathology being discovered on hip arthroscopy.

Background: Several studies have described the course and anatomical relations of the pudendal nerve. Several surgical nerve decompression techniques have been described, but only the transgluteal approach has been validated by a prospective randomized clinical trial. The purpose of this study was to describe the course of the nerve and its variants in a population of patients with pudendal neuralgia in order to guide the surgeon in the choice of surgical approach for pudendal nerve decompression., Objectives: In order to support the choice of the transgluteal approach, used in our institution, we studied the exact topography, anatomical relations, and zones of entrapment of the pudendal nerve in a cohort of operated patients., Study Design: Observational study., Setting: University hospital., Methods: One hundred patients underwent unilateral or bilateral nerve decompression performed by a single operator via a transgluteal approach. All patients satisfied the Nantes criteria for pudendal neuralgia. The operator meticulously recorded zones of entrapment, anatomical variants of the course of the nerve, and the appearance of the nerve in the operative report., Results: One hundred patients and 145 nerves were operated consecutively. Compression of at least one segment of the pudendal nerve (infrapiriform foramen, ischial spine, and Alcock's canal) was observed in 95 patients. The zone of entrapment was situated at the ischial spine between the sacrospinous ligament (or ischial spine) and the sacrotuberous ligament in 74% of patients.Anatomical variants were observed in 13 patients and 15 nerves. Seven patients presented an abnormal transligamentous course of the nerve (sacrotuberous or sacrospinous). A perineal branch of the fourth sacral nerve to the external anal sphincter was identified in 7 patients. In this population of patients with pudendal neuralgia, the pudendal nerve was stenotic in 27% of cases, associated with an extensive venous plexus that could make surgery more difficult in 25% of cases, and the nerve had an inflammatory appearance in 24% of cases., Limitations: We obviously cannot be sure that the anatomical variants identified in this study can be extrapolated to the general population, as our study population was composed of patients experiencing perineal pain due to pudendal nerve entrapment and their pain could possibly be related to these anatomical variants, especially a transligamentous course of the pudendal nerve. The absence of other prospective randomized clinical trials evaluating other surgical approaches also prevents comparison of these results with those of other surgical approaches., Conclusions: This is the first study to describe the surgical anatomy of the pudendal nerve in a population of patients with pudendal neuralgia. In more than 70% of cases, pudendal nerve entrapment was situated in the space between the sacrospinous ligament and the sacrotuberous ligament. Anatomical variants of the pudendal nerve were also observed in 13% of patients, sometimes with a transligamentous course of the nerve. In the light of these results, we believe that a transgluteal approach is the most suitable surgical approach for safe pudendal nerve decompression by allowing constant visual control of the nerve.Key words: Surgical, operative technique, pudendal, neuralgia, transgluteal approach.

Chronic vulvar pain is alarmingly common in women of reproductive age and is often accompanied by psychological distress, sexual dysfunction, and a significant reduction in quality of life. Localized provoked vulvodynia (LPV) is associated with intense vulvar pain concentrated in the vulvar vestibule (area surrounding vaginal opening). To date, the origins of vulvodynia are poorly understood, and treatment for LPV manages pain symptoms, but does not resolve the root causes of disease. Until recently, no definitive disease mechanisms had been identified; our work indicates LPV has inflammatory origins, although additional studies are needed to understand LPV pain. Bradykinin signaling is one of the most potent inducers of inflammatory pain and is a candidate contributor to LPV. We report that bradykinin receptors are expressed at elevated levels in LPV patient versus healthy control vestibular fibroblasts, and patient vestibular fibroblasts produce elevated levels of proinflammatory mediators with bradykinin stimulation. Inhibiting expression of one or both bradykinin receptors significantly reduces proinflammatory mediator production. Finally, we determined that bradykinin activates nuclear factor (NF)κB signaling (a major inflammatory pathway), whereas inhibition of NFκB successfully ablates this response. These data suggest that therapeutic agents targeting bradykinin sensing and/or NFκB may represent new, more specific options for LPV therapy., Perspective: There is an unmet need for the development of more effective vulvodynia therapies. As we explore the mechanisms by which human vulvar fibroblasts respond to proinflammatory/propain stimuli, we move closer to understanding the origins of chronic vulvar pain and identifying new therapeutic targets, knowledge that could significantly improve patient care., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is one of the most common urologic diseases, and no curative treatments have been identified. Low-intensity pulsed ultrasound (LIPUS) has been successfully used in promoting tissue healing, inhibiting inflammation and pain, differentiating stem cells, and stimulating nerve regeneration/muscle regeneration, as well as enhancing angiogenesis. Very recently, LIPUS has been proven an effective approach for CP/CPPS. This review summarizes the possible mechanisms responsible for the therapeutic effect of LIPUS for CP/CPPS. To search publications relevant to the topics of this review, the search engine for life sciences of Entrez was used. We reviewed the available evidence from 1954 through 2015 concerning LIPUS for CP/CPPS. According to the literature, both transrectal and transperineal approaches of LIPUS are effective for CP/CPPS.

Pain is the significant presenting symptom in Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS). Activation of urothelial protease activated receptor 4 (PAR4) causes pain through release of urothelial macrophage migration inhibitory factor (MIF). High Mobility Group Box-1 (HMGB1), a chromatin-binding protein, mediates bladder pain (but not inflammation) in an experimental model (cyclophosphamide) of cystitis. To determine if PAR4-induced bladder hypersensitivity depends on HMGB1 downstream, we tested whether: 1) bladder PAR4 stimulation affected urothelial HMGB1 release; 2) blocking MIF inhibited urothelial HMGB1 release; and 3) blocking HMGB1 prevented PAR4-induced bladder hypersensitivity. HMGB1 release was examined in immortalized human urothelial cultures (UROtsa) exposed to PAR4-activating peptide (PAR4-AP; 100 μM; 2 hours) or scrambled control peptide. Female C57BL/6 mice, pretreated with a HMGB1 inhibitor (glycyrrhizin: 50 mg/kg; i.p.) or vehicle, received intravesical PAR4-AP or a control peptide (100 μM; 1 hour) to determine 1) HMGB1 levels at 1 hour in the intravesical fluid (released HMGB1) and urothelium, and 2) abdominal hypersensitivity to von Frey filament stimulation 24 hours later. We also tested mice pretreated with a MIF blocker (ISO-1: 20 mg/kg; i.p.) to determine whether MIF mediated PAR4-induced urothelial HMGB1 release. PAR4-AP triggered HMGB1 release from human (in vitro) and mice (in vivo) urothelial cells. Intravesical PAR4 activation elicited abdominal hypersensitivity in mice that was prevented by blocking HMGB1. MIF inhibition prevented PAR4-mediated HMGB1 release from mouse urothelium. Urothelial MIF and HGMB1 represent novel targets for therapeutic intervention in bladder pain conditions.

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common problem with unclear etiology. Some diet and lifestyle factors were thought to correlate with CP/CPPS, but studies comprehensively investigate this correlation are rarely available. The current study was conducted to determine the potential lifestyle-related risk factors of CP/CPPS and its pain severity in Chinese population., Methods: Participants were recruited from seven hospitals in Shanghai from July 2012 to August 2013. Demographics, medical history, diet and lifestyle information, and CP/CPPS symptoms were obtained from each participant using a questionnaire. Univariate and multivariate logistic regression analyses were used to identify potential lifestyle-related risk factors for CP/CPPS and its pain severity., Results: A total of 784 men with CP/CPPS and 785 controls were enrolled in this study. Multivariate regression model indicated that age, nightshift work, stress, smoking status, alcohol consumption, less water intake, imbalanced diet, frequent sexual activity, delaying ejaculation and holding urine were identified as potential risk factors for CP/CPPS, whereas sedentary lifestyle, caffeinated drinks and less water intake were associated with severe pain in CP/CPPS patients., Conclusions: Several diet and lifestyle factors associated with CP/CPPS and pain severity were determined in this study. These modifiable conditions are potential targets for treatment of CP/CPPS. However, further studies are necessary to determine their role in the pathogenesis of CP/CPPS.

Pudendal neuralgia is a chronic neuropathic pelvic pain that is often misdiagnosed and inappropriately treated. The Nantes criteria provide a basis for the diagnosis of pudendal neuralgia due to pudendal nerve entrapment. The 5 essential diagnostic criteria are pain situated in the anatomical territory of the pudendal nerve, worsened by sitting, the patient is not woken at night by the pain, and no objective sensory loss is detected on clinical examination. The fifth criterion is a positive pudendal nerve block. We have also clarified a number of complementary diagnostic criteria and several exclusion criteria that make the diagnosis unlikely. When pudendal neuralgia due to pudendal nerve entrapment is diagnosed according to the Nantes criteria, no further investigation is required and medical or surgical treatment can be proposed. Nevertheless, a number of warning signs suggesting other possible causes of pudendal neuralgia must not be overlooked. These warning signs (red flags) are waking up at night, excessively neuropathic nature of the pain (for example, associated with hypoesthesia), specifically pinpointed pain, which can suggest neuroma and pain associated with neurological deficit. In these atypical presentations, the diagnosis of pain due to pudendal nerve entrapment should be reconsidered and a radiological examination should be performed. The 2 cases described in this report (tumor compression of the pudendal nerve) illustrate the need to recognize atypical pudendal neuralgia and clarify the role of pelvic magnetic resonance imaging (MRI), as MRI provides very valuable information for the evaluation of diseases involving the ischiorectal fossa. The presence of red flags must be investigated in all cases of pudendal neuralgia to avoid missing pudendal neuralgia secondary to a mechanism other than nerve entrapment.

Study Question: Can the presence of endometrial nerve fibres be used as a diagnostic test for endometriosis in women with pelvic pain?, Summary Answer: Endometrial fine nerve fibres were seen in the endometrium of women both with and without endometriosis, making their detection a poor diagnostic tool for endometriosis., What Is Known Already: Laparoscopy and biopsy are currently the gold standard for making a diagnosis of endometriosis. It has been reported that small density nerve fibres in the functional layer of the endometrium are unique to women with endometriosis and hence nerve fibre detection could function as a less invasive diagnostic test of endometriosis. However, it may be that other painful conditions of the pelvis are also associated with these nerve fibres. We therefore focused this prospective study on women with pelvic pain to examine the efficacy of endometrial nerve fibre detection as a diagnostic test for endometriosis., Study Design, Size, Duration: This prospective case-control study conducted between July 2009 and July 2013 included 44 women with pelvic pain undergoing laparoscopic examination for the diagnosis of endometriosis. Immunohistochemical nerve fibre detection in endometrial curettings and biopsies using anti-protein gene product 9.5 was compared with surgical diagnosis., Participants/materials, Settings, Methods: Paired endometrial biopsies and curettings were taken from patients with (n = 22, study group) and without (n = 22, control group) endometriosis. Tissue was analysed by immunohistochemistry and nerve fibres were counted whenever they were present in the functional layer of the endometrium., Main Results and the Role of Chance: Fine nerve fibres were present in the eutopic endometrium of patients both with and without endometriosis. The presence of nerve fibres in curettings was not effective for either diagnosing or excluding endometriosis; sensitivity and specificity were 31.8 and 45.5% respectively, positive predictive value was 36.8% and negative predictive value was 40.0%. Few endometrial biopsy specimens were found to have nerve fibres present; sensitivity and specificity for endometrial biopsy were 13.6 and 68.2% respectively, positive predictive value was 30.0% and negative predictive value was 44.1%., Limitations, Reasons for Caution: This was a relatively small sample size and studies like this are subject to the heterogeneous nature of the patient population and tissue samples, despite our best efforts to regulate these parameters., Wider Implications of the Findings: Our results demonstrate that fine nerve fibres are present in women with and without endometriosis. Future work should focus on the function of endometrial nerves and whether these nerves are involved with the subfertility or pain that endometriosis sufferers experience. Our study does not support the detection of endometrial nerve fibres as a non-invasive diagnostic test of endometriosis in women with pelvic pain., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Some patients have pelvic, pudendal, or low lumbar pain radiating into the legs that is worse while sitting but differs from pudendal neuralgia. The purpose of this study was to present a new clinical entity of neuropathic pelvic pain by pelvic neuro-vascular entrapment., Objectives: To report about the locations of predilection for pelvic neurovascular entrapment., Study Design: Prospective cohort pre- and post-intervention., Setting: University referral unit specializing in advanced gynecological surgery and neuropelveology., Methods: Patients, Intervention: In a prospective study, 97 patients presenting with intractable pelvic neuropathic pain (pudendal pain, gluteal pain, vulvodynia, coccygodynia, and sciatic pain) underwent laparoscopic exploration with decompression of compressed pelvic somatic nerves. The population included 76 (78.3%) women and 21 men. Indication for laparoscopic exploration of pelvic nerves suspected to be involved in pain has been indicated after neuropelveological work up, pelvic neuro-magnetic resonance imaging (MRI) and Doppler-sonography. Pain evolution was recorded over 2 years after the procedure., Measurements and Main Results: Three entities were isolated: pudendal neuralgie by compression at the less sciatic notch, sacral radiculopathy at S2-4 by compression at the infracardinal level of the sacral plexus, and sciatica L5-S1/2 by compression at the greater sciatic notch. Pain was worse sitting (98%), during menstrual bleeding in women, and during Valsalva maneuver, but the pain did not wake the patients up at night and was not accompanied by neurologic dysfunctions. A decrease in VAS scores (> 50%) at 2 years follow-up was observed in 86 patients (88.6%)., Conclusions: Neuro-vascular entrapment is a pathophysiologic phenomenon implicated in several pelvic neuropathies. The most common are L5-S1 sciatica, pudendal neuralgia, and sacral radiculopathy. After intraoperative confirmation, laparoscopic exploration of the entire sacral plexus is essential to diagnose conflict. Laparoscopic decompression is a treatment of choice, based on the separation of the offending vessel from the nerves. Those procedures are safe, with a high success rate; the neuropelveological approach is essential in order to obtain good treatment results. The laparoscopic approach gives the possibility of reducing morbidity and improving results by providing wider insight into the operating field with smaller intraoperative injury.

Studies have suggested chronic pain syndromes are associated with neural reorganization in specific regions associated with perception, processing, and integration of pain. Urological chronic pelvic pain syndrome (UCPPS) represents a collection of pain syndromes characterized by pelvic pain, namely Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) and Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS), that are both poorly understood in their pathophysiology, and treated ineffectively. We hypothesized patients with UCPPS may have microstructural differences in the brain compared with healthy control subjects (HCs), as well as patients with irritable bowel syndrome (IBS), a common gastrointestinal pain disorder. In the current study we performed population-based voxel-wise DTI and super-resolution track density imaging (TDI) in a large, two-center sample of phenotyped patients from the multicenter cohort with UCPPS (N = 45), IBS (N = 39), and HCs (N = 56) as part of the MAPP Research Network. Compared with HCs, UCPPS patients had lower fractional anisotropy (FA), lower generalized anisotropy (GA), lower track density, and higher mean diffusivity (MD) in brain regions commonly associated with perception and integration of pain information. Results also showed significant differences in specific anatomical regions in UCPPS patients when compared with IBS patients, consistent with microstructural alterations specific to UCPPS. While IBS patients showed clear sex related differences in FA, MD, GA, and track density consistent with previous reports, few such differences were observed in UCPPS patients. Heat maps illustrating the correlation between specific regions of interest and various pain and urinary symptom scores showed clustering of significant associations along the cortico-basal ganglia-thalamic-cortical loop associated with pain integration, modulation, and perception. Together, results suggest patients with UCPPS have extensive microstructural differences within the brain, many specific to syndrome UCPPS versus IBS, that appear to be localized to regions associated with perception and integration of sensory information and pain modulation, and seem to be a consequence of longstanding pain.

Endometriosis is a debilitating, estrogen-dependent, progesterone-resistant, inflammatory gynecological disease of reproductive age women. Two major clinical symptoms of endometriosis are chronic intolerable pelvic pain and subfertility or infertility, which profoundly affect the quality of life in women. Current hormonal therapies to induce a hypoestrogenic state are unsuccessful because of undesirable side effects, reproductive health concerns, and failure to prevent recurrence of disease. There is a fundamental need to identify nonestrogen or nonsteroidal targets for the treatment of endometriosis. Peritoneal fluid concentrations of prostaglandin E2 (PGE2) are higher in women with endometriosis, and this increased PGE2 plays important role in survival and growth of endometriosis lesions. The objective of the present study was to determine the effects of pharmacological inhibition of PGE2 receptors, EP2 and EP4, on molecular and cellular aspects of the pathogenesis of endometriosis and associated clinical symptoms. Using human fluorescent endometriotic cell lines and chimeric mouse model as preclinical testing platform, our results, to our knowledge for the first time, indicate that selective inhibition of EP2/EP4: (i) decreases growth and survival of endometriosis lesions; (ii) decreases angiogenesis and innervation of endometriosis lesions; (iii) suppresses proinflammatory state of dorsal root ganglia neurons to decrease pelvic pain; (iv) decreases proinflammatory, estrogen-dominant, and progesterone-resistant molecular environment of the endometrium and endometriosis lesions; and (v) restores endometrial functional receptivity through multiple mechanisms. Our novel findings provide a molecular and preclinical basis to formulate long-term nonestrogen or nonsteroidal therapy for endometriosis.

Endometrioma surgery should be planned and executed very carefully as it is associated with risks that may hamper future reproductive potential. Symptoms, age, risk of malignancy, bilaterality, ovarian reserve, and desire to have children should all be taken into account prior to surgical intervention. Cyclic and noncyclic severe pain may be an indicator or deep infiltrating diseases. Laparoscopic surgery is the gold standard, however, the issue of resection versus ablation should be further studied.

Endometriosis is characterized by development of the endometrial tissue outside the uterus like ovary, pelvic peritoneum, pelvic organs, and affects 6-10% of reproductive-aged women. The prevalence of endometrioma is 17-44% of women with endometriosis. Since endometriosis is mainly a disease for the women at their reproductive ages, it is important to consider ovarian reserve when managing the cases with ovarian endometriosis. There has been a long debate whether the endometrioma per se decreases the ovarian reserve and/or surgery for endometrioma - either by laparoscopy or by laparotomy - decreases it. Although the dispute for these questions is not totally settled down, in this article, we would like to give some clues for the answers in view of the literature.

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.

Background: Chronic pelvic pain (CPP) is a significant public health problem with 1 million affected women in the UK. Although many pathologies are associated with CPP, the pain experienced is often disproportionate to the extent of disease identified and frequently no pathology is found (chronic pelvic pain syndrome). The central nervous system (CNS) is central to the experience of pain and chronic pain conditions in general are associated with alterations in both the structure and function of the CNS. This review describes the available evidence for central changes in association with conditions presenting with CPP., Methods: A detailed literature search was performed to identify relevant papers, however, this is not a systematic review., Results: CPP is associated with central changes similar to those identified in other pain conditions. Specifically these include, alterations in the behavioural and central response to noxious stimulation, changes in brain structure (both increases and decreases in the volume of specific brain regions), altered activity of both the hypothalamic-pituitary-adrenal axis and the autonomic nervous system (ANS) and psychological distress., Conclusions: The evidence reviewed in this paper demonstrates that CPP is associated with significant central changes when compared with healthy pain-free women. Moreover, the presence of these changes has the potential to both exacerbate symptoms and to predispose these women to the development of additional chronic conditions. These findings support the use of adjunctive medication targeting the CNS in these women., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is one of the risk factors of impaired male fertility potential. Studies have investigated the effect of CP/CPPS on several semen parameters but have shown inconsistent results. Hence, we performed a systematic literature review and meta-analysis to assess the association between CP/CPPS and basic semen parameters in adult men., Methods: Systematic literature searches were conducted with PubMed, EMBASE and the Cochrane Library up to August 2013 for case-control studies that involved the impact of CP/CPSS on semen parameters. Meta-analysis was performed with Review Manager and Stata software. Standard mean differences (SMD) of semen parameters were identified with 95% confidence intervals (95% CI) in a random effects model., Results: Twelve studies were identified, including 999 cases of CP/CPPS and 455 controls. Our results illustrated that the sperm concentration and the percentage of progressively motile sperm and morphologically normal sperm from patients with CP/CPPS were significantly lower than controls (SMD (95% CI) -14.12 (-21.69, -6.63), -5.94 (-8.63, -3.25) and -8.26 (-11.83, -4.66), respectively). However, semen volume in the CP/CPPS group was higher than in the control group (SMD (95% CI) 0.50 (0.11, 0.89)). There was no significant effect of CP/CPPS on the total sperm count, sperm total motility, and sperm vitality., Conclusions: The present study illustrates that there was a significant negative effect of CP/CPPS on sperm concentration, sperm progressive motility, and normal sperm morphology. Further studies with larger sample sizes are needed to better illuminate the negative impact of CP/CPPS on semen parameters.

Objective: The aim of this preliminary study was to determine whether psychiatric disorders, psychopathological symptoms, and alexithymia are associated with endometriosis in an Italian population., Study Design: A preliminary study comprising 37 Italian patients with surgically confirmed endometriosis and 43 controls, without clinical and ultrasound signs of endometriosis, was carried out. Both patients and controls were evaluated for the presence/absence of psychiatric disorders, psychopathological symptoms, alexithymia, and pain symptoms (nonmenstrual pelvic pain, dysmenorrhea, and dyspareunia)., Results: Statistically significant differences were found between cases and controls for prevalence of mood and anxiety disorders, malfunctioning on obsessive-compulsive subscale (P < 0.01) and depression subscale (P < 0.05) of the Symptom Checklist-90-Revisited (SCL-90-R), and higher alexithymia levels (P < 0.01). Patients with endometriosis-associated pain showed greater prevalence of psychiatric disorders compared to pain-free patients but that difference was not significant. Significant correlation was found between malfunctioning in some SCL-90-R dimensions and pelvic pain, dysmenorrhea, and dyspareunia scores at the visual analog score (VAS)., Conclusion: Some psychopathological aspects, such as psychoemotional distress and alexithymia, are more frequent in women with endometriosis and might amplify pain symptoms in these patients.

The main sequelae of endometriosis are represented by infertility and chronic pelvic pain. Chronic pelvic pain causes disability and distress with a very high economic impact. In the last decades, an impressive amount of pharmacological agents have been tested for the treatment of endometriosis-associated pelvic pain. However, only a few of these have been introduced into clinical practice. Following the results of the controlled studies available, to date, the first-line treatment for endometriosis associated pain is still represented by oral contraceptives used continuously. Progestins represent an acceptable alternative. In women with rectovaginal lesions or colorectal endometriosis, norethisterone acetate at low dosage should be preferred. GnRH analogues may be used as second-line treatment, but significant side effects should be taken into account. Nonsteroidal anti-inflammatory drugs are widely used, but there is inconclusive evidence for their efficacy in relieving endometriosis-associated pelvic pain. Other agents such as GnRH antagonist, aromatase inhibitors, immunomodulators, selective progesterone receptor modulators, and histone deacetylase inhibitors seem to be very promising, but there is not enough evidence to support their introduction into routine clinical practice. Some other agents, such as peroxisome proliferator activated receptors-γ ligands, antiangiogenic agents, and melatonin have been proven to be efficacious in animal studies, but they have not yet been tested in clinical studies.

Purpose: Endometriosis-associated pelvic pain appears due to persistent nociceptive stimulation, but the precise mechanisms remain poorly understood., Methods: A search was conducted to screen and select articles from PubMed., Main Results: Neurotrophins (NTs), a family of neuronal growth factors, are overexpressed in endometriosis and encompass NGF, BDNF and NT-3 and NT-4/5. NT receptors, TrkA and p75NTR, and NT receptor-interacting proteins, MAGE and NDN, were also expressed. NTs and their receptors play a role in the development and maintenance of neural tissues in non-neuronal cell types such as endometriosis. Nerve fibers contain unmyelinated sensory C, myelinated sensory Adelta and adrenergic nerve fibers that innervate abnormal cell growths. An increased release of proinflammatory cytokines from endometriotic lesions is responsible for the excessive sensory innervation and development of chronic pelvic pain., Conclusions: The preponderance of the inflammatory milieu and subsequent hyperinnervation might be involved in the pathophysiology of pain generation in women with endometriosis.

The pathophysiology of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is poorly understood. Inflammatory and autoimmune mechanisms may play a role. We developed a murine model of experimental autoimmune prostatitis (EAP) that mimics the human phenotype of CP/CPPS. Eight-week-old mice were immunized subcutaneously with prostate-specific peptides in an emulsion of complete Freund's adjuvant. Mice were euthanized 10 days after immunization, and lymph node cells were isolated and assessed for recall proliferation to each peptide. P25 99-118 was the most immunogenic peptide. T-cell and B-cell immunity and serum levels of C-reactive protein and nitrate/nitrite levels were evaluated over a 9-wk period. Morphometric studies of prostate, 24-h micturition frequencies, and urine volume per void were evaluated. Tactile referred hyperalgesia was measured using von Frey filaments to the pelvic region. The unpaired Student's t-test was used to analyze differences between EAP and control groups. Prostates from p25 99-118-immunized mice demonstrated elevated gene expression levels of TNF-α, IL-17A, IFN-γ, and IL-1β, not observed in control mice. Compared with controls, p25 99-118-immunized mice had significantly higher micturition frequency and decreased urine output per void, and they demonstrated elevated pelvic pain response. p25 99-118 immunization of male SWXJ mice induced prostate-specific autoimmunity characterized by prostate-confined inflammation, increased micturition frequency, and pelvic pain. This autoimmune prostatitis model provides a useful tool for exploring the pathophysiology and new treatments.

Objective: To review the indications for, and the associated pathology and complications of, appendectomy performed during gynaecologic surgery in a tertiary academic health sciences centre., Methods: We performed a retrospective review of appendectomy cases performed from September 2007 to December 2011 in a tertiary level gynaecologic surgical practice. Cases were reviewed using a standardized intake sheet with surgical reports, history, and pathologic findings., Results: A total of 71 appendectomies were performed during gynaecologic surgery in the study period. All cases were primary gynaecologic surgical cases; the most common diagnoses were endometriosis, pelvic pain, and pelvic mass. Overall, 42 (59%) of the study cases had abnormal histopathology in the appendix. Of the 44 women with a primary diagnosis of endometriosis, 28 (64%) had positive appendiceal pathology. In women with chronic pelvic pain, three of eight (38%) had pathology within their appendix. Of all appendixes removed that appeared normal on gross inspection, irrespective of diagnosis, 44% had positive pathology., Conclusion: When a structured approach is taken towards assessment of the appendix during gynaecologic surgical cases, with removal when indicated, a high rate of pathology may be found. In this series, there were no complications directly related to the appendectomy, providing support for the contention that appropriately trained gynaecologists can safely perform appendectomy. The findings in this Canadian series are in keeping with previous reports and support the need for evaluation and removal of the appendix when indicated at the time of gynaecological surgery.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition that adversely affects men across a wide range of ages. A number of pharmacologic and nonpharmacologic therapies for CP/CPPS have been investigated. Our study aimed to evaluate the prevalence of CPPS in Korean men in their thirties and to investigate the effect of CPPS and medical treatment on semen quality. Of 314 men with prostatitis, 74 patients with CPPS class IIIA (23.6%) were eligible for the study; these patients underwent combined α-blocker and cyclo-oxygenase 2 inhibitor therapy. These 74 men were prospectively studied at a medical center in Seoul, Korea. A number of parameters, including ejaculations per month, semen variables, and the levels of hormones (such as follicle-stimulating hormone, estradiol [E(2)], luteinizing hormone [LH], testosterone, and prolactin) were evaluated. The mean number of ejaculations per month, the mean number of daily hours spent sitting at work, smoking, body mass index, LH and E(2) levels, and semen parameters all showed significant differences (P < .0001) between the study patients and the controls. The combined regimen was effective in improving all aspects of semen quality except morphology (P < .05). CPPS class IIIA, which is notably prevalent among Korean men in the fourth decade of life, affects semen quality and poses a challenge to fertility. Proper treatment of CPPS class IIIA results in improved semen quality. Men with CPPS therefore require proper evaluation and treatment by andrologists/urologists before planning a natural conception.

Objective: To determine the effect of uncoupling oxidative phosphorylation with 2,4-dinitrophenol (DNP) on adhesion phenotype development., Design: Prospective experimental study., Setting: Academic medical center., Patient(s): Women undergoing laparotomy for pelvic pain from whom normal peritoneum and adhesions were excised to create primary cultures of normal peritoneal and adhesion fibroblasts., Intervention(s): Treatment of normal peritoneal and adhesion fibroblasts isolated from the same patient(s) with or without 0.2 mM DNP for 24 hours., Main Outcome Measure(s): Evaluation of adhesion phenotype markers type I collagen, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor (HIF)-1α., Result(s): In agreement with prior findings, adhesion fibroblasts exhibited significantly higher basal levels of type I collagen, VEGF, and HIF-1α compared with normal peritoneal fibroblasts. Treatment of normal peritoneal fibroblasts with DNP resulted in significant increases in type I collagen (10.2 ± 1.4 vs. 18.4 ± 1.9 fg/μg RNA) and VEGF (8.2 ± 1.1 vs. 13.7 ± 0.4 fg/μg RNA) over baseline. HIF-1α levels did not increase when normal peritoneal fibroblasts were treated with DNP., Conclusion(s): The adhesion phenotype, which is normally expressed in response to hypoxia, is reproduced in a normoxic environment by uncoupling oxidative phosphorylation with DNP, as evidenced by an increase in type I collagen and VEGF. Acquisition of the adhesion phenotype was via a mechanism distinct from up-regulation of HIF-1α. These observations are consistent with the hypothesis that the adhesion phenotype represents a state of intracellular metabolic depletion., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)