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Objectives To explore if the mechanism of the voiding dysfunction caused by spinal cord injury in rats can be improved by intravenous administration of the 5-HT2A/2C receptor agonist, DOI, and discuss whether it can be ascribed to serotonin 2A and 2C receptor up-regulation in lumbosacral cord motoneurons. Materials and Methods Female Sprague-Dawley rats were used, which were divided into two groups (Spinal cord injury group VS Normal control group). Under urethane anesthesia, cystometry was performed to examine the variation of urodynamic parameters before and after successive intrathecal administration of various doses of DOI into the lumbosacral cord. Additionally, the changes of serotonin 2A and 2C receptors in the lumbosacral cord were investigated by immunohistochemical staining and Western blot. Results Compared to controls, spinal cord injured rats had higher bladder capacity and post-void residual urine volume, and lower voiding efficiency. After spinal cord injury, DOI improved voiding efficiency likely via affecting external urethral sphincter activity. Immunohistochemical staining and Western blot analysis showed that serotonin 2A and 2C receptors were up-regulated in lumbosacral cord motoneurons. Conclusion In rats with spinal cord injury, DOI can improve voiding efficiency, and this may be due to serotonin 2A and 2C receptor up-regulation in lumbosacral cord motoneurons controlling external urethral sphincter activity. This article is protected by copyright. All rights reserved.

The overactive bladder (OAB) syndrome, characterized by urinary urgency with or without urgency urinary incontinence (UUI) and usually associated with increased daytime frequency and nocturia (1), is a common condition worldwide. Independent of the methodology used (telephone survey, postal survey) several epidemiologic studies in Europe, Canada, the United States, and Japan have shown the OAB syndrome to be present in 8.0% to 16.5% of adults, with similar rates between men and women (2,3).

Half of the female population over age 50 years will experience pelvic organ prolapse. We suggest a new approach based on tissue engineering principles to functionally reconstruct the anatomical structures of the pelvic floor. The aim of this study is to investigate the mechanical performance and effect on collagen and elastin production of a degradable mesh releasing basic fibroblast growth factor (bFGF). Implantation of biodegradable mesh with or without bFGF in their core has been conducted in 40 rats in an abdominal wall defect model. Samples were explanted after 4, 8, and 24 weeks, and tested for mechanical properties and the composition of connective tissue. The study showed an increase in mRNA expression for collagen-I (p = 0.0060) and collagen-III (p = 0.0086) in the 4 weeks group with bFGF. The difference was equalized at 8 and 24 weeks. No difference was found at any time for protein amount for collagen-I, collagen-III, and fibronectin. The amount of collagen decreased from 4 to 24 weeks but the fraction of collagen increased. The maximal load of the newly formed tissue showed no effect of bFGF at any time. Exclusively, histology showed a limited ingrowth of collagen fibers after 4 weeks with bFGF but signs of elastin fibers were seen at 24 weeks. The investigation showed that a biodegradable mesh promotes tissue formation with a promising strength. The mesh with bFGF did not represent any advantage on either long or short term in comparison to the mesh without bFGF. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 680–688, 2018.

Purpose: Mixed efficacy results of autologous skeletal muscle precursor cell therapy in women with chronic intrinsic urinary sphincter deficiency have increased interest in the therapeutic value of alternative regenerative medicine approaches. The goal of this study was to compare the effects of the cell homing chemokine CXCL12 (C-X-C motif chemokine 12) and skeletal muscle precursor cells on chronic urinary sphincter regeneration in chronic intrinsic urinary sphincter deficiency.Materials and Methods: Five million autologous skeletal muscle precursor cells or 100 ng CXCL12 were injected in the urinary sphincter complex of adult female cynomolgus monkeys with chronic (6-month history) intrinsic urinary sphincter deficiency. These treatment groups of 3 monkeys per group were compared to a group of 3 with no intrinsic urinary sphincter deficiency and no injection, and a group of 3 with intrinsic urinary sphincter deficiency plus vehicle injection. Maximal urethral pressure was measured at rest, during stimu...

We summarize the current state of knowledge regarding cell therapy for stress urinary incontinence and introduce new approaches of using regenerative pharmacology as an adjunct or replacement for cell therapy.We reviewed the literature by searching PubMed®, Ovid and Biological Abstracts. The period searched was 1975 to December 2015. The inclusion terms separately or in combination were stress urinary incontinence, cell therapy, chemokine, vascularization, innervation, secretome and/or animal models. Epublished articles were not included. We did not exclude articles based on impact factor.Cell therapy is currently proposed to restore functional muscle cells and aid in closure of the sphincter in women with sphincter associated incontinence. Clinical trials have included small numbers of patients and results have varied depending on the patient cohorts and the cells used. Results of preclinical studies have also varied but show a more favorable outcome. This difference was most likely explained by the fact that animal modeling is not directly translatable to the human condition. However, preclinical studies have identified an exciting new approach to regeneration of the urinary sphincter using the components of cells (secretomes) or chemokines that home reparative cells to sites of injury.Cell therapy will continue to be explored. However, a regenerative pharmacological approach to the treatment of stress urinary incontinence holds the promise of bypassing the lengthy and expensive process of cell isolation and also increasing the availability of treatment in many clinical settings. This approach requires careful preclinical modeling and attention to its health benefit-to-risk ratio.

AIM: To review evidence for novel drug targets that can manage overactive bladder (OAB) symptoms.METHODS: A think tank considered evidence from the literature and their own research experience to propose new drug targets in the urinary bladder to characterize their use to treat OAB.RESULTS: Five classes of agents or cellular pathways were considered. (a) Cyclic nucleotide-dependent (cyclic adenosine monophosphate and cyclic guanosine monophosphate) pathways that modulate adenosine triphosphate release from motor nerves and urothelium. (b) Novel targets for β3 agonists, including the bladder wall vasculature and muscularis mucosa. (c) Several TRP channels (TRPV1 , TRPV4 , TRPA1 , and TRPM4 ) and their modulators in affecting detrusor overactivity. (d) Small conductance Ca2+ -activated K+ channels and their influence on spontaneous contractions. (e) Antifibrosis agents that act to modulate directly or indirectly the TGF-β pathway-the canonical fibrosis pathway.CONCLUSIONS: The specificity of action remains a consideration if particular classes of agents can be considered for future development as receptors or pathways that mediate actions of the above mentioned potential agents are distributed among most organ systems. The tasks are to determine more detail of the pathological changes that occur in the OAB and how the specificity of potential drugs may be directed to bladder pathological changes. An important conclusion was that the storage, not the voiding, phase in the micturition cycle should be investigated and potential targets lie in the whole range of tissue in the bladder wall and not just detrusor.

Introduction: In the lower urinary tract (LUT) several members of the TRP superfamily are involved in nociception and mechanosensory transduction. Animal studies have suggested a therapeutic potential of some of these channels, including TRPV1, TRPV4, TRPM8, TRPA1, and TRPM4, for treatment of bladder over- and underactivity and bladder pain disorders, but translation of this information to clinical application has been slow. Areas covered: An update on and discussion of current information on the potential clinical use of TRP channel agonists/antagonists in the treatment of different types of bladder dysfunction. The electronic databases PubMed and Scopus were used to identify relevant clinical and animal studies. Expert opinion: The therapeutic effect of TRPV1 channel desensitizing agonists (capsaicin, resiniferatoxin, given intravesically) has been convincingly demonstrated in some forms of bladder overactivity. However, so far, the potential of any of the small-molecule TRP channel blockers developed for non-bladder indications and tested in early human trials for safety has not been explored clinically in LUT dysfunction. The adverse effects of hyperthermia and reduction of noxious heat sensation of the first generation TRPV1 blockers have delayed development. Despite lack of translational information, TRP channels remain interesting targets for future LUT drugs.

Purpose: Bladder outflow obstruction (BOO) is common in the elderly and can result in bladder voiding dysfunction (BVD) due to severe bladder muscle damage. The goal of this research was to evaluate the use of adult stem cells for the treatment of BVD due to decreased muscle contractility in a rat model. Materials and methods: Adipose-derived stem cells (ADSCs) and muscle precursor cells (MPCs) were harvested from male Lewis rats and expanded in culture. BOO was induced by tying a suture around the urethra. Six weeks after obstruction, the development of BVD was confirmed by cystometric analysis in conscious rats, histology and molecular investigations. Injection of ADSCs or MPCs into the bladder wall and synchronous deligation was performed 6weeks after the obstruction. After stem-cell treatment, morphological and functional changes were assessed. Age-matched rats and animals without cellular therapy but deligation-only served as controls. Results: Voiding pressures decreased progressively 6weeks after obstruction with increased bladder capacities. Structural changes of the detrusor muscle occurred during the time of obstruction with an increased connective tissue-to-smooth muscle ratio and decreased SMA/smoothelin expression. After stem-cell injection, improved voiding pressures and voiding volumes were observed together with recovered tissue architecture. RT-PCR and Western blotting showed an up-regulation of important contractile proteins. Conclusions: We established a reliable model for BVD and demonstrated that ADSCs and MPCs can prevent pathophysiological remodelling and provide regenerated bladder tissue and function.

Item does not contain fulltext CONTEXT: Several drugs are approved and available for the treatment of lower urinary tract symptoms (LUTS) in men and women. However, the vast majority of available data, upon which the approval and recommendation in guidelines are based, considered only the role of the monotherapies and did not evaluate possible combination therapies. OBJECTIVE: This systematic review analyzes the efficacy and adverse events of combination therapies for male and female LUTS. EVIDENCE ACQUISITION: A systematic literature search in the PubMed/Medline, Web of Science, and Cochrane databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement to identify clinical trials, randomized controlled trials, meta-analyses, and guidelines on male and female LUTS combination therapy published from March 2012 to December 2017 for men (in order to update a previous men-focused work) and from January 1988 to December 2017 for women. A total of 58 papers were identified. EVIDENCE SYNTHESIS: The most studied combination therapy for the treatment of male LUTS is the alpha1-adrenoceptor antagonist/5alpha-reductase inhibitor combination. This combination seems to be more efficacious in terms of several outcome variables, in particular in men who have moderate-to-severe LUTS and are at risk of disease progression. Also in terms of nocturia improvements, this combination is significantly more effective than the monotherapy. The other often studied combination treatment, in both male and female patients with LUTS, was the combination of antimuscarinics (in particular solifenacin) and mirabegron. This combination seems to be more effective in comparison with the monotherapies with respect to urinary incontinence and urgency urinary incontinence episodes and several other objective and subjective parameters, without relevant increase of adverse events. The combination of hormone therapy and antimuscarinics in women with LUTS does not seem to be useful. CONCLUSIONS: For the treatment of LUTS in men and women, combination therapy appears to be a promising option to optimize the efficacy of the available drugs for those who do not experience sufficient benefit with monotherapy. This add-on scenario offers the possibility to have a more tailored approach to the management of LUTS, always seeking the optimal balance between efficacy and tolerability for a given patient. PATIENT SUMMARY: Some combination of drugs may offer advantages over monotherapies for the treatment of voiding and storage complaints in men and women.

Introduction Tramadol exhibits an effect profile similar to that of opioid agonists, and tramadol abuse seems to be a problem for a number of countries. The relationship between tramadol and sexual function appears to be controversial. Men with premature ejaculation (PE) may benefit from taking tramadol off label; however, these patients live “on a knife's edge” and are exquisitely sensitive to develop other sexual dysfunctions. Aim To review the literature regarding the problem of tramadol abuse and its relationship with sexual function. Methods We searched electronic databases from 1977 to September 2015, including PubMed MEDLINE, EMBASE, EBCSO Academic Search Complete, Cochrane Systematic Reviews Database, and GoogleScholar using the following key words: tramadol, sexual functions, and sexual dysfunction. Main Outcome Measure To define the supposed benefits and the potential risks of tramadol on different sexual functions including ejaculation, orgasm, erection, desire, and testosterone levels. Results Although tramadol is thought to have low abuse and dependence potentials worldwide, its abuse has become a serious problem in many countries, particularly in the Middle East, Africa, and West Asia. The benefit of tramadol in PE was reported in 11 clinical trials, evaluated by 6 systematic reviews, 3 of which pooled data in a meta-analysis. The evidence base on erectile dysfunction, decreased libido, hypogonadism, anorgasmia, and risky sexual behaviors in patients abusing tramadol is inadequate. Conclusions Tramadol may offer a useful intervention for treating PE. As all primary studies had suffered from selection, allocation, performance, or assessment bias, additional rigorous well-designed controlled trials are warranted to further investigate the potential long-term risks of tramadol and to determine the safe and the effective minimum daily dose. Clinical research on drug abuse and sexual dysfunction is an emerging field. To date, small numbers of studies have been performed and further studies are warranted.

Aims The pathophysiologies of nocturia (NOC) and nocturnal polyuria (NP) are multifactorial and their etiologies remain unclear in a large number of patients. Clock genes exist in most cells and organs, and the products of Clock regulate circadian rhythms as representative clock genes. Clock genes regulate lower urinary tract function, and a newly suggested concept is that abnormalities in clock genes cause lower urinary tract symptoms. In the present study, we investigated the voiding behavior of Clock mutant (ClockΔ19/Δ19) mice in order to determine the effects of clock genes on NOC/NP. Methods Male C57BL/6 mice aged 8–12 weeks (WT) and male C57BL/6 ClockΔ19/Δ19 mice aged 8 weeks were used. They were bred under 12 hr light/dark conditions for 2 weeks and voiding behavior was investigated by measuring water intake volume, urine volume, urine volume/void, and voiding frequency in metabolic cages in the dark and light periods. Results No significant differences were observed in behavior patterns between ClockΔ19/Δ19 and WT mice. ClockΔ19/Δ19 mice showed greater voiding frequencies and urine volumes during the sleep phase than WT mice. The diurnal change in urine volume/void between the dark and light periods in WT mice was absent in ClockΔ19/Δ19 mice. Additionally, functional bladder capacity was significantly lower in ClockΔ19/Δ19 mice than in WT mice. Conclusions We demonstrated that ClockΔ19/Δ19 mice showed the phenotype of NOC/NP. The ClockΔ19/Δ19 mouse may be used as an animal model of NOC and NP. Neurourol. Urodynam. © 2016 Wiley Periodicals, Inc.

In the last decades, a number of new antimuscarinic drugs have been introduced for treatment of the overactive bladder (OAB), defined symptomatically (OAB syndrome) or urodynamically (detrusor overactivity). Recently, three new drug principles have been approved for clinical use, the β3 -adrenoceptor agonist, mirabegron, the phosphodiesterase-5 inhibitor, tadalafil and the blocker of afferent and efferent nerves, botulinum toxin. However, new alternatives are continuously being explored. OAB is a filling disorder, and ATP is involved in the generation of afferent impulses. One way of blocking the ATP afferent pathway is through the use of P2X3 receptor antagonists. In animal models, this strategy appears to work very well, but whether it translates effectively to man remains to be established. Evidence suggests that components of the endocannabinoid system are involved in regulation of bladder function. Clinical studies of cannabinoid extracts on LUTS are scarce and essentially restricted to patients with MS, and the results have so far not been convincing. Amplification of endocannabinoid activity by inhibiting their degradation via fatty acid amide hydrolase inhibitors may be an attractive approach, but no clinical experiences in OAB have been reported. Studies of the lower urinary tract have indicated that several transient receptor potential (TRP) channels, including TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1, are expressed in the bladder and may act as sensors of stretch and/or chemical irritation. Animal studies have shown that inhibition of these pathways can be effective for the reduction in bladder activity. However, the roles of these channels for normal function and in pathological states have not been established, and so far adverse effects (hyperthermia) have hampered development of antagonists.

Introduction The vascular resistance of stem villous arteries is determined by the balance between different contractile and relaxant agents and in the utero-placental circulation. Thromboxane A 2 (TxA 2 ), prostaglandin F 2α (PGF 2α ) and endothelin-1 (ET-1) are considered to be among the most important contractile factors. However, it is not known if their contractile effects are consistent along the villous tree. We hypothesized that the sensitivity to different agonists could be influenced by artery diameter and thus that their contribution to placental vascular resistance may differ. Methods Using an isometric wire myograph, the contractility and sensitivity (pD 2 ) to the thromboxane A 2 mimetic U46619, PGF 2α and ET-1 were investigated in isolated human stem villous arteries and human uterine fundus and isthmus arteries obtained from healthy, pregnant women who had experienced uncomplicated pregnancy. Results In fetal arteries, the pD 2 values for U46619 correlated positively with arterial diameter with no such dependence observed for ET-1 and PGF 2α . In maternal arteries, pD 2 remained constant for all the agonists tested despite highly variable vessel diameter. Discussion A selective decrease in sensitivity to TxA 2 receptor stimulation was observed with decreasing vascular diameter in human stem villous arteries. The contractile factors PGF 2α and ET-1 show no such relationship.

Lower urinary tract (LUT) dysfunction is the most common complication of diabetes mellitus (DM). An involvement of the 5-HT

We aimed to investigate the association between nocturia and serum metabolites identified using metabolomics analysis. This study enrolled 66 men aged 65–80 years, recruited from the outpatient department of a university hospital. The participants were stratified as follows: Nocturia group [45 men with any total international prostate symptom score (IPSS) and an average of 3 nights ≥ 1.5 micturitions/night] and Control group (21 men with total IPSS

Purpose Antidiuretic therapy with desmopressin for nocturia has been hampered by formulations with high doses, low bioavailability and variable pharmacokinetics. AV002 (SER120), a novel, emulsified, microdose desmopressin nasal spray, with a permeation enhancer (cylcopentadecanolide), was developed to have pharmacokinetic characteristics suitable for nocturia treatment. Methods Twelve healthy subjects participated in an open-label, dose-escalating study. Water-loaded subjects were sequentially dosed every 48 h with AV002 0.5, 1.0, 2.0 μg and 0.12 μg desmopressin subcutaneous (SC) bolus injection. Results AV002 intranasal administration produced a time-to-maximum concentration (Tmax) between 15 and 30 min and a maximum concentration (Cmax)

Introduction Endoscopic surgical treatment represents the gold standard in patients with lower urinary tract symptoms (LUTS) when medical treatment fails. In the past years there has been a growing interest in intraprostatic injections which represent a minimally invasive alternative for those patients not suitable for surgery. Aim of our study is to systematically review all the available data on intraprostatic injections for the treatment of LUTS patients with benign prostatic enlargement (BPE). Evidence acquisition A systematic review of the literature using the Medline, Scopus and Web of Science databases for relevant articles published until June 2018 was performed using both the Medical Subjects Heading and free test protocols. The MeSH search was conducted by combining the following terms: "Intraprostatic Injections," "Botulinum Toxin A," "Onabotulinum," "Ethanol," "Lower Urinary tract Symptoms," "Benign prostatic enlargement," "Benign Prostatic Hyperplasia," "NX1207," "PRX302." Each article's title and abstract were reviewed for their appropriateness and their relevance with regards to the relationship to intraprostatic injections. Evidence synthesis Intraprostatic injections for the treatment of LUTS/BPE patients may be performed using different products as: ethanol, onabotulinum toxin A, NX1207 and PRX 302. Ethanol, the first agent for intraprostatic use, showed promising results in prospective trials, however, the rare but serious adverse events associated with extraprostatic diffusion of ethanol stopped its use. Many studies on onabotulinum toxin A (BotoxR) have been performed, however, two large randomized clinical trials showed no differences in terms of symptoms improvements and flow improvements when compared to placebo. Two new promising drugs NX 1207 and PRX 302 have been developped in the past years. NX 1207 showed lack of efficacy in the two large European phase III RCT. PRX 302 showed promising results in phase I and II studies, however, definitive results from a large phase III randomized controlled trial (RCT) are awaited before drawing any definitive conclusions. Conclusions Intraprostatic injections are still to be considered investigational for the minimally invasive management of LUTS/BPE patients. Emerging data suggest a possible role of new agents in the near future when definitive data of ongoing RCTs will be available.

New alternatives for treatment of overactive bladder (OAB) syndrome are continuously being explored. Despite ongoing nonclinical and clinical research, few new principles have evolved. We can expect future new additions to existing drug classes and different combinations of existing options. New antimuscarinics are in development, but we do not know if they offer any advantages to currently available drugs. A new β3-adrenoceptor agonist, vibegron, has an interesting profile and is in clinical development (phase 3). Combinations of agents (e.g., antimuscarinic and β3-adrenoceptor agonists) appear to have advantages in cases not responding to monotherapy. To improve intravesical treatment with botulinum toxins, novel formulations aim at increasing bioavailability at the site of action while decreasing adverse events. These new approaches have been tested in animal models and to some extent in patients. One of the most promising is liposomes containing the toxin. OAB is a filling disorder, and ATP is involved in the generation of afferent impulses. Blocking the ATP pathway by P2X3 receptor antagonists works in animal models of lower urinary tract (LUT) dysfunction, but its clinical effectiveness has not yet been established. Several transient receptor potential (TRP) channels, including TRPV1, TRPV2, TRPV4, TRPM8, and TRPA1, expressed in the LUT, may act as sensors of stretch and/or chemical irritation. Animal studies show that inhibition of some of these pathways can be effective for reduction in bladder activity. Clinical studies of LUT dysfunction are scarce, and the adverse effect of hyperthermia of the first-generation TRPV1 antagonists has delayed development. Nevertheless, TRP channels still may be the most exciting targets for future LUT drugs.

Objective Persistent urinary incontinence (UI) and/or erectile dysfunction (ED) occur in 30-50% of post-radical prostatectomy patients regardless of nerve sparing approaches. Identification of potential treatment options for these patients will require testing in an animal model that develops these chronic conditions. The objective was to characterize a nonhuman primate (NHP) model of persistent post-prostatectomy ED and UI and then test the feasibility of periurethral injection of the chemokine CXCL-12. Methods Ten adult male cynomolgus monkeys were used. Two were used for study of normal male nonhuman primate genitourinary anatomy. Five were used for measures of sexual behavior, peak intra-corporal pressure (ICP), abdominal leak point pressures (ALPP) 3 and 6-months post open radical prostatectomy (ORP). Three additional ORP animals received ultrasound-guided peri-urethral injection of chemokine CXCL12 6 weeks after ORP, and UI/ED evaluated for up to 3 months. Results The anatomy, innervation, and vascular supply to the prostate and surrounding tissues of these male NHPs are substantially similar to those of human beings. ORP resulted in complete removal of the prostate gland along with both neurovascular bundles and seminal vesicles while permitting stable restoration of vesico-urethral patency. ORP produced sustained (6 months) decreases in ALPP, ICP's, and sexual function. Transurethral injection of chemokine CXCL12 was feasible and had beneficial effects on erectile and urinary function. Conclusions ORP in NHPs produced persistent erectile and urinary tract dysfunction. Periurethral injection of CXCL-12 was feasible and improved both urinary incontinence and erectile dysfunction and suggests that this model can be used to test new approaches for both conditions.

Aims. Most benign bladder pathologies are associated with an increase of extracellular matrix (ECM – fibrosis) and may progress from formation of stiffer matrix to a more compliant structure. The aims were to summarise current knowledge of the origins of bladder fibrosis and consequences in bladder function. Methods. A meeting at the International Consultation on Incontinence Research Society 2017 congress discussed the above aims and considered paradigms to reduce the extent of fibrosis. Discussants based their arguments on the basis of their own expertise, supplemented by review of the literature through PubMed. Proposals for future work were derived from the discussionResults. Altered urodynamic compliance when ECM deposition is increased is mirrored by changes in the elastic modulus of isolated tissue, whether compliance is decreased or increased. No changes to compliance or fibrosis have been reported after botulinum toxin injections. Several paracrine and autocrine agents increase ECM deposition, the role of TGF-β was particularly emphasised. None of these agents has a net long-term effect on detrusor contractility and the reduction of contractile performance with increased ECM is due solely to a loss of detrusor mass. Several strategies to reduce fibrosis were described, ranging from potential therapeutic roles for vitamin-D or endostatin, manipulation of intracellular pathways that mediate myofibroblast differentiation and the potential role of the anti-fibrotic hormone relaxin. An understanding of epigenetic regulation of ECM deposition was also considered.Conclusions. The conclusion that reduced bladder contractile function with increased fibrosis is due largely to the replacement of detrusor with ECM offers a way forward for future research to consider approaches that will restore bladder function by reducing ECM deposition.

The nervous system is engaged by infection, indirectly through inflammatory cascades or directly, by bacterial attack on nerve cells. Here we identify a neuro-epithelial activation loop that participates in the control of mucosal inflammation and pain in acute cystitis. We show that infection activates Neurokinin-1 receptor (NK1R) and Substance P (SP) expression in nerve cells and bladder epithelial cells in vitro and in vivo in the urinary bladder mucosa. Specific innate immune response genes regulated this mucosal response, and single gene deletions resulted either in protection (Tlr4−/− and Il1b−/− mice) or in accentuated bladder pathology (Asc−/− and Nlrp3−/− mice), compared to controls. NK1R/SP expression was lower in Tlr4−/− and Il1b−/− mice than in C56BL/6WT controls but in Asc−/− and Nlrp3−/− mice, NK1R over-activation accompanied the exaggerated disease phenotype, due, in part to transcriptional de-repression of Tacr1. Pharmacologic NK1R inhibitors attenuated acute cystitis in susceptible mice, supporting a role in disease pathogenesis. Clinical relevance was suggested by elevated urine SP levels in patients with acute cystitis, compared to patients with asymptomatic bacteriuria identifying NK1R/SP as potential therapeutic targets. We propose that NK1R and SP influence the severity of acute cystitis through a neuro-epithelial activation loop that controls pain and mucosal inflammation.

Urgency is the prevalent and most bothersome symptom of overactive bladder (OAB) and the treatment of urgency is the primary objective in the management of OAB. Urgency has a major impact on other symptoms of OAB and culminates in an increased frequency of micturition and reduced volume voided, which may contribute to shorter intervals between the need to void. Antimuscarinic agents and mirabegron, a β3-adrenoceptor agonist, constitute the main oral pharmacotherapeutic options for the treatment of urgency and other OAB symptoms. The reduction of urgency and other OAB symptoms significantly improve health-related quality of life. This review will explore the distinct mechanisms of action and effects of antimuscarinic agents and mirabegron, in relation to their effect on the pathophysiology of urgency. The review will also provide an overview of the various validated measurements of urgency and the numerous clinical trials regarding antimuscarinic agent monotherapy, mirabegron monotherapy, or combination treatment with mirabegron added on to the antimuscarinic agent solifenacin. A narrative review of the literature relating to pathophysiology of urgency, the validated measurements of urgency, and clinical trials relating to the pharmacological treatment of urgency. Antimuscarinic agent monotherapy, mirabegron monotherapy, or combination treatment with mirabegron added on to the antimuscarinic agent solifenacin statistically significantly reduce the symptoms of urgency compared with placebo. Combination therapy with mirabegron added on to solifenacin also statistically significantly reduces the symptoms of severe urgency compared with antimuscarinic agent monotherapy. A critique of the clinical benefits of combination therapy is also provided. Combination therapy provides an alternative treatment in patients with OAB that includes urgency who respond poorly to first-line monotherapy and who may otherwise often move on to more invasive treatments.

Aims: Update on some molecular targets for new drugs to improve lower urinary tract (LUT) dysfunction. Methods: Using PubMed, a search for literature on molecular targets in the LUT was performed to identify relevant clinical and animal studies. Keywords were entered as Medical Subject Headings (MeSH) or as text words. The Mesh terms were used in various combinations and usually included the terms lower urinary AND pharmacology. Other Mesh term included: bladder, urethra, CNS, physiology, afferent activity, ATP, prostanoids, cannabinoids, fibrosis. Search results were assessed for their overall relevance to this review. Results: In a normal bladder, ATP contributes little to detrusor contraction, but in a diseased bladder ATP may contribute to OAB. Selective decrease of ATP release via adenosine A1 receptor stimulation offers a potential treatment possibility. Candidates for relaxation of the smooth muscle of the urethra can be found among, for example, the receptor subtypes of PGE2, and PGD2. Drugs for relaxation of the striated sphincter can target the muscle directly or the spinal sphincter control. Fibrosis is a major problem in LUT dysfunction and agents with an inhibitory effect on the TGFβ pathway, for example relaxin and BMP7, may be promising avenues. Available drugs with a CNS site of action are often limited by low efficacy or adverse effects. Inhibitors of the glycine receptor Gly-T2 or antagonists of the adenosine A2 receptor may be new alternatives. Conclusion: New molecular targets for drugs aiming at improvement of voiding function can be identified, but their translational impact remains to be established.

Oxidative stress is considered to reflect an imbalance between the systemic manifestation of reactive oxygen and nitrogen species (RONS) and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. RONS are not only harmful agents that cause oxidative damage in pathologies, they also have important roles as regulatory agents in a range of biological phenomena. They are normally generated as by-products of oxygen metabolism; however, environmental stressors (i.e., UV, ionizing radiations, pollutants, heavy metal, and xenobiotics) contribute to greatly increase RONS production. Several antioxidants have been exploited in recent years for their actual or supposed beneficial effect against oxidative stress, but so far, none has been approved for any indication because they have not met the criteria of efficacy for drug approval. The present review discusses the concept of oxidative stress, how to measure it, how to prevent it, and its occurrence in different organ systems with special reference to the lower urinary tract. This article is protected by copyright. All rights reserved.

PURPOSE OF REVIEW: To assess current pharmacological principles used for treatment of nocturia/nocturnal polyuria.RECENT FINDINGS: The pathophysiology of nocturia is often multifactorial, but two main mechanisms have been identified, occurring alone or in combination: low functional bladder capacity and nocturnal polyuria. The multifactorial pathophysiology not only implies several possible targets for therapeutic intervention but also means that it is unlikely that one treatment modality including drugs will be successful in all patients. Drugs approved for the treatment of male LUTS and male and female OAB are known to be far more effective for treatment of the daytime symptoms than for nocturia. Several pharmacological principles have been tested with varying success. The treatment of choice should depend upon the main underlying cause, thus aiming primarily to increase bladder capacity by counteracting detrusor overactivity and/or reducing nocturnal polyuria. Using current available agents, effective, personalized treatment should be designed taking into account gender, co-morbidities, and identified etiological factors. However, there is a medical need for new, approved drugs for treatments for patients with nocturia.

Endometriosis patients often complain about pelvic and abdominal pain with varying bowel and bladder symptoms unrelated to the location and extent of the disease. The pathophysiology can be multifactorial, but one possibility is that pelvic organ cross-talk may play a role. The aim of this review was to evaluate the scientific support for this hypothesis. A search was performed in PubMed to identify relevant experimental and clinical studies. Data achieved in animal models and clinical evidence suggest that endometriosis-related pain may implicate interactions between pelvic structures like the urinary tract, the bowel and the vagina, mediated by the autonomous nervous system. Such pelvic organ cross-talk with involvement of nerve fibre outgrowth into endometriosis lesions, peripheral sensitisation and convergence of afferent nerve fibres could be an explanation for the varying pain problems in endometriosis, but the precise mechanisms are still poorly understood. Some patients with chronic pelvic pain, including those with endometriosis, also seem to have a more general somatic, musculoskeletal hyperalgesia, indicating a potential viscero-somatic convergence. This might be due to continuous nociceptive input to the brain, resulting in changes in brain structures and finally leading to central sensitisation. Thus, pelvic organ cross-talk seems to represent a new paradigm for endometriosis-related pain with novel possibilities for the development of therapeutic strategies.

The expression of aquaporins (AQPs) in the fetal porcine urinary tract and its relation to gestational age has not been established. Tissue samples from the renal pelvis, ureter, bladder and urethra were obtained from porcine fetuses. Samples were examined by RT-PCR (AQPs 1-11), QPCR (AQPs positive on RT-PCR), and immunohistochemistry. Bladder samples were additionally examined by Western blotting. RNA was extracted from 76 tissue samples obtained from 19 fetuses. Gestational age was 60 (n=11) or 100 days (n=8). PCR showed that AQP1, 3, 9 and 11 mRNA was expressed in all locations. The expression of AQP3 increased significantly at all four locations with gestational age, whereas AQP11 significantly decreased. AQP1 expression increased in the ureter, bladder and urethra. AQP9 mRNA expression increased in the urethra and bladder, but decreased in the ureter. AQP5 was expressed only in the urethra. Immunohistochemistry showed AQP1 staining in sub-urothelial vessels at all locations. Western blotting analysis confirmed increased AQP1 protein levels in bladder samples during gestation. Expression levels of AQP1, 3, 5, 9 and 11 in the urinary tract change during gestation, and further studies are needed to provide insights into normal and pathophysiological water handling mechanisms in the fetus.

The 6th International Consultation on Incontinence met between September 13-15th 2016 in Tokyo and was organised by the International Consultation on Urological Diseases and the International Continence Society (ICS), in order to develop consensus statements and recommendations for the diagnosis, evaluation and treatment of urinary incontinence, faecal incontinence, pelvic organ prolapse and bladder pain syndrome.The consensus statements are evidence based following a thorough review of the available literature and the global subjective opinion of recognised experts serving on focused committees. The individual committee reports were developed and peer reviewed by open presentation and comment. The Scientific Committee, consisting of the Chairs of all the committees then refined the final consensus statements. These consensus statements published in 2017 will be periodically reevaluated in the light of clinical experience, technological progressand research.

Chronic pelvic pain (CPP) is a common condition involving multiple, organ-specific medical specialties, each with its own approach to diagnosis and treatment. Management requires knowledge of the interplay between pelvic organ function and neuro-functional anatomy, and of the neurologic and psychological aspects of CPP, but no current specialty fully encompasses this approach. Neuropelveology is an emerging discipline focusing on pathologies of the pelvic nervous system on a cross-disciplinary basis. It involves a neurological/neurosurgical approach, combining the knowledge required for a proper neurologic diagnosis, confirmation by transvaginal/transrectal examination of the pelvic nerves, and advanced laparoscopic surgery in selected cases of CPP. The management of CPP requires multidisciplinary contributions, and neuropelveology may offer an educational framework for the interdisciplinary exchange of knowledge between clinical physicians and basic researchers.

This article describes a number of changes in lower urinary tract (LUT) function that occurs in the aging population as well as in animal models. Age-related LUT dysfunctions result from complex processes controlled by multiple genetic, epigenetic and environmental factors and accounts for high costs of healthcare. While the underlying factors that contribute to patient symptoms are not known, this article will discuss a number of risk factors that may play a role in age- related LUT dysfunction. In addition, while limited data is available using animal models of aging, there is evidence that many of the structural and functional changes observed in these studies appear to be similar to those observed in humans. A better understanding of factors and mechanisms underlying LUTS in the older population may lead to therapeutic interventions which may be used to reduce these dysfunctions.

Background and purpose T16A(inh)-A01, CaCC(inh)-A01 and MONNA are identified as selective inhibitors of the TMEM16A calcium-activated chloride channel (CaCC). The aim of this study was to examine the chloride-specificity of these compounds on isolated resistance arteries in the presence and absence (±) of extracellular chloride. Experimental approach Isolated resistance arteries were maintained in a myograph and tension recorded, in some instances combined with microelectrode impalement for membrane potential measurements or intracellular calcium monitoring using fura-2. Voltage-dependent calcium currents (VDCC) were measured in A7r5 cells with voltage-clamp electrophysiology using barium as a charge carrier. Key results Rodent arteries preconstricted with noradrenaline or U46619 were concentration-dependently relaxed by T16A(inh) -A01 (0.1-10 μM): IC50 and maximum relaxation were equivalent in ±chloride (30 min aspartate substitution) and the T16A(inh) -A01-induced vasorelaxation ±chloride were accompanied by membrane hyperpolarization and lowering of intracellular calcium. However, agonist concentration-response curves ±chloride, with 10 μM T16A(inh) -A01 present, achieved similar maximum constrictions although agonist-sensitivity decreased. Contractions induced by elevated extracellular potassium were concentration-dependently relaxed by T16A(inh)-A01 ±chloride. Moreover, T16A(inh) -A01 inhibited VDCCs in A7r5 cells in a concentration-dependent manner. CaCC(inh) -A01 and MONNA (0.1-10 μM) induced vasorelaxation ±chloride and both compounds lowered maximum contractility. MONNA, 10 μM, induced substantial membrane hyperpolarization under resting conditions. Conclusions and implications T16A(inh) -A01, CaCC(inh) -A01 and MONNA concentration-dependently relax rodent resistance arteries, but an equivalent vasorelaxation occurs when the transmembrane chloride gradient is abolished with an impermeant anion. These compounds therefore display poor selectivity for TMEM16A and inhibition of CaCC in vascular tissue in the concentration range that inhibits the isolated conductance.

Objectives To examine the effects of the serotonin (5-HT)2A/2C receptor agonist (2,5-dimethoxy-4-idophenyl)-2-aminopropane hydrochloride (DOI) on micturition in rats with diabetes mellitus (DM). Methods Female Sprague–Dawley rats (n = 16) were divided into two groups: rats with Type 1 DM and age-matched control rats. DM was induced by i.p. injection of streptozotocin (65 mg/kg) and detailed cystometrogram (CMG) studies were performed 8 weeks post-injection in all rats under urethane anaesthesia. The selective 5-HT2A antagonist ketanserin was administered after each DOI dose–response curve was plotted. All drugs were administered i.v. Results Compared with controls, comprehensive urodynamic studies showed that DM rats had a higher bladder capacity and post-void residual urine volume (PVR), and a markedly lower voiding efficiency. In DM rats, DOI (0.01–0.3 mg/kg) induced significant dose-dependent increases in micturition volume and reductions in PVR, resulting in greater voiding efficiency. CMG measurements showed a dose-dependent increase in high-frequency oscillation (HFO) activity, evidenced by an increased duration of HFOs per voiding. This correlated with the improved voiding efficiency. Ketanserin (0.1 mg/kg) partially or completely reversed the DOI-induced changes. Conclusions The HFOs observed in the present study seem to correlate with external urethral sphincter bursting activity during voiding. Bladder voiding efficiency was reduced in DM rats. The 5-HT2A receptor agonist can enhance HFO activity and improves voiding efficiency, and so may represent a new strategy to improve voiding efficiency after DM in experimental studies.

Purpose of review The purpose of this study is to review and discuss recently published (2013-2014) experimental and clinical studies of intraprostatic injection therapy as an alternative treatment of lower urinary tract symptoms (LUTS). Recent findings Recent focus has been on intraprostatic injection of botulinum toxin both with regard to mechanism of action and efficacy. In contrast to the promising findings in several previous studies, a recent large, randomized, placebo-controlled trial found no differences between onabotulinumtoxin A treatment and placebo. There is little new information on the use of anhydrous ethanol and agents such as NX-1207 and PRX302, which previously have been reported to have promising effects. Summary Intraprostatic injection of different agents as a minimally invasive surgical therapy for LUTS associated with benign prostatic hyperplasia seems attractive and may have a potential as a treatment alternative, but so far, available results are not convincing. Further studies on the mechanisms of action of novel agents, and controlled clinical trials documenting their efficacy and side-effects when injected into the prostate are needed before their place in the treatment of benign prostatic hyperplasia/LUTS can be properly assessed.

The etiology of interstitial cystitis/bladder pain syndrome (IC/BPS) remains elusive and may involve multiple causes. To better understand its pathophysiology, many efforts have been made to create IC/BPS models. Most existing models of IC/BPS strive to recreate bladder-related features by applying noxious intravesical or systemic stimuli to healthy animals. These models are useful to help understand various mechanisms; however, they are limited to demonstrating how the bladder and nervous system respond to noxious stimuli, and are not representative of the complex interactions and pathophysiology of IC/BPS. To study the various factors that may be relevant for IC/BPS, at least 3 different types of animal models are commonly used: (1) bladder-centric models, (2) models with complex mechanisms, and (3) psychological and physical stressors/natural disease models. It is obvious that all aspects of the human disease cannot be mimicked by a single model. It may be the case that several models, each contributing to a piece of the puzzle, are required to recreate a reasonable picture of the pathophysiology and time course of the disease(s) diagnosed as IC/BPS, and thus to identify reasonable targets for treatment.

We investigated the characteristics of bladder mechanosensitive single-unit afferent activities (SAAs) in rats with a bladder outlet obstruction (BOO) and their relationship with bladder microcontractions. Male Wistar rats were divided into Sham and BOO groups. Four or 10 days after the surgery, rats were anesthetized with urethane. The SAAs of Aδ- or C-fibers from the L6 dorsal roots were recorded during bladder filling. The BOO group showed a higher number of microcontractions and lower SAAs of Aδ-fibers compared with those of the Sham group. These findings were significant at day 10 post-operatively. In contrast, SAAs of C-fibers were not significantly different between the groups at either day 4 or 10. In the BOO group at day 10, the SAAs of both Aδ- and C-fibers at the “ascending” phase of microcontractions were significantly higher than those at the other phases (descending or stationary), and a similar tendency was also observed at day 4. Taken together, during bladder filling, the bladder mechanosensitive SAAs of Aδ-fibers were attenuated, but SAAs of both Aδ- and C-fibers were intermittently enhanced by propagation of microcontractions.

To investigate whether the voiding dysfunction caused by spinal cord injury (SCI) in rats can be improved by i.v. administration of the serotonin (5-HT)Female Sprague-Dawley rats were divided into two groups (SCI group vs normal control [NC] group). Under urethane anaesthesia, cystometry was performed to examine the variation in urodynamic variables before and after successive intrathecal (i.t.) administration of various doses of DOI into the lumbosacral cord. Changes in 5-HTCompared with NC rats, the SCI rats had higher bladder capacity and post-void residual urine volume, and lower voiding efficiency. After SCI, DOI improved voiding efficiency, probably via external urethral sphincter (EUS) activity. Immunohistochemical staining and Western blot analysis showed that 5-HTIn rats with SCI, DOI can improve voiding efficiency; this may be attributable to 5-HT

Toll-like receptor 7 (TLR7) is associated with the pathophysiology of systemic lupus erythematosus and Sjo "gren syndrome, wellknown diseases accompanying interstitial cystitis (IC). We studied TLR7 expression in the bladder of patients with Hunner-type IC (HIC) and its functional roles in bladder inflammation and nociception using mice. Bladder biopsy specimens were obtained from patients with HIC. Specimens from the noncancerous portion of the bladder of patients with bladder cancer served as controls. The specimens were examined by immunohistochemistry and real-time polymerase chain reaction of TLR7. Loxoribine (LX), a TLR7 agonist, was instilled in the bladder of C57BL/6N female mice, and TLR7-mRNA expression and histological changes of the bladder, bladder pain-like licking behavior, voiding behavior, cystometry, and bladder afferent nerve activities were investigated. The effects of hydroxychloroquine, a TLR7 antagonist, on the LX-induced changes on cystometry and voiding behavior were studied. The number of TLR7 immuno-reactive cells and the mRNA expression of TLR7 were significantly increased in HIC specimens. Intravesical instillation of LX induced edema, congestion, inflammation, and significantly increased TLR7-mRNA expression in the mouse bladder. Loxoribine-instillation also significantly increased licking behavior, voiding frequency, and afferent nerve activities associated with decreased single-voided volume and intercontraction interval of micturitions. Hydroxychloroquine reversed the LXinduced cystometric and voiding behavioral changes. Toll-like receptor 7 was up-regulated in the bladder mucosa of patients with HIC, and activation of TLR7 in the mouse bladder induced cystitis with sensory hyperactivity of the bladder. Blocking the TLR7 pathway may be an innovative treatment target of HIC.

Awake filling cystometry has been used for a long time to evaluate bladder function in freely moving mice, however, the specific methods used, vary among laboratories. The goal of this study was to describe the microsurgical procedure used to implant an intravesical tube and the experimental technique for recording urinary bladder pressure in an awake, freely moving mouse. In addition, experimental data is presented to show how surgery, as well as tubing type and size, affect lower urinary tract function and recording sensitivity. The effect of tube diameter on pressure recording was assessed in both polyethylene and polyurethane tubing with different internal diameters. Subsequently, the best performing tube from both materials was surgically implanted into the dome of the urinary bladder of male C57BL/6 mice. Twelve-hour, overnight micturition frequency was recorded in healthy, intact animals and animals 2, 3, 5, and 7 days post-surgery. At harvest, bladders were assessed for signs of swelling using gross observation and were subsequently processed for pathological analysis. The greatest extent of bladder swelling was observed on day 2 and 3, which correlated with behavioral voiding data showing significantly impaired bladder function. By day 5, bladder histology and voiding frequency had normalized. Based on the literature and evidence provided by our studies, we propose the following steps for in vivo recording of intravesical pressure and voided volume in an awake mouse: 1) Perform the surgery using an operating microscope and microsurgical tools, 2) Use polyethylene-10 tubing to minimize movement artifacts, and 3) Perform cystometry on post-operative day 5, when bladder swelling resolves.

The selective blockade of α1-adrenoceptors (ARs) is now a well-accepted and widely used treatment for patients presenting with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and bladder outlet obstruction. The sites of action of the currently used α1-AR antagonists when relieving LUTS have not yet been established, but it seems clear that effects on prostatic as well as non-prostatic tissues are important. α1-ARs in the bladder, urethra, and vas deferens, on ganglia and nerve terminals, and in the central nervous system (CNS) may all influence LUTS and the clinical effects of α1-AR antagonists. The relevance of α1-AR subtype selectivity for the clinical usefulness of existing drug therapy has still not been clarified, but it cannot be dismissed that blockading both α1A- and α1D-ARs is necessary for optimal clinical effect. Despite the above uncertainties, there seems to be a consensus that clinically available α1-AR antagonists provide a safe, effective and generally well-tolerated therapy for patients with LUTS.

The clinical success of mirabegron as the first a3-adrenoceptor (AR) agonist for treatment of the overactive bladder (OAB) syndrome, has resulted in substantial interest in its site and mechanism of action. Even if the adrenergic innervation of the bladder and urethra has been well studied, the location(s) of a3-ARs in different structures within the bladder wall and urethra, and the mode(s) of action of a3-AR stimulation have still not been established. The recent demonstration of a3-ARs on cholinergic nerve terminals with no immunoreactivity in urothelium or detrusor smooth muscle, is not in agreement with previous morphological studies, and functional data strongly suggest that a3-ARs can be found these structures. However, recent studies suggest that the a3-ARs on detrusor smooth muscle may not be the functionally most relevant. The assumption that a3-AR activation during bladder filling inhibits acetylcholine release from parasympathetic neurons by a prejunctional mechanism and that this decreases bladder micromotions that generate afferent activity, is an attractive hypothesis. It does not exclude that other mechanisms may be contributing, and supports combined approaches to reduce afferent activity for treatment of the OAB syndrome.

Background: Cell therapy for intrinsic urinary sphincter deficiency (ISD) in women has been moderately effective, and improvements are needed. To improve treatment efficacy, it is important to better understand determinates of cell efficacy in the different patient cohorts. We have reported that in nonhuman primates the chronicity of ISD may affect cell efficacy, but additional factors (age, psychosocial stress, hormone status, body weight) can be associated with many disease/treatment outcomes in women -and these factors are the focus of this study.Methods: Adult female cynomolgus monkeys were divided into groups: (1) younger (n = 10, 5-8 years of age) versus older (n = 10, 13-18 years of age); (2) age-matched/socially subordinate (n = 15) versus socially dominant (n = 15); and (3) age-matched lower body weight (n = 6) versus higher body weight (n = 6). Autologous skeletal muscle precursor cells (skMPCs, 5 million) were injected into the urinary sphincter 6 weeks after a surgically induced ISD procedure. Resting and pudendal nerve-stimulated maximal urethral pressures (MUP) were measured before, and 3 and 6 months post-skMPC treatment and urinary sphincter muscle/collagen content within the sphincter complex was measured by quantitative histology 6 months posttreatment.Results: Efficacy of skMPCs on MUP and sphincter muscle/collagen ratios are affected by age (average 40% reduction in efficacy, p Conclusion: Multiple factors (age, stress-induced dysmenorrhea, and body weight) affect the efficacy of cell therapy to restore structure and function in the urinary sphincter complex in NHPs with ISD. Consideration of, and alternatives for, these patient cohorts should be considered.

During the last 30 years, a number of treatments and management algorithms have been developed and applied in the treatment of patients with Interstitial Cystitis/Bladder Painful Syndrome (IC/BPS), and many behavioral, dietary, interventional, pharmacologic and surgical therapies have been developed in the attempt to control the disease and to offer substantial benefits to the affected patients. Nevertheless, the complexity of the disease in terms of aetiology and pathogenesis still has made it difficult to induce significant and long-lasting benefits for any kind of these treatments. In addition, few well designed, randomised controlled trials have been conducted until now on different treatment modalities, and this still precludes the development of evidence-based management strategies. Indeed, the majority of pharmacological agents used to treat patients with IC/BPS are still off label. In this respect, the Interstitial Cystitis Data Base study noted >180 treatment modalities for IC/BPS, with poor results in the majority of cases [1]. To date, there is general agreement on the use of some agents, orally or intravesically administered, as indicated by the EAU guidelines on chronic pelvic pain [2] and the AUA Guidelines for the Diagnosis and Treatment of Interstitial Cystitis/ Bladder Pain Syndrome [3].

Context Lower urinary tract symptoms (LUTSs) and erectile dysfunction (ED) are substantial health concerns with a significant impact on the overall male quality of life. Objective To evaluate the available evidence of the association between LUTSs and ED in patients with benign prostatic hyperplasia (BPH), and discuss possible clinical implications for the management of LUTS/BPH. Evidence acquisition A systematic review of the existing literature published between 1997 and June 2017 and available in the Medline, Scopus, and Web of Science databases was conducted using both the Medical Subject Heading (MeSH) and free-text protocols. The MeSH search was conducted by combining the following terms: "lower urinary tract symptoms," "LUTS," "benign prostatic hyperplasia," "BPH," "erectile dysfunction," "sexual dysfunction," "BPE," and "benign prostatic enlargement." The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed. Evidence synthesis Several community-based studies in different geographical areas have provided strong evidence of an age-independent association between LUTSs and ED. Several biological mechanisms have been proposed to explain this association, but further research is required to better understand the molecular pathways involved. It is necessary to evaluate the possible impact of the metabolic syndrome treatment on LUTS/ED management. Considering the possible relationship between LUTSs and ED, their impact on the quality of life, and the possible adverse effects associated with LUTS medical treatment, clinicians should always evaluate ED in patients with LUTSs and take the opportunity to evaluate patients reporting ED for LUTSs. Conclusions Data from the peer-reviewed literature suggest the existence of an association between LUTS/BPH and ED, although their casual relationship has not been established yet. Emerging data also suggest that pathophysiological mechanisms involved in the metabolic syndrome are key factors in both disorders. Considering the association, it is also recommended that men presenting with LUTSs or ED should be evaluated for both disorders. A better understanding of the molecular pathways behind this association may also help identify new possible targets and develop novel therapeutic approaches to manage LUTSs and ED. Patient summary In this manuscript, we report on all the available evidence linking erectile dysfunction and lower urinary tract symptoms. Our findings suggest the existence of a strong relationship between these two conditions. On the basis of these findings, we recommend that clinicians always explore both conditions in male patients presenting with either of symptoms.

The incidence of lower urinary tract symptoms, including overactive bladder (OAB), is continuing to rise, and is associated with a negative impact on quality of life and a heavy economic burden. A major risk factor for OAB is advancing age. The etiology of OAB is multifactorial and appears to involve myogenic, neurogenic, and urotheliogenic factors. In this article, we review the strengthening preclinical evidence supporting the contribution of chronic pelvic ischemia to the pathogenesis of OAB. In animal models, chronic ischemia induced by arterial injury and a high-fat diet upregulates markers of oxidative stress and proinflammatory cytokines in the urothelium and lamina propria, and leads to increased expression of nerve growth factor. These processes result in increased afferent activity and an increased frequency of micturition, reflecting a state of bladder hyperactivity. In severe, prolonged cases, bladder overactivity may develop into underactivity. Antimuscarinic therapies are the mainstay of OAB treatment, but their usefulness is limited by modest efficacy and troublesome side-effects. Our increasing understanding of the contribution of chronic ischemia to OAB is leading toward novel therapeutic options targeting chronic pelvic ischemia and its morphological, functional, and oxidative consequences. Preclinical trials have demonstrated encouraging results with α1 -adrenoreceptor blockade, phosphodiesterase type 5 inhibition, β3 -adrenoreceptor agonism, free radical scavenging, and stem cell therapy, in preventing morphological, biochemical and functional changes induced by chronic bladder ischemia.