New Data on Tolterodine: Do Recent Findings Dispel Questions About Treating Overactive Bladder in Men?

Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence (UUI), usually with frequency and nocturia. These symptoms represent a subset of lower urinary tract symptoms (LUTS). Results from epidemiologic studies conducted in the United States and Europe suggest that OAB affects 11–16% of men. Although OAB is frequently associated with detrusor overactivity, the coexistence of OAB symptoms and prostatic conditions (e.g., benign prostatic hyperplasia, benign enlargement of the prostate, and bladder outlet obstruction [BOO]) in men adds complexity to the diagnosis and appropriate treatment. Men with OAB symptoms are more often prescribed pharmacotherapies that target the prostate (e.g., α-receptor antagonists, 5α-reductase inhibitors) rather than the bladder (e.g., antimuscarinics), possibly due to a tendency among clinicians to attribute all LUTS to prostate disease. Thus, a subset of men who receive treatment for prostatic conditions may have persistent OAB symptoms. Moreover, some physicians may be concerned that the inhibitory effect of antimuscarinic agents on detrusor contraction could aggravate the voiding difficulties of, or cause urinary retention in, men with OAB and possible BOO. Recent prospective studies and post hoc analyses of data from men with OAB symptoms and other LUTS, with or without concomitant BOO (not significant BOO at risk for urinary retention), have suggested that tolterodine improves OAB symptoms without an increased incidence of acute urinary retention. However, the literature would benefit from larger and longer placebo-controlled studies.     

Refractory overactive bladder in men: Update on novel therapies

Overactive bladder (OAB) in men is an entity that may be challenging to diagnose and treat, especially in the presence of bladder outlet obstruction. The application of oral medical treatments of lower urinary tract symptoms attributed to benign prostatic hyperplasia has traditionally utilized α-adrenergic blockers and 5α-reductase inhibitors. After failure of oral medical therapies, surgical options are traditionally offered. Even after surgical options are successful, lower urinary tract symptoms that are secondary to OAB persist. These patients merit a trial of antimuscarinic drugs. Additionally, certain patients with concomitant bladder outlet obstruction who have not been surgically relieved can still merit a trial of antimuscarinic drugs without significant risk of developing urinary retention. When these oral antimuscarinic drugs fail, options still remain for treating men with refractory OAB. Successful application of various diagnostic approaches and the initiation of conservative options as well as other options, such as neuromodulation for refractory urgency and urge incontinence, can help the patient. Finally, emerging data support the use of intradetrusor injections of botulinum toxin for refractory OAB.     

A shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: focus on the bladder

Lower urinary tract symptoms (LUTS) are highly prevalent among older men and have a negative impact on health-related quality of life. Frequent comorbidity with potential prostatic disease adds complexity to the management of male LUTS. In this review, we discuss the pathophysiological conditions that underlie male LUTS, and examine the relationship between symptoms and urodynamic findings. The contribution of bladder dysfunction to male LUTS, with a particular emphasis on overactive bladder (OAB) symptoms, is explored. We also consider pharmacotherapeutic options for male LUTS. Pharmacotherapies that target the prostate (alpha1-receptor antagonists and 5alpha-reductase inhibitors) often fail to alleviate OAB symptoms, and may not be the most appropriate therapy for men with storage LUTS. Multiple studies have suggested that antimuscarinic therapy alone or in combination with alpha1-receptor antagonists improve OAB symptoms in men with and without bladder outlet obstruction. Although these agents may represent appropriate first-line therapies for men with OAB symptoms, the therapeutic potential of antimuscarinics alone or in combination with alpha1-receptor antagonists in this population should be evaluated in large-scale, well-designed clinical trials.     

Correlation of urinary nerve growth factor level with pathogenesis of overactive bladder

AIMS: The origin of overactive bladder (OAB), which is a leading cause of lower urinary tract symptoms, remains unknown. Nerve growth factor (NGF) is one of the neurotrophic factors which are needed for the maintenance of sensory neurons. It is known that too much expression of NGF may induce bladder hyperactivity. In this study, we explored the correlation of the level of urinary NGF with various pathogenic OAB such as idiopathic, neurogenic OAB, and bladder outlet obstruction (BOO). METHODS: The study group included 51 OAB patients. Thirteen patients (7 females and 6 males) had idiopathic detrusor overactivity (DO) without BOO, 6 female idiopathic OAB without DO (sensory urgency), 16 patients with BOO due to BPH, and 16 patients with neurogenic DO (10 due to spinal cord injury (SCI), 6 due to cerebrovascular disease (CVD)). Thirty-two patients who had normal cystometric findings (23 females and 9 males) without OAB symptoms were used as controls. Urinary NGF levels were measured by enzyme-linked immunosorbent assay technique (ELISA) and the results were normalized based on creatinine (Cr) concentration. RESULTS: The urinary NGF levels in patients with neurogenic DO due to SCI, BOO, and sensory urgency were significantly higher compared with those of normal cystometric finding patients. However, the levels of urinary NGF were not statistically significant between patients with idiopathic DO without BOO, neurogenic DO due to CVD and patients with normal cystometric findings. CONCLUSIONS: These data suggest that urinary NGF levels could serve as a basis for adjunct diagnosis of OAB.     

Overactive bladder symptoms after midurethral sling surgery in women: Risk factors and management

Introduction

Overactive bladder syndrome (OAB) including urgency and urgency urinary incontinence (UUI) occurs frequently after stress urinary incontinence (SUI) surgery. It is important to identify the risk factors for the occurrence of OAB symptoms in order to adequately inform the patient before surgery. Furthermore, when facing OAB after sling surgery it is crucial to know how to manage these symptoms.

Methods

We conducted a literature review in order to assess the risk factors and management of OAB symptoms after SUI surgery. We searched for relevant articles in PubMed that specifically addressed the topic of OAB symptoms after midurethral sling surgery.

Results

The incidence of de novo and persistent urgency and UUI is reported around 15% and 30%, respectively. Several studies demonstrated that women with mixed incontinence who have a predominant urge component will have worse outcomes after surgery. Older age was also found to be a predictive factor in three studies. Furthermore, urodynamic signs of overactive bladder (eg, DO, low bladder capacity, elevated detrusor pressure) can predict postoperative urgency or UUI. The management of OAB symptoms after SUI surgery is essentially the same as in idiopathic OAB. However, before commencing therapy it is crucial to rule out other factors than can cause urgency, including bladder outlet obstruction, urinary tract infection, or sling erosion.

Conclusions

OAB symptoms are frequently reported after sling surgery. Women with mixed incontinence and older women are at risk of developing post‐operative OAB symptoms. We have proposed an algorithm for the treatment of these symptoms which can be useful in clinical practice.     

Oxybutynin: past, present, and future

Oxybutynin chloride is primarily indicated for the treatment of overactive bladder syndrome (OAB). It remains the most widely prescribed compound for OAB in the world. OAB is defined as the presence of urinary urgency, usually accompanied by daytime urinary frequency and nocturia, with or without urgency urinary incontinence, in the absence of infection or other identifiable etiology. This is a significant problem for men and women said to affect over 33 million adults in the USA, with the prevalence increasing with age. These symptoms can alter quality of life, with both physical and psychological impairment, as well as cause significant financial burden including the cost of sanitary supplies and decreased work productivity. Both pharmacological and non-pharmacological methods may be employed to aid in the treatment of OAB. The mainstay of treatment for OAB relies on pharmacological management, most specifically treatment with antimuscarinic medications. These medications are thought to prevent involuntary bladder contractions and/or urgency by inhibiting the muscarinic receptors within the urothelium and detrusor muscle. Currently, there are six different medications approved by the US Food and Drug Administration (FDA) for the treatment of OAB, with more than nine formulations including immediate- and extended-release tablets, transdermal patch and gel, vaginal ring, and suppository. This review will focus specifically on oxybutynin chloride, which has been used to treat OAB for four decades in numerous formulations.     

Mirabegron for Male Lower Urinary Tract Symptoms

Benign prostatic hyperplasia (BPH) is a common cause of lower urinary tract symptoms (LUTS) in men. Patients with BPH often present with a combination of obstructive and overactive bladder (OAB) symptoms. It is postulated that bladder outlet obstruction (BOO) from BPH results in concomitant OAB symptoms through ischemic induced variations in the response to neurotransmitters of both the detrusor and the urothelium. This altered response leads to the pathologic activation of the micturition reflex, generating sensory dysfunction and involuntary bladder contractions. Alpha-1 adrenoceptor antagonists (alpha-blockers) and 5-alpha reductase inhibitors (5-ARIs) are commonly used to treat the BOO caused by BPH. Anticholinergic agents are frequently used to treat concurrently OAB symptoms caused by the BOO. Unfortunately, anticholinergic medications demonstrate bothersome side effects and a theoretical risk of urinary retention. Basic science and clinical research has led to the development of a new class of pharmaceuticals for the treatment of overactive bladder with diminished risk of urinary retention and lacking many anticholinergic side effects. This novel compound, mirabegron (Mybertriq, Astellas Pharma US, Inc.), is a β₃-adrenoceptor agonist and represents a promising new class of oral agents designed for the treatment of OAB symptoms, with minimal effect on voiding.     

Antimuscarinic mechanisms and the overactive detrusor: an update

Context

Antimuscarinics are the drugs of choice for the treatment of detrusor overactivity (DO) and overactive bladder (OAB) syndrome. However, the mechanisms for their beneficial effects have not yet been definitely established.

Objective

Literature available on the pathophysiologic aspects of storage symptoms and of antimuscarinic actions on the bladder was reviewed.

Evidence acquisition

Medline was searched for the period ending October 2010 and included studies on human and animal tissues and animal models. Clinical studies exploring mechanisms involved in the effects of antimuscarinics were included. Searches were limited to the English language.

Evidence synthesis

Evidence for release of acetylcholine (ACh) from non-neuronal as well as neuronal sources during bladder filling has been demonstrated in isolated animal bladders as well as the human bladder. Urothelially derived ACh, probably via release of adenosine triphosphate, may stimulate afferent activity (“afferent noise”) from the bladder contributing to OAB and DO. Afferent noise may also be generated by local ACh release within the detrusor muscle. This afferent activity can be inhibited by antimuscarinics at the low concentrations obtained with doses recommended for clinical use in OAB/DO. Within this therapeutic window, antimuscarinics may decrease OAB symptoms and DO without affecting the voiding contraction. Changes in muscarinic receptor functions have been demonstrated with aging and in different disorders associated with OAB/DO.

Conclusions

ACh, derived from non-neuronal as well as neuronal sources and during bladder filling, directly or indirectly stimulates afferent activity from the bladder, contributing to OAB and DO. By inhibiting this effect, antimuscarinics may decrease OAB symptoms and DO without affecting the voiding contraction. Even if changes in muscarinic receptor functions may occur with aging and in different disorders associated with OAB/DO, such changes have not been shown convincingly to modify the beneficial effect of antimuscarinics in OAB/DO.     

Is the bladder a reliable witness for predicting detrusor overactivity?

PURPOSE: We determined how well the symptoms of OAB syndrome correlate with urodynamic DO using International Continence Society definitions. MATERIALS AND METHODS: The study included adult males and females 18 years or older who attended a tertiary referral center for urodynamics from February 2002 to February 2004. Patients were selected based on OAB syndrome symptoms (urgency, urgency urinary incontinence and frequency). The percent of patients who had symptoms alone or in combination and DO was calculated. RESULTS: There was a better correlation in results between OAB symptoms and the urodynamic diagnosis of DO in men than in women. Of men 69% and 44% of women with urgency (OAB dry) had DO, while 90% of men and 58% of women with urgency and urgency urinary incontinence (OAB wet) had DO. Stress urinary incontinence seems to have accounted for the decreased rates in women since 87% of women with urgency urinary incontinence also had the symptom of stress urinary incontinence. The ICS definition does not specify what constitutes abnormal voiding frequency. Analysis of results showed that increasing voiding frequency did not have any effect on increasing the accuracy of diagnosis of DO except in women with 10 or more daytime micturition episodes. CONCLUSIONS: The bladder is a better and more reliable witness in men than in women with a greater correlation between OAB symptoms and urodynamic DO, more so in the OAB wet than in OAB dry patients.     

Veränderungen der Muskarinrezeptoren der alternden Harnblase

The prevalence of the overactive bladder syndrome (OAB) increases with age. Unfortunately, treatment of the condition is still unsatisfactory. Since muscarinic receptor antagonists are the only effective drug treatment to date, it is logical to assume that muscarinic receptors play an important role in the pathogenesis of OAB. Muscarinic receptors are involved in both the normal and overactive detrusor contraction, and age-dependent changes in muscarinic receptor functions have been found in both animals and human detrusors. In animals as well as humans, two components of detrusor contraction have been demonstrated, the dominating one mediated by muscarinic receptors and the other by ATP (atropine-resistant component). The muscarinic receptor-mediated component decreases with age, and the ATP (purinergic) part increases. However, the clinical consequence of this is unclear, since no major age-dependent changes in the efficacy of antimuscarinic agents in the treatment of OAB have been demonstrated.     

DETRUSOR INSTABILITY IN MEN: CORRELATION OF LOWER URINARY TRACT SYMPTOMS WITH URODYNAMIC FINDINGS

PURPOSE: We evaluated the correlation of lower urinary tract symptoms suggestive of detrusor instability with urodynamic findings in men. MATERIALS AND METHODS: Enrolled in our prospective study were 160 consecutive neurologically intact men referred for urodynamic evaluation of persistent lower urinary tract symptoms. All patients had storage symptoms suggestive of detrusor instability. Patients were further clinically categorized according to the chief complaint of urge incontinence, frequency and urgency, nocturia or difficult voiding. The clinical and urodynamic diagnosis in all patients as well as specific urodynamic characteristics of those with detrusor instability were analyzed according to the these 4 clinical categories. RESULTS: Mean patient age was 61 +/- 15 years. The chief complaint was urge incontinence in 28 cases (17%), frequency and urgency in 57 (36%), nocturia in 30 (19%) and difficult voiding in 45 (28%). Detrusor instability was diagnosed in 68 cases (43%). A higher incidence of detrusor instability was associated with urge incontinence than with the other clinical categories (75% versus 36%, p <0.01). Of the patients 109 (68%) had bladder outlet obstruction, including 50 (46%) with concomitant detrusor instability. The prevalence of bladder outlet obstruction was similar in all patients regardless of the chief complaint. All other urodynamic diagnoses were also similar in the 4 clinical categories. The mean bladder volume at which involuntary detrusor contractions occurred were lower in patients with urge incontinence and frequency and urgency than in those with nocturia and difficult voiding (277.1 +/- 149.4 and 267.7 +/- 221.7 versus 346.7 +/- 204.6 and 306.2 +/- 192.1 ml., respectively, not statistically significant, p = 0.07). CONCLUSIONS: Detrusor instability and bladder outlet obstruction are common in men with lower urinary tract symptoms. The symptom of urge incontinence strongly correlated with detrusor instability. Other lower urinary tract symptoms did not correlate well with any urodynamic findings. Therefore, we believe that an accurate urodynamic diagnosis may enable focused and more efficient management of lower urinary tract symptoms in men.     

Etiology and pathogenesis of overactive bladder

The symptom complex??overactive bladder?? (OAB) affects more than 10% of adult individuals. The etiopathology is complex and multifactorial. Foremost, urinary tract infection, bladder cancer, foreign bodies, and history of radiation or intravesical instillation of chemotherapeutics must be excluded. In many cases, OAB is caused by neurogenic disorders that activate involuntary detrusor contractions (detrusor overactivity, DO). Also, non-neurogenic disorders such as bladder outlet obstruction or dysfunctions of the female pelvic floor/slack ligaments that affect the urothelium, suburothelium, detrusor and bladder afferents are substantially involved in the pathogenesis of OAB. Until now, circulatory disorders have not been adequately taken into consideration but seem to be another etiological factor that causes OAB. Henceforth, molecular changes of bladder afferents and circulatory disorders in patients suffering from OAB have to be investigated in more detail.     

Overactive bladder and men: Indications for anticholinergics

Similar to bladder outlet obstruction (BOO), overactive bladder (OAB) symptoms are very common and increase in prevalence as men age. Whether or not OAB symptoms are thought to be secondary to BOO, the goal of treatment of symptoms should result in an improved quality of life and ultimately prevent clinical deterioration. A common dilemma when treating men with obstruction and OAB is the risk of acute urinary retention or morbidities related to increasing postvoid residuals. In this article, the relationship of OAB to BOO is examined and the role of urodynamics and data on the use of anticholinergics in men with OAB and obstruction are reviewed. An algorithm for managing men with OAB also is proposed. In men with OAB without evidence of obstruction (including OAB after treatment for BOO), first-line medical therapy with anticholinergics is indicated. However, in men with OAB and concomitant BOO, nomogram has been developed to assist in the management of patients at risk for urinary retention. Men with significant obstruction should be appropriately treated to decrease bladder outlet resistance before adding anticholinergics for the treatment of OAB.     

Changes of urinary nerve growth factor and prostaglandins in male patients with overactive bladder symptom

AIM: Nerve growth factor (NGF) and prostaglandins (PG) in the urinary bladder can be affected by pathology of bladder, and this change can be noted in the urine. This study was performed to investigate the changes in urinary NGF and PG in male patient with overactive bladder (OAB) symptoms. METHODS: The study group included 75 male patients with OAB symptoms and 20 males without bladder symptoms as controls. Evaluation included history-taking, urinalysis, International Prostate Symptom Score (IPSS) and urodynamic study. The NGF, PGE2, PGF(2alpha) and PGI2 levels in voided urine were analyzed by enzyme linked immunosorbent assay and these results were compared in control and OAB patients. Also, the urinary levels of NGF and PG were correlated with IPSS score and urodynamic parameters in OAB patients. RESULTS: The urinary levels of NGF and PGE2 were signi fi cantly increased in patients with OAB compared with control (P < 0.05). The urodynamic study in OAB patients showed that more than half of the patients had detrusor overactivity and bladder outlet obstruction. The incidence of detrusor underactivity was noted in seven patients in the OAB group. The urinary level of PGE2 was decreased in patients with detrusor underactivity compared with patients without detrusor underactivity (P < 0.05), and negatively correlated with maximum bladder capacity in OAB patients (P < 0.05). CONCLUSIONS: NGF and PG may have important role in male patients with OAB, and the urinary level of PGE2 can change according to detrusor function. Therefore, these results may be used as urinary markers to evaluate the OAB symptoms.     

Epidemiology and etiology of overactive bladder

Bladder overactivity (OAB) is a common disease with a socioeconomic impact comparable to diabetes mellitus. As life expectancy rises in industrialized countries the importance of OAB will further increase. The International Continence Society (ICS) recently reported a modified terminology for lower urinary tract function and established the symptom-based term OAB. The etiology of OAB comprises neurogenic and non-neurogenic detrusor hyperactivity as well as detrusor hypersensitivity. Neurogenic detrusor hyperactivity may be caused by insufficient cortical inhibition, degenerative neuropathies, and spinal cord lesions, whereas bladder aging, bladder outlet obstruction, and chronic bladder irritation (UTI, stones, tumors) are possible causes for non-neurogenic detrusor hyperactivity. Since most epidemiologic surveys focus on urge incontinence without considering urgency frequency without incontinence, epidemiologic data concerning OAB are rare. Two recently published multinational prevalence studies from Europe and Asia show different prevalence values [Europe: 15.6% (men), 17.4% (women); Asia: 53.1%(women)], which may be due to methodological differences. Both studies report an increase of OAB prevalence corresponding with age. The cumulative incidence of OAB is rising faster in aging males than in aging females. Two-thirds of the European and one-fourth of the Asian individuals affected by OAB complained about impaired quality of life, but only 60% of the European and 21% of the Asian sufferers have talked to a doctor or sought treatment. One out of four patients visiting their health care professional for OAB symptoms is currently under medication. To avoid high treatment costs and side effects, pharmacotherapy (e.g., antimuscarinics) should only be given after detailed diagnostic evaluation.     

Local effects of antimuscarinics

Overactive bladder (OAB) syndrome has been estimated to occur in nearly 17% of the population. The most common drug treatments for OAB are antimuscarinic agents that act to increase bladder capacity and decrease the urge to urinate during the storage phase. An increasing number of studies have focused on te role and mechanism of muscarinic acetylcholine receptors for the regulation of afferent activity during urine storage. Interactions between muscarinic receptors in the urothelium, afferent nerves, or myofibroblasts and locally released acetylcholine might be involved in the emergence of detrusor overactivity and OAB. Therefore, antimuscarinic agents may be effective in treating OAB not only by suppression of muscarinic receptor-mediated detrusor muscle contractions but also by modulation of muscarinic receptor-bladder afferent interactions.     

The pathophysiology underlying overactive bladder syndrome possibly due to benign prostatic hyperplasia

The pathophysiology in the development of overactive bladder syndrome (OAB) possibly due to benign prostatic hyperplasia (BPH) has not fully been understood. The clinical study in male outpatients aged over 50 years with lower urinary tract symptoms showed that the frequency of urgency was significantly associated with aging, bladder outlet obstruction (BOO) and benign prostatic enlargement (BPE). From the results of the experiments we did using rats, the mechanisms underlying the development of OAB were suggested as follows. The functional impairment of acetylcholine neuron in the central nervous system is induced by aging and decreases the bladder capacity. Non-voiding contractions of the bladder may have some bearing on OAB associated with BOO. The C-fiber in the urethra may be involved in the generation of the detrusor overactivity associated with BPE. These results showed that the pathophysiology of OAB related to BPH is quite complex, suggesting that a multidisciplinary approach is necessary for the treatment.     

Overactive Bladder and Outlet Obstruction in Men

Lower urinary tract symptoms (LUTS), overactive bladder, (OAB), and benign prostatic hyperplasia (BPH) are very commonly experienced in men. The mainstay of pharmacotherapy for OAB is the antimuscarinic class of drugs. There has been reluctance to prescribe these agents to men with BPH due to the risk of precipitating urinary retention. Several trials have supported the efficacy and safety of antimuscarinics in treating men with LUTS, alone, or in combination with α-blocker therapy. The combination of 5-α-reductase inhibitors with antimuscarinic agents or surgery are other effective treatments for men with BPH and OAB.