Stress urinary incontinence and the forgotten female hormones.

The use of hormones to treat stress urinary incontinence (SUI) has fallen out of favor because of concerns over safety following publication of the Women's Health Initiative study. In addition, there are data that suggest that estrogen treatment does not help SUI. As women age, the decline in androgen output mirrors the increasing prevalence of SUI implying a potential causal association. Therefore, we suggest that androgens are the 'forgotten female hormone.' Vaginal estrogens can treat pelvic floor structures without significant systemic effects; we suggest that vaginal androgens can act similarly and thereby avoid the unwanted systemic effects of androgenization in women. Based on available preclinical and clinical data, we suggest that research should investigate vaginal treatment with androgen hormones as adjunctive therapy to pelvic floor exercises for SUI. In a postmenopausal woman, this could be supplemented with estrogens if trial data warrant it.

Trigone as a diagnostic and therapeutic target for bladder-centric interstitial cystitis/bladder pain syndrome.

The pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) may be bladder-centric, with afferent nerve hyperexcitability and/or due to neural central sensitization. In bladder-centric disease, the trigone's unmyelinated nociceptive C-fibers are thought to be upregulated, suggesting this as a potential target for diagnostic modalities and for treatment with local anesthetics and chemodenervation. We propose that the transvaginal trigone treatment (T3) route of administration of such treatments should be considered in women with IC/BPS, as this approach is easier and less invasive than cystoscopy. For T3, or other bladder-centric treatments to be successful, patient selection should attempt to exclude patients with predominantly neural central sensitization.

Six-Month Results of Selective Bladder Denervation in Women with Refractory Overactive Bladder.

PURPOSE: We report 6-month efficacy and safety outcomes of selective bladder denervation in women with refractory overactive bladder. MATERIALS AND METHODS: Women with refractory overactive bladder and urgency urinary incontinence were enrolled in 2 prospective feasibility studies with the same entry criteria. They underwent selective bladder denervation of the subtrigonal region containing afferent sensory nerves. Patients were followed for 6 months and assessed for adverse events, overactive bladder symptoms and health related quality of life measures. RESULTS: In the 35 women with a mean age of 66 years who were enrolled in the study all selective bladder denervation procedures were completed successfully. During 6 months of followup the symptom improvement based on 3-day bladder diaries was 59% for urgency urinary incontinence (p <0.001), 59% for urinary incontinence (p <0.001), 39% for urgency (p <0.001), 9% for urinary frequency (p = 0.01) and 27% for the total urgency and frequency score (p <0.001). Most of this treatment benefit was realized in the first month. The rate of clinical success, defined as a 50% or greater reduction in urgency urinary incontinence, was 70%, treatment benefit was reported in 75% of patients and the dry/cure rate was 27%. Statistically significant improvements during 6 months were identified on the symptom bother and health related quality of life scales on the OAB-q (Overactive Bladder Questionnaire) and on all KHQ (King's Health Questionnaire) domains except general health perception. Device or procedure related adverse events were reported in 6 patients (17%). CONCLUSIONS: Pooled results of 2 prospective feasibility studies suggest that selective bladder denervation is a promising minimally invasive treatment option in women with refractory overactive bladder.

One-year results with selective bladder denervation in women with refractory overactive bladder.

AIMS: To report 1-year results with selective bladder denervation (SBD) of the trigone in women with refractory overactive bladder (OAB). METHODS: In this prospective, international, multicenter case series, women with refractory OAB underwent a single SBD treatment of the bladder subtrigone region using temperature-controlled radiofrequency. Patients were followed for 1 year and evaluated for changes in OAB symptoms and adverse events. RESULTS: Among 35 women, 29 (83%) returned for 1-year follow up. Median symptom reductions based on 3-day bladder diaries were 68% for urgency urinary incontinence ( P < .001), 67% for urinary incontinence ( P < .001), 43% for urgency episodes ( P < .001), 5% for urinary frequency ( P = .19), and 33% for the total urgency and frequency score ( P < .001), with the majority of treatment benefit realized in the first month. Treatment benefit was reported in 72% of patients, the clinical success rate (≥50% reduction in urgency urinary incontinence) was 69%, and the dry rate was 10%. Statistically significant improvements occurred on Symptom Bother and Health-related Quality of Life scales on the Overactive Bladder questionnaire, and on 6 of 9 King's Health Questionnaire domains. Patients with less severe baseline symptoms had similar quality of life improvements as those with more severe baseline symptoms. Device- or procedure-related adverse events were reported in 6 (17%) patients. CONCLUSIONS: A single treatment with selective bladder denervation is durable for 1-year in a significant proportion of women with refractory overactive bladder.

Clinical Efficacy and Tolerability of the Nicotinic Channel Modulator Dexmecamylamine in Subjects with Overactive Bladder.

PURPOSE: We evaluated the efficacy and tolerability of the nicotinic channel modulator dexmecamylamine for overactive bladder. MATERIALS AND METHODS: This was a randomized, double-blind, placebo controlled trial in 768 randomized subjects. Those with at least a 6-month history of overactive bladder were randomized to 0.5, 1 or 2 mg dexmecamylamine or placebo in a ratio of 1:1:1:2, respectively. Subjects completed a 3-day diary before each visit associated with the 12-week treatment period. They were required to have 8 or more micturitions per day and 3 or more urinary urge incontinent episodes per day if overactive bladder wet at the end of a placebo run-in period. Co-primary end points for the study included a change from baseline 1) in micturition frequency per 24 hours at week 12 and 2) in urge urinary incontinence episodes per 24 hours at week 12. Secondary end points were voided volume, nocturia episodes, OABq (Overactive Bladder Questionnaire) and urgency questionnaire. RESULTS: Dexmecamylamine (2 mg) produced a statistically significant decrease in micturition frequency (p = 0.03) but did not produce a statistically significant decrease in urge incontinence (wet) episodes (p = 0.38). Secondary end points, including volume voided in the 1 mg group only, CGI-I (Clinical Global Impression of Improvement), visual analog scale urgency impact, intensity and severity, were statistically significant at week 12 for the 2 mg dose. Dexmecamylamine was well tolerated in this subject population with a low incidence of discontinuations due to adverse effects. Constipation, dry mouth and urinary tract infection showed a dose dependent increase in frequency. CONCLUSIONS: Dexmecamylamine does not appear to offer an enhanced therapeutic profile for the treatment of overactive bladder relative to current therapies.

Does urinary urgency drive urinary frequency in overactive bladder?

OBJECTIVES: To determine if reduction in urgency in patients with refractory overactive bladder syndrome (rOAB) is correlated with a reduction in voiding frequency and symptom bother. METHODS: Data from a prospective series of women with rOAB undergoing radiofrequency ablation of the subtrigonal tissue, termed selective bladder denervation (SBD), was analyzed. Main outcome measures included urgency voids, nonurgency voids, and urgency urinary incontinence (UUI) epidsodes from a 3-day voiding diary and quality of life (QoL) measures (Overactive Bladder Questionnaire Short Form [OAB-q SF]). RESULTS: The dataset comprised 62 completer subjects at 6 months. Compared to baseline, UUI and urgency voids were lower (P < .001), but nonurgency voids were increased (P < .001) and QoL measures were improved (P < .001), but functional bladder capacity did not increase. At baseline and 6 months post treatment, symptom bother was correlated with urgency voids (P < .05) but inversely correlated with nonurgency voids (P < .001). Urgency and nonurgency voids were inversely related at baseline and at 6 months (P < .0001). Following treatment, urgency voids decreased by 41% and nonurgency voids increased by 33%. CONCLUSIONS: As with other interventions for OAB, SBD resulted in a reduction in OAB symptoms and an improvement in QoL measures. However, the decrease in urgency voids was offset by an increase in nonurgency voids, suggesting that habit or defensive voiding is a significant driver of urinary frequency. It is not certain if this is a unique finding of the SBD effect, but these data do suggest that analyses of outcomes of other OAB interventions are warranted to gain a better understanding of the genesis of OAB symptoms.

Outcomes of a single trigone-only vs. 20 trigone-sparing injections of OnabotulinumtoxinA for refractory overactive bladder (OAB).

PURPOSE: To compare the safety and durability of a single intravesical trigonal-only versus 20 trigone-sparing injections of OnabotulinumtoxinA (BTA) for refractory OAB. METHODS: A chart review of all idiopathic OAB patients treated with BTA from January 2016 to December 2018 was performed. Outcomes measures included: inter-injection interval, post-void residual (PVR), urinary tract infections (UTI), urinary retention requiring catheterization, and procedure time (min). Statistical analyses were performed using independent sample t-tests. RESULTS: Baseline characteristics were comparable for the two groups, data on 69 treatments (19 patients trigone-only) were compared to 105 treatments (26 patients trigone-sparing). There were no differences in the inter-injection intervals or rates of UTI. The trigone-only group exhibited a lower mean PVR (113 ml vs 160 ml, p < 0.02), lower proportion with PVR > 150 ml (23% vs. 39%, p < 0.03), lower rate of urinary retention (5.3% vs. 17.4%, p < 0.02), and shorter procedure time (4.3 min vs. 5.7 min, p < 0.01). There were no cases of vesico-ureteral reflux. CONCLUSION: While interpretation remains speculative, the results of this observational study suggest that a single trigone-only injection appears to be as safe and durable as multiple trigone-sparing injections but maybe quicker to perform and appears to have a lower impact on voiding function. Larger series and adequately powered prospective randomized clinical trials are warranted to validate the findings of this pilot study.

A Preliminary Study on the Impact of Detrusor Overactivity on the Efficacy of Selective Bladder Denervation for the Treatment of Female Refractory Overactive Bladder.

OBJECTIVE: To determine whether the presence of detrusor overactivity (DO) is associated with the 12-week and 12-month clinical outcomes of selective bladder denervation (SBD) in women with refractory overactive bladder (OAB). METHODS: Prospective single institutional study of refractory OAB females who underwent a urodynamic study and were categorized according to DO status (DO- vs DO+) prior to receiving SBD. RESULTS: Among the 23 patients, 10 were DO- and 13 were DO+. Both groups reported improvement at 12 weeks on the 24-hour pad weight test, in urgency urinary incontinence (UUI) and urgency. At 12 months, both groups still reported improvement in urgency, but only the DO- group reported reduction on the pad weight test and only the DO+ group maintained improvement in the UUI rate. Clinical success (≥50% reduction in UUI) was achieved by all DO- and by 69% of DO+ patients at 12 weeks, and by 60% of DO- and 92% of DO+ patients at 12 months. Treatment benefit (Treatment Benefit Scale ≤2) was reported in 90% of DO- and 85% of DO+ patients at 12 weeks, and in 60% of DO- and 85% of DO+ patients at 12 months. When directly comparing both group outcomes, the only significant difference was the greater reduction of UUI in the DO- group at 12 weeks (-9.0 vs -6.5; P = .045). CONCLUSION: Refractory OAB females appear to be effectively treated by SBD regardless of baseline DO status. DO status does not seem to be associated with the 12-week and 12-month outcomes of SBD.

Ambulatory urodynamic monitoring: state of the art and future directions.

Urodynamic studies are a key component of the clinical evaluation of lower urinary tract dysfunction and include filling cystometry, pressure-flow studies, uroflowmetry, urethral function tests and electromyography. However, pitfalls of traditional urodynamics include physical and emotional discomfort, artificial test conditions with catheters and rapid retrograde filling of the bladder, which result in variable diagnostic accuracy. Ambulatory urodynamic monitoring (AUM) uses physiological anterograde filling and, therefore, offers a longer and more physiologically relevant evaluation. However, AUM methods rely on traditional catheters and pressure transducers and do not measure volume continuously, which is required to provide context for pressure changes. Novel telemetric AUM (TAUM) methods that use wireless, catheter-free, battery-powered devices to monitor bladder pressure and volume while patients carry out their daily activities are currently being investigated. TAUM devices under current development are innovating in the areas of remote monitoring, rechargeable energy sources, device deployment and retrieval and materials engineering to provide increased diagnostic accuracy and improved comfort for patients with incontinence or voiding dysfunction. These devices hold promise for improving the diagnosis and management of patients with lower urinary tract disorders.

DPI-289, a novel mixed delta opioid agonist / mu opioid antagonist (DAMA), has L-DOPA-sparing potential in Parkinson's disease.

L-DOPA-induced dyskinesia (LID) remains a significant problem in the management of Parkinson's disease (PD). In rodent and macaque models of PD, delta opioid receptor agonists have anti-parkinsonian actions while mu opioid antagonists can reduce the expression of LID. DPI-289 is a novel molecule with a unique combination of opioid receptor DAMA actions: delta agonist (Ki: 0.73 nM); mu antagonist (Ki: 12 nM). We demonstrated that DPI-289 has oral bioavailability and established its pharmacokinetic profile in both rat and primate. We hypothesised that these combined DAMA actions would provide an enhancement of L-DOPA effect without an associated increase in dyskinesia. In parkinsonian 6-OHDA lesioned rats and MPTP-lesioned macaques, DPI-289 provided anti-parkinsonian actions as monotherapy and an enhancement of L-DOPA benefit. Thus, acute administration of DPI-289 (3 mg/kg, p.o.) to 6-OHDA-lesioned rats produced a significant reduction in forelimb asymmetry (by 48%) that was maintained throughout the fifteen-day repeat-treatment period. Importantly, and in contrast to L-DOPA administration (6 mg/kg, i.p.), these benefits were not compromised by the development of abnormal involuntary movements. In the macaque, as monotherapy, DPI-289 (10 and 20 mg/kg) had significant, though incomplete, anti-parkinsonian actions lasting approximately 4 h. These benefits were not associated with dyskinesia. In fact, over the 6 h period of observation, DPI-289 (20 mg/kg) decreased parkinsonism by 19% and increased activity by 67% compared to vehicle treatment. By contrast, while high-dose L-DOPA (LDh) alone alleviated parkinsonism (for 3 h) this benefit was accompanied by significant dyskinesia that was disabling in nature. LDh provided a 50% reduction in parkinsonism over 6 h and 151% increase in activity. The combination of DPI-289 (20 mg/kg) and a low-dose of L-DOPA (LDl) provided anti-parkinsonian benefits greater than LDl alone without eliciting any significant dyskinesia. Treatment with LDl alone provided only transient statistically significant anti-parkinsonian benefit. However, the combination of LDl and DPI-289 reduced parkinsonism for 6 h (duration of monitoring), with parkinsonism being reduced by 35% and activity increased by 90% but with no increase in dyskinesia over that observed with LDl alone. Thus, DPI-289 has potential to improve the benefits of dopaminergic therapy in Parkinson's disease.

Validation of the urgency perception scale.

OBJECTIVE: To ascertain the validity and responsiveness of the Urgency Perception Scale (UPS) as an indicator of perceived urinary urgency. PATIENTS AND METHODS: The UPS was developed to assess perceived urinary urgency in clinical studies evaluating the efficacy of the antimuscarinic drug, tolterodine, for treating the overactive bladder (OAB) syndrome. Secondary analyses of clinical and patient assessment data from three clinical studies of tolterodine were conducted to evaluate the UPS. Construct validity was assessed by correlations between the UPS and patient voiding diary variables and other patient assessments, including: perception of bladder condition; perception of treatment benefit; the Medical Outcomes Study Short-Form 36 health survey; the King's Health Questionnaire; the OAB Questionnaire; and the Overall Treatment Effect scale. RESULTS: The UPS correlated well with the patients' perception of bladder condition (correlation coefficients - 0.29 to - 0.46; all P < 0.001) and with the voiding diary variables, especially incontinence episodes (-0.30 to - 0.41) and pad usage (-0.25 to - 0.38; all P < 0.001). An improvement in UPS score at the end of treatment was consistently reflected by significant improvements among all voiding variables. CONCLUSION: Urinary urgency is a central symptom of OAB and is particularly bothersome because of its unpredictability and consequent impact on daily life. The UPS is a valid scale by which urinary urgency can be assessed subjectively, and provides a useful tool for research into urinary urgency.

"Unblinding" in randomized controlled drug trials for urinary incontinence: Implications for assessing outcomes when adverse effects are evident.

AIMS: To determine whether women with urinary incontinence (UI) can identify their allocation in a randomized controlled trial (RCT) of tolterodine (TOL), and whether correct identification is associated with outcomes and adverse effects (AEs). METHODS: Exploratory analysis of a randomized, double-blind, placebo (PLC)-controlled trial of TOL 4 mg daily for 8 weeks in 743 women with urge-predominant mixed UI. Patient perception of their randomization was assessed at trial end. Main outcome measures were 7-day bladder diaries, patient perception of improvement, and UI-specific quality of life (QoL). RESULTS: TOL produced a significant decrease in urge UI episodes compared to PLC (78% vs. 51%, P = 0.0001). Fifty-one percent of women correctly identified their randomization (58% on TOL vs. 37% on PLC, P < 0.001). Women who assumed they took TOL had better bladder diary outcomes than those who assumed they took PLC. Within each assumption group, patient perception outcomes were similar, regardless of actual randomization. QoL improved in all domains except general health for women on TOL. In women who assumed they took TOL, significant drug benefit was evident in three domains. Moderate-severe dry mouth was higher in those who assumed they took TOL (7.3% vs. 0%, P < 0.0001). CONCLUSIONS: Greater than fifty percent of women in this RCT of antimuscarinic treatment were "unblinded" to their randomization. Patient assumption of randomization was associated with bladder diary and perception outcomes, specific QoL domains, and dry mouth. Efficacy of urge incontinence drugs should be considered in the context of patient assumptions, expectations, and "unblinding" by easily evident side effects.

The role of urinary urgency and its measurement in the overactive bladder symptom syndrome: current concepts and future prospects.

OBJECTIVE: To review the concept of urinary urgency and its practical measurement in clinical trials, and advance the hypothesis that while urge is experienced by normal people, urgency is always pathological. METHODS: According to the International Continence Society (ICS) definition, urgency is the primary symptom of the overactive bladder (OAB) syndrome, but in clinical trials there are inconsistencies in both the definition and assessment of urgency. We searched the PubMed and BIOSIS databases for publications and abstracts related to the clinical assessment of urgency in patients with OAB. RESULTS: The differentiation of urgency from the normal physiological desire to void is discussed. In clinical studies of OAB, urgency has been measured both qualitatively and quantitatively. Existing qualitative assessment scales for urgency are deficient in accuracy, validation or both, and are largely inconsistent with the currently accepted ICS definition of urgency. The quantitative assessment of urgency by diary entry has been validated and may be the most accurate, reproducible and clinically meaningful method available for measuring this variable. CONCLUSION: Based on the existing ICS definition of urgency as 'a compelling desire to pass urine that is difficult to defer', the concept of qualitative assessment of urgency may be flawed.

Efficacy of antimuscarinic therapy for overactive bladder with varying degrees of incontinence severity.

PURPOSE: We analyze the efficacy of tolterodine extended release (ER) for overactive bladder in patients with severe incontinence. MATERIALS AND METHODS: Patients with urinary frequency (8 micturitions or greater per 24 hours), urge incontinence (5 episodes or greater a week) and symptoms of overactive bladder for 6 months or greater were randomized to treatment with 4 mg tolterodine ER once daily or placebo for 12 weeks. Severe incontinence was defined as 21 episodes or greater per week at baseline. Changes in the number of incontinence episodes per week and micturition frequency after 12 weeks were compared between treatments. RESULTS: A total of 986 patients were eligible for this post-hoc analysis. After 12 weeks tolterodine ER produced a significant absolute median reduction in incontinence episodes per week compared to placebo (9.0 vs 5.0, p <0.0001). For patients with severe incontinence at baseline median absolute and percentage reductions in incontinence episodes per week were significantly greater with tolterodine ER than placebo (21.0 vs 9.5, p <0.0001; 67.6% vs 29.8%, p = 0.022). Micturition frequency decreased (p <0.02) and volume voided per micturition (p <0.0001) increased significantly more with tolterodine ER compared with placebo in these patients. For patients with nonsevere incontinence at baseline median reductions in incontinence episodes per week were also significantly greater with tolterodine ER than placebo (6.0 vs 4.0, p <0.0001; 71.4% vs 38.5%, p = 0.026). CONCLUSIONS: Patients with more severe incontinence at baseline achieved greater absolute reductions in incontinence with tolterodine compared to those with less severe symptoms. The degree of improvement, as measured by percent change, was comparable across the entire range of baseline incontinence severity strata. Benefits of antimuscarinic therapy may be greater in these patients than previously reported.

A systematic review of the effects of estrogens for symptoms suggestive of overactive bladder.

OBJECTIVE: To perform a systematic review of the effects of estrogen therapy on symptoms suggestive of overactive bladder (OAB) in postmenopausal women. MATERIALS AND METHODS: This analysis involved a literature review of Medline, Excerpta Medica, and the Science Citation Index and a manual search of popular urology, gynecology, gerontology, and primary care medicine journals from January 1969 to December 1999. Articles had to include estrogen and placebo treatment groups, published or original data presented at a scientific meeting and report symptoms suggestive of OAB. This search identified 11 randomized trials and included a total of 430 subjects. Thirty-six subjects who participated in two crossover studies received both estrogen and placebo and thus are counted twice, therefore 236 received estrogen therapy and 230 were placebo controls. Estrogen was administered systemically or locally as estriol, estradiol, conjugated estrogen, or estradiol and estriol. A meta-analysis of these studies was performed for all estrogen therapies and then separately for systemic and local therapies. RESULTS: Overall, estrogen therapies were associated with statistically significant improvements in all outcome variables: diurnal frequency (P = 0.0011), nocturnal frequency (P = 0.0371), urgency (P = 0.0425), number of incontinence episodes (P = 0.0002), first sensation to void (P = 0.0001), and bladder capacity (P = 0.0018). Local therapies had statistically significant beneficial effects on all outcome variables. However, systemic therapies were only associated with significant improvements in incontinence episodes and first sensation to void while nocturnal frequency actually worsened. CONCLUSION: Estrogen therapy may be effective in alleviating the symptoms suggestive of OAB. Local administration may be the most beneficial route of administration.