Vitamin D intake and the 10-year risk of urgency urinary incontinence in women.

Evidence indicates that higher serum 25-hydroxy vitamin D levels may be associated with decreased prevalence of urgency urinary incontinence (UI), but the impact of vitamin D consumption on development of urgency and mixed UI is unclear. The objective was to assess whether greater vitamin D intake was associated with decreased risk of incident urgency and mixed UI over 10 years using 2 large prospective cohorts of middle-aged and older women. We analyzed 38,101 women from the Nurses' Health Study I (NHS I) and 35,190 women from NHS II who were free of UI at baseline. We followed incident UI, defined as new UI occurring at least monthly, separately by subtype (urgency, mixed, stress UI), from 2002-2012. We categorized vitamin D intake from supplements and diet. We estimated relative risk for developing UI according to vitamin D intake using Cox-proportional hazard models with adjustment for covariates. Median vitamin D intake was 580IU in the older women in NHS I (age range 56-71 at baseline) and 487IU in middle-aged women in NHS II (age range 40-57). Among women taking ≥1000IU of vitamin D, median intake in the older women was 1252IU and 1202IU in the middle-aged women. Among the older women, we found no relation of vitamin D intake to risk of developing UI, across all UI subtypes. In multivariable-adjusted analysis for middle-aged women, the relative risk of developing mixed UI among women taking >1000IU was 0.79 (0.63, 0.99) and for urgency UI was 0.88 (0.71, 1.07), versus <200IU. Risks of developing stress UI were not related to vitamin D intake categories. Overall, we did not find a relationship between vitamin D intake and UI incidence in middle-aged and older women; however, the reported intake was moderate.

Essential role of transient receptor potential M8 (TRPM8) in a model of acute cold-induced urinary urgency.

BACKGROUND: Acute exposure of part of the skin to cold stimuli can evoke urinary urgency, a phenomenon termed acute cold-induced urgency (ACIU). Despite its high prevalence, particularly in patients with overactive bladder, little is known about the mechanisms that induce ACIU. OBJECTIVE: To develop an animal model of ACIU and test the involvement of cold-activated ion channels transient receptor potential (TRP) M8 and TRPA1. DESIGN, SETTING, AND PARTICIPANTS: Intravesical pressure and micturition were monitored in female mice (wild-type C57BL/6J, Trpa1(-/-), Trpm8(+/+), and Trpm8(-/-)) and Sprague Dawley rats. INTERVENTIONS: An intravesical catheter was implanted. Localized cooling of the skin was achieved using a stream of air or topical acetone. The TRPM8 antagonist (N-(3-aminopropyl)-2-{[(3-methylphenyl) methyl]oxy}-N-(2-thienylmethyl)benzamide (AMTB) or vehicle was injected intraperitoneally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Frequencies of bladder contractions and voids in response to sensory stimuli were compared using the Mann-Whitney or Kruskal-Wallis test. RESULTS AND LIMITATIONS: Brief, innocuously cold stimuli applied to different parts of the skin evoked rapid bladder contractions and voids in anesthetized mice and rats. These responses were strongly attenuated in Trpm8(-/-) mice and in rats treated with AMTB. As rodent bladder physiology differs from that of humans, it is difficult to directly extrapolate our findings to human patients. CONCLUSIONS: Our findings indicate that ACIU is an evolutionarily conserved reflex rather than subconscious conditioning, and provide a useful in vivo model for further investigation of the underlying mechanisms. Pharmacological inhibition of TRPM8 may be useful for treating ACIU symptoms in patients. PATIENT SUMMARY: Brief cold stimuli applied to the skin can evoke a sudden desire to urinate, which can be highly bothersome in patients with overactive bladder. We developed an animal model to study this phenomenon, and found that it depends on a specific molecular cold sensor, transient receptor potential M8 (TRPM8). Pharmacological inhibition of TRPM8 may alleviate acute cold-induced urinary urgency in humans.

Efficacy and safety of repeated dosing of netupitant, a neurokinin-1 receptor antagonist, in treating overactive bladder.

AIM: NK-1 receptors in sensory nerves, the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity. This study was designed to assess the efficacy and safety of a new NK-1 receptor antagonist, netupitant, in patients with OAB. METHODS: This was a phase II, multicenter, double-blind study in which adults with OAB symptoms >6 months were randomized to receive 1 of 3 doses of netupitant (50, 100, 200 mg) or placebo once daily for 8 weeks. The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8. Urinary incontinence, urge urinary incontinence (UUI), and urgency episodes were also assessed. RESULTS: The primary efficacy endpoint was similar in the treatment groups (-13.85 for placebo to -16.17 in the netupitant 200 mg group) with no statistically significant differences between netupitant and placebo. The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group. Netupitant was well tolerated with most treatment emergent adverse events (AEs) being mild. While the overall incidence of AEs increased with netupitant dose, there was no evidence for this dose dependency based on relationship to treatment, intensity, or time to onset. CONCLUSIONS: The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms, despite a trend favoring netupitant 100 mg. There were no safety concerns with daily administration of netupitant over 8 weeks.

The effect of genital and lower urinary tract symptoms on steroid receptor expression in women with genital prolapse.

INTRODUCTION AND HYPOTHESIS: This study evaluates the expression of estrogen receptor (ER) isoforms alpha (α) and beta (ß) and progesterone receptor (PR) in vaginal and periurethral tissue in women with genital prolapse in relation to genital and lower urinary tract symptoms (LUTS). METHODS: Forty-seven postmenopausal women without systemic estrogen therapy underwent pelvic organ prolapse quantification and urodynamic assessment. LUTS were evaluated by CATI questionnaire. Biopsies from vaginal and periurethral tissue were obtained during prolapse surgery. The steroid receptor gene expression was measured by RT-PCR. RESULTS: The expression of PR in periurethral and ER ß in vaginal tissue varied with prolapse extent. Nulliparous women showed a significantly higher expression of PR in periurethral tissue. Women with a positive stress test and those with overactive bladder symptoms showed a significantly lower amount of PR in vaginal tissue. CONCLUSION: Changes in PR expression in vaginal or periurethral tissue might be a marker of structural and endocrine changes.

Urinary nerve growth factor levels in overactive bladder syndrome and lower urinary tract disorders.

Overactive bladder (OAB) is a syndrome based on self-reported symptoms of urgency and frequency with or without urge incontinence. Although urgency is the core symptom of OAB, patients might have difficulty to distinguish urgency from the urge to void. Urodynamic study is a useful diagnostic tool to discover detrusor overactivity (DO) in patients with OAB; however, not all OAB patients have DO. Therefore, a more objective and non-invasive way to diagnose and assess OAB including DO is needed. Recent research has focused on urinary biomarkers in assessment of OAB. Urinary nerve growth factor (NGF) level increases in patients with OAB-wet, bladder outlet obstruction, mixed urinary incontinence and urodynamic DO. Urinary NGF levels are correlated with severity of OAB symptoms. In patients with OAB and DO who have been well treated with antimuscarinics or botulinum toxin injection, urinary NGF levels have been shown to decrease significantly in association with reduction of urgency severity. However, not all patients with OAB have an elevated urinary NGF level. It might also be increased in patients with interstitial cystitis/painful bladder syndrome, cerebrovascular accident and lower urinary tract diseases such as urinary tract stone, bacterial infection and urothelial tumor. It is possible to use urinary NGF levels as a bio-marker for diagnosis of OAB as well as for the assessment of therapeutic outcome in patients with OAB or DO. Here, we review the latest medical advances in this field.

[Influence of suoquan capsule on detrusor of D-galactose mimetic rats].

OBJECTIVE: To discuss the influence of Suoquan capsule (SQJN) on the detrusor of D-galactose mimetic rats, and to explore the mechanism of reducing urine. METHOD: Investigate the enzymes (ATPase, SDH, SOD, MDA, Na+ -K+ -ATPase, Ca2+ - Mg2+ -ATPase) which influence the production and excretion of urine and the reactivity of urinary detrusor strips to different concentrations of ISO and ATP. RESULT: Compared with the model group, the activity of SOD, Na+ -K+ -ATPase, Ca2+ -Mg2+ -ATPase and SDH increased significantly in aging rats after administrating SQJN (P < 0.01); the complaisance and elasticity of bladder also increased (P < 0.05). The frequency of spontaneous contraction and the MDA decreased significantly (P < 0.05-0.01). The decreased relaxation response to ISO and increased contractile response to ATP were also changed after administrating SQJN. CONCLUSION: SQJN can regulate the metabolism of fluid through recovering the normal physiologic function of the detrusor of bladder.

Phosphodiesterases (PDEs) and PDE inhibitors for treatment of LUTS.

Lower urinary tract (LUT) smooth muscle can be relaxed by drugs that increase intracellular concentrations of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both of these substances are degraded by phosphodiesterases (PDEs), which play a central role in the regulation of smooth muscle tone. The distribution and functional significance of PDE enzymes vary in different tissues of the LUT. Targeting specific PDE isoenzymes should thus allow organ selectivity. PDE 4 and 5 appear to predominate in the prostate, PDE 1 and 4 are thought to influence detrusor smooth muscle function, and PDE 5 may be functionally important in the urethra and vasculature. Studies on the use of PDE inhibitors to treat various LUT symptoms (LUTS), have yielded favorable results. Thus, positive effects of the PDE 5 inhibitors sildenafil and tadalafil on symptoms and quality of life in men with LUTS, erectile dysfunction, and BPH have also been demonstrated. These effects may be due to effects on cGMP signaling and/or modification of afferent input from bladder, urethral, and prostate tissue. This review gives an update on the distribution of PDEs in structures relevant for LUT function, and discusses how inhibition of these enzymes can contribute to beneficial effects on LUTS. Information for the review was obtained from searches of the PubMed database, and from the authors' files.

Rho-kinase and effects of Rho-kinase inhibition on the lower urinary tract.

Altered smooth muscle cell contractility/tone contributes, at least in part, to the lower urinary tract symptoms (LUTS) seen in men with benign prostatic obstruction (BPO). Accordingly, many of the therapies to date have focused largely on blockade of individual membrane receptors to diminish smooth muscle contractility and provide symptomatic relief. This pharmacologic approach has been associated with variable results, limited efficacy, and untoward side effects. Such limited clinical success is not surprising given the plethora of neurotransmitters, neuromodulators, and hormones that are now known to modulate LUT smooth muscle cell tone. In the pursuit of improved treatment options, more recent investigations have focused attention on intracellular signal transduction events that represent convergence points for membrane receptor activation. In particular, calcium sensitization and the role of the Rho-kinase pathway has received much attention. In this report, we review the literature on the role of the Rho-kinase pathway in the modulation of LUT smooth muscle cell tone. In short, the available data support an important role for Rho-kinase in the physiologic and pathophysiologic regulation of LUT smooth muscle cell tone. Rho-kinase inhibitors thus appear to represent a potentially attractive therapeutic possibility for the treatment of LUTS.