Role of α- and ß-adrenergic signaling in phenotypic targeting: significance in benign and malignant urologic disease.

The urinary tract is highly innervated by autonomic nerves which are essential in urinary tract development, the production of growth factors, and the control of homeostasis. These neural signals may become dysregulated in several genitourinary (GU) disease states, both benign and malignant. Accordingly, the autonomic nervous system is a therapeutic target for several genitourinary pathologies including cancer, voiding dysfunction, and obstructing nephrolithiasis. Adrenergic receptors (adrenoceptors) are G-Protein coupled-receptors that are distributed throughout the body. The major function of α1-adrenoceptors is signaling smooth muscle contractions through GPCR and intracellular calcium influx. Pharmacologic intervention of α-and ß-adrenoceptors is routinely and successfully implemented in the treatment of benign urologic illnesses, through the use of α-adrenoceptor antagonists. Furthermore, cell-based evidence recently established the antitumor effect of α1-adrenoceptor antagonists in prostate, bladder and renal tumors by reducing neovascularity and impairing growth within the tumor microenvironment via regulation of the phenotypic epithelial-mesenchymal transition (EMT). There has been a significant focus on repurposing the routinely used, Food and Drug Administration-approved α1-adrenoceptor antagonists to inhibit GU tumor growth and angiogenesis in patients with advanced prostate, bladder, and renal cancer. In this review we discuss the current evidence on (a) the signaling events of the autonomic nervous system mediated by its cognate α- and ß-adrenoceptors in regulating the phenotypic landscape (EMT) of genitourinary organs; and (b) the therapeutic significance of targeting this signaling pathway in benign and malignant urologic disease. Video abstract.

Efficacy and safety of fesoterodine 8 mg in subjects with overactive bladder after a suboptimal response to tolterodine ER.

AIMS: To assess fesoterodine 8 mg efficacy over time and vs. placebo in subjects with overactive bladder (OAB) who responded suboptimally to tolterodine extended release (ER) 4 mg. METHODS: In a 12-week, double-blind trial, subjects with self-reported OAB symptoms for ≥ 6 months, mean of ≥ 8 micturitions and ≥ 2 to < 15 urgency urinary incontinence (UUI) episodes/24 h, and suboptimal response to tolterodine ER 4 mg (defined as ≤ 50% reduction in UUI episodes during 2-week run-in) were randomised to fesoterodine (4 mg for 1 week, 8 mg for 11 weeks) or placebo once daily. Change from baseline to week 12 in UUI episodes (primary end-point) was analysed in step-wise fashion: first, baseline vs. week 12 for fesoterodine; if significant, then change from baseline to week 12 for fesoterodine vs. placebo. RESULTS: By week 12, subjects receiving fesoterodine 8 mg had significantly greater improvement from baseline vs. placebo in UUI episodes, urgency episodes and scores on the Patient Perception of Bladder Control, Urgency Perception Scale and OAB Questionnaire Symptom Bother and Health-Related Quality of Life scales and domains (all p < 0.05). 50% and 70% UUI responder rates were also significantly higher with fesoterodine 8 mg vs. placebo at week 12 (p < 0.05). Dry mouth (placebo, 4%, 12/301; fesoterodine, 16.6%, 51/308) and constipation (placebo, 1.3%, 4/301; fesoterodine, 3.9%, 12/308) were the most frequent adverse events. CONCLUSIONS: Subjects who responded suboptimally to tolterodine ER 4 mg showed significant improvements in UUI and other OAB symptoms and patient-reported outcomes, with good tolerability, during treatment with fesoterodine 8 mg vs. placebo.

Management of benign prostatic hyperplasia: role of phosphodiesterase-5 inhibitors.

Several studies have highlighted a strong association between benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) and erectile dysfunction (ED), particularly in elderly men. Many epidemiological trials, such as in vitro and in vivo studies, have reported the emerging role of metabolic syndrome, including abdominal obesity, impaired glucose metabolism, hypertriglyceridemia, low high-density lipoprotein cholesterol, and hypertension, in the development and progression of urinary and sexual symptoms. Moreover, many authors have focused their studies on the identification of all the shared pathogenetic mechanisms of LUTS/BPH and ED, including alteration of cyclic guanosine monophosphate and RhoA-ROCK pathways or vascular and neurogenic dysfunction. All these are potential targets for proposed phosphodiesterase type 5 inhibitors (PDE5-Is). Therefore, several trials have recently been designed to evaluate the role of PDE5-Is alone or in combination with conventional treatment for BPH, such as α-adrenergic blockers, in men affected by LUTS/BPH, with or without ED. Different PDE5-Is are in clinical use worldwide and currently six of them are licensed for the oral treatment of ED. All these compounds differ in pharmacokinetic factors, with influence on drug action, and subsequently in the overall safety and efficacy profile.

PDE5-Is for the Treatment of Concomitant ED and LUTS/BPH.

Epidemiologic data in adult men exhibit a strong relationship between erectile dysfunction (ED) and lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH), indicating that men affected by ED should also be investigated for LUTS/BPH and those presenting with storage or voiding LUTS should be investigated for co-morbid ED. Common pathophysiolgical mechanisms underlying both LUTS/BPH and ED, including alteration of NO/cGMP or RhoA/Rho-kinase signaling and/or vascular or neurogenic dysfunction, are potential targets for proposed phosphodiesterase type 5 inhibitors (PDE5-Is). Several randomized controlled trials and only a few reviews including all commercially available PDE5-Is demonstrated the safety and efficacy of these drugs in the improvement of erectile function and urinary symptoms, in patients affected either by ED, LUTS, or both conditions.

Systematic review of the relationship between bladder and bowel function: implications for patient management.

BACKGROUND: The complex relationship between bladder and bowel function has implications for treating pelvic disorders. In this systematic review, we discuss the relationship between bladder and bowel function and its implications for managing coexisting constipation and overactive bladder (OAB) symptoms. METHODS: Multiple PubMed searches of articles published in English from January 1990 through March 2011 were conducted using combinations of terms including bladder, bowel, crosstalk, lower urinary tract symptoms, OAB, incontinence, constipation, hypermotility, pathophysiology, prevalence, management and quality of life. Articles were selected for inclusion in the review based on their relevance to the topic. RESULTS: Animal studies and clinical data support bladder-bowel cross-sensitization, or crosstalk. In the rat, convergent neurons in the bladder and bowel as well as some superficial and deeper lumbosacral spinal neurons receive afferent signals from both bladder and bowel. On a functional level, in animals and humans, bowel distention affects bladder activity and vice versa. Clinically, the bladder-bowel relationship is evident through the presence of urinary symptoms in patients with irritable bowel syndrome and bowel symptoms in patients with acute cystitis. Functional gastrointestinal disorders, such as constipation, can contribute to the development of lower urinary tract symptoms, including OAB symptoms, and treatment of OAB with antimuscarinics can worsen constipation, a common antimuscarinic adverse effect. The initial approach to treating coexisting constipation and OAB should be to relieve constipation, which may resolve urinary symptoms. CONCLUSIONS: The relationship between bladder and bowel function should be considered when treating patients with urinary symptoms, bowel symptoms, or both.

A 5-year retrospective analysis of 5α-reductase inhibitors in men with benign prostatic hyperplasia: finasteride has comparable urinary symptom efficacy and prostate volume reduction, but less sexual side effects and breast complications than dutasteride.

OBJECTIVE: We evaluated 5-year safety, efficacy and prostate volume data from BPH patients treated with finasteride or dutasteride. METHODS: A retrospective analysis of 378 consecutive men treated with 5α-reductase inhibitor monotherapy between January 2004 and September 2009 (197 on finasteride and 211 on dutasteride) in a single clinic was performed. Efficacy assessments included International Prostate Symptom Score (IPSS), peak urinary flow rate (Qmax), postvoid residual urine volume (PVR), prostate-specific antigen (PSA) and prostate volume (PV). Safety assessments included International Index of Erectile Function (IIEF) and adverse events. Patients were evaluated at 3 months, 1 year and yearly thereafter. RESULTS: Mean age of the group was 58.7 ± 6.7 years. Maintenance of therapy at 5 years was 57.4% and 42.5% for the finasteride and dutasteride groups respectively. Changes in IPSS, Qmax, PVR, PV and PSA were similar for both groups at 5 years. The incidence of erectile dysfunction, ejaculatory dysfunction and decreased libido resulting in discontinuation from therapy was significantly (p < 0.01) higher in the dutasteride (5.1%, 2.4%, 2.7% respectively) compared with the finasteride (2.1%, 1.8%, 1.4% respectively) group. In addition, the incidence of self-reported breast tenderness and/or enlargement was significantly (p < 0.01) greater in the dutasteride (3.5%) compared with the finasteride (1.2%) group. CONCLUSIONS: In this retrospective analysis of data from consecutive patients treated at a single clinic, both finasteride and dutasteride were effective therapies for the management of lower urinary tract symptoms. However, dutasteride resulted in significantly more sexual side effects and breast complications than finasteride.

Antimuscarinics for treatment of storage lower urinary tract symptoms in men: a systematic review.

Despite potential benefits, primary care clinicians may avoid using antimuscarinics in men with overactive bladder (OAB) symptoms because of safety concerns. To review the efficacy and safety of antimuscarinics, alone or in combination with an α-blocker, for the treatment of men with OAB symptoms, we conducted a systematic review of articles published before 22 July 2010, using PubMed. Data from 12-week, randomised, double-blind, placebo-controlled trials of tolterodine extended release (ER), oxybutynin and solifenacin show that combined antimuscarinic+α-blocker treatment is generally more effective than monotherapy or placebo in men with OAB symptoms. The efficacy and safety of tolterodine ER+α-blocker treatment was not affected by prostate size or prostate-specific antigen (PSA) level. In men meeting entry criteria for OAB and benign prostatic obstruction trials, tolterodine ER alone was effective selectively in men with prostate size or PSA level below study medians. Incidence of acute urinary retention (AUR) in men receiving antimuscarinics with or without an α-blocker was ≤3% in all of these trials; changes in postvoid residual volume and maximum flow rate did not appear clinically meaningful. Post hoc analyses from double-blind, placebo-controlled trials and prospective studies of fesoterodine, oxybutynin, propiverine, solifenacin and tolterodine also suggest that antimuscarinics are generally safe and efficacious in men. A retrospective database study found that risk of AUR in men was the highest in the first month of treatment and decreased considerably thereafter. Antimuscarinics, alone or with an α-blocker, appear to be efficacious and safe in many men with predominant OAB symptoms or persistent OAB symptoms despite α-blocker or 5-α-reductase inhibitor treatment. However, antimuscarinics are not approved for the treatment of benign prostatic hyperplasia. Monitoring men for AUR is recommended, especially those at increased risk, and particularly within 30 days after starting antimuscarinic treatment.

Symptomatic and urodynamic responses in patients with reduced or no seminal emission during silodosin treatment for LUTS and BPH.

Data from phase 3 studies (NCT00224107, NCT00224120) of silodosin for treatment of BPH symptoms were analyzed to examine the relationship between treatment efficacy and occurrence of abnormal ejaculation. Men aged ≥50 years with International Prostate Symptom Scores (IPSS) ≥13 and peak urinary flow rates (Qmax) of 4-15 ml s(-1) received placebo or silodosin 8 mg once daily for 12 weeks. Silodosin-treated patients were stratified by absence or presence of 'retrograde ejaculation' (RE). Groups were compared using analysis of covariance (for change from baseline) and responder analyses. Of the 466 patients receiving silodosin, 131 (28%) reported RE and 335 (72%) did not; 4 of the 457 patients receiving placebo (0.9%) reported RE. Most RE events in silodosin-treated patients (110/134; 82%) were reported as 'orgasm with absence of seminal emission.' Silodosin-treated patients with (+) and without (-) RE showed significant improvement in IPSS, Qmax and quality of life versus placebo (P<0.02). RE+ patients versus RE- patients experienced numerically greater improvement, but differences were not statistically significant (P>0.05). For RE+ patients, the odds of achieving improvement of ≥3 points in IPSS and ≥3 ml s(-1) in Qmax by study end were 1.75 times those for RE- patients (P=0.0127). Absence of seminal emission may predict superior treatment efficacy of silodosin in individual patients.

Assessing patients' descriptions of lower urinary tract symptoms (LUTS) and perspectives on treatment outcomes: results of qualitative research.

AIMS: Understanding the patient's experience and symptom descriptions is critical to assess outcomes. Thus, there is a need for qualitative research to better understand how patients describe their symptoms and treatment expectations. METHODS: Eight focus groups were conducted in two research phases: Phase 1 focused on eliciting patient's descriptions of urinary symptoms, and Phase 2 assessed patient perspectives on treatment outcomes. Participants with a range of lower urinary tract symptoms (LUTS) were recruited from urology clinics and community settings in the United States. All interviews were audio recorded and transcribed. Content and descriptive analyses were performed. RESULTS: A total of 33 men and 30 women participated. Mean ages for men and women were 55 and 61 in Phase 1, and 57 and 61 in Phase 2, respectively. About 73% of participants were white people, and most had a high school education or greater. A wide range of LUTS were emergently described, and the words, concepts and phrases were generally similar across groups. Most participants identified with the word 'bother', and thought it was important to assess both the frequency and bother of each symptom. Reasons for seeking care included symptom bother and fears about cancer and bladder infections. Most participants thought that a 50% improvement in a single symptom or group of symptoms would be a meaningful treatment outcome. CONCLUSION: This qualitative research provides a better understanding on how men and women describe their LUTS and their perspectives on treatment outcomes. This research can be used to inform the development of a new LUTS outcomes' tool.

A practical guide to the evaluation and treatment of male lower urinary tract symptoms in the primary care setting.

AIMS: Lower urinary tract symptoms (LUTS) are common in both men and women, and are among the most prevalent patient complaints heard by primary care physicians (PCPs). This article aims to provide PCPs with a logical algorithm for the assessment and initiation of treatment for LUTS in the male patient. RESULTS: Management of LUTS involves a focused history and physical, as well as the assessment of bother. In patients for whom treatment is warranted, a series of decisions regarding therapy should be considered. Male patients commonly suffer from storage and/or voiding symptoms. Treatment of male LUTS is commonly begun with agents that are aimed at remedying the outlet symptoms of benign prostatic hyperplasia (BPH). When this intervention is ineffective or when refractory symptoms persist, consideration should be given to treating the storage symptoms characteristic of overactive bladder (OAB). DISCUSSION: This article is intended to provide the PCP with a logical guide to the treatment of male LUTS. Benign prostatic hyperplasia and OAB predominate among the causes of these symptoms, and the PCP should be comfortable treating each. Recent data detailing the safety of the use of these treatments in the male patient are reviewed and incorporated into the algorithm. CONCLUSION: Primary care physicians are in a unique position to successfully identify and treat male patients with LUTS. With this paper, they now have a tool to approach treatment logically and practically.

5alpha-reductase inhibitors: what role should they play?

The development of finasteride (PROSCAR, Merck & Co., Whitehouse Station, NJ) for the treatment of benign prostatic hyperplasia (BPH) has had variable results. Numerous short-term and long-term studies comparing finasteride with placebo have been reported. The results suggest that, physiologically, treatment with finasteride significantly decreases levels of both serum and intraprostatic dihydrotestosterone about 70% to 80% from baseline. In addition, total gland size decreases significantly-about 15% to 25% from baseline-particularly in the area of the periurethral zone of the prostate after finasteride treatment. Baseline prostate size has been found to have a relation to efficacy of finasteride treatment. The larger the prostate at baseline, the greater the urinary flow rate increase and symptom score decrease compared with placebo. Health-related quality-of-life parameters improved in those taking finasteride. In studies evaluating combination therapy, no significant differences were noted between those treated with an alpha blocker, such as terazosin or doxazosin in combination with finasteride, and those receiving an alpha blocker alone. Long-term finasteride versus placebo studies, such as the PROSCAR Long-Term Efficacy and Safety Study (PLESS), suggest that long-term medical therapy with finasteride affects the natural history of the disease as manifested by the decrease in rates of acute urinary retention and surgery. In patients who are "therapeutic responders," the degree of symptomatic improvement in those treated with finasteride appears to be equal to that seen in patients receiving alpha blockers. Prostate cancer detection rates did not differ between those treated with finasteride and those receiving a placebo. The results of these studies suggest that physicians must evaluate what role finasteride plays in the spectrum of available options for the treatment of BPH and lower urinary tract symptoms. Baseline parameters, such as prostate volume, prostate-specific antigen values, and whether to administer finasteride in combination with alpha blockers, are among the factors that will determine the appropriateness of such therapy.

Comparison of the efficacy and safety of finasteride in older versus younger men with benign prostatic hyperplasia.

OBJECTIVES: To compare the efficacy and safety of finasteride 5 mg in older (65 years old or older) versus younger (45 to younger than 65 years old) men with benign prostatic hyperplasia (BPH). METHODS: The Proscar Long-Term Efficacy and Safety Study (PLESS) was a 4-year, randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of finasteride 5 mg in 3040 men 45 to 78 years old with symptomatic BPH, enlarged prostates, and no evidence of prostate cancer. The endpoints included urinary symptoms, prostate volume, occurrence of acute urinary retention and/or BPH-related surgery, and safety. RESULTS: In both age cohorts, finasteride treatment led to a 51% reduction (P <0.001) in the relative risk for acute urinary retention and/or BPH-related surgery, a significant (P <0.001) and durable improvement in symptom score, and a significant (P <0.001) and sustained reduction in prostate volume. Within each age cohort, no significant differences were found between the placebo and finasteride-treated patients in the incidence of cardiovascular adverse events. Significant differences were evident between the placebo and finasteride groups in the incidence of the typical, known, drug-related adverse events, but no specific differences were associated with age. No drug interactions of clinical importance were observed in the finasteride-treated patients. CONCLUSIONS: The present analysis from PLESS demonstrates that in both older (65 years old or older) and younger men with symptomatic BPH and enlarged prostates, finasteride is highly effective in improving symptoms and reducing prostate volume in many men and in reducing the risk of acute urinary retention and BPH-related surgery. In addition, the safety profile of finasteride in both older and younger men is similar and no drug interactions of clinical importance were observed.

Biomarker analysis demonstrates a hypoxic environment in the castrated rat ventral prostate gland.

Within the first 24 h after castration of an adult male rat, the vascular system of the ventral prostate gland undergoes a degenerative process that drastically reduces blood flow to the tissue. Since the vascular degeneration precedes the loss of the prostatic epithelium (by apoptosis), we have proposed that the onset of epithelial cell apoptosis in this tissue is caused by an ischemic/hypoxic environment resulting from the loss of blood flow. In order to further evaluate the extent to which ischemia/hypoxia might be a factor in apoptosis of the prostate epithelium after castration, we analyzed for biomarkers of cellular hypoxia in rat ventral prostates during the first 3 days following castration. Ventral prostate tissues removed from hypoxyprobe-1-treated adult male rats (uncastrated controls; surgically castrated for 24, 48 or 72 h, or sham-castrated for equivalent times) were directly analyzed for evidence of hypoxia by in situ immunohistochemical evaluation of hypoxyprobe-1 adduct formation in the prostate cells. Protein extracts from these tissues were also tested for expression of the 120 kDa hypoxia-inducible factor-1-alpha (HIF-1-alpha) protein as well as for expression of mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) proteins using a Western blot assay. The tyrosine phosphorylation status of the latter signaling molecules was also evaluated by Western blotting using anti-tyrosine phosphate antibodies. Our results showed that epithelial cells of the rat ventral prostate stained positively for hypoxyprobe-1 adducts at all times after castration, whereas cells in control tissues were unstained by this procedure. In addition, the prostatic expression of HIF-1-alpha protein was increased approximately 20-fold at 48 h after castration compared to control tissues. Finally, although prostatic MAPK and JNK protein expression was unaltered during the early period after castration, phosphorylation of the JUN kinase protein was significantly elevated, indicating that this stress-activated cellular signaling pathway becomes more active subsequent to castration. These results support our proposal that early castration-induced degeneration and constriction of the vascular system of the rat ventral prostate gland leads to reduced oxygenation of prostatic epithelial cells and the activation of hypoxic cellular signaling in these cells through upregulation of HIF-1-alpha expression and stimulation of the JUN kinase signaling pathway.

Holmium and interstitial lasers for the treatment of benign prostatic hyperplasia: a laser revival.

With the introduction of the side-firing neodymium:yttrium-aluminum-garnet laser in the early 1990s laser prostatectomy became a widely used treatment for benign prostatic hyperplasia. However, because of prolonged postoperative catheterization times, the lack of immediate effect, and severe postoperative dysuria, many urologists became disinterested in this procedure. Recently, as a result of advances in laser technology, namely, the holmium laser and interstitial laser prostatectomy, interest in lasers for the treatment of benign prostatic hyperplasia has been rekindled. This paper will review published reports over the past year regarding these relatively new treatments.

Use of prostatic stents for the treatment of benign prostatic hyperplasia in high-risk patients.

Benign prostatic hyperplasia (BPH) is a frequent disease in men and a major cause of lower urinary tract symptoms (LUTS). Transurethral resection of the prostate (TURP) or open surgery remains the gold standard of treatment for symptomatic BPH. However, 10% to 15% of patients with BPH cannot undergo surgery due to grave concomitant diseases. For patients presenting with contraindications to surgery or anesthesia, several minimally invasive alternative treatment modalities are available. One such therapeutic alternative is prostatic stenting, which can serve as a temporary or permanent solution for bladder outlet obstruction caused by BPH. Although not a new concept, this is a relatively new treatment modality in the United States, primarily because of the strict regulatory forces governing the use of these devices. Prostatic urethral stents have been widely demonstrated to be safe and effective for the treatment of symptomatic BPH. In addition to being minimally invasive, prostatic stenting is generally rapid, easy to perform, immediately effective, and has a low cost compared with conventional surgical treatment. Prostatic stents are therefore well suited to treat the frail elderly patient who would not be able to withstand the stress of undergoing surgery. This report reviews the current use of prostatic urethral stents in the treatment of high-risk surgical patients with BPH.

Prospective analysis of 373 consecutive women with stress urinary incontinence treated with a vaginal wall sling: the Columbia-Cornell University experience.

PURPOSE: We compare the efficacy and morbidity of 373 consecutive women who underwent a vaginal wall sling for stress urinary incontinence due either to anatomical incontinence or intrinsic sphincter deficiency. To our knowledge this series is the largest prospective database on surgical management of stress urinary incontinence in the urological literature. MATERIALS AND METHODS: Preoperative evaluation included history, voiding diary, physical examination, cystoscopy, pad count and video urodynamic study. Outcome measures included postoperative presence of incontinence secondary to either stress and/or detrusor instability, number of pads used, complications, operating time, length of suprapubic catheterization, length of hospitalization and loss of work days. RESULTS: A total of 373 consecutive women 18 to 85 years old (mean age 55.7) were followed for a mean of 39.8 months. Of these patients 183 (49%) presented with anatomical incontinence and the remaining 190 (51%) had intrinsic sphincter deficiency. Preoperative detrusor instability was present in 60 (33%) patients with anatomical incontinence and 68 (36%) with intrinsic sphincter deficiency. Postoperatively, 14 patients (4%) had recurrent stress urinary incontinence. De novo detrusor instability and urge incontinence were noted in 30 women (8%), and was persistent in 22 (6%). There was no correlation between the diagnosis of anatomical incontinence or intrinsic sphincter deficiency and persistent stress urinary incontinence or detrusor instability. Daily pad use was decreased from 4.3 to 0.5 and from 4.6 to 0.4, respectively, for patients with anatomical incontinence and intrinsic sphincter deficiency. Operating time, catheter duration, length of hospital stay and days lost from work for patients with anatomical incontinence (33.3 +/- 14.3 minutes, 4.7 +/- 1.1 days, 0.9 +/- 0.7 days and 11.3 +/- 2.9 days, respectively) were similar to patients with intrinsic sphincter deficiency (38.4 +/- 17.8, 4.6 +/- 0.9, 1.1 +/- 0.7, 12.4 +/- 4.7). The most common complications were urinary tract infection (3%), wound infection (4%) and pelvic organ prolapse (7%). CONCLUSIONS: The results of this large database suggest that the vaginal wall sling is effective for the management of stress urinary incontinence. Efficacy, morbidity and reduced hospitalization time were similar for patients with either anatomical incontinence or intrinsic sphincter deficiency and independent of surgeon experience.