Kevin T. McVary

Update on AUA Guideline on the Management of Benign Prostatic Hyperplasia

PURPOSE To revise the 2003 version of the American Urological Associations (AUA) Guideline on the management of benign prostatic hyperplasia (BPH). MATERIALS AND METHODS From MEDLINE® searches of English language publications (January 1999 through February 2008) using relevant MeSH terms, articles concerning the management of the index patient, a male ≥45 years of age who is consulting a healthcare provider for lower urinary tract symptoms (LUTS) were identified. Qualitative analysis of the evidence was performed. Selected studies were stratified by design, comparator, follow-up interval, and intensity of intervention, and meta-analyses (quantitative synthesis) of outcomes of randomized controlled trials were planned. Guideline statements were drafted by an appointed expert Panel based on the evidence. RESULTS The studies varied as to patient selection; randomization; blinding mechanism; run-in periods; patient demographics, comorbidities, prostate characteristics and symptoms; drug doses; other intervention characteristics; comparators; rigor and intervals of follow-up; trial duration and timing; suspected lack of applicability to current US practice; and techniques of outcomes measurement. These variations affected the quality of the evidence reviewed making formal meta-analysis impractical or futile. Instead, the Panel and extractors reviewed the data in a systematic fashion and without statistical rigor. Diagnosis and treatment algorithms were adopted from the 2005 International Consultation of Urologic Diseases. Guideline statements concerning pharmacotherapies, watchful waiting, surgical options and minimally invasive procedures were either updated or newly drafted, peer reviewed and approved by AUA Board of Directors. CONCLUSIONS New pharmacotherapies and technologies have emerged which have impacted treatment algorithms. The management of LUTS/BPH continues to evolve.

Tadalafil Administered Once Daily for Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: A Dose Finding Study

PURPOSE Phosphodiesterase type 5 inhibitors are widely used to treat erectile dysfunction. Preliminary data have suggested phosphodiesterase type 5 inhibitor efficacy in men with lower urinary tract symptoms associated with clinical benign prostatic hyperplasia. MATERIALS AND METHODS After a 4-week placebo run-in period 1,058 men with benign prostatic hyperplasia lower urinary tract symptoms were randomly allocated to receive 12-week, once daily treatment with placebo or tadalafil (2.5, 5, 10 or 20 mg). RESULTS The International Prostate Symptom Score least squares mean change from baseline to end point was significantly improved for 2.5 (-3.9, p = 0.015), 5 (-4.9, p <0.001), 10 (-5.2, p <0.001) and 20 mg (-5.2, p <0.001) tadalafil compared to placebo (-2.3). International Prostate Symptom Score improvements at 4, 8 and 12 weeks were significant for all tadalafil doses and they demonstrated a dose-response relationship. Tadalafil (2.5 mg) significantly improved the International Prostate Symptom Score obstructive subscore and the International Index of Erectile Function-Erectile Function domain, the latter in sexually active men with a history of erectile dysfunction. Statistically significant improvements were noted for 5, 10 and 20 mg tadalafil compared to placebo, as assessed by the International Prostate Symptom Score irritative and obstructive subscores, International Prostate Symptom Score Quality of Life, Benign Prostatic Hyperplasia Impact Index (nonsignificant for 10 mg), Global Assessment Question and International Index of Erectile Function-Erectile Function domain. No statistically significant effect of treatment compared to placebo was noted for peak flow at any tadalafil dose. Treatment emergent adverse events were infrequent in all tadalafil groups. CONCLUSIONS Once daily tadalafil demonstrated clinically meaningful and statistically significant efficacy and it was well tolerated in men with benign prostatic hyperplasia lower urinary tract symptoms. Of the doses studied 5 mg tadalafil appeared to provide a positive risk-benefit profile.

Lower urinary tract symptoms and sexual dysfunction: epidemiology and pathophysiology.

There is ample evidence from many epidemiological studies that lower urinary tract symptoms (LUTS) and sexual dysfunction are strongly linked, independently of age and comorbidities such as hypertension, diabetes, dyslipidaemia and coronary heart disease. However, a causal link between both conditions is not yet established. Four pathophysiological mechanisms currently support the relationship between LUTS and erectile dysfunction (ED): (i) The nitric oxide synthase (NOS)/NO theory; there is a reduction in NOS‐containing nerves in the prostate and bladder/urethra in patients with bladder outlet obstruction (BOO), and that lack of NO or loss of protein kinase G causes ED; (ii) The autonomic hyperactivity and metabolic syndrome hypothesis: benign prostatic hyperplasia (BPH) may be part of the metabolic syndrome, which includes cardiovascular diseases (e.g. hypertension, ischaemic heart disease) and diabetes mellitus, known risk factors for ED. Hypertension, obesity, and hyperinsulinaemia have all been claimed to be associated with an increased sympathetic activity. Increased sympathetic activity is involved in LUTS/BPH and may have a role in ED/sexual dysfunction, with noradrenaline and α1‐adrenoceptors representing a common link; (iii) the Rho‐kinase activation/endothelin pathway; there can be increased Rho‐kinase activity, and consequently calcium sensitivity of the contractile machinery, in prostate smooth muscle in BPH, the detrusor in BOO, corpora cavernosa in ED, and in the resistance vessels in hypertension. The actions of several factors beside noradrenaline (e.g. endothelin‐1, angiotensin II), possibly involved in the increased smooth muscle activity found in both LUTS/BPH and sexual dysfunction, are dependent on Rho‐kinase activity. Thus increased Rho‐kinase activity might represent a common link between LUTS and sexual dysfunction; (iv) Pelvic atherosclerosis; animal models mimicking pelvic ischaemia and hypercholesterolaemia show similar smooth muscle alterations of the detrusor and corpora. Pelvic ischaemia may induce the biological modifications described above and may thus represent as well a common link between LUTS and sexual dysfunction. Studies treating one condition (e.g. ED) and measuring the impact on the other (e.g. LUTS) should further contribute to support this common link.

A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with α-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia

CONTEXT Several randomized controlled trials (RCTs) on phosphodiesterase type 5 inhibitors (PDE5-Is) have showed significant improvements in both lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) in men affected by one or both conditions, without a significant increase in adverse events. However, the results are inconsistent. OBJECTIVE Perform a systematic review and meta-analysis of available prospective and cross-sectional studies on the use of PDE5-Is alone or in combination with α1-adrenergic blockers in patients with LUTS/benign prostatic hyperplasia (BPH). EVIDENCE ACQUISITION A systematic search was performed using the Medline, Embase, and Cochrane Library databases through September 2011 including the combination of the following terms: LUTS, BPH, PDE5-Is, sildenafil, tadalafil, vardenafil, udenafil, α-blockers, and α1-adrenergic blocker. The meta-analysis was conducted according to the guidelines for observational studies in epidemiology. EVIDENCE SYNTHESIS Of 107 retrieved articles, 12 were included in the present meta-analysis: 7 on PDE5-Is versus placebo, with 3214 men, and 5 on the combination of PDE5-Is with α1-adrenergic blockers versus α1-adrenergic blockers alone, with 216 men. Median follow-up of all RCTs was 12 wk. Combining the results of those trials, the use of PDE5-Is alone was associated with a significant improvement of the International Index of Erectile Function (IIEF) score (+5.5; p<0.0001) and International Prostate Symptom Score (IPSS) (-2.8; p<0.0001) but not the maximum flow rate (Q(max)) (-0.00; p=not significant) at the end of the study as compared with placebo. The association of PDE5-Is and α1-adrenergic blockers improved the IIEF score (+3.6; p<0.0001), IPSS score (-1.8; p = 0.05), and Q(max) (+1.5; p<0.0001) at the end of the study as compared with α-blockers alone. CONCLUSIONS The meta-analysis of the available cross-sectional data suggests that PDE5-Is can significantly improve LUTS and erectile function in men with BPH. PDE5-Is seem to be a promising treatment option for patients with LUTS secondary to BPH with or without ED.

A Systematic Review and Meta-analysis of Functional Outcomes and Complications Following Transurethral Procedures for Lower Urinary Tract Symptoms Resulting from Benign Prostatic Obstruction: An Update

CONTEXT A number of transurethral ablative techniques based on the use of innovative medical devices have been introduced in the recent past for the surgical treatment of benign prostatic obstruction (BPO). OBJECTIVE To conduct a systematic review of the literature and a meta-analysis of available randomized controlled trials (RCTs), and to evaluate the efficacy and safety of transurethral ablative procedures for BPO. EVIDENCE ACQUISITION A systematic literature search was performed for all RCTs comparing any transurethral surgical technique for BPO to another between 1992 and 2013. Efficacy was evaluated after a minimum follow-up of 1 yr based on International Prostate Symptom Score, maximum flow rate, and postvoid residual volume. Efficacy at midterm follow-up, prostate volume, perioperative data, and short-term and long-term complications were also assessed. Data were analyzed using RevMan software. EVIDENCE SYNTHESIS A total of 69 RCTs (8517 enrolled patients) were included. No significant difference was found in terms of short-term efficacy between bipolar transurethral resection of the prostate (B-TURP) and monopolar transurethral resection of the prostate (M-TURP). However, B-TURP was associated with a lower rate of perioperative complications. Better short-term efficacy outcomes, fewer immediate complications, and a shorter hospital stay were found after holmium laser enucleation of the prostate (HoLEP) compared with M-TURP. Compared with M-TURP, GreenLight photoselective vaporization of the prostate (PVP) was associated with a shorter hospital stay and fewer complications but no different short-term efficacy outcomes. CONCLUSIONS This meta-analysis shows that HoLEP is associated with more favorable outcomes than M-TURP in published RCTs. B-TURP and PVP have resulted in better perioperative outcomes without significant differences regarding efficacy parameters after short-term follow-up compared with M-TURP. Further studies are needed to provide long-term comparative data and head-to head comparisons of emerging techniques. PATIENT SUMMARY Bipolar transurethral resection of the prostate, photovaporization of the prostate, and holmium laser enucleation of the prostate have shown efficacy outcomes comparable with conventional techniques yet reduce the complication rate. The respective role of these new options in the surgical armamentarium needs to be refined to propose tailored surgical treatment for benign prostatic obstruction relief.

Pharmacotherapy for erectile dysfunction.

INTRODUCTION Pharmacotherapy is the usual initial therapy for most men with erectile dysfunction. AIM To review the current data relating to the efficacy, tolerability and safety of drugs used in the treatment of men with erectile dysfunction. METHODS A critical review of the literature relating to the use of pharmacotherapeutic agents was undertaken by a committee of eight experts from five countries, building on prior reviews. MAIN OUTCOME MEASURES Expert opinion and recommendations were based on grading of evidence-based literature, internal committee dialogue, open presentation, and debate. RESULTS Almost all currently available evidence relates to sildenafil, tadalafil, and vardenafil. Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for most men with erectile dysfunction who do not have a specific contraindication to their use. There is no evidence of significant differences in efficacy, safety, and tolerability between the PDE5 inhibitors and apomorphine. Intracavernosal injection therapy with alprostadil should be offered to patients as second line therapy for erectile dysfunction. Intraurethral alprostadil is a less effective treatment than intracavernosal alprostadil for the treatment of men with erectile dysfunction. CONCLUSIONS PDE5 inhibitors are effective, safe, and well-tolerated therapies for the treatment of men with erectile dysfunction. Apomorphine, intracavernosal injection therapy with alprostadil, and intraurethral alprostadil are all effective and well-tolerated treatments for men with erectile dysfunction. We recommend some standardization of the assessment of psychosocial outcomes within clinical trials in the field of erectile dysfunction.

Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia

CONTEXT This review focuses on the relationship among sexual dysfunction (SD), lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH), and related therapies. OBJECTIVE We reviewed the current literature to provide an overview of current data regarding epidemiology and pathophysiology of SD and LUTS. Moreover, we analysed the impact of currently available therapies of LUTS/BPH on both erectile dysfunction (ED) and ejaculatory dysfunction and the effect of phosphodiesterase type 5 inhibitors (PDE5-Is) in patients with ED and LUTS. EVIDENCE ACQUISITION We conducted a Medline search to identify original articles, reviews, editorials, and international scientific congress abstracts by combining the following terms: benign prostatic hyperplasia, lower urinary tract symptoms, sexual dysfunction, erectile dysfunction, and ejaculatory dysfunction. EVIDENCE SYNTHESIS We conducted a comprehensive analysis of more relevant general population-based and BPH/LUTS or SD clinic-based trials and evaluated the common pathophysiologic mechanisms related to both conditions. In a further step, the overall impact of current BPH/LUTS therapies on sexual life, including phytotherapies, novel drugs, and surgical procedures, was scrutinized. Finally, the usefulness of PDE5-Is in LUTS/BPH was critically analysed, including preclinical and clinical research data as well as possible mechanisms of action that may contribute to the efficacy of PDE5-Is with LUTS/BPH. CONCLUSIONS Community-based and clinical data demonstrate a strong and consistent association between LUTS and ED, suggesting that elderly men with LUTS should be evaluated for SD and vice versa. Pathophysiologic hypotheses regarding common basics of LUTS and SD as discussed in the literature are (1) alteration of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, (2) enhancement of RhoA-Rho-kinase (ROCK) contractile signalling, (3) autonomic adrenergic hyperactivity, and (4) pelvic atherosclerosis. The most important sexual adverse effects of medical therapies are ejaculation disorders after the use of some α-blockers and sexual desire impairment, ED, and ejaculatory disorders after the use of α-reductase inhibitors. Minimally invasive, conventional, and innovative surgical treatments for BPH may induce both retrograde ejaculation and ED. PDE5-Is have demonstrated significant improvements in both LUTS and ED in men with BPH; combination therapy with PDE5-Is and α1-adrenergic blockers seems superior to PDE5-I monotherapy.

Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: pathophysiology and mechanism(s) of action.

The PDE5 inhibitor tadalafil is investigation for the treatment of lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). Several clinical studies of tadalafil and other PDE5 inhibitors have reported significant symptom reduction but limited urinary flow rate improvement. This manuscript reviews the published literature describing the pathophysiology of male LUTS, with an emphasis on mechanisms that may be modulated or improved by phosphodiesterase type 5 (PDE5) inhibition.

TESTOSTERONE SUPPLEMENTATION FOR ERECTILE DYSFUNCTION: RESULTS OF A META-ANALYSIS

PURPOSE To our knowledge a causal relationship between altered levels of androgens and erectile dysfunction has not yet been established. We reviewed the literature to assess the usefulness of androgen replacement for erectile dysfunction. MATERIALS AND METHODS Meta-analysis was chosen as the method of evaluating the literature. Study inclusion criteria were testosterone given as the only therapy for erectile dysfunction and a clearly stated definition of response for evaluating treatment success or failure. RESULTS We evaluated 73 articles obtained by a MEDLINE search of 1966 to 1998 and included 16 in our study. The overall response rate was 57%. In the 9 series with response rate by etiology patients with primary versus secondary testicular failure had a response rate of 64% versus 44% (p <0.001). Intramuscular and oral methods of delivery were equivalent with a response rate of 51.3% and 53.2%, respectively. However, the response to transdermal therapy was significantly different from that of intramuscular and oral treatment (80.9% versus 51.3% and 53.2%, respectively, p <0.001). The mean confidence level response for testosterone treatment was 16. 7% in the placebo and 65.4% in the treated group (p <0.0001). CONCLUSIONS Our meta-analysis of the usefulness of androgen replacement therapy for erectile dysfunction indicates that the response rate for a primary etiology was improved over that for a secondary etiology, transdermal testosterone therapy was more effective than intramuscular or oral treatment, and intramuscular and oral treatments were equivalent. In addition, there was a statistically significant difference in favor of testosterone over placebo, implying a role for supplementation in select groups.

Association of Lower Urinary Tract Symptoms and the Metabolic Syndrome: Results From the Boston Area Community Health Survey

PURPOSE In this study we investigated the relationship between lower urinary tract symptoms as defined by the American Urological Association symptom index and the metabolic syndrome, and determined the relationship between individual symptoms comprising the American Urological Association symptom index and the metabolic syndrome. MATERIALS AND METHODS The Boston Area Community Health Survey used a 2-stage cluster design to recruit a random sample of 2,301 men 30 to 79 years old. Analyses were conducted on 1,899 men who provided blood samples. Urological symptoms comprising the American Urological Association symptom index were included in the analysis. The metabolic syndrome was defined using a modification of the Adult Treatment Panel III guidelines. The association between lower urinary tract symptoms and the metabolic syndrome was assessed using odds ratios and 95% confidence intervals estimated using logistic regression models. RESULTS Increased odds of the metabolic syndrome were observed in men with mild to severe symptoms (American Urological Association symptom index 2 to 35) compared to those with an American Urological Association symptom index score of 0 or 1 (multivariate OR 1.68, 95% CI 1.21-2.35). A statistically significant association was observed between the metabolic syndrome and a voiding symptom score of 5 or greater (multivariate adjusted OR 1.73, 95% CI 1.06-2.80) but not for a storage symptom score of 4 or greater (multivariate adjusted OR 0.94, 95% CI 0.66-1.33). Increased odds of the metabolic syndrome were observed even with mild symptoms, primarily for incomplete emptying, intermittency and nocturia. These associations were observed primarily in younger men (younger than 60 years) and were null in older men (60 years old or older). CONCLUSIONS The observed association between urological symptoms and the metabolic syndrome provides further evidence of common underlying factors between lower urinary tract symptoms and chronic conditions outside the urinary tract.