Tadalafil Alone or in Combination with Tamsulosin for the Management for LUTS/BPH and ED.

PURPOSE OF REVIEW: Aim of our systematic review is to evaluate and summarize the efficacy and safety of tadalafil alone or in combination with tamsulosin for the management of lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) and erectile dysfunction (ED). RECENT FINDINGS: Daily tadalafil, in particular 5 mg, according to retrieved studies, appears to be both safe and effective in treating LUTS/BPH and ED, compared with placebo or tamsulosin. The combination of daily tadalafil 5 mg and tamsulosin 0.4 mg allows a better improvement of LUTS compared with both the monotherapies, even if with an increased, but acceptable and tolerated, adverse events rate. After discontinuation of tamsulosin or tadalafil in patients previously treated with their combination, the improvement of LUTS retains significance compared with baseline. Tadalafil 5 mg should be considered a primary treatment option for patients with LUTS/BPH and ED. Evidence highlight an excellent tolerability, safety, and effectiveness profile, both alone or in combination with tamsulosin 0.4 mg. A better efficacy on LUTS relief has been observed for combination therapy, preserving also sexual function. The further switch to monotherapy allows to preserve LUTS relief, but tadalafil only is able to retain ED improvement. Our results support the evidence for a more and more tailored and modular LUTS treatment.

Rural vs. urban disparities in association with lower urinary tract symptoms and benign prostatic hyperplasia in ageing men, NHANES 2001-2008.

OBJECTIVE: The objective of this study was to investigate rural/urban and socio-demographic disparities in lower urinary tract symptoms and benign prostatic hyperplasia (LUTS/BPH) in a nationally representative population of men. METHODS: Data on men age ≥40 years (N = 4,492) in the 2001-2008 National Health and Nutrition Examination Surveys were analysed. Self-report of physician-diagnosed enlarged prostate and/or BPH medication use defined recognised LUTS/BPH. Urinary symptoms without BPH diagnosis/medications defined unrecognised LUTS/BPH. Rural-Urban Commuting Area Codes assessed urbanisation. Unadjusted and multivariable associations (odds ratios (OR)) between LUTS/BPH and covariates were calculated using logistic regression. RESULTS: Recognised and unrecognised LUTS/BPH weighted-prevalence estimates were 16.5% and 9.6%. There were no significant associations between LUTS/BPH and rural/urban status. Significant predisposing factors for increased adjusted odds of recognised and unrecognised LUTS/BPH included age, hypertension (OR=1.4;1.4), analgesic use (OR=1.4;1.4) and PSA level >4 ng/mL (OR=2.3;1.9) when adjusted for rural/urban status, race, education, income, alcohol, health insurance, health care and proton pump inhibitor (PPI) use (all p ≤ 0.1). Restricting to urban men only (N = 3,371), healthcare use (≥4visits/year) and PPI's increased adjusted odds of recognised LUTS/BPH (OR=2.0;1.6); no health insurance and

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 inhibitors for LUTS.

To review the current literature regarding the relationship between lower urinary tract symptoms (LUTS) and erectile dysfunction (ED), and the role of phosphodiesterase-5 (PDE5) inhibitors for the treatment of LUTS. Review of recently published (1990-2009) data regarding epidemiologic and pathophysiologic mechanisms are involved in LUTS-ED, focusing on PDE5 inhibitors particularly evidenced from level 1 clinical trials. Search terms included phosphodiesterase inhibitors, nitric oxide, autonomic hyperactivity, Rho-kinase, atherosclerosis, LUTS, benign prostatic hypertrophy, and ED. Results of several epidemiologic studies show a possible causal relationship between LUTS and ED. Four possible mechanisms have been proposed to explain this association. Multiple large clinical trials have shown a benefit in LUTS after PDE5-inhibitors treatment. PDE5 inhibitors show promise as a future treatment for LUTS, either in conjunction with existing therapies or as a primary treatment.

The role of combination medical therapy in benign prostatic hyperplasia.

To review key trials of monotherapy and combination therapy of alpha(1)-adrenergic receptor antagonists (alpha(1)-ARAs), 5alpha-reductase inhibitors (5alphaRIs) and anti-muscarinic agents in the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). To assess the safety and efficacy of combination therapies for LUTS associated with BPH, a search of the MEDLINE and Cochrane databases (1976-2008) was conducted for relevant trials and reviews using the terms benign prostatic hyperplasia, lower urinary tract symptoms, alpha(1)-adrenergic receptor antagonists, 5alpha-reductase inhibitors, anti-muscarinics, anticholinergics, combination therapy, alfuzosin, doxazosin, tamsulosin, terazosin, dutasteride, finasteride, tolterodine, flavoxate, propiverine, oxybutynin, erectile dysfunction, sildenafil, vardenafil and tadalafil. Data from the Medical Therapy of Prostatic Symptoms (MTOPS) study indicated a role for long-term use of alpha(1)-ARAs and 5alphaRIs in combination. In the MTOPS study, combination therapy with the alpha(1)-ARA doxazosin and the 5alphaRI finasteride was significantly more effective than either component alone in reducing symptoms (P=0.006 vs doxazosin monotherapy; P<0.001 vs finasteride monotherapy) and in lowering the rate of clinical progression (P<0.001 vs either monotherapy). These findings were confirmed by the 2-year preliminary results of the Combination of Avodart and Tamsulosin study. In this study, combination therapy of the alpha(1)-ARA tamsulosin and the 5alphaRI dutasteride resulted in a significantly greater decrease in International Prostate Symptom Score (IPSS) when compared with either monotherapy. Several recent trials have studied the efficacy of combining alpha(1)-ARAs and anti-muscarinic agents in the treatment of BPH. These studies have found this combination to result in statistically significant benefits in quality of life scores, patient satisfaction, urinary frequency, storage symptoms and IPSS scores. Studies have not shown an increased risk of urinary retention associated with the use of anti-muscarinics in a highly select cohort of men with BPH. The available data suggest that combination therapy can be beneficial in the treatment of BPH and associated LUTS. The greatest efficacy for the alpha(1)-ARA and 5alphaRI combination was shown in patients with larger prostate size and more severe symptoms. The combination of alpha(1)-ARAs and 5alphaRIs appears to prevent disease progression in these patients. The combination of alpha(1)-ARAs with anti-muscarinic agents is useful for relieving symptoms of bladder outlet obstruction and detrusor overactivity. Theoretic concerns regarding the risk of acute urinary retention have been refuted in several recent clinical trials; however, it must be noted that the patients in these trials were a highly select cohort of men. Men with overactive bladder and BPH who are not receiving adequate alleviation of symptoms from the first-line alpha(1)-ARAs may benefit from the addition of an anti-muscarinic agent.

Sildenafil citrate improves erectile function: a randomised double-blind trial with open-label extension.

AIMS: To evaluate once-daily 100-mg sildenafil for the treatment of erectile dysfunction (ED) in men with ED and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). METHODS: This was a 12-week, randomised, double-blind, placebo-controlled (DBPC) trial, with an 8-week open-label (OL) extension, in men > or = 45 years of age who scored < or = 25 on the erectile function (EF) domain of the International Index of Erectile Function (IIEF) and > or = 12 on the International Prostate Symptom Score. RESULTS: At DBPC end of treatment (EOT), the sildenafil group (n = 189, vs. placebo, n = 180) had improved EF (IIEF), improved emotional well-being [Self-Esteem And Relationship questionnaire (SEAR)], and greater treatment satisfaction (Erectile Dysfunction Inventory of Treatment Satisfaction) (p < 0.0001). At OL EOT, IIEF and SEAR scores improved slightly in the group previously randomised to sildenafil (n = 168), but much more in the group previously randomised to placebo (N = 155), such that total improvement over the 20-week trial was comparable between the groups. Erections at baseline were hard enough for penetration on approximately half of occasions and lasted long enough for successful intercourse on less than one quarter of occasions, increasing at sildenafil DBPC and OL EOT to approximately 90% (penetration) and 80% (intercourse success) vs. 61% (penetration) and 39% (intercourse success) for DBPC placebo. At sildenafil DBPC and OL EOT, > or = 90% of men were taking sildenafil 100 mg. Sildenafil was generally well tolerated. CONCLUSIONS: In this trial of men with ED and BPH-associated LUTS, sildenafil treatment for ED was efficacious, effective and generally well tolerated.

Smoking and erectile dysfunction: evidence based analysis.

PURPOSE: We examined available evidence concerning the role of smoking in the development of erectile dysfunction. This task involved a complete review of the smoking literature as it pertained to erectile dysfunction and select endothelial diseases. MATERIALS AND METHODS: We comprehensively reviewed the literature, including PubMed and recent abstract proceedings from national meetings relevant to smoking, erectile dysfunction and endothelial diseases. The quality of the evidence was assessed by methods used to develop clinical practice guidelines. Our review involved an objective evaluation of the basic science literature and clinical studies. When necessary, we examined studies of endothelial diseases other than erectile dysfunction because of obvious gaps in the literature. RESULTS: There are strong parallels and shared risks among smoking, coronary artery disease, atherosclerosis and erectile dysfunction. Clinical and basic science studies provide strong indirect evidence that smoking may affect penile erection by the impairment of endothelium dependent smooth muscle relaxation. The association of erectile dysfunction with risk factors such as coronary artery disease and hypertension appears to be amplified by cigarette smoking. Smoking may increase the likelihood of moderate or complete erectile dysfunction 2-fold. The prevalence of erectile dysfunction in former smokers was no different from that in individuals who had never smoked, implying that smoking cessation may decrease the risk of erectile dysfunction. Case studies and retrospective series have shown an association of smoking with erectile dysfunction. CONCLUSIONS: Available evidence on the association of smoking with erectile dysfunction is not complete insofar as association linking factors are concerned. However, the evidence of such an association is likely due to the consistency of the relationship of smoking and endothelial disease, and the strength of the association of erectile dysfunction with other endothelial diseases.

Analysis of NOS isoform changes in a post radical prostatectomy model of erectile dysfunction.

Optimal treatment of erectile dysfunction (ED) following radical prostatectomy remains a subject of much controversy and is a significant concern for prostate cancer patients requiring surgical intervention. Neural stimulation involving nitric oxide synthase (NOS) is a crucial aspect of the normal erection process. In this study NOS isoform interaction was evaluated to improve our understanding of molecular changes pertaining to erection post radical prostatectomy. Bilateral cavernous nerve (CN) resected and control adult male Sprague-Dawley rats were killed 7, 14 and 21 days after injury. RT-PCR, in situ hybridization, Western blot and immunohistochemical analysis were used to evaluate changes in NOS isoform expression and distribution. NOS-I protein was dramatically decreased after CN injury while NOS-III and NOS-II remained unchanged. A profound decrease in smooth muscle and endothelium was observed in the corpora. To our knowledge this is the first report of differential altered NOS isoform protein abundance under conditions which mimic radical prostatectomy. These results show the importance of maintaining at least partial innervation of the penis after surgical intervention and that endothelial and smooth muscle changes resulting from loss of innervation may account for the ED observed in prostatectomy patients.

The usefulness of touch preparation cytological evaluation and prostatic capsule involvement in prediction of prostate cancer recurrence.

PURPOSE: Touch preparation cytology has been used in oncology as a technique to assist in predicting local tumor recurrence. We prospectively investigated the relationship between this cytological evaluation and the standard histological method of assessing specimens, measuring the distance from the tumor to the various anatomical boundaries and disease recurrence in radical retropubic prostatectomy patients. MATERIALS AND METHODS: In a prospective study of 91 consecutive clinical stages T1c and T2 cancer cases radical retropubic prostatectomy touch preparation cytology was performed intraoperatively in an anatomical fashion (apex, posterior, lateral right and left, and base). A single blinded cytopathologist reviewed all prostate touch preparation specimens and categorized them as malignant, benign or atypical cells. Benign or atypical cells were classified as negative cytology. Detailed histological margin analysis of the surgical specimens was also done in which distances between the tumor front, and prostate capsule (inner and outer edge) and surgical margins (apex, posterior, right and left lateral, and base) were measured. All specimens were re-staged by the same pathologist. Median followup was 38 months. Disease recurrence was determined biochemically (prostate specific antigen), and with bone scans, prostatic fossa biopsies and digital rectal examinations. RESULTS: Of the 91 specimens 25 were excluded from study because distance measurements could not be made for technical reasons. Multivariate analysis was performed on the remaining 66 patients based on the variables of stage, age, cytology status, distance from tumor to the inner prostatic capsule, distance from tumor to the surgical margin and postoperative Gleason sum. The only variable with independent prognostic value was postoperative Gleason sum (p = 0.04). Cytology status was not statistically significant (p = 0.07) nor were distance data to the inner capsule (p >0.05) and surgical margin (p >0.05). CONCLUSIONS: Although touch preparation cytology does not enhance prognostic information already provided by Gleason sum, it does correlate highly with postoperative Gleason sum. Other gross macroscopic variables, that is pathological stage, margin status and distance measurements, although lacking in independent predictive value, correlated with postoperative Gleason sum. The constancy of Gleason sum leads us to believe that the key to predicting prostatic cancer behavior lies not on the macroscopic but on the molecular or cellular level. Of the various factors analyzed in this study postoperative Gleason sum remains the most powerful predictor of recurrence risk.

Comparison of tunica albuginea substitutes for the treatment of Peyronie's disease.

PURPOSE: Peyronie's disease is a connective tissue disorder resulting in fibrotic plaque formation on the tunica albuginea of the penis. One approach to repair consists of plaque excision and patching with one of many potential patch materials. Because the optimal patch material for covering the resultant defect has not been determined, this study compares histological and cavernosometric changes in the penis as a result of the placement of three different types of patch grafts used in surgery for Peyronie's disease. MATERIALS AND METHODS: Eleven mongrel dogs were divided into three groups, each receiving a different patch material (superficial dorsal penile vein, silicone fabric, and dermabraded preputial flap). Each dog had dynamic infusion cavernosometry (DIC) performed prior to placement of the patch over a 6 x 3 mm. defect surgically created in the tunica albuginea. Three months later, DIC was repeated prior to sacrifice. Histology of the penis was examined using Masson's trichrome, and hematoxylin and eosin stains. RESULTS: The only difference among the cavernosometric parameters (preop versus postop) was a higher initial pressure in the dermabraded preputial flap group postoperatively. The dogs undergoing vein patch had moderate fibrosis with apparent reformation of the tunica albuginea over the patch site. The normal venous architecture of the graft was no longer recognizable. Those dogs receiving a silicone patch had moderate fibrosis with a fibrous sheath of compressed histiocytes and fibroblasts enveloping the graft site. Finally, the dermabraded preputial flap patch group had mild-moderate fibrosis with focal loss of the cavernosal space underlying the flap. CONCLUSIONS: We feel that continued use of the vein patch for repair of Peyronie's disease is warranted.

One core positive prostate biopsy is a poor predictor of cancer volume in the radical prostatectomy specimen.

PURPOSE: In view of the recent increase in patients presenting with only 1 core positive for prostate carcinoma, we examined the correlation in tumor volume between the biopsy and the subsequent radical prostatectomy specimen. MATERIALS AND METHODS: We studied a total of 169 consecutive prostate biopsies with matched radical prostatectomy specimens and selected 48 patients with only 1 positive core. RESULTS: Cancers found in the biopsy regardless of their size were associated with a wide range of cancer volume in the radical prostatectomy specimens, and the amount of cancer in the biopsy was a poor predictor of the volume of cancer in the prostatectomy specimen. Even with a cancer of 3 mm. or less in the biopsy, 57% of patients had cancer of clinically significant volume (greater than 0.5 ml.). Other modalities for the evaluation of prostate cancer such as Gleason score and clinical stage were not helpful in segregating patients with clinically significant from those with insignificant volume of cancer. However, when combined with a preoperative serum prostate-specific antigen higher than 10 ng./ml., 1 core positive biopsy could reliably predict the presence of cancer of significant volume. CONCLUSIONS: One core only positive prostate biopsy, when accompanied by an elevated serum prostate specific antigen value (greater than 10 ng./ml.), strongly suggests the presence of clinically significant cancer.

Long-term results of radical retropubic prostatectomy in men with high grade carcinoma of the prostate.

PURPOSE: We sought to determine the efficacy of radical retropubic prostatectomy in men with high grade adenocarcinoma of the prostate in a population that had not been screened for prostate specific antigen (PSA). MATERIALS AND METHODS: An inception cohort of 116 men surgically treated for prostate cancer between 1980 and 1991 was created in April 1992 and prospectively followed thereafter. Median followup was 7 years (range 2.2 to 14.6). RESULTS: The major cause of death in this group of men was prostate cancer, not competing causes. Ten-year disease specific survival was 96% for organ confined (stage pT2c or less) and 78% for unconfined (stage pT3a or greater) disease. Five and 10-year PSA progression-free survival by pathological stage was 83 and 53% for organ confined disease, and 34 and 22% for unconfined disease with negative pelvic lymph node dissection (p = 0.001). Five and 10-year metastasis-free survival was 96% for organ confined disease, and 81 and 62% for unconfined disease (p = 0.011). Men with pelvic lymph node metastasis had 70 and 30% 5 and 10-year metastasis-free survival, and 75 and 55% disease specific survival, respectively. PSA progression-free survival was 33% at 5 years. A significantly decreased risk of PSA progression was observed in men with unconfined carcinoma who received adjuvant external beam radiotherapy. CONCLUSIONS: In men with high grade prostate cancer the major cause of death was prostate cancer, not competing causes. Pathologically confined carcinoma had a significantly decreased rate of metastatic progression. These observations support the bias that early detection in these men at high risk for cause specific death may favorably impact survival.

Survival after radical retropubic prostatectomy of men with clinically localized high grade carcinoma of the prostate.

BACKGROUND: This study was performed to evaluate the efficacy of radical prostatectomy for men with clinically localized, poorly differentiated (Gleason score > or = 7) prostate cancer and to characterize further the prognostic significance of traditional pathologic variables. The effectiveness of adjuvant radiotherapy was assessed in a subpopulation of men for whom the pathologic assessment suggested a high risk of persistent disease. METHODS: Two hundred thirty-eight consecutive men, 74 of whom had clinically localized, poorly differentiated carcinoma, were followed for a median of 6.2 and 5.1 years, respectively. The disease specific outcomes were derived from a non-prostate specific antigen (PSA) screened population. RESULTS: The 5-year disease specific survival (DSS) for 52 men with a clinically localized Gleason score of 7 and for 22 men with a Gleason score greater than or equal to 8 carcinoma was 92% and 79%, respectively. The 5-year likelihood of having an undetectable PSA level was 50% for those with a Gleason score of 7 and 38% for those with a Gleason score greater than or equal to 8. Gleason score was the most powerful pathologic predictor of disease progression and survival. Pathologic stage was significantly associated with disease progression for carcinomas with Gleason scores less than 7 but was found to be less predictive of progression for carcinomas with Gleason scores greater than or equal to 7. Adjuvant radiotherapy provided a significantly reduced risk of PSA-detectable progression (P = 0.02, relative risk = 0.56, 95% CI: 0.34, 0.92); however, radiotherapy had no significant impact on DSS. CONCLUSIONS: Long term DSS is possible in a non-PSA screened series of men with poorly differentiated prostate cancer treated by radical prostatectomy. These results compare favorably with alternative treatment strategies, although they do illustrate a continued need to develop more effective adjuvant therapies for men with poorly differentiated prostate cancer.

Intraoperative blood loss and prognosis in prostate cancer patients undergoing radical retropubic prostatectomy.

PURPOSE: To assess more thoroughly the prognostic significance of perioperative transfusions, we examined a previously ignored factor, namely intraoperative blood loss. MATERIALS AND METHODS: Univariate and multivariate stepwise regression analysis was performed on results of a 10-year series of 251 consecutive men who underwent radical retropubic prostatectomy for clinically localized carcinoma. RESULTS: Gleason score, operative blood loss and pathological stage were significantly (p < 0.0001) associated with progression-free survival. A risk ratio of 1.08 (95% confidence interval 1.05 to 1.10) was demonstrated for every 100 ml. of operative blood loss. CONCLUSIONS: The operative blood loss but not the type (autologous or allogeneic) of blood transfused was significantly related to decreased recurrence-free survival after radical retropubic prostatectomy. This finding implies that the operative events necessitating transfusion are potentially more significant than the immunological effects of the transfusion.

Long-term followup of treatment of Peyronie's disease with plaque incision, carbon dioxide laser plaque ablation and placement of a deep dorsal vein patch graft.

Numerous surgical therapies have been used for Peyronie's disease in patients who maintain potency. We report on incision and carbon dioxide laser ablation of Peyronie's plaque combined with a deep dorsal vein patch graft in the treatment of 6 men (mean age 57 years). The chief indication for surgery was curvature interfering with intromission, with voiding difficulty being a secondary indication as well. Long-term followup (mean 31 months) was available in 6 men, each of whom was potent preoperatively. Potency was preserved in all men, and 5 described significant improvement in penetration and curvature. In 1 patient the curvature returned to preoperative levels. Each patient reported a subjective shortening of the penis from one-quarter to 1 inch but no case was functionally debilitating. We describe this technique, which to our knowledge has been reported previously by only 1 group with 18 patients, and conclude that it may be used with successful preservation of potency and restoration of intercourse in the treatment of Peyronie's plaques.

Reversed seromuscular flaps in the urinary tract in dogs.

Reversed seromuscular flaps of ileum and standard bowel replacement procedures were performed in 16 dogs to evaluate their potential to decrease the likelihood of recognized complications in cases of standard bowel replacement. Of 12 dogs augmentation cystoplasty was done in 6 and ureteral replacement was done in 6. In each group 4 procedures were performed using reversed seromuscular flap, while the remaining 2 were done in the conventional manner (controls). All flap animals had partial to full re-epithelialization with transitional cells but they also had gross and microscopic evidence of flap contraction at the end of 6 months. In the flap augmentation group intravesical pressure measured preoperatively at bladder volumes of 30 cc and 60 cc averaged 25.8 and 45.8 mm. Hg compared to sacrifice pressures of 56.7 and 80.8 mm. Hg. Monthly serum blood urea nitrogen measurements were lower in reversed seromuscular flap animals compared to controls. An additional 4 dogs were studied to help elucidate the etiology of graft contraction, of which 2 underwent reversed seromuscular flap enterocystoplasty with no mucosal stripping while 2 had a procedure exposing intact intestinal serosa to the lumen of the bladder and urine. All of these animals demonstrated good re-epithelialization of the serosal surface with transitional cells as well as little or no evidence of flap fibrosis or contraction. Our results demonstrate that the use of reversed seromuscular flaps in the urinary tract in dogs results in good re-epithelialization of the serosal surface with transitional cells but also flap contraction. This fibrosis and scarring process is largely due to the trauma of mucosal stripping and not urine contact.