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Introduction: Many front-line treatments for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), such as medications and transurethral resection of the prostate, have well established negative effects on sexual function. New minimally invasive surgical therapy (MIST) for LUTS/BPH need to preserve sexual function to meet the needs of men. Data from the randomized controlled blinded study of the Optilume BPH System was analyzed to evaluate the sexual side effects of this novel treatment. Objective: The PINNACLE study is a prospective, randomized, double-blind, sham controlled study evaluating the Optilume BPH System. Optilume BPH is a novel MIST that combines mechanical dilation with delivery of paclitaxel for treatment of LUTS/BPH. The mechanical dilation with Optilume BPH achieves an anterior commissurotomy, while delivery of paclitaxel is intended to maintain luminal patency during healing, while preserving sexual function. Methods: 148 subjects with symptomatic LUTS/BPH and a prostate size between 20-80 grams were randomized in a 2:1 fashion (Optilume to Sham) at 18 centers in the US and Canada. Follow-up is complete through 12-months. To evaluate the effect of the treatment on sexual function, the International Index of Erectile Function (IIEF) and Male Sexual Health Questionnaire to assess Ejaculatory Dysfunction (MSHQ-EjD) questionnaires were used. Questionnaires were administered at baseline and 3, 6, and 12-months post procedure, regardless of sexual activity at baseline. A sub-set of 15 non-randomized subjects treated with Optilume BPH underwent further testing for semen quality and measurement of the amount of paclitaxel found in semen post-treatment. Results: The average IIEF-EF score at baseline was 15-16 for both arms, mild to moderate erectile dysfunction (Figure 1). Scores across all domains improved slightly from baseline through 12 months, indicating that treatment with the Optilume BPH device had no significant impact on perceived sexual function. This finding is consistent when looking at men who were sexually active at baseline (Figure 2). Ejaculatory function also showed slight improvement from baseline to 12 months in both the overall population and the subset of men who were sexually active at baseline (Figure 1, Figure 2). There is no appreciable change in ejaculation bother from baseline to 12-months in the overall population and the sexually active subset (Figure 1, Figure 2). Overall semen quality parameters did not change post-procedure (Table 1). A slight decrease in sperm concentration was noted post-treatment, although this decrease was not significant at the 3- and 6-month timepoints. Paclitaxel was detected in semen in the majority of subjects tested at 30 days and 3 months post-procedure. The paclitaxel concentration in semen steadily decreased over time, nearing the limit of quantitation of the method by 6 months post-procedure. Conclusions: Treatment with Optilume BPH preserved erectile and ejaculatory function. IIEF and MSHQ-EjD scores were not different from control at any time point. New MISTs for LUTS/BPH need to preserve sexual function to meet the needs of men and Optilume appears to meet this objective. Disclosure: Yes, this is sponsored by industry/sponsor: Urotronic. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Urotronic. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Erectile dysfunction (ED) is a debilitating medical condition in which current treatments are minimally effective in diabetic patients due to neuropathy of the cavernous nerve, a peripheral nerve that innervates the penis. Loss of innervation causes apoptosis of penile smooth muscle, remodeling of corpora cavernosa (penile erectile tissue) morphology, and ED. In this study, microarray and pathway analysis were used to obtain a global understanding of how signaling mechanisms are altered in diabetic patients and animal models as ED develops, in order to identify novel targets for disease management, and points of intervention for clinical therapy development. Human corpora cavernosal tissue was obtained from diabetic (n=4) and Peyronie's (control, n=3) patients that were undergoing prosthesis implant to treat ED. Rat tissue was obtained from BB/WOR diabetic (n=5) and diabetes resistant (n=5) rats. RNA was extracted using TRIzol, DNase treated, and purified by Qiagen mini kit. Microarray was performed using the Human Gene 2.0 ST Array. 1) Alterations in patient and diabetic rat pathway signaling were examined using several analytical tools (ShinyGO, Metascape, WebGestalt, STRING) and databases, 2) Strengths/weaknesses of the different pathway analysis tools were compared, and 3) Comparison of human and rat (BB/WOR and Streptozotocin) pathway analysis was performed. Two technical replicates were performed. P value (FDR) < 0.15 was used as threshold for differential expression. FDR<0.05 was considered significant. Microarray identified 182 differentially expressed protein-coding genes. Pathway analysis revealed similar enrichments with different analytical tools. Down regulated pathways include development, tubular structure, sprouting, cell death, ischemia, angiogenesis, transcription, second messengers, and stem cell differentiation. ED patients, who have diabetes, incur significant loss of normal regulatory processes required for repair and replacement of injured corpora cavernosal tissue. Combined with loss of apoptotic regulatory mechanisms, this results in significant architectural remodeling of the corpora cavernosa, and loss of regenerative capacity in the penis. Penis from diabetic ED patients lacks capacity for maintenance of corpora cavernosal architecture and regeneration, which are critical points for intervention for therapy development. The analysis of tissue specific gene expression profiles provides a means of understanding drivers of disease and identifying novel pathways for clinical intervention. This first report of microarray and pathway analysis in human corpora cavernosa, is critical for identification of novel pathways pertinent to ED and for validating animal models. Work supported by industry: no. [ABSTRACT FROM AUTHOR]

Erectile dysfunction (ED) treatments are minimally effective in prostatectomy and diabetic patients due to injury to the cavernous nerve. With denervation the critical smooth muscle undergoes apoptosis and the penis becomes fibrotic, thus altering corpora cavernosal architecture. In order to devise novel ED therapies, prevention of corpora cavernosal remodeling is critical. Sonic hedgehog (SHH) treatment by peptide amphiphile (PA) nanofiber hydrogel, suppresses smooth muscle apoptosis and improves erectile function in a rat CN injury ED model. We examine if human corpora cavernosal smooth muscle responds in a similar manner to SHH treatment. In this study we: 1.) Examine if human corpora cavernosal smooth muscle cells from primary culture of ED patient tissues, respond to Sonic hedgehog (SHH) treatment by increasing growth rate, as in our in vivo animal model. 2.) Determine if human corpora cavernosal cells from patients with differing underlying mechanisms of ED development (prostatectomy, diabetes, hypertension, cardiovascular disease), respond similarly to SHH treatment. 3.) Identify if organ culture conditions (glucose) affect growth of corpora cavernosal smooth muscle and the response to SHH signaling. 4.) Examine the vascular component of ED (hypertension and cardiovascular disease). Human corpora cavernosal tissue was obtained from prostatectomy, diabetic, hypertension, cardiovascular disease and Peyronie's (control) patients (n=40) that were under going prosthesis implant to treat ED. Primary cultures (n=17) were established, and corpora cavernosal cells from passage 3-4 were treated with SHH protein, MSA (control), 5E1 SHH inhibitor, and PBS (control). Growth was quantified by counting the number of cells using a hemocytometer at 3-4 days. The concentration of SHH protein for maximal growth was examined, in addition to a lipid modified more active SHH peptide. SHH treatment increased smooth muscle growth in human corpora cavernosal cells from prostatectomy, diabetic, and Peyronie's patients in a similar manner (43-53%). SHH inhibition decreased smooth muscle growth (24-32%). There was no difference in growth using 25ug and 10ug SHH peptide. A more active (150X) SHH peptide further enhanced growth (20%). SHH protein increased growth more in diabetic smooth muscle under high glucose conditions. SHH inhibition was less effective under high glucose conditions. SHH treatment increased growth less in cells from hypertension and cardiovascular disease patients. Corpora cavernosa smooth muscle from prostatectomy, diabetic, and Peyronie's patients increased in response to SHH treatment in a similar manner, suggesting that SHH treatment would be beneficial to enhance smooth muscle regeneration in patients with ED of multiple origins. There is a threshold concentration of SHH protein above which smooth muscle growth is enhanced. Lipid modified SHH engendered a more robust growth response. High glucose conditions that may be present in under controlled diabetic patients would not detract from SHH usefulness as a protectant for corpora cavernosal morphology. Understanding how human corpora cavernosal tissue responds to SHH treatment is critical for clinical translation to ED patients. No [ABSTRACT FROM AUTHOR]

An abstract of the article "Optimization of Sonic Hedgehog Delivery from Self-assembled Nanofiber Hydrogels to Prevent Erectile Dysfunction in a Cavernous Nerve Crush Model" by S. Choe and colleagues is presented.