Long-term consequences of bilateral cavernous crush injury in normal and diabetic rats: a functional study.

A recent statement from the European-Society-for-Sexual-Medicine has highlighted the limitations of using the rat model for nerve-sparing prostatectomy. The use of young rats with no comorbidities and the early evaluation of the erectile function (EF) are deemed a source of bias. Our aim was to evaluate the long-term consequences in EF of bilateral nerve cavernous crush- injury (BNCI) in type 1 diabetic (DM) rats 30-male/12-week-old rats were divided into four groups: Sham, BNCI, DM, and BNCI + DM. Sham group underwent an intraperitoneal injection (IP) of saline solution and after 1 month underwent a sham laparotomy. BNCI underwent an IP of saline solution and after 1 month to BNCI. DM underwent an IP of 60 mg/kg-1-streptozotocin (STZ) and after 1 month to a sham laparotomy. BNCI + DM underwent an IP of 60 mg/kg-1-STZ and after 1 month to BNCI. After 5 months from the induction of diabetes, all rats underwent measurement of intracorporeal pressure (ICP) and mean arterial pressure (MAP) during CN-electrostimulation. Multiple groups were compared using Kruskal-Wallis one-way analysis of variance followed by Mann-Whitney U test for post hoc comparisons. Blood glucose-level was higher (p < 0.05) in the groups with DM and BNCI + DM. After 5-months, DM and BNCI + DM also showed a lower weight compared to other groups (p < 0.05). No differences were noted in ICP/MAP between the sham and BNCI. BNCI + DM showed lower ICP/MAP compared to all the groups (p < 0.05). DM Showed lower ICP/MAP compared to Sham and BNCI (p < 0.05). BNCI in rats without comorbidities did not induce long-term erectile dysfunction (ED) suggesting a spontaneous EF recovery. BNCI in DM induced long-term ED. The results of previous short-term studies can only provide evidence on the time to recovery of spontaneous EF as to the actual EF recovery rate.

Site-specific relapse patterns of patients with biochemical recurrence following radical prostatectomy assessed by 68Ga-PSMA-11 PET/CT or 11C-Choline PET/CT: impact of postoperative treatments.

BACKGROUND: Salvage radiotherapy (RT) (± androgen deprivation therapy (ADT)) is often used as a treatment in patients with biochemical recurrence (BCR) following radical prostatectomy (RP). Unfortunately, even after RT ± ADT, a significant number of patients will develop 'second' BCR. The aim of this study was to investigate the impact of postoperative treatments (adjuvant/salvage radiotherapy (RT) ± androgen deprivation therapy) on the recurrence pattern in patients with BCR following RP assessed by 11C-Choline PET/CT or 68 Ga-PSMA PET/CT. METHODS: Patients who developed BCR following RP and who had at least one positive lesion on PET/CT were retrospectively assessed. Positive spots were mapped as local, lymph node (LN), skeletal or visceral recurrence. A distinction was made between locoregional (prostate bed and pelvic LN) and extrapelvic recurrence (skeletal, visceral and/or extrapelvic LN). Patients were categorized according to postoperative treatment received in three subgroups (RT, ADT and RT + ADT) and compared with the reference group (RP only). The impact of the radiation field was also investigated. RESULTS: We identified 200 patients assessed by 68Ga-PSMA-11 (80%) or 11C-Choline PET/CT (20%). Patients who received postoperative RT + ADT had less LN recurrence distal to the common iliac bifurcation (26.7% vs 66.6%; p = 0.0004), but more recurrence to retroperitoneal LN than the reference group (38% vs. 14.4%, p = 0.02). Moreover, the RT + ADT subgroup had more extrapelvic recurrence compared to the reference group (66.2% vs 40.8%, p = 0.02). Patients who received RT to the prostate bed had more recurrence distal to the common iliac bifurcation compared to those who received RT to the prostate bed + pelvic LN (51.6% vs 26.1%, p = 0.0069). CONCLUSION: Post-prostatectomy treatments (ADT and/or RT) and the postoperative radiation field (prostate bed vs. prostate bed + pelvis) have a significant impact on the recurrence pattern. This knowledge can help clinicians to counsel their patients on their chances of being eligible for (locoregional) metastasis-directed therapies.

Clinical Efficacy of Serenoa repens Versus Placebo Versus Alpha-blockers for the Treatment of Lower Urinary Tract Symptoms/Benign Prostatic Enlargement: A Systematic Review and Network Meta-analysis of Randomized Placebo-controlled Clinical Trials.

CONTEXT: International guidelines do not make any specific recommendations on Serenoa repens (SeR) for the treatment of male lower urinary tract symptoms (LUTS) secondary to benign prostatic enlargement (BPE), due to product heterogeneity and methodological limitations of the published trials and meta-analyses. OBJECTIVE: We aimed to compare the clinical efficacy of hexanic extract of SeR (HESr) versus non-HESr (nHESr) versus placebo versus alpha-blockers (ABs) in patients affected by LUTS secondary to BPE through a network meta-analysis method. EVIDENCE ACQUISITION: The search was conducted until December 31, 2018 using Medline, Scopus, and Web of Science databases without restriction. We included randomized controlled trials (RCTs) with at least one comparison between SeR, ABs, or placebo for the treatment of LUTS/BPE. Outcomes of the study were the mean change in the International Prostate Symptom Score (IPSS) and peak flow (PF). This systematic review has been registered on PROSPERO (CRD42018084360). EVIDENCE SYNTHESIS: In total, 2115 articles were identified. After the global assessment, 22 RCTs matched with the inclusion criteria, including 8564 patients. For IPSS, the mean efficacies against placebo were +0.48 and -1.69 for HESr and nHESr, respectively, at 3 mo; 0.59 for nHESr at 6 mo; and -1.31 and -3.30 for nHESr and HESr, respectively, at 12 mo. For PF, the mean efficacies against placebo were +0.53 and +2.82 for HESr and nHESr, respectively, at 3 mo; +1.85 for nHESr at 6 mo; and +4.05 and +5.52 for HESr and nHESr, respectively, at 12 mo. Based on the surface under the cumulative ranking curve rankograms, terazosin showed the highest score (99.6%), while alfuzosin, tamsulosin, silodosin, HESr, and nHESr showed scores of 53.7%, 42.3%, 68.5%, 36.7%, and 47.3%, respectively. CONCLUSIONS: In this network meta-analysis, we demonstrated that SeR did not show clinically meaningful improvement in LUTS and PF. PATIENT SUMMARY: In the present study, we found no clinically meaningful improvement of Serenoa repens for the treatment of lower urinary tract symptoms/benign prostatic enlargement. The analysis showed that the benefit over placebo was minimal and may not justify its clinical use before higher level of evidence will be available.

Bone metastasis is associated with poor prognosis in metastatic papillary renal cell carcinoma patients treated with first agent angiogenesis inhibitors.

OBJECTIVE: Papillary renal cell carcinoma (papRCC) is a rare (10%-15%) subtype of renal cancer. Few prognostic biomarkers have been described in metastatic papRCC (m-papRCC) patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). We aimed to study the prognostic impact of bone metastases (BM) on response rate, progression-free and overall survival (PFS and OS) in patients with m-papRCC treated with first agent VEGFR-TKIs. PATIENTS AND METHODS: A multicentric, retrospective analysis of patient records was conducted. BM were detected by computed tomography and/or bone scintigraphy. The International Metastatic RCC Database Consortium (IMDC) score was calculated at start of first agent VEGFR-TKI treatment. RESULTS: Forty-nine patients were included. Best objective response was partial response in 20%, stable disease in 60% and early progressive disease in 20% of patients. Median PFS (mPFS) was 6.0 months and median OS (mOS) 14.0 months after start of first agent VEGFR-TKI. The IMDC score correlated with mOS: 77.5 months in good, 17.0 months in intermediate and 8.0 months in poor risk patients (P = 0.002). Patients with BM had a poorer outcome compared to patients without BM: mPFS was 4.0 vs. 7.0 months (P = 0.006) and mOS 7.5 vs. 19.0 months (P = 0.002). On bivariate analysis, the presence of BM was independently associated with PFS (P = 0.02) and OS (P = 0.049), independent of the IMDC risk groups. CONCLUSION: In m-papRCC patients treated with first agent VEGFR-TKIs, the presence of BM is an unfavorable prognostic factor, associated with shorter PFS and OS.

Making surgery safer by centralization of care: impact of case load in penile cancer.

PURPOSE: Penile cancer is a rare but aggressive disease, often requiring a rapid and extensive surgical treatment of the primary tumor and staging or treatment of the inguinal lymph node basins. Current management and guidelines of the disease are mainly based on retrospective data, as there is a lack of controlled trials or large series. The purpose of this work is to review contemporary data on the impact of centralization and formation of rare disease networks on penile cancer care and outcomes. METHODS: This narrative, non-systematic review is based on publications retrieved by a PubMed and EMBASE search and on the current guidelines of the European Association of Urology, the National Institute for Health and Care Excellence, and the National Comprehensive Cancer network. RESULTS: The low case load, particularly in non-specialized centres, combined with limited evidence regularly results in a disparity between the treatment strategy and the guidelines. The suboptimal guideline adherence is specifically the case for organ-sparing surgery and surgical staging of the groin areas in selected cases. Treatment of the disease in high-volume referral centres has been shown to improve the use of organ-sparing surgery, the utilization of invasive lymph node staging in high-risk patients, and finally has resulted in increased survival rates. CONCLUSIONS: The management of penile cancer in disease networks and in countries where centralized healthcare is offered positively influences functional and oncological outcomes. We propose that governments and health care providers should be encouraged to centralize healthcare for rare tumors such as penile cancer.

Intratunical injection of autologous adipose stromal vascular fraction reduces collagen III expression in a rat model of chronic penile fibrosis.

Previous studies have shown that the injection of adipose stem cells and stromal vascular fraction(SVF) into the tunica albuginea (TA) during the inflammatory phase in a rat model of Peyronie's disease(PD) prevented the development of TA fibrosis. Our aim was to investigate whether local injection of SVF can reduce established fibrosis in a rat model of chronic phase of PD. Eighteen-male 12-wk-old Sprague-Dawley rats were divided in three equal groups: sham, PD without treatment (PD) and PD treated with SVF(PD-SVF). Sham rats underwent 2 injections of vehicle into the TA one month apart. PD rats underwent TGF-ß1 injection and injection of vehicle one month later. PD-SVF rats underwent TGF-ß1 injection followed by SVF (1-million cells) one month later. One month after the last treatment, the animals, n = 6 rats per group, underwent measurement of intracorporal and mean arterial pressure during electrostimulation of the cavernous nerve. Following euthanasia, penises were harvested for in-vitro study. Erectile function was not statistically significantly different between groups. PD animals developed subtunical areas of fibrosis and elastosis with upregulation of collagen III protein. These fibrotic changes were reversed after injection of SVF. We provide evidence that local injection of SVF reverses TA fibrosis in a rat model of chronic phase of PD.

Intratunical injection of stromal vascular fraction prevents fibrosis in a rat model of Peyronie's disease.

OBJECTIVE: To investigate whether local injection of autologous adipose stromal vascular fraction (SVF) can prevent the development of fibrosis and elastosis in the tunica albuginea (TA) using a rat model of the acute phase of Peyronie's disease (PD). METHODS: A total of 24 male 12-week-old Sprague-Dawley rats were divided into three equal groups: sham; PD without treatment (transforming growth factor-ß [TGF -ß]); and PD treated with SVF 1 day after disease induction. Sham rats received two injections of vehicle into the TA 1 day apart. TGF -ß rats received TGF- ß1 injection and injection of vehicle 1 day later. SVF rats received TGF-ß1 injection, followed by SVF 1 day later. One month after treatment, all rats underwent measurement of intracavernosal pressure and mean arterial pressure during electrostimulation of the cavernous nerve. The rats were then killed and penises were harvested for histology and Western blot analysis. RESULTS: Erectile function was moderately reduced in the TGF-ß group and was significantly improved after SVF treatment (P < 0.05). PD rats developed areas of fibrosis with a significant upregulation of collagen III, collagen I and elastin protein expression. These fibrotic changes were prevented when treated with SVF. CONCLUSIONS: Local injection of SVF may represent treatment for the acute phase of PD.

Intratunical Injection of Human Adipose Tissue-Derived Stem Cells Restores Collagen III/I Ratio in a Rat Model of Chronic Peyronie's Disease.

INTRODUCTION: Previous studies have shown that the injection of adipose tissue-derived stem cells (ADSCs) into the tunica albuginea (TA) during the active phase of Peyronie's disease (PD) prevents the development of fibrosis. AIM: To investigate, using an animal model, whether local injection of human ADSCs (hADSCs) can alter the degree of fibrosis in the chronic phase of PD. METHODS: 27 male, 12-week-old rats were divided into 3 equal groups: sham, PD without treatment, and PD treated with hADSCs 1 month after disease induction. Sham rats underwent 2 injections of vehicle into the TA 1 month apart. PD rats underwent transforming growth factor ß1 (TGFß1) injection and injection of vehicle 1 month later. PD-hADSC rats underwent TGFß1 injection followed by 1 million hADSCs 1 month later. 1 week after treatment, n = 3 animals/group were euthanized, and the penises were harvested for quantitative polymerase chain reaction. 1 month after treatment, the other animals, n = 6 per group, underwent measurement of intracavernous pressure (ICP) and mean arterial pressure (MAP) during electrostimulation of the cavernous nerve. After euthanasia, penises were again harvested for histology and Western blot. MAIN OUTCOME MEASURE: The primary outcome measures included (a) gene expression at one week post-injection; (b) measurement of ICP/MAP upon cavernous nerve stimulation as a measure of erectile function; (c) elastin, collagen I and III protein expression; and (d) Histomorphometric analysis of the penis. Means where compared by analysis of variance (ANOVA) followed by a Student-Newman-Keuls test for post hoc comparisons or Mann-Whitney test when applicable. RESULTS: No significant difference was noted in ICP or ICP/MAP in response to cavernous nerve electrostimulation between the 3 groups at 2.5, 5, and 7.5 V (P > .05 for all voltages). PD animals developed tunical and subtunical areas of fibrosis with a significant upregulation of collagen III protein. The collagen III/I ratio was higher in the PD (4.6 ± 0.92) group compared with sham (0.66 ± 0.18) and PD-hADSC (0.86 ± 0.06) groups (P < .05) These fibrotic changes were prevented when treated with hADSCs. Compared with PD rats, PD-hADSC rats demonstrated a decreased expression of several fibrosis-related genes. CONCLUSION: Injection of hADSCs reduces collagen III expression in a rat model of chronic PD. Castiglione F, Hedlund P, Weyne E, et al. Intratunical Injection of Human Adipose Tissue-Derived Stem Cells Restores Collagen III/I Ratio in a Rat Model of Chronic Peyronie's Disease. Sex Med 2019;7:94-103.

Galanin Administration Partially Restores Erectile Function After Cavernous Nerve Injury and Mediates Endogenous Nitrergic Nerve Outgrowth In Vitro.

BACKGROUND: Previously, we found that the neuropeptide galanin was strongly upregulated soon after bilateral cavernous nerve injury (BCNI) and that galanin and its receptors were expressed in nitrergic erectile innervation. Galanin has been observed to exert neuroregenerative effects in dorsal root ganglion neurons, but evidence for these effects in the major pelvic ganglion (MPG) after BCNI is lacking. AIM: To evaluate the neurotropic effects of galanin receptor agonists and antagonists in vitro in nitrergic neurons and MPG and in vivo in rats after BCNI. METHODS: Male Sprague-Dawley rats underwent BCNI and sham surgery. Organ culture and single-cell neuron culture of the MPG were performed. Osmotic pump treatment with the galanin agonist in vivo and measurement of erectile response to electrostimulation after BCNI, immunohistochemical localization of galanin and receptors in the human neurovascular bundle, and myographic analysis of rat corpus cavernosum smooth muscle relaxation to galanin receptor agonists were investigated. OUTCOMES: Neurite outgrowth in vitro and erectile response to electrostimulation after BCNI in vivo, immunohistochemical localization of galanin and receptors, and penile muscle relaxation in vitro. RESULTS: Galanin showed neurotrophic action in vitro and inhibition of endogenous galanin significantly impaired neurite outgrowth in nitrergic but not in sympathetic MPG neurons. In vivo administration of a selective galanin receptor-2 agonist, M1145, resulted in partial recovery of erectile function (EF) after BCNI. Galanin did not act as a direct vasodilator on corpus cavernosum muscle strips. CLINICAL TRANSLATION: Endogenous neurotrophins such as galanin could be used as a strategy to improve EF for patients after BCNI from radical prostatectomy. STRENGTHS AND LIMITATIONS: We evaluated the effect of galanin on nerve regeneration and EF recovery in vivo and in vitro. Limitations include the lack of washout period for the in vivo experiment and absence of differences in the expression of neuronal markers between treatment groups. CONCLUSIONS: We identified galanin as a potential endogenous mechanism for nerve regeneration after BCNI, which could play a physiologic role in EF recovery after radical prostatectomy. In vivo treatment with exogenous galanin was beneficial in enhancing EF recovery after BCNI, but further research is necessary to understand the underlying mechanisms. Weyne E, Hannan JL, Gevaert T, et al. Galanin Administration Partially Restores Erectile Function After Cavernous Nerve Injury and Mediates Endogenous Nitrergic Nerve Outgrowth In Vitro. J Sex Med 2018;15:480-491.

Additive effects of the Rho kinase inhibitor Y-27632 and vardenafil on relaxation of the corpus cavernosum tissue of patients with erectile dysfunction and clinical phosphodiesterase type 5 inhibitor failure.

OBJECTIVES: To evaluate the expression of the Rho/Rho-associated protein kinase (ROCK) pathway in the corpus cavernosum of patients with severe erectile dysfunction (ED) compared with healthy human corpus cavernosum, and to test the functional effects of two Rho kinase inhibitors (RKIs) on erectile tissue of patients with severe ED, which did not respond to phosphodiesterase type 5 inhibitors (PDE5Is). PATIENTS AND METHODS: Human corpus cavernosum samples were obtained after consent from men undergoing penile prosthesis implantation (n = 7 for organ bath experiments, n = 17 for quantitative PCR [qPCR]). Potent control subjects (n = 5) underwent penile needle biopsy. qPCR was performed for the expression of RhoA and ROCK subtypes 1 and 2. Immunohistochemistry staining against ROCK and α smooth muscle actin (αSMA) was performed on the corpus cavernosum of patients with ED. Tissue strips were precontracted with phenylephrine and incubated with 1 µm of the PDE5I vardenafil or with DMSO (control). Subsequently, increasing concentrations of the RKIs azaindole or Y-27632 were added, and relaxation of tissue was quantified. RESULTS: The expression of ROCK1 was unchanged (P > 0.05), while ROCK2 (P < 0.05) was significantly upregulated in patients with ED compared with controls. ROCK1 and ROCK2 protein colocalized with αSMA, confirming the presence of this kinase in cavernous smooth muscle cells and/or myofibroblasts. After incubation with DMSO, 10 µm azaindole and 10 µm Y-27632 relaxed precontracted tissues with 49.5 ± 7.42% (P = 0.1470 when compared with vehicle) and 85.9 ± 10.3% (P = 0.0016 when compared with vehicle), respectively. Additive effects on relaxation of human corpus cavernosum were seen after preincubation with 1 µm vardenafil. CONCLUSION: The RKI Y-27632 causes a significant relaxation of corpus cavernosum in tissue strips of patients with severe ED. The additive effect of vardenafil and Y-27632 shows that a combined inhibition of Rho-kinase and phosphodiesterase type 5 could be a promising orally administered treatment for severe ED.

Increased expression of the neuroregenerative peptide galanin in the major pelvic ganglion following cavernous nerve injury.

INTRODUCTION: Erectile dysfunction (ED) remains a frequent complication of radical prostatectomy due to injury to the cavernous nerves (CNs). A recent microarray showed the neuropeptide galanin to be one of the most strikingly upregulated genes in the rat major pelvic ganglion (MPG) after bilateral CN crush injury (BCNI). AIM: The aim of this study is to evaluate the temporal regulation of galanin in the MPG after BCNI and its relationship to functional nerve regeneration. METHODS: Changes in galanin, galanin receptor (galR), and c-JUN mRNA expression were assessed in Sprague-Dawley rats after sham operation (n = 10) and at 48 hours (n = 10), 7 (n = 10), 14 (n = 5), 21 (n = 5), 30 (n = 5), and 60 (n = 5) days after BCNI using quantitative PCR. Erectile function was assessed by measuring intracavernous pressure (ICP) divided by mean arterial pressure (MAP) during CN electrostimulation. Immunohistochemistry was performed on the MPG in sham-operated animals and 5 days after BCNI. MAIN OUTCOME MEASURES: ICP/MAP upon CN stimulation; galanin, galR1, -2, -3, and c-JUN mRNA expression at various time points after BCNI; and nNOS, galanin, and galR distribution in the MPG of sham-operated rats and after BCNI. RESULTS: After BCNI, ICP/MAP values quickly deteriorate, while after 60 days, spontaneous restoration of erectile responses to CN stimulation is observed, reflecting CN regeneration. Galanin mRNA in the MPG is up to 186-fold upregulated compared with sham-operated rats at 48 hours and 7 days after BCNI and gradually declines with increasing time from injury, whereas galanin receptor expressions decrease and c-JUN gradually increases. Galanin expression shows a strong inverse correlation with erectile responses to CN stimulation with time from injury. Injured MPGs show a colocalization between galanin- and nNOS-positive neuronal cell population in the MPG. CONCLUSIONS: Galanin is upregulated in the MPG in the early phase after CN injury after which it gradually decreases and is present in nNOS-positive neurons of the ganglion. We hypothesize that galanin upregulation is an important factor in the endogenous neuroregenerative response to CN injury.

Effects of intravenous injection of adipose-derived stem cells in a rat model of radiation therapy-induced erectile dysfunction.

INTRODUCTION: Radiation therapy (RT) for prostate cancer is frequently associated with posttreatment erectile dysfunction (ED). AIM: To investigate whether injection of adipose-derived stem cells (ADSCs) can ameliorate RT-associated ED. METHODS: Thirty male rats were divided into three groups. The control + phosphate-buffered saline (PBS) group received tail-vein injection of PBS. The radiation + PBS group received radiation over the prostate and tail-vein injection of PBS. The radiation + ADSC group received radiation over the prostate and tail-vein injection of ADSCs, which were labeled with 5-ethynyl-2-deoxyuridine (EdU). Seventeen weeks later, erectile function was evaluated by intracavernous pressure (ICP) in response to electrostimulation of cavernous nerves (CNs). Penile tissue and major pelvic ganglia (MPG) were examined by immunofluorescence (IF) and EdU staining. MAIN OUTCOME MEASURES: Erectile function was measured by ICP. Protein expression was examined by IF, followed by image analysis and quantification. RESULTS: Radiation over the prostate caused a significant decrease in erectile function and in the expression of neuronal nitric oxide synthase (nNOS) in penis and MPG. Cavernous smooth muscle (CSM) but not endothelial content was also reduced. Injection of ADSCs significantly restored erectile function, nNOS expression, and CSM content in the irradiated rats. EdU-positive cells were visible in MPG. CONCLUSIONS: Radiation appears to cause ED via CN injury. ADSC injection can restore erectile function via CN regeneration.

Both immediate and delayed intracavernous injection of autologous adipose-derived stromal vascular fraction enhances recovery of erectile function in a rat model of cavernous nerve injury.

BACKGROUND: Intracavernous injection of cultured adipose-derived stem cells (ADSCs) effectively restores erectile function in cavernous nerve (CN)-injured rats when administered at the time of injury. However, culturing exposes ADSCs to the risk of contamination and dedifferentiation. OBJECTIVE: Explore the effect of uncultured autologous adipose-derived stromal vascular fraction (SVF) on improving erectile function in a rat model of CN injury when administered at the time of injury or 4 wk after injury. DESIGN, SETTING, AND PARTICIPANTS: Eighty-nine male Sprague Dawley rats were randomly divided into four groups. CN injury or sham surgery was performed at the start of the study, and rats were treated with either SVF or vehicle. Functional testing and histologic analysis were performed 12 wk after CN crush or sham surgery. INTERVENTION: We used intracavernous injection of saline immediately after CN crush (n=23), intracavernous injection of SVF immediately after CN crush (n=17), intracavernous injection of SVF 4 wk after CN crush (n=23), or sham surgery (n=26). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We studied intracavernous pressure (ICP) response to CN electrostimulation and performed histologic examination of midpenile cross-sections. Data were analyzed using one-way analysis of variance followed by the Tukey-Kramer test. RESULTS AND LIMITATIONS: Both immediate and delayed treatment with SVF resulted in a significantly increased ICP-to-mean arterial pressure ratio compared with the vehicle-treated group. Both immediate and delayed treatment with SVF significantly increased expression of neuronal nitric oxide synthase and neurofilament in dorsal penile nerves compared to the vehicle group. Furthermore, the smooth muscle-to-collagen ratio within the corpus cavernosum was significantly improved in both of the SVF groups compared to vehicle-treated rats. The main limitation of the study is the lack of determination of the SVF components. CONCLUSIONS: Uncultured autologous SVF injected immediately or 4 wk after CN crush improved erectile function, promoted nerve regeneration, and prevented fibrosis of the corpus cavernosum following CN injury.

Evaluation and treatment of erectile dysfunction in the aging male: a mini-review.

Before the 20th century, individuals often did not live beyond the reproductive years, and sexuality of the elderly was not an issue. However, in the current era it is known that as life expectancy improves, both men and women are seeking to preserve their sexuality into old age. While the appreciation of sexuality persists with aging, a decline in sexual activity is typically seen with, and can be attributed to both general health problems as well as specific sexual dysfunctions. Erectile dysfunction is the most frequently diagnosed sexual dysfunction in the older male population. This mini-review provides an overview of contemporary literature concerning epidemiology, pathophysiology, assessment and treatment of erectile dysfunction in the aging male.

Recruitment of intracavernously injected adipose-derived stem cells to the major pelvic ganglion improves erectile function in a rat model of cavernous nerve injury.

BACKGROUND: Intracavernous (IC) injection of stem cells has been shown to ameliorate cavernous-nerve (CN) injury-induced erectile dysfunction (ED). However, the mechanisms of action of adipose-derived stem cells (ADSC) remain unclear. OBJECTIVES: To investigate the mechanism of action and fate of IC injected ADSC in a rat model of CN crush injury. DESIGN, SETTING, AND PARTICIPANTS: Sprague-Dawley rats (n=110) were randomly divided into five groups. Thirty-five rats underwent sham surgery and IC injection of ADSC (n=25) or vehicle (n=10). Another 75 rats underwent bilateral CN crush injury and were treated with vehicle or ADSC injected either IC or in the dorsal penile perineural space. At 1, 3, 7 (n=5), and 28 d (n=10) postsurgery, penile tissues and major pelvic ganglia (MPG) were harvested for histology. ADSC were labeled with 5-ethynyl-2-deoxyuridine (EdU) before treatment. Rats in the 28-d groups were examined for erectile function prior to tissue harvest. MEASUREMENTS: IC pressure recording on CN electrostimulation, immunohistochemistry of the penis and the MPG, and number of EdU-positive (EdU+) cells in the injection site and the MPG. RESULTS AND LIMITATIONS: IC, but not perineural, injection of ADSC resulted in significantly improved erectile function. Significantly more EdU+ ADSC appeared in the MPG of animals with CN injury and IC injection of ADSC compared with those injected perineurally and those in the sham group. One day after crush injury, stromal cell-derived factor-1 (SDF-1) was upregulated in the MPG, providing an incentive for ADSC recruitment toward the MPG. Neuroregeneration was observed in the group that underwent IC injection of ADSC, and IC ADSC treatment had beneficial effects on the smooth muscle/collagen ratio in the corpus cavernosum. CONCLUSIONS: CN injury upregulates SDF-1 expression in the MPG and thereby attracts intracavernously injected ADSC. At the MPG, ADSC exert neuroregenerative effects on the cell bodies of injured nerves, resulting in enhanced erectile response.

Pentoxifylline promotes recovery of erectile function in a rat model of postprostatectomy erectile dysfunction.

BACKGROUND: Cavernous nerve (CN) injury during radical prostatectomy (RP) causes CN degeneration and secondary penile fibrosis and smooth muscle cell (SMC) apoptosis. Pentoxifylline (PTX) is a phosphodiesterase inhibitor that further inhibits multiple cytokine pathways involved in nerve degeneration, apoptosis, and fibrosis. OBJECTIVES: To evaluate whether PTX enhances erectile function in a rat model of CN injury. DESIGN, SETTING AND INTERVENTIONS: Forty male Sprague-Dawley rats underwent CN crush injury and were randomized to oral gavage feeding of phosphate-buffered saline (vehicle) or PTX 25, PTX 50, or PTX 100 mg/kg per day. Ten animals underwent sham surgery and received vehicle treatment. Treatment continued for 28 d, followed by a wash-out period of 72 h. An additional eight rats underwent resection of the major pelvic ganglion (MPG) for tissue culture and examination of direct effects of PTX on neurite sprouting. MEASUREMENTS: Intracavernous pressure recording on CN electrostimulation, immunohistologic examination of the penis and the CN distal to the injury site, and length of neurite sprouts in MPG culture. RESULTS: Daily oral gavage feeding of PTX resulted in significant improvement of erectile function compared to vehicle treatment in all treated groups. After treatment with PTX 50 and PTX 100 mg/kg per day, the expression of neuronal nitric oxide synthase in the dorsal penile nerve was significantly higher than in vehicle-treated rats. Furthermore, PTX treatment prevented collagen deposition and SMC loss in the corpus cavernosum. In the CN, signs of Wallerian degeneration were ameliorated by PTX treatment. MPG culture in medium containing PTX resulted in a significant increase of neurite length. CONCLUSIONS: PTX treatment following CN injury in rats improved erectile recovery, enhanced nerve regeneration, and preserved the corpus cavernosum microarchitecture. The clinical availability of this compound merits application in penile rehabilitation studies following RP in the near future.

Injections of adipose tissue-derived stem cells and stem cell lysate improve recovery of erectile function in a rat model of cavernous nerve injury.

INTRODUCTION: Erectile dysfunction (ED) remains a major complication after radical prostatectomy. The use of adipose tissue-derived stem cells (ADSCs) has shown promising results for the treatment of ED. However, the mechanisms of action for stem cell therapy remain controversial, with increasing evidence pointing to paracrine pathways. AIM: To determine the effects and to identify the mechanism of action of ADSC and ADSC-derived lysate in a rat model of cavernous nerve (CN) crush injury. METHODS: Thirty-two male Sprague-Dawley rats were randomly divided into four equal groups: one group underwent sham operation, while three groups underwent bilateral CN crush. Crush-injury groups were treated at the time of injury with intracavernous injection of ADSC, lysate, or vehicle only (injured controls). Erectile function was assessed by CN electrostimulation at 4 weeks. Penile tissue was collected for histology. MAIN OUTCOME MEASURES: Intracavernous pressure increase upon CN stimulation; neuronal nitric oxide synthase (nNOS) content in the dorsal penile nerve; smooth muscle content, collagen content, and number of apoptotic cells in the corpus cavernosum. RESULTS: Both ADSC and lysate treatments resulted in significant recovery of erectile function, as compared with vehicle treatment. nNOS content was preserved in both the ADSC and lysate group, with significantly higher expression compared with vehicle-treated animals. There was significantly less fibrosis and a significant preservation of smooth muscle content in the ADSC and lysate groups compared with injured controls. The observed functional improvement after lysate injection supports the hypothesis that ADSCs act through release of intracellular preformed substances or by active secretion of certain biomolecules. The underlying mechanism of recovery appears to involve neuron preservation and cytoprotection by inhibition of apoptosis. CONCLUSIONS: Penile injection of both ADSC and ADSC-derived lysate can improve recovery of erectile function in a rat model of neurogenic ED.