FK506 and Rapamycin Neuroprotect Erection and Involve Different Immunophilins in a Rat Model of Cavernous Nerve Injury

IntroductionImmunophilin ligands function by binding to receptor proteins such as FK506 binding proteins (FKBPs). FKBPs are studied for their roles in neuroprotection.AimCompare the effect of FK506 (FK) and rapamycin (RAP) on erectile function (EF) recovery and FKBP expressions in penis and major pelvic ganglion (MPG) after cavernous nerve (CN) injury.MethodsAdult male rats were divided into four groups: sham surgery (CN exposure only) + vehicle; bilateral CN injury (BCNI; bilateral crush, 3 minutes with hemostat clamp) + vehicle; BCNI + FK (5 mg/kg/day, 5 days, sc); and BCNI + RAP (2 mg/kg/day, 5 days, sc). At both 24 hours (Day 1) or 1 week (Day 7) after BCNI, EF was assessed by intracavernosal pressure measurement and FKBPs 12, 38, 52, and 65 expressions were evaluated by Western blot analysis in collected penises and MPGs.Main Outcome MeasuresEF and change in protein expressions of FKBPs in the rat penis and MPG after BCNI with and without immunophilin ligand treatment.ResultsBoth FK- and RAP-treated rats had preserved EF compared with vehicle-treated rats after BCNI. FKBPs changed variably following injury and treatment. In particular, in the penis at Day 1, FKBP 38 expression was decreased after BCNI and both FK and RAP attenuated this decrease. In MPG at Day 1, FKBP 38 expression was also decreased after BCNI and FK attenuated the decrease, while at Day 7, FKBP 38 expression was still decreased and RAP attenuated the decrease. Also, in the penis at Day 1, FKBP 65 expression decreased after BCNI and FK attenuated the decrease. In the MPG, FKBP 65 expression increased at both Days 1 and 7 with FK treatment.ConclusionsImproved EF after BCNI, as shown with RAP, further suggests a role of immunophilin ligands as a protective therapy of CN injury associated erectile dysfunction. Our findings also suggest that select FKBPs, such as FKBP 38 and FKBP 65, may mediate these effects. Lagoda G, Sezen SF, and Burnett AL. FK506 and rapamycin neuroprotect erection and involve different immunophilins in a rat model of cavernous nerve injury. J Sex Med 2009;6:1914–1923.     

GGF2 Is Neuroprotective in a Rat Model of Cavernous Nerve Injury-Induced Erectile Dysfunction

IntroductionErectile dysfunction is a major complication of radical prostatectomy, commonly associated with penile neuropathy. In animal models of peripheral nerve injury, glial growth factor-2 (GGF2), a member of the neuregulin family of growth factors, has neuroprotective and neurorestorative properties, but this potential has not been established after cavernous nerve (CN) injury.AimsThe effectiveness of GGF2 in preserving axonal integrity and recovering erectile function in a rat model of radical prostatectomy-associated CN injury.MethodsAdult male Sprague-Dawley rats underwent bilateral CN crush injury (BCNI) or sham surgery. Rats were administered GGF2 (0.5, 5, or 15 mg/kg) or vehicle subcutaneously 24 hour pre and 24-hour post-BCNI, and once weekly for 5 weeks. Erectile function was assessed in response to electrical stimulation of the CN. CN survival was assessed by fluorogold retrograde axonal tracing in major pelvic ganglia (MPG). Unmyelinated axons in the CNs were quantitated by electron microscopy.Main Outcome MeasuresErectile function recovery, CN survival, and unmyelinated CN axon preservation in response to GGF2 treatment following BCNI.ResultsErectile function was decreased (P < 0.05) after BCNI, and it was improved (P < 0.05) by all doses of GGF2. The number of fluorogold-labeled cells in the MPG was reduced (P < 0.05) by BCNI and was increased (P < 0.05) by GGF2 (0.5 and 5 mg/kg). The percentage of denervated Schwann cells in the BCNI group was higher (P < 0.05) than that in the sham-treated group and was decreased (P < 0.05) in the GGF2-treated (5 mg/kg) BCNI group. In the BCNI + GGF2 (5 mg/kg) group, the unmyelinated fiber histogram demonstrated a rightward shift, indicating an increased number of unmyelinated axons per Schwann cell compared with the BCNI group.ConclusionsGGF2 promotes erectile function recovery following CN injury in conjunction with preserving unmyelinated CN fibers. Our findings suggest the clinical opportunity to develop GGF2 as a neuroprotective therapy for radical prostatectomy. Burnett AL, Sezen SF, Hoke A, Caggiano AO, Iaci J, Lagoda G, Musicki B, and Bella AJ. GGF2 is neuroprotective in a rat model of cavernous nerve injury-induced erectile dysfunction. J Sex Med 2015;12:897–905.     

Valproic Acid Prevents Penile Fibrosis and Erectile Dysfunction in Cavernous Nerve‐Injured Rats

IntroductionBilateral cavernous nerve injury (BCNI) causes profound penile changes such as apoptosis and fibrosis leading to erectile dysfunction (ED). Histone deacetylase (HDAC) has been implicated in chronic fibrotic diseases.AimsThis study will characterize the molecular changes in penile HDAC after BCNI and determine if HDAC inhibition can prevent BCNI‐induced ED and penile fibrosis.MethodsFive groups of rats (8–10 weeks, n = 10/group) were utilized: (i) sham; (ii and iii) BCNI 14 and 30 days following injury; and (iv and v) BCNI treated with HDAC inhibitor valproic acid (VPA 250 mg/kg; 14 and 30 days). All groups underwent cavernous nerve stimulation (CNS) to determine intracavernosal pressure (ICP). Penile HDAC3, HDAC4, fibronectin, and transforming growth factor‐β1 (TGF‐β1) protein expression (Western blot) were assessed. Trichrome staining and the fractional area of fibrosis were determined in penes from each group. Cavernous smooth muscle content was assessed by immunofluorescence to alpha smooth muscle actin (α‐SMA) antibodies.Main Outcome MeasuresWe measured ICP; HDAC3, HDAC4, fibronectin, and TGF‐β1 protein expression; penile fibrosis; penile α‐SMA content.ResultsThere was a voltage‐dependent decline (P < 0.05) in ICP to CNS 14 and 30 days after BCNI. Penile HDAC3, HDAC4, and fibronectin were significantly increased (P < 0.05) 14 days after BCNI. There was a slight increase in TGF‐β1 protein expression after BCNI. Histological analysis showed increased (P < 0.05) corporal fibrosis after BCNI at both time points. VPA treatment decreased (P < 0.05) penile HDAC3, HDAC4, and fibronectin protein expression as well as corporal fibrosis. There was no change in penile α‐SMA between all groups. Furthermore, VPA‐treated BCNI rats had improved erectile responses to CNS (P < 0.05).ConclusionHDAC‐induced pathological signaling in response to BCNI contributes to penile vascular dysfunction. Pharmacological inhibition of HDAC prevents penile fibrosis, normalizes fibronectin expression, and preserves erectile function. The HDAC pathway may represent a suitable target in preventing the progression of ED occurring post‐radical prostatectomy. Hannan JL, Kutlu O, Stopak BL, Liu X, Castiglione F, Hedlund P, Burnett AL, and Bivalacqua TJ. Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve‐injured rats. J Sex Med 2014;11:1442–1451.     

Increased Level of Tumor Necrosis Factor-Alpha (TNF-α) Leads to Downregulation of Nitrergic Neurons Following Bilateral Cavernous Nerve Injury and Modulates Penile Smooth Tone

BackgroundErectile dysfunction (ED) after injury to peripheral cavernous nerve (CN) is partly a result of inflammation in pelvic ganglia, suggesting that ED may be prevented by inhibiting neuroinflammation.AimThe aim of this study is to examine temporal changes of TNF-α, after bilateral CN injury (BCNI), to evaluate effect of exogenous TNF-α on neurite outgrowth from major pelvic ganglion (MPG), and to investigate effect of TNF-α signal inhibition to evaluate effects of TNF-α on penile tone with TNF-α receptor knockout mice (TNFRKO).MethodsSeventy Sprague-Dawley rats were randomized to undergo BCNI or sham surgery. Sham rats’ MPGs were harvested after 48 hours, whereas BCNI groups’ MPGs were at 6, 12, 24, 48 hours, 7, or 14 days after surgery. qPCR was used to evaluate gene expression of markers for neuroinflammation in MPGs. Western blot was performed to evaluate TNF-α protein amount in MPGs. MPGs were harvested from healthy rats and cultured in Matrigel with TNF-α. Neurite outgrowth from MPGs was measured after 3 days, and TH and nNOS immunofluorescence was assessed. Wild type (WT) and TNFRKO mice were used to examine effect of TNF-α inhibition on smooth muscle function after BCNI. MPGs were harvested 48 hours after sham or BCNI surgery to evaluate gene expression of nNOS and TH.OutcomesGene expression of TNF-α signaling pathway, Schwann cell and macrophage markers, protein expression of TNF-α in MPGs, and penile smooth muscle function to electrical field stimulation (EFS) were evaluated.ResultsBCNI increased gene and protein expression of TNF-α in MPGs. Exogenous TNF-α inhibited MPG neurite outgrowth. MPGs cultured with TNF-α had decreased gene expression of nNOS (P < .05). MPGs cultured with TNF-α had shorter nNOS+ neurites than TH+ neurites (P < .01). Gene expression of nNOS was enhanced in TNFRKO mice compared to WT mice (P < .01). WT mice showed enhanced smooth muscle contraction of penises of WT mice was enhanced to EFS, compared to TNFKO (P < .01). Penile smooth-muscle relaxation to EFS was greater in TNFKO mice compared to WT (P < .01).Clinical TranslationTNF-α inhibition may prevent ED after prostatectomy.Strength/LimitationsTNF-α inhibition might prevent loss of nitrergic nerve apoptosis after BCNI and preserve corporal smooth muscle function but further investigation is required to evaluate protein expression of nNOS in MPGs of TNFKO mice.ConclusionsTNF-α inhibited neurite outgrowth from MPGs by downregulating gene expression of nNOS and TNFRKO mice showed enhanced gene expression of nNOS and enhanced penile smooth-muscle relaxation.Matsui H, Sopko NA, Campbell JD, et al. Increased Level of Tumor Necrosis Factor-Alpha (TNF-α) Leads to Downregulation of Nitrergic Neurons Following Bilateral Cavernous Nerve Injury and Modulates Penile Smooth Tone. J Sex Med 2021;18:1181–1190.     

Erection Hardness Score for the Evaluation of Erectile Dysfunction: Further Psychometric Assessment in Patients Treated by Intracavernous Prostaglandins Injections after Radical Prostatectomy

IntroductionErectile dysfunction (ED) affects quality of life in patients treated by radical prostatectomy (RP). The Erection Hardness Score (EHS) is a single‐item scale that has demonstrated good psychometric properties for assessing erectile function (EF) in patients treated by sildenafil, but its applicability to other treatment contexts has not yet been tested.AimThis study aims to test the validity and time and treatment responsiveness of the EHS to assess ED in men with post‐RP ED treated with alprostadil injections.MethodsThis is a 1‐year follow‐up cohort study of 75 patients treated by RP for localized prostate cancer in a urology department setting between January 2007 and December 2008. Data were prospectively collected at 6 and 12 months post‐RP.Main Outcome MeasuresThe EHS, the International Index of Erectile Function (IIEF) reference questionnaire, the Global Assessment Questionnaire (GAQ), and Numeric Pain Scale (NPS) were collected. Convergent validity (Spearman correlation coefficients with IIEF domains), known‐groups validity (comparing EHS scores across ED severity groups), time and treatment responsiveness (effect size with/without treatment and over the follow‐up period), and predictive ability (area under the receiver operating characteristics curve [AUC‐ROC]) were analyzed for this study.ResultsThe EHS showed good convergent validity (all Spearman coefficients significant at the P < 0.05 level), adequate known‐groups validity (global differentiation between IIEF‐EF severity groups; P < 0.001), and treatment responsiveness (effect size: +1.8 [6 months], +2.1 [12 months]), but limited time responsiveness and predictive ability of the EHS for a normal EF at 12 months follow‐up when compared with the IIEF‐EF domain (AUC‐ROC: 0.72 vs. 0.85; P < 0.01).ConclusionOur findings support the overall good psychometric properties of the EHS in patients with post‐RP ED treated with alprostadil injections. However, evidence for limited predictive validity and responsiveness to change over time should be considered for its use in clinical follow‐up in this population. Parisot J, Yiou R, Salomon L, de la Taille A, Lingombet O, and Audureau E. Erection hardness score for the evaluation of erectile dysfunction: Further psychometric assessment in patients treated by intracavernous prostaglandins injections after radical prostatectomy. J Sex Med 2014;11:2109–2118.     

Penile Prosthesis Implantation and Timing Disparities After Radical Prostatectomy: Results From a Statewide Claims Database

BackgroundMany patients with erectile dysfunction (ED) after radical prostatectomy (RP) improve with conservative therapy but some do not; penile prosthesis implantation rates have been sparsely reported, and have used nonrepresentative data sets.AimTo characterize rates and timing of penile prosthesis implantation after RP and to identify predictors of implantation using a more representative data set.MethodsThe Healthcare Cost and Utilization Project State Inpatient and State Ambulatory Surgery databases for Florida from 2006 to 2015 were used. Patients undergoing RP (2006–2012) were tracked longitudinally for penile prosthesis implantation. Patient and clinical data were analyzed using multivariable logistic regression.OutcomesThe primary outcome was risk-adjusted predictors of prosthesis implantation, and the secondary outcome was predictors of the highest quartile of time between RP and penile prosthesis.ResultsOf 29,288 men who had RP, 1,449 (4.9%) patients underwent subsequent prosthesis. The mean time from RP to prosthesis was 2.6 years (median: 2.1; interquartile range [IQR]: 1.2–3.5). Adjusted predictors of prosthesis implantation included open RP (odds ratio [OR]: 1.5, P < .01), African American race (OR: 1.7, P < .01) or Hispanic ethnicity (OR: 3.2, P < .01), and Medicare (OR: 1.4, P < .01) insurance. Oler patients (age >70 years; OR: 0.7, P < .01) and those from the highest income quartile relative to the lowest (OR: 0.8, P < .05) were less likely to be implanted. Adjusted predictors of longer RP-to-implantation time (highest quartile: median: 4.7 years; IQR: 3.9–6.0 years) included open RP (OR: 1.78, P < .01), laparoscopic RP (OR: 4.67, P < .01), Medicaid (OR: 3.03, P < .05), private insurance (OR: 2.57, P < .01), and being in the highest income quartile (OR: 2.52, P < .01).Clinical ImplicationsThese findings suggest ED treatment healthcare disparities meriting further investigation; upfront counseling on all ED treatment modalities and close monitoring for conservative treatment failure may reduce lost quality of life years.Strengths & LimitationsThis study is limited by its use of administrative data, which relies on accurate coding and lacks data on ED questionnaires/prior treatments, patient-level cost, and oncologic outcomes. Quartile-based analysis of income and time between RP and prosthesis limits the conclusions that can be drawn.ConclusionLess than 5% of post-RP patients undergo penile prosthesis implantation, with open RP, Medicare, African American race, and Hispanic ethnicity predicting post-RP implantation; living in the wealthiest residential areas predicts lower likelihood of implantation compared to the least wealthy areas. Patients with the longest time between RP and prosthesis are more likely to live in the wealthiest areas or have undergone open/laparoscopic RP relative to robotic RP.Bajic P, Patel PM, Nelson MH, et al. Penile Prosthesis Implantation and Timing Disparities After Radical Prostatectomy: Results From a Statewide Claims Database. J Sex Med 2020;17:1175–1181.     

Sleep Apnea is an Independent Correlate of Erectile and Sexual Dysfunction

IntroductionObstructive sleep apnea (OSA) has been linked with erectile dysfunction (ED), but it is unknown whether this association is maintained in the presence of other risk factors for ED.AimThe aim of this study was to evaluate the relationship between ED/sexual dysfunction and polysomnographic measures of sleep apnea in patients with known risk factors for ED.MethodsProspective cross‐sectional analysis of 401 male patients undergoing in‐lab polysomnography for suspected OSA. Erectile (EF) and sexual function were assessed by the 15‐item International Index of Erectile Function (IIEF‐15) questionnaire.Main Outcome MeasuresSeverity of OSA via apnea–hypopnea index (AHI) and mean/lowest nocturnal oxygen saturation (SaO₂). The IIEF‐15 including the sexual domains: EF, intercourse satisfaction, orgasmic function, sexual desire, and overall satisfaction.ResultsOSA (AHI > 5/h) was diagnosed in 92% of patients. ED (EF subdomain ≤ 25) was present in 69% of patients with, and 34% of patients without OSA (P < 0.001). Multivariate stepwise regression analyses including known risk factors for ED, such as age, obesity, coronary heart disease, peripheral occlusive disease, hypertension, diabetes, prostate surgery, and β‐blocker treatment, and measures of sleep apnea identified mean nocturnal SaO₂ as independently associated with ED (P = 0.002; mean [95% CI] normalized slope 0.126 [0.047; 0.205]). Age (P < 0.001), peripheral occlusive disease (P = 0.001), prostate surgery (P = 0.018), and hypertension (P = 0.021) were confirmed as risk factors for ED, but did not abolish the sleep apnea‐associated risk. Similar results were obtained for sexual dysfunction. Logistic regression analysis using the diagnosis of ED (EF subdomain ≤ 25) as binary dependent variable confirmed that mean nocturnal SaO₂ (P = 0.012), as well as age (P < 0.001) were independently associated with ED.ConclusionsED and overall sexual dysfunction were highly prevalent in patients with suspected OSA. Irrespective of known risk factors, mean nocturnal SaO₂ was an additional, independent correlate of these dysfunctions, suggesting that OSA‐related intermittent nocturnal hypoxemia specifically contributes to their development. Budweiser S, Enderlein S, Jörres RA, Hitzl AP, Wieland WF, Pfeifer M, and Arzt M. Sleep apnea is an independent correlate of erectile and sexual dysfunction.     

Insulin Resistance Is an Independent Predictor of Severe Lower Urinary Tract Symptoms and of Erectile Dysfunction: Results from a Cross‐Sectional Study

IntroductionSeveral studies have linked the association between lower urinary tract symptoms (LUTS), erectile dysfunction (ED), and the presence of insulin resistance (IR) due to an underlined metabolic syndrome (MetS).AimThis study aims to determine the relationship between IR, sexual function, and LUTS and to demonstrate the ability of IR in predicting ED and severe LUTS.MethodsBetween January 2008 to January 2013, 544 consecutive patients with benign prostatic hyperplasia‐related LUTS were enrolled. LUTS and sexual function of the patients were evaluated by the International Index of Erectile Function (IIEF) and the International Prostate Symptom Score (IPSS). MetS was defined by the International Diabetes Federation. IR was defined as a homeostasis model assessment (HOMA) index of 3 or greater.Main Outcome MeasuresUni‐ and multivariate logistic regression analysis was performed to assess significant predictors of severe LUTS (IPSS ≥20) and ED (IIEF‐Erectile Function [IIEF‐EF] <26), including MetS component, prostate volume, prostate‐specific antigen, total testosterone, and HOMA index.ResultsIR patients resulted in higher values of IPSS (19.0 vs. 15.0; P < 0.01), IPSS‐storage (6.0 vs. 5.0; P < 0.01), IPSS‐voiding (12.0 vs. 9.0; P < 0.01), total prostate volume (54.8 vs. 36.5; P < 0.01), and lower values of IIEF‐EF (17.0 vs. 20.0; P < 0.01), IIEF‐Intercourse Satisfaction (3.0 vs. 10.0; P < 0.01), IIEF‐Orgasmic Function (8.0 vs. 9.0; P < 0.01), IIEF‐Overall Satisfaction (6.0 vs. 8.0; P < 0.01), and total testosterone (3.83 vs. 4.44; P < 0.01). IR was demonstrated to be a strong predictor of ED (IIEF‐EF <26) (odds ratio [OR] = 6.20, P < 0.01) after adjusting for confounding factors. Finally, IR was also an independent predictor of severe LUTS (IPSS ≥20) (OR = 2.0, P < 0.01) after adjusting for confounding factors.ConclusionsIR patients are at high risk of having severe LUTS and contemporary sexual dysfunctions. We strongly suggest to prevent LUTS and ED by reducing insulin resistance. Russo GI, Cimino S, Fragalà E, Privitera S, La Vignera S, Condorelli R, Calogero AE, Castelli T, Favilla V, and Morgia G. Insulin resistance is an independent predictor of severe lower urinary tract symptoms and of erectile dysfunction: Results from a cross‐sectional study. J Sex Med 2014;11:2074–2082.     

Increased Expression of the Neuroregenerative Peptide Galanin in the Major Pelvic Ganglion Following Cavernous Nerve Injury

IntroductionErectile 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).AimThe aim of this study is to evaluate the temporal regulation of galanin in the MPG after BCNI and its relationship to functional nerve regeneration.MethodsChanges 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 MeasuresICP/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.ResultsAfter 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.ConclusionsGalanin 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. Weyne E, Albersen M, Hannan JL, Castiglione F, Hedlund P, Verbist G, De Ridder D, Bivalacqua TJ, and Van der Aa F. Increased expression of the neuroregenerative peptide galanin in the major pelvic ganglion following cavernous nerve injury. J Sex Med 2014;11:1685–1693.     

The Neuroprotective Effect of Platelet‐rich Plasma on Erectile Function in Bilateral Cavernous Nerve Injury Rat Model

IntroductionNeurogenic erectile dysfunction resulting from cavernous nerve (CN) injury is a major complication caused by radical prostatectomy. The use of platelet‐rich plasma (PRP) on the nerve‐injured site has shown promising results for the nerve regeneration. However, the effects of PRP injection in corpus cavernosum after bilateral CN injury have never been investigated.AimTo assess the neuroprotective effect of PRP injection in corpus cavernosum after bilateral CN injury.MethodsMale Sprague‐Dawley rats were randomly divided into three groups: Group I underwent sham operation, while the remaining two groups underwent bilateral CN crush. Crush injury groups were treated at the time of injury with an application of PRP or normal saline only injection in the corpus cavernosum, respectively. Four weeks later, erectile function (EF) was assessed by CN electrosimulation, and CNs as well as penile tissue were collected for histology.Main Outcome MeasuresIntracavernous pressure (ICP) monitored during electrical stimulation of CNs; myelinated axons number of CNs and dorsal penile nerve; collagen type change, number of apoptotic cells, and mRNA expression of caspase‐3 and transforming growth factor‐β1 (TGF‐β1) in the corpus cavernosum.ResultsFour weeks after surgery, in the vehicle‐only group, the functional evaluation showed a lower mean maximal ICP than that in the sham group (P < 0.05). PRP treatments resulted in significant recovery of EF, as compared with the vehicle‐only group (P < 0.05). Histologically, the PRP‐treated group had a significant preservation of myelinated axons of CNs compared with the vehicle‐only group (P < 0.05) and reduced the apoptotic index. The mRNA expression of TGF‐β1 in the corpus cavernosum tissue was significantly decreased in the PRP group compared with the vehicle‐only group (P < 0.05).ConclusionsPRP injection in the corpus cavernosum increased the number of myelinated axons and facilitated recovery of EF in the bilateral CN injury rat model. Wu C‐C, Wu Y‐N, Ho H‐O, Chen K‐C, Sheu M‐T, and Chiang H‐S. The neuroprotective effect of platelet‐rich plasma on erectile function in bilateral cavernous nerve injury rat model. J Sex Med 2012;9:2838–2848.     

Association between preoperative erectile dysfunction and prostate cancer features--an analysis from the Duke Prostate Center Database

IntroductionErectile dysfunction (ED) is related to several co‐morbidities including obesity, metabolic syndrome, cigarette smoking, and low testosterone, all of which have been reported to be associated with adverse prostate cancer features.AimTo examine whether preoperative ED has a relationship with adverse prostate cancer features in patients who underwent radical prostatectomy (RP).MethodsWe analyzed data from our institution on 676 patients who underwent RP between 2001 and 2010. Crude and adjusted logistic regression models were used to investigate the association between preoperative ED and several pathological parameters. The log‐rank test and multivariate proportional hazards model were conducted to determine the association of preoperative ED with biochemical recurrence (BCR).Main Outcome MeasuresThe Expanded Prostate Cancer Index Composite (EPIC) instrument was used to evaluate preoperative erectile function (EF). Preoperative normal EF was defined as EPIC‐SF ≥ 60 points while ED was defined as preoperative EPIC‐SF lower than 60 points.ResultsPreoperatively, a total of 343 (50.7%) men had normal EF and 333 (49.3%) men had ED. After adjusting for covariates, preoperative ED was identified a risk factor for positive extracapsular extension (OR 1.57; P = 0.029) and high percentage of tumor involvement (OR 1.56; P = 0.047). In a Kaplan‐Meier curve, a trend was identified that patients with ED had higher incidence of BCR than men with normal EF (P = 0.091). Moreover, using a multivariate Cox model, higher preoperative EF was negatively associated with BCR (HR 0.99; P = 0.014).ConclusionsThese results suggest that the likelihood for adverse pathological outcomes as well as BCR following prostatectomy is higher among men with preoperative ED, though these results require validation in larger datasets. The present study indicates that preoperative ED might be a surrogate for adverse prostate cancer outcomes following RP. Kimura M, Bañez LL, Gerber L, Qi J, Tsivian M, Freedland SJ, Satoh T, Polascik TJ, Baba S, and Moul JW. Association between preoperative erectile dysfunction and prostate cancer features—An analysis from the Duke Prostate Center Database. J Sex Med 12;9:1174–1181.     

Caspase Signaling in ED Patients and Animal Models

BackgroundCurrent treatments for erectile dysfunction (ED) are ineffective in prostatectomy and diabetic patients due to cavernous nerve (CN) injury, which causes smooth muscle apoptosis, penile remodeling, and ED. Apoptosis can occur via the intrinsic (caspase 9) or extrinsic (caspase 8) pathway.AimWe examined the mechanism of how apoptosis occurs in ED patients and CN injury rat models to determine points of intervention for therapy development.Methods and OutcomesImmunohistochemical and western analyses for caspase 3-cleaved, caspase-8 and caspase-9 (pro and active forms) were performed in corpora cavernosal tissue from Peyronie’s, prostatectomy and diabetic ED patients (n = 33), penis from adult Sprague Dawley rats that underwent CN crush (n = 24), BB/WOR diabetic and control rats (n = 8), and aged rats (n = 9).ResultsCaspase 3-cleaved was observed in corpora cavernosa from Peyronie’s patients and at higher abundance in prostatectomy and diabetic tissues. Apoptosis takes place primarily through the extrinsic (caspase 8) pathway in penis tissue of ED patients. In the CN crushed rat, caspase 3-cleaved was abundant from 1–9 days after injury, and apoptosis takes place primarily via the intrinsic (caspase 9) pathway. Caspase 9 was first observed and most abundant in a layer under the tunica, and after several days was observed in the lining of and between the sinuses of the corpora cavernosa. Caspase 8 was initially observed at low abundance in the rat corpora cavernosa and was not observed at later time points after CN injury. Aged and diabetic rat penis primarily exhibited intrinsic mechanisms, with diabetic rats also exhibiting mild extrinsic activation.Clinical translationKnowing how and when to intervene to prevent the apoptotic response most effectively is critical for the development of drugs to prevent ED, morphological remodeling of the corpora cavernosa, and thus, disease management.Strengths and limitationsAnimal models may diverge from the signaling mechanisms observed in ED patients. While the rat utilizes primarily caspase 9, there is a significant flux through caspase 8 early on, making it a reasonable model, as long as the timing of apoptosis is considered after CN injury.ConclusionsApoptosis takes place primarily through the extrinsic caspase 8 dependent pathway in ED patients and via the intrinsic caspase 9 dependent pathway in commonly used CN crush ED models. This is an important consideration for study design and interpretation that must be taken into account for therapy development and testing of drugs, and our therapeutic targets should ideally inhibit both apoptotic mechanisms.Martin S, Harrington DA, Ohlander S, et al. Caspase Signaling in ED Patients and Animal Models. J Sex Med 2021;18:711–722.     

Long‐Term Changes of Sexual Function in Men with Obstructive Sleep Apnea after Initiation of Continuous Positive Airway Pressure

IntroductionObstructive sleep apnea (OSA), particularly intermittent nocturnal hypoxemia, is associated with erectile dysfunction (ED).AimWe investigated in patients with OSA whether continuous positive airway pressure (CPAP) therapy has a long‐term effect on sexual function, including ED, in the presence of other risk factors for ED.MethodsWithin a long‐term observational design, we reassessed 401 male patients who had been referred for polysomnography, with respect to erectile and overall sexual function. Mean ± standard deviation follow‐up time was 36.5 ± 3.7 months. Patients with moderate to severe ED were stratified according to the regular use of CPAP.Main Outcome MeasureChanges of sexual function were assessed by the 15‐item International Index of Erectile Function (IIEF‐15) questionnaire, including the domains erectile function (EF), intercourse satisfaction, orgasmic function (OF), sexual desire (SD), and overall satisfaction (OS).ResultsOf the 401 patients, 91 returned a valid IIEF‐15 questionnaire at follow‐up. Their baseline characteristics were not different from those of the total study group. OSA (apnea–hypopnea index >5/hour) had been diagnosed in 91.2% of patients. In patients with moderate to severe ED (EF domain <17), CPAP users (N = 21) experienced an improvement in overall sexual function (IIEF‐15 summary score; P = 0.014) compared with CPAP non‐users (N = 18), as well as in the subdomains OF (P = 0.012), SD (P = 0.007), and OS (P = 0.033). Similar results were obtained in patients with poor overall sexual dysfunction (IIEF‐15 summary score <44). In patients with moderate to severe ED and low mean nocturnal oxygen saturation (≤93%, median), also the EF subdomain improved in CPAP users vs. non‐users (P = 0.047).ConclusionsThese data indicate that long‐term CPAP treatment of OSA and the related intermittent hypoxia can improve or preserve sexual function in men with OSA and moderate to severe erectile or sexual dysfunction, suggesting a certain reversibility of OSA‐induced sexual dysfunctions. Budweiser S, Luigart R, Jörres RA, Kollert F, Kleemann Y, Wieland WF, Pfeifer M, and Arzt M. Long‐term changes of sexual function in men with obstructive sleep apnea after initiation of continuous positive airway pressure. J Sex Med **;**:**–**.     

Persistent Erectile Dysfunction Following Radical Prostatectomy: The Association between Nerve-Sparing Status and the Prevalence and Chronology of Venous Leak

IntroductionFailure to recover erectile function after radical prostatectomy (RP) may result from venous leak as a sequela of neuropraxia-induced erectile tissue damage. Venous leak portends a poor prognosis for erections recovery as well as phosphodiesterase type 5 inhibitor (PDE5i) response.AimsTo define the impact of RP nerve-sparing status on venous leak prevalence and chronology.MethodsStudy population: men who underwent RP for localized prostate cancer, had functional erections prior to RP, developed postoperative erectile dysfunction (ED), had a Doppler ultrasonography within 6 months of RP, and did not receive any ED treatment for the first 6 months after RP other than on-demand PDE5i.Main Outcome MeasuresVenous leak prevalence and erectile function recovery at different time-points.ResultsData on 142 patients were analyzed, mean age: 58 ± 16 years. Sixty percent had bilateral nerve-sparing (BNS) surgery, 20% unilateral nerve-sparing (UNS) surgery, and 20% non-nerve-sparing (NNS) surgery. Eleven percent and 21% had venous leak by 3 and 6 months, respectively. Venous leak prevalence by 6 months was 7%, 11%, and 75% for BNS, UNS, and NNS surgery (P < 0.001). Mean end-diastolic velocity was 1.8, 2.1, and 7.2 cm/second for the three groups (P < 0.01). The only patients developing venous leak prior to 3 months were NNS patients, one-third of NNS-associated venous leak occurring before this time-point. At 18 months, the proportion of men having return of unassisted erections was 49%, 42%, and 7% with mean erectile function domain scores of 21, 18, and 12, and PDE5i response rates were 72%, 64%, and 12% for the three groups, respectively.ConclusionsNerve-sparing status impacts heavily upon the prevalence and the chronology of venous leak development post-RP. NNS RP is associated with early development of venous leak, increased prevalence of venous leak, and reduction in return of natural erections. Tal R, Valenzuela R, Aviv N, Parker M, Waters WB, Flanigan RC, and Mulhall JP. Persistent erectile dysfunction following radical prostatectomy: The association between nerve-sparing status and the prevalence and chronology of venous leak. J Sex Med 2009;6:2813–2819.     

Intravenous Preload of Mesenchymal Stem Cells Rescues Erectile Function in a Rat Model of Cavernous Nerve Injury

IntroductionWe evaluated the potential preventive effects and mechanisms of intravenously preloaded mesenchymal stem cells (MSCs) for erectile dysfunction (ED) in a cavernous nerve (CN) injury model.MethodsMale Sprague–Dawley (SD) rats were used for this study. Rats were randomized into two groups. One group was intravenously preloaded with MSCs (1.0 × 10⁶ cells in 1 mL total fluid volume) and the other was infused with medium alone (1 mL Dulbecco's modified Eagle's medium [DMEM]) for sham control, respectively. Crushed CN injury was induced immediately after infusion. The surgeon was blind to the experimental conditions (MSC or medium).Main Outcome MeasuresTo assess erectile function, we measured the intracavernous pressure (ICP) and arterial pressure (AP) at 1 hour and 2 weeks after CN injury. After measuring the initial ICP/AP of pre‐injury (normal) male SD rats, they were randomized into the two groups and infused with MSCs or medium. PKH26‐labelled MSCs were used for tracking. To investigate the mRNA expression levels of neurotrophins in the major pelvic ganglia (MPG), we performed real‐time quantitative real‐time polymerase chain reaction.ResultsThe reduction of ICP/AP and area under the curve of ICP (ICP‐AUC) in the MSC group was significantly lower than in the DMEM group (P < 0.05; P < 0.05) at 1 hour. The ICP/AP and ICP‐AUC at 2 weeks post‐injury in the MSC group was significantly higher than in the DMEM group (P < 0.01; P < 0.05). The preloaded PKH26‐labelled MSCs were detected in the MPG and CN using confocal microscopy indicating homing of the cells to the injured nerve and ganglia. Glia cell‐derived neurotrophic factor (GDNF) and neurturin, which are important neurotrophic factors for erection, had expression levels in MPG significantly higher in the MSC group than in the DMEM group (P < 0.01, 0.05).ConclusionIntravenous preload of MSCs before a CN injury may prevent or reduce experimental ED. Takayanagi A, Sasaki M, Kataoka‐Sasaki Y, Kobayashi K, Matsuda Y, Oka S, Masumori N, Kocsis JD and Honmou O. Intravenous preload of mesenchymal stem cells rescues erectile function in a rat model of cavernous nerve injury. J Sex Med 2015;12:1713–1721.     

REVIEW: Utilization of Pharmacotherapy for Erectile Dysfunction Following Treatment for Prostate Cancer

IntroductionPharmacotherapies improve sexual function following treatments for localized prostate cancer; however, patterns of care remain unknown.AimTo ascertain post-treatment utilization of pharmacotherapies for erectile dysfunction (ED) using a population-based approach.MethodsWe identified 38,958 men who underwent definitive treatment for localized prostate cancer during 2003–2006 from the MarketScan Medstat data.Main Outcome MeasuresWe compared the use of ED pharmacotherapy at baseline (up to 3 months prior) and up to 30 months following radical prostatectomy (RP) or radiotherapy (RT) for localized prostate cancer by utilizing National Drug Classification codes for phosphodiesterase-5 inhibitors (PDE5I), intracavernosal injectable therapies (IT), urethral suppositories and vacuum erection devices (VED). In adjusted analyses, we controlled for the effect of age, comorbidity, type of treatment, health plan and use of adjuvant hormone therapy on the use of pharmacotherapies.ResultsMen undergoing RP vs. RT were younger with less co-morbid conditions. Utilization of PDE5I was up to three times greater for men undergoing RP vs. RT, 25.6% vs. 8.8%, (P < 0.0001) in the first post-treatment year, and usage of these agents was greatest for men undergoing minimally-invasive RP procedures. A higher percentage of men also used IT, suppositories and VED after RP vs. RT (P < 0.001). However, more men in the RT group received adjuvant hormonal therapy (39.53% vs. 5.25% for RP, P < 0.01). In adjusted analyses, men undergoing RP vs. RT were more than two times likely (OR 2.1, 95% CI 1.98, 2.26) to use PDE5I post-treatment while men on adjuvant hormonal therapy were less likely to use PDE5I (OR 0.74, 95% CI 0.70–0.79, P < 0.0001).ConclusionMen undergoing RP vs. RT, particularly minimally-invasive RP, are more likely to employ IT, suppositories, VED, and PDE5I pharmacotherapy post-treatment. Prasad MM, Prasad SM, Hevlone ND, Gu X, Weinberg AC, Lipsitz SR, Palapattu GS, and Hu JC. Utilization of pharmacotherapy for erectile dysfunction following treatment for prostate cancer.     

ORIGINAL RESEARCH–SURGERY: Treatment of Penile Deep Dorsal Venous Leakage of Erectile Dysfunction by Embedding the Deep Dorsal Vein of the Penis: A Single Center Experience with 17 Patients

IntroductionThe common surgery for venous leakage was not very successful; unsatisfactory long-term results have reduced the indications for venous surgery for erectile dysfunction (ED).AimsTo assess the outcomes of embedding the deep dorsal vein of the penis (EDDVP), a new surgical technique used in patients with penile deep dorsal venous leakage of ED.MethodsBetween December 2001 and November 2007, 17 patients diagnosed with penile deep dorsal venous leakage of ED underwent embedding the deep dorsal vein of the penis.Main Outcome MeasuresAll cases were available for follow up by using the abridged 5-item version of the International Index of Erectile Function (IIEF-5) scoring system and penile color Doppler ultrasound. Dynamic cavernosography were also assessed in three patients at 3 months postoperatively.ResultsAfter surgery, 14 patients were able to achieve satisfactory intercourse and three had sufficient erection after oral sildenafil (50–100 mg). The IIEF-5 scoring changed from a preoperative mean IIEF-5 score of 8.8 ± 3.9 to 20.8 ± 4.1 (P < 0.05). Peak systolic velocity (average of right and left cavernosal arteries) changed from 41.9 ± 7.7 cm/second to 44.2 ± 9.2 cm/second (P > 0.05), resistance index changed from 0.79 ± 0.1 to 1.00 ± 0.0 (P < 0.05), and venous velocity changed from 8.4 ± 4.0 cm/second to 0.0 ± 0.0 cm/second (P < 0.05). Dynamic cavernosography demonstrated a smooth flow of the deep dorsal vein during the flaccid phase. During the tumescent phase, the deep dorsal vein of the penis was compressed between the dilated sinusoidal spaces and the tunica albuginea and resulted in venous drainage blockade. And then the hardness of erection was improved and maintained.ConclusionsThe new surgical technique of EDDVP is a simple operative procedure, which seems to be efficient in the treatment of penile deep dorsal venous leakage of ED. Zhang B, Chen J, Xiao H, Zhang Y, Cai L, Tao X, Qi T, and Ban D. Treatment of penile deep dorsal venous leakage of erectile dysfunction by embedding the deep dorsal vein of the penis: A single center experience with 17 patients. J Sex Med 2009;6:1467–1473.     

The Management of Erectile Dysfunction with Placebo Only: Does it Work?

IntroductionRandomized clinical trials (RCT) remain the gold standard in providing scientific evidence in medical practice in spite of the significant placebo effect in the treatment of several disorders. Although the first‐line therapy for erectile dysfunction (ED) is oral phosphodiesterase type‐5 inhibitor (iPDE5), the placebo effect in RCT of iPDE5 for ED occurs at a rate as high as 50%.AimsTo evaluate the role of therapeutic illusion in the oral treatment for ED.MethodsA prospective, controlled, single‐blind, parallel‐group study was performed at single‐center. One hundred and twenty‐three patients with ED were randomly assigned into three groups and received different letters: Group 1 (G1) was informed to be receiving a substance for ED treatment; Group 2 (G2) was informed that they could be receiving an active drug or placebo; Group 3 (G3) was conscious to be using placebo. Starch capsules were dispensed to all patients. Median follow up was 12 weeks.Main Outcome MeasuresED improvement was assessed after 8 weeks of the intervention by the erectile function domain of the International Index of Erectile Function (IIEF) and the Quality of Erection Questionnaire. ED severity was classified by the IIEF erectile function (IIEF‐EF) domain score into five categories: no ED (score of 26–30), mild (22–25), mild to moderate (17–21), moderate (11–16), and severe (6–10). Improvement in IIEF‐EF domain was considered as a change in category of severity.ResultsED severity improved in all three groups (G1 = 31.7%, P = 0.039; G2 = 36.8%, P = 0.028; G3 = 36.8%, P = 0.002) and no difference was found among groups (P = 0.857). Improvement of quality of erection score was only significant in G2 (P = 0.005) and G3 (P < 0.001).ConclusionsWritten‐suggested therapeutic illusion for patients with ED has no major influence in the outcomes. However, treatment of ED with oral placebo capsules demonstrates clinical effects, improving erectile function and quality of erection. de Araujo AC, da Silva FG, Salvi F, Awad MC, da Silva EA, and Damião R. The management of erectile dysfunction with placebo only: Does it work?     

Hypercholesterolemia-Induced Erectile Dysfunction: Endothelial Nitric Oxide Synthase (eNOS) Uncoupling in the Mouse Penis by NAD(P)H Oxidase

IntroductionHypercholesterolemia induces erectile dysfunction (ED) mostly by increasing oxidative stress and impairing endothelial function in the penis, but the mechanisms regulating reactive oxygen species (ROS) production in the penis are not understood.AimsWe evaluated whether hypercholesterolemia activates nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase in the penis, providing an initial source of ROS to induce endothelial nitric oxide synthase (eNOS) uncoupling and endothelial dysfunction resulting in ED.MethodsLow-density-lipoprotein receptor (LDLR)–null mice were fed Western diet for 4 weeks to induce early-stage hyperlipidemia. Wild type (WT) mice fed regular chow served as controls. Mice received NAD(P)H oxidase inhibitor apocynin (10 mM in drinking water) or vehicle. Erectile function was assessed in response to cavernous nerve electrical stimulation. Markers of endothelial function (phospho [P]-vasodilator-stimulated-protein [VASP]-Ser-239), oxidative stress (4-hydroxy-2-nonenal [HNE]), sources of ROS (eNOS uncoupling and NAD[P]H oxidase subunits p67^phox, p47^phox, and gp91^phox), P-eNOS-Ser-1177, and eNOS were measured by Western blot in penes.Main Outcome MeasuresThe main outcome measures are the molecular mechanisms of ROS generation and endothelial dysfunction in hypercholesterolemia-induced ED.ResultsErectile response was significantly (P < 0.05) reduced in hypercholesterolemic LDLR-null mice compared with WT mice. Relative to WT mice, hypercholesterolemia increased (P < 0.05) protein expressions of NAD(P)H oxidase subunits p67^phox, p47^phox and gp91^phox, eNOS uncoupling, and 4-HNE-modified proteins, and reduced (P < 0.05) P-VASP-Ser-239 expression in the penis. Apocynin treatment of LDLR-null mice preserved (P < 0.05) maximal intracavernosal pressure, and reversed (P < 0.05) the abnormalities in protein expressions of gp67^phox and gp47^phox, 4-HNE, P-VASP-Ser-239, and eNOS uncoupling in the penis. Apocynin treatment of WT mice did not affect any of these parameters. Protein expressions of P-eNOS-Ser-1177 and total eNOS were unaffected by hypercholesterolemia.ConclusionActivated NAD(P)H oxidase in the penis is an initial source of oxidative stress resulting in eNOS uncoupling, thus providing a mechanism of eNOS uncoupling and endothelial dysfunction in hypercholesterolemia-induced ED. Musicki B, Liu T, Lagoda GA, Strong TD, Sezen SF, Johnson JM, and Burnett AL. Hypercholesterolemia-induced erectile dysfunction: Endothelial nitric oxide synthase (eNOS) uncoupling in the mouse penis by NAD(P)H oxidase.     

FK506 neuroprotection after cavernous nerve injury is mediated by thioredoxin and glutathione redox systems

IntroductionImmunophilin ligands such as FK506 (FK) preserve erectile function (EF) following cavernous nerve injury (CNI), although the precise mechanisms are unclear. We examined whether the thioredoxin (Trx) and glutathione (GSH) redox systems mediate this effect after CNI.AimTo investigate the roles of Trx reductase 2 (TrxR2) and S‐Nitrosoglutathione reductase (GSNOR) as antioxidative/nitrosative and antiapoptotic mediators of the neuroprotective effect of FK in the penis after CNI.MethodsAdult male rats, wild‐type (WT) mice, and GSNOR deficient (GSNOR ‐/‐) mice were divided into four groups: sham surgery (CN [cavernous nerves] exposure only) + vehicle; sham surgery + FK (5 mg/kg/day/rat or 2 mg/kg/day/mouse, for 2 days, subcutaneous); CNI + vehicle; and CNI + FK. At day 4 after injury, electrically stimulated changes in intracavernosal pressure (ICP) were measured. Penises were collected for Western blot analysis of TrxR2, GSNOR, and Bcl‐2, and for immunolocalization of TrxR2 and GSNOR.Main Outcome MeasuresEF assessment represented by maximal ICP and total ICP in response to electrical stimulation. Evaluation of protein expression levels and distribution patterns of antioxidative/nitrosative and antiapoptotic factors in penile tissue.ResultsEF decreased after CNI compared with sham surgery values in both rats (P < 0.01) and WT and GSNOR ‐/‐ mice (P < 0.05). FK treatment preserved EF after CNI compared with vehicle treatment in rats (P < 0.01) and WT mice (P < 0.05) but not in GSNOR ‐/‐ mice. In rats, GSNOR (P < 0.01) and Bcl‐2 (P < 0.05) expressions were significantly decreased after CNI. FK treatment in CN‐injured rats restored expression of GSNOR and upregulated TrxR2 (P < 0.001) and Bcl‐2 (P < 0.001) expressions compared with vehicle treatment. Localizations of proteins in the penis were observed for TrxR2 (endothelium, smooth muscle) and for GSNOR (nerves, endothelium, smooth muscle).ConclusionsThe neuroprotective effect of FK in preserving EF after CNI involves antioxidative/nitrosative and antiapoptotic mechanisms mediated, to some extent, by Trx and GSH systems. Lagoda G, Xie Y, Sezen SF, Hurt KJ, Liu L, Musicki B, and Burnett AL. FK506 neuroprotection after cavernous nerve injury is mediated by thioredoxin and glutathione redox systems. J Sex Med **;**:**–**.