Technological Advancements for Treating Erectile Dysfunction and Peyronie's Disease.

Over the past decade, there have been several advancements in the technologies available to treatment erectile dysfunction and Peyronie's disease. Vacuum erection devices, penile traction devices, low-intensity extracorporeal shockwave therapy, and penile prosthesis surgery have evolved and are changing the way we treat men's health. Although significant improvements have been made, further work is needed to standardize treatment, create universal algorithms for technological applications, and simply their use.

Chronic pain associated with penile prostheses may persist despite revision or explantation.

INTRODUCTION: Inflatable penile prosthesis (IPP) implantation is the gold standard treatment for medically refractory erectile dysfunction. New chronic pain after IPP implantation is rarely discussed and the optimal treatment is unclear. We evaluated whether IPP re-operation for a primary indication of chronic pain improves patients' symptoms. Our secondary aim was to explore factors associated with resolution or persistence of pain after IPP reoperation. METHODS: We conducted a retrospective analysis of 315 patients who had an IPP revision or explantation at two high-volume prosthetic centers between May 2007 and May 2017. We excluded patients who had device malfunction, pain for <2 months, pain associated with infection or erosion, and patients without long-term followup data. Persistent pain was diagnosed based on patient self-report. RESULTS: A total of 31 patients met our criteria for having undergone a surgical revision (n=18) or explantation (n=13) for pain relief. Eighteen (58%) patients had persistent pain despite surgical intervention. Only patients who had pain secondary to a device malposition improved after re-operation (n=13). A prior diagnosis of a chronic pain syndrome was associated with persistent pain despite intervention. Pain improvement was not associated with age, comorbid conditions, duration of implant, or the number of surgical revisions performed. CONCLUSIONS: Surgical intervention for chronic penile prosthesis pain is unlikely to relieve symptoms, particularly for patients with chronic pain disorders. Patients should be counselled that IPP reoperative procedures as a treatment for pain should be avoided unless the device is identified to be malpositioned, and consideration of alternative therapeutic options may be more beneficial.

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.

BACKGROUND: Erectile 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. AIM: The 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). METHODS: Seventy 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. OUTCOMES: Gene 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. RESULTS: BCNI 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 TRANSLATION: TNF-α inhibition may prevent ED after prostatectomy. STRENGTH/LIMITATIONS: TNF-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. CONCLUSIONS: TNF-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.

Effect of Erythropoietin on Erectile Function after Radical Prostatectomy: The ERECT Randomized Clinical Trial.

PURPOSE: Erectile dysfunction significantly impacts quality of life for men undergoing radical prostatectomy for prostate cancer. Erythropoietin is a promising neurotrophic factor for neurogenic erectile dysfunction based on preclinical and retrospective data. MATERIALS AND METHODS: ERECT (NCT00737893) is a phase 2, double-blinded, randomized, placebo-controlled trial (July 2017-December 2019) evaluating the impact of perioperative erythropoietin on recovery of erectile function and other patient-reported, health-related quality of life outcomes after bilateral nerve-sparing radical prostatectomy (3, 6, 9, and 12 months). Erythropoietin (20,000 units) or saline placebo was injected subcutaneously the day before, day of, and day after surgery for 3 total doses. RESULTS: Of 63 patients assessed for eligibility, 56 patients were randomized. Arms (29 erythropoietin, 27 placebo) were well balanced (89.3% robotic, median age 55.5 years). International Index of Erectile Function-Erectile Function Domain (IIEF-EF) scores increased from median 12.5 at 3 months to 24.5 at 12 months. Median 2-week serum hemoglobin was higher for the erythropoietin arm compared to placebo (14.7 vs 13.6, p=0.02). There was no statistically significant difference in IIEF-EF scores at 6 months comparing erythropoietin to placebo (p=0.50) or at other time points (mixed model regression coefficient: -1.7, 95% CI -6.1-2.7, p=0.45). Excellent nerve-sparing rating (10/10) was associated with improved IIEF-EF recovery (+5.2, p=0.022). Other patient-reported, health-related quality of life domains as well as oncologic outcome and complications were similar between arms during followup. CONCLUSIONS: In the context of brief perioperative dosing, erythropoietin did not improve recovery of erectile function for men undergoing radical prostatectomy for prostate cancer compared to placebo. Further research to identify effective adjuncts to improve health-related quality of life for these men is needed.

Immediate preoperative blood glucose and hemoglobin a1c levels are not predictive of postoperative infections in diabetic men undergoing penile prosthesis placement.

Defining the risks associated with diabetes mellitus in patients undergoing penile prosthesis implantation remains controversial. Our study aims to assess whether preoperative hemoglobin a1c and preoperative blood glucose levels are associated with an increased risk for postoperative infection in diabetic men. We performed a retrospective review of 932 diabetic patients undergoing primary penile prosthesis implantation from 18 high-volume penile prosthesis implantation surgeons throughout the United States, Germany, Belgium, and South Korea. Preoperative hemoglobin a1c and blood glucose levels within 6 h of surgery were collected and assessed in univariate and multivariate models for correlation with postoperative infection, revision, and explantation rates. The primary outcome is postoperative infection and the secondary outcomes are postoperative revision and explantation. In all, 875 patients were included in the final analysis. There were no associations between preoperative blood glucose levels or hemoglobin a1c levels and postoperative infection rates; p = 0.220 and p = 0.598, respectively. On multivariate analysis, a history of diabetes-related complications was a significant predictor of higher revision rates (p = 0.034), but was nonsignificant for infection or explantation rates. We conclude preoperative blood glucose levels and hemoglobin a1c levels are not associated with an increased risk for postoperative infection, revision, or explantation in diabetic men undergoing penile prosthesis implantation.

Impact of Antimicrobial Dipping Solutions on Postoperative Infection Rates in Patients With Diabetes Undergoing Primary Insertion of a Coloplast Titan Inflatable Penile Prosthesis.

BACKGROUND: Modern-day penile prostheses use infection retardant coating to decrease rates of postoperative infection, subsequently reducing explantation and revision rates as well. The Coloplast Titan models are dipped into antimicrobial solutions right before implantation, and the components used for dipping can be tailored toward the patient. AIM: To compare infection, explantation, and revision rates among different dipping solutions used before implantation for patients with diabetes receiving a Coloplast Titan implant. METHODS: We systematically reviewed 932 patients with diabetes receiving a primary penile implant across 18 different centers from the period April 2003 to August 2018. Of those patients, 473 received a Coloplast device, whereas 459 received an AMS device. Data regarding the type of antimicrobial solution used before implantation were recorded for 468 patients receiving a Coloplast Titan, including whether or not they suffered a postoperative infection and if they underwent explantation and/or revision. Outcome rates were compared using Fisher's exact and Pearson's chi-square tests, and logistic regression modeling was performed to account for covariates. OUTCOMES: The main outcome measures of this study were postoperative infection, explantation, and revision rates. RESULTS: Of the total 932 patients reviewed, 33 suffered a postoperative infection. Of 468 patients receiving Coloplast implants, there was a 3.4% infection rate. The most commonly used antibiotic combination before dipping was vancomycin + gentamicin (59.0%). There was a significantly lower rate of postoperative infection, explantation, and revision when vancomycin + gentamicin was used than those associated with the use of all other dipping solutions ([1.4% vs 6.4%; P = .004], [1.1% vs 8.3%; P < .001], and [2.5% vs 12.5; P < .001], respectively). After adjusting for age, body mass index, preoperative blood glucose level, and hemoglobin A1c, the use of other dips was an independent predictor of postoperative infection (odds ratio: 0.191; P = .049). The inclusion of rifampin in the dipping solution trended toward being a significant risk factor for infection (P = .057). Including antifungals in the dipping solution did not affect infection (P = .414), explantation (P = .421), or revision (P = .328) rates. CLINICAL IMPLICATIONS: Vancomycin + gentamicin was the most efficacious combination of antibiotics used for dipping in terms of preventing postoperative infection and subsequent explantation and revision. STRENGTHS AND LIMITATIONS: Data were sampled across multiple institutions providing a large sample that may be more representative of the population of interest. A key limitation of the study was its retrospective nature, which prevented us from controlling certain variables. CONCLUSION: The use of rifampin did not provide the same type of protection, possibly representing a shift in resistance patterns of common bacteria responsible for device infection. Towe M, Huynh LM, Osman MM, et al. Impact of Antimicrobial Dipping Solutions on Postoperative Infection Rates in Patients With Diabetes Undergoing Primary Insertion of a Coloplast Titan Inflatable Penile Prosthesis. J Sex Med 2020;17:2077-2083.

The good, bad, and the ugly of regenerative therapies for erectile dysfunction.

Erectile dysfunction (ED) is a common condition which reduces quality of life of both patients and their partners, and is a significant health care expense every year. Although phosphodiesterase type-5 inhibitors are the current first-line treatment for men with ED, they are limited by their on-demand dosing, intolerance, and variable efficacy in complex patient populations such as men with multiple medical comorbidities or ED after pelvic surgery. Regenerative medicine has been introduced and investigated in andrology as an encouraging strategy to restore diseased erectile tissue structure and function. Novel regenerative therapies for ED are controversial but are perceived to offer a durable and safe tissue restorative approach to act as a long-term solution to this cumbersome disease process. Here, we review platelet-rich plasma, amniotic fluid membranes, low-intensity extracorporeal shockwave therapy, and stem cell therapy as regenerative strategies to treat ED. Most of these approaches have preclinical and occasionally clinical data to support their ongoing investigation; however, none of these treatments are currently supported for use in ED patients outside of clinical trials.

Dysregulated NO/PDE5 signaling in the sickle cell mouse lower urinary tract: Reversal by oral nitrate therapy.

AIMS: Nitric oxide (NO) has a critical, but not well understood, influence in the physiology of the lower urinary tract. We evaluated the effect of NO/phosphodiesterase (PDE)5 signaling in voiding dysfunction in the sickle cell disease (SCD) mouse, characterized by low NO bioavailability. MAIN METHODS: Adult SCD (Sickle) and wild-type (WT) male mice were treated daily with sodium nitrate (10 mM) or vehicle. After 18 days, blood was obtained for nitrite measurement, urethra was collected for organ bath study, and bladder and urethra were collected for Western blot analysis of PDE5 phosphorylation (Ser-92) (activated form). Non-anesthetized mice underwent evaluation of urine volume by void spot assay. eNOS phosphorylation (Ser-1177) and nNOS phosphorylation (Ser-1412) (positive regulatory sites) were evaluated in the bladder and urethra of untreated mice. KEY FINDINGS: Sickle mice exhibited decreased eNOS, nNOS, and PDE5 phosphorylation in the bladder and urethra, decreased plasma nitrite levels, increased relaxation of phenylephrine-contracted urethral tissue to an NO donor sodium nitroprusside, and increased total urine volume, compared with WT mice. Nitrate treatment normalized plasma nitrite levels, relaxation of urethra to sodium nitroprusside, PDE5 phosphorylation in the urethra and bladder, and urine volume in Sickle mice. SIGNIFICANCE: Derangement in PDE5 activity associated with basally low NO bioavailability in the bladder and urethra contributes to the molecular basis for voiding abnormalities in Sickle mice. Inorganic nitrate supplementation normalized voiding in Sickle mice through mechanisms likely involving upregulation of PDE5 activity. These findings suggest that interventions targeting dysregulatory NO/PDE5 signaling may ameliorate overactive bladder in SCD.

Meta-analysis of randomized controlled trials that assess the efficacy of low-intensity shockwave therapy for the treatment of erectile dysfunction.

BACKGROUND: The aim of this study was to perform a meta-analysis of randomized controlled trials (RCTs) that evaluate the efficacy of low-intensity extracorporeal shock wave therapy (LiESWT) for the treatment of erectile dysfunction (ED). MATERIALS AND METHODS: A comprehensive search of PubMed, Medline, and Cochrane databases was performed from November 2005 to July 2018. RCTs evaluating efficacy of LiESWT in the treatment of ED were selected. The primary outcomes were the mean difference between treatment and sham patients in the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score 1 month after treatment, and the mean change in IIEF-EF from baseline to 1 month post-treatment. The secondary analysis considered the percentage of men whose erectile hardness score (EHS) changed from <2 at baseline to >3 after treatment. All analyses used a random effects method to pool study-specific results. RESULTS: A total of seven RCTs provided data for 607 patients. The mean IIEF-EF 1 month post-treatment ranged from 12.8 to 22.0 in the treatment group versus 8.17-16.43 in the sham group. The mean difference between the treatment and sham groups at the 1 month follow up was a statistically significant increase in IIEF-EF of 4.23 (p = 0.012). Overall, five of the seven trials provided data on the proportion of patients with baseline EHS <2 who improved to EHS >3 at 1 month post-treatment. The proportions ranged from 3.5 to 90% in the treatment group versus 0-9% in the sham group and the pooled relative risk of EHS improvement for the treated versus sham group was 6.63 (p = 0.0095). No significant adverse events were reported. CONCLUSIONS: This is the first meta-analysis that evaluates RCTs exploring LiESWT as a treatment modality strictly for ED. This therapeutic strategy appears to be well tolerated with short-term benefits. However further studies exploring specific treatment regimens and long-term outcomes are needed.

Hydro-Jet Dissection of the Cavernous Nerves Preserves Erection Function in a Radical Prostatectomy Animal Model.

BACKGROUND: Postoperative erectile dysfunction (ED) remains a prevalent consequence of radical prostatectomy (RP) that significantly impacts patient quality of life. Water-jet technology is widely used for dissection in neurosurgical procedures but novel to urologic surgery. AIM: To establish the impact of hydro-jet dissection (HJD) of the cavernous nerves (CN) on postoperative erectile function in an animal model of RP-induced ED. METHODS: 32 male Sprague-Dawley rats were randomized to 4 groups: Sham surgery (n = 8), bilateral HJD of CN (n = 8), blunt CN injury (n = 8), or stretch CN injury (n = 8). After 4 weeks, erectile function was assessed by measuring intracavernous pressure (ICP), and penile tissues were harvested for immunohistologic studies. MAIN OUTCOME MEASURE: The peak ICP and the area under the curve were calculated for each group. Immunohistologic studies were performed for α-smooth muscle actin and neuronal nitric oxide synthase on cross-sections of penile tissue. RESULTS: Rats in the HJD group demonstrate a significantly higher mean peak ICP and area under the curve compared with both CN injury groups (P = .001). Postoperative erectile function in the HJD group returned to baseline function. Preservation of α-smooth muscle actin and neuronal nitric oxide synthase was observed in the HJD group compared with the other surgical trauma groups. CLINICAL IMPLICATIONS: Hydro-jet dissection used in an RP animal model maintains erectile function and offers a potential benefit that warrants further human studies. STRENGTHS & LIMITATIONS: This is a novel animal study comparing a new technology to established CN dissection techniques. This study uses an animal model, which may not completely translate to post-RP ED in humans. CONCLUSION: Hydro-jet dissection of the CN during RP in an animal model is associated with significantly better postoperative erectile function when compared with other CN injury. Clinical studies are needed to further investigate the putative benefit of HJD on erectile function in patients undergoing RP. Campbell JD, Alenezi H, DeYoung LX, et al. Hydrojet Dissection of the Cavernous Nerves Preserves Erection Function in a Radical Prostatectomy Animal Model. Sex Med 2019;7:104-110.

Shifting the Paradigm of Testosterone Replacement Therapy in Prostate Cancer.

Historically, testosterone and prostate cancer have been demonstrated to have a positive association leading providers to forgo testosterone replacement therapy (TRT) in men with concurrent histories of hypogonadism and prostate cancer. This paradigm has been gradually shifting with our evolving understanding of the relationship between testosterone and prostate cancer and the gaining popularity of the saturation model. Newer data suggests improved quality of life for men with hypogonadism after TRT leading to a more tempered view of the effects of this treatment and its risk in prostate cancer. As more reports emerge of TRT in men who have either undergone definitive treatment for prostate cancer or are on active surveillance, some providers see a role for TRT in these patients despite non-consensus in clinical guidelines. It is critical that we examine evidence currently available, while we await more rigorous data to emerge.

Surgical Factors Associated With Male and Female Sexual Dysfunction After Radical Cystectomy: What Do We Know and How Can We Improve Outcomes?

BACKGROUND: Sexual dysfunction after radical cystectomy (RC) is a frequent, though commonly overlooked symptom for both men and women. Improved oncological outcomes and the rising number of bladder cancer survivors mandate physicians to closely address and evaluate post-surgical sexual dysfunction and offer goal-directed treatment. Improvements in RC surgical techniques that promote post-operative sexual function have been proposed, alongside new quality-of-life inventories and sexual function therapeutic options; however, rigorous studies in the field are lacking. AIM: To provide a comprehensive overview of post-RC sexual dysfunction and discuss new surgical techniques, sexual dysfunction evaluation, and novel treatment strategies. METHODS: A non-systematic narrative review of the literature was performed through PubMed about sexual dysfunction in men and women after RC. OUTCOMES: We reported on the surgical anatomy of sexual function-sparing RC, the most common inventories used to investigate sexual function in post-RC patients, and current treatment options. RESULTS: Extensive knowledge about pelvic anatomy and nerve-sparing surgical techniques in men is well understood from studies about prostate anatomy and nerve-sparing prostatectomy. However, anatomical and surgical details of sexual-sparing RC in women needs further characterization. Several questionnaires are used to investigate sexuality after RC, but a standardized approach is still missing. Therapeutic options are available to treat sexual dysfunction, but limited studies have been conducted to specifically address the post-RC population. CONCLUSION: Further work is needed to understand the best strategies to prevent and treat sexual dysfunction in patients after RC. Pederzoli F, Campbell JD, Matsui H, et al. Surgical Factors Associated With Male and Female Sexual Dysfunction After Radical Cystectomy: What Do We Know and How Can We Improve Outcomes? Sex Med Rev 2018;6:469-481.

Neuroprotective and Nerve Regenerative Approaches for Treatment of Erectile Dysfunction after Cavernous Nerve Injury.

Erectile dysfunction (ED) is a significant cause of reduced quality of life in men and their partners. Cavernous nerve injury (CNI) during pelvic surgery results in ED in greater than 50% of patients, regardless of additional patient factors. ED related to CNI is difficult to treat and typically poorly responsive to first- and second-line therapeutic options. Recently, a significant amount of research has been devoted to exploring neuroprotective and neuroregenerative approaches to salvage erectile function in patients with CNI. In addition, therapeutic options such as neuregulins, immunophilin ligands, gene therapy, stem cell therapy and novel surgical strategies, have shown benefit in pre-clinical, and limited clinical studies. In the era of personalized medicine, these new therapeutic technologies will be the future of ED treatment and are described in this review.