Platelet-rich Plasma for the Treatment of Erectile Dysfunction: A Prospective, Randomized, Double-blind, Placebo-controlled Clinical Trial.

PURPOSE: We assessed the safety and efficacy of 2 injections of platelet-rich plasma for treating mild to moderate erectile dysfunction by conducting a prospective, randomized, double-blind, placebo-controlled clinical trial. MATERIALS AND METHODS: Men with mild to moderate erectile dysfunction (International Index of Erectile Function scores 11-25) were randomized to receive either 2 injections of platelet-rich plasma or placebo separated by 1 month. Primary outcome was percentage of men meeting minimum clinically important difference at 1 month after the second injection. Secondary outcomes were change in International Index of Erectile Function at 1, 3, and 6 months, and changes in penile vascular parameters and adverse events at 6 months. RESULTS: We randomized 61 men: 28 into platelet-rich plasma and 33 into placebo. There was no difference between groups in percentage of men meeting minimum clinically important difference at 1 month: 14 (58.3%) in platelet-rich plasma vs 15 (53.6%) in placebo (P = .730). Mean International Index of Erectile Function-Erectile Function domain changed from 17.4 (95% CI 15.8-19.0) to 21 (17.9-24.0) at 1 month in men receiving platelet-rich plasma, vs 18.6 (17.3-19.8) to 21.6 (19.1-24.1) in the placebo group; however, there was no significant difference between groups (P = .756). There were no major adverse events and only 1 minor adverse event in each group. There were no changes in penile Doppler parameters from baseline to 6 months. CONCLUSIONS: The results of our prospective, double-blind, randomized, placebo-controlled clinical trial suggest that 2 injections of intracavernosal platelet-rich plasma separated by 1 month in men with mild to moderate erectile dysfunction is safe, but we found no difference in efficacy between platelet-rich plasma and placebo.

Platelet Rich Plasma (PRP) Growth Factor Concentration Varies in Men With Erectile Dysfunction.

BACKGROUND: Platelet Rich Plasma (PRP) is a novel therapy rich in growth factors and cytokines used to target the underlying causes of erectile dysfunction (ED). It is not known, however, if the composition of growth factors in PRP varies between men. AIM: To evaluate PRP growth factor variability among men with ED. METHODS: Whole blood was collected from 8 participants with at least a 6-month history of ED. Seven men with Peyronie's disease and 1 healthy male (without sexual dysfunction) were used as the control group. PRP was extracted from whole blood using the Arthrex Angel system. A Human Growth Factor Antibody Array for 41 proteins was performed using 3 participants and the healthy control. Using all 16 samples, quantitative detection of factors from the array that were decreased by 1.5-fold were validated with western blot. OUTCOMES: From the growth factor array, 2 growth factors-granulocyte-macrophage colony stimulating factor and transforming growth factor-ß were identified as having a 1.5-fold decrease between the participants and the control. Vascular endothelial growth factor (VEGF) was selected because androgens can upregulate VEGF production. Other than a weak negative correlation between VEGF expression and age, we found no correlation between growth factor expression for granulocyte-macrophage colony stimulating factor or transforming growth factor-ß and age, body mass index, or comorbidities. CLINICAL TRANSLATION: PRP growth factor concentration appears to vary among men with ED. PRP treatment for ED may need to be personalized for patients, depending on individual growth factor concentration. STRENGTHS AND LIMITATIONS: This study demonstrates the variability in PRP growth factors among men with ED. This is an important finding in the investigation of PRP as a restorative treatment option for men with ED. Our study, however, was limited by a small sample size. CONCLUSION: PRP growth factors vary among men with ED. Khodamoradi K, Dullea A, Golan R, et al. Platelet Rich Plasma (PRP) Growth Factor Concentration Varies in Men With Erectile Dysfunction. J Sex Med 2022;19:1488-1493.

Is tadalafil associated with decreased risk of major adverse cardiac events or venous thromboembolism in men with lower urinary tract symptoms?

PURPOSE: To evaluate the association of tadalafil, a phosphodiesterase-5 inhibitor (PDE5I), with major adverse cardiac events (MACE) or venous thromboembolism (VTE) in men with lower urinary tract symptoms (LUTS). METHODS: Data was obtained from the TriNetX Research Network, ICD-10 codes were used to identify men with LUTS, MACE, and VTE. In addition, demographic characteristics and use of tadalafil or alpha-blocker was evaluated. Then, unbalanced and balanced association analyses was performed to assess the relation between tadalafil and/or alpha-blocker use with MACE/VTE. RESULTS: After participant selection, analysis included 821,592 men that did not use an alpha blocker or tadalafil, 5,004 men that used tadalafil but no alpha blocker, 327,482 men that used an alpha blocker but no tadalafil, and 6,603 men that used both an alpha blocker and tadalafil. On balanced analysis, tadalafil was independently associated with a decreased risk of MACE/VTE within a 3-year time period (OR = 0.59, 95%CI 0.49-0.70, p < 0.0001). Among men with a history of alpha blocker use, tadalafil use was also independently associated with a decreased risk of MACE or VTE, both before and after controlling for potentially confounding variables (OR = 0.57, 95%CI: 0.50-0.66; p < 0.0001). CONCLUSIONS: In our study, tadalafil was associated with a decreased risk of MACE/VTE in men with LUTS with and without a history of alpha blocker use. It is time to perform further long-term prospective randomized studies to further analyze the cardiovascular effects of PDE5Is as combination treatment with alpha blockers in the management of LUTS.

Analysis of the growing public interest in selective androgen receptor modulators.

To characterise trends and interest in selective androgen receptor modulators (SARMs). SARMs are androgen receptor ligands that bind androgen receptors selectively. SARMs have anabolic effects on muscle and bone and were originally synthesised for treatment of muscle wasting conditions, osteoporosis and breast cancer. To date, no SARM has been clinically approved and little is known about their beneficial effects and other adverse effects on users. We examined Google Trend searches of SARMs. Using Google Trends, we analysed how interest in SARMs has evolved over the last 15 years and compared it to trends in testosterone. Comparing 'TRT', 'SARMs' and 'Low Testosterone' together, we see low search interest in SARMs compared to TRT until February 2018, when the interest in both SARMs and TRT terms appear to be the same. Since February 2018, search interest for SARMs has surpassed search interest for both 'TRT' and 'Low Testosterone'. Trends for SARMs demonstrate a continuous increase over the years which has to date surpassed interest for both 'TRT' and 'low testosterone'. The rising interest in SARMs is concerning as the adverse effects of its usage, including its potential effects on fertility, have not been explored. Further investigation is necessary.

Effect of Natesto on Reproductive Hormones, Semen Parameters and Hypogonadal Symptoms: A Single Center, Open Label, Single Arm Trial.

PURPOSE: To evaluate the effect of short-acting 4.5% nasal testosterone gel (Natesto) on serum testosterone, gonadotropins, total motile sperm count, health related quality of life and sexual function. MATERIALS AND METHODS: This was a single institution, open label, single arm trial conducted between November 2017 and September 2019 at the University of Miami. Men 18 to 55 years old diagnosed with symptomatic hypogonadism (total testosterone less than 300 ng/dl on 2 occasions) were included. Men with azoospermia, vasectomy or a total motile sperm count less than 5 million were excluded. Enrolled patients were treated with Natesto, a short-acting nasal testosterone (125 µl per nostril, 11.0 mg testosterone per dose, TID) for 6 months. RESULTS: In total, 60 men were enrolled in the study. Of these, 44 and 33 patients were evaluated for testosterone at 3 and 6 months, respectively. A total of 31 patients (90.9%) reached a normal testosterone level (greater than 300 ng/dl) at 6 months. Follicle stimulating hormone and luteinizing hormone levels were maintained within the normal range in 81.8% and 72.7% of patients at 6 months, respectively. Total motile sperm count was maintained with total motile sperm count greater than 5 million over the treatment period in 88.4% of men at 3 months and 93.9% at 6 months. There were statistically significant improvements on International Index of Erectile Function sexual desire and overall satisfaction domains at 6 months. CONCLUSIONS: Natesto appears to increase testosterone while maintaining semen parameters in a majority of men. Natesto has the potential to be a safe and effective treatment for men with functional hypogonadism who wish to preserve semen parameters. Long-term studies beyond 6 months are needed before we can safely prescribe nasal testosterone gel for men interested in fertility.

Using Artificial Intelligence to Predict Surgical Shunts in Men with Ischemic Priapism.

PURPOSE: Ischemic priapism is a urological emergency that requires prompt intervention to preserve erectile function. Characteristics that influence escalation to surgical intervention remain unclear. We identified factors and developed machine learning models to predict which men presenting with ischemic priapism will require shunting. MATERIALS AND METHODS: We identified men with ischemic priapism admitted to the emergency department of our large county hospital between January 2010 and June 2019. We collected patient demographics, etiology, duration of priapism prior to intervention, interventions attempted and escalation to shunting. Machine learning models were trained and tested using R to predict which patients require surgical shunting. RESULTS: A total of 334 encounters of ischemic priapism were identified. The majority resolved with intracavernosal phenylephrine injection and/or cavernous aspiration (78%). Shunting was required in 10% of men. Median duration of priapism before intervention was longer for men requiring shunting than for men who did not (48 vs 7 hours, p=0.030). Patients with sickle cell disease as the etiology were less likely to require shunting compared to all other etiologies (2.2% vs 15.2%, p=0.035). CONCLUSIONS: Men with longer duration of priapism before treatment more often underwent shunting. However, phenylephrine injection and aspiration remained effective for priapism lasting more than 36 hours. Having sickle cell disease as the etiology of priapism was protective against requiring shunting. We developed artificial intelligence models that performed with 87.2% accuracy and created an online probability calculator to determine which patients with ischemic priapism may require shunting.

Characteristics predictive of response to collagenase clostridium histolyticum for Peyronie's disease: a review of the literature.

PURPOSE: To evaluate characteristics predictive of successful treatment outcomes of Peyronie's disease (PD) with collagenase clostridium histolyticum (CCH) METHODS: CCH is the only FDA-approved medication for treating PD. We reviewed the literature that addresses pre-treatment clinical characteristics that may predict favorable response to CCH therapy. RESULTS: Despite significant heterogeneity in reporting treatment success, we identified four well-studied characteristics that may be predictive of favorable response to CCH therapy: baseline penile curvature, baseline IIEF, duration of PD, and presence of calcification. CCH demonstrated a favorable response in those with pre-treatment curvature 30°-60°, longer duration of disease, mild to moderate baseline sexual function, and low calcification within plaques. Of all factors, calcification is emerging as the most significant factor likely because CCH is unable to degrade the calcified plaques. There is difficulty interpreting results because of differences in reporting outcomes. Some studies compared treatment groups to placebo, others reported changes in curvature, while others reported > 20% curvature correction as treatment success. Additionally, not all studies reported outcomes after completion of four cycles of CCH, and recent studies utilized a shortened, high dose, modified protocol. CONCLUSIONS: The ideal candidate for CCH therapy remains elusive. Based on the available literature, the man with PD who will have the greatest chance of curvature improvement will have curvature between 30° and 60°, longer duration of disease, an IIEF > 17, no calcification, and set to receive all four cycles. For a greater understanding of CCH treatment success in PD, prospectively collected registry reporting standardized outcomes are needed.

The role of imaging in the diagnosis and management of Peyronie's disease.

PURPOSE OF REVIEW: Several imaging modalities exist for the assessment of Peyronie's disease. However, comprehensive recommendations for using these objective modalities based on large-scale evidence-based studies do not yet exist. Our objective is to evaluate current imaging techniques and provide a model that we follow in our clinic in the workup and management of Peyronie's disease. RECENT FINDINGS: Computed tomography and radiography excellently visualize penile plaque calcifications, and MRI adeptly identifies plaques in complex locations, such as the corporal septum. Ultrasonography has extensive applications in plaque localization and characterization. Used along with color Doppler ultrasound, it is capable of detecting vascular abnormalities. Sonoelastography is an emerging subtype of ultrasongraphy that utilizes elastic properties of tissue to identify penile plaques that may not be visualized with other modalities. SUMMARY: Ultrasonography is the preferred imaging modality in Peyronie's disease and noninvasively characterizes penile plaques and monitors plaque response to various treatments. At our center, we perform ultrasonography with intracavernosal injection in all patients with Peyronie's disease to evaluate the degree of curvature, plaque characteristics, and concomitant erectile dysfunction to better guide management decisions.

A clinical algorithm for management of fertility in adolescents with the Klinefelter syndrome.

PURPOSE OF REVIEW: The review presents a clinical algorithm for the evaluation and treatment for adolescents with Klinefelter's syndrome who desire fertility preservation. RECENT FINDINGS: Sperm is present in the ejaculate in around 8% of men with Klinefelter's syndrome. Although most are severely oligospermic/azoospermic, 43-45% of men will have sperm found during a testicular sperm extraction, reaching up to 70% in adolescents. SUMMARY: Klinefelter's syndrome (47, XXY) causes hypogonadotophic hypogonadism and severe oligospermia/azoospermia rendering natural conception rare. During puberty, boys often require testosterone replacement therapy to develop secondary sexual characteristics, which can further decrease spermatogenesis. There is a progressive decrease of testicular germ cells after the onset of puberty, suggesting that fertility evaluation and preservation should begin shortly thereafter. In adolescents desiring fertility evaluation, any testosterone therapy should be discontinued, hormones and gonadotrophins measured, and a semen analysis obtained. Adolescents with low testosterone are administered aromatase inhibitors, selective estrogen receptors modulators and/or human chorionic gonadotropin to increase endogenous testosterone production. After testosterone levels are normalized, semen analysis is performed, and cryopreservation encouraged if sperm is present. For those without sperm in the ejaculate, a testicular sperm extraction is offered.

S-Nitrosoglutathione Reductase (GSNOR) Deficiency Results in Secondary Hypogonadism.

BACKGROUND: Excess reactive oxygen species and reactive nitrogen species are implicated in male infertility and impaired spermatogenesis. AIM: To investigate the effect of excess reactive nitrogen species and nitrosative stress on testicular function and the hypothalamic-pituitary-gonadal axis using the S-nitrosoglutathione reductase-null (Gsnor-/-) mouse model. METHODS: Testis size, pup number, and epididymal sperm concentration and motility of Gsnor-/- mice were compared with those of age-matched wild-type (WT) mice. Reproductive hormones testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone were compared in Gsnor-/- and WT mice. Immunofluorescence for Gsnor-/- and WT testis was performed for 3ß-hydroxysteroid dehydrogenase and luteinizing hormone receptor (LHR) and compared. Human chorionic gonadotropin and gonadotropin-releasing hormone stimulation tests were performed to assess and compare testicular and pituitary functions of Gsnor-/- and WT mice. OUTCOMES: Evaluation of fertility and reproductive hormones in Gsnor-/- vs WT mice. Response of Gsnor-/- and WT mice to human chorionic gonadotropin and gonadotropin-releasing hormone to evaluate LH and T production. RESULTS: Gsnor-/- mice had smaller litters (4.2 vs 8.0 pups per litter; P < .01), smaller testes (0.08 vs 0.09 g; P < .01), and decreased epididymal sperm concentration (69 vs 98 × 106; P < .05) and motility (39% vs 65%; P < .05) compared with WT mice. Serum T (44.8 vs 292.2 ng/dL; P < .05) and LH (0.03 vs 0.74 ng/mL; P = .04) were lower in Gsnor-/- than in WT mice despite similar follicle-stimulating hormone levels (63.98 vs 77.93 ng/mL; P = .20). Immunofluorescence of Gsnor-/- and WT testes showed similar staining of 3ß-hydroxysteroid dehydrogenase and LHR. Human chorionic gonadotropin stimulation of Gsnor-/- mice increased serum T (>1,680 vs >1,680 ng/dL) and gonadotropin-releasing hormone stimulation increased serum LH (6.3 vs 8.9 ng/mL; P = .20) similar to WT mice. CLINICAL TRANSLATION: These findings provide novel insight to a possible mechanism of secondary hypogonadism from increased reactive nitrogen species and excess nitrosative stress. STRENGTHS AND LIMITATIONS: Limitations of this study are its small samples and variability in hormone levels. CONCLUSION: Deficiency of S-nitrosoglutathione reductase results in secondary hypogonadism, suggesting that excess nitrosative stress can affect LH production from the pituitary gland. Masterson TA, Arora H, Kulandavelu S, et al. S-Nitrosoglutathione Reductase (GSNOR) Deficiency Results in Secondary Hypogonadism. J Sex Med 2018;15:654-661.

Risk Factors for Penile Fracture After Intralesional Collagenase Clostridium histolyticum in Peyronie's Disease.

OBJECTIVE: To evaluate risk factors leading to corporal rupture after Collagenase Clostridium histolyticum (CCh). Peyronie's disease (PD) is a fibrotic condition of the penis characterized by abnormal plaque formation. Intralesional CCh is the only FDA-approved medication for PD, however, it can lead to corporal rupture, a potential surgical emergency. METHODS: We retrospectively reviewed medical records from Veterans diagnosed with PD who were under treatment with CCh using the Veterans Administration Informatics and Computing Infrastructure (VINCI). Using International Classification of Diseases and Current Procedural Terminology codes, we identified men who suffered a corporal rupture after CCh. Individual charts were reviewed to determine potential risk factors and events leading to corporal rupture. RESULTS: We identified 17,647 veterans who were diagnosed with PD, of which 8.7% (1541) received at least one injection of CCh for PD. Of them, 0.7% (11/1541) veterans suffered corporal rupture. Within these 11 patients, the median number of CCH injections was 6 with a median initial curvature of 35°. Fracture occurred at a median of 8days after CCH injection. The majority of fractures were secondary to spontaneous erections or sexual intercourse. Finally, six patients had their fracture repaired surgically while the remaining were managed conservatively. CONCLUSION: Most fractures occurred within 2weeks of CCh injections and were associated with sexual intercourse and spontaneous morning erections.

Eosinophilic cystitis mimicking bladder tumor: A case report.

Eosinophilic cystitis (EC) is a rare inflammatory condition characterized by eosinophilic infiltration into the bladder wall. It often presents symptoms common to urological issues such as urinary tract infections, hematuria, bladder stones, or bladder neoplasms. Here, we describe a case of a 44-year-old male veteran with a history of multiple tuberculosis episodes who presented to the Emergency Department with dysuria, suprapubic pain, and gross hematuria. Initial imaging and cystoscopy concerned bladder neoplasia; however, subsequent pathological evaluation showed EC. This case underscores the importance of considering EC in the differential diagnosis of bladder tumors, especially when imaging describes bladder wall thickening in a patient without risk factors for bladder malignancy.

Restorative therapy clinical trials for erectile dysfunction: a scoping review of endpoint measures.

Given the lack of regulatory approval for restorative therapies for the treatment of erectile dysfunction, we hypothesized that clinical trials would vary in methodology and endpoint measurements. Our objective was to analyze methodological approaches and outcome measures of clinical trials evaluating restorative therapies for erectile dysfunction. Data was extracted from clinicaltrials.gov on trials which contained the keywords "erectile dysfunction". We evaluated trials initiated between 2004 and 2021 which listed a restorative therapy intervention. We identified 95 trials investigating energy-based/shockwave therapies (60/95), stem cell therapies (25/95), platelet-based therapies (6/95), and others (4/95). Only 41.1% of the trials evaluated safety. The most common efficacy endpoint was International Index of Erectile Function and Sexual Health Inventory for Men, and only 29.5% utilized penile Doppler. Thirty (31.6%) trials had been completed yet only 3 (3.2%) have published results. We found substantial heterogeneity in methodological approach in the trials. Subjective measures of erectile function were commonly reported, but definitions of inclusion criteria and objective outcome measures were inconsistent. These results provide a basis for the design of future clinical trials to improve the quality of trial data and aid in the development of standardized criteria for erectile dysfunction clinical trials.

Rationale and Design for the COCKTAIL Trial: A Single-center, Randomized, Double-blind, Sham-controlled Study Combining Shockwave Therapy and Platelet-rich Plasma for Erectile Dysfunction.

Restorative therapies are a promising option for the treatment of erectile dysfunction. Several studies have assessed platelet-rich plasma and shockwave therapy alone. However, COCKTAIL is the first study to evaluate the synergistic effects of these two therapies in combination.