Ahmet Gokce

PDE5 inhibitors: considerations for preference and long‐term adherence

Introduction:  Erectile dysfunction (ED) is a highly prevalent condition affecting nearly one in five men worldwide. The advent of phosphodiesterase type 5 inhibitors (PDE5i) has revolutionised the ED treatment landscape and provided effective, minimally invasive therapies to restore male sexual function.

Long‐Term Revision Rate due to Infection in Hydrophilic‐Coated Inflatable Penile Prostheses: 11‐Year Follow‐up

INTRODUCTION Penile implant surgery continues to be an important option for men with erectile dysfunction. Advancements in technology of implants have contributed to improved survival from mechanical breakdown. Prosthesis infection remains a serious adverse event. For the last 8 years, the Titan implant (Coloplast Corporation, Minneapolis, MN, USA) has been available with an infection-retardant polyvinylpyrrolidone coating. AIM To compare the infection rates between coated three-piece inflatable penile prostheses (IPPs) with the previous non-coated model. MAIN OUTCOME MEASURES Infection-related revisions reported in the physician-generated, manufacturer-tabulated patient information forms (PIFs). METHODS PIFs reported into the voluntary, post-market registry of Coloplast Corporation from July 14, 2000 to September 30, 2011 were retrospectively reviewed. Infection-related revisions entered into the product evaluation database for coated and non-coated IPPs were compared. Data were analyzed using Pearsons chi-squared test. RESULTS The database included 36,391 PIFs related to primary IPP implantation. At 11 years of follow-up, 4.6% (7,031) of non-coated IPPs were removed or replaced due to infections, whereas 1.4% (29,360) of hydrophilic-coated implants reported replacements due to device infections. The hydrophilic coating of the IPP components makes the device slippery and prevents bacterial attachment. The hydrophilic coating allows rapid absorption of antibiotics in an aqueous solution and allows these water-soluble antibiotics to elute off the device into the implant spaces. Unfortunately, information pertaining to what agents were used in the studies patients was not tabulated. The rate of revision due to device infection was reduced 69.56% in patients with hydrophilic-coated IPPs (P<0.001). CONCLUSION To the best of our knowledge, this is the longest post-marketing registry report related to IPP infections. At 8 years of follow-up, the hydrophilic-coated IPPs demonstrated a significant reduction in revision rates due to infection when compared with the 11-year follow-up of non-coated implants. Since there was no information or uniformity of antibiotics used in the soaking solution, it is uncertain which antibiotic selection provided the best results. In vitro testing against known infectious agents may further benefit IPP patients by reducing the prosthesis infection rate.

Adipose tissue–derived stem cell therapy for prevention and treatment of erectile dysfunction in a rat model of Peyronie's disease

Peyronies disease (PD) is a localized connective tissue disorder that involves the tunica albuginea (TA) of the penis. While surgical correction remains the gold standard, the search for an effective and less invasive therapy continues. The objective of this study was to evaluate the effects of intratunical injection of adipose tissue–derived stem cells (ADSCs) for the prevention and treatment of erectile dysfunction in a rat model of PD. Twenty‐four male Sprague–Dawley rats (300–350 g) were randomly divided into four groups: sham, PD, PD + ADSC (prevention) and PD + ADSC (treatment). All rats underwent penile injections into the TA with 50 μL vehicle (sham) or 0.5 μg transforming growth factor (TGF)‐β1 (remaining groups). The ADSC groups received intratunical injections with 0.5 million rat‐labelled ADSCs on day 0 (prevention) or day 30 (treatment). Forty‐five days following TGF‐β1 injection, rats underwent cavernous nerve stimulation (CNS) with total intracavernous‐to‐mean arterial pressure ratio (ICP/MAP) and total ICP recorded to measure response to therapy. Tissues were evaluated histologically and for mRNA expression of tissue inhibitors of metalloproteinases (TIMPs), matrix metalloproteinases (MMPs) and zymographic activity of MMPs. Statistical analysis was performed by analysis of variance followed by the Tukey test for post hoc comparisons. In both prevention and treatment groups, intratunical injection of ADSCs resulted in significantly higher ICP/MAP and total ICP in response to CNS compared with the PD group. Local injection of ADSCs prevented and/or reduced Peyronies‐like changes by decreasing the expression of TIMPs, and stimulating expression and activity of MMPs. This study documents the preventive and therapeutic benefits of ADSC on penile fibrosis and erectile function in an animal model of PD.

Intratunical Injection of Genetically Modified Adipose Tissue‐Derived Stem Cells with Human Interferon α‐2b for Treatment of Erectile Dysfunction in a Rat Model of Tunica Albugineal Fibrosis

INTRODUCTION Peyronies disease (PD) has frequently been associated with erectile dysfunction (ED) and may further compromise coitus. AIM To investigate the efficacy of intratunical injection of genetically modified rat adipose tissue-derived stem cells (ADSCs) expressing human interferon α-2b (ADSCs-IFN) in decreasing fibrosis and restoring erectile function in a rat model of tunica albugineal fibrosis (TAF). METHODS A total of 36 Sprague-Dawley rats (12 weeks old; 300-350 g) were randomly divided in six equal groups: (i) sham group (50 μL saline-injected into the tunica albuginea [TA]); (ii) TAF group (transforming growth factor [TGF]-β1 [0.5 μg/50 μL] injected into the TA); (iii) TGF-β1 plus 5 × 10(5) control ADSCs injected same day; (iv) TGF-β1 plus 5 × 10(5) ADSCs-IFN injected same day; (v) TGF-β1 plus 5 × 10(5) control ADSCs injected after 30 days; and (vi) TGF-β1 plus 5 × 10(5) ADSCs-IFN injected after 30 days. Rat allogeneic ADSCs were harvested from inguinal fat tissue. MAIN OUTCOME MEASURES Forty-five days following the TGF-β1 injection, erectile function was assessed, and penile tissues were harvested for further evaluations. RESULTS In the same-day injection groups, intratunical injection of ADSCs and ADSC-IFN improved erectile response observed upon stimulation of cavernous nerve compared with TAF group. Intratunical ADSC-IFN injection at day 30 improved erectile responses 3.1, 1.8, and 1.3 fold at voltages of 2.5, 5.0, and 7.0, respectively, when compared with TAF group. Furthermore, at voltages of 2.5 and 5.0, treatment on day 30 with ADSCs-IFN improved erectile responses 1.6- and 1.3-fold over treatment with ADSCs alone. Local injection of ADSCs or ADSCs-IFN reduced Peyronies-like manifestations, and these effects might be associated with a decrease in the expression of tissue inhibitors of metalloproteinases. CONCLUSION This study documents that transplantation of genetically modified ADSCs, with or without human IFN α-2b, attenuated Peyronies-like changes and enhanced erectile function in a rat model of TAF.

Androgen Deprivation Therapy Impact on Quality of Life and Cardiovascular Health, Monitoring Therapeutic Replacement

INTRODUCTION Androgen deprivation therapy (ADT) is commonly utilized in the management of both localized and advanced adenocarcinoma of the prostate. The use of ADT is associated with several adverse events, physical changes, and development of medical comorbidities/mortality. AIM The current article reviews known adverse events associated with ADT as well as treatment options, where available. Current recommendations and guidelines are cited for ongoing monitoring of patients receiving ADT. METHODS A PubMed search of topics relating to ADT and adverse outcomes was performed, with select articles highlighted and reviewed based on level of evidence and overall contribution. MAIN OUTCOME MEASURES Reported outcomes of studies detailing adverse effects of ADT were reviewed and discussed. Where available, randomized trials and meta-analyses were reported. RESULTS ADT may result in several adverse events including decreased libido, erectile dysfunction, vasomotor symptoms, cognitive, psychological and quality of life impairments, weight gain, sarcopenia, increased adiposity, gynecomastia, reduced penile/testicular size, hair changes, periodontal disease, osteoporosis, increased fracture risk, diabetes and insulin resistance, hyperlipidemia, and anemia. The definitive impact of ADT on lipid profiles, cardiovascular morbidity/mortality, and all-cause mortality is currently unknown with available data. Treatment options to reduce ADT-related adverse events include changing to an intermittent treatment schedule, biophysical therapy, counseling, and pharmacotherapy. CONCLUSIONS Patients treated with ADT are at increased risk of several adverse events and should be routinely monitored for the development of potentially significant morbidity/mortality. Where appropriate, physicians should reduce known risk factors and counsel patients as to known risks and benefits of therapy.

Transforming Growth Factor-β1 Induced Urethral Fibrosis in a Rat Model

PURPOSE We sought to develop a reproducible TGF-β1 injection technique to induce urethral fibrosis in the rat urethra. MATERIALS AND METHODS A total of 32 male Sprague Dawley® rats weighing 300 to 350 gm were anesthetized with ketamine/xylazine intraperitoneally. Using a 5 mm penoscrotal incision the rat urethra was exposed. In the experimental group varying doses of TGF-β1 (5, 10 and 25 μg) were injected in each side of the urethral wall. Normal saline infiltration was used in the sham treated group. Rats were sacrificed 2 and 4 weeks following TGF-β1 injection. Urethral specimens were stained with hematoxylin and eosin, and Masson trichrome, and Western blot evaluations were performed. Normal and strictured urethral tissues from patients were collected and evaluated in the same fashion. RESULTS There was no evidence of urethral wall thickening or fibrosis in the sham treated group. Varied histological evidence of fibrosis was noted in all experimental groups. There was a significant increase in collagen type I expression 2 weeks after injection of 5, 10 and 25 μg TGF-β1. Collagen type III expression was significantly increased 2 weeks after injecting 10 and 25 μg of TGF-β1, which persisted to 28 days after injection. CONCLUSIONS TGF-β1 injection can successfully generate a reproducible rat model of urethral spongiofibrosis. This technique is simple, inexpensive and reproducible. Our series is a proof of concept study. Additional studies in larger animals are needed to further confirm our findings.

Re: Prevalence of ejaculatory disorders in urban men–results of a random-sample survey

With great interest, we read the article by Vakalopouloset al. (2011), which evaluated the prevalence of ejacula-tory disorders in Greek urban men. After reflection, thereare several concerns that deserve further discussion andexplanation.First, the title is inaccurate. The authors use the term‘ejaculatory disorders’, but should consider using the term‘early ejaculation disorders’ (EED), as ejaculatory disorderis too broad in respect to this article. ‘Ejaculatory disor-ders’ encompasses not only EED, but also anejaculation,delayed ejaculation, retrograde ejaculation and painfulejaculation (Colpi et al., 2004). The authors state that thedefinition of the prevalence of lifelong PE according tothe International Society for Sexual Medicine has not yetbeen determined. However, in a recent peer-reviewedpublication, the prevalence of lifelong PE was noted to be2.3% (Serefoglu et al., 2011), which also matches thefindings of Waldinger (2008) who estimated the preva-lence at 2–5%. In the present study, the authors deter-mine the prevalence of lifelong PE to be 17.7%, which ismuch higher than expected and determined by otherrecent research. Further clarification is needed to explainthis discrepancy.In conclusion, we have a number of questions that theauthors should address to help the readers interpret thedata. What differentiates lifelong PE from the other PEsyndromes? Similarly, what were the criteria for definingEED? What were the ranges of intravaginal ejaculationlatency times (IELT) for EED and lifelong PE?A. Gokce, E. C. Serefoglu & W. J. G. HellstromTulane University School of Medicine – Urology,New Orleans, LA, USAE-mail: whellst@tulane.eduReferenceColpi G, Weidner W, Jungwirth A, Pomerol J, Papp G, Harg-reave T, Dohle G (2004) EAU guidelines on ejaculatory dys-function. Eur Urol 46:555–558.Serefoglu EC, Yaman O, Cayan S, Asci R, Orhan I, Usta MF,Ekmekcioglu O, Kendirci M, Semerci B, Kadioglu A (2011)Prevalence of the complaint of ejaculating prematurely andthe four premature ejaculation syndromes: results from theTurkish Society of Andrology Sexual Health Survey. J SexMed 8:540–548.Vakalopoulos I, Dimitriadis G, Varnava C, Herodotou Y,Gkotsos G, Radopoulos D (2011) Prevalence of ejaculatorydisorders in urban men: results of a random-sample survey.Andrologia 43:327–333.Waldinger MD (2008) Premature ejaculation: advantages of anew classification for understanding etiology and prevalencerates. Sexologies 17:30–35.

Chronic escitalopram treatment induces erectile dysfunction by decreasing nitric oxide bioavailability mediated by increased nicotinamide adenine dinucleotide phosphate oxidase activity and reactive oxygen species production.

OBJECTIVE To investigate the effects of escitalopram, a selective serotonin reuptake inhibitor, on erectile and penile vascular function in the rat. METHODS The effect of chronic treatment with escitalopram (0.286 mg/kg/day) on change in intracavernosal pressure, maximum intracavernosal pressure/mean arterial pressure, and area under the intracavernosal pressure curve in response to cavernosal nerve stimulation was measured. The effect of chronic escitalopram treatment on endothelial-dependent relaxant responses was investigated in isolated mesenteric and internal pudendal resistance arteries. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and nitric oxide synthase levels were determined with enzymatic assay and Western blot, respectively. RESULTS Chronic treatment with escitalopram resulted in a significant reduction in the erectile response to cavernosal nerve stimulation without an effect on the response to intracavernosal injection of the nitric oxide donor sodium nitroprusside. The decrease in erectile function was associated with marked increases in NADPH oxidase activity in the corpora cavernosa. Treatment with escitalopram also caused a significant reduction in the relaxant response to acetylcholine in isolated internal pudendal and mesenteric resistance arteries without altering the response to sodium nitroprusside. The decreased response to acetylcholine in the isolated vascular segments was associated with a marked increase in NADPH oxidase activity that was corrected by treatment with the NAPDH oxidase inhibitor apocynin. CONCLUSION The inhibitory effects of escitalopram on erectile and vascular function were not accompanied by a change in endothelial nitric oxide synthase, neuronal nitric oxide synthase, inducible nitric oxide synthase expression, or endothelial nitric oxide synthase activity, suggesting that the inhibitory effect is caused by a decrease in nitric oxide bioavailability mediated by increased NADPH oxidase and reactive oxygen species production.

Adipose Tissue-Derived Stem Cells for the Treatment of Erectile Dysfunction

Although a spectrum of options is available for erectile dysfunction (ED) treatment, ED in diabetics, post-prostatectomy patients, and those with Peyronie’s disease (PD) may be more severe in degree and less likely to respond to conventional medical therapies. Unfortunately, there have been limited breakthroughs in therapeutic options for severe ED during the past decade. However, one of the more fascinating strategies in preclinical development to treat ED is stem cell transplantation. Depending on the cell type, recent research has demonstrated that with transplantation, these stem cells can exert a paracrine effect on surrounding penile tissues and differentiate into smooth muscle, endothelium, and neurons. Adipose tissue-derived stem cells (ADSCs) have become a valuable resource because of their abundance and ease of isolation. It is evident that ADSCs may provide a realistic, therapeutic modality for the treatment of ED. In this review, we will cover the literature that has evaluated ADSCs in the treatment of ED.

Current and emerging treatment options for Peyronie's disease

Peyronie’s disease (PD) is a condition of the penis, characterized by the presence of localized fibrotic plaque in the tunica albuginea. PD is not an uncommon disorder, with recent epidemiologic studies documenting a prevalence of 3–9% of adult men affected. The actual prevalence of PD may be even higher. It is often associated with penile pain, anatomical deformities in the erect penis, and difficulty with intromission. As the definitive pathophysiology of PD has not been completely elucidated, further basic research is required to make progress in the understanding of this enigmatic condition. Similarly, research on effective therapies is limited. Currently, nonsurgical treatments are used for those men who are in the acute stage of PD, whereas surgical options are reserved for men with established PD who cannot successfully penetrate. Intralesional treatments are growing in clinical popularity as a minimally invasive approach in the initial treatment of PD. A surgical approach should be considered when men with PD do not respond to conservative, medical, or minimally invasive therapies for approximately 1 year and cannot have satisfactory sexual intercourse. As scientific breakthroughs in the understanding of the mechanisms of this disease process evolve, novel treatments for the many men suffering with PD are anticipated.