Peyronie's Disease Plaque Research Articles

PD48-02 SUBCORONAL APPROACH TO INFLATABLE PENILE PROSTHESIS IMPLANTATION

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Peyronie's Disease1 Apr 2015PD48-02 SUBCORONAL APPROACH TO INFLATABLE PENILE PROSTHESIS IMPLANTATION Aaron Weinberg, Christopher Deibert, Matthew Pagano, Paulo Egydio, and Robert Valenzuela Aaron WeinbergAaron Weinberg More articles by this author , Christopher DeibertChristopher Deibert More articles by this author , Matthew PaganoMatthew Pagano More articles by this author , Paulo EgydioPaulo Egydio More articles by this author , and Robert ValenzuelaRobert Valenzuela More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2759AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The surgical treatment for disorders of male sexual function requires specific exposure to safely and efficiently correct the underlying problem. Currently, subcoronal exposure is utilized for treatment of phimosis, Peyronie's Disease plaque (PDP) and semi-rigid penile prosthesis insertion. Infrapubic and scrotal incisions are used for inflatable penile prosthesis (IPP) placement. However men who present with several disorders may require multiple procedures and surgical incisions. We report a prospective review of our surgical experience and outcomes with a single subcoronal incision for IPP placement with a modified no touch technique. This approach allows for access to the entire corporal shaft for multiple reconstructive procedures. METHODS 91 men had IPPs placed through our modified no touch technique, via a subcoronal incision. The penis was degloved to the level of the penoscrotal junction and the cremaster muscle was everted and secured to the drapes. This allowed scrotal and penile skin exclusion from the operative field. Following artificial erection the patient's corpora were inspected for PDP and other abnormalities; and subsequently repaired. Penoscrotal IPP models were placed in all cases with insertion proximal to the everted cremaster muscle (Figure 1). RESULTS Of the 91 men who had IPP placement, 22 had PDP which were treated, 35 men consented to circumcision, and 18 men who were found to have hypermobile glans after IPP placement received glanulopexies. Mean operative time was 54 (36-228) minutes. Three complications, specifically one partial necrosis of a suture line and two had contracture at the site of a PDP which required release; none were infectious. CONCLUSIONS Specialists in the surgical treatment of disorders of male sexual function can perform multiple procedures safely and easily through a modified no touch single subcoronal incision. IPP placement, circumcision, glanulopexy, management of PSP and correction of penile angulation can be accomplished through this exposure. This approach allows for access to the entire corporal shaft providing excellent visibility and allowing the surgeon to perform multiple penile reconstructive surgeries through a single incision. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e966 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Aaron Weinberg More articles by this author Christopher Deibert More articles by this author Matthew Pagano More articles by this author Paulo Egydio More articles by this author Robert Valenzuela More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The transcriptional signatures of cells from the human Peyronie's disease plaque and the ability of these cells to generate a plaque in a rat model suggest potential therapeutic targets.

The success of medical therapies for Peyronie's disease (PD) has not been optimal, possibly because many of them went directly to clinical application without sufficient preclinical scientific research. Previous studies revealed cellular and molecular pathways involved in the formation of the PD plaque and in particular the role of the myofibroblast. The current work aimed to determine under normal and fibrotic conditions what differentiates PD cells from tunica albuginea (TA) and corpora cavernosa (CC) cells by defining their global transcriptional signatures and testing in vivo whether PD cells can generate a PD-like plaque. Human TA, PD, and CC cells were grown with transforming growth factor beta 1 (TGFβ1; TA+, PD+, CC+) or without it (TA-, PD-, CC-) and assayed by (i) immunofluorescence, Western blot and RT-PCR for myofibroblast, smooth muscle cell and stem cell markers; (ii) collagen content; and (iii) DNA microarray analysis. The ability of PD+ cells to induce a PD-like plaque in an immuno-suppressed rat model was assessed by Masson trichrome and Picrosirius Red stainings. Fibroproliferative features of PD cells and identification of related key genes as novel targets to reduce plaque size. Upon TGFβ1stimulation, collagen levels were increased by myofibroblasts in the PD+ but not in the CC+ cells. The transcriptional signature of the PD- cells identified fibroproliferative, myogenic (myofibroblasts), inflammatory, and collagen turnover genes that differentiate them from TA- or CC- cells and respond to TGFβ1 with a PD+ fibrotic phenotype, by upregulation of IGF-1, ACTG2, MYF5, ACTC1, PSTN, COL III, MMP3, and others. The PD+ cells injected into the TA of the rat induce a PD-like plaque. This suggests a novel combination therapy to eliminate a PD plaque by targeting the identified genes to (i) improve collagenase action by stimulating endogenous metalloproteinases specific to key collagen types and (ii) counteract fibromatosis by inhibiting myofibroblast generation, proliferation, and/or apoptosis.

Effect of SMAD7 gene overexpression on TGF-β1-induced profibrotic responses in fibroblasts derived from Peyronie's plaque.

Transforming growth factor-β1 (TGF-β1) has been identified as one of the most important fibrogenic cytokines associated with Peyronie's disease (PD). The mothers against decapentaplegic homolog 7 (SMAD7) is an inhibitory Smad protein that blocks TGF-β signaling pathway. The aim of this study was to examine the anti-fibrotic effect of the SMAD7 gene in primary fibroblasts derived from human PD plaques. PD fibroblasts were pretreated with the SMAD7 gene and then stimulated with TGF-β1. Treated fibroblasts were used for Western blotting, fluorescent immunocytochemistry, hydroxyproline determination, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assays. Overexpression of the SMAD7 gene inhibited TGF-β1-induced phosphorylation and nuclear translocation of SMAD2 and SMAD3, transdifferentiation of fibroblasts into myofibroblasts, and quashed TGF-β1-induced production of extracellular matrix protein and hydroxyproline. Overexpression of the SMAD7 gene decreased the expression of cyclin D1 (a positive cell cycle regulator) and induced the expression of poly (ADP-ribose) polymerase 1, which is known to terminate Smad-mediated transcription, in PD fibroblasts. These findings suggest that the blocking of the TGF-β pathway by use of SMAD7 may be a promising therapeutic strategy for the treatment of PD.

Silencing histone deacetylase 2 using small hairpin RNA induces regression of fibrotic plaque in a rat model of Peyronie's disease.

To examine the therapeutic effect of adenovirus encoding histone deacetylase 2 (HDAC2) small hairpin RNA (Ad-HDAC2 shRNA) in a rat model of Peyronie's disease (PD) and to determine the mechanisms by which HDAC2 knockdown ameliorates fibrotic responses in primary fibroblasts derived from human PD plaque. Rats were distributed into four groups (n = 6 per group): age-matched controls without treatment; rats in which PD has been induced (PD rats) without treatment; PD rats receiving a single injection of control adenovirus encoding scrambled small hairpin RNA (Ad-shRNA) (day 15; 1 × 10(8) pfu/0.1 mL phosphate-buffered saline [PBS]); and PD rats receiving a single injection of Ad-HDAC2 shRNA (day 15; 1 × 10(8) pfu/0.1 mL PBS) into the lesion. PD-like plaque was induced by repeated intratunical injections of 100 μL each of human fibrin and thrombin solutions on days 0 and 5. On day 30, the penis was harvested for histological examination. Fibroblasts isolated from human PD plaque were pretreated with HDAC2 small interfering (si)RNA (100 pmoL) and then stimulated with transforming growth factor (TGF)-β1 (10 ng/mL) to determine hydroxyproline levels, procollagen mRNA, apoptosis and protein expression of poly(ADP-ribose) polymerase 1 (PARP1) and cyclin D1. We observed that Ad-HDAC2 shRNA decreased inflammatory cell infiltration, reduced transnuclear expression of phospho-Smad3 and regressed fibrotic plaque of the tunica albuginea in PD rats in vivo. siRNA-mediated silencing of HDAC2 significantly decreased the TGF-β1-induced transdifferentiation of fibroblasts into myofibroblasts and collagen production, and induced apoptosis by downregulating the expression of PARP1, and decreased the expression of cyclin D1 (a positive cell-cycle regulator) in primary cultured fibroblasts derived from human PD plaque in vitro. Specific inhibition of HDAC2 with RNA interference may represent a novel targeted therapy for PD.

Peyronie's Disease Plaque Calcification—Prevalence, Time to Identification, and Development of a New Grading Classification

Peyronie's disease (PD) is a connective tissue disorder of the penis in which a fibrous scar in the tunica albuginea can result in multiple penile deformities. The study aims to investigate the prevalence and time to identification of plaque calcification (PC) in our PD patient population and whether stratification of calcification based on severity seen on ultrasound would serve as a predictor of treatment progression to surgery. A retrospective review of 1,041 men presenting with PD from 1993 to 2009 was performed. Eight hundred thirty-four underwent penile duplex ultrasound. PC was graded as: grade 1 (<0.3 cm), grade 2 (>0.3 cm, <1.5 cm), grade 3 (>1.5 cm; or ≥ 2 plaques >1.0 cm). A matched control group with noncalcified plaques (n = 236) was selected for comparison. Two hundred eighty-four men (34%) were found to have PC noted on ultrasound, and 98 had fully documented dimensions of the PC. Forty-one percent were found to have grade 1, 28% grade 2, and 32% grade 3. When analyzed by grade and progression to surgery, 23% of grade 1, 32% of grade 2, and 55% of grade 3 patients had surgery. Those with grade 3 PC were more likely to undergo surgical intervention for PD (OR 2.28 95% CI 1.07-4.86) and more likely to undergo a grafting procedure than control patients (P < 0.0001). Men with PC are not more likely to undergo surgery than those without PC (OR 0.95, 95% CI 0.58-1.57). PC is not uncommon, as it was found in 34% of our cohort. PC does not appear to be an indication of mature or stable disease, as it was identified by ultrasound in 37% of patients less than 12 months after onset of symptoms. Men with grade 3 PC have an increased likelihood of progression to surgical intervention and a higher likelihood of undergoing a grafting procedure.

Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie's plaque

Epigenetic modifications, such as histone acetylation/deacetylation, have been shown to play a role in the pathogenesis of fibrotic disease. Peyronie's disease (PD) is a localized fibrotic process of the tunica albuginea, which leads to penile deformity. This study was undertaken to determine the anti-fibrotic effect of small interfering RNA (siRNA)-mediated silencing of histone deacetylase 2 (HDAC2) in primary fibroblasts derived from human PD plaque. PD fibroblasts were pre-treated with HDAC2 siRNA and then stimulated with transforming growth factor-β1 (TGF-β1). Protein was extracted from treated fibroblasts for Western blotting and the membranes were probed with antibody to phospho-Smad2/Smad2, phospho-Smad3/Smad3, smooth muscle α-actin and extracellular matrix proteins, including plasminogen activator inhibitor-1, fibronectin, collagen I and collagen IV. We also performed immunocytochemistry to detect the expression of extracellular matrix proteins and to examine the effect of HDAC2 siRNA on the TGF-β1-induced nuclear translocation of Smad2/3 in fibroblasts. Knockdown of HDAC2 in PD fibroblasts abrogated TGF-β1-induced extracellular matrix production by blocking TGF-β1-induced phosphorylation and nuclear translocation of Smad2 and Smad3, and by inhibiting TGF-β1-induced transdifferentiation of fibroblasts into myofibroblasts. Decoding the individual function of the HDAC isoforms by use of siRNA technology, preferably siRNA for HDAC2, may lead to the development of specific and safe epigenetic therapies for PD.

Penile Duplex Ultrasonography in Men with Peyronie's Disease: Is it Veno‐Occlusive Dysfunction or Poor Cavernosal Arterial Inflow that Contributes to Erectile Dysfunction?

At least 20% of men with Peyronie's disease (PD) suffer from erectile dysfunction (ED). The fundamental mechanism is thought to arise from the progression of penile fibrosis, which was initially limited to the PD plaque within the tunica albuginea. However, recent studies have highlighted the possibility of fibrosis of the cavernosal vessel media wall leading to impairment of arterial inflow. To evaluate the penile duplex ultrasonographic findings in PD of impotent men and to determine whether early features of PD might predict clinical progression. Patient demographic, comorbidities, International Index of Erectile Function-5 scores, surgical intervention, and physical findings were documented. Penile curvature, plaque size, and peak systolic velocity (PSV) and end-diastolic velocity (EDV) on color duplex ultrasonography (CDU) were recorded. We performed a retrospective review of all men presenting with penile curvature and length loss who underwent penile CDU between January 2001 and January 2010. A total of 1,120 men underwent penile CDU during the 10-year period. Complete information was obtained in 810 men; 250 men complained of decreased penile rigidity, while 150 men were unable to sustain erection. Comorbidities were similar between men with PD with and without ED. Tunical thickening (65%) was the most common CDU feature, and mean cumulative calcifications was 24.2 mm(2) (1-360 mm(2) , standard deviation 76). The PSV and EDV on the right cavernosal artery were 14.2 cm/second and 3.5 cm/second, while the left cavernosal artery measurements were 15.1 cm/second and 3.2 cm/second. Multivariate logistic regression model showed strong correlation between plaque size and development of ED. Both veno-occlusive dysfunction and impaired cavernosal arterial inflow were associated with ED. Veno-occlusive dysfunction and impaired cavernosal arterial inflow contributed to the development of ED, and larger plaque size is a strong predictor of surgical intervention.

Pentoxifylline treatment and penile calcifications in men with Peyronie's disease

This retrospective cohort study from a single clinical practice enrolled patients with evidence of calcified Peyronie's disease (PD) plaques detected on penile ultrasound at the time of initial presentation. The primary objective was to describe the effect of pentoxifylline (PTX) treatment on subtunical calcifications in men with PD. A PD-specific questionnaire was administered and sonographic evaluations were performed at baseline and follow-up visits. Descriptive statistics and χ(2) analysis were used to characterize the effect of PTX on calcified tunical plaques. In all, 71 men (mean age: 51.9 years) with PD and sonographic evidence of calcification were identified. Of them, 62 of these men were treated with PTX for a mean duration of 1 year, and nine with vitamin E or no treatment. Improvement or stabilization in calcium burden at follow-up was noted in 57 (91.9%) of men treated with PTX versus four (44.4%) of those not treated with PTX (P<0.001). PTX users were much less likely to have a subjective worsening of their clinical condition (25.0% versus 78.3%, P=0.002). Treatment with PTX appeared to stabilize or reduce calcium content in PD plaques. A randomized controlled trial is warranted to further explore this effect.

Protein Biomarker Analysis of Primary Peyronie's Disease Cells

The molecular pathogenesis of Peyronie's Disease (PD) remains unclear more than 250 years after its initial description. Because of this, no test is currently available to accurately predict PD progression among those affected. To investigate the expression of wound healing and fibrosis-associated proteins in primary cell cultures of PD fibroblasts to determine whether altered protein expression patterns can be used as predictors of clinical course and natural history. Primary cell cultures derived from normal Tunica albuginea tissue and PD plaque tissue were examined by immuno-cytochemistry. Protein expression profiles were analyzed by Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS) and Western immunoblotting. Expression of wound healing and fibrosis-associated proteins and protein expression patterns were assessed. Statistically significant increases in smooth muscle alpha-actin, beta-catenin, and Heat shock proteins (Hsp47) were identified in cells derived from PD relative to cells derived from normal Tunica albuginea tissue. Changes in TGFbeta-1 receptor and Fibronectin were also observed. In addition, altered expression of additional as yet unidentified proteins at 4.7, 8.9, 10.8, 16.8, and 76.8 kDa were detected by complementary SELDI-TOF-MS approaches. Primary cells derived from PD plaques display up-regulated expression of several proteins that are established components of fibrosis and wound healing. In addition, changes in other, as yet unidentified proteins were measured. It will be of interest to conduct further studies to see whether these dysregulated protein peaks represent potential biological markers of disease progression.

Surgical and minimally invasive treatments for Peyronieʼs disease

Peyronie's disease is a relatively common condition affecting men with estimates of current prevalent rates ranging from 1 to 4%. However, it has no clear management protocols, primarily due to a lack of high quality evidence in support of treatment options. This article aims to review the recent published literature on management strategies for Peyronie's disease. Intralesional interferon therapy has shown to result in significant improvement in Peyronie's disease plaques and curvature. Intralesional verapamil and extracorporeal shock wave therapy may help retard the progression of disease. Acellular, extracellular matrix-based grafts provide durable long-term satisfactory results in men requiring complex reconstruction. Further clinical trails are warranted to evaluate the role of oral systemic therapies for early Peyronie's disease. Injection therapy, primarily with interferon, seems to be the most promising treatment for early stage Peyronie's disease. For men with established plaques, surgery using either plication or grafts forms the mainstay. There is an increasing trend to use autologous graft material that is commercially available and avoids donor site complications from autologous tissue.

Laboratory Forum: Experimental Models of Peyronie's Disease. Implications for New Therapies

Despite its high prevalence and impact on the quality of life of patients, and that it is an excellent model for the study of fibrotic processes, Peyronie's disease (PD) is an orphan disease in biomedical research. The development of animal and cell culture models has advanced substantially the understanding of its molecular and cellular pathology and the proposal of new therapies. To review the literature pertaining to the use of these models for the study of PD. PubMed search conducted from the first report of an animal model for PD. This model, based on the finding that transforming growth factor beta1 (TGF beta 1) is overexpressed in the PD plaque, consists on the injection of TGF beta 1 into the tunica albuginea of the rat. This leads to a PD-like plaque retaining many of the histological and biochemical features of human PD. Another rat model, based on the hypothesis that the PD plaque arises from trauma to the penis, causing fibrinogen extravasation that initiates as fibrin a fibrotic response, consists on injection of fibrin into the tunica. The cell culture model is based on the demonstration that myofibroblasts are abundant in the human PD plaque. These models have: (i) clarified the role of microtrauma, myofibroblasts, and oxidative stress in plaque development; (ii) demonstrated that this tissue is under sustained turnover by fibrotic and antifibrotic mechanisms; (iii) showed the interplay of collagenolytic and fibrinolytic systems and their inhibitors; (iv) detected an endogenous antifibrotic process consisting of the expression of inducible nitric oxide synthase that counteracts oxidative stress, collagen synthesis, and myofibroblast generation; (v) characterized the antifibrotic effects of chronic treatment with phosphodiesterase type 5 (PDE5) inhibitors; (vi) discovered the cytogenetic instability of PD cells and alterations in their gene expression; and (vii) detected stem cells in the tunica albuginea with a potential role in fibrosis and ossification.

Upregulation of mRNA expression of MCP-1 by TGF-β1 in fibroblast cells from Peyronie’s disease

Peyronie's disease (PD) is a localized connective tissue disorder of the penile tunica albuginea (TA) with a still obscure etiopathology. Recent studies from our laboratory have demonstrated differences in Smad3 and Smad4 gene expression of PD-fibroblasts and non-PD-fibroblasts after stimulation with recombinant TGF-beta1 for 1 h. In the present study, we investigated gene expression of Smad2-Smad4 and Smad7 up to 6 h after stimulation with TGF-beta1. As a positive control, MCP-1 gene expression was monitored. Cells with fibroblast characteristics were isolated from seven PD plaques and three TA controls. The cells were incubated with recombinant TGF-beta1 for 2-6 h and expression of Smad2-Smad4, Smad7, and monocyte chemotactic protein-1 (MCP-1) was determined by quantitative real-time PCR. TGF-beta1 treatment resulted in a statistically significant up-regulation of Smad7 and MCP-1 gene expression. Smad7 expression was increased after 2 h (P < 0.001) and was still high after 4 h (P < 0.05). No significant differences between fibroblasts from PD-patients compared to non-PD-patients were observed. MCP-1 peaked after 4 h (P < 0.001) and remained high up to 6 h (P < 0.01). PD-fibroblasts revealed a significantly increased MCP-1 gene expression compared to non-PD-fibroblasts (P = 0.013) after 2 h and remained significantly different also after 6 h (P = 0.038). Gene expression of Smad2-Smad4 did not change during stimulation with TGF-beta1. In conclusion, analysis of MCP-1 expression might be a useful marker for Peyronie's disease.

Profibrotic Role of Myostatin in Peyronie's Disease

The primary histologic finding in many urologic disorders, including Peyronie's disease (PD), is fibrosis, mainly mediated by the transforming growth factor beta1 (TGFbeta1). To determine whether another member of the TGFbeta family, myostatin, (i) is expressed in the human PD plaque and normal tunica albuginea (TA), their cell cultures, and the TGFbeta1-induced PD lesion in the rat model; (ii) is responsible for myofibroblast generation, collagen deposition, and plaque formation; and (iii) mediates the profibrotic effects of TGFbeta1 in PD. Human TA and PD tissue sections, and cell cultures from both tissues incubated with myostatin and TGFbeta1 were subjected to immunocytochemistry for myostatin and alpha-smooth muscle actin (ASMA). The cells were assayed by western blot, Real time-Polymerase chain reaction (RT-PCR), and ribonuclease protection. Myostatin cDNA and shRNA were injected, with or without TGFbeta1, in the rat penile TA, and plaque size was estimated by Masson. Myostatin expression in the human TA, the PD plaque, and their cell cultures, and myostatin effects on the PD-like plaque in the rat. A threefold overexpression of myostatin was found in the PD plaque as compared with the TA. In PD cells, myostatin expression was mainly in the myofibroblasts, and in the TA cells, it increased upon passage paralleling myofibroblast differentiation and was up-regulated by TGFbeta1. Myostatin or its cDNA construct increased the myofibroblast number and collagen in TA cells. Myostatin was detected in the TGFbeta1-induced PD-like plaque of the rat partly in the myofibroblasts, and in the TA. Myostatin cDNA injected in the TA induced a plaque and intensified the TGFbeta1 lesion, which was not reduced by myostatin shRNA. Myostatin is overexpressed in the PD plaque, partly because of myofibroblast generation. Although myostatin induces a plaque in the rat TA, it does not appear to mediate the one triggered by TGFbeta1, thus suggesting that both proteins act concurrently and that therapy should target their common downstream effectors.

Differential Calcium Independent Regulation of Matrix Metalloproteinases and Tissue Inhibitors of Matrix Metalloproteinases by Interleukin-1β and Transforming Growth Factor-β in Peyronie's Plaque Fibroblasts

Peyronie's disease is a fibrotic disorder of the tunica albuginea characterized by the localized formation of an inelastic plaque. We characterized matrix metalloproteinases and TIMPs (tissue inhibitors of matrix metalloproteinase) in Peyronie's disease tissue. Matrix metalloproteinases and TIMPs were investigated in Peyronie's disease plaque tunica removed from patients with stable Peyronie's disease. Immunological methods were used to characterize the matrix metalloproteinases and TIMPs produced by cell cultures stimulated with transforming growth factor-beta or interleukin-1beta (PreproTech, Rocky Hill, New Jersey). Enzyme activity was quantified with a fluorescent substrate and correlated with mRNA levels using real-time polymerase chain reaction. Interleukin-1beta significantly induced (p <0.01) matrix metalloproteinase-1, 3, 10 and 13 protein production, endogenous matrix metalloproteinase-13 activity (12-fold) and matrix metalloproteinase-13 mRNA expression (11.2-fold) through a Ca(2+) independent mechanism in cultured fibroblasts. Transforming growth factor-beta stimulation failed to induce any detectable matrix metalloproteinase protein production or activity and conditioned culture medium even had the capacity to inhibit (p <0.01) the activity of purified recombinant human matrix metalloproteinase-13. Intact Peyronie's disease plaques were highly enriched with TIMP-1 to 4 compared to donor matched perilesional tunica. These data show that, while interleukin-1beta strongly induces matrix metalloproteinase expression, transforming growth factor-beta strongly induces TIMP expression without any effect on matrix metalloproteinases and may represent an important downstream biochemical mechanism that leads to the progression of Peyronie's disease. The localized accumulation of TIMPs together with decreased matrix metalloproteinase activity in the Peyronie's disease lesion may be the biochemical consequence of the transforming growth factor-beta over expression that has been reported in many fibrotic disorders, including Peyronie's disease.

ORIGINAL RESEARCH–PEYRONIE'S DISEASE: The Use of Intralesional Clostridial Collagenase Injection Therapy for Peyronie's Disease: A Prospective, Single-Center, Non-Placebo-Controlled Study

Peyronie's disease afflicts at least 3% of sexually active men over the age of 30. Many pharmacologic therapies have been tried, but to date, no systemic or local therapy has been proven to provide predictable and lasting results. This study was designed to assess the efficacy and safety of intralesional clostridial collagenase injection therapy in a series of patients with Peyronie's disease. Twenty-five patients aged 21-75 years who were referred to a single institution with a well-defined Peyronie's disease plaque were treated with three intralesional injections of clostridial collagenase 10,000 units in a small volume (0.25 cm(3) per injection) administered over 7-10 days, with a repeat treatment (i.e., three injections of collagenase 10,000 units/25 cm(3) injection over 7-10 days) at 3 months. Primary efficacy measures were changes from baseline in the deviation angle and plaque size. Secondary efficacy end points were patient responses to a Peyronie's disease questionnaire and improvement according to the investigators' global evaluation of change. The primary efficacy measures were change in deviation angle and change in plaque size. Secondary end points were patient questionnaire responses and improvement according to the investigators' global evaluation of change. Significant decreases from baseline were achieved in the mean deviation angle at months 3 (P = 0.0001) and 6 (P = 0.0012), plaque width at months 3 (P = 0.0052), 6 (P = 0.0239), and 9 (P = 0.0484), and plaque length at months 3 (P = 0.0018) and 6 (P = 0.0483). More than 50% of patients in this series considered themselves "very much improved" or "much improved" at all time points in the study, and the drug was generally well tolerated. The benefits of intralesional clostridial collagenase injections in this trial lend support to prior studies supporting its use in the management of Peyronie's disease. A double-blind, placebo-controlled study is currently under development.

A new mouse model of Peyronie's disease: An increased expression of hypoxia-inducible factor-1 target genes during the development of penile changes

Peyronie's disease (PD) is characterized by an inflammatory response beneath the tunica albuginea with fibroblast proliferation forming a thickened fibrous plaque that may cause pain, penile curvature and erectile dysfunction. The progression of the PD plaque may eventually lead to calcification or ossification. Current therapeutic success is often unsatisfactory because of limited insight into disease mechanisms. Research has been hampered by the lack of a universally accepted animal model. We describe an animal model of spontaneous PD in tight skin ( Tsk) mice , a C57Bl/6J subline that reproduces with age important features of the human disease (fibrous plaque formation, penile bending and areas of chondroid metaplasia with heterotopic ossification). Histological analysis demonstrated an evident structural disorganization of the tunica albuginea with excessive accumulation of type I collagen. At 12 months of age, fibrous plaques with areas of chondroid metaplasia and heterotopic ossification characterized Tsk penises. The up-regulation of hypoxia-inducible factor-1 (HIF-1) leads to an increased downstream expression of HIF-1 target genes, such as TGFβ and iNOS. These factors, together with some PDGF family members, can cause collagen deposition in Tsk penises. They can also influence chondrocyte differentiation and heterotopic bone formation. In conclusion, hypoxia, HIF-1 and HIF-1 target genes appear to play an important role in the pathogenesis of PD in Tsk mice. This mouse model that is the first example of naturally occurring model of PD in laboratory animals may aid in the identification of signalling pathways crucial for PD and should facilitate the designing and testing of new therapeutic interventions.

748: Surgical Correction of Peyronie's Disease Via Tunica Albuginea Plication or Plaque Incision with Pericardial Graft: Long Term Follow-Up

748: Surgical Correction of Peyronie's Disease Via Tunica Albuginea Plication or Plaque Incision with Pericardial Graft: Long Term Follow-Up

Complications of Porcine Small Intestine Submucosa Graft for Peyronie’s Disease

We report outcomes and complications of the use of porcine small intestine submucosa for correcting penile curvature due to Peyronie's disease. A retrospective study was performed in patients with severe penile curvature (greater than 60 degrees) requiring surgical correction for sexual function. Preoperatively all patients underwent evaluation, including history, physical and penile duplex ultrasound. Of these patients 19 underwent tunical grafting with 1-layer Surgisis small intestine submucosa. Postoperatively patients were evaluated with clinic visits and telephone interviews to assess results. A total of 19 patients 46 to 69 years old (mean age 54) were treated with tunical incision or excision and grafting with small intestine submucosa between March 2002 and July 2005. Average followup was 15 months (range 3 to 43). Patients reported less penile pain with intercourse after surgery. There was no difference in Sexual Health Inventory for Men scores. Preoperatively 12 men (63%) had erectile dysfunction, defined as Sexual Health Inventory for Men less than 21, while 10 (53%) reported postoperative erectile dysfunction. Seven of the 19 patients (37%) had recurrent penile curvature (greater than 10 degrees) and 5 (26%) had recurrent Peyronie's disease plaque. Our complication rate was 37%, including hematoma at the graft site in 5 cases (26%), graft infection in 1 (5%) and Peyronie's disease recurrence requiring plication in 1 (5%). Small intestine submucosa carries potential for grafting applications because it is easy to use and readily available. Our experience resulted in a 37% complication rate, which exceeds those previously reported with saphenous vein graft repair.

Prospective analysis of single nucleotide polymorphisms of the transforming growth factor beta-1 gene in Peyronie's disease.

The detection of increased expression of transforming growth factor beta-1 (TGF-beta1) in Peyronie's disease plaques and the possibility of initiating a Peyronie's disease-like condition by intratunical injection of a synthetic heptopeptide with TGF-beta-like activity in an animal model has provided evidence for the central role of this cytokine in the pathogenesis of this entity. Recently 2 defined single nucleotide polymorphisms in the coding region of the TGF-beta1 gene have been described that are associated with different levels of TGF-beta1 production. Based on these data we prospectively investigated the genetic association of distinct TGF-beta1 genotypes with Peyronie's disease. DNA samples from 111 consecutive patients with idiopathic Peyronie's disease and 100 controls were genotyped for the 2 defined dimorphic single nucleotide polymorphisms T869C and G915C in the coding region of the TGF-beta1 gene using allele specific polymerase chain reaction. We found an increased frequency of the homozygous genotype of the single nucleotide polymorphism G915C in patients with Peyronie's disease compared with healthy controls (89.2% versus 79%, p = 0.04). However, there were no significant differences in allele frequencies of the single nucleotide polymorphism T869C. Experimental data from other investigators have shown that TGF-beta1 has an important role in the etiopathology of Peyronie's disease. Our results indicate that the homozygous wild type of the G915C single nucleotide polymorphism in the coding region of the TGF-beta1 gene, which was recently associated with elevated TGF-beta1 production and pulmonary fibrosis, may influence the predisposition to Peyronie's disease. However, it does not represent a major genetic risk factor.

Mechanisms of Disease: new insights into the cellular and molecular pathology of Peyronie's disease

Peyronie's disease (PD) is characterized by fibrotic plaques in the penile tunica albuginea that cause curvature of the erect penis, and is often accompanied by pain and/or erectile dysfunction. This condition affects up to 9% of men. Treatment is mainly surgical, as pharmacologic therapy has limited efficacy. The pathophysiology of PD is poorly understood, but development of two rat models, extrapolation of what is known about the molecular pathology of other fibrotic conditions, and emphasis on the role of myofibroblasts and adult stem cells are helping to clarify etiology and identify new pharmacologic targets. Recent studies demonstrate a role for oxidative stress and cytokine release-primarily transforming-growth-factor beta1-in development of PD fibrotic plaques. There is evidence indicating that these profibrotic factors interact with antifibrotic defense mechanisms, such as decrease of myofibroblast accumulation, elimination of reactive oxygen species by inducible nitric oxide synthase and neutralization of transforming-growth-factor beta1 by decorin, such that some plaques are in dynamic turnover. Injury to the erect penis is thought to trigger PD by inducing extravasation of fibrin and subsequent synthesis of transforming-growth-factor beta1. Despite the lack of statistical support for a causal association between trauma and PD, it is possible that undetected microtrauma is involved. It is not known whether ossification of PD plaques is linked to fibrosis progression or is a manifestation of an alternative pathway. Both processes seem to be related to activation of fibroblast/myofibroblast differentiation in the tunica albuginea and to osteogenic commitment of stem cells in this tissue.