New in vivo model to assess macroscopic, histological, and molecular changes in Peyronie's disease.

BACKGROUND: Peyronie's Disease (PD) is a connective tissue disorder that affects the tunica albuginea (TA) of the penis causing curvature and erectile dysfunction. The pathophysiology is not well understood and, for this reason, treatment options are limited. OBJECTIVE: The aim of the present study is to analyze and compare whether single or multiple instillations of plasma in the TA of rats is capable of triggering macroscopic, histopathological, and molecular changes consistent with PD. MATERIAL/METHODS: Fifty male Wistar rats were divided into four groups: Group 1: a single instillation of plasma in the TA; Group 2: a single instillation of distilled water in the TA; Group 3: four instillations of plasma in the TA (1x per week); and Group 4: four instillations of distilled water in the TA (1× per week). Forty-five days after the last instillation a manual inspection of the corpus cavernosum, a penile erection test and a penectomy were performed to obtain material for histopathological and molecular analysis. RESULTS: It was observed that 31.25% of the rats that received repeated instillations of plasma presented penile curvature according to the erection test, while none of the rats from the control group or group with one instillation of plasma presented curvature. In the animals that received four instillations of plasma, the following differences were observed in relation to the control group: increase in fibrosis and the deposition of collagen I. The protein expression of heparanase (HPSE) and TGF-ß increased in the groups that received a single or four instillations of plasma, and the protein expression of heparanase-2 (HPSE-2), metalloproteinases (MMP-2, MMP-9) and metalloproteinase inhibitor (TIMP-2) showed an increase in the group that received four instillations of plasma. There was a significant increase in the gene expression of HPSE, MMP-9, and TGF-ß in the group that received four instillations of plasma. In the analysis of the glycosaminoglycans, an increase was observed in the secretion of galactosaminoglycans chondroitin sulfate and dermatan sulfate (CS/DS) in the group that received four instillations of plasma. DISCUSSION: Previous studies have demonstrated increased protein expression. of HPSE, MMP-9 and TGF-ß with instillation of blood in the TA; however, there was no increase in gene expression. In the present study, the increase in the expression of TGF-ß with plasma instillations, proved to be more reliable. The two models with plasma (one or four instillations) demonstrated significant histopathological and molecular changes when compared to the control group. However, only in the group with four plasma instillations there was a macroscopic change. The idea is that repeatedly extravasation of TGF-ß present in plasma of predisposed individuals acts as a trigger for the development and maintenance of changes in the extracellular matrix that perpetuate an anomalous inflammatory process present in PD. CONCLUSION: The present study shows that the repeated instillation of plasma is a low cost in vivo model for the study of PD.

Anti-fibrotic effect of mycophenolate mofetil on Peyronie's disease experimentally induced with TGF-ß.

The aim of the present study was to evaluate the histological, histochemical, and stereological changes caused by mycophenolate mofetil (MMF) on the tunica albuginea of rat penises submitted to an injection of transforming growth factor beta (TGF-ß) for the induction of Peyronie's disease (PD). Twenty adult male Wistar rats were divided into four groups: Control group; TGF-ß group (TGF-ß injection); MMF-7d group (treated with MMF 7 days after induction with TGF-ß); and MMF-30d group (treated with MMF 30 days after induction with TGF-ß). The steorological evaluation included the relative volume of different types of connective fibres of the tunica albuginea. The histochemical analysis revealed the fragmentation and degradation of elastin in the tunica albuginea. This process was partially reversed in the MMF-7d group and a situation very close to normality was observed in the MMF-30d group. In the collagen III/collagen I ratio it was observed increase in this ratio in the TGF-ß (59.4 ± 5.53) and MMF-7d (49 ± 18.2) groups and a decrease in the MMF-30d group (28.7 ± 4), approaching normality. The injection of TGF-ß promoted fibrotic alterations in the penile tunica albuginea in Wistar rats corresponding to PD. In this model, MMF acts as a regenerating anti-fibrotic agent.

Objective measurements of the penile angulation are significantly different than self-estimated magnitude among patients with penile curvature

ABSTRACT Introduction: The study was aimed to assess the presence of actual differences between the objective and the perceived magnitude of a curvature between patients affected by Peyronie's disease (PD) and congenital penile curvature (CPC). Materials and Methods: Wee analysed a cohort of 88 consecutive patients seeking medi- cal help for either CPC or PD. All patients were invited to provide a self-made drawing of their penis in erection in order to obtain self-provided description of the deformity. An objective measurement of the deformity was also performed drawing two intersecting lines through the center of the distal and proximal straight section of the penile shaft. Results: Our findings showed significant differences between patient self-estimation and the objective measurements of the penile angulation performed by trained experts, with only 32% of patients correctly assessing their own curvature. Overall, patients tended to overestimate (56%) their degree of curvature, but the results are different in patients with PD than those with CPC. In the 60 men (68%) who did not accurately assess their curvature, PD patients generally overestimated their curvature versus CPC patients (67% vs 16%). On the contrary CPC patients underestimated their curvature compared to PD (42% vs. 4%). Conclusion: In order to improve patients' satisfaction rates, the surgeon needs to take into consideration the patient's perception of the deformity when planning the type of surgical correction.

Objective measurements of the penile angulation are significantly different than self-estimated magnitude among patients with penile curvature.

INTRODUCTION: The study was aimed to assess the presence of actual differences between the objective and the perceived magnitude of a curvature between patients affected by Peyronie's disease (PD) and congenital penile curvature (CPC). MATERIALS AND METHODS: Wee analysed a cohort of 88 consecutive patients seeking medical help for either CPC or PD. All patients were invited to provide a self-made drawing of their penis in erection in order to obtain self-provided description of the deformity. An objective measurement of the deformity was also performed drawing two intersecting lines through the center of the distal and proximal straight section of the penile shaft. RESULTS: Our findings showed significant differences between patient self-estimation and the objective measurements of the penile angulation performed by trained experts, with only 32% of patients correctly assessing their own curvature. Overall, patients tended to overestimate (56%) their degree of curvature, but the results are different in patients with PD than those with CPC. In the 60 men (68%) who did not accurately assess their curvature, PD patients generally overestimated their curvature versus CPC patients (67% vs 16%). On the contrary CPC patients underestimated their curvature compared to PD (42% vs. 4%). CONCLUSION: In order to improve patients' satisfaction rates, the surgeon needs to take into consideration the patient's perception of the deformity when planning the type of surgical correction.

Extracellular matrix alterations after blood instillation in tunica albuginea of rats.

The cause of Peyronie's disease (PD) is still not completely understood. The objective of this study, therefore, was to analyze the histological and biochemical alterations that occur after the instillation of blood in the tunica albuginea (TA) of rats with an emphasis on the remodeling process of ECM. Thirty male Wistar rats were divided into 4 groups: two control groups with instillation of distilled water in TA followed by penectomy after 15 days or 45 days, respectively and two experimental groups with instillation of blood in TA followed by penectomy after 15 days or 45 days, respectively. Histological, immunofluorescent and immunohistochemical analyses were performed. The higher presence of fibrotic tissue in rats injected with blood demonstrated alterations in TA similar to inflammation found in PD. The increased expression of TGF-ß, MMP9, HPSE, and biglycan associated with the decreased expression of syndecan-1 and aggrecan in the experimental groups suggested an enhancement in the remodeling of ECM. The results contribute to show that blood instillation on TA appears to trigger alterations in the ECM similar to the ones found in inflammatory diseases such as PD.

Application of human amniotic membrane in canine penile tunica albuginea defect: first step toward an innovating new method for treatment of Peyronie's disease.

PURPOSES: To evaluate the efficacy of human amniotic membrane (AM) grafting in the canine penile tunica albuginea defect; we developed an animal model as the first step toward an innovating new method for the treatment of Peyronie's disease, penile cancers, and congenital deformities of the penis. MATERIAL AND METHODS: From August to September 2011, ten healthy male dogs were selected. A rhomboid incision about 3 x 2 cm over the tunica albuginea and its overlying squamous epithelium was made and then excised. The amniotic membrane was folded twice on itself and grafted on the defect. After 8 weeks, artificial erection was made for 5 dogs and for the other 5 dogs after 12 weeks. After artificial erection, partial penectomy was done and histopathological evaluation was performed on the grafts. RESULTS: Artificial erection performed successfully in all of the dogs. No infection or any other complication was seen. Histopathological examination showed complete re-epithelialization with squamous epithelium and collagen fiber deposition. Also, no dysplasia was seen. CONCLUSIONS: The amniotic membrane can be used as a suitable substitution for tunica albuginea. It is safe, inexpensive, biodegradable, and available and may be used for the treatment of Peyronie ' s disease, penile cancers, congenital penile deformities, and penile reconstructive surgery.

Application of Human Amniotic Membrane in Canine Penile Tunica Albuginea Defect: First Step toward an Innovating New Method for Treatment of Peyronie?s Disease

Purposes To evaluate the efficacy of human amniotic membrane (AM) grafting in the canine penile tunica albuginea defect; we developed an animal model as the first step toward an innovating new method for the treatment of Peyronie’s disease, penile cancers, and congenital deformities of the penis. Material and Methods From August to September 2011, ten healthy male dogs were selected. A rhomboid incision about 3x2cm over the tunica albuginea and its overlying squamous epithelium was made and then excised. The amniotic membrane was folded twice on itself and grafted on the defect. After 8 weeks, artificial erection was made for 5 dogs and for the other 5 dogs after 12 weeks. After artificial erection, partial penectomy was done and histopathological evaluation was performed on the grafts. Results Artificial erection performed successfully in all of the dogs. No infection or any other complication was seen. Histopathological examination showed complete re-epithelialization with squamous epithelium and collagen fiber deposition. Also, no dysplasia was seen. Conclusions The amniotic membrane can be used as a suitable substitution for tunica albuginea. It is safe, inexpensive, biodegradable, and available and may be used for the treatment of Peyronie’s disease, penile cancers, congenital penile deformities, and penile reconstructive surgery. .

A geometric model of plaque incision and graft for Peyronie's disease with geometric analyses of different techniques.

INTRODUCTION: A surgical approach with plaque incision and graft (PIG) to correct Peyronie's disease is the best method for complex, large deviations. However, the geometric and mechanical consequences of this intervention are poorly understood. AIM: The aim of this study was to analyze the geometric and mechanical consequences of PIG on penile straighten surgery. METHOD: A tridimensional penile simile model with a curvature of 85° was created to test all of the most common PIG techniques. PIG with double-Y, H-shape, and Egydio techniques were used to rectify the curved penile model. MAIN OUTCOME MEASUREMENTS: The results that differed from a rectified cylinder shape were highlighted. RESULTS: All of the analyzed techniques created a geometric distortion that could be linked to poor surgical results. We suggest a new technique to resolve these abnormalities. CONCLUSION: Current techniques designed to correct penile deviation using PIG present geometric and mechanical imperfections with potential consequences to the postoperative success rate. The new technique proposed in this report could be a possible solution to solve the geometric distortion caused by PIG.

Penile length and girth restoration in severe Peyronie's disease using circular and longitudinal grafting.

OBJECTIVE: To report patient outcomes and satisfaction with our technique for penile length and girth restoration in severe Peyronie's disease (PD). PATIENTS AND METHODS: Between November 2006 and November 2011, 105 men with severe PD and erectile dysfunction (ED) underwent surgical correction using our new approach. The technique consists of penile prosthesis implantation with concomitant penile lengthening and girth restoration through circular and longitudinal incisions in the tunica albuginea according to geometric principles. RESULTS: The overall patient satisfaction rate was 89.4%. The mean (sd; range) functional penile length gain was 3.6 (0.7; 2-5) cm. Patient satisfaction with penile length gain was 95.2%. Three patients (2.9%) developed retraction with residual curvature of up to 30°, but no re-operation was necessary. In one (1%) patient, the prosthesis had to be removed because of wound infection. At a mean (sd; range) follow-up of 18.2 (5.9; 6-46) months, 104 patients (99%) were able to have sexual intercourse. CONCLUSIONS: Our surgical approach for penile length and girth restoration leads to high patient satisfaction rates and excellent functional outcomes. Our surgical approach is a safe and valid therapeutic method for the treatment of severe PD associated with ED.

Risk factors of Peyronie's disease. What does our clinical experience show?

INTRODUCTION: Peyronie's disease (PD) is a localized fibrosis that affects the tunica albuginea of the penis. Its origin can be associated with coital penile trauma in men with autoimmune hypersensitivity and a presumed genetic predisposition. AIM: To identify clinical and traumatic risk factors in a patient population with PD, when compared to a control group. METHODS: From November 2007 to March 2010, 317 patients sought medical attention for PD. As control group, 147 consecutive patients, who came for a prostate exam, were studied. Clinical, traumatic, and sexual history of these patients was gathered. Risks factors were considered only if they had been present before the onset of PD symptoms. MAIN OUTCOME MEASURE: The International Index of Erectile Function and the International Prostate Symptoms Score. A univariate logistic regression model (chi-square) (odds ratios [ORs] and 95% confidence intervals [CI]) was used to estimate the association of risk factors with PD; and the Student's t-test was implemented for age. RESULTS: The mean age of patients with PD and control group was 56.7 and 58.8, respectively (P<0.923). The mean evolution time of the disease was 17.7 months (2-48). Erectile dysfunction (ED) and coital trauma constituted the only two independent risk factors for PD compared to the control group (P<0.05 and 0.002, respectively) with an OR of 1.5 (95% CI 1.0-2.3) and 2.69 (95% CI 1.41-5.21), respectively. Patients with ED and diabetes mellitus and with a mild-to-moderate ED also presented a higher predisposition (P=0.008 and 0.00001), with an OR of 3.64 (95% CI 1.33-10.79) and 5.58 (95% CI 3.03-10.42), respectively. CONCLUSION: Erectile dysfunction and coital trauma have proven to be independent risk factors for the development of PD.

Stereological and biochemical analysis of muscular and connective tissue components in the penile corpus cavernosum adjacent to the fibrous plaque of Peyronie's disease.

OBJECTIVE: To investigate the structural organization of the connective tissue in the corpus cavernosum (CC) adjacent to the fibrous plaque in Peyronie's disease (PD) using stereological and biochemical techniques, as most studies on PD have focused on the analysis of the fibrous plaque that forms in the tunica albuginea (TA). Because this fibrotic reaction is mediated by various inflammatory soluble factors, adjacent connective tissues might also be affected and this secondary effect might explain, for example, the erectile dysfunction that occurs in PD. PATIENTS AND METHODS: During surgery biopsies were taken from the CC adjacent to the fibrous plaque and from the plaque itself in seven patients with PD (mean age 48.3 years). All the patients had normal erections. Control samples were similarly located samples from 'normal' penises obtained during autopsy of five men (mean age 52.3 years). Tissue samples were stained with Weigert's stain (elastic fibres), Van Gieson's stain (connective tissue), and Sirius red (collagen). Stereological analysis was done using a 42-point grid to determine volumetric densities (Vv). Total collagen content was estimated as micrograms of hydroxyproline per milligram dry CC. RESULTS: The Vv of elastic fibres was significantly reduced in PD by 17.3% compared with controls, at a mean (sd) of 19.49 (3.27)% vs 23.56 (1.87)% (P < 0.05). While in PD the Vv of smooth muscle at 34.46 (2.06)% and connective tissue at 35.39 (6.15)% were not significantly different from those of controls at 38.38 (3.17)% and 38.02 (5.03)%, respectively. The Vv of elastic fibres in the fibrous plaque was decreased by 38.3% compared with the normal TA, at 20.25 (5.49)% vs 32.81 (4.75)% (P < 0.02). The mean (sd) collagen concentration in the CC from controls was 77.94 (24.26) microg/mg and in the patients with PD was 66.57 (19.39) microg/mg, which did not differ significantly. Sirius red-stained sections under polarized light showed that, in the normal CC, collagen-associated colours were homogeneously distributed. However, in the PD samples, stained collagen had a disrupted orientation and had a more heterogeneous birefringence, implying looser collagen bundles. CONCLUSIONS: The quantitative analyses indicated that collagen in the CC close to the fibrous plaque was not affected, although its organization was noticeably altered. The CC elastic fibres were reduced though, and there was a similar change in the fibrous plaque of the TA. These results suggest that, although occurring primarily in the TA, the PD fibrous plaque may induce changes in the adjacent CC.

Preliminary findings from a new animal model for Peyronie's disease involving extracorporeal shock waves.

OBJECTIVE: To develop an experimental model in rabbits to analyse the efficiency of extracorporeal shock wave therapy (ESWT) for Peyronie's disease. MATERIALS AND METHODS: We used 15 adult male rabbits divided into three equal groups. In group 1 (no penile ESWT) rabbits had three sessions of ESWT with 2000 shocks each (15 kV), but a rubber mat was placed between the shock head and rabbit to protect the penis; the rabbits were killed at 7 days after the last session of ESWT. In group 2 the rabbits had three sessions of ESWT using the same parameters, and were killed immediately after the last session to analyse the penis. In group 3 the rabbits had three sessions of ESWT as before but were killed at 7 days after the last session, and the penile tissue analysed macroscopically and histologically. RESULTS: The results showed clearly that the model was efficient, creating a similar situation to that when applying ESWT in the human penis. All of the rabbits in groups 2 and 3 had haematomas and diffuse petechiae after ESWT, and only four had urethral and penile bleeding. Almost all macroscopic changes disappeared after 48 h and only one rabbit in group 3 after 7 days had a haematoma on the dorsal penile surface. The histology (assessed using haematoxylin and eosin staining) of the cavernous body of the penis showed: unchanged histology in group 1; in group 2 there was a dilated and congested vascular space in the cavernous body, with interstitial extensive bleeding in the dermis; and in group 3 there was an increase in interstitial fibrous tissue in the cavernous septum, with deposition of collagen fibres and thickening of the tunica albuginea. CONCLUSION: The present model was efficient in producing tissue injury in the normal penis when treated with ESWT, suggesting that this promising model should be considered for use future studies of Peyronie's disease.

Surgical treatment of Peyronie's disease: choosing the best approach to improve patient satisfaction.

AIM: To discuss important points on medical history, preoperative evaluation, real expectations, and selection of the appropriate surgical procedure to improve patient satisfaction after surgical procedures for Peyronie's disease. METHODS: Recent advances in approaches to Peyronie's disease are discussed based on the literature and personal experiences. Issues concerning surgical indication, patient selection, surgical techniques, and grafting are discussed. Lengthening procedures on the convex side of the penile curvature by means of grafting offer the best possible gain from a reconstruction standpoint. Penile rectification and rigidity are required to achieve a completely functional penis. Most patients experience associated erectile dysfunction (ED), and penile straightening alone may not be enough to restore complete function. Twenty-five patients were submitted to total penile reconstruction on length and girth with concomitant penile prosthesis implant. The maximum length restoration was possible and limited by the length of the dissected neurovascular bundle. The mean age was 55.4 years (32-69 years) and the mean angle of curvature 74.2+/-22.4 degree (0-100 degree). Pericardial grafting was used to cover the defect. The mean follow-up time was 11.2 +/- 5.9 months (3-22 months). RESULTS: Mean functional penile length gain was 3.40+/-0.73 cm (2-5 cm). Penile prosthesis maintained the penis straight. No infections occurred. Sexual intercourse was restored in all patients and all reported recovered self-esteem. CONCLUSION: Improving patient satisfaction with the surgical treatment includes proper preoperative evaluation on stable disease, penile shortening, vascular and erectile status, patient decision and selection as well as extensive discussion on surgical technique for restoring functional penis (length and rigidity). Length and girth restoration is very important for self-esteem and patient satisfaction.

Human penile ossification: case report

CONTEXT: Ossification in the human penis is such a rare condition that only 34 histologically evident cases have previously been reported. Among several conditions that have been correlated with this problem the most frequent is Peyronie disease. In all these conditions, human penile ossification appears to be a metaplastic bone formation process. CASE REPORT: A 59-year-old white man presented with a one-year history of slight pain upon erection and during intercourse. He also complained of hard plaque near the base of the penis. One year earlier, he had sustained blunt trauma during intercourse. Examination of the penis revealed a fixed firm mass extending over the proximal third of the penile shaft, measuring 3.0 x 3.0 x 2.0 cm and involving the corporal sponge, without surface extension. There was no impotence or other relevant clinical finding. Radiography on the penis revealed irregular calcification in the same position as the palpable mass and in the septum of the proximal inner third of the penis. The importance of this report lies in the extent of the human penile ossification, as demonstrated by the radiological and histological confirmation.

CONTEXTO: Ossificação do pênis humano é uma condição rara e apenas 34 casos histologicamente evidentes foram relatados. Várias condições foram relacionadas com o problema e o mais freqüente foi a Doença de Peyronie. Em todas, as ossificações parecem ser resultado de um processo de metaplasia com formação óssea. RELATO DO CASO: Um homem de 59 anos branco apresentou-se com história de leve dor no pênis durante as ereções há um ano. Ele também referia a presença de uma placa dura na base do pênis, que começou a crescer após um trauma na relação sexual. O exame do pênis revelou tratar-se de uma massa fixa, firme, no terço proximal do pênis de aproximadamente 3.0 x 3.0 x 2.0 cm, sem extensão para a superfície. Não havia impotência ou outra alteração clínica relevante. A radiografia do pênis identificou extensa área calcificada no corpo esponjoso e região do septo, em correspondência à massa palpada. A importância deste relato é a extensão da ossificação de acordo com a radiologia e confirmação histológica.

Doença de Peyronie: etiopatogenia e diagnóstico / Peyronie's disease: clinical and pathological findings and diagnosis

Os autores apresentam os achados clínicos e patológicos e indicam as possibilidades diagnósticas para a doença de Peyronie. Frente às condutas terapêuticas definidas, o diagnóstico seguro e a extensäo do processo passam a ser mais importantes.