Penile surgery for patients with Peyronie's disease initially treated with collagenase clostridium histolyticum or surgery: a claims database analysis.

Collagenase clostridium histolyticum (CCH) is an injectable therapy targeting collagen present in penile plaques in Peyronie's disease (PD). Data comparing CCH to penile surgery are limited, and long-term therapeutic outcomes are unknown. This retrospective analysis used a US claims database (January 2014-June 2017) to determine the percentage of men with subsequent penile surgery among those who initially received CCH (n = 1227) or surgery (index treatment; n = 620) for PD. Eligible patients were aged ≥18 years with continuous enrollment ≥6 months before and ≥12 months after index treatment date. During 12 months of post-index treatment follow-up, fewer patients with PD initially treated with CCH (4.6% [56/1227]) had subsequent penile surgery versus those initially treated with penile surgery (10.3% [64/620]; p < 0.0001). Mean ± SD time to first subsequent surgery after initial PD treatment was longer in the CCH versus surgery cohort (7.7 ± 3.0 vs 1.7 ± 3.2 months). The likelihood of subsequent surgery varied by initial surgery type: 18.2% after plaque incision or excision with grafting; 11.6% after penile implant; and 8.2% after tunical plication. Patients with PD who received CCH first were less likely to undergo subsequent surgery compared with those who received surgery first within a 12-month post-treatment follow-up.

X-ray micro-computed tomography in the assessment of penile cavernous fibrosis in a rabbit castration model.

BACKGROUND: Current assessment methods of penile cavernous fibrosis in animal models have limitations due to the inability to provide complex and volume analysis of fibrotic alterations. OBJECTIVE: The aim was to evaluate micro-computed tomography for assessment of cavernous fibrosis and compare it with histological, histochemical, immunohistochemical, and RT-PCR analysis. MATERIALS AND METHODS: A controlled trial was performed involving 25 New Zealand male rabbits with induced testosterone deficiency by orchidectomy. Penile samples were obtained before and after 7, 14, 21, and 84 days from orchidectomy. We consistently performed (a) gray value analysis of corpora cavernosa 3D models reconstructed after micro-computed tomography, (b) morphometry of smooth muscles/connective tissue ratio, collagen type I/III ratio, and area of TGF-beta-1 expression in corpora cavernosa, and (c) RT-PCR of TGF-beta-1 expression. RESULTS: Micro-computed tomography allowed visualization of penile structures at a resolution comparable to light microscopy. Gray values of corpora cavernosa decreased from 1673 (1512-1773) on the initial day to 1184 (1089-1232) on the 21st day (p < 0.005). However, on the 84th day, it increased to 1610 (1551-1768). On 21st and 84th days, there was observed a significant decrease in smooth muscle/connective tissue ratio and a significant increase in collagen type I/III ratio (p < 0.05). TGF-beta1 expression increased on the 84th day according to immunohistochemistry (p < 0.005). RT-PCR was impossible to conduct due to the absence of RNA in obtained samples after micro-CT. DISCUSSION AND CONCLUSIONS: Micro-computed tomography provided 3D visualization of entire corpora cavernosa and assessment of radiodensity alterations by gray value analysis in fibrosis progression. We speculate that gray value changes at early and late fibrosis stages could be related to tissue reorganization. RT-PCR is impossible to conduct on tissue samples studied by micro-CT due to RNA destruction. We also suggest that micro-computed tomography could negatively affect the immunohistochemical outcome, as a significant increase of TGF-beta-1 expression occurs later than histological fibrotic signs.

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.

Dupuytren, Ledderhose, and Peyronie Diseases After Primidone Use For Essential Tremor.

INTRODUCTION: Dupuytren, Ledderhose, and Peyronie diseases are chronic fibrotic conditions related to progressive fibrosis of the palmar fascia, plantar fascia, and tunica albuginea, respectively. These conditions have been associated with antiepileptic drug use, mainly phenobarbital and primidone. CASE REPORT: A 71-year-old man developed simultaneous Dupuytren, Ledderhose, and Peyronie diseases after primidone use for essential tremor. CONCLUSIONS: There are a few reports associating barbiturate use to connective tissue disorders, and some suggest that drug withdrawal may result in a better prognosis. Therefore, physicians must be aware of such adverse events when caring for patients on long-term barbiturate use.

Peyronie's disease and Dupuytren's contracture secondary to topical timolol.

INTRODUCTION: Topical beta-blockers are a proven and safe medication used in the treatment of glaucoma and ocular hypertension. Local and systemic side effects are, however, well documented. Systemic side effects can include severe cardio-respiratory impairment, endocrine dysfunction, as well as headache and hyper-somnolence. Disorders involving fibrosis such as Peyronie's disease, Dupuytren's contracture, and retroperitoneal fibrosis are rarely described in the literature. CASE REPORT: We describe a case of a 55-year-old male patient undergoing treatment for ocular hypertension with topical timolol 0.25% to both eyes, who subsequently developed both Peyronie's disease and Dupuytren's contracture. To our knowledge, this is the first case of Dupuytren's contracture secondary to the use of topical timolol. CONCLUSIONS: Whilst uncommon, beta-blockers are known to be associated with such fibrotic conditions and have been reported with the use of topical timolol. This case serves to increase the current understanding of this association.

Repeated Micro-Trauma of the Penile Tunica Albuginea: A New Animal Model of Peyronie's Disease.

OBJECTIVES: To compare effects of repairing injured tunica albuginea (PTA) of rat penis by single or repeated local injections of chlorhexidine ethanol (ChE) into the PTA and to establish a new animal model of Peyronie's disease (PD). MATERIALS AND METHODS: Forty-two rats were divided into 7 groups. Rats either served as the normal control group with 1-5 injections of 0.9% saline or they received a single injection, 2, 3, 4, or 5 injections of ChE (0.1% chlorhexidine gluconate plus 15% ethanol dissolved in saline); rats in the positive control group were injected with TGF-ß1. At 60 days after the last injection, the intracavernous pressure, degree of penile curvature, and histology were evaluated. RESULTS: Compared with the single injection of the ChE group, we found the following in the repeat ChE injections groups: an increase in the degree of penile curvature, fibrous plaques in the PTA and/or corpus cavernosum, broken elastic fibers, slightly decreased erectile function, and an increased expression of TGF-ß1 and αSMA. CONCLUSIONS: Repeated ChE injuries of PTA may lead to fibrosis. This represents an excellent model of PD that involves repeated injections of ChE into the local PTA as well as reveals the pathophysiologic mechanism of PD.

[Animal models of Peyronie's disease: An update].

Peyronie's disease is characterized by local fibrosis of the tunica albuginea and relatively rare clinically. Few relevant basic researches could be retrieved, which might be attributed to the absence of a robust animal model of the disease as well as to its rareness. At present, some animal models available for Peyronie's disease have their own merits and demerits. TGF-ß1-induced and Fibrin-induced models are lack of penile curvature and calcification/ossification. A surgical model might be established for the acute phase of the disease. The characteristic of a widespread fibrotic process involving many organs in the spontaneous model is quite different from that of human Peyronie's disease. Therefore, choosing the right model is essential for researches. This paper presents an overview of the animal models of Peyronie's disease, meant to provide some reference for the basic research of the disease.

Peyronie disease in association with carvedilol: a case report.

Beta blockade is associated with the onset and progression of Peyronie disease (PD). To date, there has not been a report of PD occurring with the alpha/beta blocker carvedilol. It remains unproven but likely that carvedilol was the cause of the PD in the patient described in this case. It is hypothesized that because of carvedilol's vasodilating alpha adrenergic receptor stimulation and its anti-inflammatory effect, PD occurs less frequently with carvedilol than with other beta blockers. However, in this case the protective properties of carvedilol, like vasodilation and the anti-inflammatory effect, may not be sufficient to overcome its vasoconstricting beta adrenergic receptor blockade.

Effects of long-term vardenafil treatment on the development of fibrotic plaques in a rat model of Peyronie's disease.

OBJECTIVES: To determine whether the phosphodiesterase-5 (PDE5) inhibitor, vardenafil, given orally and in different regimens, has a similar effect to that of the PDE5 inhibitor sildenafil, which prevented the development of a Peyronie's disease (PD)-like plaque formation induced by injecting transforming growth factor beta1 (TGF-beta1) into the tunica albuginea of the rat. MATERIALS AND METHODS: Vardenafil was given to male rats (eight per group) either in the drinking water or as an oral instillation once daily, at approximately 1 and approximately 3 mg/kg/day for 45 days after one injection with TGF-beta1 into the tunica albuginea, as an 'early preventive' treatment for TGF-beta1-induced formation of a PD-like plaque. Other groups received the two doses of vardenafil only in the drinking water, starting with a well-formed plaque, for 42 days ('late, therapeutic' administration). Sections of penile tissue were stained histochemically or immunohistochemically, followed by quantitative image analysis for collagen/smooth muscle and collagen III/I ratios, myofibroblast content (alpha-smooth muscle actin), TGF-beta1 expression, and apoptotic index. RESULTS: Preventative treatment with vardenafil at the higher dose (both continuous and once-daily treatments) reduced the collagen/smooth muscle and collagen III/I ratios, and the numbers of myofibroblasts and TGF-beta1-positive cells, and selectively increased the apoptotic index in the PD-like plaque. The lower dose was less effective, When vardenafil was given continuously in the drinking water for 41 days after the PD-like plaque was formed, there was only a partial reduction of the plaque. CONCLUSIONS: Long-term oral treatment with vardenafil slows and reverses the early stages of an experimental PD-like plaque in the rat, and might ameliorate a more advanced plaque.

Peyronie's disease in men with HIV responding to highly active antiretroviral therapy.

The pathogenesis of Peyronie's disease (induratio penis plastica) is unclear, but immune phenomena appear likely to be involved. Two cases are presented where the condition developed in temporal association with a virological response to highly active antiretroviral therapy (HAART) in men with HIV infection. It is suggested that this may represent another manifestation of immune restoration disease.

Development of Peyronie's disease during long-term colchicine treatment.

Colchicine has been reported to be a safe and effective medication in the treatment of early phase of Peyronie's disease (PD). However here we reported two patients, presenting with PD during high dose colchicine treatment for familiar mediterranean fever (FMF).

Evaluation of nitric oxide synthase and arginase in the induction of a Peyronie's-like condition in the rat.

Peyronie's disease is an idiopathic, localized connective tissue disorder of the penis, involving the tunica albuginea of the corpus cavernosum and adjacent areolar space. Current proposals as to the origin of Peyronie's disease suggest that fibrosis and collagen changes of the tunica are the result of an inflammatory process following vascular trauma. Our laboratory and other investigators have recently proposed an animal model for the study of Peyronie's disease. When transforming growth factor-beta1 (TGF-beta1) was injected into the rat tunica albuginea, tissue fibrosis was observed at 6 weeks. Therefore, our aim was to assess arginase II, endothelial and inducible nitric oxide synthase isoforms, and nitrotyrosine levels--all factors involved in inflammatory reactions--in the cavernosal tissue of saline-injected and TGF-beta1-injected rats after 6 weeks in order to evaluate the roles these enzymes may play in the induction of a Peyronie's-like condition in the rat. To examine the expression of endothelial nitric oxide synthase (eNOS), iNOS, and arginase II protein, and mRNA in the corpus cavernosum, immunoblot analysis, and reverse transcriptase-polymerase chain reaction were performed. We also determined immunohistochemically the expression of nitrotyrosine, a marker of peroxynitrite formation, in the rat penis. After 6 weeks, iNOS protein and gene expression was up-regulated and eNOS protein and gene expression was down-regulated in the corpora cavernosa of the TGF-beta1-injected penises. Furthermore, arginase II protein expression as well as immunohistochemical localization of nitrotyrosine was significantly higher in the TGF-beta1-injected corpora cavernosa. These results suggest that iNOS is the key control element for peroxynitrite formation, arginase II expression, and eNOS down-regulation in the induction of a Peyronie's-like condition in the rat.

Histological and ultrastructural alterations in an animal model of Peyronie's disease.

OBJECTIVE: To determine the role of transforming growth factor beta (TGF-beta), one of the cytokines known to induce tissue fibrosis, in the induction of a Peyronie's-like condition, and to produce an animal model for the further study of Peyronie's disease. MATERIALS AND METHODS: Twenty-four adult male Sprague-Dawley rats were divided into two groups: in group 1, different concentrations of cytomodulin, a synthetic heptapeptide with TGF-beta-like activity, were injected into the tunica of each of 18 rats and six rats group 2 received saline injections as a control. The tunical tissues were taken after 3 days, 2 and 6 weeks and were examined histologically using Hart and trichrome stains. Electron microscopy was used to examine the ultrastructural changes in the same tissue samples. RESULTS: There were histological and ultrastructural alterations in 15 of 18 rats in group 1 (cytomodulin-injected), especially in tissue examined after 6 weeks. The most prominent histological changes were chronic inflammatory cellular infiltration, focal and diffuse elastosis, thickening, disorganization and clumping of the collagen bundles. The ultrastructural changes were in the form of densely packed collagen, fragmented and scarce elastic fibres, separation of neuronal fibres by interposing clumps of packed collagen, and perivascular collagen deposition as a part of the reorganization of the interstitial matrix. CONCLUSION: Cytomodulin can induce a Peyronie's-like condition in the rat penis, which may explain the role of TGF-beta in the pathogenesis of Peyronie's disease. With further refinement, such rats may be used as an experimental model for studies of Peyronie's disease.

Peyronie's-like plaque after penile injection of prostaglandin E1.

Intracavernous injection of vasoactive medication may cause fibrosis of the tunica albuginea or corpus cavernosum. These adverse effects have been clearly linked to papaverine and phentolamine but to our knowledge the development of fibrosis or a Peyronie's-like plaque after the injection of prostaglandin E1 has not been previously described. We report a case of intracavernous hematoma, penile curvature deformity and Peyronie's-like plaque that developed after initiating intracorporeal self-injection of prostaglandin E1 for erectile dysfunction.