Pathophysiology and Medical Management

Peyronie’s disease (indurato penis plastica) is an inflammatory condition that is characterized by the formation of fibrous, noncompliant nodules within the tunica albuginea. These plaques impede tunical expansion during erection, resulting in penile bending. In some extreme cases, these plaques can induce a collar-like or an hourglass-like appearance in the erect penis. Unlike normal wound healing following trauma, plaques in patients with Peyronie’s disease do not resolve. Subsequent to inflammation and cessation of pain, in the chronic stages of the disease, the plaques may ossify.

One can sub-classify Peyronie’s patients into three categories: (1) patients with asymptomatic plaques or some penile bending, which does not affect intercourse; (2) patients whose plaques exacerbate penile bending to the point that intercourse is either painful and/or no longer physically possible; and (3) patients whose Peyronie’s disease is also associated with erectile dysfunction. In patients with erectile dysfunction, penile arterial inflow is usually unimpeded, with the major abnormality observed being venous leakage, usually at the site of the plaque.

Genetics and Occurrence

The search for a genetic link for Peyronie’s disease has yet to identify a genetically-predisposed population. However, there are reports associating this condition and Paget’s disease of the bone, Dupuytren’s contracture, and specific human leukocyte antigen (HLA) subtypes. In all of these studies, patients reporting one of the traits (Paget’s disease of the bone, Dupuytren’s contracture, or specific HLA subtypes), did not always report symptoms of Peyronie’s disease. Studies of Peyronie’s patients have implicated an autoimmune component. It was shown that Peyronie’s disease patients had at least one abnormal immunologic test (7 5.8 %), alterations in cell-mediated immunity (48.5%), and in markers of autoimmune disease (37.9%). Another study found higher than normal levels of anti-elastin antibodies in the serum of patients with Peyronie’s disease, suggesting an autoimmune etiology. It is likely that a certain proportion of men in this age group respond to mechanical tunical stress and mi-crovascular trauma with an aberrant or hyperactive wound healing response. Thus, there may be a subpopulation whose genetic background is such that response to wound healing predisposes development of Peyronie’s plaques.

There are few reports examining the incidence and prevalence of Peyronie’s disease. The incidence is estimated to be 0.4 to 3.2%. Unfortunately multi-national, multi-institutional data is lacking. However, there are some insights relating to a higher incidence. A thirty-five year retrospective study in Rochester, Minnesota, is notable. In this study, comprised primarily of Caucasian men, the average age of onset was 53 years old, with a prevalence of 388.6/100 000 (0.4%), and an age-adjusted annual incidence rate of 25.7/100 000 men (0.3%). At the time of the study nine years ago, this translated into 32 000 new cases in the United States annually, with approximately 423 000 men with Peyronie’s disease at any given time. Contrary to the genetic studies described above, there was no significant association between Dupuytren’s contracture and Peyronie’s disease. Further, over the thirty-five year period, both total Peyronie’s disease, and Peyronie’s disease associated with pain and impotence, increased. This may be an actual increase in disease occurrence or due to heightened patient awareness and seeking of medical attention. Interestingly, rheumatoid arthritis (p < 0.0001) and hypertension (p < 0.01) were the most commonly associated conditions reported in this group of Peyronie’s disease patients. It should be noted that the study described above probably underestimates the true prevalence of Peyronie’s disease, as indicated by autopsy studies. In a study of 100 men who had no known Peyronie’s disease, 22/100 had asymptomatic, fibrotic lesions of the tunica albug-inea. This suggests that in the natural course of aging and sexual activity, these asymptomatic lesions may develop. The prevalence of Peyronie’s disease is probably much higher than 0.4% if one includes subclinical, asymptomatic cases, Regardless, the number of patients presenting with Peyronie’s disease in the United States is expected to increase as the “baby boom” generation progresses through ages 50 to 70.

Therapeutics and the Molecular Pathology of Peyronie’s Disease

How do these mechanisms correlate with current therapeutic treatment of this disease? There are two basic categories of pharmacotherapeutics that have been used in Peyronie’s disease: anti-oxidants and collagen synthesis inhibitors. As described briefly above, it has been hypothesized that oxidative damage may be causal in the initiation and progression of tissue fibrosis.

Presently, non-surgical options for the treatment of Peyronie’s disease are based on anecdotal experiences with studies limited by a small number of patients, limited follow-up, the absence of placebo-control groups, and no objective measures to represent improvement. The historical reporting of spontaneous remission rates ranges from seven to 29%.

Peyronie’s Disease: Oral Therapies

Topical Therapies

Mechanism of action: Increased extracellular matrix collagenic secretion, and decreased collagen and fibronectin synthesis and secretion. Martin and co-workers in 2002 investigated tissue concentrations in men who applied verapamil topically. While this drug was found to be present in urine samples, no verapamil was detected in the tunica albuginea specimens obtained at the time of penile prostheses implantations. The authors subsequently concluded that topical application of verapamil had no scientific basis, and given the fact that no control trial has been performed, the current use of topical verapamil is not recommended.

Peyronie’s Disease: Intra-lesional Therapies

External Energy Therapy

Shock wave therapy

Mechanism of action: Local penile electro Shockwave therapy (ESWT) has been potentially recommended to induce inflammatory response leading to plaque lyses and improved vascularity.

Most studies on the efficacy of ESWT are limited to subjective reports of improvements of deformity, plaque size, or pain. Hauck et al. in a controlled trial, randomized 43 men to ESWT or an oral placebo for six months. No significant effect of treatment was noted on curvature, plaque size, or subjective improvements in sexual function or rigidity.

Iontophoresis

Several studies have recently investigated the efficacy of topically-applied verapamil, with or without dexamethasone, with enhanced penetration using iontophoresis (electromotive drug administration). Di Stasi and associates randomized 96 patients to treatment with verapamil 5 mg plus dexamethasone 8mg, using electromotive drug administration. Of the 73 patients who completed the study, 43 % in the verapamil oblique dexamethasone noted improvement objectively in plaque size, as measured by ultrasonography, and curvature as noted by photography. No change in parameters in the Lido cream group was noted. Preliminary results of iontophoresis with verapamil versus saline were reported at the 2003 meeting of the American Urologic Association, with similar results in both groups. Further investigation in this modality maybe warranted.

Combination Therapies

Various combinations of therapies have been evaluated and investigated as potential treatments for Peyronie’s disease. A controlled study by Pieto Castro et al. randomized 45 patients to receive vitamin E plus colchicine and/or ibuprofen (placebo). Patients in the treatment group reported a higher percentage of pain relief, although the difference was not significant. Mirone et al. examined two populations of patients with Peyronie’s disease: electromotive drug administration plus perilesional verapamil, versus electromotive drug administration alone. A 52% improvement in plaque size was noted for the E SWT group only, compared to 19 % in the combination arm. Authors have randomized patients to receive intralesional verapamil plus oral carnitine, or intralesional verapamil plus oral tamoxifen as well. Cavalini et al. demonstrated no significant difference in pain between the two groups.

Summary

Peyronie’s disease is a fibrotic disorder of the tunica albuginea involving potential trauma to the penis and an inflammatory response. The fibrotic plaques that form are produced most likely by tunical flbroblasts in response to cytokine stimulation. Of the candidate cytokines, TGF-Pl and possibly platelet-derived growth factor (PDGF) play a role. To date, pharmacotherapy has not been effective or widely accepted, and surgery to either remove the plaque or insert penile prostheses remains the mainstay of treatment. A better understanding of the molecular pathology of this disease is expected to improve pharmacotherapeutic strategies to treat this condition.

The investigation for medical options in the management of Peyronie’s disease currently lacks controlled clinical trials with standardized assessments and objective measurements of improvement in curvature, circumferential deformities, and/or sexual function. Research into the pathophysiology of this disorder is likely to yield new insights into potential treatment options. At the present time, no ideal non-surgical cure is noted.

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