Summary of “Pathophysiology and Future Therapeutic Perspectives for Resolving Fibrosis in Peyronie’s Disease”

***Trost Commentary and Key Take-Home Points***

The current review article discusses some of the complexities of the process by which Peyronie’s Disease leads to penile fibrosis and scarring. The key take home point is that, to date, there are no good treatments which have been shown to prevent the progression of Peyronie’s Disease scarring. Although there are many websites, ads, blogs, forums, or other locations which may purport to have a treatment that prevents development or progression of the fibrosis associated with Peyronie’s disease, these therapies have not been investigated in a way that it is possible to know if they actually do anything for the condition or not. That’s not to say that there aren’t treatments available for PD in the early phase, including treatments which SHOULD be started as soon as possible to limit the extent of curvature, length loss, and deformity, but rather, the key take home is that any oral, topical, injectable, or any other form of therapy which is supposed to prevent the fibrosis of Peyronie’s Disease is misleading and has not been proven to be effective.

Introduction

Peyronie’s disease is a connective tissue disorder of the penis. It has been underestimated since being discovered in 1743, with early doctors using a conservative approach.  Despite early case series reporting spontaneous resolution as commonplace, recent studies have shown it to be less frequent, just 13%.  In contrast, most studies show that it is far more common for the disease to worsen with time. 

Peyronie’s disease is characterized by a fibrous plaque that begins with inflammation (and sometimes pain) before the plaque fully forms with stable deformity and curvature. This curvature frequently results in the inability to engage in intercourse and is often associated with erectile dysfunction.

Treatments

The most common treatment options include surgery and collagenase or interferon injections. Collagenase injections break down the plaque tissue, while interferon has an antifibrotic effect on fibroblasts. Surgery has also proven effective, though it can be accompanied by volume loss, glanular hypoesthesia, and new or worsening erectile dysfunction.  

Although these treatments have proven effective, they do not focus on the underlying pathophysiological process that leads to Peyronie’s disease. The etiology and pathophysiology of the disease are still relatively unknown, despite the disease being known for 250+ years. It is mainly thought to be related to penile trauma, either a remembered event or small repetitive traumas during intercourse. This is consistent with the formation of fibrotic tissue and calcification.  

Fibrosis

ibrosis is a factor in many disorders and can occur in many organs of the body, including skin, heart, liver, lung and kidney. It is caused by chronic inflammation which leads to excess extracellular matrix (ECM). In its early stages, fibrosis is reversible, but it eventually becomes permanent scar tissue, which leads to organ failure. The role of the ECM has shown to be key in fibrotic formation, as it interacts with macrophages and myofibroblasts.  

In Peyronie’s disease, fibrosis occurs as the penis is subjected to repeated micro-traumas during intercourse, though there may be other systemic or genetic factors that contribute as well. It is thought that transforming growth factor (TGF-𝛽1) plays a role as it increases fibrillary extracellular matrix proteins.  

Genetic Factors

Some studies have shown several chromosomal issues in men with Peyronie’s disease, including instability, duplication and deletion. RNA sequencing has shown significant differentially expressed genes, which could play a role in sustained fibrosis.  

Drug Discovery

Since the 1990s, drugs are now being focused on modifying target proteins involved in the pathogenesis of disease, though there is the risk that the target molecules are not linked to the pathogenesis of the disease. This target-based screening is in contrast to the previous phenotypic screening, which did not factor in the molecular mechanisms of action. However, phenotypic screening should be used to explore drugs for fibrotic diseases, as pathologic phenotypes are more relevant than an isolated pathway.  

Tissue repair is a natural evolutionary survival response of our bodies and several elements work closely together to repair damage.  In cases where one pathway of tissue repair is impaired, other compensatory pathways are activated.    

Many oral treatments have been recommended for Peyronie’s disease, including potassium para-aminobenzoate, vitamin E, colchicine, pentoxifylline and acetyl-L-carnitine, but only PDE5is are endorsed by the American Urological Association for use in treating combined erectile dysfunction. All of these drugs are used for chronic, stable phase of the disease, and few drugs have been studied or used to treat the early phase of Peyronie’s disease. 

Conclusion

The etiology of Peyronie’s disease is complex and unknown, other than some characteristics of the fibrotic plaques that form in the shaft of the penis. Many treatments have been tried, though only few are recommended for the treatment of Peyronie’s disease.  There are several areas of Peyronie’s disease and many new technologies that need to be explored and studied in relation to the disease.  

References

Milenkovic U, Ilg MM, Cellek S, et al. Pathophysiology and Future Therapeutic Perspectives for Resolving Fibrosis in Peyronie’s Disease. Sex Med Rev 2019;7:679–689 

https://www.smr.jsexmed.org/action/showPdf?pii=S2050-0521%2819%2930011-3

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