madman
Super Moderator
Peyronie’s disease (PD) is a localized fibrotic lesion of the penis that has adverse effects on men’s health. In this review, we summarized the molecular mechanisms and pharmacotherapies of PD. A literature search was conducted using PubMed and Cochrane Library during 2001–2020. Although no oral or topical medication demonstrated efficacy in monotherapy of PD, several intralesional medications have yielded promising results. Currently, the effective strategy in the management of PD should be combined modality therapy, including but not limited to pharmacotherapy, mechanical therapy, and psychotherapy. Meanwhile, basic research is still necessary to facilitate the development of novel and more reliable treatments. In the future, more attention should be given simultaneously to epigenetic changes, inflammatory cytokines, the abnormal wound-healing process, and profibrotic and anti-fibrotic factors to provide more options for this refractory disease.
INTRODUCTION
In the spectrum of fibrotic conditions, penile fibrosis is characterized by disproportionate accumulation of collagen components in the tunica albuginea, penile corpora cavernosa, and corpus spongiosum, termed as Peyronie’s disease (PD), corporal fibrosis, and urethral stricture respectively (Garaffa et al., 2013; Milenkovic et al., 2019a). Among them, PD is a localized penile lesion possibly associated with micro-trauma during intercourse and an abnormal wound-healing process (Gonzalez-Cadavid and Rajfer, 2005). As a progressive fibrotic disease, PD often results in local pain, penile deformity, difficult penetrative intercourse, erectile dysfunction (ED), mental diseases, and relationship difficulties, which have several adverse impacts on the life quality of males, sometimes seriously (Gaffney and Kashanian, 2020). It is reported that the incidence of PD might be 22.4 to 25.7 per 100,000 men, with the average age of patients being 55 years (Herati and Pastuszak, 2016). However, the prevalence of PD is likely underestimated due to under-reporting bias from those never seeking treatment (Chung et al., 2020). Although the mechanisms of PD are not fully understood several molecular pathological changes of the PD plaque have been recognized recently (Graziottin, 2015; Paulis et al., 2017). Currently, available satisfactory treatments for PD are limited and in certain situations, non-surgical medication might be an important alternative therapeutic approach to PD. This review summarizes the current perspectives on molecular mechanisms and available pharmacotherapies of PD, in order to provide reasonable therapy regimens for clinicians.
*PATHOPHYSIOLOGY
*GENETIC PREDISPOSITION
*MOLECULAR MECHANISMS
*PHARMACOTHERAPY FOR PD
Oral Medication
L-Arginine
Pentoxifylline
Tamoxifen
Phosphodiesterase Type 5 Inhibitors
Intralesional Medication
Verapamil
Interferon-α2b
Corticosteroids
Hyaluronic Acid
Collagenase Clostridium Histolyticum
*Topical Medication
*Potential Novel Drugs of PD
*Stem Cell Therapy of PD
SUMMARY
The research on molecular mechanisms and treatment of PD has attracted attention in recent years. Actually, PD shares some similar molecular mechanisms with other fibrotic disorders, which facilitates the development of novel pharmacological experiments and therapies. However, the exploration of a small segment of complicated fibrotic processes in PD is still a mainstream view in current studies. It means that the efficacy of monotherapy could be offset by other signaling pathways. So far, multiple agents with diverse delivery routes have been investigated and applied in the treatment of PD. However, the efficacy of these agents is limited.
Although no oral medication in monotherapy has demonstrated reliable results, data from some basic studies appear to support some oral medication. Together with few side effects and low cost, we hold the opinion that taking oral medications, such as L-arginine, pentoxifylline, and PDE5Is, into consideration as a part of a combination regimen for PD is reasonable and pragmatic. Meanwhile, no strong evidence supports the use of vitamin E, potassium aminobenzoate, carnitine, and colchicine to date. As the efficacy of a treatment for PD is evaluated partly using subjective PD and ED questionnaires, we hypothesize that some effects of these drugs might be attributed to a placebo effect as opposed to a real response. By contrast, the intralesional therapy used for PD seems to yield better results, meaning clostridial collagenase is considered as an optimal medication. However, clostridial collagenase is very expensive and not suitable for all PD patients. As an alternative drug delivery route, topical medications have not shown promising results and need further evaluation in future trials.
It seems that all fibrotic diseases have the transformation of fibroblast to myofibroblast as a common fundamental. Drugs targeting the inhibition of myofibroblast transformation are gaining increasing attention from researchers. Despite the lack of further confirmation, 17β-estradiol, adenosine receptor A2B agonist and ROCK inhibitor have shown to be effective for acute PD. Regenerative medicine as a new branch of medical science has developed rapidly in recent years. Several studies explored the antifibrotic effects of ADSCs on PD-like plaque and found exciting results. Despite the limited data from human trials, current studies have focused on specific molecular mechanisms and used representative animal models of PD. Meanwhile, the use of SC could redress the balance between pro-fibrotic and anti-fibrotic roles as a whole. Thus, SC therapy has the potential to be integrated into the combination treatment of PD.
Taken together, the effective non-surgical treatment for PD should be a combination modality, including various pharmacotherapies, mechanical therapies, shock wave therapies, psychotherapies, and so on, which might generate synergy benefits to PD patients. Meanwhile, basic research on pathogenesis is still necessary to provide more perspectives on therapeutic options. In the future, more effective regimens should focus simultaneously on the epigenetic changes, inflammatory cytokines, abnormal wound-healing process, and balance between profibrotic and anti-fibrotic factors in order to provide promising options for this refractory disease. Due to the lack of specific markers used in the diagnostic and therapeutic evaluation, treatment for penile fibrotic diseases is still lacking. Thus, it is of equal importance to bring genetic phenotyping and biomarkers into clinical studies of patients with PD. Ultimately, how to regain balance between ECM deposition and degradation might become the cornerstone to attenuate PD and other fibrotic conditions.
INTRODUCTION
In the spectrum of fibrotic conditions, penile fibrosis is characterized by disproportionate accumulation of collagen components in the tunica albuginea, penile corpora cavernosa, and corpus spongiosum, termed as Peyronie’s disease (PD), corporal fibrosis, and urethral stricture respectively (Garaffa et al., 2013; Milenkovic et al., 2019a). Among them, PD is a localized penile lesion possibly associated with micro-trauma during intercourse and an abnormal wound-healing process (Gonzalez-Cadavid and Rajfer, 2005). As a progressive fibrotic disease, PD often results in local pain, penile deformity, difficult penetrative intercourse, erectile dysfunction (ED), mental diseases, and relationship difficulties, which have several adverse impacts on the life quality of males, sometimes seriously (Gaffney and Kashanian, 2020). It is reported that the incidence of PD might be 22.4 to 25.7 per 100,000 men, with the average age of patients being 55 years (Herati and Pastuszak, 2016). However, the prevalence of PD is likely underestimated due to under-reporting bias from those never seeking treatment (Chung et al., 2020). Although the mechanisms of PD are not fully understood several molecular pathological changes of the PD plaque have been recognized recently (Graziottin, 2015; Paulis et al., 2017). Currently, available satisfactory treatments for PD are limited and in certain situations, non-surgical medication might be an important alternative therapeutic approach to PD. This review summarizes the current perspectives on molecular mechanisms and available pharmacotherapies of PD, in order to provide reasonable therapy regimens for clinicians.
*PATHOPHYSIOLOGY
*GENETIC PREDISPOSITION
*MOLECULAR MECHANISMS
*PHARMACOTHERAPY FOR PD
Oral Medication
L-Arginine
Pentoxifylline
Tamoxifen
Phosphodiesterase Type 5 Inhibitors
Intralesional Medication
Verapamil
Interferon-α2b
Corticosteroids
Hyaluronic Acid
Collagenase Clostridium Histolyticum
*Topical Medication
*Potential Novel Drugs of PD
*Stem Cell Therapy of PD
SUMMARY
The research on molecular mechanisms and treatment of PD has attracted attention in recent years. Actually, PD shares some similar molecular mechanisms with other fibrotic disorders, which facilitates the development of novel pharmacological experiments and therapies. However, the exploration of a small segment of complicated fibrotic processes in PD is still a mainstream view in current studies. It means that the efficacy of monotherapy could be offset by other signaling pathways. So far, multiple agents with diverse delivery routes have been investigated and applied in the treatment of PD. However, the efficacy of these agents is limited.
Although no oral medication in monotherapy has demonstrated reliable results, data from some basic studies appear to support some oral medication. Together with few side effects and low cost, we hold the opinion that taking oral medications, such as L-arginine, pentoxifylline, and PDE5Is, into consideration as a part of a combination regimen for PD is reasonable and pragmatic. Meanwhile, no strong evidence supports the use of vitamin E, potassium aminobenzoate, carnitine, and colchicine to date. As the efficacy of a treatment for PD is evaluated partly using subjective PD and ED questionnaires, we hypothesize that some effects of these drugs might be attributed to a placebo effect as opposed to a real response. By contrast, the intralesional therapy used for PD seems to yield better results, meaning clostridial collagenase is considered as an optimal medication. However, clostridial collagenase is very expensive and not suitable for all PD patients. As an alternative drug delivery route, topical medications have not shown promising results and need further evaluation in future trials.
It seems that all fibrotic diseases have the transformation of fibroblast to myofibroblast as a common fundamental. Drugs targeting the inhibition of myofibroblast transformation are gaining increasing attention from researchers. Despite the lack of further confirmation, 17β-estradiol, adenosine receptor A2B agonist and ROCK inhibitor have shown to be effective for acute PD. Regenerative medicine as a new branch of medical science has developed rapidly in recent years. Several studies explored the antifibrotic effects of ADSCs on PD-like plaque and found exciting results. Despite the limited data from human trials, current studies have focused on specific molecular mechanisms and used representative animal models of PD. Meanwhile, the use of SC could redress the balance between pro-fibrotic and anti-fibrotic roles as a whole. Thus, SC therapy has the potential to be integrated into the combination treatment of PD.
Taken together, the effective non-surgical treatment for PD should be a combination modality, including various pharmacotherapies, mechanical therapies, shock wave therapies, psychotherapies, and so on, which might generate synergy benefits to PD patients. Meanwhile, basic research on pathogenesis is still necessary to provide more perspectives on therapeutic options. In the future, more effective regimens should focus simultaneously on the epigenetic changes, inflammatory cytokines, abnormal wound-healing process, and balance between profibrotic and anti-fibrotic factors in order to provide promising options for this refractory disease. Due to the lack of specific markers used in the diagnostic and therapeutic evaluation, treatment for penile fibrotic diseases is still lacking. Thus, it is of equal importance to bring genetic phenotyping and biomarkers into clinical studies of patients with PD. Ultimately, how to regain balance between ECM deposition and degradation might become the cornerstone to attenuate PD and other fibrotic conditions.
