madman
Super Moderator
Abstract
Introduction: Peyronie’s disease (PD) is a disorder of the tunica albuginea from the disordered and excessive deposition of collagen resulting in a palpable scar, pain, erect penile deformity, and erectile dysfunction that significantly impacts patients both physically and emotionally.
Areas Covered: Several treatment options have been described for PD, including shockwave therapy, traction therapy, both oral and intralesional pharmacological options, and surgery. This review seeks to examine the data for different types of non-surgical treatments for PD. We review how various treatment modalities impact several relevant clinical endpoints for Peyronie’s disease, including effects on pain, penile curvature, plaque formation, and erectile function. We performed a literature search using PubMed and SCOPUS while referencing AUA, EAU, and CUA guidelines for the management of Peyronie’s Disease for studies published 1980- 2020.
Expert opinion: Intralesional collagenase injections have the strongest evidence and are the only FDA-approved intralesional treatment for PD. Penile traction therapy (PTT) is low risk and may be beneficial in patients willing to invest significant time using the devices. Furthermore, oral combination therapy with other modalities may provide some benefit. Further investigation is required to better understand the pathophysiology of PD and clarify the therapeutic utility of existing treatments, potentially with a multimodal strategy.
1. Introduction
1.1 Definitions and History
Peyronie’s disease (PD) is an acquired structural abnormality of the penis due to fibrosis of the tunica albuginea from the disordered and excessive deposition of collagen, which may lead to pain, penile deformity, erectile dysfunction, and profound emotional distress [1]. PD was described as “induratio penis plastica” in the 18th century by Francois Gigot de la Peyronie of France, after whom the disease is named [2]. However, there are descriptions of the disease many centuries prior, as far back as the 13th century by Theodoricus Borgognoni and Guilielmus Saliceto [3]. Current estimates of the incidence of PD range from 0.5%-20.3%, and it remains an underdiagnosed condition [4, 5]. The 2 phases of PD are the acute phase and the chronic phase. In the acute phase, which may last up to 12 months, the patient may have penile pain, palpable plaques, and worsening penile curvature. In the chronic phase, the penile curvature is stable for >3 months and penile pain generally subside. Currently, the AUA only recommends surgical intervention in the chronic phase, and generally, the acute phase is managed conservatively with many of the treatments discussed in this review (1).
1.2 Pathophysiology of PD
PD is likely caused by either one episode of acute trauma or repeated trauma to the tunica albuginea followed by impaired tissue healing leading to scar formation through deposition of collagen and decreases in elastin [6]. The tunica albuginea is an organized structure involving inner circular and outer longitudinal layers of connective tissue, and Peyronie’s Disease is often associated with disruption and disorganization of these connective tissue layers [7]. Therefore, PD is classically associated with various causes of penile trauma, including sexual intercourse, history of penile surgery, or prostatectomy which cause either microscopic or macroscopic trauma to the tunica albuginea. Repetitive trauma to the tunica albuginea in the setting of impaired tissue response to healing leads to increased pro-fibrotic factors such as transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF) while decreasing antifibrotic factors. Eventually, fibrin develops a meshwork of fibers attracting inflammatory cells and fibroblasts to form scar tissue which is further exacerbated for the formation of reactive oxygen species [8]. Other disease states with an impaired healing response, such as Dupuytren’s contracture and Paget’s disease of the bone are associated with PD, as is a family history of PD. Furthermore, in vitro studies suggest that failure of the plaque tissue to remodel properly may be due to excess TIMPs (tissue inhibitors of metalloproteinases), which results in a persistent scar [9]. Furthermore, cardiovascular diseases such as diabetes mellitus, hypertension, hyperlipidemia, heart disease, and smoking decrease perfusion to the penis and can also negatively impact penile healing. This disordered healing leads to scar/plaque formation which ultimately results in penile curvature. The pathophysiology of PD is complex and multifactorial but is thought to arise from repeated traumatic insult followed by the dysregulated healing response in the setting of genetic predisposition and cardiovascular comorbidities (Figure 1).
2. Intralesional therapies
2.1 Intralesional Verapamil
2.2 Interferon α-2b
2.3 Collagenase Clostridium Histolyticum
3. Extracorporeal Shockwave Therapy (ESWT)
4. Traction Therapy
5. Topical Therapy
5.1 Topical Verapamil
5.2 Transdermal Electromotive Drug Administration (EMDA)
5.3 Topical Liposomal Recombinant Human Superoxide Dismutase (LrhSOD)
5.4 H100 Gel
6. Oral therapy
6.1 Pentoxifylline
6.2 Potassium para-aminobenzoate (POTABA™)
6.3 Colchicine
6.4 Vitamin E
6.5 Tamoxifen
6.6 Carnitine
6.7 PDE-5 Inhibitors
*Lastly, PDE-5 inhibitors, while primarily used in the treatment of ED, exhibit anti-fibrotic activity through increased nitric oxide levels [87]. The administration of sildenafil has been shown to decrease plaque size and collagen/fibroblast ratio in rat models of PD. Vardenafil also decreases collagen/smooth muscle & collagen III/I ratios, TGF-beta positive cells, myofibroblasts, and rat plaque burden [88]. In a retrospective cohort study, Chung and colleagues evaluated the presence of septal scarring on penile ultrasound in 35 men treated with tadalafil 2.5 mg daily over 6 months to 30 untreated men. Patients treated with tadalafil had a higher proportion of septal scar resolution (69%) than those in the control group (10%) [89]. Tadalafil in combination with extracorporeal shockwave therapy has been compared to shockwave therapy alone. In this randomized trial (N=100), patients receiving combined treatment had higher degrees of erectile function and quality of life but not curvature [90]. Although both groups did not have worsening of either plaque size and curvature, the value of tadalafil in this study is confounded by the use of shockwave therapy. Altogether, while PDE-5 inhibitors are well-tolerated and commonly used to treat ED concomitant with PD, higher quality data is necessary to assess their role in altering the pathophysiology of PD.
7. Conclusion
A variety of non-invasive and minimally invasive therapies exist for PD, but many options have been under-investigated and/or lacking in robust studies. For patients who are not indicated for or declining surgery, these interventions are an important treatment strategy for those with symptoms or bother. Intralesional collagenase remains the only FDA-approved treatment for PD but has been withdrawn from the market in the European Union, Canada, and Australia. Many other therapies reviewed here, such as PTT and oral therapies, have been implemented into clinical practice, sometimes contrary to recommendations, due to their potential benefit and absence of risk. Because of the paucity of high-quality evidence, patients should be appropriately counseled about the risks and limitations of agents prior to initiation, especially those not recommended by professional guidelines.
8. Expert Opinion
Peyronie’s disease arises from excessive collagen deposition in the tunica albuginea, resulting in plaque formation, erect penile deformity, and pain. Currently, intralesional collagenase is the only FDA-approved treatment for PD, but given varying degrees of evidence, there are many off-label treatments. When prescribing off-label therapies, providers should discuss the evidence as well as potential risks and benefits with patients. Among intralesional treatments, interferon α-2b A and verapamil remain off-label treatments but have conflicting data suggesting efficacy. Likewise, the data for ESWT is conflicting, and ESWT is currently approved for penile pain but does not provide durable responses for decreasing penile curvature or plaque size. Penile traction therapy can be effective in improving penile length, decreasing curvature, and increasing penile girth in areas of indentation, but the patient must wear the device consistently for at least 3-4 hours a day for several months to show clinical improvement, which may be a limiting factor. Topical therapies have not been shown to be effective, but topical verapamil is currently approved by the EAU. For oral agents, the data suggests limited efficacy for monotherapy for disease-modifying intent, but combination treatments, such as verapamil, colchicine, and Vitamin E, show promise in improving Peyronie’s disease. Overall, the multitude of treatment options, very few with strong evidence demonstrating consistent efficacy and reproducibility, opens the potential for further investigation with high-quality trials as well as the possibility for multimodal treatment.
Further research must augment our understanding of PD pathophysiology, which may bring about new therapies or management approaches. Identification of molecular targets such as tissue inhibitors of matrix metalloproteinases (TIMPs), which regulate inflammation and subsequent fibrosis, as well as genetic markers will yield further targets for potential therapies [ 9, 91]. For example, genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) differentially regulated in Peyronie’s disease, six of which are related to the WNT signaling pathway [92]. Furthermore, stem cell therapies may guide the development of novel oral or intralesional agents [93]. Biomarkers are needed to help predict those who may benefit from non-surgical treatment. Basic scientific research will be critical to providing insight on how we can best use our existing tools to treat PD and identify potential new therapies.
Clinically, we must also strengthen the evidence to help identify which of the existing options to support and which to discourage. Many studies in this space have small sample sizes, often lack control arms, and are retrospective in nature, making the data vulnerable to confounding variables and bias. Many therapies require high-quality RCTs with large sample sizes, true controls, and objective, clinically meaningful outcomes to elucidate their therapeutic value as individual therapies. Furthermore, how we conduct PD studies must also be optimized, by creating standardized protocols for measuring pre- and post-intervention assessments as well as creating a consensus as to what is considered a “clinically meaningful” change in the PD literature [94]. Additionally, some studies suggest that a multimodal approach may have improved efficacy compared to monotherapy, so we must also conduct high quality trials as agents may be synergistic and/or may sensitize the disease to other treatment modalities. Altogether, better understanding the pathophysiology of Peyronie’s disease will identify new targets for treatment as well as factors that may predict response to certain therapies, and higher quality trials on existing treatments for medical management of PD can better elucidate their therapeutic value.
Introduction: Peyronie’s disease (PD) is a disorder of the tunica albuginea from the disordered and excessive deposition of collagen resulting in a palpable scar, pain, erect penile deformity, and erectile dysfunction that significantly impacts patients both physically and emotionally.
Areas Covered: Several treatment options have been described for PD, including shockwave therapy, traction therapy, both oral and intralesional pharmacological options, and surgery. This review seeks to examine the data for different types of non-surgical treatments for PD. We review how various treatment modalities impact several relevant clinical endpoints for Peyronie’s disease, including effects on pain, penile curvature, plaque formation, and erectile function. We performed a literature search using PubMed and SCOPUS while referencing AUA, EAU, and CUA guidelines for the management of Peyronie’s Disease for studies published 1980- 2020.
Expert opinion: Intralesional collagenase injections have the strongest evidence and are the only FDA-approved intralesional treatment for PD. Penile traction therapy (PTT) is low risk and may be beneficial in patients willing to invest significant time using the devices. Furthermore, oral combination therapy with other modalities may provide some benefit. Further investigation is required to better understand the pathophysiology of PD and clarify the therapeutic utility of existing treatments, potentially with a multimodal strategy.
1. Introduction
1.1 Definitions and History
Peyronie’s disease (PD) is an acquired structural abnormality of the penis due to fibrosis of the tunica albuginea from the disordered and excessive deposition of collagen, which may lead to pain, penile deformity, erectile dysfunction, and profound emotional distress [1]. PD was described as “induratio penis plastica” in the 18th century by Francois Gigot de la Peyronie of France, after whom the disease is named [2]. However, there are descriptions of the disease many centuries prior, as far back as the 13th century by Theodoricus Borgognoni and Guilielmus Saliceto [3]. Current estimates of the incidence of PD range from 0.5%-20.3%, and it remains an underdiagnosed condition [4, 5]. The 2 phases of PD are the acute phase and the chronic phase. In the acute phase, which may last up to 12 months, the patient may have penile pain, palpable plaques, and worsening penile curvature. In the chronic phase, the penile curvature is stable for >3 months and penile pain generally subside. Currently, the AUA only recommends surgical intervention in the chronic phase, and generally, the acute phase is managed conservatively with many of the treatments discussed in this review (1).
1.2 Pathophysiology of PD
PD is likely caused by either one episode of acute trauma or repeated trauma to the tunica albuginea followed by impaired tissue healing leading to scar formation through deposition of collagen and decreases in elastin [6]. The tunica albuginea is an organized structure involving inner circular and outer longitudinal layers of connective tissue, and Peyronie’s Disease is often associated with disruption and disorganization of these connective tissue layers [7]. Therefore, PD is classically associated with various causes of penile trauma, including sexual intercourse, history of penile surgery, or prostatectomy which cause either microscopic or macroscopic trauma to the tunica albuginea. Repetitive trauma to the tunica albuginea in the setting of impaired tissue response to healing leads to increased pro-fibrotic factors such as transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF) while decreasing antifibrotic factors. Eventually, fibrin develops a meshwork of fibers attracting inflammatory cells and fibroblasts to form scar tissue which is further exacerbated for the formation of reactive oxygen species [8]. Other disease states with an impaired healing response, such as Dupuytren’s contracture and Paget’s disease of the bone are associated with PD, as is a family history of PD. Furthermore, in vitro studies suggest that failure of the plaque tissue to remodel properly may be due to excess TIMPs (tissue inhibitors of metalloproteinases), which results in a persistent scar [9]. Furthermore, cardiovascular diseases such as diabetes mellitus, hypertension, hyperlipidemia, heart disease, and smoking decrease perfusion to the penis and can also negatively impact penile healing. This disordered healing leads to scar/plaque formation which ultimately results in penile curvature. The pathophysiology of PD is complex and multifactorial but is thought to arise from repeated traumatic insult followed by the dysregulated healing response in the setting of genetic predisposition and cardiovascular comorbidities (Figure 1).
2. Intralesional therapies
2.1 Intralesional Verapamil
2.2 Interferon α-2b
2.3 Collagenase Clostridium Histolyticum
3. Extracorporeal Shockwave Therapy (ESWT)
4. Traction Therapy
5. Topical Therapy
5.1 Topical Verapamil
5.2 Transdermal Electromotive Drug Administration (EMDA)
5.3 Topical Liposomal Recombinant Human Superoxide Dismutase (LrhSOD)
5.4 H100 Gel
6. Oral therapy
6.1 Pentoxifylline
6.2 Potassium para-aminobenzoate (POTABA™)
6.3 Colchicine
6.4 Vitamin E
6.5 Tamoxifen
6.6 Carnitine
6.7 PDE-5 Inhibitors
*Lastly, PDE-5 inhibitors, while primarily used in the treatment of ED, exhibit anti-fibrotic activity through increased nitric oxide levels [87]. The administration of sildenafil has been shown to decrease plaque size and collagen/fibroblast ratio in rat models of PD. Vardenafil also decreases collagen/smooth muscle & collagen III/I ratios, TGF-beta positive cells, myofibroblasts, and rat plaque burden [88]. In a retrospective cohort study, Chung and colleagues evaluated the presence of septal scarring on penile ultrasound in 35 men treated with tadalafil 2.5 mg daily over 6 months to 30 untreated men. Patients treated with tadalafil had a higher proportion of septal scar resolution (69%) than those in the control group (10%) [89]. Tadalafil in combination with extracorporeal shockwave therapy has been compared to shockwave therapy alone. In this randomized trial (N=100), patients receiving combined treatment had higher degrees of erectile function and quality of life but not curvature [90]. Although both groups did not have worsening of either plaque size and curvature, the value of tadalafil in this study is confounded by the use of shockwave therapy. Altogether, while PDE-5 inhibitors are well-tolerated and commonly used to treat ED concomitant with PD, higher quality data is necessary to assess their role in altering the pathophysiology of PD.
7. Conclusion
A variety of non-invasive and minimally invasive therapies exist for PD, but many options have been under-investigated and/or lacking in robust studies. For patients who are not indicated for or declining surgery, these interventions are an important treatment strategy for those with symptoms or bother. Intralesional collagenase remains the only FDA-approved treatment for PD but has been withdrawn from the market in the European Union, Canada, and Australia. Many other therapies reviewed here, such as PTT and oral therapies, have been implemented into clinical practice, sometimes contrary to recommendations, due to their potential benefit and absence of risk. Because of the paucity of high-quality evidence, patients should be appropriately counseled about the risks and limitations of agents prior to initiation, especially those not recommended by professional guidelines.
8. Expert Opinion
Peyronie’s disease arises from excessive collagen deposition in the tunica albuginea, resulting in plaque formation, erect penile deformity, and pain. Currently, intralesional collagenase is the only FDA-approved treatment for PD, but given varying degrees of evidence, there are many off-label treatments. When prescribing off-label therapies, providers should discuss the evidence as well as potential risks and benefits with patients. Among intralesional treatments, interferon α-2b A and verapamil remain off-label treatments but have conflicting data suggesting efficacy. Likewise, the data for ESWT is conflicting, and ESWT is currently approved for penile pain but does not provide durable responses for decreasing penile curvature or plaque size. Penile traction therapy can be effective in improving penile length, decreasing curvature, and increasing penile girth in areas of indentation, but the patient must wear the device consistently for at least 3-4 hours a day for several months to show clinical improvement, which may be a limiting factor. Topical therapies have not been shown to be effective, but topical verapamil is currently approved by the EAU. For oral agents, the data suggests limited efficacy for monotherapy for disease-modifying intent, but combination treatments, such as verapamil, colchicine, and Vitamin E, show promise in improving Peyronie’s disease. Overall, the multitude of treatment options, very few with strong evidence demonstrating consistent efficacy and reproducibility, opens the potential for further investigation with high-quality trials as well as the possibility for multimodal treatment.
Further research must augment our understanding of PD pathophysiology, which may bring about new therapies or management approaches. Identification of molecular targets such as tissue inhibitors of matrix metalloproteinases (TIMPs), which regulate inflammation and subsequent fibrosis, as well as genetic markers will yield further targets for potential therapies [ 9, 91]. For example, genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) differentially regulated in Peyronie’s disease, six of which are related to the WNT signaling pathway [92]. Furthermore, stem cell therapies may guide the development of novel oral or intralesional agents [93]. Biomarkers are needed to help predict those who may benefit from non-surgical treatment. Basic scientific research will be critical to providing insight on how we can best use our existing tools to treat PD and identify potential new therapies.
Clinically, we must also strengthen the evidence to help identify which of the existing options to support and which to discourage. Many studies in this space have small sample sizes, often lack control arms, and are retrospective in nature, making the data vulnerable to confounding variables and bias. Many therapies require high-quality RCTs with large sample sizes, true controls, and objective, clinically meaningful outcomes to elucidate their therapeutic value as individual therapies. Furthermore, how we conduct PD studies must also be optimized, by creating standardized protocols for measuring pre- and post-intervention assessments as well as creating a consensus as to what is considered a “clinically meaningful” change in the PD literature [94]. Additionally, some studies suggest that a multimodal approach may have improved efficacy compared to monotherapy, so we must also conduct high quality trials as agents may be synergistic and/or may sensitize the disease to other treatment modalities. Altogether, better understanding the pathophysiology of Peyronie’s disease will identify new targets for treatment as well as factors that may predict response to certain therapies, and higher quality trials on existing treatments for medical management of PD can better elucidate their therapeutic value.
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