madman
Super Moderator
An update on the current status and future prospects of erectile dysfunction following radical prostatectomy (2022)
Heba Asker PhD | Didem Yilmaz‐Oral PhD | Cetin Volkan Oztekin MD | Serap Gur PhD
Abstract
Background: Radical prostatectomy (RP) and radiation treatment are standard options for localized prostate cancer. Even though nerve‐sparing techniques have been increasingly utilized in RP, erectile dysfunction (ED) due to neuropraxia remains a frequent complication. Erectile function recovery rates after RP remain unsatisfactory, and many men still suffer despite the availability of various therapies.
Objective: This systematic review aims to summarize the current treatments for post‐RP‐ED, assess the underlying pathological mechanisms, and emphasize promising therapeutic strategies based on the evidence from basic research.
Method: Evaluation and review of articles on the relevant topic published between 2010 and 2021, which are indexed and listed in the PubMed database.
Results: Phosphodiesterase type 5 inhibitors, intracavernosal and intraurethral injections, vacuum erection devices, pelvic muscle training, and surgical procedures are utilized for penile rehabilitation. Clinical trials evaluating the efficacy of erectogenic drugs in this setting are conflicting and far from being conclusive. The use of androgen deprivation therapy in certain scenarios after RP further exacerbates the already problematic situation and emphasizes the need for effective treatment strategies.
Conclusion: This article is a detailed overview focusing on the pathophysiology and mechanism of the nerve injury developed during RP and a compilation of various strategies to induce cavernous nerve regeneration to improve erectile function (EF). These strategies include stem cell therapy, gene therapy, growth factors, low-intensity extracorporeal shockwave therapy, immunophilins, and various pharmacological approaches that have induced improvements in EF in experimental models of cavernous nerve injury. Many of the mentioned strategies can improve EF following RP if transformed into clinically applicable safe, and effective techniques with reproducible outcomes.
1 | INTRODUCTION
As well as being the second most diagnosed cancer (about 15% of all diagnosed tumors), prostate cancer (PCa) is also the second cause of cancer deaths in men.1 PCa affected 1.1 million patients in 2012 and is predicted to affect 1.7 million in 2030.2 North American and European countries have traditionally high PCa incidence rates. However, recently, the numbers have also been significantly increasing in Asia.3
The treatment of PCa impacts patients' quality of life and their functional status.4 Furthermore, PCa patients frequently suffer from decreased sexual function (SF) as a long‐term side effect after treatments, impacting their quality of life. To overcome long‐term effects, there is a growing need for optimization in treatment selection and posttreatment rehabilitation.
Radical prostatectomy (RP) is one of the standard treatments in localized PCa; radiation treatment (either in the form of external beam RT or brachytherapy) and active surveillance (in selected cases) are other options.5 Regardless of the advances in surgical techniques and increasingly‐utilized robotic procedures, RP has a significant potential to cause cavernous nerve injury (CNI) and resultant pathologic changes in cavernous vasculature.6
Neurogenic erectile dysfunction (ED) is a consequence of CNI after RP leading to pathophysiological alterations in the corpus cavernosum (CC) and cavernosal nerve. Prevalence of ED following RP was documented to be between 14% and 90%.7
Nitric oxide (NO) is the primary mediator in penile erection, released from the nerves innervating CC and cavernosal endothelium.8–10 This release of NO activates soluble guanylyl cyclase (sGC), which boosts cyclic guanosine monophosphate (cGMP) levels and induces penile erection.11–13 Phosphodiesterase inhibition causes accumulation of cGMP and potentiates erection. Based on this mechanism of action, oral phosphodiesterase type 5 inhibitors (PDE5is) are currently considered the first‐line ED treatment. However, the response rate to PDE5is is usually lower in post‐RP‐ ED compared to the general ED population.14
After RP, achieving a healthy erectile function (EF) is a great struggle for many patients and a real challenge for urologists. Despite the developments in minimally invasive surgery and surgical techniques over time, the recovery of EF remains a long and costly process. Therefore, this systematic review aimed to summarize and update the current treatments for post‐RP‐ED and, more importantly, to evaluate the underlying pathological mechanisms and promising therapeutic strategies suggested by the evidence from basic research.
1.1 | ED as a frequent complication of RP
CNI during RP is the major cause of ED, which is observed frequently despite advanced surgical methods, particularly nerve‐sparing techniques.15–18 The widely adopted use of nerve‐sparing surgical procedures and robot‐assisted laparoscopic techniques in RP can not completely prevent post‐RP‐ED. It may become persistent in some patients.19
The main mechanism of postoperative ED is related to CN damage caused by surgery. The direct contact during surgical intervention, mechanical traction, and thermal disturbance resulting from electrocautery use may induce neuronal ischemia, apoptosis, and regional inflammatory reactions, which can cause damage to the CN.20,21 This damage initiates a cascade of neuropathological events, called Wallerian degeneration, that results in the degeneration of the distal axon and, at the same time, causes a disrupted NO release.22,23 Attempts are made to prevent the degeneration and fibrosis of the CC caused by the invasion of the surgery itself or the postoperative hypoxic state by oxygenating the penis from an early postoperative stage.24 Recovery from ED requires rapid regeneration of the CN; otherwise, CNI could result in fibrosis of the CC.25,26 Elevated reactive oxygen species, CC hypoxia, apoptosis, and the increase in profibrotic factors, such as transforming growth factor‐beta1 (TGF‐ β1), are involved in changing the structure of the CC tissue leading to the decrease in smooth muscle content, damage to endothelium and fibrosis of CC22,23,27–29 (Figure 1)
Similarly, several studies in a radiation‐induced CNI model showed that oxidative stress has a significant role in the pathology of nerve injury.30–32 Therefore, minimizing oxidative stress can be a feasible approach to CN recovery. Also, it was found that calpain, a calcium‐dependent, non‐lysosomal neutral cysteine endopeptidase, and its activation have a role in the pathogenesis of CNI-related ED.33 Calpain inhibition improved erectile responses and neuronal NOS (nNOS) expression with a decrease in TGF‐β1 and collagen expression in penile tissue from CNI rats.33 The inhibition of calpain could be a choice among the new approaches to prevent the development of ED after CNI.33 In another study, S‐nitrosylation of endothelial NOS34 and sGC in penile tissue was investigated as another mechanism for disrupting the NO signaling pathway in CNI‐ induced ED.35 Protection of EF by saving the function of the NO/cGMP signaling pathway can be provided by denitrosylation in CNI (Figure 1).35
Penile rehabilitation is defined as “the use of any drug or device at or after RP to maximize EF recovery.” 36 Although the efficacy of penile rehabilitation as a concept is not proven yet, various major approaches are already in use. Men with post‐RP ED have diverse treatment choices like PDE5is, intracavernosal injections (ICI) of vasoactive agents, vacuum erection devices (VED), and others. The efficiency of penile rehabilitation using prostaglandin E1 injection into the CC was reported first in 1997 by Montorsi et al.37 These options are only partially successful, which makes the research for more dependable interventions obligatory.
1.1.1 | Animal models of CNI
1.2 | Surgical techniques for managing postprostatectomy ED
1.2.1 | Penile prosthesis (PP)
1.2.1.1 | Clinical studies
1.2.2 | Nerve grafting after RP
1.2.2.1 | Preclinical studies
1.2.2.2 | Clinical studies
1.3 | Stem cell therapy
1.3.1 | Preclinical studies
1.3.2 | Clinical studies
1.4 | Gene therapy
1.4.1 | Preclinical studies
1.5 | Pharmacological approaches
1.5.1 | sGC Stimulators
1.5.1.1 | Preclinical studies
1.5.2 | The Role of PDE5is
1.5.2.1 | Preclinical studies
1.5.2.2 | Clinical studies
1.5.3 | Immunophilin Ligands
1.5.3.1 | Preclinical studies
1.5.3.2 | Clinical studies
1.6 | Growth factors
1.6.1 | Preclinical studies
1.6.2 | Clinical studies
1.7 | Low‐intensity extracorporeal shockwave therapy (LI‐ESWT)
1.7.1 | Preclinical studies
1.7.2 | Clinical studies
1.8 | Intraurethral Alprostadil Injection and Medicated Urethral System for Erection (MUSE)
1.8.1 | Clinical studies
1.9 | Vacuum erection devices (VED)
1.9.1 | Preclinical studies
1.9.2 | Clinical studies
1.10 | Pelvic floor muscle training (PFMT)
1.10.1 | Clinical studies
1.11 | Other treatment strategies
1.11.1 | Hyperbaric oxygen therapy (HBOT)
1.11.2 | Platelet‐rich plasma
1.11.3 | Losartan
1.11.4 | Atorvastatin
1.11.5 | LIM‐kinase 2 (LIMK2) pathway
1.11.6 | Mitogen‐activated protein kinases
1.11.7 | Galanin
1.11.8 | Hydrogen sulfide (H2S)
1.11.9 | Herbal medicine
1.12 | Future perspectives
2 | CONCLUSIONS
ED is frequently observed after RP despite the increasing adoption of minimally‐invasive and nerve‐sparing surgical techniques. Although it has distinct aspects regarding its etiology and pathophysiology, ED‐RP is currently managed using the same treatment options available for standard ED. Limited by the clinical applicability, evidence from basic research suggests a wide variety of possible therapeutic approaches for ED‐RP, which should be meticulously investigated for clinical adoption by urologists and the industry.
Heba Asker PhD | Didem Yilmaz‐Oral PhD | Cetin Volkan Oztekin MD | Serap Gur PhD
Abstract
Background: Radical prostatectomy (RP) and radiation treatment are standard options for localized prostate cancer. Even though nerve‐sparing techniques have been increasingly utilized in RP, erectile dysfunction (ED) due to neuropraxia remains a frequent complication. Erectile function recovery rates after RP remain unsatisfactory, and many men still suffer despite the availability of various therapies.
Objective: This systematic review aims to summarize the current treatments for post‐RP‐ED, assess the underlying pathological mechanisms, and emphasize promising therapeutic strategies based on the evidence from basic research.
Method: Evaluation and review of articles on the relevant topic published between 2010 and 2021, which are indexed and listed in the PubMed database.
Results: Phosphodiesterase type 5 inhibitors, intracavernosal and intraurethral injections, vacuum erection devices, pelvic muscle training, and surgical procedures are utilized for penile rehabilitation. Clinical trials evaluating the efficacy of erectogenic drugs in this setting are conflicting and far from being conclusive. The use of androgen deprivation therapy in certain scenarios after RP further exacerbates the already problematic situation and emphasizes the need for effective treatment strategies.
Conclusion: This article is a detailed overview focusing on the pathophysiology and mechanism of the nerve injury developed during RP and a compilation of various strategies to induce cavernous nerve regeneration to improve erectile function (EF). These strategies include stem cell therapy, gene therapy, growth factors, low-intensity extracorporeal shockwave therapy, immunophilins, and various pharmacological approaches that have induced improvements in EF in experimental models of cavernous nerve injury. Many of the mentioned strategies can improve EF following RP if transformed into clinically applicable safe, and effective techniques with reproducible outcomes.
1 | INTRODUCTION
As well as being the second most diagnosed cancer (about 15% of all diagnosed tumors), prostate cancer (PCa) is also the second cause of cancer deaths in men.1 PCa affected 1.1 million patients in 2012 and is predicted to affect 1.7 million in 2030.2 North American and European countries have traditionally high PCa incidence rates. However, recently, the numbers have also been significantly increasing in Asia.3
The treatment of PCa impacts patients' quality of life and their functional status.4 Furthermore, PCa patients frequently suffer from decreased sexual function (SF) as a long‐term side effect after treatments, impacting their quality of life. To overcome long‐term effects, there is a growing need for optimization in treatment selection and posttreatment rehabilitation.
Radical prostatectomy (RP) is one of the standard treatments in localized PCa; radiation treatment (either in the form of external beam RT or brachytherapy) and active surveillance (in selected cases) are other options.5 Regardless of the advances in surgical techniques and increasingly‐utilized robotic procedures, RP has a significant potential to cause cavernous nerve injury (CNI) and resultant pathologic changes in cavernous vasculature.6
Neurogenic erectile dysfunction (ED) is a consequence of CNI after RP leading to pathophysiological alterations in the corpus cavernosum (CC) and cavernosal nerve. Prevalence of ED following RP was documented to be between 14% and 90%.7
Nitric oxide (NO) is the primary mediator in penile erection, released from the nerves innervating CC and cavernosal endothelium.8–10 This release of NO activates soluble guanylyl cyclase (sGC), which boosts cyclic guanosine monophosphate (cGMP) levels and induces penile erection.11–13 Phosphodiesterase inhibition causes accumulation of cGMP and potentiates erection. Based on this mechanism of action, oral phosphodiesterase type 5 inhibitors (PDE5is) are currently considered the first‐line ED treatment. However, the response rate to PDE5is is usually lower in post‐RP‐ ED compared to the general ED population.14
After RP, achieving a healthy erectile function (EF) is a great struggle for many patients and a real challenge for urologists. Despite the developments in minimally invasive surgery and surgical techniques over time, the recovery of EF remains a long and costly process. Therefore, this systematic review aimed to summarize and update the current treatments for post‐RP‐ED and, more importantly, to evaluate the underlying pathological mechanisms and promising therapeutic strategies suggested by the evidence from basic research.
1.1 | ED as a frequent complication of RP
CNI during RP is the major cause of ED, which is observed frequently despite advanced surgical methods, particularly nerve‐sparing techniques.15–18 The widely adopted use of nerve‐sparing surgical procedures and robot‐assisted laparoscopic techniques in RP can not completely prevent post‐RP‐ED. It may become persistent in some patients.19
The main mechanism of postoperative ED is related to CN damage caused by surgery. The direct contact during surgical intervention, mechanical traction, and thermal disturbance resulting from electrocautery use may induce neuronal ischemia, apoptosis, and regional inflammatory reactions, which can cause damage to the CN.20,21 This damage initiates a cascade of neuropathological events, called Wallerian degeneration, that results in the degeneration of the distal axon and, at the same time, causes a disrupted NO release.22,23 Attempts are made to prevent the degeneration and fibrosis of the CC caused by the invasion of the surgery itself or the postoperative hypoxic state by oxygenating the penis from an early postoperative stage.24 Recovery from ED requires rapid regeneration of the CN; otherwise, CNI could result in fibrosis of the CC.25,26 Elevated reactive oxygen species, CC hypoxia, apoptosis, and the increase in profibrotic factors, such as transforming growth factor‐beta1 (TGF‐ β1), are involved in changing the structure of the CC tissue leading to the decrease in smooth muscle content, damage to endothelium and fibrosis of CC22,23,27–29 (Figure 1)
Similarly, several studies in a radiation‐induced CNI model showed that oxidative stress has a significant role in the pathology of nerve injury.30–32 Therefore, minimizing oxidative stress can be a feasible approach to CN recovery. Also, it was found that calpain, a calcium‐dependent, non‐lysosomal neutral cysteine endopeptidase, and its activation have a role in the pathogenesis of CNI-related ED.33 Calpain inhibition improved erectile responses and neuronal NOS (nNOS) expression with a decrease in TGF‐β1 and collagen expression in penile tissue from CNI rats.33 The inhibition of calpain could be a choice among the new approaches to prevent the development of ED after CNI.33 In another study, S‐nitrosylation of endothelial NOS34 and sGC in penile tissue was investigated as another mechanism for disrupting the NO signaling pathway in CNI‐ induced ED.35 Protection of EF by saving the function of the NO/cGMP signaling pathway can be provided by denitrosylation in CNI (Figure 1).35
Penile rehabilitation is defined as “the use of any drug or device at or after RP to maximize EF recovery.” 36 Although the efficacy of penile rehabilitation as a concept is not proven yet, various major approaches are already in use. Men with post‐RP ED have diverse treatment choices like PDE5is, intracavernosal injections (ICI) of vasoactive agents, vacuum erection devices (VED), and others. The efficiency of penile rehabilitation using prostaglandin E1 injection into the CC was reported first in 1997 by Montorsi et al.37 These options are only partially successful, which makes the research for more dependable interventions obligatory.
1.1.1 | Animal models of CNI
1.2 | Surgical techniques for managing postprostatectomy ED
1.2.1 | Penile prosthesis (PP)
1.2.1.1 | Clinical studies
1.2.2 | Nerve grafting after RP
1.2.2.1 | Preclinical studies
1.2.2.2 | Clinical studies
1.3 | Stem cell therapy
1.3.1 | Preclinical studies
1.3.2 | Clinical studies
1.4 | Gene therapy
1.4.1 | Preclinical studies
1.5 | Pharmacological approaches
1.5.1 | sGC Stimulators
1.5.1.1 | Preclinical studies
1.5.2 | The Role of PDE5is
1.5.2.1 | Preclinical studies
1.5.2.2 | Clinical studies
1.5.3 | Immunophilin Ligands
1.5.3.1 | Preclinical studies
1.5.3.2 | Clinical studies
1.6 | Growth factors
1.6.1 | Preclinical studies
1.6.2 | Clinical studies
1.7 | Low‐intensity extracorporeal shockwave therapy (LI‐ESWT)
1.7.1 | Preclinical studies
1.7.2 | Clinical studies
1.8 | Intraurethral Alprostadil Injection and Medicated Urethral System for Erection (MUSE)
1.8.1 | Clinical studies
1.9 | Vacuum erection devices (VED)
1.9.1 | Preclinical studies
1.9.2 | Clinical studies
1.10 | Pelvic floor muscle training (PFMT)
1.10.1 | Clinical studies
1.11 | Other treatment strategies
1.11.1 | Hyperbaric oxygen therapy (HBOT)
1.11.2 | Platelet‐rich plasma
1.11.3 | Losartan
1.11.4 | Atorvastatin
1.11.5 | LIM‐kinase 2 (LIMK2) pathway
1.11.6 | Mitogen‐activated protein kinases
1.11.7 | Galanin
1.11.8 | Hydrogen sulfide (H2S)
1.11.9 | Herbal medicine
1.12 | Future perspectives
2 | CONCLUSIONS
ED is frequently observed after RP despite the increasing adoption of minimally‐invasive and nerve‐sparing surgical techniques. Although it has distinct aspects regarding its etiology and pathophysiology, ED‐RP is currently managed using the same treatment options available for standard ED. Limited by the clinical applicability, evidence from basic research suggests a wide variety of possible therapeutic approaches for ED‐RP, which should be meticulously investigated for clinical adoption by urologists and the industry.
