madman
Super Moderator
Great paper!
Of course 2 in the top of the field Dr. Mulhall and Dr. Burnett contributed!
* An ideal treatment capable of fully restoring normal and spontaneous erectile function (EF) has yet to be discovered.
Fig. 2 – Current and emerging treatments for erectile dysfunction.
Abstract
Background and objective
Erectile dysfunction (ED) is a common condition affecting patients’ quality of life. Clinical management has changed over the past three decades, new diagnostic and therapeutic options available. Our aim was to provide an overview of novel evidence regarding clinical management of ED.
Methods
A non-systematic literature review was conducted to identify relevant studies on the diagnosis and treatment of erectile dysfunction. The review encompassed pharmacological, regenerative, and surgical approaches, summarising recent advances and highlighting persisting gaps in clinical practice.
Key findings and limitations
ED is a common reason for seeking medical consultation.The correlation between ageing and ED prevalence is rooted in neurovascular tissue impairment. Medical history, along with the use of validated questionnaires, still represents the mainstay of ED assessment because of the lack of reliable imaging tests. The most widely used and effective treatment is an oral phosphodiesterase type 5 inhibitor, but this is lifelong therapy that is associated with high dropout rates. Among novel regenerative treatments, low-intensity shockwave therapy is supported by more evidence, although high-quality trials and long-term data are lacking. More conclusive evidence is needed for platelet-rich plasma injections and stem cell treatment. Botulinumneurotoxin and new emerging oral drugs are also under investigation.
Conclusions
Several treatment options are available for ED. Clinical tailoring of treatment for individual patients and rigorous research are crucial for further advances.
1. Introduction
Erectile dysfunction (ED) is one of the most common conditions affecting men worldwide [1]. According to the latest epidemiology studies, up to 71% of men will experience ED at some point in their life [1]. These numbers provide insight into the high social impact of this condition. For this reason, research aimed at improving quality of life for men suffering from ED has been active field over the past three decades. Despite these efforts, numerous questions remain unanswered regarding both the pathophysiology and thetreatment of ED [2]. An ideal treatment capable of fully restoring normal and spontaneous erectile function (EF) has yet to be discovered.
3.1. Epidemiology and etiology of ED
The etiology of ED can be broadly categorized as primary organic (vasculogenic, neurogenic, hormonal, iatrogenic, post-traumatic, or a combination of these factors) or primary psychogenic. Organic ED often coexists with other systemic diseases, including diabetes, cardiovascular diseases, and metabolic disorders [10,11]. Most of these conditions share a common pathophysiological pathway involving neurovascular impairment; in the penis, this eventually leads to a fibrotic process at the level of the cavernous bodies [12]. Iatrogenic ED also accounts for a significant proportion of cases. The ED can be drug-induced or secondary to therapeutic interventions such as pelvic surgery and radiotherapy [2]. Drug-induced ED is frequently observed: according to the US Food and Drug Administration (FDA) adverse event reporting system, more than 40%of ED reports are attributed to use of 5a-reductase inhibitors or neuropsychiatric medications [13]. In addition to the well-known organic causes of ED, psychogenic ED remains a significant yet often underdiscussed condition. Psychogenic ED is primarily linked to psychological conditions, including stress, anxiety, and depression, that disrupt neurochemical pathways involved in sexual arousal [2,14].Depression in particular increases the risk of ED and is often worsened by certain antidepressants [15].
3.2. ED assessment
3.3. Conducting clinical research on ED treatments
3.4. ED management
3.4.1. Phosphodiesterase type 5 inhibitors: new evidence
Recent research has placed a greater emphasis on the cardiovascular safety of PDE5I agents. Kloner et al [33] conducted a retrospective analysis of data from a large insurance claims database and found a 19% decrease in the occurrence of major adverse cardiovascular events and a 44% decrease in overall mortality among individuals exposed to tadalafil in comparison to those not exposed to PDE5Is. Given that ED is often an early marker of cardiovascular disease, this underscores the importance of assessing cardiovascular health in patients presenting with ED [34].
In addition to potential benefits for cardiovascular health, PDE5Is have demonstrated preventive effects in various other health disorders [35]. For example, research has shown that PDE5Is have renoprotective properties [36].Indeed, boosting of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling protects kidney function via regulation of blood flow and direct protection of kidney tissue through multiple cellular mechanisms [36],which are advantageous in conditions such as diabetic nephropathy and chronic kidney disease. PDE5Is also have potential advantages in heart failure, as they enhance cardiac function and decrease myocardial stress [35]. Furthermore, a growing body of data suggests potential PDE5I involvement in reducing cognitive decline [37], anticancer effects mediated by different mechanisms (eg, cell growth arrest; chemotherapy sensitization; modulation of immune responses [38]), and the treatment of immunological disorders and systemic sclerosis [39]. All of these findings needto be confirmed in large clinical trials
3.4.2. Intracavernous pharmacological treatment
Intracavernos injections (ICI) of vasoactive agents was one of the first treatments for ED and is currently considered a valid option for patients with no response to PDE5Is [2].
Overall, 30–65.9% of patientsare able to achieve erections adequate for sexual intercourse with these formulations [2,44,45].
Bimix and Trimix are combinations of off-label vasoactive agents that are often used to treat ED in patients who are poor responders to alprostadil, and have a good efficacy profile [46,47]
Botulinum neurotoxin type A (BoNT-A) has also been investigated as a potential treatment for ED.
Overall, these data suggest that BoNT-A could be an asset in delaying surgical treatment in patients who are unresponsive to medical treatment for ED. However, larger trials are needed to validate these findings and ascertain the efficacy and safety of BoNT-A for ED treatment. Current international guidelines still consider this treatment as experimental [2].
3.4.3. Regenerative therapies
Regenerative medicine, an experimental branch of medicine in which the aim is to regrow, repair, or replace damaged tissues, has potential as a curative treatment for ED.
Changes in the penile microenvironment are characteristic of advanced ED and researchers have been attempting to reverse these changes using regenerative therapies [57–59]. However, it should be borne in mind that ED is largely secondary to systemic disease, as are the penile changes observed. Therefore, there is a limited rationale for therapies directed solely at the penis. Moreover, our understanding of the penile microarchitecture and cellular functions remains incomplete [60]. Consequently, results for these therapeutic innovations must be interpreted with caution, considering that their limited effect sizes probably result from an incomplete understanding and opportunistic testing of therapies not specifically designed for this purpose. Table 1 summarizes the current evidence on regenerative therapies for ED according to data from primary sources and reflecting the collective expert opinion of the authors
3.4.3.1. SWT
In the past two decades, low-intensity SWT has been extensively investigated as a regenerative treatment for ED [61]. It is believed that the mechanical energy produced by acoustic shockwaves triggers restoration of cavernosal tissue via various pathways, including enhanced neoangiogenesis due to release of VEGF, recruitment of progenitor stem cells, nerve recovery, and regeneration directly through stimulation of neuronal proliferation or indirectly via activation of Schwann cells, an increase in the production of vasodilatory NO in affected tissues, and an anti inflammatory effect [57]. However, these hypotheses are grounded in data from animal studies, mainly murine ED models, which limits direct replication in human ED [57].
Despite inconclusive evidence on the biological effects o fSWT on cavernosal tissues, more than 20 RCTs and 14 meta analyses have investigated the efficacy of SWT for ED treatment [61]. Overall, these trials are affected by several limitations that reduce the quality of the evidence provided. (1
Despite these considerations, the excellent safety profile of SWT and the costs related to this out-of-pocket therapy have led to wide its use as a treatment option for ED. The European Association of Urology is the only international society to date to formally recommend this treatment as an option for patients with mild ED [2]; other international guidelines advise caution regarding SWT use and still consider the treatment as investigational [64,65].
3.4.3.2. Platelet-rich plasma.
The aim of platelet-rich plasma (PRP) treatment is to address various pathophysiological aspects of ED, including vascular issues, nerve protection and growth, tissue repair, and inflammation [66].
PRP therapy is widely marketed online and is primarily provided by clinics specialized in cosmetic or naturopathic medicine, often under supervision by cosmetic surgeons or general practitioners. However, the costs of this treatment are largely undisclosed, which obscures the financial aspect of PRP therapy for ED [58]. The paucity and low quality of the evidence does not support current use of PRP treatment in routine clinical practice.
3.4.3.3. Stem cell therapy.
The aim of stem cell therapy (SCT) in the ED setting is to regenerate damaged tissue to restore normal EF [12].
Basic science studies have shown that stem cells can self-renew and differentiate into various mature cell types, which makes them suitable for regenerative therapies, while animal studies have demonstrated the potential of stem cells to cure ED by improving various aspects of penile function, including mitigation of penile fibrosis [12]. However, these studies have limitations, and the scarcity of high-quality clinical evidence makes it challenging to translate the findings to human clinical applications [72,73]
The future of SCT for ED treatment will rely on the development of well-designed, multicenter, placebo-controlled RCTs to determine the optimal stem cell sources and their safety, effectiveness, doses, and administration routes. There is also a need to identify the type of patient and ED severity most suited to SCT. Until then, SCT should be considered experimental and restricted to clinical trials [74].
3.4.4. New potential treatments for ED: Rho-associated inhibitors and more
Novel pharmaceutical targets for the treatment of organic ED have been discovered that act at either the peripheralor central level.
In summary, these new treatments address different facets of the complex pathogenesis of ED. However, the lack of significant evidence supporting the efficacy and safety of these compounds has limited their use in clinical practice
3.4.5. New medical devices
Novel medical devices to assist patients in reaching desirable EF have been developed and investigated.
3.4.6. Surgery for ED: the era of implants
Penile prosthesis implantation remains the last bastion of ED treatment in refractory cases, and can also be considered in patients who prefer a definitive therapy and are not compliant with medical treatment [2]. Numerous advances in materials and surgical techniques over time have led to increases in patient satisfaction and a decrease in complication rates [105]. Data show satisfaction rates of 92–100% after proper preoperative counseling [106–108]. Infection and mechanical failure are the most common complications: infection rates of 1–2% have been reported in the most up-to-date series [109]. A recent meta-analysis showed that the penile prosthesis survival rate is as highas 76.8% at 10 yr [110].
Newer penile prosthesis designs in development seek to broaden the range of patients who can safely use implants while enhancing functionality and spontaneity by providing alternatives to manual pump activation and the need for reservoir placement.
While these advances have not yet been implemented in clinical practice, they are close on the horizon and represent the next phase in the evolution of penile prosthetic devices.
5. Conclusions
A diverse array of treatments is currently available for ED. Physicians should tailor every treatment to the patient’sclinical characteristics and expectations. There remains a need for further high-quality studies to define the role of novel and emerging treatments.
Of course 2 in the top of the field Dr. Mulhall and Dr. Burnett contributed!
* An ideal treatment capable of fully restoring normal and spontaneous erectile function (EF) has yet to be discovered.
Fig. 2 – Current and emerging treatments for erectile dysfunction.
Abstract
Background and objective
Erectile dysfunction (ED) is a common condition affecting patients’ quality of life. Clinical management has changed over the past three decades, new diagnostic and therapeutic options available. Our aim was to provide an overview of novel evidence regarding clinical management of ED.
Methods
A non-systematic literature review was conducted to identify relevant studies on the diagnosis and treatment of erectile dysfunction. The review encompassed pharmacological, regenerative, and surgical approaches, summarising recent advances and highlighting persisting gaps in clinical practice.
Key findings and limitations
ED is a common reason for seeking medical consultation.The correlation between ageing and ED prevalence is rooted in neurovascular tissue impairment. Medical history, along with the use of validated questionnaires, still represents the mainstay of ED assessment because of the lack of reliable imaging tests. The most widely used and effective treatment is an oral phosphodiesterase type 5 inhibitor, but this is lifelong therapy that is associated with high dropout rates. Among novel regenerative treatments, low-intensity shockwave therapy is supported by more evidence, although high-quality trials and long-term data are lacking. More conclusive evidence is needed for platelet-rich plasma injections and stem cell treatment. Botulinumneurotoxin and new emerging oral drugs are also under investigation.
Conclusions
Several treatment options are available for ED. Clinical tailoring of treatment for individual patients and rigorous research are crucial for further advances.
1. Introduction
Erectile dysfunction (ED) is one of the most common conditions affecting men worldwide [1]. According to the latest epidemiology studies, up to 71% of men will experience ED at some point in their life [1]. These numbers provide insight into the high social impact of this condition. For this reason, research aimed at improving quality of life for men suffering from ED has been active field over the past three decades. Despite these efforts, numerous questions remain unanswered regarding both the pathophysiology and thetreatment of ED [2]. An ideal treatment capable of fully restoring normal and spontaneous erectile function (EF) has yet to be discovered.
3.1. Epidemiology and etiology of ED
The etiology of ED can be broadly categorized as primary organic (vasculogenic, neurogenic, hormonal, iatrogenic, post-traumatic, or a combination of these factors) or primary psychogenic. Organic ED often coexists with other systemic diseases, including diabetes, cardiovascular diseases, and metabolic disorders [10,11]. Most of these conditions share a common pathophysiological pathway involving neurovascular impairment; in the penis, this eventually leads to a fibrotic process at the level of the cavernous bodies [12]. Iatrogenic ED also accounts for a significant proportion of cases. The ED can be drug-induced or secondary to therapeutic interventions such as pelvic surgery and radiotherapy [2]. Drug-induced ED is frequently observed: according to the US Food and Drug Administration (FDA) adverse event reporting system, more than 40%of ED reports are attributed to use of 5a-reductase inhibitors or neuropsychiatric medications [13]. In addition to the well-known organic causes of ED, psychogenic ED remains a significant yet often underdiscussed condition. Psychogenic ED is primarily linked to psychological conditions, including stress, anxiety, and depression, that disrupt neurochemical pathways involved in sexual arousal [2,14].Depression in particular increases the risk of ED and is often worsened by certain antidepressants [15].
3.2. ED assessment
3.3. Conducting clinical research on ED treatments
3.4. ED management
3.4.1. Phosphodiesterase type 5 inhibitors: new evidence
Recent research has placed a greater emphasis on the cardiovascular safety of PDE5I agents. Kloner et al [33] conducted a retrospective analysis of data from a large insurance claims database and found a 19% decrease in the occurrence of major adverse cardiovascular events and a 44% decrease in overall mortality among individuals exposed to tadalafil in comparison to those not exposed to PDE5Is. Given that ED is often an early marker of cardiovascular disease, this underscores the importance of assessing cardiovascular health in patients presenting with ED [34].
In addition to potential benefits for cardiovascular health, PDE5Is have demonstrated preventive effects in various other health disorders [35]. For example, research has shown that PDE5Is have renoprotective properties [36].Indeed, boosting of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling protects kidney function via regulation of blood flow and direct protection of kidney tissue through multiple cellular mechanisms [36],which are advantageous in conditions such as diabetic nephropathy and chronic kidney disease. PDE5Is also have potential advantages in heart failure, as they enhance cardiac function and decrease myocardial stress [35]. Furthermore, a growing body of data suggests potential PDE5I involvement in reducing cognitive decline [37], anticancer effects mediated by different mechanisms (eg, cell growth arrest; chemotherapy sensitization; modulation of immune responses [38]), and the treatment of immunological disorders and systemic sclerosis [39]. All of these findings needto be confirmed in large clinical trials
3.4.2. Intracavernous pharmacological treatment
Intracavernos injections (ICI) of vasoactive agents was one of the first treatments for ED and is currently considered a valid option for patients with no response to PDE5Is [2].
Overall, 30–65.9% of patientsare able to achieve erections adequate for sexual intercourse with these formulations [2,44,45].
Bimix and Trimix are combinations of off-label vasoactive agents that are often used to treat ED in patients who are poor responders to alprostadil, and have a good efficacy profile [46,47]
Botulinum neurotoxin type A (BoNT-A) has also been investigated as a potential treatment for ED.
Overall, these data suggest that BoNT-A could be an asset in delaying surgical treatment in patients who are unresponsive to medical treatment for ED. However, larger trials are needed to validate these findings and ascertain the efficacy and safety of BoNT-A for ED treatment. Current international guidelines still consider this treatment as experimental [2].
3.4.3. Regenerative therapies
Regenerative medicine, an experimental branch of medicine in which the aim is to regrow, repair, or replace damaged tissues, has potential as a curative treatment for ED.
Changes in the penile microenvironment are characteristic of advanced ED and researchers have been attempting to reverse these changes using regenerative therapies [57–59]. However, it should be borne in mind that ED is largely secondary to systemic disease, as are the penile changes observed. Therefore, there is a limited rationale for therapies directed solely at the penis. Moreover, our understanding of the penile microarchitecture and cellular functions remains incomplete [60]. Consequently, results for these therapeutic innovations must be interpreted with caution, considering that their limited effect sizes probably result from an incomplete understanding and opportunistic testing of therapies not specifically designed for this purpose. Table 1 summarizes the current evidence on regenerative therapies for ED according to data from primary sources and reflecting the collective expert opinion of the authors
3.4.3.1. SWT
In the past two decades, low-intensity SWT has been extensively investigated as a regenerative treatment for ED [61]. It is believed that the mechanical energy produced by acoustic shockwaves triggers restoration of cavernosal tissue via various pathways, including enhanced neoangiogenesis due to release of VEGF, recruitment of progenitor stem cells, nerve recovery, and regeneration directly through stimulation of neuronal proliferation or indirectly via activation of Schwann cells, an increase in the production of vasodilatory NO in affected tissues, and an anti inflammatory effect [57]. However, these hypotheses are grounded in data from animal studies, mainly murine ED models, which limits direct replication in human ED [57].
Despite inconclusive evidence on the biological effects o fSWT on cavernosal tissues, more than 20 RCTs and 14 meta analyses have investigated the efficacy of SWT for ED treatment [61]. Overall, these trials are affected by several limitations that reduce the quality of the evidence provided. (1
Despite these considerations, the excellent safety profile of SWT and the costs related to this out-of-pocket therapy have led to wide its use as a treatment option for ED. The European Association of Urology is the only international society to date to formally recommend this treatment as an option for patients with mild ED [2]; other international guidelines advise caution regarding SWT use and still consider the treatment as investigational [64,65].
3.4.3.2. Platelet-rich plasma.
The aim of platelet-rich plasma (PRP) treatment is to address various pathophysiological aspects of ED, including vascular issues, nerve protection and growth, tissue repair, and inflammation [66].
PRP therapy is widely marketed online and is primarily provided by clinics specialized in cosmetic or naturopathic medicine, often under supervision by cosmetic surgeons or general practitioners. However, the costs of this treatment are largely undisclosed, which obscures the financial aspect of PRP therapy for ED [58]. The paucity and low quality of the evidence does not support current use of PRP treatment in routine clinical practice.
3.4.3.3. Stem cell therapy.
The aim of stem cell therapy (SCT) in the ED setting is to regenerate damaged tissue to restore normal EF [12].
Basic science studies have shown that stem cells can self-renew and differentiate into various mature cell types, which makes them suitable for regenerative therapies, while animal studies have demonstrated the potential of stem cells to cure ED by improving various aspects of penile function, including mitigation of penile fibrosis [12]. However, these studies have limitations, and the scarcity of high-quality clinical evidence makes it challenging to translate the findings to human clinical applications [72,73]
The future of SCT for ED treatment will rely on the development of well-designed, multicenter, placebo-controlled RCTs to determine the optimal stem cell sources and their safety, effectiveness, doses, and administration routes. There is also a need to identify the type of patient and ED severity most suited to SCT. Until then, SCT should be considered experimental and restricted to clinical trials [74].
3.4.4. New potential treatments for ED: Rho-associated inhibitors and more
Novel pharmaceutical targets for the treatment of organic ED have been discovered that act at either the peripheralor central level.
In summary, these new treatments address different facets of the complex pathogenesis of ED. However, the lack of significant evidence supporting the efficacy and safety of these compounds has limited their use in clinical practice
3.4.5. New medical devices
Novel medical devices to assist patients in reaching desirable EF have been developed and investigated.
3.4.6. Surgery for ED: the era of implants
Penile prosthesis implantation remains the last bastion of ED treatment in refractory cases, and can also be considered in patients who prefer a definitive therapy and are not compliant with medical treatment [2]. Numerous advances in materials and surgical techniques over time have led to increases in patient satisfaction and a decrease in complication rates [105]. Data show satisfaction rates of 92–100% after proper preoperative counseling [106–108]. Infection and mechanical failure are the most common complications: infection rates of 1–2% have been reported in the most up-to-date series [109]. A recent meta-analysis showed that the penile prosthesis survival rate is as highas 76.8% at 10 yr [110].
Newer penile prosthesis designs in development seek to broaden the range of patients who can safely use implants while enhancing functionality and spontaneity by providing alternatives to manual pump activation and the need for reservoir placement.
While these advances have not yet been implemented in clinical practice, they are close on the horizon and represent the next phase in the evolution of penile prosthetic devices.
5. Conclusions
A diverse array of treatments is currently available for ED. Physicians should tailor every treatment to the patient’sclinical characteristics and expectations. There remains a need for further high-quality studies to define the role of novel and emerging treatments.
