madman
Super Moderator
We analyzed the efficacy of penile low-intensity extracorporeal shockwave treatment for erectile dysfunction (ED) combined with cavernous artery disease (CAD). ED was evaluated by the International Index of Erectile Function, subdividing patients into mild and moderate/severe forms. CAD was assessed using penile color Doppler ultrasonography. Patients (n = 111) with a positive outcome after treatment, based upon the minimal clinically important difference of the International Index of ED, were followed up for 3 months and 6 months. We found a significant mean increase in the index of erectile function, with an overall improvement in hemodynamic parameters of the cavernous artery. In particular, 93.9% of the patients with mild ED without CAD responded to treatment and 72.7% resumed normal erectile function. Only 31.2% of the patients with moderate/severe ED and CAD responded to treatment, and none resumed normal erectile function. All patients with mild ED and no CAD maintained the effects of therapy after 3 months, while no patients with moderate/severe ED and CAD maintained the benefits of treatment after 3 months. Thus, patients with mild ED and no CAD have better and longer-lasting responses to such treatment, with a higher probability of resuming normal erectile function than patients with moderate/severe ED and CAD.
INTRODUCTION
Erectile dysfunction (ED) is defined as the consistent or recurrent inability to obtain or maintain an erection sufficient for normal sexual intercourse. ED is a common disorder in middle-aged men that profoundly affects their quality of life.1–3 ED can result from impairment of any of the complex mechanisms that underlie penile erection. Hormonal imbalance (e.g., hypogonadism), neurological disease, pelvic surgery (e.g., radical prostatectomy), and atherosclerosis of the cavernous arteries can lead to ED. Vasculogenic ED is the most frequent subtype found in 70% of all cases,4 and it can represent an early manifestation of generalized vascular disease. In addition, ED may be the first sign of cardiovascular disease (CVD) and may precede coronary and peripheral artery disease by some years.5–7 The link between ED and CVD involves endothelial dysfunction.8,9 In 2010, Vardi et al. 10 proposed the use of low-intensity extracorporeal shockwave therapy (Li-ESWT) as a new treatment option for ED, and studies have shown promising results for this therapy in patients with mild-to-severe ED.11,12 In such patients, as has also been shown in animal models, it has been hypothesized that the improvement of the blood flow of the penis might be related to a cascade of biological responses. In particular, the release of molecules such as vascular endothelial growth factor can induce cell proliferation, recruitment, and activation of endogenous stem cells with a final antifibrotic and anti-inflammatory effect.8,11–15 Unlike the use of a phosphodiesterase type 5 inhibitor (PDE5i), Li-ESWT therapy aims to induce tissue repair by introducing a new aspect of ED treatment that attempts to modify the underlying pathological process, providing regenerative elements and not merely alleviating the symptoms. Taking into account the regenerative properties of Li-ESWT therapy, as well as its noninvasiveness, favorable safety profile, and cost-effectiveness, it is a potentially revolutionary treatment modality but has yet to be fully validated in human clinical trials. Currently, there are still no available studies regarding the effects of Li-ESWT on patients with ED and atherosclerotic alterations to the penile cavernous arteries. Here, we aimed to evaluate the influence of atherosclerotic cavernous artery disease on the efficacy of Li-ESWT for ED.
Li-ESWT treatment
The treatment protocol and evaluation methods were identical for all patients. Li-ESWT was supplied by an electromagnetic unit with a focused shockwave source (Duolith SD1; Storz Medical AG, Tägerwilen, Switzerland). The attached probe was aimed at the penis and crura after applying commercial ultrasonography gel. During each 25-min session, 2400 pulses were delivered with an energy density of 0.12 mJ mm−2 and a frequency of 3 Hz. By manually stretching the penis, 300 pulses were delivered to the distal, medium, proximal shaft, and crura on the right and left sides. Our protocol consisted of one treatment session per week over a period of 6 weeks. Success was determined at the end of treatment on the basis of a change in the IIEF score from baseline (before treatment), equal to or greater than the minimal clinically important difference,19 i.e., an increase of at least 7, 5, and 2 points for severe, moderate, and mild ED, respectively. All the included patients were followed up at 3 months and 6 months after the last Li-ESWT session.
DISCUSSION
ED is a common disorder in middle-aged men that profoundly affects their quality of life.3,4 There is growing evidence of pathophysiological and epidemiological associations between ED and CVD in relation to endothelial dysfunction, which frequently represents a common trait of both conditions. In fact, the vascular endothelium is not just a simple blood barrier but also an organ that synthesizes and releases substances, playing paracrine and endocrine roles in vascular tone and platelet aggregation.12 Studies have shown promising results of Li-ESWT for patients with ED.12,20 Li-ESWT was able to improve impaired erectile function in a variety of animal models of ED. Li-ESWT with energy levels above 0.12 mJ mm−2 has been shown to induce irreversible alterations to cell structure and organelles, so we decided to treat our patients with an energy limit of 0.12 mJ mm−2. 12,21 It has been shown that this Li-ESWT energy level induces cell membrane modifications and functional changes such as the stimulation of mechanosensor, induction of neoangiogenesis, recruitment, improvement, and activation of endothelial progenitor cells, nerve regeneration, erectile tissue remodeling through an increase in the muscle/collagen ratio and by reducing inflammatory and cellular stress responses.21–32 To date, there are no data regarding the effects of Li-ESWT on patients with ED with or without atherosclerotic cavernous artery disease. The results of our study, although limited to a relatively small cohort, show that patients with mild ED and without cavernous artery disease are younger and have a better and longer-lasting response to treatment. At the same time, this group of subjects has also a high probability to recover normal erectile function. In contrast, patients with moderate/severe ED and cavernous artery disease are older and more likely to experience treatment failure. This observation is confirmed by the fact that patients without cavernous artery disease were prone to have a greater improvement in PSV and AccT values paralleled by better erectile function when compared with patients with cavernous artery disease.
These data confirm previously reported findings by Sönmez and Kara33 showing that Li-ESWT therapy is not effective in patients with severe ED and by Chung et al. 34 showing that the patient selection appears paramount to treatment success and those patients with mild ED and who are younger are likely to report high erectile function recovery and spontaneous erections. In contrast, Yee et al. 35 reported those patients with severe ED, with probably primary vasculogenic etiology, benefitted from Li-ESWT, and the European Society of Sexual Medicine recommends limiting this therapy to subjects with vasculogenic ED.36
We assume that the differences in published responses to Li-ESWT treatment are probably linked to different protocols and in the severity of the atherogenic nature of ED. In fact, with the increase of atherosclerotic disease, there is a greater impairment in cavernous endothelial function as a result of a reduced activation and upregulation of endothelial nitric oxide synthase (eNOS), neural nitric oxide synthase (nNOS), and vascular endothelial growth factor receptor 2 (VEGFR2). This condition could be responsible for the reduced production of vasodilating agents such as nitric oxide (NO).37 Thus, some studies have highlighted the positive influence of Li-ESWT on the mobilization of endothelial progenitor cells from the bone marrow and their homing to the treated vessel.38,39 Furthermore, in a study in naturally aged rats, Li-ESWT seemed to alter the expression ratios of adrenergic receptors in the corpora cavernosa (increasing expression of alpha-2-adrenergic receptor and simultaneously decreasing expression of the alpha-1-adrenergic receptor), indicating a possible decrease in sympathetic activity. This action could enhance smooth muscle relaxation through NO or similar agents, resulting in vasodilation and enabling an erection.40
Finally, patients with mild ED and cavernous artery disease had a worse outcome after treatment and at 3 months of follow-up than those with moderate/severe ED and no artery disease as a consequence of trends in the increase in cardiovascular risk factors such as diabetes. The lack of correlation between the cardiovascular risk factors and the P-CDU parameters is probably related to concomitant drug therapies and the small number of patients. A control group would provide more insight into the direct effects of Li-ESWT, both in patients with/ without atherosclerosis. It appears that Li-ESWT therapy can induce tissue repair, introducing a new form of treatment for ED aimed at modifying the underlying pathogenesis. Thus, unlike treatment using PDE5i, this treatment appears to act along with regenerative elements and not just by alleviating symptoms.
Interestingly, patients with atherosclerotic cavernous artery disease had a Li-ESWT response that was less durable than among patients without vascular alterations. Therefore, in patients with moderate/severe ED and/or cavernous disease, different Li-ESWT protocols should be investigated to identify more effective energy flux density, number of sessions of treatment, and the total number of shockwaves able to improve erectile function. Furthermore, it will be interesting to perform treatment protocols with the combined use of Li-ESWT and PDE5i.
CONCLUSIONS
Here, we found that patients with mild ED, particularly those without cavernous artery disease tended to be younger and have a better and longer-lasting response to treatment with Li-ESWT, with a high probability of resuming normal erectile function. In contrast, patients with moderate/severe ED, especially those with cavernous artery disease tended to be older with a high probability of treatment failure. Further studies will be needed to evaluate different Li-ESWT treatment protocols (greater number of session, frequency, or intensity) associated with PDE5i in patients with moderate/severe ED and/or cavernous artery disease
INTRODUCTION
Erectile dysfunction (ED) is defined as the consistent or recurrent inability to obtain or maintain an erection sufficient for normal sexual intercourse. ED is a common disorder in middle-aged men that profoundly affects their quality of life.1–3 ED can result from impairment of any of the complex mechanisms that underlie penile erection. Hormonal imbalance (e.g., hypogonadism), neurological disease, pelvic surgery (e.g., radical prostatectomy), and atherosclerosis of the cavernous arteries can lead to ED. Vasculogenic ED is the most frequent subtype found in 70% of all cases,4 and it can represent an early manifestation of generalized vascular disease. In addition, ED may be the first sign of cardiovascular disease (CVD) and may precede coronary and peripheral artery disease by some years.5–7 The link between ED and CVD involves endothelial dysfunction.8,9 In 2010, Vardi et al. 10 proposed the use of low-intensity extracorporeal shockwave therapy (Li-ESWT) as a new treatment option for ED, and studies have shown promising results for this therapy in patients with mild-to-severe ED.11,12 In such patients, as has also been shown in animal models, it has been hypothesized that the improvement of the blood flow of the penis might be related to a cascade of biological responses. In particular, the release of molecules such as vascular endothelial growth factor can induce cell proliferation, recruitment, and activation of endogenous stem cells with a final antifibrotic and anti-inflammatory effect.8,11–15 Unlike the use of a phosphodiesterase type 5 inhibitor (PDE5i), Li-ESWT therapy aims to induce tissue repair by introducing a new aspect of ED treatment that attempts to modify the underlying pathological process, providing regenerative elements and not merely alleviating the symptoms. Taking into account the regenerative properties of Li-ESWT therapy, as well as its noninvasiveness, favorable safety profile, and cost-effectiveness, it is a potentially revolutionary treatment modality but has yet to be fully validated in human clinical trials. Currently, there are still no available studies regarding the effects of Li-ESWT on patients with ED and atherosclerotic alterations to the penile cavernous arteries. Here, we aimed to evaluate the influence of atherosclerotic cavernous artery disease on the efficacy of Li-ESWT for ED.
Li-ESWT treatment
The treatment protocol and evaluation methods were identical for all patients. Li-ESWT was supplied by an electromagnetic unit with a focused shockwave source (Duolith SD1; Storz Medical AG, Tägerwilen, Switzerland). The attached probe was aimed at the penis and crura after applying commercial ultrasonography gel. During each 25-min session, 2400 pulses were delivered with an energy density of 0.12 mJ mm−2 and a frequency of 3 Hz. By manually stretching the penis, 300 pulses were delivered to the distal, medium, proximal shaft, and crura on the right and left sides. Our protocol consisted of one treatment session per week over a period of 6 weeks. Success was determined at the end of treatment on the basis of a change in the IIEF score from baseline (before treatment), equal to or greater than the minimal clinically important difference,19 i.e., an increase of at least 7, 5, and 2 points for severe, moderate, and mild ED, respectively. All the included patients were followed up at 3 months and 6 months after the last Li-ESWT session.
DISCUSSION
ED is a common disorder in middle-aged men that profoundly affects their quality of life.3,4 There is growing evidence of pathophysiological and epidemiological associations between ED and CVD in relation to endothelial dysfunction, which frequently represents a common trait of both conditions. In fact, the vascular endothelium is not just a simple blood barrier but also an organ that synthesizes and releases substances, playing paracrine and endocrine roles in vascular tone and platelet aggregation.12 Studies have shown promising results of Li-ESWT for patients with ED.12,20 Li-ESWT was able to improve impaired erectile function in a variety of animal models of ED. Li-ESWT with energy levels above 0.12 mJ mm−2 has been shown to induce irreversible alterations to cell structure and organelles, so we decided to treat our patients with an energy limit of 0.12 mJ mm−2. 12,21 It has been shown that this Li-ESWT energy level induces cell membrane modifications and functional changes such as the stimulation of mechanosensor, induction of neoangiogenesis, recruitment, improvement, and activation of endothelial progenitor cells, nerve regeneration, erectile tissue remodeling through an increase in the muscle/collagen ratio and by reducing inflammatory and cellular stress responses.21–32 To date, there are no data regarding the effects of Li-ESWT on patients with ED with or without atherosclerotic cavernous artery disease. The results of our study, although limited to a relatively small cohort, show that patients with mild ED and without cavernous artery disease are younger and have a better and longer-lasting response to treatment. At the same time, this group of subjects has also a high probability to recover normal erectile function. In contrast, patients with moderate/severe ED and cavernous artery disease are older and more likely to experience treatment failure. This observation is confirmed by the fact that patients without cavernous artery disease were prone to have a greater improvement in PSV and AccT values paralleled by better erectile function when compared with patients with cavernous artery disease.
These data confirm previously reported findings by Sönmez and Kara33 showing that Li-ESWT therapy is not effective in patients with severe ED and by Chung et al. 34 showing that the patient selection appears paramount to treatment success and those patients with mild ED and who are younger are likely to report high erectile function recovery and spontaneous erections. In contrast, Yee et al. 35 reported those patients with severe ED, with probably primary vasculogenic etiology, benefitted from Li-ESWT, and the European Society of Sexual Medicine recommends limiting this therapy to subjects with vasculogenic ED.36
We assume that the differences in published responses to Li-ESWT treatment are probably linked to different protocols and in the severity of the atherogenic nature of ED. In fact, with the increase of atherosclerotic disease, there is a greater impairment in cavernous endothelial function as a result of a reduced activation and upregulation of endothelial nitric oxide synthase (eNOS), neural nitric oxide synthase (nNOS), and vascular endothelial growth factor receptor 2 (VEGFR2). This condition could be responsible for the reduced production of vasodilating agents such as nitric oxide (NO).37 Thus, some studies have highlighted the positive influence of Li-ESWT on the mobilization of endothelial progenitor cells from the bone marrow and their homing to the treated vessel.38,39 Furthermore, in a study in naturally aged rats, Li-ESWT seemed to alter the expression ratios of adrenergic receptors in the corpora cavernosa (increasing expression of alpha-2-adrenergic receptor and simultaneously decreasing expression of the alpha-1-adrenergic receptor), indicating a possible decrease in sympathetic activity. This action could enhance smooth muscle relaxation through NO or similar agents, resulting in vasodilation and enabling an erection.40
Finally, patients with mild ED and cavernous artery disease had a worse outcome after treatment and at 3 months of follow-up than those with moderate/severe ED and no artery disease as a consequence of trends in the increase in cardiovascular risk factors such as diabetes. The lack of correlation between the cardiovascular risk factors and the P-CDU parameters is probably related to concomitant drug therapies and the small number of patients. A control group would provide more insight into the direct effects of Li-ESWT, both in patients with/ without atherosclerosis. It appears that Li-ESWT therapy can induce tissue repair, introducing a new form of treatment for ED aimed at modifying the underlying pathogenesis. Thus, unlike treatment using PDE5i, this treatment appears to act along with regenerative elements and not just by alleviating symptoms.
Interestingly, patients with atherosclerotic cavernous artery disease had a Li-ESWT response that was less durable than among patients without vascular alterations. Therefore, in patients with moderate/severe ED and/or cavernous disease, different Li-ESWT protocols should be investigated to identify more effective energy flux density, number of sessions of treatment, and the total number of shockwaves able to improve erectile function. Furthermore, it will be interesting to perform treatment protocols with the combined use of Li-ESWT and PDE5i.
CONCLUSIONS
Here, we found that patients with mild ED, particularly those without cavernous artery disease tended to be younger and have a better and longer-lasting response to treatment with Li-ESWT, with a high probability of resuming normal erectile function. In contrast, patients with moderate/severe ED, especially those with cavernous artery disease tended to be older with a high probability of treatment failure. Further studies will be needed to evaluate different Li-ESWT treatment protocols (greater number of session, frequency, or intensity) associated with PDE5i in patients with moderate/severe ED and/or cavernous artery disease
