madman
Super Moderator
Thinking About Pathomechanisms and Current Treatment of Erectile Dysfunction—“The Stanley Beamish Problem.” Review, Recommendations, and Proposals
ABSTRACT
Introduction: Up to 50% of all men over 50 years of age suffer from erectile dysfunction. Since the late 1990s erectile dysfunction has been treated mostly with phosphodiesterase 5 inhibitors (PDE5I). Over the past 20 years, numerous scientific findings on the development of erectile dysfunction have been collected, which have so far received little attention in the treatment of erectile dysfunction.
Objectives: The objectives of this study were to review the existing medical literature on erectile dysfunction regarding physiology, pathophysiology, and especially therapeutic options beyond treatment with PDE5I and to enable more effective and especially sustainable treatment for erectile dysfunction.
Methods: A literature review was performed by using PubMed from 1985 to 2020 regarding the physiology, pathophysiology, and treatment of erectile dysfunction. Results: Since the end of the 1990s an enormous amount of knowledge has been gained about the physiology/ pathophysiology of erection/erectile dysfunction. Based on these findings, numerous physical, drug, and holistic therapeutic options (beyond the application of PDE5I) have been developed for the treatment of erectile dysfunction. However, these are still relatively rarely used in the therapeutic concept of erectile dysfunction today.
Conclusion: Based on scientific findings of the last 20 years, there are numerous therapeutic approaches, including lifestyle modification, specific pelvic floor exercises, shock wave treatment, and the application of different supplements. The long-term treatment of erectile dysfunction should now go beyond the purely symptomatic use of PDE5I.
INTRODUCTION
In 1967 the television series “Mr. Terrific” was broadcast on American television for the first time. In terms of content, it was about a rather slender, shy, and somewhat dull protagonist (Stanley Beamish), who at times gains superpowers by taking a pill. Through the pill, Beamish develops supernatural powers and gains self-confidence, but despite all his heroic actions the somewhat nerdy character remains. When the pill loses its effect (after 1 hour), Beamish transforms back into his original personality.
In an amazing way, the drug-induced transformation of this serial character is reminiscent of the effect of drug therapy on patients with erectile dysfunction. If the affected patients achieve an erection capable of sexual intercourse for a short time, this gained effect fades away without improving the overall situation of the patient or achieving long-term recovery. This symptomatic treatment of erectile dysfunction, which is currently carried out almost exclusively on the basis of the use of phosphodiesterase 5 inhibitors (PDE5I), does not take into account the scientific knowledge of the causes and treatment options for erectile dysfunction over the last 20 years. We refer to this fact as the “Stanley Beamish Problem.”
Fatally, the possibility of the simple and symptomatically effective treatment of erectile dysfunction with a “pill” has led to a frequently unreflective prescription without diagnostic clarification of the underlying causes. Therefore, underlying findings that trigger and intensify erectile dysfunction are not identified and also not addressed therapeutically. Associated with this the procedure is a creeping further development of the underlying disease, a reduced effect of the symptomatic drug therapy over time, and the risk of fatal events associated with unrecognized secondary disease.
Drug treatment with PDE5I is by far the most common first-line therapy for patients with erectile dysfunction.1 Different therapeutic regimens, such as on-demand or continuous application of the various active drugs, have become widely established. In particular, the continuous administration of tadalafil over many months was expected to have a curative effect over time. Unfortunately, a curative effect could never be shown in scientific studies.2 Combination therapies with tadalafil and additional active ingredients (such as L-arginine) have in some studies produced a slightly better effect, but not a lasting one.3 In this respect, the treatment of erectile dysfunction with PDE5I is purely symptomatic treatment. Patients acquire, comparable to Stanley Beamish, for a short time a “supernatural” ability which they can use more or less effectively (the ability to fly acquired by Beamish seems somewhat awkward and bumbling in practice).
Medical treatments should have a curative intention if possible. If curative treatment is not possible due to a lack of existing therapeutic drugs or procedures, by definition a chronic therapy concept (permanent treatment) is aimed at. Many diseases of civilization, such as arterial hypertension or diabetes mellitus, are considered chronic diseases and are treated with chronic therapeutic concepts. Chronic therapy concepts aim to alleviate symptoms and, if possible, to slow down the progression of the underlying disease and prevent adverse consequences of the underlying disease. Against this background, when considering erectile dysfunction, it seems particularly important to note that there are certain underlying causes of this disease that allow for curative treatment (venous leakage, psychological factors). Thus, the diagnosis of the underlying findings of erectile dysfunction has to be a trend-setting aspect for the therapy and should not be neglected. Even the isolated introduction of the purely symptomatic, drug treatment of erectile dysfunction appears questionable in view of the neglected therapeutic aspects of preventing adverse effects of underlying findings and slowing down the progression of the underlying disease. The basic principle of medicine—no therapy before a definite diagnosis—should also be observed and followed in the treatment of erectile dysfunction.
The basis of every therapeutic option is a comprehensive knowledge of the physiology and pathophysiology of the entity to be treated. Therefore, in this review, we focus on the physiological-pathophysiological aspects of an erection and erectile dysfunction and associate them with possible therapeutic applications that go beyond purely symptomatic drug treatment with PDE5I.
*We hope to contribute to a better therapeutic approach to the multifactorial genesis of erectile dysfunction and, in the medium term, to shift the therapy of erectile dysfunction away from a purely symptomatic character toward a more regenerative and perhaps curative approach.
CONSIDERATION OF THE PHYSIOLOGY/ PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION
It has been scientifically shown that the development of erectile dysfunction is a multifactorial process that is associated with conditions like metabolic syndrome, coronary heart disease, diabetes mellitus, hyperlipidemia, hypogonadism, trauma, prostate hyperplasia, depression, and numerous other psychological and physiological states which negatively affect nerve activity, hormone secretion and perception, blood supply and disposal, biochemical processes, and microanatomical structures.4 The composition of the underlying factors can vary greatly, and the respective leading components can lead to differently structured forms of erectile dysfunction. It is obvious that these differently structured forms of erectile dysfunction require different therapeutic approaches. Therefore, the detailed diagnostic classification of erectile dysfunction (in individual cases) must absolutely precede any therapeutic intervention. A prerequisite for adequate diagnostics is knowledge of the physiology, pathophysiology, and pathogenesis of erection and erectile dysfunction. Therefore, we will shed light on the complex pathogenesis of erectile dysfunction in different levels (genetic, biochemical/molecular, and microanatomical).
*A normal erection is based on a meticulous interplay of hormonal, neuronal, and vascular processes, which can be compromised at the genetic, molecular, and microanatomical level.
THERAPEUTIC ASPECTS OF ERECTILE DYSFUNCTION
* 5 Inhibitors (PDE5I)
* Intracavernosal Self-Injection Therapy (ICI)/ Medicated Urethral System for Erection (MUSE)
* Lifestyle Modification
* Physiotherapeutic Exercises
* Testosterone
Nutraceuticals
* L-Arginine/L-Citrulline
Altogether it can be concluded on the basis of the available medical literature that the supplementation of L-arginine has a definite effect on mild and moderate erectile dysfunction. No conclusions can be made about the recommended daily dose and the application period due to the heterogeneity of the applied protocols. In severe erectile dysfunction, arginine has no place as a mono-therapeutic agent, but in combination with, for example, tadalafil it shows an additional effect that is statistically relevant (increased IIEF-ED from þ4.9 to þ6.6 points).3
*Ginseng (Panax Ginseng)
Overall, based on the available medical literature, we conclude that ginseng might improve erectile performance in mild and moderate erectile dysfunction. Somewhat questionable are the relatively low amounts of active ingredients used in combination preparations (10-150 mg) compared to the mono-preparations (1,400-3,000 mg).
*Vitamin D
Based on the available medical literature, we believe that supplementation of vitamin D is probably useful for improving erectile performance due to several activities of this steroid hormone: (i) the direct effect on NO synthase and associated NO increase, (ii) the possible stimulating effect on testosterone production, and (iii) the direct stimulation of the testosterone receptor.
Since vitamin D is a fat-soluble vitamin that can accumulate in the body, medical literature also shows critical comments on high-dose supplementation.105 However, despite the fat solubility of vitamin D, intoxication is extremely rare and only possible if excessive doses are taken over long periods of time.105 Due to the extensive studies, high safety profile, and positive effects on erectile function, we support the idea to include vitamin D in the therapeutic armamentarium of erectile dysfunction. Especially in patients with mild erectile dysfunction and testosterone deficiency, an attempt can be made to increase testosterone with vitamin D.
*Curcumin
Based on our literature research, we conclude that curcumin cannot be recommended as a generic medication for men with erectile dysfunction due to insufficient data. However, we see an application in connection with neurologically induced erectile dysfunction, for example in the context of radical prostatectomy. On the basis of the data from the meta-analysis, albeit purely animal-based, which also showed a dose-dependent effect, one should probably aim for relatively high doses (1,000 plus mg/day) around the surgical procedure.116 Whether this has a positive effect on the severity of erectile dysfunction after radical prostatectomy needs to be clarified in prospective studies.
PSYCHOTHERAPY/COUNSELING
In summary, in our opinion, the treatment of erectile dysfunction should always be combined with causal and therapeutic knowledge transfer, as well as psychological support and counseling for the patient/couple adapted to the situation.
@Mountain Man
VACUUM PUMP REHABILITATION
We recommend the integration of erection pumps in rehabilitative and/or causal therapeutic concepts, especially for patients who only rarely have sexual intercourse and who do not succeed in achieving an erection sufficiently frequently. In the purely symptomatic treatment of erectile dysfunction, the vacuum pump is also successfully used in otherwise therapy refractory cases, such as after removal of a defective penile prosthesis.12
SHOCK WAVE THERAPY
In our opinion, ESWT may have a definite value in the treatment of erectile dysfunction as a non-invasive method with few side effects. Due to the presumed mechanism of action via an increase in vascular cross-section, by the induction of angiogenesis, as well as stimulation of cell proliferation (smooth muscle cells and endothelial cells in the erectile tissue) and tissue regeneration, ESWT very well fits the concept of a curative and regenerative therapy of erectile dysfunction.142,143
*However, more independent, comparable, and long-term studies are needed to prove this effect. A disadvantage of the ESWT treatment is the repetitive character of the treatment (complex therapy, poor patient compliance), as well as the relatively high therapy costs.
CONCLUSIONS AND POSTULATES ON ERECTILE DYSFUNCTION
The collected data on the pathology and treatment of erectile dysfunction allows a differentiated consideration of this common male problem. Drug therapy with PDE5I represents a very good and rapidly effective, but symptomatic, treatment. However, in medium and long-term treatment, we see multidimensional and differentiated therapy options integrated into various treatment concepts.
Based on the data collected on the effectiveness of different therapeutic measures and medications, we could imagine integrated concepts for the treatment of different forms of erectile dysfunction; for example, the combination of L-arginine/L-citrulline and ginseng for the treatment of mild erectile dysfunction, or the combination of curcumin and vacuum pump rehabilitation as part of erectile rehabilitation after radical prostatectomy. Combinations of vitamin D and ginseng in the treatment of mild and moderate erectile dysfunction combined with libido deficiency and a lowered testosterone serum level would certainly be interesting. Psychological support, counseling, and lifestyle changes and psychotherapy/counseling should regularly be integrated into the treatment of erectile dysfunction. The integration of PDE5I (as an on-demand or continuous dose) into any erectile dysfunction treatment regimen can of course be helpful and valuable.
In order to get closer to a cause-related therapy of the different underlying causes of erectile dysfunction, further scientific studies are required. In order to advance scientific research in a meaningful way, we have come up with a number of postulates, the implementation of which we believe can improve the therapy of erectile dysfunction to a high medical level.
Based on our research and the resulting considerations, we offer the following postulates for the diagnosis and treatment of patients with erectile dysfunction:
1. We need to define different erection types—neuronal/ vascular, central/peripheral, visual/tactile—and to understand their molecular physiology. The defined erection type must then be included in diagnostic and especially therapeutic considerations.
2. Multimodal therapy concepts should be conceived, investigated, and implemented based on the pathophysiology of erectile dysfunction and a detailed investigation of causation.
3. It is noticeable that large meta-analyses concerning the therapeutic effects of supplements always refer to older studies. In addition, the study quality is usually low, and the treatment protocols used are very heterogeneous with regard to formation, dosage, and control instruments; up to date, standardized studies are needed.
4. When investigating the effects of different therapeutic approaches, treatment periods of 412 weeks are usually examined. With the long-term development of erectile dysfunction, such short-term therapy concepts seem unrealistic to us.
ABSTRACT
Introduction: Up to 50% of all men over 50 years of age suffer from erectile dysfunction. Since the late 1990s erectile dysfunction has been treated mostly with phosphodiesterase 5 inhibitors (PDE5I). Over the past 20 years, numerous scientific findings on the development of erectile dysfunction have been collected, which have so far received little attention in the treatment of erectile dysfunction.
Objectives: The objectives of this study were to review the existing medical literature on erectile dysfunction regarding physiology, pathophysiology, and especially therapeutic options beyond treatment with PDE5I and to enable more effective and especially sustainable treatment for erectile dysfunction.
Methods: A literature review was performed by using PubMed from 1985 to 2020 regarding the physiology, pathophysiology, and treatment of erectile dysfunction. Results: Since the end of the 1990s an enormous amount of knowledge has been gained about the physiology/ pathophysiology of erection/erectile dysfunction. Based on these findings, numerous physical, drug, and holistic therapeutic options (beyond the application of PDE5I) have been developed for the treatment of erectile dysfunction. However, these are still relatively rarely used in the therapeutic concept of erectile dysfunction today.
Conclusion: Based on scientific findings of the last 20 years, there are numerous therapeutic approaches, including lifestyle modification, specific pelvic floor exercises, shock wave treatment, and the application of different supplements. The long-term treatment of erectile dysfunction should now go beyond the purely symptomatic use of PDE5I.
INTRODUCTION
In 1967 the television series “Mr. Terrific” was broadcast on American television for the first time. In terms of content, it was about a rather slender, shy, and somewhat dull protagonist (Stanley Beamish), who at times gains superpowers by taking a pill. Through the pill, Beamish develops supernatural powers and gains self-confidence, but despite all his heroic actions the somewhat nerdy character remains. When the pill loses its effect (after 1 hour), Beamish transforms back into his original personality.
In an amazing way, the drug-induced transformation of this serial character is reminiscent of the effect of drug therapy on patients with erectile dysfunction. If the affected patients achieve an erection capable of sexual intercourse for a short time, this gained effect fades away without improving the overall situation of the patient or achieving long-term recovery. This symptomatic treatment of erectile dysfunction, which is currently carried out almost exclusively on the basis of the use of phosphodiesterase 5 inhibitors (PDE5I), does not take into account the scientific knowledge of the causes and treatment options for erectile dysfunction over the last 20 years. We refer to this fact as the “Stanley Beamish Problem.”
Fatally, the possibility of the simple and symptomatically effective treatment of erectile dysfunction with a “pill” has led to a frequently unreflective prescription without diagnostic clarification of the underlying causes. Therefore, underlying findings that trigger and intensify erectile dysfunction are not identified and also not addressed therapeutically. Associated with this the procedure is a creeping further development of the underlying disease, a reduced effect of the symptomatic drug therapy over time, and the risk of fatal events associated with unrecognized secondary disease.
Drug treatment with PDE5I is by far the most common first-line therapy for patients with erectile dysfunction.1 Different therapeutic regimens, such as on-demand or continuous application of the various active drugs, have become widely established. In particular, the continuous administration of tadalafil over many months was expected to have a curative effect over time. Unfortunately, a curative effect could never be shown in scientific studies.2 Combination therapies with tadalafil and additional active ingredients (such as L-arginine) have in some studies produced a slightly better effect, but not a lasting one.3 In this respect, the treatment of erectile dysfunction with PDE5I is purely symptomatic treatment. Patients acquire, comparable to Stanley Beamish, for a short time a “supernatural” ability which they can use more or less effectively (the ability to fly acquired by Beamish seems somewhat awkward and bumbling in practice).
Medical treatments should have a curative intention if possible. If curative treatment is not possible due to a lack of existing therapeutic drugs or procedures, by definition a chronic therapy concept (permanent treatment) is aimed at. Many diseases of civilization, such as arterial hypertension or diabetes mellitus, are considered chronic diseases and are treated with chronic therapeutic concepts. Chronic therapy concepts aim to alleviate symptoms and, if possible, to slow down the progression of the underlying disease and prevent adverse consequences of the underlying disease. Against this background, when considering erectile dysfunction, it seems particularly important to note that there are certain underlying causes of this disease that allow for curative treatment (venous leakage, psychological factors). Thus, the diagnosis of the underlying findings of erectile dysfunction has to be a trend-setting aspect for the therapy and should not be neglected. Even the isolated introduction of the purely symptomatic, drug treatment of erectile dysfunction appears questionable in view of the neglected therapeutic aspects of preventing adverse effects of underlying findings and slowing down the progression of the underlying disease. The basic principle of medicine—no therapy before a definite diagnosis—should also be observed and followed in the treatment of erectile dysfunction.
The basis of every therapeutic option is a comprehensive knowledge of the physiology and pathophysiology of the entity to be treated. Therefore, in this review, we focus on the physiological-pathophysiological aspects of an erection and erectile dysfunction and associate them with possible therapeutic applications that go beyond purely symptomatic drug treatment with PDE5I.
*We hope to contribute to a better therapeutic approach to the multifactorial genesis of erectile dysfunction and, in the medium term, to shift the therapy of erectile dysfunction away from a purely symptomatic character toward a more regenerative and perhaps curative approach.
CONSIDERATION OF THE PHYSIOLOGY/ PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION
It has been scientifically shown that the development of erectile dysfunction is a multifactorial process that is associated with conditions like metabolic syndrome, coronary heart disease, diabetes mellitus, hyperlipidemia, hypogonadism, trauma, prostate hyperplasia, depression, and numerous other psychological and physiological states which negatively affect nerve activity, hormone secretion and perception, blood supply and disposal, biochemical processes, and microanatomical structures.4 The composition of the underlying factors can vary greatly, and the respective leading components can lead to differently structured forms of erectile dysfunction. It is obvious that these differently structured forms of erectile dysfunction require different therapeutic approaches. Therefore, the detailed diagnostic classification of erectile dysfunction (in individual cases) must absolutely precede any therapeutic intervention. A prerequisite for adequate diagnostics is knowledge of the physiology, pathophysiology, and pathogenesis of erection and erectile dysfunction. Therefore, we will shed light on the complex pathogenesis of erectile dysfunction in different levels (genetic, biochemical/molecular, and microanatomical).
*A normal erection is based on a meticulous interplay of hormonal, neuronal, and vascular processes, which can be compromised at the genetic, molecular, and microanatomical level.
THERAPEUTIC ASPECTS OF ERECTILE DYSFUNCTION
* 5 Inhibitors (PDE5I)
* Intracavernosal Self-Injection Therapy (ICI)/ Medicated Urethral System for Erection (MUSE)
* Lifestyle Modification
* Physiotherapeutic Exercises
* Testosterone
Nutraceuticals
* L-Arginine/L-Citrulline
Altogether it can be concluded on the basis of the available medical literature that the supplementation of L-arginine has a definite effect on mild and moderate erectile dysfunction. No conclusions can be made about the recommended daily dose and the application period due to the heterogeneity of the applied protocols. In severe erectile dysfunction, arginine has no place as a mono-therapeutic agent, but in combination with, for example, tadalafil it shows an additional effect that is statistically relevant (increased IIEF-ED from þ4.9 to þ6.6 points).3
*Ginseng (Panax Ginseng)
Overall, based on the available medical literature, we conclude that ginseng might improve erectile performance in mild and moderate erectile dysfunction. Somewhat questionable are the relatively low amounts of active ingredients used in combination preparations (10-150 mg) compared to the mono-preparations (1,400-3,000 mg).
*Vitamin D
Based on the available medical literature, we believe that supplementation of vitamin D is probably useful for improving erectile performance due to several activities of this steroid hormone: (i) the direct effect on NO synthase and associated NO increase, (ii) the possible stimulating effect on testosterone production, and (iii) the direct stimulation of the testosterone receptor.
Since vitamin D is a fat-soluble vitamin that can accumulate in the body, medical literature also shows critical comments on high-dose supplementation.105 However, despite the fat solubility of vitamin D, intoxication is extremely rare and only possible if excessive doses are taken over long periods of time.105 Due to the extensive studies, high safety profile, and positive effects on erectile function, we support the idea to include vitamin D in the therapeutic armamentarium of erectile dysfunction. Especially in patients with mild erectile dysfunction and testosterone deficiency, an attempt can be made to increase testosterone with vitamin D.
*Curcumin
Based on our literature research, we conclude that curcumin cannot be recommended as a generic medication for men with erectile dysfunction due to insufficient data. However, we see an application in connection with neurologically induced erectile dysfunction, for example in the context of radical prostatectomy. On the basis of the data from the meta-analysis, albeit purely animal-based, which also showed a dose-dependent effect, one should probably aim for relatively high doses (1,000 plus mg/day) around the surgical procedure.116 Whether this has a positive effect on the severity of erectile dysfunction after radical prostatectomy needs to be clarified in prospective studies.
PSYCHOTHERAPY/COUNSELING
In summary, in our opinion, the treatment of erectile dysfunction should always be combined with causal and therapeutic knowledge transfer, as well as psychological support and counseling for the patient/couple adapted to the situation.
@Mountain Man
VACUUM PUMP REHABILITATION
We recommend the integration of erection pumps in rehabilitative and/or causal therapeutic concepts, especially for patients who only rarely have sexual intercourse and who do not succeed in achieving an erection sufficiently frequently. In the purely symptomatic treatment of erectile dysfunction, the vacuum pump is also successfully used in otherwise therapy refractory cases, such as after removal of a defective penile prosthesis.12
SHOCK WAVE THERAPY
In our opinion, ESWT may have a definite value in the treatment of erectile dysfunction as a non-invasive method with few side effects. Due to the presumed mechanism of action via an increase in vascular cross-section, by the induction of angiogenesis, as well as stimulation of cell proliferation (smooth muscle cells and endothelial cells in the erectile tissue) and tissue regeneration, ESWT very well fits the concept of a curative and regenerative therapy of erectile dysfunction.142,143
*However, more independent, comparable, and long-term studies are needed to prove this effect. A disadvantage of the ESWT treatment is the repetitive character of the treatment (complex therapy, poor patient compliance), as well as the relatively high therapy costs.
CONCLUSIONS AND POSTULATES ON ERECTILE DYSFUNCTION
The collected data on the pathology and treatment of erectile dysfunction allows a differentiated consideration of this common male problem. Drug therapy with PDE5I represents a very good and rapidly effective, but symptomatic, treatment. However, in medium and long-term treatment, we see multidimensional and differentiated therapy options integrated into various treatment concepts.
Based on the data collected on the effectiveness of different therapeutic measures and medications, we could imagine integrated concepts for the treatment of different forms of erectile dysfunction; for example, the combination of L-arginine/L-citrulline and ginseng for the treatment of mild erectile dysfunction, or the combination of curcumin and vacuum pump rehabilitation as part of erectile rehabilitation after radical prostatectomy. Combinations of vitamin D and ginseng in the treatment of mild and moderate erectile dysfunction combined with libido deficiency and a lowered testosterone serum level would certainly be interesting. Psychological support, counseling, and lifestyle changes and psychotherapy/counseling should regularly be integrated into the treatment of erectile dysfunction. The integration of PDE5I (as an on-demand or continuous dose) into any erectile dysfunction treatment regimen can of course be helpful and valuable.
In order to get closer to a cause-related therapy of the different underlying causes of erectile dysfunction, further scientific studies are required. In order to advance scientific research in a meaningful way, we have come up with a number of postulates, the implementation of which we believe can improve the therapy of erectile dysfunction to a high medical level.
Based on our research and the resulting considerations, we offer the following postulates for the diagnosis and treatment of patients with erectile dysfunction:
1. We need to define different erection types—neuronal/ vascular, central/peripheral, visual/tactile—and to understand their molecular physiology. The defined erection type must then be included in diagnostic and especially therapeutic considerations.
2. Multimodal therapy concepts should be conceived, investigated, and implemented based on the pathophysiology of erectile dysfunction and a detailed investigation of causation.
3. It is noticeable that large meta-analyses concerning the therapeutic effects of supplements always refer to older studies. In addition, the study quality is usually low, and the treatment protocols used are very heterogeneous with regard to formation, dosage, and control instruments; up to date, standardized studies are needed.
4. When investigating the effects of different therapeutic approaches, treatment periods of 412 weeks are usually examined. With the long-term development of erectile dysfunction, such short-term therapy concepts seem unrealistic to us.
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