madman
Super Moderator
Abstract
Penile erection is a perfect example of microcirculation modulated by psychological factors and hormonal status. It is the result of a complex neurovascular process that involves the integrative synchronized action of vascular endothelium; smooth muscle; and psychological, neuronal, and hormonal systems. Therefore, the fine coordination of these events is essential to maintain penile flaccidity or allow erection; an alteration of these events leads to erectile dysfunction (ED). ED is defined as the consistent or recurrent inability of a man to attain and/or maintain a penile erection sufficient for sexual activity. A great boost to this research field was given by commercialization of phosphodiesterase-5 (PDE5) inhibitors.
Indeed, following the discovery of sildenafil, research on the mechanisms underlying penile erection has had an enormous boost, and many preclinical and clinical papers have been published in the last 10 years. This review is structured to provide an overview of the mediators and peripheral mechanism(s) involved in penile function in men, the drugs used in therapy, and the future prospective in the management of ED. Indeed, 30% of patients affected by ED are classified as “nonresponders,” and there is still an unmet need for therapeutic alternatives. A flowchart suggesting the guidelines for ED evaluation and the ED pharmacological treatment is also provided.
Table of Contents
1. INTRODUCTION – PHYSIOLOGY OF PENILE FUNCTION
1.1 Penile erection and detumescence
1.2 Central and peripheral control of penile erection
2. MEDIATORS IN ERECTILE FUNCTION
2.1 Contracting mediators
2.1.1 Noradrenaline
2.1.2 Serotonin
2.1.3 Endothelin
2.1.4 Renin-angiotensin system
2.1.5 Rho-Kinase pathway
2.2 Relaxing mediators
2.2.1 Gasotransmitters
2.2.1.1 Nitric Oxide
2.2.1.2 Carbon monoxide/Heme Oxygenase
2.2.1.3 Hydrogen sulfide
2.2.2 Prostanoids
2.2.3 Dopamine
2.2.4 Vasoactive Intestinal Peptide
3. ERECTILE DYSFUNCTION
3.1 Erectile dysfunction and risk factors
3.1.1 Smoking
3.1.2 Alcohol
3.1.3 Metabolic syndrome and obesity
3.1.4 Diabetes
3.1.5 Depression
4. ERECTILE DYSFUNCTION AND CARDIOVASCULAR DISEASE
5. TESTOSTERONE AND ERECTILE DYSFUNCTION
6. ERECTILE DYSFUNCTION DIAGNOSIS
7. PHARMACOLOGICAL THERAPY
7.1 Oral Therapy
7.1.1 Phosphodiesterase inhibitors
7.2 Intracavernous therapy
7.2.1 Prostaglandin E-1
7.2.2 Papaverine
7.2.3 Phentolamine
7.2.4 Vasoactive intestinal peptide
7.3 Intraurethral therapy 7.3.1 Prostaglandin E-1
7.4 Topical therapy
7.4.1 Prostaglandin E-1
7.5 Low-intensity Extracorporeal Shockwave Therapy
8. PREFERENCES AND SWITCH STUDIES: ARE ALL THE PDE5 INHIBITORS THE SAME?
9. FUTURE THERAPEUTIC APPROACHES
9.1 Stem cell therapy
9.2 sGC stimulators and activators: BAY 60-4552
9.3 Rho/RhoA Kinase inhibitor
9.4 Maxi-potassium channel activators
9.5 NO donors
9.6 Melanocortin agonist
9.7 Botulinum toxin
10. ONGOING CLINICAL TRIALS
10.1 A Study to Assess the Safety and Tolerability Profile of TR399 in Healthy Volunteers and Patients with Erectile Dysfunction
10.2 Botulinum Toxin for Erectile Dysfunction
10.3 Clinical Trial of Topically applied Glyceryl Trinitrate (GTN) for the Treatment of Erectile Dysfunction
10.4 Very Small Embryonic-like Stem Cells for Erectile Dysfunction
11. CONCLUSION
The prevalence of ED increases with advanced age and with the presence of a systemic disease; in fact, the vasculogenic ED is a complex multifactorial event linked to many morbidity factors, of which the most important are risk factors common with that indicated for CVD. Thus, clinical evaluations may not always be enough for the assessment of ED, and it is widely accepted that laboratory testing such as fasting blood glucose, HbA1c, and lipid profile or the use of penile Doppler ultrasonography should be considered for the evaluation of penile vascular structures in patients with ED. Moreover, ED in the absence of CVD is now considered a “sentinel symptom” in patients with occult undiagnosed CVD where the endothelial dysfunction has a key role.
The introduction of sildenafil on the market in 1998 as an oral remedy for ED has opened an entirely new field of research that has been flourishing in the past 20 years. This increase in interest contributed to a better understanding of the pathophysiology of erection function. As has been described and discussed in the above sections, we now have much information and we are in the process of identifying new therapeutic targets that should allow us to cure those cohorts of patients who are nonresponsive to PDE5 therapy. Another important issue is that there is still an unmet need for objective parameters, instead of validated questionnaires, to better classify the grade of ED. The development of these objective markers will also be instrumental to increase our knowledge of the efficacy of PDE5 inhibitors and even more relevant the relative potency of the drug under examination. In this regard, the measurement of cGMP levels in platelets could be considered one such marker, as it can be determined in the peripheral blood in case of PDE5 inhibitor treatments. The review focuses on data collected from human preclinical and clinical research only. The reader will realize that there are still many unanswered questions that need to be addressed and more efforts need to be made to improve ED therapy. The emerging strategies from basic science toward the anticipation of features, treatment of ED, and new treatments using pharmacological and innovative therapies could represent a real change in ED therapy.
Penile erection is a perfect example of microcirculation modulated by psychological factors and hormonal status. It is the result of a complex neurovascular process that involves the integrative synchronized action of vascular endothelium; smooth muscle; and psychological, neuronal, and hormonal systems. Therefore, the fine coordination of these events is essential to maintain penile flaccidity or allow erection; an alteration of these events leads to erectile dysfunction (ED). ED is defined as the consistent or recurrent inability of a man to attain and/or maintain a penile erection sufficient for sexual activity. A great boost to this research field was given by commercialization of phosphodiesterase-5 (PDE5) inhibitors.
Indeed, following the discovery of sildenafil, research on the mechanisms underlying penile erection has had an enormous boost, and many preclinical and clinical papers have been published in the last 10 years. This review is structured to provide an overview of the mediators and peripheral mechanism(s) involved in penile function in men, the drugs used in therapy, and the future prospective in the management of ED. Indeed, 30% of patients affected by ED are classified as “nonresponders,” and there is still an unmet need for therapeutic alternatives. A flowchart suggesting the guidelines for ED evaluation and the ED pharmacological treatment is also provided.
Table of Contents
1. INTRODUCTION – PHYSIOLOGY OF PENILE FUNCTION
1.1 Penile erection and detumescence
1.2 Central and peripheral control of penile erection
2. MEDIATORS IN ERECTILE FUNCTION
2.1 Contracting mediators
2.1.1 Noradrenaline
2.1.2 Serotonin
2.1.3 Endothelin
2.1.4 Renin-angiotensin system
2.1.5 Rho-Kinase pathway
2.2 Relaxing mediators
2.2.1 Gasotransmitters
2.2.1.1 Nitric Oxide
2.2.1.2 Carbon monoxide/Heme Oxygenase
2.2.1.3 Hydrogen sulfide
2.2.2 Prostanoids
2.2.3 Dopamine
2.2.4 Vasoactive Intestinal Peptide
3. ERECTILE DYSFUNCTION
3.1 Erectile dysfunction and risk factors
3.1.1 Smoking
3.1.2 Alcohol
3.1.3 Metabolic syndrome and obesity
3.1.4 Diabetes
3.1.5 Depression
4. ERECTILE DYSFUNCTION AND CARDIOVASCULAR DISEASE
5. TESTOSTERONE AND ERECTILE DYSFUNCTION
6. ERECTILE DYSFUNCTION DIAGNOSIS
7. PHARMACOLOGICAL THERAPY
7.1 Oral Therapy
7.1.1 Phosphodiesterase inhibitors
7.2 Intracavernous therapy
7.2.1 Prostaglandin E-1
7.2.2 Papaverine
7.2.3 Phentolamine
7.2.4 Vasoactive intestinal peptide
7.3 Intraurethral therapy 7.3.1 Prostaglandin E-1
7.4 Topical therapy
7.4.1 Prostaglandin E-1
7.5 Low-intensity Extracorporeal Shockwave Therapy
8. PREFERENCES AND SWITCH STUDIES: ARE ALL THE PDE5 INHIBITORS THE SAME?
9. FUTURE THERAPEUTIC APPROACHES
9.1 Stem cell therapy
9.2 sGC stimulators and activators: BAY 60-4552
9.3 Rho/RhoA Kinase inhibitor
9.4 Maxi-potassium channel activators
9.5 NO donors
9.6 Melanocortin agonist
9.7 Botulinum toxin
10. ONGOING CLINICAL TRIALS
10.1 A Study to Assess the Safety and Tolerability Profile of TR399 in Healthy Volunteers and Patients with Erectile Dysfunction
10.2 Botulinum Toxin for Erectile Dysfunction
10.3 Clinical Trial of Topically applied Glyceryl Trinitrate (GTN) for the Treatment of Erectile Dysfunction
10.4 Very Small Embryonic-like Stem Cells for Erectile Dysfunction
11. CONCLUSION
The prevalence of ED increases with advanced age and with the presence of a systemic disease; in fact, the vasculogenic ED is a complex multifactorial event linked to many morbidity factors, of which the most important are risk factors common with that indicated for CVD. Thus, clinical evaluations may not always be enough for the assessment of ED, and it is widely accepted that laboratory testing such as fasting blood glucose, HbA1c, and lipid profile or the use of penile Doppler ultrasonography should be considered for the evaluation of penile vascular structures in patients with ED. Moreover, ED in the absence of CVD is now considered a “sentinel symptom” in patients with occult undiagnosed CVD where the endothelial dysfunction has a key role.
The introduction of sildenafil on the market in 1998 as an oral remedy for ED has opened an entirely new field of research that has been flourishing in the past 20 years. This increase in interest contributed to a better understanding of the pathophysiology of erection function. As has been described and discussed in the above sections, we now have much information and we are in the process of identifying new therapeutic targets that should allow us to cure those cohorts of patients who are nonresponsive to PDE5 therapy. Another important issue is that there is still an unmet need for objective parameters, instead of validated questionnaires, to better classify the grade of ED. The development of these objective markers will also be instrumental to increase our knowledge of the efficacy of PDE5 inhibitors and even more relevant the relative potency of the drug under examination. In this regard, the measurement of cGMP levels in platelets could be considered one such marker, as it can be determined in the peripheral blood in case of PDE5 inhibitor treatments. The review focuses on data collected from human preclinical and clinical research only. The reader will realize that there are still many unanswered questions that need to be addressed and more efforts need to be made to improve ED therapy. The emerging strategies from basic science toward the anticipation of features, treatment of ED, and new treatments using pharmacological and innovative therapies could represent a real change in ED therapy.
Last edited:
