Roumeguere_EU Urological Review 19/05/2011 15:38 Page 56 Overview of Conservative Erectile Dysfunction Treatment
B e n j a m i n H e n r i e t 1 a n d T h i e r r y R o u m e g u è r e 2 1. Fellow; 2. Professor of Urology and Head, Department of Urology, University Clinic of Brussels, Erasme Hospital Abstract
Recent societal evolutions have enabled more and more men to talk about erectile dysfunction (ED). There is a strong association between
ED and cardiovascular disease and ED should now be considered as an early clinical evidence of vascular disorder. This is an important concern when considering the treatment of ED. Phosphodiesterase type 5 (PDE-5) inhibitors have revolutionised the treatment of ED. Three drugs (Sildenafil, Vardenafil and Tadalafil) are currently available as first-line therapeutic options that are well tolerated and highly effective in improving erectile function. All the potential cardiac and vascular effects of PDE-5 inhibitors have recently been reviewed. Despite the fact that millions of patients with ED worldwide have been successfully treated with one of these PDE-5 inhibitors, some men are always going to be difficult to treat. Several new PDE-5 inhibitors have recently been developed and are now being investigated in trials. However, 30% of patients need alternative therapies and intracavernous injections are the most successful second-line treatment. Some of the new therapeutic approaches available are currently under investigation, such as gene transfer therapy and stem cells therapy, melanocortin activators or extracorporeal shockwave therapy. Such approaches are still at an early stage but remain exciting new targets in difficult to Keywords
Erectile dysfunction, phosphodiesterase type 5 (PDE-5) inhibitors, Sildenafil, Vardenafil, Tadalafil, new PDE-5 inhibitors, alternative therapeutic
approach, centrally acting pharmaceutical agents, gene therapy, stem-cell therapy Disclosure: Benjamin Henriet has no conflicts of interest to declare. Thierry Roumeguère is a consultant for Pfizer, Bayer and Lilly companies in Belgium.
Received: 17 January 2011 Accepted: 2 March 2011 Citation: European Urological Review, 2011;6(1):56–9
Correspondence: Thierry Roumeguère, Department of Urology, University Clinic of Brussels, Erasme Hospital, Route de Lennik 808, 1070 Brussels, Belgium.
Erectile dysfunction (ED) is defined as the consistent or recurrent General Measures
inability to attain and/or maintain penile erection sufficient to permit Some lifestyle changes, including an increase in physical exercises and satisfactory sexual performance, with a three-month minimum duration periods of relaxation concomitantly with a decrease of responsibilities of symptoms.1 Psychological effects of ED considerably compromise can help restore sexual function in men under stress at home or at health-related quality of life and could impair mental and physical work.8 The control of the risk factors including diabetes, hypertension health.2 Recent societal evolutions have enabled more and more and hypercholesterolaemia may improve sexual function.3,9 The men to talk about this disability. This seems to account for an increase cessation of smoking and of excessive alcohol or recreational drugs in the number of people affected relative to what was previously intake may also be helpful. A focused physical examination may thought. According to epidemiological studies and depending on suggest hormonal disorders and should lead to laboratory tests the definition used, prevalence of ED range from 19.2 to 52%.2,3 The and specific treatment. If depression or other psychological causes incidence rate of ED was 26 new cases per 1,000 men annually in of ED are suspected, the patient should be referred for treatment.
the Massachusetts Male Aging Study.4 In a recent Dutch study, this Concomitant treatments that are well known to cause ED, such as incidence rate ranged from 28 for the clinically relevant ED up to 99 beta-blockers, thiazide diuretics, clonidine, spironolactone and when ED is simply defined as reduced rigidity.5 When the iatrogenic or antidepressant pharmacotherapies should be changed to a medication psychological origins are excluded, it has been demonstrated that carrying less risk of causing sexual dysfunction in a multidisciplinary there is a strong association between ED and cardiovascular disease.
approach. All of these simple measures may improve sexual They share common risk factors such as hypertension, diabetes, satisfaction and even if they are not sufficient, they are nevertheless obesity, hypercholesterolaemia, smoking, alcohol and lack of exercise.
necessary before starting any specific treatment. ED should now be considered as an early clinical evidence of vascular disorder.6,7 This is an important concern when considering the treatment Phospodiesterase Inhibitors
of ED because it is not only treating a functional trouble but also The physiological pathway of penile erection starts from supraspinal a generalised vascular disease. Inhibitors of the phosphodiesterase centres where the sexual arousal creates a stimulus running through type 5 (PDE-5) inhibitors have revolutionised the treatment of ED. New spinal cord and peripheral nerves. The non-adrenergic, non-cholinergic administration modalities are now available to improve the response neurons (NANC) of terminal penile nerve branches release nitric oxide rate with implications for subclinical endothelial inflammation (NO), which diffuses into the smooth muscle of the corpora cavernosa.
treatment’s target. New molecules are still being developed.
In the smooth muscle cells, NO stimulates guanylyl cyclase and then Roumeguere_EU Urological Review 19/05/2011 15:39 Page 57 Overview of Conservative Erectile Dysfunction Treatment induces increasing of cyclic guanosine monophospate (cGMP). This it seems that Tadalafil is frequently preferred, likely because of its elevation of intracellular cGMP activates a protein kinase G, which longer half-life, which allows more flexibility in the administration.
phosphorylates proteins and causes an increase in uptake of calcium into endoplasmic reticulum together with a decrease of calcium influx.
Several new PDE-5 inhibitors have recently been developed and The lowering of intracellular calcium finally results in smooth muscle are now being investigated in trials. Lodenafil carbonate is a dimmer relaxation. The initial inflow of blood increases the shear stress and of lodenafil, which is delivered into the bowel after ingestion stimulates a NO synthase in the endothelium leading to production of by breaking of the carbonate bridge. A phase III, prospective, randomised, double-blind, placebo-controlled clinical trial has recently been completed in Brazil.27 Three hundred and fifty men Vasculogenic ED results from impairment of endothelial smooth muscle with ED of various aetiologies were randomised to receive lodenafil relaxation and occlusion of the cavernosal arteries by atherosclerosis.
(40 or 80mg) or placebo for four weeks. Lodenafil 40 and 80mg Both disorders are due to the presence of persistent inflammatory state significantly improved erectile function with adverse events similar to and increased oxidative stress.11 Studies have already demonstrated that the presence of certain inflammatory mediators, including high-sensitivity C-reactive protein (hsCRP), fibrinogen, tumour Avanafil is a highly selective PDE-5 inhibitor that is rapidly absorbed necrosis factor alpha (TNF-α) or interleukins 1β and 6, is associated with a response rate of 76 to 84% depending on doses from 50 to with the severity of ED.12–14 In the same way, elevation of reactive 300mg and with a favourable side effect profile.28 Udenafil is PDE-5 oxygen species reduces the NO concentration, which is used in inhibitors already approved for the treatment of ED in South Korea. the conversion of superoxide into peroxynitrite.15 The decreased NO It shows both clinical properties of rapid onset and long half-life with concentration, together with cytotoxic effects of peroxynitrite, led to a comparable safety with other PDE-5 inhibitors. A multicentre, double-blind, placebo-controlled phase II trial randomised 167 men with ED to receive undenafil 100 or 200mg or placebo for 12 PDE-5 inhibitors act in the pathway of relaxation of smooth muscle cells weeks.29 The results demonstrated that udenafil was an effective by inhibiting the conversion of cGMP into 5’ guanosine monophosphate and well-tolerated treatment for ED with an efficacy up to 12 hours (5 GMP). This augmentation of bioavailability of intracellular cGMP after intake. Microdenafil is also approved in South Korea but has a promotes and amplifies the physiological cascade of penile erection. long time of onset and a short terminal time (two and a half hours). A trial was conducted by the same team, with 223 men randomised The first PDE-5 inhibitors, sildenafil, appeared in 1998. It is effective to microdenafil 50 or 100mg or placebo and demonstrated a good 60 minutes from administration and the efficacy can last for up to 12 tolerability and an improved erectile function.30 hours. Its absorption may be reduced or prolonged if taken with a fatty meal. Most of the studies demonstrate an overall response Even if comparative data are not available, it seems that new PDE-5 rate of about 65% when considering every subgroup of ED patients.16,17 inhibitors do not offer any advantages over older ones. They are Side effects, including facial flushing, headache, nasal congestion, unlikely to be used for difficult-to-treat patients and they probably dyspepsia and dizziness, are quite frequent (>60%), but do not seem will not be released onto European market, but non-responsive patients still need to receive treatment. One important way of managing ED is through the support given to the patient. It has been The selectivity for PDE-5 has been improved with Vardenafil.18 The demonstrated that appropriate usage instructions and correct dose response rate reaches 80% with the dose of 20mg and is effective 30 titration may improve the response rate.31–33 We have to keep in mind minutes from administration. The terminal half-life is quite shorter, that treating ED is not only a prescription of pills, it is mainly taking but nevertheless it has been shown that efficacy may last for up care of a patient in his entirety with his history, his social and to eight hours after dosing.19 The frequency and the nature of the relationship habits and his other medical disorders. adverse events are similar to sildenafil and the absorption is delayed All of the potential cardiac and vascular effects of PDE-5 inhibitors have recently been reviewed.34,35 Sildenafil is already indicated for Tadalafil is the most selective for PDE-5 inhibition. It has been licensed treatment of pulmonary arterial hypertension and other indications in Europe since 2003, like Vardenafil. The peak of efficacy occurs are being evaluated.36 PDE-5 inhibitors improve cardiac contraction about two hours after administration but lasts for up to 36 hours, with and cardiac pre-conditioning, which could lead to eventual benefits on a half-life of 17 hours and 30 minutes.20,21 The response rate can reach cardiac hypertrophy and ischaemic events. The generalised arterial 75% and interestingly, drug absorption is not affected by food intake.
vasodilatation, combined with inhibition of superoxide formation and The prolonged half-life of Tadalafil lends itself to a once-daily regimen, reduction of subclinical inflammation could be of great interest for the with the potential advantage of distinguishing pill intake from sexual treatment of multiple vascular disorders. intercourse. Once-a-day regimens are well tolerated and have shown efficacy in several prospective studies and real-life settings.22,23 The effect of PDE-5 inhibitors on low urinary tract syndrome (LUTS) is also being investigated. The reduction of oxidative stress and the Patients and physicians need to choose a PDE-5 inhibitor depending improvement of smooth muscle cells relaxation could be involved.37 on the various clinical characteristics that may be suited to individual Several studies have demonstrated that daily dosing of Sildenafil, expectation. Several comparative studies failed to demonstrate a Vardenafil and Tadalafil significantly increase the International Prostate superior efficacy of one of the three agents over the others.24–26 All Symptom Score (IPSS) but without improvement in uroflowmetry drugs are well tolerated and are highly effective in improving erectile parameters.38–42 These results encourage the PDE-5 inhibitors once-daily function, even in patients considered as difficult to treat. Nevertheless, regimen for patients suffering both of ED and of LUTS.
E U R O P E A N U R O L O G I C A L R E V I E W Roumeguere_EU Urological Review 19/05/2011 15:39 Page 58 Alternative Therapies
respond to PDE-5 inhibitors.51 Side effects including nausea, flushing, Some patients still have no response to PDE-5 inhibitors. About diaphoresis, low back pain, taste disturbance, headache and 40% of patients with diabetes and 50% of patients after radical somnolence are quite frequent and increase with dosage. Further prostatectomy do not respond to PDE-5 inhibitors.43 Alprostadil studies are needed to assess its utility and to define plainly its position (PGE1) is approved for intracavernous treatment of ED for more than 20 years and represents the most efficacious second-line therapy.44,45 The response rate is about 70% and the adverse events include A recently published study has evaluated the effect of extracorporeal penile pain, prolonged erections, priapism and fibrosis. The shockwave therapy (ESWT) on men with ED. The hypothesis is that adjunction of papaverine and/or phentolamine seems to increase ESWT could enhance the expression of vascular endothelial growth the efficacy but significantly increases the risk of fibrosis. Intraurethral factor and its receptors and induce neovascularisation. Twenty administration has also been described but resulted in lower efficacy men with vasculogenic ED who had previously responded to PDE-5 than intracavernosal injections. The combination of PDE-5 inhibitors inhibitors were enrolled and underwent two treatment sessions with the intracavernous tri-therapy is the ultimate strategy which can per week for three weeks. Significant increase in the IIEF-ED be considered before proceeding with surgical treatment. questionnaire were noted at one month and remained unchanged at six months. These results are encouraging, but there is still a need for Vacuum constriction devices remain an acceptable and purely a randomised, placebo-controlled study to validate it.52 mechanical approach. When used with a constrictor ring placed on the base of the penis, they provide a good efficacy in terms of erection, Other potential therapeutic pathways are still to be investigated.53 but with poor satisfaction rates because of the non-physiological The use of soluble guanylyl cyclase stimulators (sGC) could bypass nature of the erection.46 Adverse events include pain, inability to the NO stimulating step in the physiological pathway of erection. These ejaculate, petechiae, bruising and numbness and skin necrosis have could be of great interest when the NO bioavailability is reduced as in patients with comorbidities such as diabetes, high blood pressure or after radical prostatectomy. The inhibition of Rho-kinase – which New Approaches
is implicated in the contractile tone within the smooth muscle Gene transfer therapy is one of the most promising techniques for cells – could entertain the vasodilatation of arteries in the corpus multiple medical disorders. A phase I study has already demonstrated cavernous and then improve erectile function. Sodium nitrite – an NO the safety and the tolerability of the transfer of a plasmid expressing donor with a powerful hypotensive effect – could be used directly in the human Maxi-K potassium channel in the corpus cavernosum of 11 intracavernous injections to provide penile erection.
men with ED.47 These potassium channels provide a cell’s membrane hyperpolarisation with a consequent reduction of calcium influx Conclusion
and then smooth muscle relaxation. Other targets for gene transfer
There is a growing number of patients in demand for ED treatment.
therapy have already been identified, but more data are needed to The development of PDE-5 inhibitors has revolutionised the evaluate and define clearly the interest of such techniques in ED.
management of ED and these molecules are today considered as the first-line therapy for the treatment of vasculogenic ED. Correct The use of stem cells in ED is also being investigated. Several studies in counselling and adaptation of treatment to each individual and rat models have demonstrated that injection of adipose tissue-derived expectation may help to transform non-responder into responder stem cells improves the recovery of erectile function associated with patients. New PDE-5 inhibitors do not appear to be more effective hyperlipidaemia and diabetes, or due to nerve injury.48–50 at this time. Nevertheless, a certain percentage of patients do not respond to the classical approach and need alternative therapies.
Bremelanotide is an analogue of α-melanocyte stimulating hormone Intracavernous injection efficacy has been demonstrated, but this (αMSH) which activates a melanocortin receptor (MC4R) probably approach remains quite aggressive and binding. Several promising implicated in initiating or facilitating penile erection in the central techniques and molecules are being evaluated. In the same way, nervous system. A recent study has demonstrated that it improves potential new targets in the physiological pathway of penile erection erectile function in about one-third of the patients who did not Montorsi F, Adaikan G, Becher E, et al., Summary of the hyperlipidemia and coronary heart disease risk, Eur Urol, dysfunction patients with or without coronary artery disease, recommendations on sexual dysfunctions in men, J Sex Med, Esposito K, Giugliano F, Maiorino MI, Giugliano D, Dietary 15. Agarwal A, Nandipati KC, Sharma RK, et al., Role of oxidative Braun M, Wassmer G, Klotz T, et al., Epidemiology of erectile factors, Mediterranean diet and erectile dysfunction, stress in the pathophysiological mechanism of erectile dysfunction: results of the ‘Cologne Male Survey’, Int J Impot J Sex Med, 2010;7(7):2338–45.
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