- Email: [email protected]
Type 5 Phosphodiesterase Inhibitors: Curing Erectile Dysfunction
european urology 49 (2006) 942–945
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Editorial
Type 5 Phosphodiesterase Inhibitors: Curing Erectile Dysfunction Wayne J.G. Hellstrom *, Muammer Kendirci Section of Andrology, Department of Urology, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
Basic science research on erectile physiology has focused on the pathogenesis of erectile dysfunction (ED) and has provided convincing evidence that ED is predominately a disease of vascular etiology correlating with coronary artery disease, hypertension, atherosclerosis, hyperlipidemia, smoking, and diabetes mellitus [1,2]. ED is also associated with aging and pelvic surgeries, specifically radical prostatectomy (RP). Scientific evidence supports the concept that endothelial dysfunction and the resulting reduction in the release of nitric oxide (NO) from the endothelium during sexual stimulation is an important contributor to the pathophysiology of vasculogenic ED [3]. Furthermore, the oxygen tensiondependent changes in the penis during erection are proposed to have an impact on corpus cavernosal structure by inducing various cytokines, vasoactive factors, and growth factors, which, in turn, alter smooth muscle metabolism and connective tissue synthesis [4]. The absence of regular sexually stimulated or nocturnal penile erections causes, in theory, an insufficient oxygen supply to the penis, resulting in increased fibrogenesis and reduced smooth muscle content that further augment ED. Vasoactive pharmacotherapy (ie, type 5 phosphodiesterase [PDE5] inhibitors) traditionally uses an ‘‘on demand,’’ acute method of administration. However, recent data propose ‘‘chronic’’ long-term administration of these agents as a ‘‘curative purpose’’ in the management of ED [5]. There have
been clinical and basic research findings supportive of this application of PDE5 inhibitors in ‘‘curing’’ ED. Commonly known vascular risk factors are associated with endothelial dysfunction. Rosano and colleagues investigated whether continuous, regular treatment with tadalafil improves endothelial function in patients with increased cardiovascular risk factors and whether this effect is sustained after discontinuation of therapy [6]. These investigators reported that chronic tadalafil therapy can improve endothelial function, as assessed by flow-mediated dilation of the brachial artery, plasma nitrite/nitrate levels and endothelin-1 production, in men with increased cardiovascular risk. Of note, this improvement in endothelial function was sustained for 2 weeks after discontinuation of treatment, suggesting that chronic administration of tadalafil may lead to fundamental biologic changes that provide long-term benefits even after cessation of treatment. Similarly, Desouza et al. assessed the acute and prolonged effects of a low dose of sildenafil (25 mg) on flow-mediated dilation in patients with type 2 diabetes in a double-blind, placebo-controlled, crossover trial in 16 patients [7]. The authors reported that acute and prolonged sildenafil treatment had a favourable effect on brachial artery flow-mediated dilatation that persisted for at least 24 h after the last dose. Caretta et al. investigated the effect of continuous, regular administration of tadalafil on erectile
DOI of original article: 10.1016/j.eururo.2005.12.055 * Corresponding author. Section of Andrology, Department of Urology, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-42, New Orleans, LA 70112, USA. Tel. +1 504 988 7308; Fax: +1 504 988 5059. E-mail address: [email protected] (Wayne J.G. Hellstrom). 0302-2838/$ – see back matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2006.02.063
european urology 49 (2006) 942–945
function in elderly men with ED [8]. Sixty subjects, aged 60–70 yr, with a history of ED for 6–12 mo received 20 mg tadalafil on alternate days for 3 mo. Men younger than 40 yr old with psychogenic ED served as controls. At baseline and 1 mo after the end of treatment, all patients were evaluated with nocturnal penile tumescence and rigidity (NPTR) monitoring and penile Doppler ultrasound evaluation of the carotid artery intima-media thickness (IMT). They reported that in elderly men with increased or normal carotid IMT, chronic treatment with tadalafil improved endothelial function and concomitantly induced spontaneous resumption of erectile function. In a similar manner, Sommer et al. investigated whether daily intake of sildenafil 50 mg at bedtime over a 1-yr period in patients with vascular ED could induce a long-term improvement in erectile function compared to patients who took medication on an ‘‘as needed’’ basis [9]. These authors reported that daily administration of sildenafil at bedtime produced a significant improvement in erectile function, which was maintained even after treatment discontinuation. This symptomatic improvement in erectile function was documented by improved cavernosal arterial blood flows during pharmacologically induced erections. They hypothesised that improvement in erectile function may be a result of physiologic changes in the erectile tissues related to increased NO production that contributes to a normalisation of endothelial function. Although, evidence from studies on penile rehabilitation after RP support the concept of chronic administration of vasoactive agents to recover spontaneous erectile function, the rationale and mechanism for their use in penile rehabilitation programs after RP have not been fully elucidated nor have they been replicated in large multicentre placebo-controlled trials. In an early study, Montorsi and colleagues evaluated the use of intracavernous alprostadil injections for 6 mo in men undergoing RP and demonstrated an increased recovery rate of spontaneous erections postoperatively in 67% of men receiving alprostadil compared to 20% without treatment [10]. Researchers have demonstrated that nightly use of sildenafil significantly increased the overall quality and quantity of nocturnal erections as recorded by NPTR in men with ED when compared to placebo [11]. A recent prospective study reported a significant benefit of either 50 mg or 100 mg of sildenafil administration each night for 7 mo, compared to placebo, in men after undergoing bilateral nerve-sparing RP [12]. In this study, the
943
patients receiving sildenafil for 36 wk documented a 27% return of spontaneous, normal erectile activity compared to 4% in the placebo group. This study remains in abstract form and still has not been published. In a recent prospective study, Mulhall et al. evaluated the use of an erectogenic pharmacotherapy regimen following RP as to whether it improved recovery of spontaneous erectile function [13]. Chronic use of oral and intracavernous vasoactive agents in this study resulted in improvements in a number of outcomes including the proportion of men who had recovery of spontaneous functional erections, the ability and diminished time course to respond to sildenafil, the ability to respond to intracavernous injections, the percentage of men who had normalisation of the erectile function domain scores, the fewer number of men left with severe ED after RP, and the lower dose of vasoactive medication required to obtain an erection rigid enough for penetration. These preliminary results suggest a rationale for early prophylaxis with PDE5 inhibitors to promote earlier recovery of spontaneous erectile function after nerve-sparing RP. A number of animal studies support the concept of chronic use of PDE5 inhibitors to improve endothelial dysfunction. Behr-Roussel et al. treated rats with sildenafil versus saline solution via subcutaneous injections for 8 wk [14]. Results from the in vitro assays in this study revealed that endothelial-mediated relaxation induced by acetylcholine was significantly enhanced by 35% in rats pretreated with sildenafil compared to control rats. In addition, rats pretreated with sildenafil documented a greater erectile response to electrical field stimulation following an acute injection of sildenafil compared to control rats. These authors concluded that long-term treatment with sildenafil potentiates acetylcholine-induced endotheliumdependent cavernosal responses and enhances the erectile response in rats, supporting the benefits of regular treatment with a PDE5 inhibitor beyond the effect observed with acute administration. The overall concept of penile rehabilitation is to prevent cavernous tissue damage that occurs during the period of neural recovery, by providing adequate oxygenation to the cavernous tissues. This oxygenation leads to an increase in the production of intracavernous prostanoids, which are postulated to protect the cavernosal smooth muscle [15]. A recent clinical study by Schwartz et al. demonstrated the protective effects of sildenafil on intracorporeal smooth muscle [16]. In this small study, patients were instructed to use 50 mg or 100 mg sildenafil nightly for 6 mo after nerve-sparing RP. The authors
944
european urology 49 (2006) 942–945
documented on penile biopsy studies preserved cavernosal smooth muscle content with 50 mg sildenafil at 6 mo (52.67%) compared with baseline (51.52%) and an even greater increase in mean cavernosal smooth muscle content (56.85%) with 100 mg sildenafil at 6 mo compared to baseline (42.82%). Given the importance of the NO/cyclic guanosine monophosphate pathway in cavernosal smooth muscle function, chronic administration of vasoactive agents (including PDE5 inhibitors) may offer long-term beneficial effects on erectile tissue. Vardenafil has recently been shown to increase circulating progenitor cells in humans [17]. These cells are recognised to play a role in the process of neovascularisation and the continuous repair of the endothelium [18]. Another report showed that a decrease in circulatory progenitor cells in ED was associated with cardiovascular risk factors, that is, endothelial dysfunction [19]. Other potential beneficial effects of chronic PDE5 inhibitor therapy in the recovery of spontaneous erections may be related to the promotion of neurogenesis, the protection of cavernosal endothelium, antifibrinogenic activity, angiogenesis, cavernosal smooth muscle growth, and differentiation [20]. The field of sexual medicine has made tremendous advances in our knowledge base and treatment practices over the past few decades. In many circumstances, clinical and base scientific gains have been complimentary and have supported the notion of the clinician–scientist union. Techniques in surgery have heralded pharmacologic breakthroughs that, in turn, will propel new initiatives in molecular-based therapies. The concept of chronic administration of PDE5 inhibitors as a cure for ED is both intellectually interesting and therapeutically captivating. The theory that prolonged endothelial stimulation can either prevent or reverse end-organ failure has been proposed. A number of animal model experiments, where induced ED has shown benefit from longterm PDE5 inhibitor administration, is the most plausible evidence that we have on supporting this concept. However, in short, more is certainly still needed at the basic research level to further elucidate these biologic concepts. On the clinical front, although many clinicians have instituted chronic PDE5 inhibitor therapy as the standard of care in their prostate cancer treatment and diabetic patients, with the hopes of improving erectile function, the reality is that there is a paucity of published studies available on which to base their claims. For the most part, studies are of short duration, are in abstract form, are single
centre, have few subjects, and often confuse preference with documented physiologic benefit. Many are not placebo-controlled and, as most investigators in sexual medicine are aware, the placebo effect has a strong psychogenic benefit. It is important not to appear overly negative or pessimistic about these new data, and we remain cautiously optimistic. However, evidence to support the reversal of ED by chronic administration of a PDE5 inhibitor is still not convincing to many. Individual investigators are at a disadvantage and it is somewhat surprising that societal, institutional, or pharmacologic company support for such research endeavours on a larger scale have not appeared. Further well-designed studies are encouraged and need to focus on optimal route of drug delivery, dosing schedule, patient selection, optimal duration, and timing of application. The downside of continuing to promote the precept of chronic dosing as a cure for ED, without more substantial data, is the emotional and financial cost to our patients, the disillusionment by our referring professional colleagues, and the loss of scientific credibility for our domain of medicine.
References [1] NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA 1993;270:83–90. [2] Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151:54–61. [3] Bivalacqua TJ, Usta MF, Champion HC, Kadowitz PJ, Hellstrom WJ. Endothelial dysfunction in erectile dysfunction: role of the endothelium in erectile physiology and disease. J Androl 2003;24:S17–37. [4] Moreland RB. Pathophysiology of erectile dysfunction: the contributions of trabecular structure to function and the role of functional antagonism. Int J Impot Res 2000;12:S39–46. [5] Montorsi F, Briganti A, Salonia A, Rigatti P, Burnett AL. Can phosphodiesterase type 5 inhibitors cure erectile dysfunction? Eur Urol 2006;49:979–86. [6] Rosano GM, Aversa A, Vitale C, Fabbri A, Fini M, Spera G. Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk. Eur Urol 2005;47:214–20, discussion p. 220–2. [7] Desouza C, Parulkar A, Lumpkin D, Akers D, Fonseca VA. Acute and prolonged effects of sildenafil on brachial artery flow-mediated dilatation in type 2 diabetes. Diabetes Care 2002;25:1336–9. [8] Caretta N, Palego P, Ferlin A, et al. Resumption of spontaneous erections in selected patients affected by erectile dysfunction and various degrees of carotid wall altera-
european urology 49 (2006) 942–945
[9]
[10]
[11]
[12]
[13]
tion: role of tadalafil. Eur Urol 2005;48:326–31, discussion p. 331–2. Sommer F, Schulze W. Treating erectile dysfunction by endothelial rehabilitation with phosphodiesterase 5 inhibitors. World J Urol 2005;23:385–92. Montorsi F, Guazzoni G, Strambi LF, et al. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol 1997;158: 1408–10. Montorsi F, Maga T, Strambi LF, et al. Sildenafil taken at bedtime significantly increases nocturnal erections: results of a placebo-controlled study. Urology 2000;56: 906–11. Padma-Nathan H, McCullough A, Giuliano F, Toler SM, Wohlhuter C, Shpilsky AB. Postoperative nightly administration of sildenafil citrate significantly improved the return of normal spontaneous erectile function after bilateral nerve-sparing radical prostatectomy. J Urol 2003;4:375. Mulhall J, Land S, Parker M, Waters WB, Flanigan RC. The use of an erectogenic pharmacotherapy regimen
[14]
[15]
[16]
[17]
[18] [19]
[20]
945
following radical prostatectomy improves recovery of spontaneous erectile function. J Sex Med 2005;2:532–42. Behr-Roussel D, Gorny D, Mevel K, et al. Chronic sildenafil improves erectile function and endothelium-dependent cavernosal relaxations in rats: lack of tachyphylaxis. Eur Urol 2005;47:87–91. Moreland RB, Albadawi H, Bratton C, et al. O2-dependent prostanoid synthesis activates functional PGE receptors on corpus cavernosum smooth muscle. Am J Physiol Heart Circ Physiol 2001;281:H552–8. Schwartz EJ, Wong P, Graydon RJ. Sildenafil preserves intracorporeal smooth muscle after radical retropubic prostatectomy. J Urol 2004;171:771–4. Foresta C, Lana A, Cabrelle A, et al. PDE-5 inhibitor, Vardenafil, increases circulating progenitor cells in humans. Int J Impot Res 2005;17:377–80. Garmy-Susini B, Varner JA. Circulating endothelial progenitor cells. Br J Cancer 2005;93:855–8. Foresta C, Caretta N, Lana A, Cabrelle A, Palu G, Ferlin A. Circulating endothelial progenitor cells in subjects with erectile dysfunction. Int J Impot Res 2005;17:288–90. Burnett AL. Vasoactive pharmacotherapy to cure erectile dysfunction: fact or fiction? Urology 2005;65:224–30.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Editorial
Type 5 Phosphodiesterase Inhibitors: Curing Erectile Dysfunction Wayne J.G. Hellstrom *, Muammer Kendirci Section of Andrology, Department of Urology, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
Basic science research on erectile physiology has focused on the pathogenesis of erectile dysfunction (ED) and has provided convincing evidence that ED is predominately a disease of vascular etiology correlating with coronary artery disease, hypertension, atherosclerosis, hyperlipidemia, smoking, and diabetes mellitus [1,2]. ED is also associated with aging and pelvic surgeries, specifically radical prostatectomy (RP). Scientific evidence supports the concept that endothelial dysfunction and the resulting reduction in the release of nitric oxide (NO) from the endothelium during sexual stimulation is an important contributor to the pathophysiology of vasculogenic ED [3]. Furthermore, the oxygen tensiondependent changes in the penis during erection are proposed to have an impact on corpus cavernosal structure by inducing various cytokines, vasoactive factors, and growth factors, which, in turn, alter smooth muscle metabolism and connective tissue synthesis [4]. The absence of regular sexually stimulated or nocturnal penile erections causes, in theory, an insufficient oxygen supply to the penis, resulting in increased fibrogenesis and reduced smooth muscle content that further augment ED. Vasoactive pharmacotherapy (ie, type 5 phosphodiesterase [PDE5] inhibitors) traditionally uses an ‘‘on demand,’’ acute method of administration. However, recent data propose ‘‘chronic’’ long-term administration of these agents as a ‘‘curative purpose’’ in the management of ED [5]. There have
been clinical and basic research findings supportive of this application of PDE5 inhibitors in ‘‘curing’’ ED. Commonly known vascular risk factors are associated with endothelial dysfunction. Rosano and colleagues investigated whether continuous, regular treatment with tadalafil improves endothelial function in patients with increased cardiovascular risk factors and whether this effect is sustained after discontinuation of therapy [6]. These investigators reported that chronic tadalafil therapy can improve endothelial function, as assessed by flow-mediated dilation of the brachial artery, plasma nitrite/nitrate levels and endothelin-1 production, in men with increased cardiovascular risk. Of note, this improvement in endothelial function was sustained for 2 weeks after discontinuation of treatment, suggesting that chronic administration of tadalafil may lead to fundamental biologic changes that provide long-term benefits even after cessation of treatment. Similarly, Desouza et al. assessed the acute and prolonged effects of a low dose of sildenafil (25 mg) on flow-mediated dilation in patients with type 2 diabetes in a double-blind, placebo-controlled, crossover trial in 16 patients [7]. The authors reported that acute and prolonged sildenafil treatment had a favourable effect on brachial artery flow-mediated dilatation that persisted for at least 24 h after the last dose. Caretta et al. investigated the effect of continuous, regular administration of tadalafil on erectile
DOI of original article: 10.1016/j.eururo.2005.12.055 * Corresponding author. Section of Andrology, Department of Urology, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-42, New Orleans, LA 70112, USA. Tel. +1 504 988 7308; Fax: +1 504 988 5059. E-mail address: [email protected] (Wayne J.G. Hellstrom). 0302-2838/$ – see back matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2006.02.063
european urology 49 (2006) 942–945
function in elderly men with ED [8]. Sixty subjects, aged 60–70 yr, with a history of ED for 6–12 mo received 20 mg tadalafil on alternate days for 3 mo. Men younger than 40 yr old with psychogenic ED served as controls. At baseline and 1 mo after the end of treatment, all patients were evaluated with nocturnal penile tumescence and rigidity (NPTR) monitoring and penile Doppler ultrasound evaluation of the carotid artery intima-media thickness (IMT). They reported that in elderly men with increased or normal carotid IMT, chronic treatment with tadalafil improved endothelial function and concomitantly induced spontaneous resumption of erectile function. In a similar manner, Sommer et al. investigated whether daily intake of sildenafil 50 mg at bedtime over a 1-yr period in patients with vascular ED could induce a long-term improvement in erectile function compared to patients who took medication on an ‘‘as needed’’ basis [9]. These authors reported that daily administration of sildenafil at bedtime produced a significant improvement in erectile function, which was maintained even after treatment discontinuation. This symptomatic improvement in erectile function was documented by improved cavernosal arterial blood flows during pharmacologically induced erections. They hypothesised that improvement in erectile function may be a result of physiologic changes in the erectile tissues related to increased NO production that contributes to a normalisation of endothelial function. Although, evidence from studies on penile rehabilitation after RP support the concept of chronic administration of vasoactive agents to recover spontaneous erectile function, the rationale and mechanism for their use in penile rehabilitation programs after RP have not been fully elucidated nor have they been replicated in large multicentre placebo-controlled trials. In an early study, Montorsi and colleagues evaluated the use of intracavernous alprostadil injections for 6 mo in men undergoing RP and demonstrated an increased recovery rate of spontaneous erections postoperatively in 67% of men receiving alprostadil compared to 20% without treatment [10]. Researchers have demonstrated that nightly use of sildenafil significantly increased the overall quality and quantity of nocturnal erections as recorded by NPTR in men with ED when compared to placebo [11]. A recent prospective study reported a significant benefit of either 50 mg or 100 mg of sildenafil administration each night for 7 mo, compared to placebo, in men after undergoing bilateral nerve-sparing RP [12]. In this study, the
943
patients receiving sildenafil for 36 wk documented a 27% return of spontaneous, normal erectile activity compared to 4% in the placebo group. This study remains in abstract form and still has not been published. In a recent prospective study, Mulhall et al. evaluated the use of an erectogenic pharmacotherapy regimen following RP as to whether it improved recovery of spontaneous erectile function [13]. Chronic use of oral and intracavernous vasoactive agents in this study resulted in improvements in a number of outcomes including the proportion of men who had recovery of spontaneous functional erections, the ability and diminished time course to respond to sildenafil, the ability to respond to intracavernous injections, the percentage of men who had normalisation of the erectile function domain scores, the fewer number of men left with severe ED after RP, and the lower dose of vasoactive medication required to obtain an erection rigid enough for penetration. These preliminary results suggest a rationale for early prophylaxis with PDE5 inhibitors to promote earlier recovery of spontaneous erectile function after nerve-sparing RP. A number of animal studies support the concept of chronic use of PDE5 inhibitors to improve endothelial dysfunction. Behr-Roussel et al. treated rats with sildenafil versus saline solution via subcutaneous injections for 8 wk [14]. Results from the in vitro assays in this study revealed that endothelial-mediated relaxation induced by acetylcholine was significantly enhanced by 35% in rats pretreated with sildenafil compared to control rats. In addition, rats pretreated with sildenafil documented a greater erectile response to electrical field stimulation following an acute injection of sildenafil compared to control rats. These authors concluded that long-term treatment with sildenafil potentiates acetylcholine-induced endotheliumdependent cavernosal responses and enhances the erectile response in rats, supporting the benefits of regular treatment with a PDE5 inhibitor beyond the effect observed with acute administration. The overall concept of penile rehabilitation is to prevent cavernous tissue damage that occurs during the period of neural recovery, by providing adequate oxygenation to the cavernous tissues. This oxygenation leads to an increase in the production of intracavernous prostanoids, which are postulated to protect the cavernosal smooth muscle [15]. A recent clinical study by Schwartz et al. demonstrated the protective effects of sildenafil on intracorporeal smooth muscle [16]. In this small study, patients were instructed to use 50 mg or 100 mg sildenafil nightly for 6 mo after nerve-sparing RP. The authors
944
european urology 49 (2006) 942–945
documented on penile biopsy studies preserved cavernosal smooth muscle content with 50 mg sildenafil at 6 mo (52.67%) compared with baseline (51.52%) and an even greater increase in mean cavernosal smooth muscle content (56.85%) with 100 mg sildenafil at 6 mo compared to baseline (42.82%). Given the importance of the NO/cyclic guanosine monophosphate pathway in cavernosal smooth muscle function, chronic administration of vasoactive agents (including PDE5 inhibitors) may offer long-term beneficial effects on erectile tissue. Vardenafil has recently been shown to increase circulating progenitor cells in humans [17]. These cells are recognised to play a role in the process of neovascularisation and the continuous repair of the endothelium [18]. Another report showed that a decrease in circulatory progenitor cells in ED was associated with cardiovascular risk factors, that is, endothelial dysfunction [19]. Other potential beneficial effects of chronic PDE5 inhibitor therapy in the recovery of spontaneous erections may be related to the promotion of neurogenesis, the protection of cavernosal endothelium, antifibrinogenic activity, angiogenesis, cavernosal smooth muscle growth, and differentiation [20]. The field of sexual medicine has made tremendous advances in our knowledge base and treatment practices over the past few decades. In many circumstances, clinical and base scientific gains have been complimentary and have supported the notion of the clinician–scientist union. Techniques in surgery have heralded pharmacologic breakthroughs that, in turn, will propel new initiatives in molecular-based therapies. The concept of chronic administration of PDE5 inhibitors as a cure for ED is both intellectually interesting and therapeutically captivating. The theory that prolonged endothelial stimulation can either prevent or reverse end-organ failure has been proposed. A number of animal model experiments, where induced ED has shown benefit from longterm PDE5 inhibitor administration, is the most plausible evidence that we have on supporting this concept. However, in short, more is certainly still needed at the basic research level to further elucidate these biologic concepts. On the clinical front, although many clinicians have instituted chronic PDE5 inhibitor therapy as the standard of care in their prostate cancer treatment and diabetic patients, with the hopes of improving erectile function, the reality is that there is a paucity of published studies available on which to base their claims. For the most part, studies are of short duration, are in abstract form, are single
centre, have few subjects, and often confuse preference with documented physiologic benefit. Many are not placebo-controlled and, as most investigators in sexual medicine are aware, the placebo effect has a strong psychogenic benefit. It is important not to appear overly negative or pessimistic about these new data, and we remain cautiously optimistic. However, evidence to support the reversal of ED by chronic administration of a PDE5 inhibitor is still not convincing to many. Individual investigators are at a disadvantage and it is somewhat surprising that societal, institutional, or pharmacologic company support for such research endeavours on a larger scale have not appeared. Further well-designed studies are encouraged and need to focus on optimal route of drug delivery, dosing schedule, patient selection, optimal duration, and timing of application. The downside of continuing to promote the precept of chronic dosing as a cure for ED, without more substantial data, is the emotional and financial cost to our patients, the disillusionment by our referring professional colleagues, and the loss of scientific credibility for our domain of medicine.
References [1] NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA 1993;270:83–90. [2] Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151:54–61. [3] Bivalacqua TJ, Usta MF, Champion HC, Kadowitz PJ, Hellstrom WJ. Endothelial dysfunction in erectile dysfunction: role of the endothelium in erectile physiology and disease. J Androl 2003;24:S17–37. [4] Moreland RB. Pathophysiology of erectile dysfunction: the contributions of trabecular structure to function and the role of functional antagonism. Int J Impot Res 2000;12:S39–46. [5] Montorsi F, Briganti A, Salonia A, Rigatti P, Burnett AL. Can phosphodiesterase type 5 inhibitors cure erectile dysfunction? Eur Urol 2006;49:979–86. [6] Rosano GM, Aversa A, Vitale C, Fabbri A, Fini M, Spera G. Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk. Eur Urol 2005;47:214–20, discussion p. 220–2. [7] Desouza C, Parulkar A, Lumpkin D, Akers D, Fonseca VA. Acute and prolonged effects of sildenafil on brachial artery flow-mediated dilatation in type 2 diabetes. Diabetes Care 2002;25:1336–9. [8] Caretta N, Palego P, Ferlin A, et al. Resumption of spontaneous erections in selected patients affected by erectile dysfunction and various degrees of carotid wall altera-
european urology 49 (2006) 942–945
[9]
[10]
[11]
[12]
[13]
tion: role of tadalafil. Eur Urol 2005;48:326–31, discussion p. 331–2. Sommer F, Schulze W. Treating erectile dysfunction by endothelial rehabilitation with phosphodiesterase 5 inhibitors. World J Urol 2005;23:385–92. Montorsi F, Guazzoni G, Strambi LF, et al. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol 1997;158: 1408–10. Montorsi F, Maga T, Strambi LF, et al. Sildenafil taken at bedtime significantly increases nocturnal erections: results of a placebo-controlled study. Urology 2000;56: 906–11. Padma-Nathan H, McCullough A, Giuliano F, Toler SM, Wohlhuter C, Shpilsky AB. Postoperative nightly administration of sildenafil citrate significantly improved the return of normal spontaneous erectile function after bilateral nerve-sparing radical prostatectomy. J Urol 2003;4:375. Mulhall J, Land S, Parker M, Waters WB, Flanigan RC. The use of an erectogenic pharmacotherapy regimen
[14]
[15]
[16]
[17]
[18] [19]
[20]
945
following radical prostatectomy improves recovery of spontaneous erectile function. J Sex Med 2005;2:532–42. Behr-Roussel D, Gorny D, Mevel K, et al. Chronic sildenafil improves erectile function and endothelium-dependent cavernosal relaxations in rats: lack of tachyphylaxis. Eur Urol 2005;47:87–91. Moreland RB, Albadawi H, Bratton C, et al. O2-dependent prostanoid synthesis activates functional PGE receptors on corpus cavernosum smooth muscle. Am J Physiol Heart Circ Physiol 2001;281:H552–8. Schwartz EJ, Wong P, Graydon RJ. Sildenafil preserves intracorporeal smooth muscle after radical retropubic prostatectomy. J Urol 2004;171:771–4. Foresta C, Lana A, Cabrelle A, et al. PDE-5 inhibitor, Vardenafil, increases circulating progenitor cells in humans. Int J Impot Res 2005;17:377–80. Garmy-Susini B, Varner JA. Circulating endothelial progenitor cells. Br J Cancer 2005;93:855–8. Foresta C, Caretta N, Lana A, Cabrelle A, Palu G, Ferlin A. Circulating endothelial progenitor cells in subjects with erectile dysfunction. Int J Impot Res 2005;17:288–90. Burnett AL. Vasoactive pharmacotherapy to cure erectile dysfunction: fact or fiction? Urology 2005;65:224–30.