Introduction. ET Mastalir 1, GF Carvalhal 2 and VL Portal 3

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1 (2011) 23, & 2011 Macmillan Publishers Limited All rights reserved /11 ORIGINAL ARTICLE : a randomized, double-blind, placebo-controlled clinical trial (Simvastatin treatment for erectile dysfunction STED TRIAL) ET Mastalir 1, GF Carvalhal 2 and VL Portal 3 1 Urology Division from Santa Casa de Porto Alegre, Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia Rio Grande do Sul, Porto Alegre, Brazil; 2 Urology Division from PUCRS, Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia, Porto Alegre, Brazil and 3 Cardiology Division from Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia, Porto Alegre, Brazil The aim of the study is to evaluate the effect of simvastatin in erectile dysfunction (ED) secondary to endothelial dysfunction. This study is a double-blind, randomized, placebo-controlled, clinical trial in patients with ED and endothelial dysfunction. Patients were randomized to receive 20 mg simvastatin or placebo daily for 6 months and subsequently 10 mg of vardenafil on demand for 4 weeks. Serum cholesterol, hormone profile, ultrasensitive C-reactive protein, the International Index of Erectile Dysfunction (IIEF) and the ED Index of Treatment Satisfaction were evaluated. There was a significant reduction in serum cholesterol in the treatment group. The hormonal profile remained unaltered. There was no difference in the IIEF between the groups at follow-up, although, at the beginning, 26% of the patients of both groups presented with mild ED and 74% with moderate-to-severe ED; at the end of the 7th month, all patients from the simvastatin group progressed to mild ED, compared with only 83% in the placebo group. There was no statistically significant difference in penile erection after intake of simvastatin or placebo. This study does not support the use of simvastatin as erectogenic medication. Further studies are necessary to verify if simvastatin has any beneficial effect on ED. (2011) 23, ; doi: /ijir ; published online 30 June 2011 Keywords: endothelial dysfunction; erectile dysfunction; C-reactive protein; simvastatin; vardenafil Introduction Recent evidence has suggested that erectile dysfunction (ED) is strongly correlated with other correlates of endothelial dysfunction, 1,2 such as coronary atherosclerotic disease. Obesity, dyslipidemia, smoking, sedentarism, systemic arterial hypertension and diabetes mellitus are all risk factors for the development of vascular dysfunction and atherosclerosis, often present in men with ED. 3 According to Thompson et al., 2 in some situations ED can even precede the onset of clinically manifested vascular disease. Endothelial dysfunction contributes to ED mainly through a change in nitric oxide (NO) metabolism. High levels of ultrasensitive C-reactive Correspondence: Dr ET Mastalir, Rua Vinte de Setembro, 3825, Sala 05, Sapiranga, Rio Grande do Sul, Porto Alegre, Brazil. edumastalir@via-rs.net Received 2 February 2011; revised 12 May 2011; accepted 26 May 2011; published online 30 June 2011 protein (uscrp) indicate the presence of endothelial dysfunction. 4 6 Statins, primarily used for the treatment of hypercholesterolemia, have pleiotropic effects such as reducing the risk of cardiovascular events. This occurs through the upregulation of the systemic vascular endothelial activity and the NO metabolism. 7,8 Current knowledge about the physiopathology of ED has led to the development of clinical trials to assess the role of statins in men with ED. However, published data about the interaction of ED and statins are sparse and conflicting. Earlier studies suggested that ED could develop as a consequence of statin use, 9 12 whereas others did not demonstrate any such association. 8,13 15 By contrast, more recent studies have suggested the possibility that statins may improve ED in men with endothelial dysfunction Therefore, research evaluating the potential benefit of statin use in the treatment of men with ED determined by endothelial dysfunction is needed, especially regarding the pleiotropic effects of this class of medication.

2 The aim of this study is to evaluate the effects of simvastatin in ED secondary to endothelial dysfunction, using the International Index of Erectile Dysfunction (IIEF) and the ED Index of Treatment Satisfaction as instruments. Materials and methods We performed a double-blind, randomized, placebocontrolled, prospective clinical trial to evaluate the effect of simvastatin (20 mg per day) on the erectile function of patients with ED secondary to endothelial dysfunction. The study was performed in patients selected at an andrology outpatient clinic of the Urology Service of Santa Casa de Porto Alegre, from January 2006 to December The study protocol was approved by the committee on ethics in research of Santa Casa de Porto Alegre and by the ethics committee of the Instituto de Cardiologia and is registered at ClinicalTrials.gov under identification number NCT (Simvastatin Treatment for Erectile Dysfunction STED TRIAL). The calculated sample size (34 patients) was estimated based on a P a o0.05 and on a P b o0.2, to ascertain an expected 40% difference in the IIEF score between treatment groups. We included patients with ED based on clinical history and an IIEF-5 score under 22, aged years with levels of uscrp X1.1 mg l 1 and no other medical indication or contraindication for the use of statins. We excluded patients with a history of acute myocardial infarction or stroke, diabetes mellitus, Peyronie s disease, hypogonadism, hyperprolactinemia or any active inflammatory or infectious disease. We also excluded from the study alcohol abusers and patients who underwent radical prostatectomy, pelvic surgery or radiation therapy, as well as those who had used any phosphodiesterase- 5 inhibitor (ipde5) during the 6 months before enrollment. After being informed about the details of the study orally and in printed matter, those who agreed to participate signed a free and informed consent form. Patients were randomized to receive 20 mg simvastatin or placebo orally in a single nightly capsule for 6 months, by randomly drawing lots previously defined by a non-participant of the study. The medication was administered in a double-blinded manner. The patients were not allowed to take any erectogenic drug during the 6 months of treatment with simvastatin or placebo, in order to avoid any influence of erectogenic medication or confusion bias during the evaluation of the response to the treatment with simvastatin. In addition, all patients were oriented to intake 10 mg of vardenafilat 1 h before sexual intercourse, twice a week, for 4 weeks, after the initial 6 months of daily simvastatin or placebo. A pharmacist alien to the study was responsible for both the release and the control of the medications. The substance contained in the blinded medication was only disclosed after the final statistical analysis of the data. The patients erectile function was evaluated by validated questionnaires (IIEF and ED Index of Treatment Satisfaction) in native language Portuguese. The severity of ED was evaluated by IIEF erection function domain (normal X26, mild ED ¼ 22 25, mild-to-moderate ED ¼ 17 21, moderate ED ¼ and severe EDp10). All blood tests and questionnaires were applied at enrollment in the study and repeated every 2 months, for 6 months, and after 1 month of on-demand use of 10 mg vardenafil. The questionnaires were applied at two distinct moments, after simvastatin alone and after vardenafil, in order to evaluate the effect of the previous intake of simvastatin on the vardenafil response. At the end of the study, the patients answered an additional question about overall efficacy: Did the treatment you underwent improve your erections? The primary end point was to evaluate the penile erection after the use of simvastatin; the secondary one was to evaluate the response to vardenafil with previous use of simvastatin, to check the effect of ipde5 after endothelial dysfunction correction with statin. Once the patients had completed the 7 months of the study, they remained under follow-up at the andrology clinic, receiving standard treatment for ED. The study was monitored by an external committee, unconnected to the research group. Any clinical event reported by the patient after the beginning of the medication was noted and classified as an adverse effect whenever applicable. Results were analyzed using the Statistical Package for the Social Sciences (SPSS, DMSS, São Paulo, SP, Brazil), version Analysis was performed by intention to treat, without revealing which medication the patient had received. The statistical tests applied were Student s t-test, Mann Whitney test, Wilcoxon Signed Rank, w 2 and analysis of variance for repeated measures. Results Of the 263 patients initially evaluated, 43 who fulfilled the inclusion/exclusion criteria and agreed to sign the letter of informed consent were randomly assigned to the simvastatin or placebo groups. Of these, two patients were lost during follow-up, one from each group, having dropped out of the study without an apparent cause. In all, 41 patients were followed until the end of the study, and constitute our final sample. The baseline characteristics of the randomized patients are shown in Table 1, which demonstrates that there is no difference between the groups after 243

3 244 Table 1 Baseline characteristics of the randomized patients P-value Age (years) a 56.4± ± ED duration (months) b 17.0 ( ) 24.0 ( ) uscrp ( mg l 1 ) b 2.8 ( ) 3.8 ( ) BMI a 27.8± ± SAH (n;%) c 10.0 (50) 11.0 (52.4) Cigarette smoking (current or past; n;%) 14.0 (70) 12.0 (57.1) TC (o200 mg dl 1 ) 194.2± ± LDL (o130 mg dl 1 ) a 117.2± ± HDL (455 mg dl 1 ) a 46.2± ± Triglycerides (o160 mg dl 1 ) b (74 158) ( ) Total testosterone ( ng dl 1 ) a 432.2± ± Estradiol (o56 pg ml 1 ) a 22.1± ± FSH ( miu ml 1 ) b 5.1 ( ) 4.4 ( ) LH ( miu ml 1 ) b 3.5 ( ) 3.7 ( ) Prolactin ( ng ml 1 ) a 6.4± ± IIEF15 a 31.4± ± IIEF-5 (erection) a 10.7± ± IIEF (intercourse) a 5.5± ± IIEF (orgasm) a 5.0± ± IIEF (desire) a 5.4± ± IIEF (general satisfaction) a 4.7± ± Abbreviations: BMI, body mass index; ED duration, duration of the erectile dysfunction; FSH, follicle-stimulating hormone; HDL, highdensity lipoprotein cholesterol; IIEF, International Index of Erectile Dysfunction; LDL, low-density lipoprotein cholesterol; LH, luteinizing hormone; SAH, systemic arterial hypertension; TC, total cholesterol; uscrp, ultrasensitive C-reactive protein. a Values expressed in means±s.d. b Values expressed in median (percentile 25 75). c Values expressed in absolute numbers (percentage). randomization. Their mean age was 57.5±8.3 years, 89% of them were Caucasian. Table 2 shows that, although non-significant, the uscrp levels reduced from 3.8 to 2.5 mg dl 1 in the simvastatin group (reduction of 32%), whereas in the placebo group it reduced from 2.8 to 2.6 mg dl 1 (reduction of 8.3%). Table 2 also shows that there was a significant reduction in the total cholesterol, LDL and triglyceride levels in the simvastatin group. After 6 months of treatment, there was no difference between the groups in terms of testosterone, luteinizing hormone, follicle-stimulating hormone, prolactin and estradiol. The body mass index did not vary significantly, ranging from to in the placebo group and from to in the simvastatin group (P ¼ 0.556). Erectile function evidenced no statistical significant difference neither after 6 months of treatment with simvastatin (20 mg) or placebo nor after vardenafil, according to IIEF and ED Index of Treatment Satisfaction, as seen in Table 3. Figure 1 shows the evolution of IIEF Erection over time in both groups. Table 4 shows that, although there was no statistically significant difference between the groups at the beginning of the study, 73.6% and 73.7% of the patients in the simvastatin and placebo group, respectively, had moderate-to-severe ED. After 6 months of treatment with simvastatin, 100% of the simvastatin-treated group had evolved to mild ED compared with 83.3% of the placebo group. As to adverse effects, two patients in the placebo group reported events (one case of insomnia and the other of dyspepsia). A patient in the simvastatin group mentioned insomnia. Discussion The results of this study show that simvastatin did not determine a statistically significant difference of erectile function compared with the placebo even after the vardenafil intake. We can see, however, that at the beginning of the study, 26% of the patients in both groups were classified as having mild ED and approximately 74% as having moderate-to-severe ED. At the end of 7 months, all the patients treated with simvastatin had evolved to mild ED, whereas in the placebo group, 83% had evolved to this degree of dysfunction, though this was not statistically significant. There was no statistically significant difference between the groups as regards reduction in the uscrp levels. However, the group treated with simvastatin 20 mg presented a 32% reduction, whereas the placebo group presented a reduction

4 Table 2 Inflammatory, lipidic and hormonal profiles after 6 months of treatment with simvastatin 245 P-value uscrp (mg l 1 ) a Baseline 2.8 ( ) 3.8 ( ), After 6 months 2.6 ( ) 2.5 ( ) Simvastatin, TC (mg dl 1 ) b Baseline 194.2± ±56.2, After 6 months 199.2± ±49.7 Simvastatin, LDL (mg dl 1 ) b Baseline 117.2± ±45.5, After 6 months 118.2± ±44.2 Simvastatin, o0.001 HDL (mg dl 1 ) b Baseline 46.2± ±8.8 After 6 months 49.0± ± Triglycerides (mg dl 1 ) a Baseline (74 158) ( ), After 6 months (85 169) 96.0 (72 127) Simvastatin, Total testosterone (ng dl 1 ) b Baseline 432.2± ± After 6 months 441.1± ±118.7 Estradiol (pg ml 1 ) b Baseline 22.1± ± After 6 months 25.5± ±12.3 FSH (miu ml 1 ) a Baseline 5.1 ( ) 4.4 ( ), After 6 months 5.6 ( ) 3.7 ( ) Simvastatin, LH (miu ml 1 ) a Baseline 3.5 ( ) 3.7 ( ), After 6 months 4.0 ( ) 4.0 ( ) Simvastatin, Prolactin (ng ml 1 ) b Baseline 6.4± ± After 6 months 6.5± ±2.0 Abbreviations: FSH, follicle-stimulating hormone; LDL, low-density lipoprotein cholesterol; LH, luteinizing hormone; HDL, high-density lipoprotein cholesterol; uscrp, ultrasensitive C-reactive protein; TC, total cholesterol. a Values expressed in median (percentile 25 75). b Values expressed in means±s.d. of only 8%. It is important to consider that the reduction in uscpr may represent the modulation of the endothelial function induced by simvastatin, although there was no statistical significant difference in terms of ED between the groups, probably because of the small number of the patients. As to changes in the lipid profile, however, it became very clear that simvastatin at the 20 mg dose significantly reduced the total cholesterol, lowdensity lipoprotein and triglyceride levels. As to ED, our results are opposite to those of previous studies, which suggested that the statins may trigger ED. Actually, in those studies, most of which were case reports or small historical series, there was a selection of very ill patients with many associated morbidities, confounding a careful evaluation of ED In other publications, the relationship between the use of statins and the development of ED has been considered an undefined topic. 8,13 15 In our study, with patients without clinical manifestation of vascular disease and no associated comorbidities, simvastatin proved safe and effective to reduce the cholesterol levels. It did not lead to any improvement in ED or determine any reduction in the levels of testosterone and the other hormones evaluated. As to maintaining the hormone levels, our results find physiological basis in the studies by Dobs et al., 15 in which, according to the authors, patients treated with pravastatin 40 mg, simvastatin 20 and 40 mg or placebo did not present differences in the measures of total and free testosterone. ED is currently much discussed from the perspective of endothelial dysfunction. It is known that in

5 246 Table 3 Erectile function according to the questionnaires applied and the period of evaluation P-value b IIEF 5 (erection) a Baseline 10.7± ± After 6 months 15.0±8.7 ( þ 34%) c 15.6±7.0 ( þ 17%) c After vardenafil 22.2±4.5 ( þ 99%) c 22.7±3.68 ( þ 70%) c IIEF (intercourse) a Baseline 5.5± ± After 6 months 7.2±4.5 ( þ 25%) 7.3±4.0 ( þ 14%) After vardenafil 10.5±2.5 ( þ 82%) 10.2±2.0 ( þ 58%) IIEF (orgasm) a Baseline 5.0± ± After 6 months 6.0±3.7 ( þ 13%) c 5.9± 3.2 ( þ 8%) c After vardenafil 7.4±2.6 ( þ 41%) c 8.2±1.3 ( þ 49%) c IIEF (desire) a Baseline 5.4± ± After 6 months 5.5± 2.6 (0) c 6.4± 2.0 ( þ 8%) c After vardenafil 6.7±2.2 ( þ 21%) c 7.2±1.4 ( þ 21%) c IIEF (general satisfaction) a Baseline 4.7± ± After 6 months 6.2±2.9 ( þ 25%) c 6.0±2.6 ( þ 21%) c After vardenafil 7.5±2.5 ( þ 52%) c 8.1±1.6 ( þ 63%) c EDITS patient a After 6 months 63.2± ± After vardenafil 82.6±13.8 ( þ 30%) c 80.9±16.7 ( þ 12%) c EDITS partner a After 6 months 58.5± ± After vardenafil 77.8±25.1 ( þ 33%) c 79.7±13.3 ( þ 14%) c Overall satisfaction (after 6 months) d Got better? Yes 8.0 (40%) 8.0 (38%) Abbreviations: EDITS, Erectile Dysfunction Index of Treatment Satisfaction; IIEF, International Index of Erectile Dysfunction. a Values expressed in means±s.d. b P-value is related to the comparison between the groups at follow-up. c Variation of the values related to the baseline. d Absolute values (percentage). IIEF-5 (erection) Simvastatin Baseline Six months Period of evaluation Vardenafil P=0.733 Figure 1 International Index of Erectile Dysfunction according to the group Simvastatin or and the period of evaluation. about 50% of men with ED above the age of 50 years, there is an association with vascular disease. It is postulated that endothelial dysfunction occurs in the presence of risk factors, and its consequences are felt throughout the vascular endothelial bed, including the penis. In this dysfunction, there is a change in the NO metabolism in the penile corpus cavernosum, determining a state of arteriolar vasoconstriction, with a reduction of the blood inflow and consequent deficiency in penile erection. In this sense, the use of statins and the acquisition of their pleiotropic effects, especially on the vascular endothelial bed, may be relevant for the management of patients with ED and endothelial dysfunction. Our study looked at the use of statins in potentially healthy patients, in which the main indication of endothelial dysfunction was elevated levels of uscrp. The JUPITER study showed the safety and efficacy of the use of statins in primary prevention, selecting patients according to the uscrp levels. 27 Some authors showed that the treatment of dyslipidemia with

6 Table 4 Severity of erectile dysfunction, stratified by IIEF erection function domain, according to the period of evaluation P-value IIEF baseline Severe, % Moderate, % Mild, % IIEF after 6 months Severe, % Moderate, % Mild, % IIEF vardenafil Severe, % 0 0 Moderate, % Mild, % Abbreviation: IIEF ¼ International Index of Erectile Dysfunction. statins can determine the improvement of ED in selected patients. 16,18,19,21 23,26 The explanations of how statins could improve ED are based mainly on the pleiotropic effects of this class of medication, that is, effects that go beyond simply lowering cholesterol levels. 7,8 Outstanding among these effects are the stabilization and posterior reduction of the atherosclerotic plaque, improved endothelial function and regulation of NO production, with consequent arteriolar vasodilation and diminished inflammatory activity, oxidative stress and thrombotic events. Another point discussed in the literature is that the use of statins may modulate the response to ipde5, so that patients who are initially nonresponsive to ipde5 benefit from these medications, especially through the mechanism mediated by NO. 18,19,21,22,26 Our results do not support this supposed improved response to ipde5 after the use of simvastatin, although the studies that signal this endothelial modulation used atorvastatin. 16,18,19,22,23,26 It may be that the improved response to ipde5 reported in these studies is related to the potency of the statin s 1 used. This is suggested by three randomized clinical trials using atorvastatin (from 40 to 80 mg daily), that showed a significant improvement in ED compared with the placebo 19,21,26 after less than 6 months using the medication. These studies suggest that the length of the treatment with simvastatin in our patients (6 months) should have been sufficient to detect changes in ED. A study that evaluated 50 men without previous ED and without dyslipidemia submitted to radical prostatectomy, were randomized to receive sildenafil on demand or sildenafil on demand plus atorvastatin 10 mg daily for 90 days, after discharge from hospital. The patients who received atorvastatin presented a significant increase in IIEF-5 (13.5 against 10.6 in the patients who did not receive atorvastatin P ¼ 0.003), suggesting that the use of atorvastatin after radical prostatectomy with nerve preservation may contribute to a better recovery of erectile function. However, in this study there was no placebo group, which may limit the interpretation of the results. There are several limitations to be considered in this study, including the small size sample, the limited dose ranges of the simvastatin-treated group and the lack of a physiological study of penile vascular function, such as Doppler ultrasound measures that could assess the endothelial function by flow-mediated dilation (such as endo-pat 2000, Itamar Medical Inc., Framingham, MA, USA). Further limitations would be that the most significant benefits for ED with simvastatin may be reached at higher doses, such as 40 mg, or higher, and that the difference between groups may be o40%, which determines the need for a greater number of patients for evaluation. It is possible that with the simvastatin dose administered, we did not achieve a sufficiently robust improvement in endothelial function to provoke modification in the ED. These questions could be better answered with clinical tests evaluating simvastatin at larger doses or using a more potent statin. The results of this study demonstrated that simvastatin did not determine a statistically significant improvement of erectile function compared with the placebo and do not support the use of simvastatin as erectogenic medication. It seems unlikely that simvastatin determines ED. On the other hand, the evolution observed in the severity of ED suggests that simvastatin may help improve the erectile function of patients with ED and endothelial dysfunction concomitantly with administration of ipde5. Additional studies with more patients will be necessary to detect smaller differences in the responses obtained with simvastatin in relation to the placebo. Conflict of interest The authors declare no conflict of interest. References 1 Kaya C, Uslu Z, Karaman I. Is endothelial function impaired in erectile dysfunction patients? Int J Impot Res 2006; 18: Thompson IM, Tangen CM, Goodman PJ, Probstfield JL, Moinpour CM, Coltman CA. Erectile dysfunction and subsequent cardiovascular disease. JAMA 2005; 294: Müller A, Mulhall JP. Cardiovascular disease, metabolic syndrome and erectile dysfunction. Curr Opin Urol 2006; 16: Departamento de Aterosclerose da Sociedade Brasileira de Cardiologia. IV Diretriz Brasileira Sobre Dislipidemias e Prevenção da Aterosclerose do Departamento de Aterosclerose 247

7 248 da Sociedade Brasileira de Cardiologia. Arq Bras Cardiol 2007; 88(Suplemento I): Giugliano F, Esposito K, Di Palo C, Ciotola M, Giugliano G, Marfella R et al. Erectile dysfunction associates with endothelial dysfunction and raised proinflammatory cytokine levels in obese men. J Endocrinol Invest 2004; 27: Billups KL, Kaiser DR, Kelly AS, Wetterling RA, Tsai MY, Hanson N et al. Relation of C-reactive protein and other cardiovascular risk factors to penile vascular disease in men with erectile dysfunction. Int J Impot Res 2003; 15: Erratum in: Int J Impot Res 2003;15: McFarlane SI, Muniyappa R, Francisco R, Sowers JR. Pleiotropic effects of statins: lipid reduction and beyond. J Clin Endocrinol Metab 2002; 87: Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: Rizvi K, Hampson JP, Harvey JN. Do lipid-lowering drugs cause erectile dysfunction? A systematic review. Farm Prac 2002; 19: Solomon H, Samarasinghe YP, Feher MD, Man J, Rivas-Toro H, Lumb PJ et al. Erectile dysfunction and statin treatment in high cardiovascular risk patients. Int J Clin Pract 2006; 60: Carvajal A, Macias D, Sáinz M, Ortega S, Martín Arias LH, Velasco A et al. HMG CoA reductase inhibitors and impotence: two case series from the Spanish and French drug monitoring systems. Drug Saf 2006; 29: Do C, Huyghe E, Lapeyre-Mestre M, Montastruc JL, Bagheri H. Statins and erectile dysfunction: results of a case/non-case study using the French Pharmacovigilance System Database. Drug Saf 2009; 32: Pedersen TR, Faergeman O. Simvastatin seems unlikely to cause impotence. BMJ 1999; 318: Miner M, Billups KL. Erectile dysfunction and dyslipidemia: relevance and role of phosphodiesterase type-5 inhibitors and statins. J Sex Med 2008; 5: Dobs AS, Miller S, Neri G, Weiss S, Tate AC, Shapiro DR et al. Effects of simvastatin and pravastatin on gonadal function in male hypercholesterolemic patients. Metabolism 2000; 49: Saltzman EA, Guay AT, Jacobson J. Improvement in erectile function in men with organic erectile dysfunction by correction of elevated cholesterol levels: a clinical observation. J Urol 2004; 172: Nangle MR, Cotter MA, Cameron NE. Effects of rosuvastatin on nitric oxide-dependent function in aorta and corpus cavernosum of diabetic mice. Relationship to cholesterol biosynthesis pathway inhibition and lipid lowering. Diabetes 2003; 52: Castro MM, Rizzi E, Rascado RR. Atorvastatin enhances sildenafil-induced vasodilation through nitric oxide-mediated mechanisms. Eur J Pharmacol 2004; 13: Herrmann HC, Levine LA, Macaluso Jr J, Walsh M, Bradbury D, Schwartz S et al. Can atorvastatin improve the response to sildenafil in men with erectile dysfunction not initially responsive to sildenafil? Hypothesis and pilot trial results. J Sex Med 2006; 3: Miner M, Gilderman L, Bailen J, Cook D, Dawson K, Stanislaus M et al. Vardenafil in men with stable therapy and dyslipidemia. J Sex Med 2008; 5: Bank AJ, Kelly AS, Kaiser DR, Crawford WW, Waxman B, Schow DA et al. The effects of quinapril and atorvastatin on the responsiveness to sildenafil in men with erectile dysfunction. Vasc Med 2006; 11: Gokkaya SC, Ozden C, Levent O, Hakan Koyuncu H, Guzel O, Memis A. Effect of correcting serum cholesterol levels on erectile function in patients with vasculogenic erectile dysfunction. Scand J Urol Nephrol 2008; 42: Hong SK, Han BK, Jeong SJ, Byun SS, Lee SE. Effect of statin therapy on early return of potency after nerve sparing radical retropubic prostatectomy. J Urol 2007; 178: Morelli A, Chavalmane AK, Filippi S, Fibbi B, Silvestrini E, Sarchielli E et al. Atorvastatin ameliorates sildenafil-induced penile erections in experimental diabetes by inhibiting diabetes-induced RhoA/Rho-kinase signaling hyperactivation. J Sex Med 2009; 6: Rhoden EL, Mastalir ET, Teloken PE, Blaya R, Teloken C. Effects of statins on nitric oxide metabolites in the corpora cavernosa of rats fed a hyperlipidic diet. In: American Urological Association Annual Meeting 2007, Anahein. J Urol 2007, volume 177 (Abstracts). 26 Dadkhah F, Safarinejad MR, Asgari MA, Hosseini SY, Lashay A, Amini E. Atorvastatin improves the response to sildenafil in hypercholesterolemic men with erectile dysfunction not initially responsive to sildenafil. Int J Impot Res 2010; 22: Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ et al. Reduction in C-reative protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373: