title: Atorvastatin Restores Endothelial Function in Normocholesterolemic Smokers Independent of Changes in Low-Density Lipoprotein The effects of quinapril and atorvastatin on the responsiveness to sildenafil in men with erectile dysfunction Male sexuality and cardiovascular risk. A cohort study in patients with erectile dysfunction. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts male aging study. Can atorvastatin improve the response to sildenafil in men with erectile dysfunction not initially responsive to sildenafil? Hypothesis and pilot trial results. The effect of simvastatin in penile erection: a randomized, double-blind, placebo-controlled clinical trial (Simvastatin treatment for erectile dysfunction—STED TRIAL) Effect of statin therapy on early return of potency after nerve sparing radical retropubic prostatectomy. Atorvastatin improves the response to sildenafil in hypercholesterolemic men with erectile dysfunction not initially responsive to sildenafil
abstract: Cigarette smoking impairs endothelial function . Hydroxymethylglutaryl ( HMG ) CoA reductase inhibitors ( statins ) may favorably affect endothelial function via nonlipid mechanisms . We tested the hypothesis that statins would improve endothelial function independent of changes in lipids in cigarette smokers . Twenty normocholesterolemic cigarette smokers and 20 matched healthy control subjects were r and omized to atorvastatin 40 mg daily or placebo for 4 weeks , washed out for 4 weeks , and then crossed-over to the other treatment . Baseline low-density lipoprotein ( LDL ) levels were similar in smokers and healthy subjects , 103±22 versus 95±27 mg/dL , respectively ( P = NS ) and were reduced similarly in smokers and control subjects by atorvastatin , to 55±30 and 58±20 mg/dL , respectively ( P = NS ) . Vascular ultrasonography was used to determine brachial artery , flow-mediated , endothelium-dependent , and nitroglycerin-mediated , endothelium-independent vasodilation . To eluci date potential molecular mechanisms that may account for changes in endothelial function , skin biopsy specimens were assayed for eNOS mRNA , eNOS activity , and nitrotyrosine . Endothelium-dependent vasodilation was less in smokers than nonsmoking control subjects during placebo treatment , 8.0±0.6 % versus 12.1±1.1 % , ( P=0.003 ) . Atorvastatin  increased endothelium-dependent vasodilation in smokers to 10.5±1.3 % ( P=0.017 versus placebo ) but did not change endothelium-dependent vasodilation in control subjects ( to 11.0±0.8 % , P = NS ) . Endothelium-independent vasodilation did not differ between groups during placebo treatment and was not significantly affected by atorvastatin . Multivariate analysis did not demonstrate any association between baseline lipid levels or the change in lipid levels and endothelium-dependent vasodilation . Cutaneous nitrotyrosine levels and skin microvessel eNOS mRNA , but not ENOS activity , were increased in smokers compared with controls but unaffected by atorvastatin treatment . Atorvastatin  restores endothelium-dependent vasodilation in normocholesterolemic cigarette smokers independent of changes in lipids . These results are consistent with a lipid-independent vascular benefit of statins but could not be explained by changes in eNOS message and tissue oxidative stress . These findings implicate a potential role for statin therapy to restore endothelial function and thereby investigate vascular disease in cigarette smokers Phosphodiesterase-5 ( PDE-5 ) inhibitors are an effective therapy for the majority of men with erectile dysfunction ( ED ) . However , many men with ED still report a suboptimal or partial response even after an adequate trial of oral PDE-5 therapy . Since ED is associated with impaired vascular function and both atorvastatin and quinapril have been previously shown to improve vascular function , we examined the effects of adjunctive treatment with these medications in men with vasculogenic ED who were suboptimal responders to 100 mg of sildenafil . Men with ED and suboptimal response to sildenafil  were r and omly assigned to 3 months of treatment with atorvastatin 40 mg ( n = 12 ) , quinapril 10 mg ( n = 10 ) , or placebo ( n = 13 ) , along with continued adjunctive sildenafil use . Measured variables included : International Index of Erectile Function ( IIEF ) question naire , brachial artery flow-mediated dilation ( FMD ) , endothelium-independent dilation ( EID ) via nitroglycerin , penile Doppler blood flow , blood pressure ( BP ) , lipids , and C-reactive protein ( CRP ) . Compared to placebo , quinapril ( p < 0.01 ) significantly improved symptoms of ED as measured by the IIEF-5 question naire . There was a trend toward a significant improvement in IIEF-5 with atorvastatin . Similarly , quinapril significantly improved the IIEF ED Domain ( p < 0.05 ) . Other peripheral and penile vascular parameters were unchanged with drug therapy as compared to placebo . In conclusion , treatment with quinapril , in combination with sildenafil , improved ED in men with suboptimal response to sildenafil alone . Atorvastatin demonstrated a trend toward improved ED in this group INTRODUCTION Although penile blood flow ( PBF ) has been recommended as an additional diagnostic test in identifying erectile dysfunction ( ED ) patients at risk for latent cardiovascular disease , no study has ever assessed the possible association of PBF and the relational component of sexual function with incident major cardiovascular events ( MACE ) . AIM The aim of this study is to investigate whether severity of ED , PBF , and other factors related to a couple 's relationship predict incident MACE . METHODS A consecutive series of 1,687 patients was studied . Different clinical , biochemical , and instrumental  ( penile flow at color Doppler ultrasound )  parameters were evaluated . MAIN OUTCOME MEASURES Information on MACE was obtained through the City of Florence Registry Office . RESULTS During a mean follow-up of 4.3 + /- 2.6 years , 139 MACE , 15 of which were fatal , were observed . Cox regression analysis , after adjustment for age and Chronic Disease Score , showed that severe ED predicted MACE ( hazard ratio [ HR ] 1.75 ; 95 % confidence interval 1.10 - 2.78 ; P < 0.05 ) . In addition , lower PBF , evaluated both in flaccid ( before ) and dynamic ( after prostagl and in-E1 stimulation ) conditions , was associated with an increased risk of MACE ( HR = 2.67 [ 1.42 - 5.04 ] and 1.57 [ 1.01 - 2.47 ] , respectively , for flaccid [ < 13 cm/second ] and dynamic [ < 25 cm/second ] peak systolic velocity ; both P < 0.05 ) . Reported high sexual interest in the partner and low sexual interest in the patient proved to have a protective effect against MACE . CONCLUSIONS The investigation of male sexuality , and in particular PBF , and sexual desire , could provide insights not only into present cardiovascular status but also into prospect i ve risk BACKGROUND Sildenafil is a potent inhibitor of cyclic guanosine monophosphate hydrolysis [ corrected ] in the corpus cavernosum and therefore increases the penile response to sexual stimulation . We evaluated the efficacy and safety of sildenafil , administered as needed in two sequential double-blind studies of men with erectile dysfunction of organic , psychogenic , and mixed causes . METHODS In a 24-week dose-response study , 532 men were treated with oral sildenafil  ( 25 , 50 , or 100 mg ) or placebo . In a 12-week , flexible dose-escalation study , 329 different men were treated with sildenafil or placebo , with dose escalation to 100 mg based on efficacy and tolerance . After this dose-escalation study , 225 of the 329 men entered a 32-week , open-label extension study . We assessed efficacy according to the International Index of Erectile Function , a patient log , and a global-efficacy question . RESULTS In the dose-response study , increasing doses of sildenafil were associated with improved erectile function ( P values for increases in scores for questions about achieving and maintaining erections were < 0.001 ) . For the men receiving 100 mg of sildenafil , the mean score for the question about achieving erections was 100 percent higher after treatment than at base line ( 4.0 vs. 2.0 of a possible score of 5 ) . In the last four weeks of treatment in the dose-escalation study , 69 percent of all attempts at sexual intercourse were successful for the men receiving sildenafil , as compared with 22 percent for those receiving placebo ( P<0.001 ) . The mean numbers of successful attempts per month were 5.9 for the men receiving sildenafil and 1.5 for those receiving placebo ( P<0.001 ) . Headache , flushing , and dyspepsia were the most common adverse effects in the dose-escalation study , occurring in 6 percent to 18 percent of the men . Ninety-two percent of the men completed the 32-week extension study . CONCLUSIONS Oral sildenafil is an effective , well-tolerated treatment for men with erectile dysfunction PURPOSE We estimated the incidence of  erectile dysfunction in men 40 to 69 years old at study entry during an average 8.8-year followup , and determined how risk varied with age , socioeconomic status and medical conditions . MATERIAL S AND METHODS Data from a r and omly sample d population based longitudinal study of Massachusetts men were analyzed . A total of 1,709 men completed the baseline interview during 1987 to 1989 and 1,156 survivors completed followup from 1995 to 1997 . The analysis sample consisted of 847 men without erectile dysfunction at baseline and with complete followup information .  Erectile dysfunction was assessed by discriminant analysis of 13 questions from a self-administered sexual function question naire and a single global self-rating question . RESULTS The crude incidence rate for erectile dysfunction was 25.9 cases per 1,000 man-years ( 95 % confidence interval [ CI ] 22.5 to 29.9 ) . The annual incidence rate increased with each decade of age and was 12.4 cases per 1,000 man-years ( 95 % CI 9.0 to 16.9 ) , 29.8 ( 24.0 to 37.0 ) and 46.4 ( 36.9 to 58.4 ) for men 40 to 49 , 50 to 59 and 60 to 69 years old , respectively . The age adjusted risk of erectile dysfunction was higher for men with lower education , diabetes , heart disease and hypertension . Population projections for men 40 to 69 years old suggest that 17,781 new cases of erectile dysfunction in Massachusetts and 617,715 in the United States ( white males only ) are expected annually . CONCLUSIONS Although prevalence estimates and cross-sectional correlates of erectile dysfunction have recently been established , incidence estimates were lacking . Incidence is necessary to assess risk , and plan treatment and prevention strategies . The risk of erectile dysfunction was about 26 cases per 1,000 men annually , and increased with age , lower education , diabetes , heart disease and hypertension BACKGROUND Erectile dysfunction ( ED ) may be one manifestation of a generalized vascular disorder characterized by endothelial dysfunction . Statin drugs may improve endothelial function , even before altering the lipid profile . OBJECTIVE We sought to determine whether the addition of a statin with sildenafil would improve ED in men who initially responded poorly to sildenafil .  METHODS Men with moderate-to-severe ED despite an adequate sildenafil trial were enrolled in this r and omized , double-blind , placebo-controlled pilot study . ED was defined using a vali date d self-administered question naire as a score of < or=16 on the International Index of Erectile Function ( erectile function domain score range of 6 - 30 ) . Improvement in ED score with sildenafil was reassessed at 6 and 12 weeks of treatment with atorvastatin ( 80 mg daily ) or matching placebo . RESULTS Twelve men ( mean age 58 + /- 13 years ) with a mean domain score of 8.2 + /- 6.9 and a mean duration of ED of 3.7 years were enrolled in the study . Treatment with atorvastatin decreased mean low-density lipoprotein cholesterol by 43 % and result ed in an improvement with  sildenafil in domain score of 7.8 ( P = 0.036 ) ; an effect was apparent by 6 weeks . The increase in domain score in placebo patients was not statistically significant . CONCLUSIONS Treatment with atorvastatin improved sexual function and the response to oral sildenafil  in men who did not initially respond to treatment with sildenafil .  The results of this pilot study support the hypothesis that vascular endothelial dysfunction contributes to ED in sildenafil nonresponders and deserves further testing in a large clinical trial 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 , r and omized , placebo-controlled , clinical trial in patients with ED and endothelial dysfunction . Patients were r and omized to receive 20 mg simvastatin  ( n=21 ) or placebo  ( n=20 ) daily for 6 months and subsequently 10 mg of vardenafil on dem and 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 PURPOSE We prospect ively investigated whether postoperative statin use would contribute to earlier recovery of erectile function in men who underwent bilateral nerve sparing radical retropubic prostatectomy for clinical ly localized prostate cancer . MATERIAL S AND METHODS A total of 50 potent men without hypercholesterolemia undergoing bilateral nerve sparing radical retropubic prostatectomy for clinical ly localized prostate cancer were prospect ively r and omized into 2 equal groups . Group 1 patients were instructed to ingest only 50 mg sildenafil per day if needed following hospital discharge after radical retropubic prostatectomy . Group 2 patients were prescribed atorvastatin at a dose of 10 mg daily from postoperative days 1 to 90 and they were also instructed to ingest sildenafil , as in group 1 . Patient status regarding potency and adverse events were assessed 6 months after surgery . RESULTS The 2 groups demonstrated no significant differences regarding various baseline factors , including International Index of Erectile Function-5 scores . Group 2 had a significantly higher postoperative International Index of Erectile Function-5 score than group 1 at 6 months postoperatively ( p = 0.003 ) . Meanwhile , as judged by a preset definition , the incidence of potent patients 6 months after prostatectomy was 26.1 % in group 1 and 55 % in group 2 ( p = 0.068 ) . Also , 17.4 % and 40 % of the men reported achieving intercourse by vaginal penetration without a phosphodiesterase 5 inhibitor in groups 1 and 2 , respectively ( p = 0.172 ) . No serious adverse events associated with medication were reported . CONCLUSIONS Postoperative treatment with atorvastatin in men who report normal erectile function preoperatively may contribute to earlier recovery of erectile function after nerve sparing radical retropubic prostatectomy Despite the initial enthusiasm , the significant number of patients in whom sildenafil is contraindicated or ineffective is a major challenge to all urologists . Our aim was to determine the safety and efficacy of adjunctive atorvastatin in restoring normal erectile function in hypercholesterolemic ( low-density lipoprotein ( LDL ) cholesterol > 120 mg per 100 ml ) sildenafil nonresponders . The study comprised 131 men with ED not responding to sildenafil citrate .  They were r and omized either to 40 mg atorvastatin daily ( n=66 , group 1 ) or matching placebo ( n=65 , group 2 ) for 12 weeks while they were taking on-dem and 100 mg sildenafil . Erectile function was subjectively assessed using the 5-item version of the International Index of Erectile Function ( IIEF-5 ) question naire and response to the global efficacy question ( GEQ ) . Serum biochemical and lipid profile ( total cholesterol , triglycerides , LDL cholesterol and high-density lipoprotein cholesterol ) analyses were performed at baseline and repeated at post-treatment weeks 6 and 12 . Compared with the placebo group ( 59 patients , mean age±s.d . 61.9±6.1 , mean years ED 3.9±1.8 ) , the atorvastatin group ( 59 patients , mean age±s.d . 63.9±6.9 , mean years ED 3.7±1.6 ) had significantly greater improvements in all IIEF-5 questions ( P=0.01 ) and GEQ ( P=0.001 ) . Subgroup analyses did reveal trends in the atorvastatin group to indicate that a change in the IIEF-5 score is affected by age , severity of ED and baseline serum levels of LDL . Patients with moderate ( r=0.28 , P=0.01 ) and severe ( r=0.20 , P=0.01 ) ED had better positive response rates  to adjunctive atorvastatin than patients with mild to moderate ED . None of the patients taking atorvastatin achieved a response of 5 to the IIEF-5 questions and none of the patients regained normal erectile function as defined by the IIEF-5 score > 21 . Subjects experienced a statistically significant but modest improvement in erectile function . Further investigation is needed to test the usefulness of long-term atorvastatin administration to restore erectile function in sildenafil nonresponders
target: RESULTS For the comparison of statins ( + /- sildenafil ) with placebo ( + /- sildenafil ) , the mean International Index of Erectile Function ( IIEF-5 ) ( the st and ardized mean difference [ SMD ] = 3.23 , 95 % confidence interval [ CI ] = -1.65 to 4.80 , P < 0.0001 ) indicated that statins ( + /- sildenafil ) showed statistically significantly greater improvements in the mean IIEF-5 compared with placebo ( + /- sildenafil ) .
  For the comparison of statins plus sildenafil with placebo plus sildenafil , the mean IIEF-5 ( SMD = 3.60 , 95 % CI = 2.64 to 4.56 , P < 0.00001 ) , the IIEF domain ( SMD = 4.88 , 95%CI = 3.01 to 6.74 , P < 0.00001 ) , and the global efficacy question ( odds ratio = 6.44 , 95 % CI = 2.92 to 14.23 , P < 0.00001 ) showed that compared with placebo plus sildenafil , statins plus sildenafil clearly improved erectile function .
  CONCLUSIONS This meta- analysis indicates that statins ( + /- sildenafil ) may improve ED compared with placebo ( + /- sildenafil )
background: INTRODUCTION It is not known if statins will improve symptoms in patients with established erectile dysfunction ( ED ) .
  AIM We carried out a systematic review and meta- analysis to assess the effect of statins on ED .