0
Clinical Guidelines |

Oral Phosphodiesterase-5 Inhibitors and Hormonal Treatments for Erectile Dysfunction: A Systematic Review and Meta-analysis FREE

Alexander Tsertsvadze, MD, MSc; Howard A. Fink, MD, MPH; Fatemeh Yazdi, MSc; Roderick MacDonald, MSc; Anthony J. Bella, MD; Mohammed T. Ansari, MBBS, MMedSc, MPhil; Chantelle Garritty, MSc; Karla Soares-Weiser, MD, PhD; Raymond Daniel, BA; Margaret Sampson, MLIS; Steven Fox, MD, MPH; David Moher, PhD; and Timothy J. Wilt, MD, MPH
[+] Article and Author Information

From Ottawa Health Research Institute, University of Ottawa, and Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada; Geriatric Research Education and Clinical Center, Center for Chronic Disease Outcomes Research, Minneapolis Veterans Affairs Medical Center, and Minneapolis Evidence-based Practice Center, Minneapolis, Minnesota; Enhance Reviews, Kfar-Saba, Israel; and Agency for Healthcare Research and Quality, Rockville, Maryland.


Disclaimer: The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Grant Support:Honoraria: A.J. Bella (Pfizer, Lilly, Bayer).

Potential Conflicts of Interest: None disclosed.

Requests for Single Reprints: Howard A. Fink, MD, MPH, Veterans Affairs Medical Center (11-G), One Veterans Drive, Minneapolis, MN 55417; e-mail, howard.fink@va.gov.

Current Author Addresses: Dr. Tsertsvadze, Ms. Yazdi, and Mr. Daniel: Ottawa Hospital Research Institute, 501 Smyth Road, Room W0575, Box 208, Ottawa, Ontario K1H 8L6, Canada.

Dr. Fink: Veterans Affairs Medical Center (11-G), One Veterans Drive, Minneapolis, MN 55417.

Mr. MacDonald and Dr. Wilt: Veterans Affairs Medical Center (111-0), One Veterans Drive, Minneapolis, MN 55417.

Dr. Bella: University of Ottawa, Faculty of Medicine, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.

Dr. Ansari: Ottawa Hospital Research Institute, 501 Smyth Road, Room W0589, Box 208, Ottawa, Ontario K1H 8L6, Canada.

Ms. Garritty: Ottawa Hospital Research Institute, 501 Smyth Road, Room W0585, Box 208, Ottawa, Ontario K1H 8L6, Canada.

Dr. Soares-Weiser: PO Box 137, Enhance Reviews, Kfar-Saba 44101, Israel.

Ms. Sampson: Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada.

Dr. Fox: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850.

Dr. Moher: Ottawa Hospital Research Institute, 501 Smyth Road, Room W6112, Box 208, Ottawa, Ontario K1H 8L6, Canada.

Author Contributions: Conception and design: A. Tsertsvadze, H.A. Fink, F. Yazdi, M.T. Ansari, M. Sampson, S. Fox, D. Moher, T.J. Wilt.

Analysis and interpretation of the data: A. Tsertsvadze, H.A. Fink, R. MacDonald, A.J. Bella, K. Soares-Weiser, S. Fox, D. Moher, T.J. Wilt.

Drafting of the article: A. Tsertsvadze, H.A. Fink, A.J. Bella.

Critical revision of the article for important intellectual content: A. Tsertsvadze, H.A. Fink, A.J. Bella, M. Sampson, S. Fox, D. Moher, T.J. Wilt.

Final approval of the article: A. Tsertsvadze, H.A. Fink, R. MacDonald, A.J. Bella, M.T. Ansari, K. Soares-Weiser, M. Sampson, S. Fox, D. Moher, T.J. Wilt.

Provision of study materials or patients: C. Garritty.

Statistical expertise: A. Tsertsvadze, R. MacDonald.

Obtaining of funding: D. Moher, T.J. Wilt.

Administrative, technical, or logistic support: A. Tsertsvadze, H.A. Fink, F. Yazdi, R. MacDonald, M.T. Ansari, C. Garritty, R. Daniel, S. Fox, D. Moher, T.J. Wilt.

Collection and assembly of data: A. Tsertsvadze, H.A. Fink, F. Yazdi, R. MacDonald, A.J. Bella, M.T. Ansari, C. Garritty, K. Soares-Weiser, M. Sampson, T.J. Wilt.

Other: M. Sampson (search expertise).


Ann Intern Med. 2009;151(9):650-661. doi:10.7326/0003-4819-151-9-200911030-00150
Text Size: A A A

Background: Erectile dysfunction (ED) is a common male sexual disorder. The relative benefits and harms of pharmacologic therapies for ED, as well as the value of hormonal testing in men with ED, are uncertain.

Purpose: To evaluate the efficacy and harms of oral phosphodiesterase-5 (PDE-5) inhibitors and hormonal treatments for ED and assess the effect of measuring serum hormone levels on treatment outcomes for ED.

Data Sources: English-language studies from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, PsycINFO, AMED, and SCOPUS through April 2009. Trial reference lists also were scanned.

Study Selection: Randomized, controlled trials (RCTs) of oral PDE-5 inhibitors and hormonal treatment for ED, and observational studies reporting measurement of serum hormone levels, prevalence of hormonal abnormalities, or both in men with ED.

Data Extraction: Two independent reviewers abstracted data on study, participant, and treatment characteristics; efficacy and harms outcomes; and prevalence of hormonal abnormalities.

Data Synthesis: Data, primarily from short-term trials (≤12 weeks), indicate that PDE-5 inhibitors were more effective than placebo in improving sexual intercourse success (69.0% vs. 35.0%). The proportion of men with improved erections was significantly greater among those treated with PDE-5 inhibitors (range, 67.0% to 89.0%) than with placebo (range, 27.0% to 35.0%). The PDE-5 inhibitors were associated with increased risk for any adverse events compared with placebo (for example, relative risk with sildenafil, 1.72 [95% CI, 1.53 to 1.93]). In 4 head-to-head RCTs comparing sildenafil, vardenafil, and tadalafil, improvement of ED and adverse events did not differ among treatments. Results from 15 RCTs evaluating hormonal treatment of ED were inconsistent on whether treatment improved outcomes. Evidence was insufficient regarding whether men with ED had a higher prevalence of hypogonadism than men without ED.

Limitations: Many RCTs were of low methodological and reporting quality, particularly those involving hormonal treatments or directly comparing different PDE-5 inhibitors. Most RCTs provided only short-term efficacy and harms data.

Conclusion: Oral PDE-5 inhibitors improved erectile functioning and had similar efficacy and safety profiles. Results on the efficacy of hormonal treatments and the value of hormone testing in men with ED were inconclusive.

Primary Funding Source: Agency for Healthcare Research and Quality.

Erectile dysfunction (ED) is a common male sexual disorder and is defined as the persistent inability to achieve or maintain penile erection sufficient for satisfactory sexual performance (1). Advanced age, diabetes, vascular diseases, psychiatric disorders, and possibly hypogonadism are associated with increased prevalence of ED (14). According to data from the Massachusetts Male Aging Study (2), the prevalence of ED in men aged 40 to 70 years is about 50%.

Unless contraindicated, oral phosphodiesterase-5 (PDE-5) inhibitors, such as sildenafil, tadalafil, or vardenafil, are currently first-line treatments of ED (5). Alternative treatments include hormones, vacuum constriction devices, intraurethral suppositories, intracavernosal injections, or surgery (for example, penile prosthesis implants) (57). Direct comparisons between treatments have been limited, and the relative long-term efficacy and safety profiles of different therapies have not been adequately explored.

Estimates from the National Health and Nutrition Examination Survey suggested that annual U.S. treatment costs of ED could reach $15 billion if all affected men sought care (8). In the past decade, the use of diagnostic tests for underlying causes of ED markedly decreased and use of pharmacologic therapy, especially with oral PDE-5 inhibitors, increased (8). In 2005, sales of sildenafil, tadalafil, and vardenafil were $1.6 billion, $747 million, and $327 million, respectively (911).

The value of hormonal blood tests (such as testosterone) in routine evaluation of men with ED is uncertain (1215). The European Association of Urology and the British Society for Sexual Medicine guidelines recommend endocrinologic screening in the initial evaluation of all men with ED (1520). In contrast, the American Urological Association recommends that hormone testing in men with ED be based on initial clinical assessment (for example, decreased libido, small testes, and reduced body hair) or failure of initial PDE-5 therapy management (5). Whether this targeted approach for identifying and treating hormonal disorders as underlying causes of ED is appropriate has not been rigorously evaluated (13, 15, 2021).

The aims of our review were to systematically identify and synthesize the published evidence to determine 1) the relative benefits and harms of oral PDE-5 inhibitors and hormonal treatments of ED, including the effect of patient characteristics and comorbid conditions on the likelihood of treatment success and 2) the clinical value of hormonal blood testing for identifying treatable causes of ED (for example, hypogonadism) and improving its outcomes.

We summarized and updated evidence from a technical review prepared for the Agency for Healthcare Research and Quality (22) and adapted the article in collaboration with the American College of Physicians' Clinical Efficacy Assessment Subcommittee to inform the development of its clinical practice guideline on this topic. The article focuses more specifically than the Agency for Healthcare Research and Quality technical review on treatments likely to be prescribed by primary care physicians. The topic of diagnosis and treatment of ED, as a subject for systematic review, was originally nominated by the American College of Physicians.

Data Sources and Searches

We searched for English-language articles in MEDLINE (1966 to May 2007), EMBASE (1980 to week 22 of 2007), Cochrane Central Register of Controlled Trials (second quarter of 2007), PsycINFO (1985 to June 2007), AMED (1985 to June 2007), and SCOPUS (2006). Search terms were impotence; erectile dysfunction; randomized, controlled trial; and controlled clinical trial. We also scanned reference lists of retrieved publications. We updated the review by searching MEDLINE and EMBASE (May 2007 to April 2009).

Study Selection

To assess the relative benefits and harms of pharmacologic treatments for ED, we selected randomized, controlled trials (RCTs) of pharmacologic treatments in men aged 18 years or older with ED. Treatments not generally prescribed by primary care physicians, such as vacuum constriction devices, intraurethral suppositories, intracavernosal injections, or psychotherapy, were considered beyond the scope of this review and are addressed in the technical report.

To assess the risks for nonarteritic anterior ischemic optic neuropathy (NAION) in PDE-5 inhibitor users, we selected RCTs; nonrandomized, controlled trials; and observational studies. To assess the clinical value of routine hormonal blood tests in men with ED, we selected studies that reported prevalence of hypogonadism, hyperprolactinemia, or both in men with ED and all RCTs comparing hormone treatment alone or in combination versus control in men with ED.

We excluded reviews, pooled analyses, editorials, commentaries, and letters. Two independent reviewers screened all identified titles and abstracts and, for articles considered potentially eligible, abstracted their full-text reports. Discrepancies were discussed and resolved by consensus. Appendix Figure 1 shows the literature selection process.

Grahic Jump Location
Appendix Figure 1.
Literature search and selection.

NAION = nonarteritic anterior ischemic optic neuropathy.

Grahic Jump Location
Data Extraction and Quality Assessment

Two reviewers independently abstracted data on study, population, and treatment characteristics. Treatment efficacy outcomes were the proportion of successful sexual intercourse attempts based on either participants' diaries or event logs (erection sufficiently hard and long-lasting for satisfactory intercourse) or participants' responses to question 3 of the Sexual Encounter Profile (SEP) (erection lasted long enough for successful intercourse) (23); the improvement in erectile function based on either participants' self-reports of improved erections (global assessment or efficacy question 1) or the mean Erectile Function domain score of the International Index of Erectile Function (IIEF) (24); and participants' responses to IIEF questions 3 (successful penile penetration) and 4 (maintenance of erection after penetration) (24).

Abstracted adverse events data were the number of patients with any adverse event, specific adverse events, withdrawals due to adverse events, serious adverse events, and serious cardiovascular adverse events. We assessed the prevalence of hypogonadism or hyperprolactinemia by using the definitions provided by study authors, even though these may have differed between studies.

We evaluated the overall strength of evidence by using a method developed by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group (25). We used the Jadad scale to assess the methodological and reporting quality of RCTs (score range, 0 to 5; higher score indicates better quality) (26). We judged the adequacy of allocation concealment to be adequate, inadequate, or unclear by using the approach proposed by Schulz and Grimes (27). We assessed the quality of studies reporting serum hormonal levels by using a subset of the Quality Assessment Tool of Diagnostic Accuracy Studies (questions 1, 2, 8, 12, and 14) (28). To explore the overall risk for bias, we generated risk-for-bias graphs (29). Appendix A includes all evidence and quality assessment tables and risk-for-bias graphs for the included studies.

Data Synthesis and Analysis

We qualitatively summarized data on study (design, reporting quality, and sample size), population (age, severity of ED, and comorbid conditions), and treatment characteristics (dose, frequency, and duration). We considered studies suitable for pooling if they used the same design (RCT), enrolled similar populations (trials restricted to participants with a specific comorbid condition vs. those enrolling participants with a heterogeneous profile of comorbid conditions), evaluated the same type of treatment (for example, sildenafil), and reported the same efficacy or safety outcomes. We used DerSimonian and Laird random-effects models to generate pooled estimates of relative risks (RRs) and weighted mean differences (WMDs) with 95% CIs (30). To avoid double-counting during pooling of a trial with several PDE-5 dose groups versus placebo, we used a generic inverse variance method to combine data from these groups for a single estimate of mean response rate versus placebo. Statistical heterogeneity was evaluated using a chi-square test and the I2 statistic (low = 25.0%; moderate = 50.0%; high = 75.0%) and was explored through subgroup and sensitivity analyses (for example, study quality and random- or fixed-effects model) (31). We defined the subgroups a priori with respect to severity (mild, severe, or moderate) and cause (psychogenic, mixed, or organic) of ED, treatment (for example, dose [50 mg or 100 mg], dosing [fixed or flexible], type [sildenafil, tadalafil, or vardenafil], and duration [≤12 weeks vs. >12 weeks]), and underlying or concurrent condition (for example, diabetes, cardiovascular disease, depression, or prostatectomy).

When studies did not adequately report summary statistics (such as treatment group mean score and SD), we calculated the needed variables if data for individual patients were reported. If a study reported only an SE of the mean response, we converted it to an SD. Trials were not incorporated into meta-analyses if the needed data (means [SDs]) could not be derived, and crossover trials did not report precrossover data. We included trials with no events for harms in the meta-analyses.

We examined the extent of publication bias through visual inspection of funnel plot asymmetry (32) and linear regression–based tests proposed by Egger and colleagues (33). We performed analyses with R software, version 2.4.0 (www.r-project.org), and STATA software, version 11 (StataCorp, College Station, Texas).

Role of the Funding Source

The Agency for Healthcare Research and Quality provided funding. The funding source suggested the initial research questions and provided copyright release for this manuscript but had no role in the design, conduct, analysis, or reporting of the data or in the decision to submit the manuscript for publication.

Literature Flow

Our literature search (Appendix Figure 1) identified 10 882 publications, of which 191 unique studies (222 publications) were included in the review. Of these included studies, 32 (23 PDE-5 inhibitor trials, 1 trial of hormonal treatment, 5 prevalence studies, and 3 NAION case reports) were identified through the updated EMBASE and MEDLINE search (May 2007 to April 2009).

Oral PDE-5 Inhibitors
Study and Population Characteristics

In total, 130 RCTs (160 main and secondary publications) evaluating oral PDE-5 inhibitors met eligibility criteria. These included 72 RCTs of sildenafil (34102), 27 RCTs of vardenafil (23, 103128), 28 RCTs of tadalafil (129156), 2 RCTs of mirodenafil (157158), and 1 RCT of udenafil (159). In addition, 4 RCTs directly compared PDE-5 inhibitors (160163).

Most trials (>70.0%) were parallel-group and placebo-controlled and had only short-term follow-up (≤12 weeks). Most were conducted in North America or Europe and were funded by the pharmaceutical industry. Trials enrolled heterosexual adult men with ED of various causes. Exclusion criteria common to most trials were penile or testicular deformity, cardiovascular conditions, use of nitrates, prostate cancer, HIV/AIDS, major hepatic or renal disease, spinal cord injury, and major psychiatric disorder. Nearly half of vardenafil trials and one third of tadalafil trials excluded men with ED that did not respond to previous PDE-5 inhibitor therapy or those who had discontinued PDE-5 inhibitor therapy because of adverse events. The efficacy and harms for 2 novel PDE-5 inhibitors, mirodenafil (157158) and udenafil (159), were evaluated only in Asian men. The PDE-5 inhibitors were administered at flexible doses (initial dose could be titrated up or down on the basis of individual participant response, with the following dose ranges: sildenafil, 25 to 100 mg/d; vardenafil, 5 to 20 mg/d; and tadalafil, 5 to 20 mg/d) or fixed (sildenafil, 25 to 100 mg/d; vardenafil, 5 to 40 mg/d; tadalafil, 5 to 20 mg/d; and mirodenafil, 50 to 150 mg/d) doses. About 80.0% of the trials were double-blind, and 30.0% used an appropriate randomization method. The adequacy of allocation concealment and blinding method was not clear for a high proportion of trials (85.0% and 60.0%, respectively) (Appendix A: Figure 1).

Among 4 RCTs that directly compared PDE-5 inhibitors, all had a crossover design and reported patient treatment preference as their primary outcome measure (160163). It was not clear whether these trials used an appropriate randomization method, 2 trials were not described as double-blind (160, 163), and 2 restricted sildenafil to less than the standard maximum dosing (161162). All 4 trials reported reasons for and proportions of withdrawals or dropouts. Three trials were sponsored by the manufacturer of tadalafil (Appendix A: Figure 2) (160162).

Efficacy
PDE-5 Inhibitor Versus Placebo.

In 116 RCTs, all PDE-5 inhibitors consistently improved erectile functioning more than placebo. The mean scores for the Erectile Function domain and questions 3 and 4 of the IIEF were statistically significantly greater in PDE-5 inhibitor–treated men than in placebo recipients (data not shown).

On the basis of participants' diaries or event logs in 16 trials that enrolled men with a wide spectrum of comorbid conditions, the mean per-patient percentage of successful sexual intercourse attempts for sildenafil-treated patients was 69.0% (range, 52.0% to 85.0%) versus 35.5% (range, 19.0% to 68.0%) for placebo recipients (Table 1). In 4 trials from which data pooling was possible (Appendix B: Figure 1), the WMD in improvement from baseline in the percentage of successful intercourse attempts was 34.3 (95% CI, 25.8 to 42.8) in favor of sildenafil (85, 88, 9798).

Table Jump PlaceholderTable 1.  Summary of Findings of Effectiveness

In 13 trials of vardenafil that enrolled men with a wide spectrum of comorbid conditions, the percentages of successful sexual intercourse attempts based on SEP question 3 in vardenafil and placebo groups were 68.0% (range, 50.0% to 88.0%) and 35.0% (range, 20.0% to 49.0%), respectively (23, 104, 106, 109110, 115, 117119, 121122, 125, 127). The diary or event log–based, weighted mean per-patient percentage of successful sexual intercourse attempts for vardenafil-treated patients was 73.0% versus 38.0% for placebo recipients (107, 112) (Table 1). In 2 trials from which data pooling was possible (Appendix B: Figure 2), the WMD in improvement from baseline in the percentage of successful intercourse attempts was 33.2 (CI, 26.0 to 40.3) in favor of vardenafil (106, 117).

In 15 trials of tadalafil that enrolled men with a wide spectrum of comorbid conditions, the percentages of successful sexual intercourse attempts based on SEP question 3 were 69% (range, 50.0% to 85.0%) for tadalafil versus 33% (range, 23.0% to 52.0%) for placebo (131132, 134136, 138139, 142, 144, 148152, 154). The mean per-patient percentage of successful intercourse attempts was 48.0% for tadalafil-treated patients and 9.0% for placebo recipients, based on diary or event logs (1 trial) (Table 1) (153). In 5 trials from which data pooling was possible (Appendix B: Figure 3), the WMD in improvement from baseline in the percentage of successful intercourse attempts was 35.1 (CI, 26.9 to 43.3) in favor of tadalafil (132, 135, 139, 142, 148).

All 5 agents (sildenafil, vardenafil, tadalafil, mirodenafil, and udenafil) consistently increased the proportion of men with improved erections (range, 73.0% to 88.0%) more than placebo (range, 26.0% to 32.0%) (see overall grade of evidence in Table 1). Appendix Figures 2, 3, and 4 provide the corresponding pooled RR estimates and studies.

Grahic Jump Location
Appendix Figure 2.
Improvement in erections: sildenafil versus placebo.

CAD = coronary artery disease; CVD = cardiovascular disease; RR = relative risk.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 3.
Improvement in erections: vardenafil versus placebo.

RR = relative risk.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 4.
Improvement in erections: tadalafil versus placebo.

RR = relative risk.

Grahic Jump Location

Men with specific medical conditions were significantly more likely to experience improved erections with PDE-5 inhibitors relative to placebo, on the basis of trials limited to men with diabetes (37, 4849, 53, 55, 99, 102103, 121122, 141, 156), depression (35, 47, 61, 86, 116), cardiovascular disease (40, 56, 59, 69, 75, 77, 90, 114, 128), prostate cancer (68, 91, 96, 105, 126, 137, 153, 164), multiple sclerosis (57, 101), colorectal cancer (66), schizophrenia (87), liver failure (58), and renal failure (84, 123) (Appendix Figures 2, 3, and 4).

Improvement in sexual intercourse success and erectile function was greater with higher versus lower doses of sildenafil (50 mg vs. 25 mg, but not 100 mg vs. 50 mg) and vardenafil (20 mg vs. 10 mg vs. 5 mg) but not tadalafil (20 mg vs. 10 mg vs. 5 mg) or mirodenafil (50 mg vs. 100 mg vs. 150 mg) (42, 48, 51, 72, 103, 107108, 110, 112, 122, 156159). In 1 trial, men preferred tadalafil on-demand therapy rather than scheduled dosing 3 times per week, although the mean per-patient proportion of successful intercourse attempts or mean IIEF Erectile Function domain score did not differ (129). In another trial, on-demand and once-daily vardenafil, 10 mg, produced similar treatment effects on the mean Erectile Function domain score in men with mild to moderate ED (124).

Among men assigned to PDE-5 inhibitors, those with severe baseline ED experienced significantly greater absolute improvements in the IIEF scores than did those with mild baseline ED. However, men with severe ED still had worse end-of-treatment Erectile Function domain scores than did men with mild baseline ED (37, 46, 66, 110, 112, 131, 149, 151152). There was no obvious treatment effect modification by the duration or cause of ED (42, 44, 51, 70, 74, 112).

PDE-5 Inhibitor Versus PDE-5 Inhibitor.

In 4 trials (160163), improvements in outcomes between PDE-5 inhibitors were inconsistent. Between-group differences in the mean IIEF Erectile Function domain scores were either statistically nonsignificant or significant but of small magnitude. In 1 trial (160), the use of 10- to 20-mg tadalafil was associated with a small but statistically significantly greater improvement in the mean proportion of successful sexual intercourse attempts compared with 25- to 100-mg sildenafil (76.9% vs. 72.2%; P = 0.003). In the same trial, mean change in Erectile Function domain scores did not differ between groups. In a second trial, mean Erectile Function domain scores were similar between men receiving 100-mg sildenafil and men receiving 20-mg tadalafil (163) (Table 1). More men preferred 20-mg tadalafil (range, 52.2% to 73.0%) to 50-mg sildenafil (range, 27.0% to 33.7%) or 20-mg vardenafil (20.0%).

Extent of Publication Bias

Visual inspection suggested asymmetry in the sildenafil, vardenafil, and tadalafil funnel plots for the rates of improved erection (Appendix C). The linear regression test confirmed statistically significant asymmetry for all 3 funnel plots: sildenafil (P < 0.001), vardenafil (P = 0.003), and tadalafil (P < 0.001).

Harms
PDE-5 Inhibitor Versus Placebo.

A greater proportion of men treated with PDE-5 inhibitors than men who received placebo had at least 1 adverse event (Table 2). The most commonly reported adverse events were headache, flushing, rhinitis, and dyspepsia (Appendix D). Other reported events were visual disturbances, myalgia, nausea, diarrhea, vomiting, dizziness, and chest pain. In general, these events were mild to moderate and were transient. Serious adverse events were reported in fewer than 2.0% of participants, and incidence did not differ between PDE-5 inhibitor recipients and placebo recipients. In 58 placebo-controlled trials reporting data, risk for a serious cardiovascular event (such as fatal or nonfatal myocardial infarction, stroke, or severe angina) seemed higher in men treated with sildenafil (0.5%) than in men receiving placebo (0.1%). The risk for serious cardiovascular events was similar in men treated with vardenafil (0.2%) or tadalafil (0.3%) compared with placebo (range, 0.1% to 0.2%). Because many PDE-5 inhibitor trials were unbalanced with respect to the number of men randomly assigned in each treatment group, the estimated Peto odds ratios may have been prone to bias (29) and therefore are not presented here.

Table Jump PlaceholderTable 2.  Summary of Findings on AEs
PDE-5 Inhibitor Versus PDE-5 Inhibitor.

Differences in the incidence of any adverse events among men treated with sildenafil (range, 24.0% to 34.0%), tadalafil (range, 28.0% to 35.0%), and vardenafil (27.0%) were not statistically significant (Table 2) (160163). Discontinuation due to adverse effects ranged from 0.5% to 3.8% during tadalafil treatment, 0.5% to 3.8% during sildenafil treatment, and 1.0% during vardenafil treatment. The frequency of specific adverse events (headache, flushing, dyspepsia, and nasal congestion) seemed similar among treatments. Tadalafil may have been associated with more frequent myalgia (range, 2.3% to 4.4%) than sildenafil or vardenafil (range, 0% to 0.5%).

NAION or Priapism.

Evidence on the incidence of NAION associated with use of PDE-5 inhibitors was limited to 10 case reports (165174), 2 case series (175176), and 1 retrospective cohort study (177). In the cohort study, NAION and “possible” optic neuropathy were identified by using medical diagnostic codes, with NAION defined as ischemic nonarteritic optic neuropathy in the absence of temporal arteritis and polymyalgia rheumatica and “possible” NAION defined as papillitis, optic neuritis, or both in the absence of temporal arteritis, polymyalgia rheumatica, and previous optic neuropathies. Among more than 4 million male veterans aged 50 years or older, those prescribed PDE-5 inhibitors (11.5% of the cohort) had a risk for NAION similar to that of those who were not prescribed PDE-5 inhibitors (absolute rates of 4.6 and 4.5 cases per 10 000 men per year, respectively; RR, 1.02 [95% CI, 0.92 to 1.12]), but they had an increased risk for “possible” NAION (RR, 1.34 [CI, 1.17 to 1.55]) (177). Trials did not report the incidence of priapism, although the incidence of prolonged erection and priapism has been reported infrequently in PDE-5 inhibitor users during postmarketing surveillance (178).

Hormonal Treatments
Study and Population Characteristics

Fifteen RCTs evaluated the efficacy of hormonal therapy (oral, intramuscular, gel, cream, or patch testosterone) in hypogonadal men with ED (179193). The criteria for defining men as hypogonadal varied widely across the trials, and some trials enrolled men both with and without ED (187189, 191). Three trials were restricted to men with HIV (186), major depressive disorder (190), or diabetes (185). Only 60.0% of the trials were described as double-blind. The appropriateness of randomization and blinding method was not clear for 87.0% and 93.0% of trials, respectively. Only 1 trial reported adequate allocation concealment (182). Given the uncertainty in these quality domains (randomization, blinding, and allocation concealment) and the differences among study populations, the overall strength of evidence was graded as low (Table 1 and Appendix A: Figure 3).

Efficacy
Hormonal Therapy Versus Placebo.

Results of trials comparing oral, intramuscular, or patch testosterone with placebo in hypogonadal men with ED were inconsistent regarding their effects on erectile function, degree of erection, or improved erection, with most indicating that testosterone was no more effective than placebo (Table 1). In 1 trial, gel testosterone (50 to 100 mg) but not patch testosterone modestly improved sexual intercourse frequency compared with placebo (180). In another trial (193), men treated with testosterone gel (50 mg/d) had slightly higher mean IIEF Erectile Function domain scores than did placebo recipients (21.6 vs. 18.1; P < 0.01).

Hormonal Therapy Plus PDE-5 Inhibitor Versus PDE-5 Inhibitor Alone.

Three small trials in hypogonadal men with ED refractory to previous PDE-5 inhibitor therapy yielded inconsistent results on whether oral PDE-5 inhibitor plus testosterone improved sexual function more than did PDE-5 inhibitor alone (Table 1). In the first trial, 100-mg sildenafil plus 5-mg/d patch testosterone improved several measures of sexual intercourse success and erectile function compared with sildenafil plus placebo (183). In the second trial, men randomly assigned to 100-mg sildenafil plus 1.0% gel testosterone had no greater frequency of sexual intercourse success than men randomly assigned to sildenafil plus placebo; they had small improvements on IIEF scores that were statistically significant at 4 weeks but not at 8 or 12 weeks (181). In the third trial, sildenafil plus 120-mg/d oral testosterone was associated with a small improvement in the mean Erectile Function domain score compared with sildenafil plus placebo (187).

Harms
Hormonal Therapy Versus Placebo.

The incidence of any (or treatment-related) adverse events did not differ between oral or gel testosterone and placebo groups (179180, 193). Men receiving patch testosterone had a higher rate of application-site skin reactions and increased hematocrit than men receiving gel testosterone or placebo (180, 194195). In 1 trial (180), 2 men treated with patch testosterone developed prostate cancer (Table 2). Prostate-specific antigen levels were similar in testosterone and placebo groups in 3 trials reporting these data (182, 191192).

Hormonal Therapy Plus PDE-5 Inhibitor Versus PDE-5 Inhibitor Alone.

In 3 trials, the incidence of adverse events was low and did not differ between sildenafil alone versus sildenafil plus patch, gel, or oral testosterone groups (Table 2) (181, 183, 187). Prostate-specific antigen levels were not significantly higher in the sildenafil plus testosterone groups than in the sildenafil-alone groups in 2 trials reporting these data (183, 187).

Clinical Utility of Routine Hormonal Blood Tests in Men With Erectile Dysfunction
Study and Population Characteristics

Twenty-nine studies (30 publications) were included, of which 28 (13, 15, 196222) and 10 (13, 15, 197, 199200, 205, 207, 212213, 223) reported measurements of testosterone and prolactin, respectively. Patients were recruited predominately from specialty clinics (for example, urology, sexual dysfunction, and endocrinology). Participants' mean age across studies ranged from 47 to 60 years.

About 80.0% of the studies reported at least some information on the hormonal test method. Most of the studies did not report on withdrawals or dropouts. Only 60.0% of studies described participant selection criteria clearly (Appendix A: Figure 4). Given between-study variability in populations, hormone measurement methods, and prevalence rates of hormonal abnormalities, we rated the overall quality of evidence for the association of hormonal abnormalities with ED as low.

Prevalence of Hypogonadism and Hyperprolactinemia in Men With ED

The prevalence of low total testosterone levels (197, 208, 219220), low free testosterone levels (206, 214), and hyperprolactinemia (199, 212213) in men with ED varied widely across studies, with limited data from U.S. primary care settings or U.S. population representative samples. In 1 primary care clinic study, 24.1% of men with ED had total testosterone levels less than 10 nmol/L (<288 ng/dL) (205). In a study of veterans recruited from an outpatient registry, 14.0% with “inadequate” erectile function had free testosterone levels less than 9.0 pg/mL (206).

By comparison, in a study based in 1 ED specialty clinic, 36.0% of 157 consecutively referred men with ED had hypogonadism (total testosterone level <300 ng/dL) (219). In a retrospective chart review of 2794 men presenting to a Veterans Affairs ED specialty clinic between 1987 and 2002 with a symptom of ED, 654 (23.0%) had androgen deficiency (total testosterone level <300 ng/dL) (220).

In Boston Area Community Health Survey's population-based stratified random sample of men aged 30 to 79 years, the prevalence of total testosterone levels less than 300 ng/dL was 35.0% in men with ED and 22.7% in men without ED (216). In another population-based cohort of men aged 40 to 70 years, the Massachusetts Male Aging Study, there was no association between ED and total testosterone, bioavailable testosterone, or sex hormone–binding globulin after adjustment for potentially confounding variables (217).

Overall, these data suggest that variability in prevalence estimates may reflect between-study differences in population characteristics, hormonal measurement methods, or diagnostic criteria for ED or hormonal abnormalities. Studies were inconsistent regarding whether, among men with ED, those with and without hypogonadism differed in age, severity or duration of ED, or prevalence of chronic diseases (13, 15, 199, 201, 204, 207, 212, 218, 224). Among men with ED in specialty clinic populations, those with low sexual desire, premature ejaculation, or testicular atrophy tended to have low testosterone levels (13, 15, 204, 207, 218). In 1 of these studies, the men with low sexual desire also were more likely to have hyperprolactinemia (207). We could not identify studies examining the rate of hormonal abnormalities in men whose initial PDE-5 inhibitor treatment failed. Overall, evidence was insufficient to determine whether, in primary care clinics, men with ED (or specific subgroups of men with ED) had a higher prevalence of hypogonadism or hyperprolactinemia than did men without ED.

In our systematic review, we found a large quantity of “high-grade” evidence indicating that sildenafil, vardenafil, and tadalafil are more effective than placebo in improving erectile function in men with ED over the short term (≤12 weeks), both in mixed study populations and study populations of men with specific comorbid conditions. The observed between-treatment differences were of clinically meaningful and statistically significant (104, 115, 127). In trials that directly compared sildenafil, vardenafil, and tadalafil, the magnitude of improvement in erectile function from baseline was similar among the agents. Compared with lower doses, higher doses of sildenafil and vardenafil (but not tadalafil) were associated with modestly greater improvements in erectile function.

Evidence on whether 1 PDE-5 inhibitor was more or less harmful than another was inconclusive. All PDE-5 inhibitors were associated with increased risk for any or specific adverse events. The reporting of all serious adverse or cardiovascular adverse events was inconsistent and incomplete. The overall rate of serious adverse events in men randomly assigned to PDE-5 inhibitors was about 2.0% or lower and was similar to that in men randomly assigned to placebo. Evidence was insufficient to determine whether treatment with PDE-5 inhibitors increases risk for serious cardiovascular events or NAION in men not receiving nitrates.

Several sources of potential bias may have affected PDE-5 inhibitor trials. First, exclusion of men intolerant of or poorly responsive to previous sildenafil treatment from many tadalafil and vardenafil placebo-controlled trials may have resulted in overestimation of efficacy and underestimation of harms for these agents. Second, the design of head-to-head trials that compared PDE-5 inhibitors may have had biased results in favor of tadalafil through their funding by the manufacturer of tadalafil and their restriction of sildenafil doses. Furthermore, funnel-plot asymmetry and regression analyses suggested possible publication bias for PDE-5 inhibitor trials, although the asymmetry may be explained by methodological or clinical heterogeneity across published studies. Publication bias, if present, may have led to overestimation of the true effect size of clinical benefits associated with use of PDE-5 inhibitors.

Results of trials on the effectiveness and harms of hormonal treatments for ED were inconsistent, probably because of low methodological and reporting quality, differences in patient inclusion criteria, types and doses of testosterone treatment, and outcomes. Results for most trials suggested that testosterone was no more effective than placebo in improving erections or increasing frequency of sexual intercourse.

The evidence on the utility of hormonal blood tests in identifying and affecting therapeutic outcomes for treatable causes of ED is inconclusive. This is in part attributable to the high variability in prevalence of hormonal abnormalities in men with ED across studies and insufficient data on the comparative treatment effectiveness of hormones and PDE-5 inhibitors in men with ED and hormonal abnormalities. Furthermore, consistent evidence was lacking on whether specific clinical features (such as age, comorbid conditions, obesity, hyperlipidemia, and nonresponse to PDE-5 inhibitors) help identify men with hormonal abnormalities among those with ED in primary care settings.

Our review has several limitations. First, many trials had limited methodological and reporting quality, particularly those that directly compared PDE-5 inhibitors and those that evaluated hormonal therapies. Moreover, clinical or methodological heterogeneity and missing information limited the extent of statistical data pooling. Second, the low number and selective reporting of serious cardiovascular events should be interpreted with caution. Third, most RCTs were of short duration (≤12 weeks), and longer-term efficacy and safety data (≥6 months) were unavailable.

It is striking that we identified a dearth of credible information on hormonal therapies used in the treatment of ED but an impressive amount of “high-grade” evidence on therapeutic effects of PDE-5 inhibitors compared with placebo for men with ED. This sharp contrast may be explained by the fact that more than 70% of the PDE-5 inhibitor trials in this review were industry funded. This gap in our research base is especially noteworthy in light of the growing popularity of androgen supplementation for various indications in aging men and controversial findings for hormone replacement therapies in women, which are far more extensively studied.

Future efforts are needed to help improve the reporting quality of primary studies. The CONSORT (Consolidated Standards of Reporting Trials) Statement could be considered as a guide for authors reporting trials and journals that publish research related to ED (225). The conduct of studies using standardized hormonal tests and those designed to identify subgroups of men with ED at increased risk for hormonal disorders would help to further determine the utility of routine hormonal blood tests (226). Well-designed, long-term PDE-5 inhibitor trials (≥6 months) are also warranted. In the presence of comorbid conditions or specific causes of ED, the comparison of cause-specific therapies (those targeting underlying causes of ED) to empirical treatments (for example, PDE-5 inhibitors) is important. More direct comparison trials of PDE-5 inhibitor drugs are also needed.

NIH Consensus Conference.  Impotence. NIH Consensus Development Panel on Impotence. JAMA. 1993; 270:83-90. PubMed
CrossRef
 
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. PubMed
 
Virag R.  Indications and early results of sildenafil (Viagra) in erectile dysfunction. Urology. 1999; 54:1073-7. PubMed
 
Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB.  Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts male aging study. J Urol. 2000; 163:460-3. PubMed
 
Montague DK, Jarow JP, Broderick GA, Dmochowski RR, Heaton JP, Lue TF, et al. Erectile Dysfunction Guideline Update Panel.  Chapter 1: The management of erectile dysfunction: an AUA update. J Urol. 2005; 174:230-9. PubMed
 
Porst H.  The rationale for prostaglandin E1 in erectile failure: a survey of worldwide experience. J Urol. 1996; 155:802-15. PubMed
 
Fazio L, Brock G.  Erectile dysfunction: management update. CMAJ. 2004; 170:1429-37. PubMed
 
Wessells H, Joyce GF, Wise M, Wilt TJ.  Erectile dysfunction. J Urol. 2007; 177:1675-81. PubMed
 
Bayer Annual Report 2005. Leverkusen, Germany: Bayer AG; 2006. Accessed atwww.bayer.com/en/GB-2005-en.pdfxon 21 September 2009.
 
Eli Lilly Annual Report 2005. Indianapolis: Eli Lilly; 2006. Accessed athttp://investor.lilly.com/annuals.cfmon 22 May 2009.
 
Pfizer Annual Report 2005. New York: Pfizer; 2006. Accessed athttp://media.pfizer.com/files/annualreport/2005/annual/review2005.pdfon 21 September 2009.
 
Burnett AL, Johns DG, Kriegsfeld LJ, Klein SL, Calvin DC, Demas GE. et al.  Ejaculatory abnormalities in mice with targeted disruption of the gene for heme oxygenase-2. Nat Med. 1998; 4:84-7. PubMed
 
Johnson AR 3rd, Jarow JP.  Is routine endocrine testing of impotent men necessary? J Urol. 1992;147:1542-3; discussion 1543-4. [PMID: 1593685]
 
Noldus J, Huland H.  [Erectile dysfunction and hypogonadism. Is routine endocrine screening necessary?]. Urologe A. 1994; 33:73-5. PubMed
 
Buvat J, Lemaire A.  Endocrine screening in 1,022 men with erectile dysfunction: clinical significance and cost-effective strategy. J Urol. 1997; 158:1764-7. PubMed
 
Bancroft J, Wu FC.  Changes in erectile responsiveness during androgen replacement therapy. Arch Sex Behav. 1983; 12:59-66. PubMed
 
Morelli A, Filippi S, Mancina R, Luconi M, Vignozzi L, Marini M. et al.  Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Endocrinology. 2004; 145:2253-63. PubMed
 
Aversa A, Isidori AM, De Martino MU, Caprio M, Fabbrini E, Rocchietti-March M. et al.  Androgens and penile erection: evidence for a direct relationship between free testosterone and cavernous vasodilation in men with erectile dysfunction. Clin Endocrinol (Oxf). 2000; 53:517-22. PubMed
 
Wespes E, Amar E, Hatzichristou D, Hatzimouratidis K, Montorsi F, Pryor J, et al. EAU.  EAU Guidelines on erectile dysfunction: an update. Eur Urol. 2006; 49:806-15. PubMed
 
Lue TF, Broderick G.  Evaluation and nonsurgical management of erectile dysfunction and priapism. Walsh P, Retik A, Vaughan E Campbell's Urology. 7th ed. Philadelphia: Saunders; 1998; 1181-214.
 
Miller TA.  Diagnostic evaluation of erectile dysfunction. Am Fam Physician. 2000; 61. PubMed
 
Tsertsvadze A, Yazdi F, Fink HA, MacDonald R, Wilt TJ, Soares-Weiser K, et al.  Diagnosis and Treatment of Erectile Dysfunction. AHRQ Evidence Report/Technology Assessment no. 171. Bethesda, MD: Agency for Healthcare Research and Quality; May 2009. AHRQ publication no. 08(09)-E016. Accessed atwww.ahrq.gov/downloads/pub/evidence/pdf/erectiledys/erecdys.pdfon 26 May 2009.
 
Montorsi F, Padma-Nathan H, Buvat J, Schwaibold H, Beneke M, Ulbrich E, et al. Vardenafil Study Group.  Earliest time to onset of action leading to successful intercourse with vardenafil determined in an at-home setting: a randomized, double-blind, placebo-controlled trial. J Sex Med. 2004; 1:168-78. PubMed
 
Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A.  The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997; 49:822-30. PubMed
 
Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al. GRADE Working Group.  Grading quality of evidence and strength of recommendations. BMJ. 2004; 328:1490. PubMed
 
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ. et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996; 17:1-12. PubMed
 
Schulz KF, Grimes DA.  Allocation concealment in randomised trials: defending against deciphering. Lancet. 2002; 359:614-8. PubMed
 
Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J.  The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol. 2003; 3:25. PubMed
 
Higgins JPT, Green S, eds.  Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008. Accessed atwww.cochrane-handbook.orgon 3 February 2009.
 
DerSimonian R, Laird N.  Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177-88. PubMed
 
Higgins JP, Thompson SG, Deeks JJ, Altman DG.  Measuring inconsistency in meta-analyses. BMJ. 2003; 327:557-60. PubMed
 
Light RJ, Pillemer DB.  Summing Up: The Science of Reviewing Research. Cambridge, MA: Harvard Univ Pr; 1984.
 
Egger M, Davey Smith G, Schneider M, Minder C.  Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315:629-34. PubMed
 
Palmer JS, Kaplan WE, Firlit CF.  Erectile dysfunction in patients with spina bifida is a treatable condition. J Urol. 2000; 164:958-61. PubMed
 
Seidman SN, Roose SP, Menza MA, Shabsigh R, Rosen RC.  Treatment of erectile dysfunction in men with depressive symptoms: results of a placebo-controlled trial with sildenafil citrate. Am J Psychiatry. 2001; 158:1623-30. PubMed
 
Kongkanand A, Ratana-Olarn K, Ruangdilokrat S, Tantiwong A, Thai investigators in ASSESS-2 Study Group.  The efficacy and safety of oral sildenafil in Thai men with erectile dysfunction: a randomized, double-blind, placebo controlled, flexible-dose study. J Med Assoc Thai. 2003; 86:195-205. PubMed
 
Stuckey BG, Jadzinsky MN, Murphy LJ, Montorsi F, Kadioglu A, Fraige F. et al.  Sildenafil citrate for treatment of erectile dysfunction in men with type 1 diabetes: results of a randomized controlled trial. Diabetes Care. 2003; 26:279-84. PubMed
 
Choi HK, Ahn TY, Kim JJ, Kim SC, Paick JS, Suh JK. et al.  A double-blind, randomised- placebo, controlled, parallel group, multicentre, flexible-dose escalation study to assess the efficacy and safety of sildenafil administered as required to male outpatients with erectile dysfunction in Korea. Int J Impot Res. 2003; 15:80-6. PubMed
 
Levinson IP, Khalaf IM, Shaeer KZ, Smart DO.  Efficacy and safety of sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men in Egypt and South Africa. Int J Impot Res. 2003; 15:Suppl 1S25-9. PubMed
 
DeBusk RF, Pepine CJ, Glasser DB, Shpilsky A, DeRiesthal H, Sweeney M.  Efficacy and safety of sildenafil citrate in men with erectile dysfunction and stable coronary artery disease. Am J Cardiol. 2004; 93:147-53. PubMed
 
Boolell M, Gepi-Attee S, Gingell JC, Allen MJ.  Sildenafil, a novel effective oral therapy for male erectile dysfunction. Br J Urol. 1996; 78:257-61. PubMed
 
Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA.  Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med. 1998; 338:1397-404. PubMed
 
Tan HM, Moh CL, Mendoza JB, Gana T, Albano GJ, de la Cruz R. et al.  Asian sildenafil efficacy and safety study (ASSESS-1): a double-blind, placebo-controlled, flexible-dose study of oral sildenafil in Malaysian, Singaporean, and Filipino men with erectile dysfunction. The Assess-1 Study Group. Urology. 2000; 56:635-40. PubMed
 
Meuleman E, Cuzin B, Opsomer RJ, Hartmann U, Bailey MJ, Maytom MC. et al.  A dose-escalation study to assess the efficacy and safety of sildenafil citrate in men with erectile dysfunction. BJU Int. 2001; 87:75-81. PubMed
 
Eardley I, Morgan R, Dinsmore W, Yates P, Boolell M.  Efficacy and safety of sildenafil citrate in the treatment of men with mild to moderate erectile dysfunction. Br J Psychiatry. 2001; 178:325-30. PubMed
 
Young JM, Bennett C, Gilhooly P, Wessells H, Ramos DE.  Efficacy and safety of sildenafil citrate (Viagra) in black and Hispanic American men. Urology. 2002; 60:39-48. PubMed
 
Nurnberg HG, Hensley PL, Gelenberg AJ, Fava M, Lauriello J, Paine S.  Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial. JAMA. 2003; 289:56-64. PubMed
 
Price DE, Gingell JC, Gepi-Attee S, Wareham K, Yates P, Boolell M.  Sildenafil: study of a novel oral treatment for erectile dysfunction in diabetic men. Diabet Med. 1998; 15:821-5. PubMed
 
Rendell MS, Rajfer J, Wicker PA, Smith MD.  Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. Sildenafil Diabetes Study Group. JAMA. 1999; 281:421-6. PubMed
 
Christiansen E, Guirguis WR, Cox D, Osterloh IH, Sildenafil Multicentre Study Group.  Long-term efficacy and safety of oral Viagra (sildenafil citrate) in men with erectile dysfunction and the effect of randomised treatment withdrawal. Int J Impot Res. 2000; 12:177-82. PubMed
 
Olsson AM, Speakman MJ, Dinsmore WW, Giuliano F, Gingell C, Maytom M, et al. Sildenafil Multicentre Study Group.  Sildenafil citrate (Viagra) is effective and well tolerated for treating erectile dysfunction of psychogenic or mixed aetiology. Int J Clin Pract. 2000; 54:561-6. PubMed
 
Chen KK, Hsieh JT, Huang ST, Jiaan DB, Lin JS, Wang CJ, ASSESS-3 Study Group.  ASSESS-3: a randomised, double-blind, flexible-dose clinical trial of the efficacy and safety of oral sildenafil in the treatment of men with erectile dysfunction in Taiwan. Int J Impot Res. 2001; 13:221-9. PubMed
 
Boulton AJ, Selam JL, Sweeney M, Ziegler D.  Sildenafil citrate for the treatment of erectile dysfunction in men with Type II diabetes mellitus. Diabetologia. 2001; 44:1296-301. PubMed
 
Hussain IF, Brady CM, Swinn MJ, Mathias CJ, Fowler CJ.  Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson's disease or multiple system atrophy with observations on orthostatic hypotension. J Neurol Neurosurg Psychiatry. 2001; 71:371-4. PubMed
 
Safarinejad MR.  Oral sildenafil in the treatment of erectile dysfunction in diabetic men: a randomized double-blind and placebo-controlled study. J Diabetes Complications. 2004; 18:205-10. PubMed
 
Webster LJ, Michelakis ED, Davis T, Archer SL.  Use of sildenafil for safe improvement of erectile function and quality of life in men with New York Heart Association classes II and III congestive heart failure: a prospective, placebo-controlled, double-blind crossover trial. Arch Intern Med. 2004; 164:514-20. PubMed
 
Fowler CJ, Miller JR, Sharief MK, Hussain IF, Stecher VJ, Sweeney M.  A double blind, randomised study of sildenafil citrate for erectile dysfunction in men with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005; 76:700-5. PubMed
 
Mahon A, Sidhu PS, Muir G, Macdougall IC.  The efficacy of sildenafil for the treatment of erectile dysfunction in male peritoneal dialysis patients. Am J Kidney Dis. 2005; 45:381-7. PubMed
 
Katz SD, Parker JD, Glasser DB, Bank AJ, Sherman N, Wang H. et al.  Efficacy and safety of sildenafil citrate in men with erectile dysfunction and chronic heart failure. Am J Cardiol. 2005; 95:36-42. PubMed
 
Abdel-Naser MB, Imam A, Wollina U.  Sildenafil citrate significantly improves nocturnal penile erections in sildenafil non-responding patients with psychogenic erectile dysfunction. Int J Impot Res. 2004; 16:552-6. PubMed
 
Tignol J, Furlan PM, Gomez-Beneyto M, Opsomer R, Schreiber W, Sweeney M. et al.  Efficacy of sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men in remission from depression. Int Clin Psychopharmacol. 2004; 19:191-9. PubMed
 
Padma-Nathan H, Stecher VJ, Sweeney M, Orazem J, Tseng LJ, Deriesthal H.  Minimal time to successful intercourse after sildenafil citrate: results of a randomized, double-blind, placebo-controlled trial. Urology. 2003; 62:400-3. PubMed
 
Seibel I, Poli De Figueiredo CE, Telöken C, Moraes JF.  Efficacy of oral sildenafil in hemodialysis patients with erectile dysfunction. J Am Soc Nephrol. 2002; 13:2770-5. PubMed
 
Gómez F, Davila H, Costa A, Acuña A, Wadskier LA, Plua P, Andean Group of Erectile Dysfunction Study.  Efficacy and safety of oral sildenafil citrate (Viagra) in the treatment of male erectile dysfunction in Colombia, Ecuador, and Venezuela: a double-blind, multicenter, placebo-controlled study. Int J Impot Res. 2002; 14:Suppl 2S42-7. PubMed
 
Becher E, Tejada Noriega A, Gomez R, Decia R, Southern Latin America Sildenafil Study Group, Buenos Aires, Argentina.  Sildenafil citrate (Viagra) in the treatment of men with erectile dysfunction in southern Latin America: a double-blind, randomized, placebo-controlled, parallel-group, multicenter, flexible-dose escalation study. Int J Impot Res. 2002; 14:Suppl 2S33-41. PubMed
 
Lindsey I, George B, Kettlewell M, Mortensen N.  Randomized, double-blind, placebo-controlled trial of sildenafil (Viagra) for erectile dysfunction after rectal excision for cancer and inflammatory bowel disease. Dis Colon Rectum. 2002; 45:727-32. PubMed
 
Eardley I, Ellis P, Boolell M, Wulff M.  Onset and duration of action of sildenafil for the treatment of erectile dysfunction. Br J Clin Pharmacol. 2002; 53:Suppl 161S-65S. PubMed
 
Incrocci L, Koper PC, Hop WC, Slob AK.  Sildenafil citrate (Viagra) and erectile dysfunction following external beam radiotherapy for prostate cancer: a randomized, double-blind, placebo-controlled, cross-over study. Int J Radiat Oncol Biol Phys. 2001; 51:1190-5. PubMed
 
Olsson AM, Persson CA, Swedish Sildenafil Investigators Group.  Efficacy and safety of sildenafil citrate for the treatment of erectile dysfunction in men with cardiovascular disease. Int J Clin Pract. 2001; 55:171-6. PubMed
 
Montorsi F, Maga T, Strambi LF, Salonia A, Barbieri L, Scattoni V. et al.  Sildenafil taken at bedtime significantly increases nocturnal erections: results of a placebo-controlled study. Urology. 2000; 56:906-11. PubMed
 
Cappelleri JC, Siegel RL, Osterloh IH, Rosen RC.  Relationship between patient self-assessment of erectile function and the erectile function domain of the international index of erectile function. Urology. 2000; 56:477-81. PubMed
 
Montorsi F, McDermott TE, Morgan R, Olsson A, Schultz A, Kirkeby HJ. et al.  Efficacy and safety of fixed-dose oral sildenafil in the treatment of erectile dysfunction of various etiologies. Urology. 1999; 53:1011-8. PubMed
 
Dinsmore WW, Hodges M, Hargreaves C, Osterloh IH, Smith MD, Rosen RC.  Sildenafil citrate (Viagra) in erectile dysfunction: near normalization in men with broad-spectrum erectile dysfunction compared with age-matched healthy control subjects. Urology. 1999; 53:800-5. PubMed
 
Padma-Nathan H, Steers WD, Wicker PA.  Efficacy and safety of oral sildenafil in the treatment of erectile dysfunction: a double-blind, placebo-controlled study of 329 patients. Sildenafil Study Group. Int J Clin Pract. 1998; 52:375-9. PubMed
 
Albuquerque DC, Miziara LJ, Saraiva JF, Rodrigues US, Ribeiro AB, Wajngarten M.  Efficacy, safety and tolerability of sildenafil in Brazilian hypertensive patients on multiple antihypertensive drugs. Int Braz J Urol. 2005;31:342-53; discussion 354-5. [PMID: 16137403]
 
Gingell C, Sultana SR, Wulff MB, Gepi-Attee S.  Duration of action of sildenafil citrate in men with erectile dysfunction. J Sex Med. 2004; 1:179-84. PubMed
 
Pickering TG, Shepherd AM, Puddey I, Glasser DB, Orazem J, Sherman N. et al.  Sildenafil citrate for erectile dysfunction in men receiving multiple antihypertensive agents: a randomized controlled trial. Am J Hypertens. 2004; 17:1135-42. PubMed
 
Glina S, Bertero E, Claro J, Damião R, Faria G, Fregnosi A. et al.  Efficacy and safety of sildenafil citrate for the treatment of erectile dysfunction in Latin America. Brazilian Journal of Urology. 2001; 27:148-54.
 
Heiman JR, Talley DR, Bailen JL, Oskin TA, Rosenberg SJ, Pace CR. et al.  Sexual function and satisfaction in heterosexual couples when men are administered sildenafil citrate (Viagra) for erectile dysfunction: a multicentre, randomised, double-blind, placebo-controlled trial. BJOG. 2007; 114:437-47. PubMed
 
Sommer F, Klotz T, Engelmann U.  Improved spontaneous erectile function in men with mild-to-moderate arteriogenic erectile dysfunction treated with a nightly dose of sildenafil for one year: a randomized trial. Asian J Androl. 2007; 9:134-41. PubMed
 
McVary KT, Monnig W, Camps JL Jr, Young JM, Tseng LJ, van den Ende G.  Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol. 2007; 177:1071-7. PubMed
 
Zinner N.  Do food and dose timing affect the efficacy of sildenafil? A randomized placebo-controlled study. J Sex Med. 2007; 4:137-44. PubMed
 
Orr G, Weiser M, Polliack M, Raviv G, Tadmor D, Grunhaus L.  Effectiveness of sildenafil in treating erectile dysfunction in PTSD patients: a double-blind, placebo-controlled crossover study. J Clin Psychopharmacol. 2006; 26:426-30. PubMed
 
Sharma RK, Prasad N, Gupta A, Kapoor R.  Treatment of erectile dysfunction with sildenafil citrate in renal allograft recipients: a randomized, double-blind, placebo-controlled, crossover trial. Am J Kidney Dis. 2006; 48:128-33. PubMed
 
Althof SE, O'Leary MP, Cappelleri JC, Hvidsten K, Stecher VJ, Glina S, et al. International SEAR Study Group.  Sildenafil citrate improves self-esteem, confidence, and relationships in men with erectile dysfunction: Results from an international, multi-center, double-blind, placebo-controlled trial. J Sex Med. 2006; 3:521-9. PubMed
 
Fava M, Nurnberg HG, Seidman SN, Holloway W, Nicholas S, Tseng LJ. et al.  Efficacy and safety of sildenafil in men with serotonergic antidepressant-associated erectile dysfunction: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2006; 67:240-6. PubMed
 
Gopalakrishnan R, Jacob KS, Kuruvilla A, Vasantharaj B, John JK.  Sildenafil in the treatment of antipsychotic-induced erectile dysfunction: a randomized, double-blind, placebo-controlled, flexible-dose, two-way crossover trial. Am J Psychiatry. 2006; 163:494-9. PubMed
 
O'Leary MP, Althof SE, Cappelleri JC, Crowley A, Sherman N, Duttagupta S, United States Self-Esteem and Relationship Questionnaire Study Group.  Self-esteem, confidence and relationship satisfaction of men with erectile dysfunction treated with sildenafil citrate: a multicenter, randomized, parallel group, double-blind, placebo controlled study in the United States. J Urol. 2006; 175:1058-62. PubMed
 
Koulikov D, Fridmans A, Chertin B, Shenfeld O, Farkas A, Spitz IM.  Is sildenafil citrate associated with an amelioration of the symptomatology of androgen decline in the aging male? J Urol. 2007; 177:2267-71. PubMed
 
Buranakitjaroen P, Mangklabruks A, Leungwattanakij S, Ngaothamatasn W, Malhotra C, Chee C, et al. Thai-Malaysian-Singapore Erectile Dysfunction Study Group (THAMES Group).  Efficacy and safety of sildenafil in Asian males with erectile dysfunction and cardiovascular risk. J Med Assoc Thai. 2007; 90:1100-8. PubMed
 
Bannowsky A, Schulze H, van der Horst C, Hautmann S, Jünemann KP.  Recovery of erectile function after nerve-sparing radical prostatectomy: improvement with nightly low-dose sildenafil. BJU Int. 2008; 101:1279-83. PubMed
 
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; 178:613-6. PubMed
 
Hundertmark J, Esterman A, Ben-Tovim D, Austin MA, Dougherty M.  The South Australian couples sildenafil study: double-blind, parallel-group randomized controlled study to examine the psychological and relationship consequences of sildenafil use in couples. J Sex Med. 2007; 4:1126-35. PubMed
 
Kadioglu A, Grohmann W, Depko A, Levinson IP, Sun F, Collins S.  Quality of erections in men treated with flexible-dose sildenafil for erectile dysfunction: multicenter trial with a double-blind, randomized, placebo-controlled phase and an open-label phase. J Sex Med. 2008; 5:726-34. PubMed
 
Jones LA, Klimberg IW, McMurray JG, Padula R, Tseng LJ, Stecher VJ.  Effect of sildenafil citrate on the male sexual experience assessed with the Sexual Experience Questionnaire: a multicenter, double-blind, placebo-controlled trial with open-label extension. J Sex Med. 2008; 5:1955-64. PubMed
 
McCullough AR, Levine LA, Padma-Nathan H.  Return of nocturnal erections and erectile function after bilateral nerve-sparing radical prostatectomy in men treated nightly with sildenafil citrate: subanalysis of a longitudinal randomized double-blind placebo-controlled trial. J Sex Med. 2008; 5:476-84. PubMed
 
McCullough AR, Steidle CP, Klee B, Tseng LJ.  Randomized, double-blind, crossover trial of sildenafil in men with mild to moderate erectile dysfunction: efficacy at 8 and 12 hours postdose. Urology. 2008; 71:686-92. PubMed
 
McCullough AR, Steidle CP, Kaufman J, Goldfischer ER, Klee B, Carlsson M.  Sildenafil citrate efficacy 8 h postdose in men with mild to moderate erectile dysfunction. Int J Impot Res. 2008; 20:388-95. PubMed
 
Morano S, Mandosi E, Fallarino M, Gatti A, Tiberti C, Sensi M. et al.  Antioxidant treatment associated with sildenafil reduces monocyte activation and markers of endothelial damage in patients with diabetic erectile dysfunction: a double-blind, placebo-controlled study. Eur Urol. 2007; 52:1768-74. PubMed
 
Buvat J, Hatzichristou D, Maggi M, Farmer I, Martínez-Jabaloyas JM, Miller PJ. et al.  Efficacy, tolerability and satisfaction with sildenafil citrate 100-mg titration compared with continued 50-mg dose treatment in men with erectile dysfunction. BJU Int. 2008; 102:1645-50. PubMed
 
Safarinejad MR.  Evaluation of the safety and efficacy of sildenafil citrate for erectile dysfunction in men with multiple sclerosis: a double-blind, placebo controlled, randomized study. J Urol. 2009; 181:252-8. PubMed
 
Burnett AL, Strong TD, Trock BJ, Jin L, Bivalacqua TJ, Musicki B.  Serum biomarker measurements of endothelial function and oxidative stress after daily dosing of sildenafil in type 2 diabetic men with erectile dysfunction. J Urol. 2009; 181:245-51. PubMed
 
Goldstein I, Young JM, Fischer J, Bangerter K, Segerson T, Taylor T, Vardenafil Diabetes Study Group.  Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: a multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care. 2003; 26:777-83. PubMed
 
Valiquette L, Young JM, Moncada I, Porst H, Vézina JG, Stancil BN, et al. Vardenafil Study Group.  Sustained efficacy and safety of vardenafil for treatment of erectile dysfunction: a randomized, double-blind, placebo-controlled study. Mayo Clin Proc. 2005; 80:1291-7. PubMed
 
Nehra A, Grantmyre J, Nadel A, Thibonnier M, Brock G.  Vardenafil improved patient satisfaction with erectile hardness, orgasmic function and sexual experience in men with erectile dysfunction following nerve sparing radical prostatectomy. J Urol. 2005; 173:2067-71. PubMed
 
Carson CC, Hatzichristou DG, Carrier S, Lording D, Lyngdorf P, Aliotta P, et al. Patient Response with Vardenafil in Slidenafil Non-Responders (PROVEN) Study Group.  Erectile response with vardenafil in sildenafil nonresponders: a multicentre, double-blind, 12-week, flexible-dose, placebo-controlled erectile dysfunction clinical trial. BJU Int. 2004; 94:1301-9. PubMed
 
Nagao K, Ishii N, Kamidono S, Osada T, Vardenafil (Levitra) Clinical Trial Group.  Safety and efficacy of vardenafil in patients with erectile dysfunction: result of a bridging study in Japan. Int J Urol. 2004; 11:515-24. PubMed
 
Stief C, Porst H, Sáenz De Tejada I, Ulbrich E, Beneke M, Vardenafil Study Group.  Sustained efficacy and tolerability with vardenafil over 2 years of treatment in men with erectile dysfunction. Int J Clin Pract. 2004; 58:230-9. PubMed
 
Hatzichristou D, Montorsi F, Buvat J, Laferriere N, Bandel TJ, Porst H; European Vardenafil Study Group.  The efficacy and safety of flexible-dose vardenafil (levitra) in a broad population of European men. Eur Urol. 2004;45:634-41; discussion 641. [PMID: 15082207]
 
Hellstrom WJ, Gittelman M, Karlin G, Segerson T, Thibonnier M, Taylor T. et al.  Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized, double-blind, placebo-controlled trial. J Androl. 2002; 23:763-71. PubMed
 
Stark S, Sachse R, Liedl T, Hensen J, Rohde G, Wensing G, et al.  Vardenafil increases penile rigidity and tumescence in men with erectile dysfunction after a single oral dose. Eur Urol. 2001;40:181-8; discussion 189-90. [PMID: 11528196]
 
Porst H, Rosen R, Padma-Nathan H, Goldstein I, Giuliano F, Ulbrich E. et al.  The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial. Int J Impot Res. 2001; 13:192-9. PubMed
 
Klotz T, Sachse R, Heidrich A, Jockenhövel F, Rohde G, Wensing G. et al.  Vardenafil increases penile rigidity and tumescence in erectile dysfunction patients: a RigiScan and pharmacokinetic study. World J Urol. 2001; 19:32-9. PubMed
 
van Ahlen H, Wahle K, Kupper W, Yassin A, Reblin T, Neureither M.  Safety and efficacy of vardenafil, a selective phosphodiesterase 5 inhibitor, in patients with erectile dysfunction and arterial hypertension treated with multiple antihypertensives. J Sex Med. 2005; 2:856-64. PubMed
 
Goldstein I, Fisher WA, Sand M, Rosen RC, Mollen M, Brock G, et al. Vardenafil Study Group.  Women's sexual function improves when partners are administered vardenafil for erectile dysfunction: a prospective, randomized, double-blind, placebo-controlled trial. J Sex Med. 2005; 2:819-32. PubMed
 
Rosen R, Shabsigh R, Berber M, Assalian P, Menza M, Rodriguez-Vela L, et al. Vardenafil Study Site Investigators.  Efficacy and tolerability of vardenafil in men with mild depression and erectile dysfunction: the depression-related improvement with vardenafil for erectile response study. Am J Psychiatry. 2006; 163:79-87. PubMed
 
Martin-Morales A, Meijide F, García N, Artes M, Muñoz A.  Efficacy of vardenafil and influence on self-esteem and self-confidence in patients with severe erectile dysfunction. J Sex Med. 2007; 4:440-7. PubMed
 
Edwards D, Hackett G, Collins O, Curram J.  Vardenafil improves sexual function and treatment satisfaction in couples affected by erectile dysfunction (ED): a randomized, double-blind, placebo-controlled trial in PDE5 inhibitor-naïve men with ED and their partners. J Sex Med. 2006; 3:1028-36. PubMed
 
Porst H, Sharlip ID, Hatzichristou D, Rubio-Aurioles E, Gittelman M, Stancil BN, et al; Vardenafil Study Group.  Extended duration of efficacy of vardenafil when taken 8 hours before intercourse: a randomized, double-blind, placebo-controlled study. Eur Urol. 2006;50:1086-94; discussion 1094-5. [PMID: 16820261]
 
Mazo E, Gamidov S, Iremashvili V.  The effect of vardenafil on endothelial function of brachial and cavernous arteries. Int J Impot Res. 2006; 18:464-9. PubMed
 
Ziegler D, Merfort F, van Ahlen H, Yassin A, Reblin T, Neureither M.  Efficacy and safety of flexible-dose vardenafil in men with type 1 diabetes and erectile dysfunction. J Sex Med. 2006; 3:883-91. PubMed
 
Ishii N, Nagao K, Fujikawa K, Tachibana T, Iwamoto Y, Kamidono S.  Vardenafil 20-mg demonstrated superior efficacy to 10-mg in Japanese men with diabetes mellitus suffering from erectile dysfunction. Int J Urol. 2006; 13:1066-72. PubMed
 
Demir E, Balal M, Paydas S, Sertdemir Y, Erken U.  Efficacy and safety of vardenafil in renal transplant recipients with erectile dysfunction. Transplant Proc. 2006; 38:1379-81. PubMed
 
Zumbé J, Porst H, Sommer F, Grohmann W, Beneke M, Ulbrich E.  Comparable efficacy of once-daily versus on-demand vardenafil in men with mild-to-moderate erectile dysfunction: findings of the RESTORE study. Eur Urol. 2008; 54:204-10. PubMed
 
Ralph D, Eardley I, Kell P, Dean J, Hackett G, Collins O. et al.  Improvement in erectile function on vardenafil treatment correlates with treatment satisfaction in both patients and their partners. BJU Int. 2007; 100:130-6. PubMed
 
Montorsi F, Brock G, Lee J, Shapiro J, Van Poppel H, Graefen M. et al.  Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. Eur Urol. 2008; 54:924-31. PubMed
 
Tan HM, Chin CM, Chua CB, Gatchalian E, Kongkanand A, Moh CL. et al.  Efficacy and tolerability of vardenafil in Asian men with erectile dysfunction. Asian J Androl. 2008; 10:495-502. PubMed
 
Miner M, Gilderman L, Bailen J, Cook D, Dawson K, Stanislaus M. et al.  Vardenafil in men with stable statin therapy and dyslipidemia. J Sex Med. 2008; 5:1455-67. PubMed
 
Mirone V, Costa P, Damber JE, Holmes S, Moncada I, Van Ahlen H, et al.  An evaluation of an alternative dosing regimen with tadalafil, 3 times/week, for men with erectile dysfunction: SURE study in 14 European countries. Eur Urol. 2005;47:846-54; discussion 854. [PMID: 15925082]
 
Young JM, Feldman RA, Auerbach SM, Kaufman JM, Garcia CS, Shen W. et al.  Tadalafil improved erectile function at twenty-four and thirty-six hours after dosing in men with erectile dysfunction: US trial. J Androl. 2005; 26:310-8. PubMed
 
McMahon CG, Stuckey BG, Lording DW, Wittert GA, Murphy A, Shin J. et al.  A 6-month study of the efficacy and safety of tadalafil in the treatment of erectile dysfunction: a randomised, double-blind, parallel-group, placebo-controlled study in Australian men. Int J Clin Pract. 2005; 59:143-9. PubMed
 
Carson C, Shabsigh R, Segal S, Murphy A, Fredlund P, Kuepfer C, Trial Evaluating the Activity of Tadalafil for Erectile Dysfunction-United States (TREATED-US) Study Group.  Efficacy, safety, and treatment satisfaction of tadalafil versus placebo in patients with erectile dysfunction evaluated at tertiary-care academic centers. Urology. 2005; 65:353-9. PubMed
 
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 220-2. [PMID: 15661417]
 
De Rose AF, Gallo F, Carmignani G.  Evaluation of sexual activity in patients treated with tadalafil: a randomized prospective placebo-controlled trial. Int J Impot Res. 2005; 17:76-9. PubMed
 
Eardley I, Gentile V, Austoni E, Hackett G, Lembo D, Wang C. et al.  Efficacy and safety of tadalafil in a Western European population of men with erectile dysfunction. BJU Int. 2004; 94:871-7. PubMed
 
Staab A, Tillmann C, Forgue ST, Mackie A, Allerheiligen SR, Rapado J. et al.  Population dose-response model for tadalafil in the treatment of male erectile dysfunction. Pharm Res. 2004; 21:1463-70. PubMed
 
Montorsi F, Nathan HP, McCullough A, Brock GB, Broderick G, Ahuja S. et al.  Tadalafil in the treatment of erectile dysfunction following bilateral nerve sparing radical retropubic prostatectomy: a randomized, double-blind, placebo controlled trial. J Urol. 2004; 172:1036-41. PubMed
 
Skoumal R, Chen J, Kula K, Breza J, Calomfirescu N, Basson BR. et al.  Efficacy and treatment satisfaction with on-demand tadalafil (Cialis) in men with erectile dysfunction. Eur Urol. 2004; 46:362-9. PubMed
 
Seftel AD, Wilson SK, Knapp PM, Shin J, Wang WC, Ahuja S.  The efficacy and safety of tadalafil in United States and Puerto Rican men with erectile dysfunction. J Urol. 2004; 172:652-7. PubMed
 
Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R.  Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology. 2003;62:121-5; discussion 125-6. [PMID: 12837435]
 
Sáenz de Tejada I, Anglin G, Knight JR, Emmick JT.  Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care. 2002; 25:2159-64. PubMed
 
Carrier S, Brock GB, Pommerville PJ, Shin J, Anglin G, Whitaker S. et al.  Efficacy and safety of oral tadalafil in the treatment of men in Canada with erectile dysfunction: a randomized, double-blind, parallel, placebo-controlled clinical trial. J Sex Med. 2005; 2:685-98. PubMed
 
McMahon C.  Comparison of efficacy, safety, and tolerability of on-demand tadalafil and daily dosed tadalafil for the treatment of erectile dysfunction. J Sex Med. 2005;2:415-25; discussion 425-7. [PMID: 16422874]
 
Chen KK, Jiann BP, Lin JS, Lee SS, Huang ST, Wang CJ. et al.  Efficacy and safety of on-demand oral tadalafil in the treatment of men with erectile dysfunction in Taiwan: a randomized, double-blind, parallel, placebo-controlled clinical study. J Sex Med. 2004; 1:201-8. PubMed
 
Rosen RC, Padma-Nathan H, Shabsigh R, Saikali K, Watkins V, Pullman W.  Determining the earliest time within 30 minutes to erectogenic effect after tadalafil 10 and 20 mg: a multicenter, randomized, double-blind, placebo-controlled, at-home study. J Sex Med. 2004; 1:193-200. PubMed
 
Aversa A, Greco E, Bruzziches R, Pili M, Rosano G, Spera G.  Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: a pilot study. Int J Impot Res. 2007; 19:200-7. PubMed
 
McVary KT, Roehrborn CG, Kaminetsky JC, Auerbach SM, Wachs B, Young JM. et al.  Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007; 177:1401-7. PubMed
 
Saylan M, Khalaf I, Kadioglu A, Shoair KZ, Beheiry A, Wang WC. et al.  Efficacy of tadalafil in Egyptian and Turkish men with erectile dysfunction. Int J Clin Pract. 2006; 60:812-9. PubMed
 
Rajfer J, Aliotta PJ, Steidle CP, Fitch WP 3rd, Zhao Y, Yu A.  Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study in the US. Int J Impot Res. 2007; 19:95-103. PubMed
 
Yip WC, Chiang HS, Mendoza JB, Tan HM, Li MK, Wang WC. et al.  Efficacy and safety of on demand tadalafil in the treatment of East and Southeast Asian men with erectile dysfunction: a randomized double-blind, parallel, placebo-controlled clinical study. Asian J Androl. 2006; 8:685-92. PubMed
 
Guo YL, Zhu JC, Pan TM, Ding Q, Wang YX, Cheong NF. et al.  Efficacy and safety of on-demand tadalafil for the treatment of erectile dysfunction in South-East Asian men. Int J Urol. 2006; 13:721-7. PubMed
 
Nagao K, Kimoto Y, Marumo K, Tsujimura A, Vail GM, Watts S. et al.  Efficacy and safety of tadalafil 5, 10, and 20 mg in Japanese men with erectile dysfunction: results of a multicenter, randomized, double-blind, placebo-controlled study. Urology. 2006; 68:845-51. PubMed
 
Incrocci L, Slagter C, Slob AK, Hop WC.  A randomized, double-blind, placebo-controlled, cross-over study to assess the efficacy of tadalafil (Cialis) in the treatment of erectile dysfunction following three-dimensional conformal external-beam radiotherapy for prostatic carcinoma. Int J Radiat Oncol Biol Phys. 2006; 66:439-44. PubMed
 
Choi HK, Kim JJ, Kim SC, Suh J, Park YK, Choi S. et al.  A randomised, double-blind, parallel, placebo-controlled study of the efficacy and safety of Tadalafil administered on-demand to men with erectile dysfunction in Korea. Taehan Pinyogikwa Hakhoe Chapchi. 2006; 47:852-58.
 
Bocchio M, Pelliccione F, Passaquale G, Mihalca R, Necozione S, Desideri G. et al.  Inhibition of phosphodiesterase type 5 with tadalafil is associated to an improved activity of circulating angiogenic cells in men with cardiovascular risk factors and erectile dysfunction. Atherosclerosis. 2008; 196:313-9. PubMed
 
Hatzichristou D, Gambla M, Rubio-Aurioles E, Buvat J, Brock GB, Spera G. et al.  Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction. Diabet Med. 2008; 25:138-46. PubMed
 
Paick JS, Ahn TY, Choi HK, Chung WS, Kim JJ, Kim SC. et al.  Efficacy and safety of mirodenafil, a new oral phosphodiesterase type 5 inhibitor, for treatment of erectile dysfunction. J Sex Med. 2008; 5:2672-80. PubMed
 
Paick JS, Choi HK, Kim SC, Ahn TY, Kim JJ, Park JK. et al.  Efficacy and safety of oral SK3530 for the treatment of erectile dysfunction in Korean men: a multicenter, randomized, double-blind, placebo-controlled, fixed dose, parallel group clinical trial. Asian J Androl. 2008; 10:791-8. PubMed
 
Paick JS, Kim SW, Yang DY, Kim JJ, Lee SW, Ahn TY. et al.  The efficacy and safety of udenafil, a new selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction. J Sex Med. 2008; 5:946-53. PubMed
 
Eardley I, Mirone V, Montorsi F, Ralph D, Kell P, Warner MR. et al.  An open-label, multicentre, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in men naïve to phosphodiesterase 5 inhibitor therapy. BJU Int. 2005; 96:1323-32. PubMed
 
von Keitz A, Rajfer J, Segal S, Murphy A, Denne J, Costigan T, et al.  A multicenter, randomized, double-blind, crossover study to evaluate patient preference between tadalafil and sildenafil. Eur Urol. 2004;45:499-507; discussion 507-9. [PMID: 15041116]
 
Govier F, Potempa AJ, Kaufman J, Denne J, Kovalenko P, Ahuja S.  A multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction. Clin Ther. 2003; 25:2709-23. PubMed
 
Tolrà JR, Campaña JM, Ciutat LF, Miranda EF.  Prospective, randomized, open-label, fixed-dose, crossover study to establish preference of patients with erectile dysfunction after taking the three PDE-5 inhibitors. J Sex Med. 2006; 3:901-9. PubMed
 
Cavallini G, Modenini F, Vitali G, Koverech A.  Acetyl-L-carnitine plus propionyl-L-carnitine improve efficacy of sildenafil in treatment of erectile dysfunction after bilateral nerve-sparing radical retropubic prostatectomy. Urology. 2005; 66:1080-5. PubMed
 
Akash R, Hrishikesh D, Amith P, Sabah S.  Case report: association of combined nonarteritic anterior ischemic optic neuropathy (NAION) and obstruction of cilioretinal artery with overdose of Viagra. J Ocul Pharmacol Ther. 2005; 21:315-7. PubMed
 
Cunningham AV, Smith KH.  Anterior ischemic optic neuropathy associated with viagra. J Neuroophthalmol. 2001; 21:22-5. PubMed
 
Dheer S, Rekhi GS, Merlyn S.  Sildenafil associated anterior ischaemic optic neuropathy. J Assoc Physicians India. 2002; 50:265. PubMed
 
Egan R, Pomeranz H.  Sildenafil (Viagra) associated anterior ischemic optic neuropathy. Arch Ophthalmol. 2000; 118:291-2. PubMed
 
Gedik S, Yilmaz G, Akova YA.  Sildenafil-associated consecutive nonarteritic anterior ischaemic optic neuropathy, cilioretinal artery occlusion, and central retinal vein occlusion in a haemodialysis patient [Letter]. Eye. 2007; 21:129-30. PubMed
 
Gruhn N, Fledelius HC.  Unilateral optic neuropathy associated with sildenafil intake [Letter]. Acta Ophthalmol Scand. 2005; 83:131-2. PubMed
 
Sinha S, Pathak-Ray V, Ahluwalia H, Morgan JE.  Viagra or what? [Letter]. Eye. 2004; 18:446-8. PubMed
 
Gupta B, Paul S, Sharma V, Natha S.  Visual field loss after tadalafil: a case report [Letter]. Acta Ophthalmol. 2008; 86:924-5. PubMed
 
Pepin S, Pitha-Rowe I.  Stepwise decline in visual field after serial sildenafil use [Letter]. J Neuroophthalmol. 2008; 28:76-7. PubMed
 
Su DH, Ang PS, Tow SL.  Bilateral posterior ischemic optic neuropathy associated with use of sildenafil [Letter]. J Neuroophthalmol. 2008; 28:75. PubMed
 
Pomeranz HD, Smith KH, Hart WM Jr, Egan RA.  Sildenafil-associated nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 2002; 109:584-7. PubMed
 
Pomeranz HD, Bhavsar AR.  Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (viagra): a report of seven new cases. J Neuroophthalmol. 2005; 25:9-13. PubMed
 
Margo CE, French DD.  Ischemic optic neuropathy in male veterans prescribed phosphodiesterase-5 inhibitors. Am J Ophthalmol. 2007; 143:538-9. PubMed
 
McEvoy GK.  Atenolol: AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2008.
 
Haren M, Chapman I, Coates P, Morley J, Wittert G.  Effect of 12 month oral testosterone on testosterone deficiency symptoms in symptomatic elderly males with low-normal gonadal status. Age Ageing. 2005; 34:125-30. PubMed
 
Seftel AD, Mack RJ, Secrest AR, Smith TM.  Restorative increases in serum testosterone levels are significantly correlated to improvements in sexual functioning. J Androl. 2004; 25:963-72. PubMed
 
Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H.  Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J Urol. 2004; 172:658-63. PubMed
 
Cavallini G, Caracciolo S, Vitali G, Modenini F, Biagiotti G.  Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging. Urology. 2004; 63:641-6. PubMed
 
Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A.  Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction. Clin Endocrinol (Oxf). 2003; 58:632-8. PubMed
 
Clopper RR, Voorhess ML, MacGillivray MH, Lee PA, Mills B.  Psychosexual behavior in hypopituitary men: a controlled comparison of gonadotropin and testosterone replacement. Psychoneuroendocrinology. 1993; 18:149-61. PubMed
 
Boyanov MA, Boneva Z, Christov VG.  Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male. 2003; 6:1-7. PubMed
 
Rabkin JG, Wagner GJ, Rabkin R.  A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms. Arch Gen Psychiatry. 2000;57:141-7; discussion 155-6. [PMID: 10665616]
 
Shamloul R, Ghanem H, Fahmy I, El-Meleigy A, Ashoor S, Elnashaar A. et al.  Testosterone therapy can enhance erectile function response to sildenafil in patients with PADAM: a pilot study. J Sex Med. 2005; 2:559-64. PubMed
 
Schiavi RC, White D, Mandeli J, Levine AC.  Effect of testosterone administration on sexual behavior and mood in men with erectile dysfunction. Arch Sex Behav. 1997; 26:231-41. PubMed
 
Yassin AA, Saad F, Diede HE.  Testosterone and erectile function in hypogonadal men unresponsive to tadalafil: results from an open-label uncontrolled study. Andrologia. 2006; 38:61-8. PubMed
 
Seidman SN, Roose SP.  The sexual effects of testosterone replacement in depressed men: randomized, placebo-controlled clinical trial. J Sex Marital Ther. 2006; 32:267-73. PubMed
 
Gomaa AA, Hamed HA.  Improvement of sexual function in partial testosterone-deficient ageing men treated with cream containing testosterone and vasoactive agents. J Mens Health Gend. 2006; 3:47-55.
 
Merza Z, Blumsohn A, Mah PM, Meads DM, McKenna SP, Wylie K. et al.  Double-blind placebo-controlled study of testosterone patch therapy on bone turnover in men with borderline hypogonadism. Int J Androl. 2006; 29:381-91. PubMed
 
Chiang HS, Hwang TI, Hsui YS, Lin YC, Chen HE, Chen GC. et al.  Transdermal testosterone gel increases serum testosterone levels in hypogonadal men in Taiwan with improvements in sexual function. Int J Impot Res. 2007; 19:411-7. PubMed
 
Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, et al. Testosterone Gel Study Group.  Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab. 2000; 85:2839-53. PubMed
 
McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones .  A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. BJU Int. 2003; 91:69-74. PubMed
 
Citron JT, Ettinger B, Rubinoff H, Ettinger VM, Minkoff J, Hom F. et al.  Prevalence of hypothalamic-pituitary imaging abnormalities in impotent men with secondary hypogonadism. J Urol. 1996; 155:529-33. PubMed
 
Hatzichristou D, Hatzimouratidis K, Bekas M, Apostolidis A, Tzortzis V, Yannakoyorgos K.  Diagnostic steps in the evaluation of patients with erectile dysfunction. J Urol. 2002; 168:615-20. PubMed
 
Martínez-Jabaloyas JM, Queipo-Zaragozá A, Pastor-Hernández F, Gil-Salom M, Chuan-Nuez P.  Testosterone levels in men with erectile dysfunction. BJU Int. 2006; 97:1278-83. PubMed
 
Acar D, Cayan S, Bozlu M, Akbay E.  Is routine hormonal measurement necessary in initial evaluation of men with erectile dysfunction? Arch Androl. 2004; 50:247-53. PubMed
 
Earle CM, Stuckey BG.  Biochemical screening in the assessment of erectile dysfunction: what tests decide future therapy? Urology. 2003; 62:727-31. PubMed
 
Rhoden EL, Telöken C, Mafessoni R, Souto CA.  Is there any relation between serum levels of total testosterone and the severity of erectile dysfunction? Int J Impot Res. 2002; 14:167-71. PubMed
 
Rhoden EL, Telöken C, Sogari PR, Souto CA.  The relationship of serum testosterone to erectile function in normal aging men. J Urol. 2002; 167:1745-8. PubMed
 
Bunch TJ, Abraham D, Wang S, Meikle AW.  Pituitary radiographic abnormalities and clinical correlates of hypogonadism in elderly males presenting with erectile dysfunction. Aging Male. 2002; 5:38-46. PubMed
 
Fahmy AK, Mitra S, Blacklock AR, Desai KM.  Is the measurement of serum testosterone routinely indicated in men with erectile dysfunction? BJU Int. 1999; 84:482-4. PubMed
 
Akpunonu BE, Mutgi AB, Federman DJ, York J, Woldenberg LS.  Routine prolactin measurement is not necessary in the initial evaluation of male impotence. J Gen Intern Med. 1994; 9:336-8. PubMed
 
Drinka PJ, Voeks S, Bauwens S, Binkley N.  Sensitivity and positive predictive value of clinical signs of hypogonadism in elderly men. South Med J. 1993; 86:1264-5. PubMed
 
El-Sakka AI, Hassoba HM, Sayed HM, Tayeb KA.  Pattern of endocrinal changes in patients with sexual dysfunction. J Sex Med. 2005; 2:551-8. PubMed
 
Tsujimura A, Matsumiya K, Miyagawa Y, Takao T, Fujita K, Takada S. et al.  Comparative study on evaluation methods for serum testosterone level for PADAM diagnosis. Int J Impot Res. 2005; 17:259-63. PubMed
 
Guay AT, Bansal S, Hodge MB.  Possible hypothalamic impotence. Male counterpart to hypothalamic amenorrhea? Urology. 1991; 38:317-22. PubMed
 
Forsberg L, Gustavii B, Höjerback T, Nilsson A, Olsson AM.  One hundred impotent men. Scand J Urol Nephrol. 1990; 24:83-7. PubMed
 
Reyes-Vallejo L, Lazarou S, Morgentaler A.  Subjective sexual response to testosterone replacement therapy based on initial serum levels of total testosterone. J Sex Med. 2007; 4:1757-62. PubMed
 
El-Sakka AI, Hassoba HM.  Age related testosterone depletion in patients with erectile dysfunction. J Urol. 2006; 176:2589-93. PubMed
 
Low WY, Khoo EM, Tan HM, Hew FL, Teoh SH.  Depression, hormonal status and erectile dysfunction in the aging male: results from a community study in Malaysia. J Mens Health Gend. 2006; 3:263-70.
 
Guay A, Jacobson J.  The relationship between testosterone levels, the metabolic syndrome (by two criteria), and insulin resistance in a population of men with organic erectile dysfunction. J Sex Med. 2007; 4:1046-55. PubMed
 
Zohdy W, Kamal EE, Ibrahim Y.  Androgen deficiency and abnormal penile duplex parameters in obese men with erectile dysfunction. J Sex Med. 2007; 4:797-808. PubMed
 
Araujo AB, Esche GR, Kupelian V, O'Donnell AB, Travison TG, Williams RE. et al.  Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007; 92:4241-7. PubMed
 
Kupelian V, Shabsigh R, Travison TG, Page ST, Araujo AB, McKinlay JB.  Is there a relationship between sex hormones and erectile dysfunction? Results from the Massachusetts Male Aging Study. J Urol. 2006; 176:2584-8. PubMed
 
El-Sakka AI.  Association of risk factors and medical comorbidities with male sexual dysfunctions. J Sex Med. 2007; 4:1691-700. PubMed
 
Makhlouf AA, Mohamed MA, Seftel AD, Niederberger C, Neiderberger C.  Hypogonadism is associated with overt depression symptoms in men with erectile dysfunction. Int J Impot Res. 2008; 20:157-61. PubMed
 
Köhler TS, Kim J, Feia K, Bodie J, Johnson N, Makhlouf A. et al.  Prevalence of androgen deficiency in men with erectile dysfunction. Urology. 2008; 71:693-7. PubMed
 
Corona G, Mannucci E, Fisher AD, Lotti F, Petrone L, Balercia G. et al.  Low levels of androgens in men with erectile dysfunction and obesity. J Sex Med. 2008; 5:2454-63. PubMed
 
Müezzinoğu T, Gümüş B, Temeltaş G, Ari Z, Büyüksu C.  A relationship of sex hormone levels and erectile dysfunction: which tests should be done routinely? Yonsei Med J. 2007; 48:1015-9. PubMed
 
Netto Júnior NR, Claro Jde A.  The importance of hyperprolactinemia in impotence. Rev Paul Med. 1993; 111:454-5. PubMed
 
Umrani DN, Goyal RK.  Pharmacology of sildenafil citrate. Indian J Physiol Pharmacol. 1999; 43:160-4. PubMed
 
Moher D, Schulz KF, Altman DG, CONSORT GROUP (Consolidated Standards of Reporting Trials).  The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. Ann Intern Med. 2001; 134:657-62. PubMed
 
Swerdloff RS, Wang C.  Androgens and the ageing male. Best Pract Res Clin Endocrinol Metab. 2004; 18:349-62. PubMed
 

Figures

Grahic Jump Location
Appendix Figure 1.
Literature search and selection.

NAION = nonarteritic anterior ischemic optic neuropathy.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.
Improvement in erections: sildenafil versus placebo.

CAD = coronary artery disease; CVD = cardiovascular disease; RR = relative risk.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 3.
Improvement in erections: vardenafil versus placebo.

RR = relative risk.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 4.
Improvement in erections: tadalafil versus placebo.

RR = relative risk.

Grahic Jump Location

Tables

Table Jump PlaceholderTable 1.  Summary of Findings of Effectiveness
Table Jump PlaceholderTable 2.  Summary of Findings on AEs

Videos

Video News Release - Guideline on the Benefits and Risks of PED-5 Inhibitor Drugs

References

NIH Consensus Conference.  Impotence. NIH Consensus Development Panel on Impotence. JAMA. 1993; 270:83-90. PubMed
CrossRef
 
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. PubMed
 
Virag R.  Indications and early results of sildenafil (Viagra) in erectile dysfunction. Urology. 1999; 54:1073-7. PubMed
 
Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB.  Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts male aging study. J Urol. 2000; 163:460-3. PubMed
 
Montague DK, Jarow JP, Broderick GA, Dmochowski RR, Heaton JP, Lue TF, et al. Erectile Dysfunction Guideline Update Panel.  Chapter 1: The management of erectile dysfunction: an AUA update. J Urol. 2005; 174:230-9. PubMed
 
Porst H.  The rationale for prostaglandin E1 in erectile failure: a survey of worldwide experience. J Urol. 1996; 155:802-15. PubMed
 
Fazio L, Brock G.  Erectile dysfunction: management update. CMAJ. 2004; 170:1429-37. PubMed
 
Wessells H, Joyce GF, Wise M, Wilt TJ.  Erectile dysfunction. J Urol. 2007; 177:1675-81. PubMed
 
Bayer Annual Report 2005. Leverkusen, Germany: Bayer AG; 2006. Accessed atwww.bayer.com/en/GB-2005-en.pdfxon 21 September 2009.
 
Eli Lilly Annual Report 2005. Indianapolis: Eli Lilly; 2006. Accessed athttp://investor.lilly.com/annuals.cfmon 22 May 2009.
 
Pfizer Annual Report 2005. New York: Pfizer; 2006. Accessed athttp://media.pfizer.com/files/annualreport/2005/annual/review2005.pdfon 21 September 2009.
 
Burnett AL, Johns DG, Kriegsfeld LJ, Klein SL, Calvin DC, Demas GE. et al.  Ejaculatory abnormalities in mice with targeted disruption of the gene for heme oxygenase-2. Nat Med. 1998; 4:84-7. PubMed
 
Johnson AR 3rd, Jarow JP.  Is routine endocrine testing of impotent men necessary? J Urol. 1992;147:1542-3; discussion 1543-4. [PMID: 1593685]
 
Noldus J, Huland H.  [Erectile dysfunction and hypogonadism. Is routine endocrine screening necessary?]. Urologe A. 1994; 33:73-5. PubMed
 
Buvat J, Lemaire A.  Endocrine screening in 1,022 men with erectile dysfunction: clinical significance and cost-effective strategy. J Urol. 1997; 158:1764-7. PubMed
 
Bancroft J, Wu FC.  Changes in erectile responsiveness during androgen replacement therapy. Arch Sex Behav. 1983; 12:59-66. PubMed
 
Morelli A, Filippi S, Mancina R, Luconi M, Vignozzi L, Marini M. et al.  Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Endocrinology. 2004; 145:2253-63. PubMed
 
Aversa A, Isidori AM, De Martino MU, Caprio M, Fabbrini E, Rocchietti-March M. et al.  Androgens and penile erection: evidence for a direct relationship between free testosterone and cavernous vasodilation in men with erectile dysfunction. Clin Endocrinol (Oxf). 2000; 53:517-22. PubMed
 
Wespes E, Amar E, Hatzichristou D, Hatzimouratidis K, Montorsi F, Pryor J, et al. EAU.  EAU Guidelines on erectile dysfunction: an update. Eur Urol. 2006; 49:806-15. PubMed
 
Lue TF, Broderick G.  Evaluation and nonsurgical management of erectile dysfunction and priapism. Walsh P, Retik A, Vaughan E Campbell's Urology. 7th ed. Philadelphia: Saunders; 1998; 1181-214.
 
Miller TA.  Diagnostic evaluation of erectile dysfunction. Am Fam Physician. 2000; 61. PubMed
 
Tsertsvadze A, Yazdi F, Fink HA, MacDonald R, Wilt TJ, Soares-Weiser K, et al.  Diagnosis and Treatment of Erectile Dysfunction. AHRQ Evidence Report/Technology Assessment no. 171. Bethesda, MD: Agency for Healthcare Research and Quality; May 2009. AHRQ publication no. 08(09)-E016. Accessed atwww.ahrq.gov/downloads/pub/evidence/pdf/erectiledys/erecdys.pdfon 26 May 2009.
 
Montorsi F, Padma-Nathan H, Buvat J, Schwaibold H, Beneke M, Ulbrich E, et al. Vardenafil Study Group.  Earliest time to onset of action leading to successful intercourse with vardenafil determined in an at-home setting: a randomized, double-blind, placebo-controlled trial. J Sex Med. 2004; 1:168-78. PubMed
 
Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A.  The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997; 49:822-30. PubMed
 
Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al. GRADE Working Group.  Grading quality of evidence and strength of recommendations. BMJ. 2004; 328:1490. PubMed
 
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ. et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996; 17:1-12. PubMed
 
Schulz KF, Grimes DA.  Allocation concealment in randomised trials: defending against deciphering. Lancet. 2002; 359:614-8. PubMed
 
Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J.  The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol. 2003; 3:25. PubMed
 
Higgins JPT, Green S, eds.  Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008. Accessed atwww.cochrane-handbook.orgon 3 February 2009.
 
DerSimonian R, Laird N.  Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177-88. PubMed
 
Higgins JP, Thompson SG, Deeks JJ, Altman DG.  Measuring inconsistency in meta-analyses. BMJ. 2003; 327:557-60. PubMed
 
Light RJ, Pillemer DB.  Summing Up: The Science of Reviewing Research. Cambridge, MA: Harvard Univ Pr; 1984.
 
Egger M, Davey Smith G, Schneider M, Minder C.  Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315:629-34. PubMed
 
Palmer JS, Kaplan WE, Firlit CF.  Erectile dysfunction in patients with spina bifida is a treatable condition. J Urol. 2000; 164:958-61. PubMed
 
Seidman SN, Roose SP, Menza MA, Shabsigh R, Rosen RC.  Treatment of erectile dysfunction in men with depressive symptoms: results of a placebo-controlled trial with sildenafil citrate. Am J Psychiatry. 2001; 158:1623-30. PubMed
 
Kongkanand A, Ratana-Olarn K, Ruangdilokrat S, Tantiwong A, Thai investigators in ASSESS-2 Study Group.  The efficacy and safety of oral sildenafil in Thai men with erectile dysfunction: a randomized, double-blind, placebo controlled, flexible-dose study. J Med Assoc Thai. 2003; 86:195-205. PubMed
 
Stuckey BG, Jadzinsky MN, Murphy LJ, Montorsi F, Kadioglu A, Fraige F. et al.  Sildenafil citrate for treatment of erectile dysfunction in men with type 1 diabetes: results of a randomized controlled trial. Diabetes Care. 2003; 26:279-84. PubMed
 
Choi HK, Ahn TY, Kim JJ, Kim SC, Paick JS, Suh JK. et al.  A double-blind, randomised- placebo, controlled, parallel group, multicentre, flexible-dose escalation study to assess the efficacy and safety of sildenafil administered as required to male outpatients with erectile dysfunction in Korea. Int J Impot Res. 2003; 15:80-6. PubMed
 
Levinson IP, Khalaf IM, Shaeer KZ, Smart DO.  Efficacy and safety of sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men in Egypt and South Africa. Int J Impot Res. 2003; 15:Suppl 1S25-9. PubMed
 
DeBusk RF, Pepine CJ, Glasser DB, Shpilsky A, DeRiesthal H, Sweeney M.  Efficacy and safety of sildenafil citrate in men with erectile dysfunction and stable coronary artery disease. Am J Cardiol. 2004; 93:147-53. PubMed
 
Boolell M, Gepi-Attee S, Gingell JC, Allen MJ.  Sildenafil, a novel effective oral therapy for male erectile dysfunction. Br J Urol. 1996; 78:257-61. PubMed
 
Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA.  Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med. 1998; 338:1397-404. PubMed
 
Tan HM, Moh CL, Mendoza JB, Gana T, Albano GJ, de la Cruz R. et al.  Asian sildenafil efficacy and safety study (ASSESS-1): a double-blind, placebo-controlled, flexible-dose study of oral sildenafil in Malaysian, Singaporean, and Filipino men with erectile dysfunction. The Assess-1 Study Group. Urology. 2000; 56:635-40. PubMed
 
Meuleman E, Cuzin B, Opsomer RJ, Hartmann U, Bailey MJ, Maytom MC. et al.  A dose-escalation study to assess the efficacy and safety of sildenafil citrate in men with erectile dysfunction. BJU Int. 2001; 87:75-81. PubMed
 
Eardley I, Morgan R, Dinsmore W, Yates P, Boolell M.  Efficacy and safety of sildenafil citrate in the treatment of men with mild to moderate erectile dysfunction. Br J Psychiatry. 2001; 178:325-30. PubMed
 
Young JM, Bennett C, Gilhooly P, Wessells H, Ramos DE.  Efficacy and safety of sildenafil citrate (Viagra) in black and Hispanic American men. Urology. 2002; 60:39-48. PubMed
 
Nurnberg HG, Hensley PL, Gelenberg AJ, Fava M, Lauriello J, Paine S.  Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial. JAMA. 2003; 289:56-64. PubMed
 
Price DE, Gingell JC, Gepi-Attee S, Wareham K, Yates P, Boolell M.  Sildenafil: study of a novel oral treatment for erectile dysfunction in diabetic men. Diabet Med. 1998; 15:821-5. PubMed
 
Rendell MS, Rajfer J, Wicker PA, Smith MD.  Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. Sildenafil Diabetes Study Group. JAMA. 1999; 281:421-6. PubMed
 
Christiansen E, Guirguis WR, Cox D, Osterloh IH, Sildenafil Multicentre Study Group.  Long-term efficacy and safety of oral Viagra (sildenafil citrate) in men with erectile dysfunction and the effect of randomised treatment withdrawal. Int J Impot Res. 2000; 12:177-82. PubMed
 
Olsson AM, Speakman MJ, Dinsmore WW, Giuliano F, Gingell C, Maytom M, et al. Sildenafil Multicentre Study Group.  Sildenafil citrate (Viagra) is effective and well tolerated for treating erectile dysfunction of psychogenic or mixed aetiology. Int J Clin Pract. 2000; 54:561-6. PubMed
 
Chen KK, Hsieh JT, Huang ST, Jiaan DB, Lin JS, Wang CJ, ASSESS-3 Study Group.  ASSESS-3: a randomised, double-blind, flexible-dose clinical trial of the efficacy and safety of oral sildenafil in the treatment of men with erectile dysfunction in Taiwan. Int J Impot Res. 2001; 13:221-9. PubMed
 
Boulton AJ, Selam JL, Sweeney M, Ziegler D.  Sildenafil citrate for the treatment of erectile dysfunction in men with Type II diabetes mellitus. Diabetologia. 2001; 44:1296-301. PubMed
 
Hussain IF, Brady CM, Swinn MJ, Mathias CJ, Fowler CJ.  Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson's disease or multiple system atrophy with observations on orthostatic hypotension. J Neurol Neurosurg Psychiatry. 2001; 71:371-4. PubMed
 
Safarinejad MR.  Oral sildenafil in the treatment of erectile dysfunction in diabetic men: a randomized double-blind and placebo-controlled study. J Diabetes Complications. 2004; 18:205-10. PubMed
 
Webster LJ, Michelakis ED, Davis T, Archer SL.  Use of sildenafil for safe improvement of erectile function and quality of life in men with New York Heart Association classes II and III congestive heart failure: a prospective, placebo-controlled, double-blind crossover trial. Arch Intern Med. 2004; 164:514-20. PubMed
 
Fowler CJ, Miller JR, Sharief MK, Hussain IF, Stecher VJ, Sweeney M.  A double blind, randomised study of sildenafil citrate for erectile dysfunction in men with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005; 76:700-5. PubMed
 
Mahon A, Sidhu PS, Muir G, Macdougall IC.  The efficacy of sildenafil for the treatment of erectile dysfunction in male peritoneal dialysis patients. Am J Kidney Dis. 2005; 45:381-7. PubMed
 
Katz SD, Parker JD, Glasser DB, Bank AJ, Sherman N, Wang H. et al.  Efficacy and safety of sildenafil citrate in men with erectile dysfunction and chronic heart failure. Am J Cardiol. 2005; 95:36-42. PubMed
 
Abdel-Naser MB, Imam A, Wollina U.  Sildenafil citrate significantly improves nocturnal penile erections in sildenafil non-responding patients with psychogenic erectile dysfunction. Int J Impot Res. 2004; 16:552-6. PubMed
 
Tignol J, Furlan PM, Gomez-Beneyto M, Opsomer R, Schreiber W, Sweeney M. et al.  Efficacy of sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men in remission from depression. Int Clin Psychopharmacol. 2004; 19:191-9. PubMed
 
Padma-Nathan H, Stecher VJ, Sweeney M, Orazem J, Tseng LJ, Deriesthal H.  Minimal time to successful intercourse after sildenafil citrate: results of a randomized, double-blind, placebo-controlled trial. Urology. 2003; 62:400-3. PubMed
 
Seibel I, Poli De Figueiredo CE, Telöken C, Moraes JF.  Efficacy of oral sildenafil in hemodialysis patients with erectile dysfunction. J Am Soc Nephrol. 2002; 13:2770-5. PubMed
 
Gómez F, Davila H, Costa A, Acuña A, Wadskier LA, Plua P, Andean Group of Erectile Dysfunction Study.  Efficacy and safety of oral sildenafil citrate (Viagra) in the treatment of male erectile dysfunction in Colombia, Ecuador, and Venezuela: a double-blind, multicenter, placebo-controlled study. Int J Impot Res. 2002; 14:Suppl 2S42-7. PubMed
 
Becher E, Tejada Noriega A, Gomez R, Decia R, Southern Latin America Sildenafil Study Group, Buenos Aires, Argentina.  Sildenafil citrate (Viagra) in the treatment of men with erectile dysfunction in southern Latin America: a double-blind, randomized, placebo-controlled, parallel-group, multicenter, flexible-dose escalation study. Int J Impot Res. 2002; 14:Suppl 2S33-41. PubMed
 
Lindsey I, George B, Kettlewell M, Mortensen N.  Randomized, double-blind, placebo-controlled trial of sildenafil (Viagra) for erectile dysfunction after rectal excision for cancer and inflammatory bowel disease. Dis Colon Rectum. 2002; 45:727-32. PubMed
 
Eardley I, Ellis P, Boolell M, Wulff M.  Onset and duration of action of sildenafil for the treatment of erectile dysfunction. Br J Clin Pharmacol. 2002; 53:Suppl 161S-65S. PubMed
 
Incrocci L, Koper PC, Hop WC, Slob AK.  Sildenafil citrate (Viagra) and erectile dysfunction following external beam radiotherapy for prostate cancer: a randomized, double-blind, placebo-controlled, cross-over study. Int J Radiat Oncol Biol Phys. 2001; 51:1190-5. PubMed
 
Olsson AM, Persson CA, Swedish Sildenafil Investigators Group.  Efficacy and safety of sildenafil citrate for the treatment of erectile dysfunction in men with cardiovascular disease. Int J Clin Pract. 2001; 55:171-6. PubMed
 
Montorsi F, Maga T, Strambi LF, Salonia A, Barbieri L, Scattoni V. et al.  Sildenafil taken at bedtime significantly increases nocturnal erections: results of a placebo-controlled study. Urology. 2000; 56:906-11. PubMed
 
Cappelleri JC, Siegel RL, Osterloh IH, Rosen RC.  Relationship between patient self-assessment of erectile function and the erectile function domain of the international index of erectile function. Urology. 2000; 56:477-81. PubMed
 
Montorsi F, McDermott TE, Morgan R, Olsson A, Schultz A, Kirkeby HJ. et al.  Efficacy and safety of fixed-dose oral sildenafil in the treatment of erectile dysfunction of various etiologies. Urology. 1999; 53:1011-8. PubMed
 
Dinsmore WW, Hodges M, Hargreaves C, Osterloh IH, Smith MD, Rosen RC.  Sildenafil citrate (Viagra) in erectile dysfunction: near normalization in men with broad-spectrum erectile dysfunction compared with age-matched healthy control subjects. Urology. 1999; 53:800-5. PubMed
 
Padma-Nathan H, Steers WD, Wicker PA.  Efficacy and safety of oral sildenafil in the treatment of erectile dysfunction: a double-blind, placebo-controlled study of 329 patients. Sildenafil Study Group. Int J Clin Pract. 1998; 52:375-9. PubMed
 
Albuquerque DC, Miziara LJ, Saraiva JF, Rodrigues US, Ribeiro AB, Wajngarten M.  Efficacy, safety and tolerability of sildenafil in Brazilian hypertensive patients on multiple antihypertensive drugs. Int Braz J Urol. 2005;31:342-53; discussion 354-5. [PMID: 16137403]
 
Gingell C, Sultana SR, Wulff MB, Gepi-Attee S.  Duration of action of sildenafil citrate in men with erectile dysfunction. J Sex Med. 2004; 1:179-84. PubMed
 
Pickering TG, Shepherd AM, Puddey I, Glasser DB, Orazem J, Sherman N. et al.  Sildenafil citrate for erectile dysfunction in men receiving multiple antihypertensive agents: a randomized controlled trial. Am J Hypertens. 2004; 17:1135-42. PubMed
 
Glina S, Bertero E, Claro J, Damião R, Faria G, Fregnosi A. et al.  Efficacy and safety of sildenafil citrate for the treatment of erectile dysfunction in Latin America. Brazilian Journal of Urology. 2001; 27:148-54.
 
Heiman JR, Talley DR, Bailen JL, Oskin TA, Rosenberg SJ, Pace CR. et al.  Sexual function and satisfaction in heterosexual couples when men are administered sildenafil citrate (Viagra) for erectile dysfunction: a multicentre, randomised, double-blind, placebo-controlled trial. BJOG. 2007; 114:437-47. PubMed
 
Sommer F, Klotz T, Engelmann U.  Improved spontaneous erectile function in men with mild-to-moderate arteriogenic erectile dysfunction treated with a nightly dose of sildenafil for one year: a randomized trial. Asian J Androl. 2007; 9:134-41. PubMed
 
McVary KT, Monnig W, Camps JL Jr, Young JM, Tseng LJ, van den Ende G.  Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol. 2007; 177:1071-7. PubMed
 
Zinner N.  Do food and dose timing affect the efficacy of sildenafil? A randomized placebo-controlled study. J Sex Med. 2007; 4:137-44. PubMed
 
Orr G, Weiser M, Polliack M, Raviv G, Tadmor D, Grunhaus L.  Effectiveness of sildenafil in treating erectile dysfunction in PTSD patients: a double-blind, placebo-controlled crossover study. J Clin Psychopharmacol. 2006; 26:426-30. PubMed
 
Sharma RK, Prasad N, Gupta A, Kapoor R.  Treatment of erectile dysfunction with sildenafil citrate in renal allograft recipients: a randomized, double-blind, placebo-controlled, crossover trial. Am J Kidney Dis. 2006; 48:128-33. PubMed
 
Althof SE, O'Leary MP, Cappelleri JC, Hvidsten K, Stecher VJ, Glina S, et al. International SEAR Study Group.  Sildenafil citrate improves self-esteem, confidence, and relationships in men with erectile dysfunction: Results from an international, multi-center, double-blind, placebo-controlled trial. J Sex Med. 2006; 3:521-9. PubMed
 
Fava M, Nurnberg HG, Seidman SN, Holloway W, Nicholas S, Tseng LJ. et al.  Efficacy and safety of sildenafil in men with serotonergic antidepressant-associated erectile dysfunction: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2006; 67:240-6. PubMed
 
Gopalakrishnan R, Jacob KS, Kuruvilla A, Vasantharaj B, John JK.  Sildenafil in the treatment of antipsychotic-induced erectile dysfunction: a randomized, double-blind, placebo-controlled, flexible-dose, two-way crossover trial. Am J Psychiatry. 2006; 163:494-9. PubMed
 
O'Leary MP, Althof SE, Cappelleri JC, Crowley A, Sherman N, Duttagupta S, United States Self-Esteem and Relationship Questionnaire Study Group.  Self-esteem, confidence and relationship satisfaction of men with erectile dysfunction treated with sildenafil citrate: a multicenter, randomized, parallel group, double-blind, placebo controlled study in the United States. J Urol. 2006; 175:1058-62. PubMed
 
Koulikov D, Fridmans A, Chertin B, Shenfeld O, Farkas A, Spitz IM.  Is sildenafil citrate associated with an amelioration of the symptomatology of androgen decline in the aging male? J Urol. 2007; 177:2267-71. PubMed
 
Buranakitjaroen P, Mangklabruks A, Leungwattanakij S, Ngaothamatasn W, Malhotra C, Chee C, et al. Thai-Malaysian-Singapore Erectile Dysfunction Study Group (THAMES Group).  Efficacy and safety of sildenafil in Asian males with erectile dysfunction and cardiovascular risk. J Med Assoc Thai. 2007; 90:1100-8. PubMed
 
Bannowsky A, Schulze H, van der Horst C, Hautmann S, Jünemann KP.  Recovery of erectile function after nerve-sparing radical prostatectomy: improvement with nightly low-dose sildenafil. BJU Int. 2008; 101:1279-83. PubMed
 
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; 178:613-6. PubMed
 
Hundertmark J, Esterman A, Ben-Tovim D, Austin MA, Dougherty M.  The South Australian couples sildenafil study: double-blind, parallel-group randomized controlled study to examine the psychological and relationship consequences of sildenafil use in couples. J Sex Med. 2007; 4:1126-35. PubMed
 
Kadioglu A, Grohmann W, Depko A, Levinson IP, Sun F, Collins S.  Quality of erections in men treated with flexible-dose sildenafil for erectile dysfunction: multicenter trial with a double-blind, randomized, placebo-controlled phase and an open-label phase. J Sex Med. 2008; 5:726-34. PubMed
 
Jones LA, Klimberg IW, McMurray JG, Padula R, Tseng LJ, Stecher VJ.  Effect of sildenafil citrate on the male sexual experience assessed with the Sexual Experience Questionnaire: a multicenter, double-blind, placebo-controlled trial with open-label extension. J Sex Med. 2008; 5:1955-64. PubMed
 
McCullough AR, Levine LA, Padma-Nathan H.  Return of nocturnal erections and erectile function after bilateral nerve-sparing radical prostatectomy in men treated nightly with sildenafil citrate: subanalysis of a longitudinal randomized double-blind placebo-controlled trial. J Sex Med. 2008; 5:476-84. PubMed
 
McCullough AR, Steidle CP, Klee B, Tseng LJ.  Randomized, double-blind, crossover trial of sildenafil in men with mild to moderate erectile dysfunction: efficacy at 8 and 12 hours postdose. Urology. 2008; 71:686-92. PubMed
 
McCullough AR, Steidle CP, Kaufman J, Goldfischer ER, Klee B, Carlsson M.  Sildenafil citrate efficacy 8 h postdose in men with mild to moderate erectile dysfunction. Int J Impot Res. 2008; 20:388-95. PubMed
 
Morano S, Mandosi E, Fallarino M, Gatti A, Tiberti C, Sensi M. et al.  Antioxidant treatment associated with sildenafil reduces monocyte activation and markers of endothelial damage in patients with diabetic erectile dysfunction: a double-blind, placebo-controlled study. Eur Urol. 2007; 52:1768-74. PubMed
 
Buvat J, Hatzichristou D, Maggi M, Farmer I, Martínez-Jabaloyas JM, Miller PJ. et al.  Efficacy, tolerability and satisfaction with sildenafil citrate 100-mg titration compared with continued 50-mg dose treatment in men with erectile dysfunction. BJU Int. 2008; 102:1645-50. PubMed
 
Safarinejad MR.  Evaluation of the safety and efficacy of sildenafil citrate for erectile dysfunction in men with multiple sclerosis: a double-blind, placebo controlled, randomized study. J Urol. 2009; 181:252-8. PubMed
 
Burnett AL, Strong TD, Trock BJ, Jin L, Bivalacqua TJ, Musicki B.  Serum biomarker measurements of endothelial function and oxidative stress after daily dosing of sildenafil in type 2 diabetic men with erectile dysfunction. J Urol. 2009; 181:245-51. PubMed
 
Goldstein I, Young JM, Fischer J, Bangerter K, Segerson T, Taylor T, Vardenafil Diabetes Study Group.  Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: a multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care. 2003; 26:777-83. PubMed
 
Valiquette L, Young JM, Moncada I, Porst H, Vézina JG, Stancil BN, et al. Vardenafil Study Group.  Sustained efficacy and safety of vardenafil for treatment of erectile dysfunction: a randomized, double-blind, placebo-controlled study. Mayo Clin Proc. 2005; 80:1291-7. PubMed
 
Nehra A, Grantmyre J, Nadel A, Thibonnier M, Brock G.  Vardenafil improved patient satisfaction with erectile hardness, orgasmic function and sexual experience in men with erectile dysfunction following nerve sparing radical prostatectomy. J Urol. 2005; 173:2067-71. PubMed
 
Carson CC, Hatzichristou DG, Carrier S, Lording D, Lyngdorf P, Aliotta P, et al. Patient Response with Vardenafil in Slidenafil Non-Responders (PROVEN) Study Group.  Erectile response with vardenafil in sildenafil nonresponders: a multicentre, double-blind, 12-week, flexible-dose, placebo-controlled erectile dysfunction clinical trial. BJU Int. 2004; 94:1301-9. PubMed
 
Nagao K, Ishii N, Kamidono S, Osada T, Vardenafil (Levitra) Clinical Trial Group.  Safety and efficacy of vardenafil in patients with erectile dysfunction: result of a bridging study in Japan. Int J Urol. 2004; 11:515-24. PubMed
 
Stief C, Porst H, Sáenz De Tejada I, Ulbrich E, Beneke M, Vardenafil Study Group.  Sustained efficacy and tolerability with vardenafil over 2 years of treatment in men with erectile dysfunction. Int J Clin Pract. 2004; 58:230-9. PubMed
 
Hatzichristou D, Montorsi F, Buvat J, Laferriere N, Bandel TJ, Porst H; European Vardenafil Study Group.  The efficacy and safety of flexible-dose vardenafil (levitra) in a broad population of European men. Eur Urol. 2004;45:634-41; discussion 641. [PMID: 15082207]
 
Hellstrom WJ, Gittelman M, Karlin G, Segerson T, Thibonnier M, Taylor T. et al.  Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized, double-blind, placebo-controlled trial. J Androl. 2002; 23:763-71. PubMed
 
Stark S, Sachse R, Liedl T, Hensen J, Rohde G, Wensing G, et al.  Vardenafil increases penile rigidity and tumescence in men with erectile dysfunction after a single oral dose. Eur Urol. 2001;40:181-8; discussion 189-90. [PMID: 11528196]
 
Porst H, Rosen R, Padma-Nathan H, Goldstein I, Giuliano F, Ulbrich E. et al.  The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial. Int J Impot Res. 2001; 13:192-9. PubMed
 
Klotz T, Sachse R, Heidrich A, Jockenhövel F, Rohde G, Wensing G. et al.  Vardenafil increases penile rigidity and tumescence in erectile dysfunction patients: a RigiScan and pharmacokinetic study. World J Urol. 2001; 19:32-9. PubMed
 
van Ahlen H, Wahle K, Kupper W, Yassin A, Reblin T, Neureither M.  Safety and efficacy of vardenafil, a selective phosphodiesterase 5 inhibitor, in patients with erectile dysfunction and arterial hypertension treated with multiple antihypertensives. J Sex Med. 2005; 2:856-64. PubMed
 
Goldstein I, Fisher WA, Sand M, Rosen RC, Mollen M, Brock G, et al. Vardenafil Study Group.  Women's sexual function improves when partners are administered vardenafil for erectile dysfunction: a prospective, randomized, double-blind, placebo-controlled trial. J Sex Med. 2005; 2:819-32. PubMed
 
Rosen R, Shabsigh R, Berber M, Assalian P, Menza M, Rodriguez-Vela L, et al. Vardenafil Study Site Investigators.  Efficacy and tolerability of vardenafil in men with mild depression and erectile dysfunction: the depression-related improvement with vardenafil for erectile response study. Am J Psychiatry. 2006; 163:79-87. PubMed
 
Martin-Morales A, Meijide F, García N, Artes M, Muñoz A.  Efficacy of vardenafil and influence on self-esteem and self-confidence in patients with severe erectile dysfunction. J Sex Med. 2007; 4:440-7. PubMed
 
Edwards D, Hackett G, Collins O, Curram J.  Vardenafil improves sexual function and treatment satisfaction in couples affected by erectile dysfunction (ED): a randomized, double-blind, placebo-controlled trial in PDE5 inhibitor-naïve men with ED and their partners. J Sex Med. 2006; 3:1028-36. PubMed
 
Porst H, Sharlip ID, Hatzichristou D, Rubio-Aurioles E, Gittelman M, Stancil BN, et al; Vardenafil Study Group.  Extended duration of efficacy of vardenafil when taken 8 hours before intercourse: a randomized, double-blind, placebo-controlled study. Eur Urol. 2006;50:1086-94; discussion 1094-5. [PMID: 16820261]
 
Mazo E, Gamidov S, Iremashvili V.  The effect of vardenafil on endothelial function of brachial and cavernous arteries. Int J Impot Res. 2006; 18:464-9. PubMed
 
Ziegler D, Merfort F, van Ahlen H, Yassin A, Reblin T, Neureither M.  Efficacy and safety of flexible-dose vardenafil in men with type 1 diabetes and erectile dysfunction. J Sex Med. 2006; 3:883-91. PubMed
 
Ishii N, Nagao K, Fujikawa K, Tachibana T, Iwamoto Y, Kamidono S.  Vardenafil 20-mg demonstrated superior efficacy to 10-mg in Japanese men with diabetes mellitus suffering from erectile dysfunction. Int J Urol. 2006; 13:1066-72. PubMed
 
Demir E, Balal M, Paydas S, Sertdemir Y, Erken U.  Efficacy and safety of vardenafil in renal transplant recipients with erectile dysfunction. Transplant Proc. 2006; 38:1379-81. PubMed
 
Zumbé J, Porst H, Sommer F, Grohmann W, Beneke M, Ulbrich E.  Comparable efficacy of once-daily versus on-demand vardenafil in men with mild-to-moderate erectile dysfunction: findings of the RESTORE study. Eur Urol. 2008; 54:204-10. PubMed
 
Ralph D, Eardley I, Kell P, Dean J, Hackett G, Collins O. et al.  Improvement in erectile function on vardenafil treatment correlates with treatment satisfaction in both patients and their partners. BJU Int. 2007; 100:130-6. PubMed
 
Montorsi F, Brock G, Lee J, Shapiro J, Van Poppel H, Graefen M. et al.  Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. Eur Urol. 2008; 54:924-31. PubMed
 
Tan HM, Chin CM, Chua CB, Gatchalian E, Kongkanand A, Moh CL. et al.  Efficacy and tolerability of vardenafil in Asian men with erectile dysfunction. Asian J Androl. 2008; 10:495-502. PubMed
 
Miner M, Gilderman L, Bailen J, Cook D, Dawson K, Stanislaus M. et al.  Vardenafil in men with stable statin therapy and dyslipidemia. J Sex Med. 2008; 5:1455-67. PubMed
 
Mirone V, Costa P, Damber JE, Holmes S, Moncada I, Van Ahlen H, et al.  An evaluation of an alternative dosing regimen with tadalafil, 3 times/week, for men with erectile dysfunction: SURE study in 14 European countries. Eur Urol. 2005;47:846-54; discussion 854. [PMID: 15925082]
 
Young JM, Feldman RA, Auerbach SM, Kaufman JM, Garcia CS, Shen W. et al.  Tadalafil improved erectile function at twenty-four and thirty-six hours after dosing in men with erectile dysfunction: US trial. J Androl. 2005; 26:310-8. PubMed
 
McMahon CG, Stuckey BG, Lording DW, Wittert GA, Murphy A, Shin J. et al.  A 6-month study of the efficacy and safety of tadalafil in the treatment of erectile dysfunction: a randomised, double-blind, parallel-group, placebo-controlled study in Australian men. Int J Clin Pract. 2005; 59:143-9. PubMed
 
Carson C, Shabsigh R, Segal S, Murphy A, Fredlund P, Kuepfer C, Trial Evaluating the Activity of Tadalafil for Erectile Dysfunction-United States (TREATED-US) Study Group.  Efficacy, safety, and treatment satisfaction of tadalafil versus placebo in patients with erectile dysfunction evaluated at tertiary-care academic centers. Urology. 2005; 65:353-9. PubMed
 
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 220-2. [PMID: 15661417]
 
De Rose AF, Gallo F, Carmignani G.  Evaluation of sexual activity in patients treated with tadalafil: a randomized prospective placebo-controlled trial. Int J Impot Res. 2005; 17:76-9. PubMed
 
Eardley I, Gentile V, Austoni E, Hackett G, Lembo D, Wang C. et al.  Efficacy and safety of tadalafil in a Western European population of men with erectile dysfunction. BJU Int. 2004; 94:871-7. PubMed
 
Staab A, Tillmann C, Forgue ST, Mackie A, Allerheiligen SR, Rapado J. et al.  Population dose-response model for tadalafil in the treatment of male erectile dysfunction. Pharm Res. 2004; 21:1463-70. PubMed
 
Montorsi F, Nathan HP, McCullough A, Brock GB, Broderick G, Ahuja S. et al.  Tadalafil in the treatment of erectile dysfunction following bilateral nerve sparing radical retropubic prostatectomy: a randomized, double-blind, placebo controlled trial. J Urol. 2004; 172:1036-41. PubMed
 
Skoumal R, Chen J, Kula K, Breza J, Calomfirescu N, Basson BR. et al.  Efficacy and treatment satisfaction with on-demand tadalafil (Cialis) in men with erectile dysfunction. Eur Urol. 2004; 46:362-9. PubMed
 
Seftel AD, Wilson SK, Knapp PM, Shin J, Wang WC, Ahuja S.  The efficacy and safety of tadalafil in United States and Puerto Rican men with erectile dysfunction. J Urol. 2004; 172:652-7. PubMed
 
Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R.  Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology. 2003;62:121-5; discussion 125-6. [PMID: 12837435]
 
Sáenz de Tejada I, Anglin G, Knight JR, Emmick JT.  Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care. 2002; 25:2159-64. PubMed
 
Carrier S, Brock GB, Pommerville PJ, Shin J, Anglin G, Whitaker S. et al.  Efficacy and safety of oral tadalafil in the treatment of men in Canada with erectile dysfunction: a randomized, double-blind, parallel, placebo-controlled clinical trial. J Sex Med. 2005; 2:685-98. PubMed
 
McMahon C.  Comparison of efficacy, safety, and tolerability of on-demand tadalafil and daily dosed tadalafil for the treatment of erectile dysfunction. J Sex Med. 2005;2:415-25; discussion 425-7. [PMID: 16422874]
 
Chen KK, Jiann BP, Lin JS, Lee SS, Huang ST, Wang CJ. et al.  Efficacy and safety of on-demand oral tadalafil in the treatment of men with erectile dysfunction in Taiwan: a randomized, double-blind, parallel, placebo-controlled clinical study. J Sex Med. 2004; 1:201-8. PubMed
 
Rosen RC, Padma-Nathan H, Shabsigh R, Saikali K, Watkins V, Pullman W.  Determining the earliest time within 30 minutes to erectogenic effect after tadalafil 10 and 20 mg: a multicenter, randomized, double-blind, placebo-controlled, at-home study. J Sex Med. 2004; 1:193-200. PubMed
 
Aversa A, Greco E, Bruzziches R, Pili M, Rosano G, Spera G.  Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: a pilot study. Int J Impot Res. 2007; 19:200-7. PubMed
 
McVary KT, Roehrborn CG, Kaminetsky JC, Auerbach SM, Wachs B, Young JM. et al.  Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007; 177:1401-7. PubMed
 
Saylan M, Khalaf I, Kadioglu A, Shoair KZ, Beheiry A, Wang WC. et al.  Efficacy of tadalafil in Egyptian and Turkish men with erectile dysfunction. Int J Clin Pract. 2006; 60:812-9. PubMed
 
Rajfer J, Aliotta PJ, Steidle CP, Fitch WP 3rd, Zhao Y, Yu A.  Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study in the US. Int J Impot Res. 2007; 19:95-103. PubMed
 
Yip WC, Chiang HS, Mendoza JB, Tan HM, Li MK, Wang WC. et al.  Efficacy and safety of on demand tadalafil in the treatment of East and Southeast Asian men with erectile dysfunction: a randomized double-blind, parallel, placebo-controlled clinical study. Asian J Androl. 2006; 8:685-92. PubMed
 
Guo YL, Zhu JC, Pan TM, Ding Q, Wang YX, Cheong NF. et al.  Efficacy and safety of on-demand tadalafil for the treatment of erectile dysfunction in South-East Asian men. Int J Urol. 2006; 13:721-7. PubMed
 
Nagao K, Kimoto Y, Marumo K, Tsujimura A, Vail GM, Watts S. et al.  Efficacy and safety of tadalafil 5, 10, and 20 mg in Japanese men with erectile dysfunction: results of a multicenter, randomized, double-blind, placebo-controlled study. Urology. 2006; 68:845-51. PubMed
 
Incrocci L, Slagter C, Slob AK, Hop WC.  A randomized, double-blind, placebo-controlled, cross-over study to assess the efficacy of tadalafil (Cialis) in the treatment of erectile dysfunction following three-dimensional conformal external-beam radiotherapy for prostatic carcinoma. Int J Radiat Oncol Biol Phys. 2006; 66:439-44. PubMed
 
Choi HK, Kim JJ, Kim SC, Suh J, Park YK, Choi S. et al.  A randomised, double-blind, parallel, placebo-controlled study of the efficacy and safety of Tadalafil administered on-demand to men with erectile dysfunction in Korea. Taehan Pinyogikwa Hakhoe Chapchi. 2006; 47:852-58.
 
Bocchio M, Pelliccione F, Passaquale G, Mihalca R, Necozione S, Desideri G. et al.  Inhibition of phosphodiesterase type 5 with tadalafil is associated to an improved activity of circulating angiogenic cells in men with cardiovascular risk factors and erectile dysfunction. Atherosclerosis. 2008; 196:313-9. PubMed
 
Hatzichristou D, Gambla M, Rubio-Aurioles E, Buvat J, Brock GB, Spera G. et al.  Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction. Diabet Med. 2008; 25:138-46. PubMed
 
Paick JS, Ahn TY, Choi HK, Chung WS, Kim JJ, Kim SC. et al.  Efficacy and safety of mirodenafil, a new oral phosphodiesterase type 5 inhibitor, for treatment of erectile dysfunction. J Sex Med. 2008; 5:2672-80. PubMed
 
Paick JS, Choi HK, Kim SC, Ahn TY, Kim JJ, Park JK. et al.  Efficacy and safety of oral SK3530 for the treatment of erectile dysfunction in Korean men: a multicenter, randomized, double-blind, placebo-controlled, fixed dose, parallel group clinical trial. Asian J Androl. 2008; 10:791-8. PubMed
 
Paick JS, Kim SW, Yang DY, Kim JJ, Lee SW, Ahn TY. et al.  The efficacy and safety of udenafil, a new selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction. J Sex Med. 2008; 5:946-53. PubMed
 
Eardley I, Mirone V, Montorsi F, Ralph D, Kell P, Warner MR. et al.  An open-label, multicentre, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in men naïve to phosphodiesterase 5 inhibitor therapy. BJU Int. 2005; 96:1323-32. PubMed
 
von Keitz A, Rajfer J, Segal S, Murphy A, Denne J, Costigan T, et al.  A multicenter, randomized, double-blind, crossover study to evaluate patient preference between tadalafil and sildenafil. Eur Urol. 2004;45:499-507; discussion 507-9. [PMID: 15041116]
 
Govier F, Potempa AJ, Kaufman J, Denne J, Kovalenko P, Ahuja S.  A multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction. Clin Ther. 2003; 25:2709-23. PubMed<