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Home Guidelines Clinical Guidelines Erectile Dysfunction (2005; Reviewed and Validity Confirmed 2011)

Erectile Dysfunction

Published 2005; Reviewed and Validity Confirmed 2011

Unabridged version of this Guideline [pdf]

Panel Members

Drogo K. Montague, MD, Co-Chair; Jonathan P. Jarow, MD, Co-Chair; Gregory A. Broderick, MD; Roger R. Dmochowski, MD; Jeremy P.W. Heaton, MD; Tom F. Lue, MD; Aaron J. Milbank, MD; Ajay Nehra, MD; Ira D. Sharlip, MD

Introduction

In 1996, the Erectile Dysfunction Clinical Guideline Panel published the Report on the Treatment of Organic Erectile Dysfunction (the 1996 Report), an evidence-based guideline for the diagnosis and treatment of erectile dysfunction (ED).1 Since that time, impotence, more precisely termed "erectile dysfunction," has received increasing attention because of the availability of new treatments approved by the U.S. Food and Drug Administration (FDA). In addition, the overall quality of clinical research and the methods of measuring outcomes have improved substantially. The 1996 analysis was based mainly on the outcomes of clinical series. The randomized, controlled trial has now become the norm.

An Erectile Dysfunction Guideline Update Panel (the Panel) was appointed by the American Urological Association (AUA) Practice Guidelines Committee in the year 2000 to update the existing document. Using a consensus-based approach, the Panel concluded that (1) informed patient decision making should remain the standard; (2) no new evidence has suggested that the guideline statements on the diagnostic evaluation should be changed; (3) a psychologic overlay frequently exists in patients with ED; and (4) endocrine disorders are an important consideration in the etiology of ED. Although sex therapy and the diagnosis and treatment of endocrine disorders are important management issues, the Panel agreed that these issues were beyond the scope of the guideline and would, therefore, not be discussed.

The Panel's major focus was to use an evidence-based approach to develop a guideline for the ED treatment modalities that had become available in the United States after publication of the 1996 Report. Guideline statements from the 1996 Report on previously available therapeutic modalities were either revised or brought forward unchanged depending on the existing evidence.

All guideline statements were graded according to the degree of flexibility in clinical application: standard, recommendation, or option, with standard being the least flexible and option being the most flexible (Table 1). Grading is based on two characteristics: knowledge of the health outcomes of the alternative intervention and preference for the intervention.

Table 1. Grades of Guideline Statements Based on Levels of Flexibility of Application

Grade

Knowledge of Health Outcomes of the Alternative Interventions

Preference for Intervention

StandardSufficiently well known to permit meaningful decisionsVirtual unanimity
RecommendationSufficiently well known to permit meaningful decisionsAn appreciable but not unanimous majority agrees
OptionNot sufficiently well known to permit meaningful decisionsUnknown or equivocal

The Panel believed that the patient, with physician guidance, must make his own decision in selecting treatment. Outcome estimates derived from review and meta-analysis of evidence provide physicians and patients with scientifically based information to assist them in making appropriate treatment decisions. Thus, a second Panel objective was to determine whether or not there was sufficient evidence for outcomes (both benefits and risks) to be estimated.

Definitions

The National Institutes of Health (NIH) Consensus Development Conference on Impotence (December 7-9, 1992) defined impotence as "male erectile dysfunction, that is, the inability to achieve or maintain an erection sufficient for satisfactory sexual performance."2 ED is the more precise term, especially given the fact that sexual desire and the ability to have an orgasm and ejaculate may well be intact despite the inability to achieve or maintain an erection. The recommendations and findings of the Panel were based upon the management of an Index Patient that represents the most prevalent presentation of this disorder since management may vary in atypical patients. The Index Patient for this document is defined as a man with no evidence of hypogonadism or hyperprolactinemia who develops, after a well-established period of normal erectile function, ED that is primarily organic in nature. This definition is a slightly modified version of the definition used to develop the 1996 Report.

Methodology

The Panel's task was to prepare a guideline on therapies for ED that became available after the publication of the 1996 Report and to revise those portions that required updating so that patients and physicians could participate in a scientifically based, informed decision-making process. In addition to ED, the Panel elected to address three topics relevant to erection, Peyronie's disease, priapism, and premature ejaculation. Guidelines for priapism and premature ejaculation are currently available.

In the year 2000, MEDLINE® searches of English-language references on human subjects were initiated for each of the four topics. Search strategies ranged from very general to very specific. Citations identified through subsequent targeted searches, such as those specifically focused on individual treatments, and through Panel member suggestions also were added to the database. The ED portion of the searches spanned the years from 1994, when the final literature search for the 1996 Report was completed, to February 2004. The Panel continued to scrutinize key references that were identified up until the peer-review process.

Panel chairmen reviewed each citation title and abstract. Papers that presented outcomes data resulting from the evaluation of ED therapies were winnowed from the other publications. Sufficient new evidence was available to update the recommendations for many of the treatments discussed in the 1996 Report on ED. The initial plan was to conduct a full review, data extraction, and meta-analysis of the FDA-approved oral agents and alprostadil intra-urethral suppositories. Because of data limitations, varying types of analyses were undertaken for the other treatment modalities.

Data from 112 articles selected by the chairmen were extracted and recorded on a data extraction form. The Panel determined that although there were many different outcome measures used in the studies, only a limited number would be considered adequate for this review: the International Index of Erectile Function (IIEF) (including the erectile function and intercourse satisfaction domains as well as questions 3 and 4 individually) (Appendix 1-A;3,4) and the specific measures "ability to have intercourse," "return to normal," and erection grade of 4 or 5 (on a five-point scale). The extracted data were entered into a database, and evidence tables were generated and reviewed by the Panel. Twenty-seven papers were rejected for lack of relevant data or inadequate quality. Of the accepted articles, nine reported the results of two or more trials that were extracted as separate studies. A detailed meta-analysis of study outcomes was attempted. Difficulties were encountered in developing outcome estimates for all therapies because of study inconsistencies in patient selection and outcome measures, the lack of sufficient data, and the reporting of adjusted results. Given these problems with the data, the Panel ultimately decided that meta-analysis was inappropriate.

The Panel performed focused reviews and analyses of the surgical therapies, implantable devices, and vascular surgery. Each topic was assigned to a Panel member for review and development of evidence tables or reports. The review of implantable devices was restricted to the question of mechanical failure/replacement rates. The review of arterial vascular surgical therapy focused on an Index Patient which differed from the standard Index Patient defined for other treatments. A special review of herbal therapies was performed later in the guideline process since few citations on herbal therapies were initially extracted. The search for herbal therapies included non-English language journals with abstracts written in English. Of the articles on herbal therapies that were identified, only three were randomized controlled trials using objective outcome criteria. The sections on vacuum constriction devices and intracavernous vasoactive drug injection were not updated as no new evidence was found that materially affected the recommendations for these treatments. The Panel also decided against reviewing the data on testosterone as it was beyond the scope of the guideline, and on apomorphine, which was not approved for use in the United States.

As in the 1996 Report, the Panel generated guideline statements based on the strength of the evidence and the expected amount of variation in patient preferences for treatments. In some cases, guideline statements were supported solely by the Panel's expert opinion and are designated as such in the text. The Panel also outlined suggestions for future clinical research priorities.

This guideline was drafted, reviewed by the Panel and by 80 peer reviewers, and finally approved by the Practice Guidelines Committee and the Board of Directors of the AUA. A full description of the methodology is presented in Chapter 2. 

Diagnostic Evaluation

The Panel unanimously agreed that the present update should reflect current practices in the diagnostic evaluation of a new patient with ED. As in the 1996 Report, the discussion is based solely on Panel opinion and is handled similarly herein. The Panel did not conduct a rigorous systematic review of the literature; therefore, the following discussion is not intended to be all- inclusive or limiting with regard to assessment of individual patients.

The typical initial evaluation of a man complaining of ED is conducted in person and includes sexual, medical, and psychosocial histories as well as laboratory tests thorough enough to identify comorbid conditions that may predispose the patient to ED and that may contraindicate certain therapies. History may reveal causes or comorbidities such as cardiovascular disease (including hypertension, atherosclerosis, or hyperlipidemia), diabetes mellitus, depression, and alcoholism. Related dysfunctions such as premature ejaculation, increased latency time associated with age, and psychosexual relationship problems may also be uncovered. Most importantly, a history can reveal specific contraindications for drug therapy. Additional risk factors include smoking, pelvic, perineal, or penile trauma or surgery, neurologic disease, endocrinopathy, obesity, pelvic radiation therapy, Peyronie's disease, and prescription or recreational drug use. Other critical elements are alterations of sexual desire, ejaculation, and orgasm, presence of genital pain, and lifestyle factors, such as sexual orientation, presence of spouse or partner, and quality of the relationship with the partner. Finally, a history of the partner's sexual function may be helpful. Attention is given to defining the problem, clearly distinguishing ED from complaints about ejaculation and/or orgasm, and establishing the chronology and severity of symptoms. An assessment of patient/partner needs and expectations of therapy is equally important.

A focused physical examination evaluating the abdomen, penis, testicles, secondary sexual characteristics and lower extremity pulses is usually performed. Established patients with a new complaint of ED typically are not re-examined. Prostate-specific antigen measurement and rectal examination may assume additional significance when considering the use of testosterone in the management of male sexual dysfunctions. Additional testing, such as testosterone level measurement, vascular and/or neurological assessment, and monitoring of nocturnal erections, may be indicated in select patients.

Discussion of Treatment Options

Recommended Therapies and Patient Information

Guideline Statement 1

Standard: The management of erectile dysfunction begins with the identification of organic comorbidities and psychosexual dysfunctions; both should be appropriately treated or their care triaged. The currently available therapies that should be considered for the treatment of erectile dysfunction include the following:Â oral phosphodiesterase type 5 [PDE5] inhibitors, intra-urethral alprostadil, intracavernous vasoactive drug injection, vacuum constriction devices, and penile prosthesis implantation. These appropriate treatment options should be applied in a stepwise fashion with increasing invasiveness and risk balanced against the likelihood of efficacy.

Discussion


Guideline Statement 2

Standard: The patient and, when possible, his partner should be informed of the relevant treatment options and their associated risks and benefits. The choice of treatment should be made jointly by the physician, patient, and partner, when possible, taking into consideration patient preferences and expectations and the experience and judgment of the physician.

Erectile Dysfunction and Comorbidities

Modifying Risk Factors

Erectile function is the result of a complex interplay between vascular, neurologic, hormonal, and psychologic factors. The attainment and maintenance of a firm erection requires good arterial inflow of blood as well as efficient reduction of venous outflow. Risk factors and disease processes that affect the function of the arterial or venous systems would therefore be expected to have a negative impact on erectile function. Since the risk of developing ED is increased in the presence of diabetes, heart disease, and hypertension, it is logical to conclude that optimal management of these diseases may prevent the development of ED.7,8,9 It is also logical to assume that lifestyle modifications to improve vascular function such as avoiding smoking, maintaining ideal body weight and engaging in regular exercise might either prevent or reverse ED, however, only minimal data exists today to support this supposition.10,11

Managing ED with Cardiovascular Disease

Cardiovascular disease and ED may share a common etiology when endothelial dysfunction and atherosclerosis affect both coronary arteries and penile vasculature.12 Consequently, patients with ED frequently have concurrent cardiovascular disease.13 Treatment of ED in patients with cardiovascular disease is complicated by a small increase in the risk of myocardial infarction (MI) related to sexual activity in these patients independent of the method of treatment. Sexual activity increases physical exertion levels to 3 to 4 METS (1 MET is the amount of energy used at the resting state associated with oxygen consumption of approximately 3.5 mL/kg/min), and sympathetic activation during sexual activity may increase blood pressure and heart rate more than other types of exercise.14 Together, these factors result in a 2.5-fold (95% CI, 1.7-3.7) greater relative risk of nonfatal MI following sexual activity in healthy men than during noncoital activities and a 2.9-fold (95% CI, 1.3-6.5) greater risk in men with a history of MI.14

Even with this effect, however, the absolute risk of MI during and for 2 hours following sexual activity is extremely low — only 20 chances per million per hour in post-MI patients and even less in men without a history of MI.15 The major risk factors associated with cardiovascular disease are age, hypertension, diabetes mellitus, obesity, smoking, dyslipidemia, and sedentary lifestyle. Patients with three or more of these risk factors16 are considered to be at increased risk for MI during sexual activity.

Guidelines for managing ED in patients with cardiovascular disease developed by the Princeton Consensus Panel14 recommend assigning patients to one of three risk levels (high, intermediate, and low) based on their cardiovascular risk factors. High-risk patients are defined as those with unstable or refractory angina; uncontrolled hypertension; congestive heart failure (CHF; New York Heart Association class III, IV); MI or a cardiovascular accident within the previous 2 weeks; high-risk arrhythmias; hypertrophic obstructive and other cardiomyopathies; or moderate-to-severe valvular disease. The document states that patients at high risk should not receive treatment for sexual dysfunction until their cardiac condition has stabilized. Patients at low risk may be considered for all first-line therapies. The majority of patients treated for ED are in the low-risk category defined as those who have asymptomatic coronary artery disease and less than three risk factors for coronary artery disease (excluding gender); controlled hypertension; mild, stable angina; a successful coronary revascularization; uncomplicated past MI; mild valvular disease; or CHF (left ventricular dysfunction and/or New York Heart Association class I). Patients whose risk is indeterminate should undergo further evaluation by a cardiologist before receiving therapies for sexual dysfunction.

Treatment Guideline Statements

The nonsurgical therapies for ED considered for review by the Panel include the PDE5 inhibitors, sildenafil, tadalafil, and vardenafil; alprostadil intra-urethral suppositories; intracavernous injection with alprostadil, papaverine, or phentolamine or combinations; vacuum constriction devices; trazodone; and herbal therapies including yohimbine. Chapter 3 provides the results of the evidence-based, outcomes analyses of the noninvasive therapies to the extent that the outcomes evidence was available. The following practice guideline statements are specific to the nonsurgical therapies.

Phosphodiesterase Type 5 (PDE5) Inhibitors

Guideline Statement 1

Standard: Oral phosphodiesterase type 5 inhibitors, unless contraindicated, should be offered as a first-line of therapy for erectile dysfunction.

Discussion


Guideline Statement 2

Standard: Phosphodiesterase type 5 inhibitors are contraindicated in patients who are taking organic nitrates.

Discussion


Guideline Statement 3

Recommendation: The monitoring of patients receiving continuing phosphodiesterase type 5 inhibitor therapy should include a periodic follow-up of efficacy, side effects, and any significant change in health status including medications.

Discussion


Guideline Statement 4

Recommendation: Prior to proceeding to other therapies, patients reporting failure of phosphodiesterase type 5 (PDE5) inhibitor therapy should be evaluated to determine whether the trial of PDE5 inhibition was adequate.

Discussion


Guideline Statement 5

Recommendation: Patients who have failed a trial with phosphodiesterase type 5 (PDE5) inhibitor therapy should be informed of the benefits and risks of other therapies, including the use of a different PDE5 inhibitor, alprostadil intra-urethral suppositories, intracavernous drug injection, vacuum constriction devices, and penile prostheses.

Discussion


Alprostadil Intra-urethral Suppositories

Guideline Statement 6

Standard: The initial trial dose of alprostadil intra-urethral suppositories should be administered under healthcare provider supervision due to the risk of syncope.

Discussion


Intracavernous Vasoactive Drug Injection Therapy

Intracavernous injection therapy is the most effective nonsurgical treatment for ED; however, it is invasive and has the highest potential for priapism among ED treatments. Alprostadil (PGE1), papaverine, and phentolamine are the most widely used vasoactive drugs for injection therapy. As monotherapy, alprostadil is the most popular vasoactive agent; however, combination therapy with the other vasoactive drugs (bimix and trimix) can either increase efficacy or reduce side effects. The advantage of monotherapy with either papaverine or alprostadil is that they are readily available at most pharmacies whereas bimix and trimix are only available from pharmacies that offer compounding services. Physician preference guides the initial choice of therapy. Final choice is based on efficacy, side effects, and cost.

Because the Panel believed that the new body of evidence on the efficacy and safety of intracavernous therapy would not substantially change the outcome estimates of the 1996 Report, the literature on this topic was not reviewed. The co-administration of oral PDE5 inhibitors and intracavernous injection therapy has not been adequately evaluated at this time.

Guideline Statement 7

Standard: The initial trial dose of intracavernous injection therapy should be administered under healthcare provider supervision.

Discussion


Guideline Statement 8

Standard: Physicians who prescribe intracavernous injection therapy should (1) inform patients of the potential occurrence of prolonged erections, (2) have a plan for the urgent treatment of prolonged erections and (3) inform the patient of the plan.

(See AUA guideline on priapism)

Discussion


Vacuum Constriction Devices

Guideline Statement 9

Recommendation: Only vacuum constriction devices containing a vacuum limiter should be used whether purchased over-the-counter or procured with a prescription.

Discussion


Treatment Modalities With Limited Data

Trazodone

Recommendation: The use of trazodone in the treatment of erectile dysfunction is not recommended.

Discussion


Testosterone

Recommendation: Testosterone therapy is not indicated for the treatment of erectile dysfunction in the patient with a normal serum testosterone level.

Discussion


Yohimbine

Recommendation: Yohimbine is not recommended for the treatment of erectile dysfunction.

Discussion


Other Herbal Therapies

Recommendation: Herbal therapies are not recommended for the treatment of erectile dysfunction.

Discussion


Topical Therapies

Alternative routes of administration of vasoactive drugs for the treatment of ED that are less threatening than injection therapy have been explored. Agents that are approved by the FDA for other indications or other routes of administration, including alprostadil, organic nitrates, minoxidil, papaverine, and yohimbine, have been tested via topical administration to the glans penis or penile shaft. Although these therapies are not currently approved by the FDA, they may be available through compounding pharmacies. A specific literature search was not conducted on this topic due to the lack of both FDA approval and widespread application. Based upon the limited studies available and expert consensus, there does not appear to be significant efficacy beyond that observed with intraurethral administration of alprostadil.

Surgical Therapies

Penile Prothesis Implantation

Standard: The patient considering prosthesis implantation and, when possible, his partner should be informed of the following: types of prostheses available; possibility and consequences of infection and erosion, mechanical failure, and resulting reoperation; differences from the normal flaccid and erect penis, including penile shortening; and potential reduction of the effectiveness of other therapies if the device is subsequently removed.

Discussion


Standard: Prosthetic surgery should not be performed in the presence of systemic, cutaneous, or urinary tract infection.

Discussion


Standard: Antibiotics providing Gram-negative and Gram-positive coverage should be administered preoperatively.

Discussion


Penile Venous Reconstructive Surgery

Recommendation: Surgeries performed with the intent to limit the venous outflow of the penis are not recommended.

Discussion


Penile Arterial Reconstructive Surgery

Option: Arterial reconstructive surgery is a treatment option only in healthy individuals with recently acquired erectile dysfunction secondary to a focal arterial occlusion and in the absence of any evidence of generalized vascular disease.

Discussion


Future Research

Many of the future research needs outlined in the 1996 Report have been addressed in the past 8 years. The development of the PDE5 inhibitors has answered the requirement for an oral therapy that has broad-based usage with minimal side effects. While new and better designed studies, i.e., prospective, randomized controlled trials, have allowed fresh insight into the treatment of ED, drawbacks of the methodologies employed have been identified. Despite these advances, however, many of the issues raised still remain controversial while other knowledge gaps have arisen.

In order to develop new and more effective agents for treatment, research is needed in the areas of pathophysiology, natural history, and epidemiology. Specifically, the Panel recognizes that data concerning the role of hypogonadism in ED are seriously lacking, as are the proportion of men with ED and the prevalence of bothersomeness in men and their partners before and after treatment. The prevalence and severity of ED in men with specific risk factors, such as those with hypertension, hyperlipidemia, diabetes, and smoking, should be identified and compared.

Although diagnostic testing was not evaluated in the guideline, after review of the published clinical trials, the Panel noted that new, clinically applicable instruments are needed to diagnose ED and to assess treatment satisfaction. In addition, a clinically applicable test of neurological function of the corpora cavernosa should be developed. The best measure of venous-occlusive dysfunction must also be determined. Since the advent of oral pharmacotherapy, there has been a shift in the evaluation paradigm for ED away from the objective (evidence-based) toward the subjective (historical) that has impeded our appreciation of the clinical impact of veno-occlusive dysfunction. Evidence-based criteria are needed in order to categorize patients to arterial or venous etiologies.

The therapeutic armamentarium has changed considerably since 1996, and the PDE5 inhibitors are enjoying widespread use. However, many questions still remain unanswered regarding these and other therapeutic modalities:

  • Outcomes of oral PDE5 inhibitors should be characterized/stratified based on serum testosterone levels.
  • Additional research also is needed to characterize, in greater detail, the adverse events associated with the use of ED therapies such as their duration.
  • Effect of lifestyle modification on PDE5 inhibitor use should be clarified.
  • The cohort of patients who should not be sexually active with or without PDE5 inhibitors should be identified.
  • PDE11 is present in the anterior pituitary and the testes. While studies, to date, have demonstrated no effect on spermatogenesis when PDE5 inhibitors are administered daily for 6 months in healthy individuals, further assessment of the effect of PDE5 inhibitors that cross react with PDE11 in patients with abnormal spermatogenesis is needed.
  • The applicability of PDE5 inhibitors after radical prostatectomy needs to be characterized.
  • Whether vasoactive intracavernous therapy will cause improvement in spontaneous erectile function needs to be clarified.
  • The role of testosterone therapy in men with sexual dysfunction with low, borderline normal, and normal testosterone levels should be better defined.
  • Additional randomized controlled trials of various herbal therapies are needed.
  • Additional prospective patient-partner satisfaction studies are needed using standardized questionnaires both pre- and post-penile prostheses implantation.
  • The role of prophylactic antibiotics in penile prostheses implantation and the use of impregnated prostheses needs to be studied further.
  • The efficacy and safety of combining pharmacotherapies and/or mechanical therapies such as oral and intrapenile vasoconstrictive therapies, PDE5 inhibitors and prostheses, or vacuum constriction and vasoconstriction devices should be explored.
  • Additional research also is needed to evaluate the efficacy and safety of arterial reconstruction in the treatment of ED.
  • No randomized controlled trial to date has addressed the particular efficacy of drugs in the management of veno-occlusive ED or defined those patients thought to have veno- occlusive dysfunction who would benefit from surgical application.
  • Cost-effectiveness analyses of the fixed and unfixed costs involved with the various ED treatment modalities need to be undertaken.

Despite the increasing number of properly planned and executed randomized controlled clinical trials in the literature, extraction of data for comparison and meta-analysis remains a challenge. Drawbacks of the methodologies employed have been identified. The Panel now recognizes a need for standardized inclusion and exclusion criteria, as well as outcome measures to be incorporated in future study designs:

  • Patients enrolled in these studies have varied in their disease severity and duration, etiology, success with other treatments, and in-office success with therapy. If outcomes are not stratified by patient characteristics, both study and guideline results are biased. A crossover design also may compensate for variation in patient characteristics. While statistically adjusting results can be a useful way to overcome patient differences, reporting results stratified by those characteristics can be more useful for later patient/physician decision making.
  • Although the IIEF provides a uniform measure, not all studies use the IIEF and many of those that do report only limited and variable subsets of the IIEF. Many studies still use other measures as well. A standardized measure of patient-partner satisfaction beyond the IIEF could be developed, for example, in the case of penile prosthesis implantation or in general an instrument to measure sexual desire.
  • The Panel noted that future research in penile prosthesis implantation should always express survival using Kaplan-Meier methods and include data on the numbers of patients censored.
  • Data presentation that facilitates meta-analysis:

Measures of variance (standard error, standard deviation, confidence interval) are needed to perform meta-analysis on continuous or discrete outcome measures. Change from baseline, mean change, and/or percentage change are frequently the most meaningful outcome measures particularly when patients vary with regard to baseline values. In addition, measures of variance of change and percentage of change are needed to meta-analyze change data.

While presentation of results adjusted for patient variables compensates for patient differences, meta-analysis is possible only if adjustments are identical. Because investigators do not report details of the adjustment process, raw data should be made available.

When previously reported study outcomes are regrouped or reanalyzed in a subsequent publication, the investigator should indicate such so that patients will not be counted more than once in a meta-analysis.

Because direct comparisons of the therapies via meta-analyses are not possible with the available data, comparative trials still are required. Trial design should use comparable doses and not use titration-to-response, which can be biased by the available doses. If data presentation among studies is compatible, one-on-one comparisons for all agents may not be required to produce valid conclusions.

References

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2. Impotence. NIH Consens Statement, 10: 1, 1992

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27. Kloner, R.A., Mitchell, M. and Emmick, J.T.: Cardiovascular effects of tadalafil. Am J Cardiol, 92: 37M, 2003

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