Published: November 2012
Since the 1990s, there has been increasing recognition that erectile dysfunction (ED) is a common problem. Increasing awareness of effective treatment strategies on behalf of patients, effective advertising by drug companies, and acknowledgement by health care providers that screening may help identify cardiovascular and other medical risks have led to higher rates of reporting, diagnosis, and treatment of ED.
Erectile dysfunction is the inability to develop and maintain an erection for satisfactory sexual intercourse or activity in the absence of an ejaculatory disorder such as premature ejaculation. Erectile dysfunction is the preferred term rather than impotence. There are no universally agreed criteria for how consistent the problem has to be and for what duration it needs to be present to fulfill the definition. A period of persistence of longer than 3 months has been suggested as a reasonable clinical guideline.
Several studies have looked at the prevalence of ED. The Massachusetts Male Aging Study1 reported a prevalence of 52%. The study demonstrated that ED is increasingly prevalent with age. At age 40, approximately 40% of men are affected. The rate increases to nearly 70% in men aged 70 years. The prevalence of complete ED increases from 5% to 15% as age increases from 40 to 70 years.1 Age was the variable most strongly associated with ED.
Following adjustment for age, a higher probability was noted in patients with heart disease, hypertension, diabetes, and those taking associated medications. Cigarette smoking in this study did not correlate with a greater probability of complete ED. However, when it was associated with heart disease and hypertension, a higher probability of ED was noted.
Incidence estimates have been published using data compiled from the Massachusetts Male Aging Study.2 Incidence data are necessary to assess risk and plan treatment and prevention strategies. The Massachusetts study data suggest there will be approximately 17,781 new cases of ED in Massachusetts and 617,715 in the United States annually.
A larger national study, the National Health and Social Life Survey, looked at sexual function in men and women.3 This study surveyed 1410 men aged 18 to 59 years, and it also documented an increase in ED with age. Additionally, the study found a decrease in sexual desire with increasing age. Men in the oldest cohort (those aged 50-59 years) were more than 3 times as likely to experience erection problems and to report low sexual desire compared to men aged 18 to 29 years. Experience of sexual dysfunction was more likely among men in poor physical and emotional health. It was also concluded that sexual dysfunction is an important public health concern and added that emotional issues are likely to contribute to the experience of these problems.
The development of an erection is a complex event involving integration of psychologic, neurologic, endocrine, vascular, and local anatomic systems. Positron emission tomography (PET) scanning studies4 have suggested that sexual arousal is activated in higher cortical centers which then stimulate the medial preoptic and paraventricular nuclei of the hypothalamus. These signals ultimately descend through a complex neural network involving the parasympathetic nervous system and eventually activate parasympathetic nerves in the sacral area (S2 to S4).
The neurovascular events that ultimately occur result in the inhibition of adrenergic tone and the release of the nonadrenergic, noncholinergic (NANC) neurotransmitter nitric oxide. Nitric oxide is believed to be released from NANC nerves and endothelial cells. It subsequently stimulates the guanylate cyclase enzyme system in penile smooth muscle. This results in increased levels of cyclic guanosine monophosphate (GMP) and ultimately in smooth muscle relaxation, enhancement of arterial inflow, and veno-occlusion, producing adequate firmness for sexual activity.
Recognized risk factors for ED include cardiovascular disease (hypertension, atherosclerosis, and hyperlipidemia), diabetes, depression, alcohol use, smoking, pelvic/perineal surgery or trauma, neurologic disease, obesity, pelvic radiation, and Peyronie disease. Examples of common neurologic conditions that can lead to ED include cerebral vascular accident, multiple sclerosis, Parkinson disease, and spinal cord injury. More commonly, vascular disease and diabetes can produce neurovascular abnormalities resulting in ED. Surgery for cancers of the prostate, bladder, and colon may disrupt both neural and vascular pathways, resulting in ED.
Hormone deficiency or hypogonadism, whether primary or secondary, can result in ED. Hormone deficiency, however, is less often the cause of ED than is diabetes or vascular disease. How often ED is caused by hormone deficiency remains somewhat controversial, but estimates of approximately 3% to 5% of cases are reasonable. Medications and recreational drugs can also produce erectile dysfunction by various poorly understood mechanisms.
Some health questionnaires help screen for and evaluate erectile dysfunction5 and may help in the primary care setting. It is important, however, to recognize that abbreviated questionnaires might not evaluate specific areas of the sexual cycle, such as sexual desire, ejaculation, and orgasm. Nonetheless, they can be useful in helping patients discuss the problem and in signaling the need for an evaluation.
If it is determined that ED is a problem, a detailed sexual and medical history should be taken and a physical examination should be done to evaluate the patient. In particular, it is important to evaluate the ED and to rule out premature ejaculation, which is also a common sexual dysfunction.6
A number of specific questions relating to sexual function can help the clinician evaluate the complaint of ED. Questions should focus on the following:
Once questions related to the specific erectile complaint have been reviewed, additional questions relating to medical and psychosocial factors need to be evaluated. In particular, these include the following: symptoms suggesting the presence of diabetes, peripheral vascular disease, neurologic disease, or chronic liver or kidney disease; a complete list of medications and recreational drugs, including alcohol, and questions about cigarette smoking; history of surgery or radiation therapy, particularly procedures related to genitourinary or gastrointestinal malignancy; a history of pelvic genital, perineal, or spinal cord trauma; and the quality of the marital or partner relationship and expectations of both patient and partner.
Following a review of the medical history, the salient features of the physical examination should include the following:
Once a complete sexual and medical history has been completed, appropriate laboratory studies should be conducted. In the initial evaluation of ED, sophisticated laboratory testing is rarely necessary. For example, when history or physical exam directs, it may be appropriate to include hormonal evaluation to exclude a diagnosis of hypogonadism (low testosterone and prolactin levels) or hypothyroidism (low thyroid stimulating hormone [TSH] levels) or to screen for diabetes if the patient is not known to be diabetic (hemoglobin A1c or glucose tolerance testing). A basic metabolic panel and/or urinalysis may identify patients at risk for liver or kidney disease. A lipid panel may also be warranted as a screen for cardiac risk factors.
In most cases, a tentative diagnosis can be established with a complete sexual and medical history, physical examination, and limited laboratory testing. In many cases, the diagnosis remains somewhat ambiguous. However, with the availability of oral medication for treatment of ED that is safe and has minimal or tolerable side effects, additional diagnostic testing is probably unnecessary or can be delayed until a therapeutic trial of oral medication has proved ineffective.
Although there are numerous options for nonsurgical treatment, oral phosphodiesterase-5 (PDE5) inhibitors should be offered as first-line treatment of patients with ED unless contraindicated.7 A summary of the 3 oral PDE5 drugs approved for use by the U.S. Food and Drug Administration (FDA) is found in Table 1.
|Peak effect||0.5-1 hr||0.7-0.9 hr||2 hr|
|Alcohol or fatty meal decreases absorption||Yes||Yes||Yes|
|Duration of effect||4 hr||4 hr||24-36 hr|
|Side effects||Visual changes||Back and limb muscle pain|
|Side effects (all)||
All 3 drugs reversibly inhibit penile-specific PDE5 and enhance the nitric oxide–cyclic GMP pathways of cavernous smooth muscle relaxation; that is, all 3 prevent the breakdown of cyclic GMP by PDE5.
According to a review of all randomized, controlled trials evaluating sildenafil by the American Urological Association (AUA) Consensus Panel on Erectile Dysfunction, 36% to 76% of patients receiving the drug were "able to achieve intercourse" during treatment. For tadalafil, a smaller number (4) of randomized controlled trials revealed that 11% to 47% of patients were "able to achieve intercourse" (dose-dependant). Similar efficacy has been observed with vardenafil, although studies are fewer.7
The success rate of all 3 drugs is reduced in some patient groups. For example, efficacy in diabetic patients is probably closer to 50% to 60%, with demonstrated effectiveness for those with type 1 or 2 diabetes. Although patients who have had a radical prostatectomy might respond to any of these drugs, the best response occurs in patients whose procedure was bilateral nerve sparing. In these patients, success rates vary but approach 70% in some series. However, if a single nerve was spared, success is reduced and, if no nerves were spared, results are generally poor, with a success rate of less than 15%.
All 3 drugs require sexual stimulation to be effective. The usual dose of sildenafil is 50 mg or 100 mg taken approximately 1 hour before intercourse, on an empty stomach. Vardenafil is also taken 1 hour before intercourse, with a usual dose of 10 mg or 20 mg. Vardenafil may be less affected by food intake, but absorption may be delayed if a high-fat meal has recently been ingested. Tadalafil may be taken 2 hours before intercourse, but its longer half-life (17.5 hours) allows greater patient flexibility in deciding when to initiate intercourse (eg, 6, 8, or perhaps 12 hours before). Tadalafil may be taken without regard to food intake.
All 3 drugs are generally well tolerated. Side effects include headache, flushing, dyspepsia, and nasal congestion. Visual abnormalities are encountered with sildenafil, but are unlikely with vardenafil and tadalafil. Back pain and myalgia can occur with tadalafil, but are unusual with sildenafil or vardenafil. Patients deemed to be of highest cardiovascular risk should not be treated for ED until their cardiac condition has been stabilized. These conditions include unstable/refractory angina, myocardial infarction/cerebrovascular accident (MI/CVA) within the past 2 weeks, uncontrolled hypertension, NYHA Class III-IV congestive heart failure, high-risk arrhythmias, hypertrophic obstructive cardiomyopathies, and moderate-to-severe valvular disease.8 In addition, all 3 drugs are contraindicated in patients who use nitroglycerin or nitrate-containing compounds.9,10 Combining any of these 3 drugs with nitroglycerin or nitrates can result in significant hypotension. Vardenafil is contraindicated in patients using doxazosin, terazosin, or tamsulosin. Tadalafil is contraindicated in patients using doxazosin or terazosin. It may be safely taken with tamsulosin at the 0.4-mg dose. In patients who take 50 mg of sildenafil or more and use alpha blockers, sildenafil dosing should be avoided for at least 4 hours after the dose of the alpha blocker. In patients who take 25 mg of sildenafil, use of any of the alpha blockers is considered safe. These drugs are often used for the treatment of benign prostatic hypertrophy and perhaps less often for hypertension.
Although vardenafil does not seem to produce significant clinical QT prolongation, it has been suggested that it be avoided in patients who have congenital QT prolongation abnormalities and in patients using class I antiarrhythmic drugs, such as quinidine and procainamide. It is also best to avoid the use of vardenafil with Class III antiarrhythmic drugs, such as amiodarone or sotalol.
Dose-adjustment is recommended in patients with hepatic failure and with co-administration of drugs also metabolized by the cytochrome p450 enzymes.
It is extremely important to take a complete drug history, particularly with regard to antihypertensive medications and drugs used for cardiovascular disease, anxiety, depression, or psychosis in any patient complaining of ED (Table 2). Antihypertensive drugs, such as diuretics and beta blockers, may be associated with ED and perhaps can be discontinued or switched to alternative drugs, such as angiotensin-converting enzyme inhibitors or calcium channel blockers (eg, diltiazem, nifedipine, amlodipine), which might cause less of a problem. The newer angiotensin II receptor antagonists may also be less problematic, but more long-term data are needed to confirm this.
* This list is by no means comprehensive
© 2004 The Cleveland Clinic Foundation.
Of the drugs used for depression, tricyclic antidepressants may be associated with erectile problems and other drugs may be substituted to prevent this complication. Currently available substitutes include bupropion, nefazodone, and trazodone. The selective serotonin reuptake inhibitors (eg, fluoxetine, sertraline, paroxetine, citalopram) can also cause difficulties with ED, but they might also have other significant sexual side effects, including decreased libido and anorgasmia.
Clinical experience in switching medications has overall been disappointing, and improvement does not often seem to occur. Nonetheless, it is important to try to discontinue possible offending medications before proceeding to more invasive options. Oral therapy has changed the ways that clinicians discontinue medications in patients with ED, and has improved the approach. For example, a patient might develop erectile dysfunction on a thiazide diuretic. The drug may be withdrawn, but a trial of oral ED therapy can be initiated during the observation period while the patient is waiting to see whether any spontaneous improvement in erectile function occurs after drug withdrawal. Alternatively, if diuretic therapy is effective, well tolerated, and controlling the blood pressure, oral ED therapy can be used to deal with the sexual side effects on an ongoing basis.
If a trial of oral therapy and withdrawal of offending medications prove to be ineffective in restoring erectile function, it is probably appropriate for most primary care practitioners to consider referral to a specialist for additional evaluation and discussion of alternative treatment options. These include intracavernous injection therapy, vacuum constriction devices, intraurethral therapy, and possible surgery.
As noted, if a trial of oral therapy and withdrawal of offending medications do not restore erectile function, most primary care practitioners should consider referring the patient to a specialist for additional evaluation and discussion of alternative treatment options. However, some primary care practitioners may recommend vacuum constriction devices. Two treatment guidelines have suggested that such devices are a first-line treatment modality.11,12
The device consists of an acrylic cylinder placed over the penis that uses a lubricant to achieve a good seal between the penile body and cylinder. An erection is then achieved by creating a vacuum inside the cylinder with a pump connected to the cylinder. Once an erection is achieved, a constriction band is applied to the base of the penis to maintain the erection. The cylinder can then be removed and the patient can engage in intercourse with the constriction band(s) at the base of the penis maintaining the erection. The bands can remain on for approximately 30 minutes and then must be removed. The erection produced by the device differs from a normal erection likely because of venous occlusion from the constriction band resulting in generalized swelling of the entire penis, with probable preservation of arterial inflow.
Clinical studies have suggested that these devices are effective and acceptable to a large number of patients with ED of varying causes, including psychogenic erectile failure. The initial overall response rate is approximately 80% to 90%. However, satisfaction with this treatment modality typically wanes with time, as patients report dissatisfaction with how cumbersome or unnatural the devices are to use, hinging or buckling of the erection with thrusting, and dissatisfaction with the fact that the erection is ischemic (and therefore cold) which can be off-putting to the partner.
There are relatively few contraindications to the use of vacuum devices. Some conditions can predispose to priapism or perhaps bleeding with constriction, such as sickle cell disease, polycythemia, and other blood dyscrasias. Patients taking anticoagulants (warfarin) can safely use vacuum constriction devices but need to accept a higher risk of bleeding (ecchymosis). Good manual dexterity is also needed to use the device; if manual dexterity is impaired, a willing sexual partner can learn to apply the device.
Complications from the use of a vacuum constriction device are relatively minor. They include the development of petechiae or ecchymosis, numbness or coolness of the penis, trapping of the ejaculate, and pivoting of the penis at the base.
Alprostadil (also known as prostaglandin E1 [PGE1]) is the prominent known smooth-muscle dilator of the corpus cavernosum. Its mechanism of action is believed to be the promotion intracellular accumulation of cAMP, thereby causing decreased intracellular accumulation of calcium and resulting smooth muscle relaxation. Alprostadil can be delivered to the erectile tissue either via an intraurethral suppository that is massaged and then absorbed across the corpus spongiosum of the urethra to the corpora cavernosa, or directly injected into the corpora cavernosa. When administered urethrally, doses are approximately 10 times higher than when directly injected (125 mcg to 250 mcg intraurethral compared with 2.5 mcg to 25 mcg intracavernosal).
Side effects include feeling light-headed, fainting, priapism, urethral bleeding (intraurethral), dyspareunia in partner (intraurethral), hematoma (intracavernosal) or penile curvature secondary to scar (intracavernosal). Efficacy of intraurethral alprostadil has been demonstrated to be around 50% ("able to have intercourse") in randomized controlled trials.13,14 For intracorporeal injection, typically alprostadil is tried alone, or compounded with papaverine (nonspecific phosphodiesterase inhibitor that increases intracellular cAMP and cGMP) and/or phentolamine (competitive, non-selective alpha1- and alpha2-adrenoreceptor blocker).
An extensive review of the benefits and drawbacks of the combinations of these drugs is beyond the scope of this chapter, but can be found in the review by Pinsky et al.15 Given the high risk of priapism during escalation of therapy for intracorporeal injection, it is recommended that the drugs be administered in a supervised office visit initially and that the patient be given a well-articulated plan for treatment of priapism if it occurs. Escalation guidelines for alprostadil alone vary, but a general guideline is to start at 2.5 mcg and increase by 2.5 mcg to a dose of 5 mcg and then in increments of 5 mcg to 10 mcg until an erection sufficient for penetration, not lasting more than 1 hour, is achieved. If there is no response to the initial 2.5-mcg dose, escalation dosing can be slightly more liberal. A European prospective 4-year trial of the drug also evaluated success of PGE1 alone and demonstrated rates ranging from 89% to 97%.16
Several treatments were promoted in the pre-PGE1, pre-prostaglandin era, including yohimbine, trazodone, testosterone, and various herbal remedies. None of these is currently recommended under the updated AUA Guidelines for the Treatment of Erectile Dysfunction. Testosterone supplementation is only recommended for men with low testosterone levels. One small randomized trial of Korean red ginseng has been published17 which demonstrated modest improvements in International Index of Erectile Function (IIEF) and RigiScan scores compared with placebo.
Implantation of penile prosthesis remains an important option for men in whom medical treatment of ED has failed or is in appropriate. Prostheses are available as a saline-filled silicone device or a malleable device. The benefit of the former is a more natural appearance in the deflated state, closely approximating the appearance of a flaccid penis. The trade-off is a higher mechanical failure rate and higher cost. Satisfaction rates for patients who underwent penile prosthesis surgery have been reported to be higher than 90%.18 However, in the majority of patients who receive this treatment, less invasive alternatives have failed and therefore satisfaction with this treatment would be expected to be higher in this subset of patients. Risks of these devices include surgical and anesthetic risk, device infection, and device malfunction. Mechanical failure rates depend on the specific device being investigated. Overall, the percentage of devices that are free from mechanical failure at 5 years ranges from 80% to 90%.7 Infection rates in the era of coated devices and improved techniques are reported to be less than 1%.19
All devices that are currently FDA approved are considered safe for use in a magnetic resonance imaging (MRI) environment. However, 2 previously approved devices–the OmniPhase and the DuraPhase penile prostheses–are not considered safe in this environment.
Other surgical procedures–including venous ligation to limit penile venous outflow and penile revascularization procedures–are rarely successful and are not recommended.7 These surgeries are only indicated when a patient demonstrates recent-onset ED and an occlusive lesion seen on angiogram or MR angiography and should be performed only in centers of excellence for ED.