In the last 20 years, there has been increasing recognition that erectile dysfunction is a common problem. Although many patients may come to their general practitioner's or internist's office with erectile dysfunction as a primary complaint, there are still many patients who feel reluctant or embarrassed to discuss this problem. Many physicians also feel uncomfortable discussing and evaluating sexual dysfunction. It is important for us as physicians to feel comfortable discussing and evaluating sexual dysfunction and hopefully to help our patients feel comfortable talking about these issues.

Definition

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 the more commonly used term of impotence. There are no universally agreed on 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 for longer than 3 months has been suggested as a reasonable clinical guideline.

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Prevalence

Several recent studies have looked at the prevalence of erectile dysfunction. The Massachusetts male aging study, conducted from 1987 to 1989 in areas around Boston, was a cross-sectional random sample community-based survey of 1290 men ages 40 to 70 years. ¹ Erectile dysfunction was self-reported and the condition was classified as mild, moderate, or complete. The combined prevalence of minimal, moderate, and complete erectile dysfunction was 52%. The study demonstrated that erectile dysfunction is increasingly prevalent with age. At age 40, there is an approximately 40% prevalence rate, increasing to almost 70% in men at age 70. The prevalence of moderate erectile dysfunction increases from 17% to approximately 34% the prevalence of complete erectile dysfunction increases from 5% to 15% as age increases from 40 to 70 years.

Although age was the variable most strongly associated with erectile dysfunction, following adjustment for age, a higher probability was noted with heart disease, hypertension, diabetes, and associated medications. Cigarette smoking in this study did not show a greater probability of complete erectile dysfunction. However, when it was associated with heart disease and hypertension, a higher probability of erectile dysfunction was noted. The study concluded that erectile dysfunction is a major health concern in light of its high prevalence.

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 have suggested there will be approximately 17,781 new cases of erectile dysfunction in Massachusetts and 617,715 in the United States annually. The national incidence estimate may underestimate the true incidence, because Massachusetts is largely white, so likely the data are underestimated nationally for African Americans, Hispanics. and other groups.

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 ages 18 to 59 years, and it also documented an increase in erectile dysfunction with age. Additionally, the study found a decrease in sexual desire with increasing age. The oldest cohort of men (ages 50 to 59 years) was more than three times as likely to experience erection problems and to report low sexual desire in comparison with men ages 18 to 29 years. In this study, there was a higher prevalence of sexual dysfunction in men who had never married or were divorced. 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.

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Pathophysiology

The development of an erection is a complex event involving integration of psychological, neurologic, endocrine, vascular, and local anatomic systems. Positron emission tomography (PET) scanning studies ⁴ 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 release of the nonadrenergic, noncholinergic neurotransmitter nitric oxide. Nitric oxide is believed to be released from nonadrenergic noncholinergic (NANC) nerves and endothelial cells. Nitric oxide 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.

Abnormalities in any of these systems may produce erectile dysfunction. For example, cerebral vascular accidents, multiple sclerosis, Parkinson's disease, and spinal cord injury may result in neurogenic erectile dysfunction. More commonly, vascular disease and diabetes may produce neurovascular abnormalities resulting in erectile dysfunction. Surgery for cancers of the prostate, bladder, and colon may also produce neurovascular abnormalities resulting in erectile dysfunction. Diseases such as Peyronie's disease, in which patches or strands of dense tissue surround the cavernous body of the penis, and traumatic perineal and penile injuries may also interfere with neurovascular and anatomic structures, producing erectile dysfunction.

Hormone deficiency or hypogonadism, whether primary or secondary, can result in erectile dysfunction. Hormone deficiency, however, is less often the cause of erectile dysfunction than diabetes or vascular disease. How often erectile dysfunction is caused by hormone deficiency remains somewhat controversial, but estimates of approximately 3% to 5% of cases are probably reasonable. Medications and recreational drugs may also produce erectile dysfunction by various poorly understood mechanisms.

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Signs and Symptoms

Although erectile dysfunction is a common problem, many patients are reluctant to discuss it. Certainly, some patients who present with issues relating to depression or anxiety disorders may actually have a significant problem with erectile dysfunction. Additionally, patients who are poorly compliant with medication prescribed for hypertension may be experiencing significant erectile dysfunction. The best way to elicit whether the problem is present is to ask questions about sexual function as a routine part of the examination.

Some health questionnaires help screen for and evaluate erectile dysfunction ⁵ and may help in the primary care setting. It is important, however, to recognize that abbreviated questionnaires may 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.

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Diagnosis

If it is determined that erectile dysfunction is a problem, a detailed sexual and medical history should be elicited and a physical examination should be done to evaluate the problem. In particular, it is important to evaluate the erectile dysfunction and make sure that the problem is not premature ejaculation, which is also a frequent sexual dysfunction. ⁶

A number of specific questions relating to sexual function help evaluate the complaint of erectile dysfunction. Questions should focus on the following:

1. How long has the erectile dysfunction been a problem, and did it start gradually or suddenly?
2. How frequent is intercourse currently, and how frequent was it in the past? Is there difficulty with vaginal penetration and/or loss of the erection intravaginally in the absence of premature ejaculation?
3. How firm are the erections (use a scale of 1 to 10)? Do erections vary under different circumstances, such as with different partners, oral stimulation, or masturbation?
4. Are morning or evening erections present and, if so, what is the quality of these erections?
5. Is there any new curve or bend to the penis to suggest Peyronie's disease? If curvature is present, is it painful? What are the location and severity of the curvature?
6. Are there any difficulties with sexual desire, arousal, ejaculation, or orgasm (climax)? If there are difficulties, did these difficulties occur with the onset of the erectile dysfunction or are they separate issues?

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: (1) symptoms suggesting the presence of diabetes, peripheral vascular disease, neurologic disease, or chronic liver or kidney disease; (2) a complete list of medications and recreational drugs, including alcohol, and questions about cigarette smoking; (3) previous history of surgery or radiation therapy, particularly procedures related to genitourinary or gastrointestinal malignancy; (4) a history of pelvic genital, perineal, or spinal cord trauma; and (5) 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:

1. An assessment of the patient's general health and affect, as well as secondary sexual characteristics, noting in particular gynecomastia and hair loss (axillary or pubic)
2. Careful peripheral vascular examination that includes palpation of the lower extremity pulses as well as auscultation for bruits in the abdominal and femoral regions
3. Detailed neurologic examination to include gait and postural instability, with blood pressure changes, distal extremity and saddle sensation, and reflexes, including cremasterics and bulbocavernosus
4. Careful genital examination, noting testicular size and palpating for Peyronie's plaques
5. Rectal examination to assess sphincter tone and evaluate the prostate
6. Careful abdominal examination looking for organomegaly masses or other signs of liver or kidney disease
7. Cardiopulmonary examination to help evaluate the patient's fitness for future treatment options

Once a complete sexual and medical history has been completed, appropriate laboratory studies can be considered. In the initial evaluation of erectile dysfunction, sophisticated laboratory testing is rarely necessary. Laboratory studies should include hormonal evaluation to exclude a diagnosis of hypogonadism (testosterone and prolactin levels) and testing to screen for diabetes if the patient is not known to be diabetic (hemoglobin A or glucose tolerance testing). Most patients will usually have had a general survey but this is certainly appropriate if it has not been done to assess for kidney or liver disease. A lipid panel is also appropriate as a screen for 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 may still remain somewhat ambiguous. However, with the availability of oral medication for treatment of erectile dysfunction 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 proven ineffective.

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Treatment

Oral Treatment

The current nonsurgical treatments are listed in Box 1 . Although there are a number of options available for nonsurgical treatment, it is clear that oral therapy has revolutionized the treatment approach to patients with erectile dysfunction. As noted, once an initial appropriate evaluation has been performed and a tentative diagnosis is made, a trial of oral therapy is usually the preferred treatment choice for most patients. Currently, there are three oral agents approved for use by the U.S. Food and Drug Administration (FDA). These are sildenafil citrate (Viagra), vardenafil hydrochloride (Levitra), and tadalafil (Cialis).

All three drugs reversibly inhibit the penile-specific phosphodiesterase type 5 (PDE5) and enhance the nitric oxide–cyclic GMP pathways of cavernous smooth muscle relaxation—that is, all three prevent the breakdown of cyclic GMP by PDE5. In several double-blind, placebo-controlled studies of patients with erectile dysfunction of varied causes, all three drugs demonstrated improvement in erectile function, with success rates varying between 70% and 90%, depending on the populations studied. ^7–10

Clinical studies have demonstrated that sildenafil is a durable therapy, with patients able to remain on the medication and use it effectively. Some of these studies have also documented improved quality of life for both patient and partner with use of this medication. Vardenafil and tadalafil were more recently approved by the FDA, so existing clinical studies documenting effectiveness are short term. Hopefully, studies investigating their durability will be forthcoming.

The success rate of all three drugs is reduced in some patient groups. For example, success 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 may respond to any of these drugs, the best response occurs in patients whose procedure was bilateral nerve sparing. In patients whose procedure was bilateral nerve sparing, success rates may 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 three drugs require sexual stimulation to be effective. The usual dose of sildenafil is 50 or 100 mg taken approximately 1 hour before intercourse, on an empty stomach and avoiding a fatty meal. Vardenafil is also taken 1 hour before intercourse, with a usual dose of 10 or 20 mg. Vardenafil may be less affected by food intake, but absorption may be delayed if a high-fat meal is ingested. Tadalafil may be taken 2 hours before intercourse, but its longer half-life (17.5 hours) allows for greater flexibility in deciding when it can be taken before initiating intercourse (e.g., 6, 8, or perhaps 12 hours before). Tadalafil may be taken without regard to food intake.

All three drugs are generally well tolerated. Side effects of all three include headache, flushing, dyspepsia, and nasal congestion. Visual abnormalities are encountered with sildenafil, but are less likely with vardenafil and unlikely with tadalafil. Back pain and myalgia may occur with tadalafil, but are unusual with sildenafil or vardenafil.

All three drugs are contraindicated in patients who use nitroglycerin or nitrate-containing compounds. Combining any of these three drugs with nitroglycerin or nitrates may result in significant hypotension. Vardenafil is contraindicated in patients using doxazosin (Cardura), terazosin (Hytrin), or tamsulosin (Flomax). 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 higher 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 frequently used for the treatment of benign prostatic hypertrophy and, perhaps less often, used for hypertension.

Although some initial concerns were raised about the use of sildenafil and other PDE5 inhibitors in patients with cardiovascular disease, ongoing studies, as well as clinical experience, have suggested that these medications are safe in patients with stable cardiovascular disease who are not using nitroglycerin or nitrate-containing compounds. Guidelines for evaluating cardiac patients before using PDE5 inhibitors have been published. ^11,12

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.

Withdrawal of Offending Medications

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 erectile dysfunction (Box 2 ). Antihypertensive drugs, such as diuretics and beta blockers, may be associated with erectile dysfunction and perhaps can be discontinued or switched to alternative drugs, such as angiotensin-converting enzyme inhibitors or calcium channel blockers (e.g., diltiazem, nifedipine, amlodipine), which may 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.

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 drugs such as bupropion, nefazodone, and trazodone may be helpful in this regard. The selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline,paroxetine, citalopram) may also cause difficulties with erectile dysfunction, but might also have other significant sexual side effects, including decreased libido and anorgasmia.

Clinical experience in switching medication has overall been disappointing and improvement does not seem to occur often. Nonetheless, it is important to try to discontinue possible offending medications before moving on to more invasive options. Oral therapy has also basically changed how discontinuing medications may work as well and has improved the approach. For example, a patient may develop erectile dysfunction on a thiazide diuretic. The drug may be withdrawn, but a trial of oral 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 therapy can be used to deal with the sexual side effects on an ongoing basis, which is frequently what is done.

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.

Vacuum Constriction Devices

As noted, if a trial of oral therapy and withdrawal of offending medications do not restore erectile function, most primary care practitioners will probably consider referral to a specialist for additional evaluation and discussion of alternative treatment options. Some, however, may recommend vacuum constriction devices, and several treatment guidelines have suggested that they represent a first-line treatment modality. ^13,14 The concept of using a vacuum constriction device to help facilitate erectile function is almost 75 years old but it is only within the past 15 years that such devices have become widely used.

The device consists of an acrylic cylinder placed over the penis that uses a lubricant to achieve a good seal between the 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; it is believed to involve venous occlusion from the constriction band resulting in generalized swelling of the entire penis, with probable preservation of arterial inflow.

A growing body of clinical studies has suggested that these devices are effective and acceptable to a large number of patients with erectile dysfunction of varying causes, including psychogenic erectile failure. Although the initial overall response rate is approximately 80% to 90%, longer term follow-up studies would suggest that satisfaction with this device approaches other modalities, such as that of intracavernous injection therapy, which may be in the range of 50% to 60%. There are relatively few contraindications to the use of this device. These are conditions that may predispose to priapism or perhaps bleeding with constriction, such as sickle cell disease, polycythemia, and other blood dyscrasias. Patients on anticoagulation (with 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.

These devices are alternatives for patients who have failed or otherwise are unable to use oral therapy or injection therapy and do not desire surgery. Vacuum constriction devices are considered first-line therapy but in most cases, if oral therapy is effective, patients find that taking a pill is more desirable then using these devices. These devices, however, are useful for patients with marginal cardiac function or cerebral vascular disease who are not good candidates for any treatment, such as oral therapy or injection therapy.

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. Although these complications may be troublesome to some patients, they are not significant for most patients. Other complaints regarding the device include its being cumbersome, nonspontaneous and, in some cases, unacceptable to the partner. Despite problems, these devices have become an important nonsurgical option for some patients with erectile dysfunction.

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National Practice Guidelines

The American Urological Association published treatment guidelines for organic erectile dysfunction in 1996. ¹⁵ At that time, oral therapy was unavailable so these guidelines are not likely to be very beneficial to primary care physicians. They did emphasize, as this chapter does, that yohimbine is not effective for organic erectile dysfunction. Newer guidelines are expected to be published in 2005.

The American Association of Clinical Endocrinologists (AACE) issued clinical practice guidelines in 1998 and then updated them in 2003. ¹⁶ This was the first year that oral therapy became available. The basic recommendations in this guideline have been incorporated into this chapter. This guideline mentions trying nonspecific treatment such as yohimbine but, as noted earlier, clinical experience suggests that this drug is generally ineffective for organic erectile dysfunction and probably should be avoided.

The Veterans Health Administration (VHA) guidelines and the process of care model are useful; these incorporate the notion of lifestyle changes and interventions that may be helpful to patients with risk factors for erectile dysfunction. ^13,14 It is important, how-ever, to emphasize that currently there is limited evidence that these lifestyle interventions will actually be beneficial for erectile dysfunction.

An additional interesting observation in the VHA guidelines ¹⁴ relates to some patients with spinal cord injury lesions above the T5-6 level who may be prone to autonomic dysreflexia. This is a life-threatening situation that may occasionally require nitrites for the emergency management of hypertension and may interact adversely with sildenafil, producing severe hypotension. I have not personally seen this, but it is perhaps worth remembering if a physician is evaluating a patient with spinal cord injury for the treatment of erectile dysfunction.

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Summary

• Erectile dysfunction, defined as the inability to develop and maintain an erection for satisfactory sexual intercourse, is common in men with diabetes mellitus.
• Associated risk factors include increasing age, dyslipidemia, hypertension, and antihypertensive and psychotropic medications.
• Proper evaluation includes a careful history, physical examination, and evaluation for possible endocrine causes (e.g. low testosterone, high prolactin levels).
• Because erectile dysfunction is caused by a complex set of psychosocial, neurologic, and vascular factors, a specific cause in a patient may remain ambiguous.
• Oral therapy with PDE5 inhibitors is often successful and safe for appropriately selected diabetic patients.
• Vacuum constriction devices provide acceptable alternative therapy for some patients.

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Suggested Readings

• American Association of Clinical Endocrinologists Male Sexual Dysfunction Task Force . American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of male sexual dysfunction: A couple's problem—2003 update. Endocr Pract. 9: 2003; 77-95.
• Brock GB, McMahon CG , Chen KK. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: Results of integrated analyses. J Urol. 168: 2002; 1332-1336.
• DeBusk R, Drory Y , Goldstein I. Management of sexual dysfunction in patients with cardiovascular disease: Recommendations of the Princeton Consensus Panel. Am J Cardiol. 86: 2000; 175-181.
• DeBusk RF, Pepine CJ , Glasser DB. Efficacy and safety of sildenafil citrate in men with erectile dysfunction and stable coronary artery disease. Am J Cardiol. 93: 2004; 147-153.
• Feldman HA, Goldstein I , Hatzichristou DG. Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study. J Urol. 151: 1994; 54-61.
• Goldstein I, Lue TF , Padma-Nathan H. Oral sildenafil and the treatment of erectile dysfunction. N Engl J Med. 338: 1998; 1397-1404.
• Goldstein I. Male sexual circuitry. Working Group for the Study of Central Mechanisms in Erectile Dysfunction. Sci Am. 283: 2000; 70-75.
• Hellstrom WJ, Gittelman M , Karlin G. Vardenafil for the treatment of men with erectile dysfunction: Efficacy and safety in a randomized double-blind placebo-controlled trial. J Androl. 23: 2002; 763-771.
• Johannes CB, Araujo AB , Feldman HA. Incidence of erectile dysfunction in men 40 to 69 years old: Longitudinal results from the Massachusetts Male Aging Study. J Urol. 163: 2000; 460-463.
• Lakin M. The evaluation and nonsurgical management of impotence. Semin Nephrol. 14: 1994; 544-550.
• Langtry HD, Markham A. Sildenafil: A review of its use in erectile dysfunction. Drugs. 57: 1999; 967-989.
• Laumann EO, Paik A , Rosen RC. Sexual dysfunction in the United States: Prevalence and predictors. JAMA. 281: 1999; 537-544.
• Montague DK, Barada JH , Belker AM. Clinical guidelines panel on erectile dysfunction: Summary report on the treatment of organic erectile dysfunction. The American Urological Association. J Urol. 156: 1996; 2007-2011.
• Pharmacy Benefits Management-Medical Advisory Panel .
• Process of Care Consensus Panel . The process of care model for evaluation and treatment of erectile dysfunction. Int J Impot Res. 11: 1999; 59-70.
• Rosen RC, Cappelleri JC , Smith MD. Development and evaluation of an abridged five-item version of the International Index of Erectile Function (IIEF 5) as a diagnostic tool for erectile dysfunction. Intl J Impot Res. 11: 1999; 319-326.