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Table of Contents

Revised April 18, 2005

Milton Lakin, MD

Departments of
Urology and
Internal Medicine

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In the last 20 years there has been increasing recognition that erectile dysfunction is a common problem. While many patients may come to their general practitioner's or internist's offices 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 discussing these issues.

Definition

Prevalence

Pathophysiology

Signs and
Symptoms

Diagnosis

Therapy

References

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 is no universally agreed upon 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 over 3 months has been suggested as a reasonable clinical guideline.

Several recent studies have looked at the prevalence of erectile dysfunction. The Massachusetts male aging study was a cross-sectional random sample community-based survey of 1,290 men ages 40 to 70 years and was conducted from 1987 to 1989 in areas around Boston.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 was an approximately 40% prevalence rate increasing to close to 70% in men age 70. The prevalence of moderate erectile dysfunction increased from 17% to about 34% with that of complete erectile dysfunction increasing from 5% to 15% as age increased from 40 to 70.

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 greater probability of erectile dysfunction was noted. The study concluded that erectile dysfunction was a major health concern in view of its high prevalence.

Incidence estimates were published recently using data compiled from the Massachusetts male aging study.² Incidence data is necessary to assess risk and plan treatment and prevention strategies. The Massachusetts study data 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 caucasian, so likely the data is 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 1,410 men aged 18 to 59 years. This study 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 - 59 years) was more than 3 times as likely to experience erection problems and to report low sexual desire in comparison to men aged 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 with poor physical and emotional health. This study also concluded that sexual dysfunction is an important public health concern and added that emotional issues were likely to contribute to the experience of these problems.

The development of an erection is a complex event involving integration of psychological, neurological, endocrine, vascular and local anatomic systems. Recent PET (positron emission tomographic) scanning studies suggest sexual arousal is activated in higher cortical centers that 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-S4).⁴

The neurovascular events that ultimately occur result in inhibition of adrenergic tone and in release of the nonadrenergic, noncholinergic neurotransmitter nitric oxide. Nitric oxide is thought 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 GMP (guanosine monophosphate) and ultimately in smooth muscle relaxation, enhancement of arterial inflow, and veno-occlusion producing adequate firmness for sexual activity.

Abnormalities in any of the systems mentioned above 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 cancer of the prostate, bladder and colon may also likewise 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 a variety of poorly understood mechanisms.

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 in fact have a significant problem with erectile dysfunction. Additionally patients who are poorly compliant with medication prescribed for hypertension may well be having 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 examinations.

Some health questionnaires help screen for and evaluate erectile dysfunction.⁵ These questionnaires 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 quite useful in helping patients discuss the problem and in signaling the need for an evaluation.

If it is determined that erectile dysfunction is a problem, then a detailed sexual and medical history and 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 - 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 is 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: 1) symptoms suggesting the presence of diabetes, peripheral vascular disease, neurologic disease, or chronic liver or kidney disease. 2) a complete list of medications, 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 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 lower extremity pulses as well as auscultation for bruits in the abdominal and femoral region. 3) a 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) a careful genital examination noting testicular size and palpating for Peyronie's plaques. 5) a rectal exam 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 a 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. Lab 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 A1C 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 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 which is safe and has minimal or tolerable side effects, additional diagnostic testing is probably not necessary or can be delayed until a therapeutic trial of oral medication has proven ineffective.

Oral Therapy
The current non-surgical treatments are listed in Table 1. Although there are a number of options available for non-surgical treatment, it is clear that oral therapy has revolutionized the treatment approach to patients with erectile dysfunction. As previously mentioned, once an initial appropriate evaluation has been performed and a tentative diagnosis 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 Food and Drug Administration (FDA). These are Sildenafil Citrate (Viagra approved March 1998) and Vardenafil Hydrochloride (Levitra approved September 2003) and Tadalafil (Cialis approved November 2003).

All three drugs reversibly inhibit the penile-specific phosphodiesterase (type 5; PDE-5) and enhance the nitric oxide-cyclic GMP pathway of cavernous smooth muscle relaxation (ie, all three prevent breakdown of cyclic GMP by PDE-5). In several double-blind, placebo-controlled studies of patients with erectile dysfunction of varied etiology, 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 continuing to 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 only 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 instance, success in diabetic patients is probably closer to 50% to 60%, with demonstrated effectiveness in both type 1 and type 2 diabetes. While 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 approaches 70% in some series. However, if a single nerve was spared success is reduced, and if no nerves were spared results are generally quite 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 mg 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 mg 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 prior to intercourse, but its longer half-life (17.5 hours) allows for greater flexibility in deciding when it can be taken before initiating intercourse (ie, 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 either 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 and 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 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 PDE-5 inhibitors in patients with cardiovascular disease, ongoing studies as well as clinical experience suggest that these medications are safe in patients with stable cardiovascular disease who are not using nitroglycerine or nitrate-containing compounds. Guidelines for evaluating cardiac patients prior to using PDE-5 inhibitors have recently been published.^11,12

Withdrawal of Offending Medication
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 (Table 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 (diltiazem, nifedipine, amlodipine) which may cause less of a problem. The newer angiotensin II receptor antagonists may also cause less of a problem but more long-term data will be needed to confirm this.

Of the drugs used for depression, tricyclic antidepressants may be associated with erectile problems and other drugs hopefully can be substituted to prevent this complication. Of those currently available it would appear that bupropion, nefazodone and trazadone may be helpful in this regard. The selective serotonin reuptake inhibitors (such as fluoxetine, sertraline, paroxetine, and citalopram) may also cause difficulties with erectile dysfunction, but perhaps more commonly have other significant sexual side effects which include decreased libido and anorgasmia.

Clinical experience in switching medication has overall been rather disappointing and improvement does not seem to occur very 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 the way in which discontinuing medications may work as well, and has improved the approach. An example of this is a patient who may develop erectile dysfunction on a thiazide diuretic. The drug may be withdrawn but also a trial of oral therapy can be initiated during the observation period while the patient is waiting to see if 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 effect on an ongoing basis which is frequently what is done.

If a trial of oral therapy and withdrawal of offending medications proves 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 such as intracavernous injection therapy, vacuum constriction devices, intraurethral therapy or possible surgery.

Vacuum Constriction Devices
As mentioned above, if a trial of oral therapy and withdrawal of offending medications is ineffective in restoring erectile function probably most primary care practitioners will consider referral to a specialist for additional evaluation and discussion of alternative treatment options. Some primary care physicians however, may recommend vacuum constriction devices and several treatment guidelines have suggested that they do represent a first line treatment modality.^13,14 The concept of utilizing 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. A vacuum constriction device consists of an acrylic cylinder placed over the penis using a lubricant to achieve a good seal between the body and the cylinder. An erection is then achieved by creating a vacuum inside the cylinder using 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 thirty minutes and then must be removed. The erection produced by the device differs from a normal erection and is thought 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 suggest that these devices are effective and acceptable to a large number of patients with erectile dysfunction of varying etiology including psychogenic erectile failure. While 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 more realistically in the range of 50% to 60%. There are relatively few contraindications to the use of this device and 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 or if manual dexterity is impaired a willing sexual partner can learn to apply the device.

These devices are an alternative for patients who have failed or otherwise are unable to utilize oral therapy or injection therapy and do not desire surgery. Although vacuum constriction devices are considered first line therapy, there is little doubt that in most cases if oral therapy is effective that patients find taking a pill more desirable then using these devices. Vacuum constriction devices however, are useful in patients with very marginal cardiac function or cerebral vascular disease who are not good candidates for any treatment either with 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 in the majority of patients. Other complaints regarding the device include its being cumbersome, non-spontaneous, and in some cases unacceptable to the partner. Despite problems, these devices have become an important non-surgical option for some patients with erectile dysfunction.

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 terribly 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 published in 1998.¹⁶ This was the first year that oral therapy became available. The basic recommendations in this guideline have been incorporated into this current chapter. This guideline mentions trying nonspecific treatment such as Yohimbine but as mentioned above, clinical experience suggests that this drug is generally ineffective in organic erectile dysfunction and probably should be avoided.

The VA guidelines and the process of care model are useful and do incorporate the notion of life style changes and interventions which may be helpful to patients who have risk factors for erectile dysfunction.^13,14 It is important however to emphasize that currently there is very limited evidence that these lifestyle interventions will actually produce an improvement in the erectile dysfunction.

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

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