The evolution of vascular testing in erectile dysfunction

Abstract Over the past 20 years, many contributions have been made to our understanding of the mechanisms of erection as a result of penile vascular testing. The greatest medical advances in the management of male sexual dysfunction since the identification of androgens have been two discoveries: 1) that nitric oxide is the primary neuromodulator of penile smooth muscle relaxation, and 2) that oral phosphodiesterase type 5 inhibitors enhance erection quality through the nitric oxide mechanism. As a consequence of oral pharmacotherapies, the role of invasive diagnostics has diminished. Most guidelines recommend only history, physical examination, and limited laboratory testing before instituting oral therapies for erectile dysfunction (ED). We still have unanswered questions about ED. Can lifestyle changes alone improve erectile function? Is ED a marker for the development of atherosclerotic heart disease? What are the specific effects of known cardiovascular morbidities on penile vascular integrity? These questions will frame the role of future penile vascular diagnostics.

Friday, September 19, 2008


Age-Associated Changes

As men age, their sexuality changes. The frequency of sexual intercourse and the prevalence of engaging in any sexual activity decrease. Young men report having intercourse three to four times per week, whereas only 7% of men aged 60 to 69 years and 2% of those aged 70 years and older report the same frequency. Fifty percent to 80% of men 60 to 70 years old engage in any sexual activity, a prevalence rate that declines to 15% to 25% among those aged 80 years and older. However, sexual interest often persists despite decreased activity. The man’s level of sexual activity, interest, and enjoyment in younger years often determines his sexual behavior with aging. Factors contributing to a man’s decreased sexual activity include poor health, social issues, partner availability, decreased libido, and erectile dysfunction.

Aging is associated not only with changes in sexual behavior but also with changes in the stages of sexual response. During the excitement phase, there is a delay in erection, decreased tensing of the scrotal sac, and loss of testicular elevation. The duration of the plateau stage is prolonged, and pre-ejaculatory secretion is decreased. Orgasm is diminished in duration and intensity, with decreased quantity and force of seminal emission. During the resolution phase, there is rapid detumescence and testicular descent. The refractory period between erections is also prolonged. However, erectile dysfunction is not a part of healthy aging.

Erectile Dysfunction

Erectile dysfunction is the inability to achieve or maintain an erection adequate for sexual intercourse. The prevalence of erectile dysfunction increases with age; by age 70 years, 67% of men have erectile dysfunction. This high prevalence is important; in a study comparing affected and unaffected men, men with sexual dysfunction reported impaired quality of life. The causes of sexual dysfunction in men are summarized in Table 52.2.

The most common cause of erectile dysfunction in older men is vascular disease. Risk for vascular erectile dysfunction increases with traditional vascular risk factors such as diabetes mellitus, hypertension, hyperlipidemia, and smoking. In fact, erectile dysfunction is a predictor of future major atherosclerotic vascular disease (ie, myocardial infarction and stroke).

Obstruction from atherosclerotic arterial occlusive disease likely impedes the intracavernosal blood flow and pressure needed to achieve a rigid erection. In addition, atherosclerotic disease may cause ischemia of trabecular smooth muscle and result in fibrotic changes leading to failure of venous closure mechanisms. Venous leakage leading to vascular erectile dysfunction may also result from Peyronie’s disease, arteriovenous fistula, or trauma-induced communication between the glans and the corpora. In anxious men who have excessive adrenergic-constrictor tone and in men with injured parasympathetic dilator nerves, erectile dysfunction can occur from insufficient relaxation of trabecular smooth muscle.

The second most common cause of erectile dysfunction in older men is neurologic disease. Disorders that affect the parasympathetic sacral spinal cord or the peripheral efferent autonomic fibers to the penis impair penile smooth muscle relaxation and prevent the vasodilation necessary for erection. In patients with spinal cord injury, the extent of erectile dysfunction largely depends on the completeness and the level of the spinal injury; those who have complete lesions or injury to the sacral spinal cord are more likely to have loss of erectile function. Common health problems such as diabetes mellitus, stroke, and Parkinson’s disease can cause autonomic dysfunction that results in erectile failure. Finally, surgical procedures such as radical prostatectomy, cystoprostatectomy, and proctocolectomy commonly disrupt the autonomic nerve supply to the penis, resulting in postoperative erectile dysfunction.

Numerous commonly used medications have been associated with erectile dysfunction for which the mechanism, for the most part, is unknown. Those medications with anticholinergic effects, such as antidepressants, antipsychotics, and antihistamines, may cause erectile dysfunction by blocking parasympathetic-mediated penile artery vasodilatation and trabecular smooth muscle relaxation. Almost all antihypertensive agents have been associated with erectile dysfunction; of these, β-blockers, clonidine, and thiazide diuretics have higher incidence rates. One mechanism may be the lowering of blood pressure below the critical threshold needed to maintain sufficient blood flow for penile erection, especially in those men who already have penile arterial disease. Over-the-counter medications such as cimetidine and ranitidine may also cause erectile dysfunction. Cimetidine, an H2-receptor antagonist, acts as an antiandrogen and increases prolactin secretion and thus has been associated with loss of libido and erectile failure. Ranitidine can also increase prolactin secretion, although less commonly than does cimetidine.

The prevalence of psychogenic erectile dysfunction correlates inversely with age. Psychogenic erectile dysfunction may occur via increased sympathetic stimuli to the sacral cord, inhibiting the parasympathetic dilator nerves and thus inhibiting erection. Common causes of psychogenic erectile dysfunction include relationship conflicts, performance anxiety, childhood sexual abuse, and fear of sexually transmitted diseases. Older men may have “widower’s syndrome,” in which the man involved in a new relationship feels guilt as a defense against subconscious unfaithfulness to his deceased spouse.

The role of androgens in erection is unclear. Hypogonadal men show smaller and slower developing erections in response to fantasy, which is improved with androgen replacement. However, even men with castrate levels of testosterone can attain erections in response to direct penile stimulation. It may be that erection to certain types of sexual stimuli (ie, direct penile stimulation) are androgen independent, whereas response to fantasy may be androgen sensitive. Overall, testosterone appears to play a minor role in erectile function and a larger role in libido. In addition, hypogonadal patients respond better to phosphodiesterase inhibitors after testosterone replacement therapy.

Hyperthyroidism, hypothyroidism, and hyperprolactinemia have been associated with erectile dysfunction. However, less than 5% of erectile dysfunction is caused by endocrine abnormalities. Thus, endocrine evaluation of men with erectile dysfunction but intact libido is of limited value.

Evaluation of Erectile Dysfunction

The initial step in evaluation is to obtain a sexual, medical, and psychosocial history. Sexual history should clarify whether the problem consists of inadequate erections, decrease in libido, or orgasmic failure. The onset and duration of erectile dysfunction, the presence or absence of sleep-associated erections, and associated decline in libido may lead the clinician to the likely cause.

Sudden onset suggests psychogenic or drug-induced erectile dysfunction. A psychogenic cause is likely if there is sudden onset but sleep-associated erections or if erections with masturbation or another partner are intact. However, if the sudden onset is accompanied by lack of sleep-associated erections and lack of erection with masturbation, temporal association with new medication should be sought. A gradual onset of erectile dysfunction associated with loss of libido suggests hypogonadism.

Medical history is directed at discerning those factors likely to be contributing to erectile dysfunction. Vascular risk factors include diabetes mellitus, hypertension, coronary artery disease, peripheral arterial disease, hyperlipidemia, and smoking. Neurogenic risk factors include diabetes mellitus, history of pelvic injury or surgery, spinal injury or surgery, Parkinson’s disease, multiple sclerosis, and alcoholism. An extensive medication review, including over-the-counter medications, is also essential. Finally, the psychosocial history should assess the patient’s relationship with the sexual partner, the partner’s health and attitude toward sex, economic or social stresses, living situation, alcohol use, and affective disorders.

On physical examination, signs of vascular or neurologic diseases must be sought. Peripheral pulses should be palpated. Signs of autonomic neuropathy and loss of the bulbocavernosus reflex suggest neurologic dysfunction. The genital examination includes palpating the penis for Peyronie’s plaques and assessing for testicular atrophy. A femoral bruit and diminished (or absent) pedal pulses suggests arterial insufficiency. An absent bulbocavernosus reflex in a patient with diabetes mellitus suggests penile neuropathy. A loss of secondary sexual characteristics, small testes, and gynecomastia suggest hypogonadism.

Appropriate laboratory evaluation are those that target relevant comorbid conditions such as diabetes mellitus and vascular disease or that evaluate neurologic disorders if suggested by the physical examination. Consider the measurement of total testosterone in the setting of other symptoms of androgen deficiency. (See Endocrine and Metabolic Disorders.)

An office-based diagnostic tool that can help direct the treatment of erectile dysfunction is intracavernous injection of a vasoactive drug, such as papaverine or alprostadil (formerly prostaglandin E1, or PGE1). An initial test dose of 15 to 30 mg of papaverine is used if the history and examination suggest a neurogenic cause. A 30-gauge needle and 1-cc syringe are typically used for the injection. Hold the glans of the penis with one hand and clean the injection site with an alcohol swab. Then, holding the needle parallel to the floor, insert the needle into the side of the penis to avoid the urethra. Inject the vasoactive agent over 30 to 60 seconds. After withdrawing the needle, apply pressure to the injection site for 1 minute to prevent bruising. An erectile response will occur within 15 minutes and may last up to 40 minutes. A poor response suggests arteriogenic or venogenic erectile dysfunction, inadequate dose of vasoactive agent, or anxiety with excessive adrenergic tone. A second trial injection at the next office visit with a higher dose (30 to 60 mg papaverine) or alprostadil (5 to 20 μg) may be used.

An at-home therapeutic trial of a phosphodiesterase inhibitor (sildenafil or vardenafil) is easier than the in-office diagnostic penile injection of a vasodilator. The initial dose should be low (sildenafil 25 to 50 mg or vardenafil 5 to 10 mg) in men suspected of having neurogenic erectile dysfunction. A poor response suggests vasculogenic erectile dysfunction. Further therapeutic trial with sildenafil 100 mg or vardenafil 20 mg may prove to be effective. An at-home therapeutic trial using tadalafil (5 to 10 mg) can be considered, but the long half-life complicates matters if an adverse reaction occurs with the first dose.

More extensive diagnostic tools are available but not commonly used. Nocturnal penile tumescence testing is of little value, except to confirm a psychogenic cause. The penile brachial pressure index may be helpful in assessing arteriogenic erectile dysfunction. This index measures the loss of systolic pressure between the arm and the penis. When measured before and after exercise, it can be used to assess for a pelvic steal syndrome, which is the loss of erection associated with initiation of active pelvic thrusting, presumably due to the transfer of blood flow from the penis to the pelvic musculature. More invasive and expensive tests such as Doppler ultrasound to assess penile arterial function, dynamic infusion cavernosometry to assess venous leakage syndrome, and penile arteriography are generally reserved for research or penile vascular surgery candidates.

Treatment of Erectile Dysfunction

Multiple effective therapeutic options are now available for the treatment of erectile dysfunction. Treatment should be individualized and based on cause, personal preference, partner issues, cost, and practicality of the therapeutic modality (Table 52.3).

Oral therapy for erectile dysfunction consists of sildenafil, vardenafil, or tadalafil. Sildenafil is a type-5 phosphodiesterase inhibitor that potentiates the penile response to sexual stimulation. It is effective in improving the rigidity and duration of erection. It is taken 1 hour before sexual activity and has no effect until sexual stimulation occurs. Because absorption is attenuated when sildenafil is ingested with a fatty meal, patients need to be educated about this issue. Vardenafil is a more potent and specific phosphodiesterase inhibitor. A lower effective dose and better side-effect profile (no effect on color vision) make vardenafil a reasonable option. Tadalafil is a longer acting phosphodiesterase inhibitor with a similar side-effect profile. All three of these agents are contraindicated for concomitant use with nitrate drugs, since the combination can produce profound and fatal hypotension. Choosing between the three currently available phosphodiesterase inhibitors should likely be based on price. There are also labeling differences with the α-blockers that need to be taken into consideration.

Vacuum tumescence devices are an effective and accepted treatment. The apparatus consists of a plastic cylinder with an open end into which the penis is inserted. A vacuum device attached to the cylinder creates negative pressure within the cylinder, and blood flows into the penis to produce penile rigidity. A penile constriction ring placed at the base of the penis then traps the blood in the corpora cavernosa to maintain an erection for about 30 minutes. The vacuum device is effective for psychogenic, neurogenic, and venogenic erectile dysfunction, but it requires manual dexterity. Local pain, swelling, bruising, coolness of penile tip, and painful ejaculation are potential side effects. It is important to remove the constriction ring after 30 minutes.

Intracavernous injection of vasoactive drugs such as papaverine, phentolamine, and alprostadil are effective in producing erections adequate for sexual activity. Alprostadil, which is the only agent approved by the FDA for intracavernous injection, produces erections that last 40 to 60 minutes. PhentolamineOL is mainly used in combination therapy with papaverineOL or alprostadil, or both. Potential side effects are bruising, ecchymoses or hematoma, local pain, fibrosis from repeated injections, and priapism. Alprostadil appears to cause less scarring and priapism than papaverine. If an erection lasts longer than 4 hours, detumescence is necessary by aspiration of blood from the corpora cavernosa or injection of phenylephrine, since there is the potential for intracavernous hypoxia and fibrosis of trabecular smooth muscle, which may prevent future erections. In general, intracavernosal therapy should probably be reserved for patients who fail oral therapy with a phosphodiesterase inhibitor. Alprostadil can also be administered intraurethrally using MUSE (medicated urethral system for erection). This system contains a small pellet of alprostadil that is placed within the urethra and is rapidly absorbed through the urethral mucosa to produce an erection within 10 to 15 minutes. Possible side effects are penile pain, urethral burning, and a throbbing sensation in the perineum.

Testosterone supplementation increases libido and may improve erectile dysfunction in men with true hypogonadism. It is available as an intramuscular injection (testosterone enanthate or cypionate) or topical transdermal patch and gel. Possible side effects associated with testosterone include polycythemia, increase in prostate size, gynecomastia, and fluid retention. It is important to perform a digital rectal examination to assess the prostate and obtain a baseline prostate-specific antigen level prior to initiation of therapy. If there is a rise in prostate-specific antigen or hematocrit with testosterone therapy, it usually occurs within 6 months. Therefore, it is advisable to check these levels at 3-month intervals during the first year of therapy, then every 12 months thereafter.

Surgical implantation of a penile prosthesis is another therapeutic option. Mechanical failure, infection, device erosion, and fibrosis are possible complications. However, since the availability of alprostadil and, more recently, phosphodiesterase inhibitors, surgical implantation of a penile prosthesis is rarely used (ie, men with severe arterial occlusive disease). Penile revascularization surgery has limited success.

Psychogenic erectile dysfunction should be referred for further evaluation and treatment.