Preview: The advent of "the pill" for erectile dysfunction has prompted discussion in the news as well as jokes on late-night talk shows. However, the underlying causes of the condition are complex, and no single treatment is right for all patients. To select the best therapy for each patient, it is important to understand how an erection works and how the available treatments address the various causes of dysfunction. Dr Jordan presents a comprehensive, straightforward (sometimes humorous) look at the mechanisms involved in erectile function and offers an approach to management of dysfunction.
An erection is a complex, involuntary, neuropsychological, hormone-mediated vascular event that occurs when blood rapidly flows into the penis and becomes trapped in its spongy chambers (1-6). Erectile dysfunction, the preferred term for impotence, was defined at the National Institutes of Health Consensus Conference, December 1992, as "the inability to achieve or maintain an erection satisfactory for sexual intercourse." Satisfaction is determined by both patient and partner, making erectile dysfunction a "couple's disease."
Understanding the mechanisms involved in erectile function is helpful in treatment of dysfunction.
Anatomy of the penis
The anatomy of the male genitalia is very complex; however, for the purposes of discussion of erectile function, the corpora cavernosa are "where the action is" (figure 1: not shown). These two columns of erectile tissue in the shaft of the penis are surrounded by the tunica albuginea and separated by an incompetent septum composed of fibers. The fibers interweave with the inner layer of the tunica albuginea (7,8). A third erectile body, the corpus spongiosum, is located on the ventrum of the corpora cavernosa and contains the urethra. Although this body becomes tumescent, it does not contribute to rigidity and may, in fact, serve only to make the urethra an efficient conduit for the ejaculate.
The sensation of the glans penis is mediated via the dorsal nerves of the penis, which are branches of the pudendal nerve. Erectile function is controlled both parasympathetically and sympathetically. The parasympathetic input is excitatory in function (3,7). The parasympathetic nerves adjacent to the prostate gland (nervi erigentes) coalesce in the hilum of the penis and penetrate into the corpora cavernosa (3,7-9). The sympathetic input is an extension of the thoracolumbar plexus and is inhibitory in function (3,7).
Arterial inflow to the deep structures of the penis is dependent on the deep internal pudendal vessels via the common penile arteries (figure 2: not shown). These branches provide vascularity to the deep structures as well as the glans penis. The venous outflow from the penis is a bit more complex and has been divided into three separate systems: (1) superficial, consisting of the superficial veins, (2) intermediate, consisting of the emissary, circumflex, and deep dorsal veins, and (3) deep, consisting of the hilar and cavernosal veins (1,7,8,10-12) (figure 3: not shown).
Physiology of an erection
The basic physiology of an erection can be described by a simplistic model that presumes a single lacunar space as the entire corpora (figure 4: not shown). The helicine artery drains into the lacunar space. The lacunar space is bounded by the intracavernosal smooth musculature and lined with endothelial cells. Exiting from the lacunar space are one or more venules that coalesce to become a subtunical venule, which then drains through the tunica albuginea as the emissary vein.
When the penis is flaccid (figure 4a: not shown), the intralacunar smooth muscle is in a contracted state; the tonus is maintained by norepinephrine (alpha stimulation). With stimulation of the cavernous nerve (alpha blockade), active relaxation of the cavernosal smooth muscle occurs. The lacunar space and the helicine arteries dilate, the subtunical venules are compressed physically and possibly neurologically, and the emissary veins are constricted physically (figure 4b: not shown). In short, the lacunar space becomes a large vascular "sink" into which blood rapidly flows and becomes trapped, thereby elevating the pressure within the lacunar space to that of mean arterial pressure (2,13-17).
Relaxation of cavernosal smooth muscle is initiated by the following neurotransmitters: (1) acetylcholine, (2) vasoactive intestinal polypeptide (VIP) via the VIP-ergic system, (3) prostaglandin via the prostacyclin system, and (4) nitric oxide via the nitrergic system (5,6,14,15,18-20) (figure 5: not shown).
Causes of erectile dysfunction
Erectile dysfunction can be categorized as either functional (psychological) or organic (physical). Although erectile failure of a purely functional or organic origin is rare, analysis of the two as independent entities sheds light on some of the characteristic features.
Episodic erectile dysfunction is usually indicative of a functional cause. Affected patients have normal nocturnal or morning erections and can often have erections with fantasizing or masturbation. The classic presentation includes sudden onset often preceded by a period of high stress. The patient usually firmly maintains that he has a "physical problem."
Erectile dysfunction of organic origin is characterized by gradual onset of deterioration of function. The patient first notices diminishing firmness and a decrease in the frequency of erections. Often, attempts at intercourse are unsuccessful during periods of fatigue or stress. Loss of nocturnal erections, poor morning erections, and no improvement in erections with masturbation are also noted. The patient often has reactive psychological concerns and is more than willing to assume that he has a "psychological problem." His libido is usually normal, but it is not uncommon for libido to diminish with any kind of erectile dysfunction. Avoidance of intercourse after failed attempts is also a contributing factor.
The many organic causes of erectile dysfunction include:
- Inflammatory conditions of the prostate (eg, prostatitis), urethra, or seminal vesicles
- Surgical procedures (eg, perineal surgery, radical prostatectomy, cystoprostatectomy, abdominal-perineal resection, vascular surgery)
- Pelvic fractures with or without urethral distraction injuries
- Lumbar neurologic injuries
- Vascular disease affecting large or small vessels
- Neurologic conditions (eg, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, tabes, peripheral neuropathies)
- Endocrine disorders (eg, pituitary problems, gonadal failure, adrenal disorders, thyroid disorders, diabetes mellitus)
- Local factors (eg, cavernous veno-occlusive dysfunction)
- Poor overall health (eg, severe angina or shortness of breath that limits or prevents the physical act of intercourse)
- Smoking and consumption of alcohol
- Medication use
Erectile dysfunction is a side effect of many common medications, including antidepressants, inotropic agents, cytotoxic agents, histamine2 agonists, lipid-lowering drugs, opiates, antihypertensives, diuretics, hormones, and nonsteroidal anti-inflammatory drugs. However, not all agents within each drug class produce the same effects. For example, the antidepressant trazodone hydrochloride (Desyrel) has been used in small institutional studies (albeit with limited success) as a treatment for erectile dysfunction, whereas sertraline hydrochloride (Zoloft) and fluoxetine hydrochloride (Prozac) can adversely affect erectile function. In short, if a patient is having problems with one medication, it is reasonable to substitute another medication that may have fewer ill effects.
When erectile function is viewed as a brain-mediated event, the influence of central factors as well as local factors becomes evident (1,6,13,16). In the simplistic analogy illustrated in figure 6 (now shown), the brain is the "boss" that controls the master switch. An "off" switch represents functional erectile dysfunction (figure 6a: not shown). An "on" switch but broken "machinery" (eg, plugged arteries, broken nerves) is the sine qua non of organic erectile dysfunction (figure 6b: not shown). Interestingly, when the boss is asleep, the master switch is always left on (figure 6c: not shown), hence urologists' interest in nocturnal studies.
Nocturnal studies present a true picture of erectile dysfunction due to organic causes. The most complete evaluation of nocturnal erectile function is obtained in a sleep laboratory, where patients are monitored for rapid eye movement (REM) sleep. Under normal conditions, an erection would be expected to occur with each REM episode. The erection can be described in terms of tumescence and buckling force (a measure of rigidity).
Vascular erectile testing
Duplex Doppler ultrasonography has been used extensively, and likely overused, in evaluation of erectile function. It provides information about both arterial and venous flow. The value of the test is questionable unless the information obtained is needed for treatment selection (16). Dynamic infusion pharmacocavernosometry and pharmacocavernosography (DICC) also provides detailed data about pressure related to erectile function, but this information often is more extensive than is required for treatment of erectile dysfunction (6).
Office pharmacologic testing is used by some physicians. The test involves intracavernosal injection of a small amount of an active agent (eg, 10 micrograms of alprostadil [prostaglandin E1]) that, theoretically, would produce a normal or priapic erection in a patient with normal erectile function but a poor response in a patient with erectile dysfunction. The problem with this test is that unless the patient's sympathetic nerve impulses are completely overcome by the injected agent, he may have a poor erection even though his erectile function is normal.
Measuring serum levels of testosterone (both total and free), gonadotropins, and gonadotropin-releasing hormone may be helpful in a patient in whom history taking or physical examination suggests lack of androgen stimulation. Clues to low androgen levels include poor libido, a disproportionately small prostate gland relative to the patient's age, small or soft testicles, and noticeable thinning or diminished growth of the beard. If the patient's total testosterone level is low, the prolactin level should be checked, because hyperprolactinemia alone may be the cause.
Not long ago, penile prostheses were the only option for the treatment of erectile dysfunction. However, many new treatments are currently available.
Vacuum erection devices
The vacuum erection device (eg, ErecAid, Post-T-Vac, VED) is an excellent option for many patients. A vacuum tube placed around the penis enhances the effects of the inherent pressure within the penis, causing it to become longer and thicker. Some passive dilation of the intracavernosal spaces also occurs. A band is then placed around the base of the penis to maintain the erection.
A number of oral drugs for treating erectile dysfunction are being used experimentally, and a few are now available for clinical use. All of the agents have indications for both organic and functional erectile dysfunction.
Yohimbine is a naturally-occurring alpha blocker. Its efficacy in erectile dysfunction is questionable. In my experience, yohimbine therapy is most successful in patients who have very minimal organic dysfunction with a large functional overlay. The newer oral alpha blockers will likely replace use of this agent.
As mentioned, trazodone has been used clinically in small institutional settings as therapy for erectile dysfunction. The usual dosage is 50 mg taken 2 hours before coitus. However, a more realistic approach may be 50 or 100 mg nightly for a couple of weeks to allow evaluation of the effects.
Sildenafil citrate (Cenforce 100mg) inhibits phosphodiesterase type V, the enzyme that converts cyclic guanosine monophosphate (GMP) to inactive 5-GMP. When this chemical action is blocked, the levels of cyclic GMP increase and smooth-muscle relaxation is enhanced, thereby increasing and maintaining relaxation of the lacunar spaces (14).
Two other agents, sublingual apomorphine hydrochloride (Zydis), a central dopamine stimulant, and oral phentolamine (Levitra), an alpha-adrenergic blocker, are undergoing clinical trials. The chief adverse effect of apomorphine is nausea, sometimes accompanied by vomiting. The agent is indicated specifically for patients with functional erectile dysfunction.
Patients with low testosterone levels should undergo evaluation to determine the cause. Exogenous testosterone therapy may be helpful in some patients. Testosterone transdermal systems (Androderm, Testoderm) are available. Oral testosterone (ie, methyltestosterone) generally is not indicated. If the decrease in testosterone is associated with hyperprolactinemia, treatment with bromocriptine mesylate (Parlodel) is warranted.
Injection and intraurethral therapy
Intracavernosal injection therapy involves three drugs given alone or in combination ("tri-mix"): alprostadil (Caverject, Edex), the alpha blocker phentolamine (Regitine), and papaverine hydrochloride (6,16). Another injectable agent, vasoactive intestinal polypeptide, is currently undergoing clinical trials.
An intraurethral suppository form of alprostadil (Muse) is also available (21,22). This delivery method is based on the theory that the venous connections between the corpus spongiosum and corpora cavernosa allow for absorption via the urethral epithelium and immediate transport to the corpora cavernosa. In fact, the systemic absorption is substantial, and intraurethral alprostadil therapy can have systemic side effects. Up to 50% of patients have a measurable drop in blood pressure, although only about 3% are aware of it. Some patients have significant symptoms of hypotension. With both intraurethral and intracavernosal injection therapy, dose levels should be tested and adjusted under supervision by a physician.
A study by the MUSE Study Group (21) showed that few patients responded to doses below 500 micrograms. Therefore, in my practice, all patients are given a 500-micrograms challenge in the office. "Super responders" are switched to a lower dose; "under responders" are rechallenged at 1,000 micrograms.
At one time, surgery for cavernous veno-occlusive dysfunction (23) was thought to be "the answer" to erectile dysfunction. However, the vast majority of patients with cavernous veno-occlusive dysfunction are not candidates for surgery. The best candidates should (1) be less than 50 years of age, (2) have minimal or no inflow abnormalities, (3) have no Peyronie's disease or other abnormalities of the tunica albuginea, and (4) probably have a relatively insignificant smoking history. Revascularization of the corpora cavernosa does not address the pathologic cause of erectile dysfunction (1,12,24,25). Instead, it is based on a premise similar to that of coronary artery bypass grafting: When vessels are blocked, new vessels are brought to the area to provide better inflow. Although the results vary widely among medical centers, vascular surgery is most successful in young patients who have had pelvic or perineal trauma and have few vascular risk factors.(26-28)
Since the development of other options, prostheses have assumed a much smaller role in the treatment of erectile dysfunction. However, various types of prostheses are still marketed: (1) simple rod, (2) malleable rod, (3) self-contained hydraulic, (4) multiple-component hydraulic, and (5) articulated prostheses. Each type has advantages and disadvantages, which should be matched to the patient's individual preferences. Although implantation is not without complications, the complication rate is quite acceptable. The infection rate is slightly less than 3%. Mechanical failure rates are now within very acceptable ranges, and most prostheses are extremely reliable (29,30).
Approach to management
In initial management of erectile dysfunction, it is imperative to determine whether the dysfunction is primarily organic with a small overlay of functional "baggage" or predominantly functional with only a small component of organic dysfunction.
In patients with functional erectile dysfunction, counseling by a skilled sex therapist is usually successful. A trial of yohimbine, intraurethral alprostadil, or testosterone is not indicated, and in some cases, it may be dangerous. Yohimbine may cause hypotension in some patients, and alprostadil can cause hypotension as well as priapism. Testosterone therapy is not indicated in any patient who has not been proven to be hypogonadal. Cases have been described of patients with occult carcinoma of the prostate who had an apparent flare after administration of exogenous testosterone. However, yohimbine may have a role in selected patients (31). If clinical trials of sublingual apomorphine confirm the efficacy seen in pilot studies, this agent may be another first-line option.
In management of organic erectile dysfunction, the first decision point is whether the patient is a surgical candidate. If he is, referral to a urologic surgeon for evaluation (eg, sleep laboratory testing, duplex ultrasonography) is warranted. For most patients, however, search for an effective nonsurgical treatment is indicated.
Sildenafil is a safe drug but not the panacea that media reports have suggested. Great caution must be taken with patients who have coronary artery disease or, in my estimation, any type of vascular disease. However, in other patients, sildenafil is an excellent choice. Patients should be instructed in proper use of the medication (ie, take while fasting, 30 to 60 minutes before intercourse) and counseled regarding the side effects (ie, facial flushing, headache, "blueing out").
If sildenafil therapy is unsuccessful and the patient has no medical problems that would be adversely affected by hypotension (eg, carotid stenosis, angina), intraurethral alprostadil therapy is a logical next step. This option is effective in 35% to 40% of patients (21). When it is unsuccessful, the next step in patients who remain motivated to find an effective treatment is intracavernosal injection therapy. In my opinion, unless the primary care physician is prepared to provide proper in-office instruction and to treat priapism that can arise with use of this method, the patient should be referred to a urologist.
The available oral medications have acceptable side-effect profiles and are an appropriate option for many patients. Therapy with trazodone or yohimbine in the vast majority of patients appears to be effective primarily as a placebo. However, sildenafil (and possibly oral phentolamine, when it becomes available) would definitely be worth a try in patients with mild erectile dysfunction. It must be kept in mind that sildenafil is a facilitator, not an initiator. The patient must, therefore, have some erectile function to facilitate.
When other therapies are unsuccessful, patients may consider a vacuum erection device, which can be highly effective in motivated patients. Proper instruction and counseling from a device manufacturer's representative, if available, are important. For many patients, however, the vacuum erection device seems cumbersome or unnatural and is a barrier to spontaneity.
The management of erectile dysfunction has come a long way in the last 15 years. The medical profession has gone from a total lack of understanding of how an erection occurs to a very sophisticated understanding. Whereas physicians once thought there was only one "solution" for erectile dysfunction--that is, acceptance of the condition--they now can offer a host of options, all of which can be individualized to the patient's needs and wants. In spite of the range of current options, the fact remains that outcome studies have shown a high dropout rate with all therapies (23). Thus, the search for a "miracle cure" likely will continue.