Erectile Dysfunction

Pejman Cohan and Stanley G. Korenman

Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, University of California, Los Angeles, California 90095

Address correspondence and requests for reprints to: Pejman Cohan, M.D., 200 UCLA Medical Plaza, Suite 530, Los Angeles, California 90095. E-mail: pcohan{at}mednet.ucla.edu

Erectile dysfunction (ED) is defined as the persistent inability to achieve or maintain an erection adequate for satisfactory sexual activity (1). After premature ejaculation, it is the most common disorder of sexual function in men, affecting nearly 30 million individuals in the United States (2). Despite this startling prevalence and the undisputed impact that erectile function has on a man’s self-esteem and quality of life, ED remained largely an under-diagnosed disorder until the recent availability of an effective oral therapy. Care of ED has moved into the realm of the primary care physician and those who care for patients at risk for loss of erectile function, such as cardiologists, psychiatrists, and endocrinologists.

Here, we provide an overview of the clinical epidemiology and pathophysiology of ED and offer a practical diagnostic and therapeutic approach.

Clinical epidemiology

The Massachusetts Male Aging Study, a community-based survey of primarily white noninstitutionalized married men, estimated that 25% of men aged 40–70 had a moderate degree of ED (2). In the same population, an additional 10% of men had a completely absent erectile response. These findings were corroborated by more recent data from the larger National Health and Social Life Survey (3). Such studies also demonstrate that the prevalence of ED increases with age and is associated with depression, heart disease, hypertension, and diabetes, as well as the medications used to treat these conditions.

However, disease risk can only be reliably measured if incidence rates (i.e. new events) are known. Incidence rates of ED were lacking until the recent availability of follow-up data from Massachusetts Male Aging Study (4). Of the original sample of 1709 men, 847 who were not dysfunctional at baseline were studied. Approximately 200 new cases of ED in 7500 person years of follow-up were detected, for a crude incidence rate of 26 cases per 1000 man-years. The incidence of ED increased with each decade of life and was higher for men with diabetes, treated heart disease, or hypertension at baseline. The risk of ED was nearly four times higher for men aged 60–69 than for those aged 40–49 and was inversely related to education and income.

Pathophysiology

{alpha}-Adrenergically mediated contraction of cavernosal and vascular smooth muscle limits blood flow to the penis and maintain the usual flaccid state. An erection occurs when erotic stimuli, received via any of the five senses and processed in the hypothalamus, results in inhibition of sympathetic tone and release of nitric oxide (NO) from nonadrenergic, noncholinergic (NANC) nerves and endothelial cells of the arterioles in the penis (5). NO activates guanyl cyclase, thereby generating cyclic guanosine monophosphate (cGMP). cGMP decreases calcium uptake into vascular and cavernosal smooth muscle and induces relaxation. Smooth muscle relaxation permits engorgement of cavernosal sinusoids with blood and the development of an erection. In addition to NO, other neurotransmitters postulated to play a role in the erectile mechanism include prostaglandins, vasoactive intestinal peptide, serotonin, and dopamine.

Equally important to increased cavernosal blood flow is inhibition of venous outflow. This is accomplished passively: the distending corporal sinusoids compress the subtunical venous plexus against an unyielding tunica albuginea, thereby preventing venous drainage. Detumescence is achieved through restoration of the contractile state by increasing sympathetic tone and loss of NANC nerve-induced relaxation due to the hydrolysis of cGMP by phosphodiesterase 5 (PDE 5).

Any derangement in this sequence of neurovascular events can result in ED. For example, compromise of neural pathways either centrally (as seen in Parkinson’s disease, multiple sclerosis, or stroke) or peripherally (as seen in spinal cord/pelvic injury or diabetic autonomic neuropathy) may lead to ED. Alternatively, veno-occlusive failure may occur from intrapenile lesions such as alterations of the tunica albuginea secondary to Peyronie’s disease or deterioration of cavernosal smooth musculature or intersinusoidal fibrosis, presumably secondary to ischemia. These latter abnormalities may also compromise NO-generating capacity and prevent cavernosal smooth muscle relaxation that, in turn, impairs vascular inflow.

Endocrinopathy is generally an uncommon principal cause of ED (6) and, at best, androgens seem to play an indirect role. Androgens stimulate libido at the level of the central nervous system. In rodents, androgens also stimulate corpus cavernosal NO synthase (7). In humans, however, surgical or pharmacological castration does not necessarily alter erectile capacity (8, 9). Moreover, although hypogonadism is common in older men, it occurs independently of ED (10). However, androgen replacement may improve sexual function in hypogonadal men by restoring libido and sexual interest.

Diagnostic evaluation

The availability of therapies that are effective for a variety of etiologies has simplified the diagnostic evaluation of ED. With such final common pathway agents, starting with a therapeutic trial is cost-effective (11) and preferred over extensive diagnostic testing in the vast majority of cases.

ED is associated with many risk factors. Thorough knowledge of the medical condition of your patient is essential. Initiation of ED with loss of a spouse, acute medical problem, or new medication may identify a pathogenic mechanism. An appraisal of the initiation, severity, and duration of ED is valuable. The International Index of Erectile Function, a validated questionnaire, may be incorporated as part of the history to document the degree of dysfunction and gauge response to therapy (12). The characteristics of the relationship with the partner help in predicting the success of therapy and determining the degree of psychogenic component. There is no substitute for seeing both members of the couple and eliciting their perceptions of the problem. Invariably, they both benefit from understanding the pathogenesis of the problem and the encouragement to communicate about their sexuality. The physical examination may reveal neurological or cardiovascular disease or intrinsic penile pathology. Palpation of femoral and distal pulses, evaluation for gynecomastia, inspection of the outstretched penis for fibrosis/plaques, and measurement of testicular size and density may provide significant etiological clues.

In addition to routine chemistries, which are usually available, a TSH and morning bioavailable (i.e. nonsex hormone-binding globulin-bound) testosterone (BT) should be obtained. Of course, a thyroid disorder must be treated. If hypogonadism is documented, then serum PRL and LH are measured. In the age group in which ED is common, hypogonadism is not associated with a reciprocal rise in LH. The use of pituitary magnetic resonance imaging to evaluate for a pituitary tumor should be restricted to men with either a very low BT (<20 ng/dL) or an elevated PRL (13).

In general, sophisticated anatomic testing should be limited to patients who fail a trial of oral therapy or who have a history of penile trauma or congenital anomaly for which a surgical approach to therapy is under consideration.

Therapy

Androgens. Unless there is a contraindication, we offer testosterone replacement to hypogonadal men with ED and discourage its use in those whom ED is not associated with hypogonadism. We define hypogonadism as a fasting morning BT below 67 ng/dL (2.3 nM), a value that is 2 SD below the mean for young men. In addition to improving sexual function, androgen replacement improves mood, bone mineral density, muscle strength, and body composition (14, 15).

Sildenafil. Sildenafil (Viagra) acts through the selective inhibition of PDE 5, the predominant PDE isozyme of the corpus cavernosum. The result is inhibition of cGMP breakdown and cavernosal smooth muscle relaxation. Sildenafil is the most effective oral therapy currently available for ED and, in double-blind placebo-controlled clinical trials, permitted successful sexual intercourse in approximately two thirds of patients with ED of various etiologies (16, 17). In the clinical practice setting, similar response rates are observed and substantiated by surveys of partners’ satisfaction (18). Sildenafil does not alter libido, so for it to be effective some cGMP must be generated via NANC neurogenic sexual stimulation. Thus, at least, a partially intact penile nerve supply is necessary. This explains the higher failure rate in men who develop ED after radical retropubic prostatectomy, particularly if a nonnerve sparing procedure was performed (19).

Patients should be given clear instructions regarding the use of sildenafil. The pill is most effective if taken about 2 h before anticipated sexual activity. A starting dose of 50 mg is recommended, which can then be increased to 100 mg or decreased to 25 mg, based on efficacy and tolerability. The 50-mg tablet may be split in half. In our experience, the vast majority of diabetics require 100 mg. Sildenafil is metabolized in the liver by the cytochrome P450 3A4 isozyme (CYP3A4). Simultaneous use of drugs like erythromycin or cimetidine will decrease fist pass metabolism and increase serum sildenafil levels. In these circumstances and in patients with hepatic or severe renal impairment, a lower starting dose (i.e. 25 mg) of sildenafil is recommended. The risk of priapism is low; the most common side effects include flushing, headaches, dyspepsia, and transient visual changes. After 20 million prescriptions, its safety profile is similar to that observed in the extensive clinical trials. In combination with nitrates, it can and has caused fatal hypotension. It should not be prescribed to patients on nitrates or NO-donor drugs. Additionally, nitrates should not be administered to anyone who has recently ingested sildenafil. Synergistic blood pressure lowering has not been observed when sildenafil was used with other classes of antihypertensives (i.e. calcium channel blockers, diuretics, angiotensin-converting enzyme inhibitors, or ß-blockers) (20). In a study of 14 men (mean age, 61) with severe coronary artery disease, oral sildenafil had no effect on pulmonary-capillary wedge pressure, right atrial pressure, heart rate, cardiac output, or coronary hemodynamics (21). Nevertheless, in our practice, sildenafil is not offered to patients with low cardiac output states or those on intensive regimens to prevent heart failure.

Yohimbine, oral phentolamine, and trazadone. Yohimbine, an {alpha}-adrenergic blocker, has been available in the United States for many years. Although better than placebo, its overall efficacy is disappointing, particularly in those patients whom ED stems from a primarily organic etiology (22, 23). Side effects include hypertension and palpitations. Oral phentolamine, another {alpha}-adrenergic receptor antagonist, was shown to have a beneficial effect on erectile capacity in a small, randomized double blind study (24). Larger studies are needed to substantiate these findings, and it is not currently available in the United States. Trazadone is a serotonin antagonist and reuptake inhibitor. Like yohimbine, it has been shown to improve erectile function in men with psychogenic ED (25), but has a marginal effect in men with organic ED (26). Prolonged erection and priapism are potential rare side effects.

Sublingual (SL) apomorphine. Apomorphine is a centrally acting, nonselective (D1/D2) dopamine receptor agonist. Its erectogenic properties were demonstrated many years ago in animal studies and are felt to occur through activation of the medial preoptic and paraventricular nucleus of the hypothalamus. In humans, parenteral administration of apomorphine was also effective in inducing erections, but caused severe nausea. A SL formulation of apomorphine has been developed and is currently undergoing Phase III clinical trials. In a recent multicenter, double blind clinical trial involving 569 patients with ED of various etiologies, approximately 50% of SL apomorphine-treated subjects achieved erections firm enough for intercourse compared with 35% in the placebo-treated group (P < 0.001) (27). Thirty percent of patients in the dose-optimization group reported nausea (98% of nausea events were mild or moderate).

Intracavernosal and transurethral alprostadil. Intracavernosal or transurethral vasodilators may be offered to patients who fail sildenafil despite proper use. Alprostadil, a synthetic prostaglandin E1, is the only vasoactive agent approved by the FDA for this indication. Intracavernosal alprostadil (marketed as Caverject or Edex) was shown to restore erectile function in nearly 70% of subjects in a large multicenter trial (28). A small test dose (5 µg) should be administered in the office. In general, 5–20 µg intracavernosal alprostadil will produce a firm to hard erection that may last 30–60 min. Side effects include penile pain, fibrosis at the injection site, hypotension, and priapism. If an erection lasts for more than 60 min, 30 mg pseudoephedrine may be given orally to ensure detumescence.

Alprostadil may also be administered via a transuretheral system (MUSE). A plastic applicator is used to introduce the medicated pellet into the urethra. Four doses, ranging from 125-1000 µg, are available. This modality may be more acceptable than penile injection for some patients, and the response rate is reported to be approximately 60% (29). However, more recent evidence suggests that intraurethral instillation is substantially less effective than intracavernosal injection (30). Furthermore, significant systemic absorption can occur from transurethral therapy resulting in severe hypotension in some patients.

Vacuum tumescence device. In general, both sildenafil and intracavernosal/intraurethral vasodilators are contraindicated in men with severe cardiovascular disease or low cardiac output states. In this setting, vacuum tumescence devices are the preferred treatment modality. These devices are cost-effective and highly efficacious, producing successful erections in 70% of couples who use them. However, the patient must be motivated to use them efficiently. Penile petechiae, numbness, and retarded ejaculation are occasional side effects.

Surgery. Once used in a large number of men, penile prosthesis placement has now assumed a tertiary role in the armamentarium against ED and is typically reserved for patients who fail less invasive therapies. They are expensive (approximately $10,000); require replacement after 5–10 yr; and may be complicated by mechanical failure, infection, or silicone granuloma formation in the cavernosa. Direct surgical intervention to restore vascular inflow or inhibit venous return should be reserved for patients with congenital or traumatic ED and only performed in specialized centers.

Future directions

The success of sildenafil guarantees the development of other oral agents for the treatment of ED. BAY 38-9456 (Bayer Corp., West Haven, CT) and IC351 (Icos, Bothell, WA) are two new PDE 5 inhibitors currently under evaluation in Phase I and II studies, respectively. Moreover, the recent identification and cloning of three distinct PDE 5 isoforms in human cavernosal tissue may permit the development of new therapeutic targets. Finally, cloning of penile-inducible NO synthase heralds the potential use of gene therapy for ED.

Received February 22, 2001.

Accepted March 12, 2001.

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