A Pill for Impotence
Robert D. Utiger, M.D.
Impotence -- the preferred term is now erectile dysfunction -- is a common problem, especially among older men, (1) and if it is not caused by psychological problems it certainly can cause them. Among the components of sexual function and satisfaction in men -- desire, erectile function, orgasmic function, ejaculation, and fertility -- decreased erectile function is not only the most common but also the most distressing and threatening. It can destroy a man's ego and threaten happy relationships.
In this issue of the Journal, Goldstein et al. describe the efficacy of oral sildenafil in men with erectile dysfunction. (2) This is the third study of the treatment of erectile dysfunction published in the Journal since 1996. The first study described the efficacy of intracavernosal injection of alprostadil (prostaglandin E1), (3) and the second the efficacy of intraurethral application of alprostadil. (4) These studies attest to the rapid increase in knowledge about the physiology of erectile function and the application of that knowledge and of pharmaceutical expertise to the development of new treatments for men with this disorder.
In this new, two-part study, men with organic, psychogenic, or mixed erectile dysfunction took various doses of sildenafil at home in anticipation of intercourse. (2) Efficacy was evaluated by the men on a 15-item questionnaire for rating erectile function. (5) In part one of the study, a 24-week trial in which 532 men took placebo or various doses of sildenafil, the latter caused a dose-dependent increase in erectile function. In part two, a 12-week trial in which 329 men could increase the dose of sildenafil or placebo on their own initiative, sildenafil was more effective than placebo. In no treatment group, however, were the mean scores for the key questions about the strength and maintenance of erections as high as those of normal men, nor did all the men have successful sexual intercourse. The efficacy of sildenafil was unrelated to the cause of the erectile dysfunction, and it had few side effects. Unfortunately, the report contains no information from the men's sexual partners or about the onset and duration of action of the drug and the factors affecting efficacy. (In a preliminary study the drug, when combined with visual sexual stimulation 30 minutes later, resulted in erections within 2 hours. (6))
The studies of alprostadil and sildenafil are not directly comparable, because of differences in study subjects, assessments of efficacy, and duration. Nevertheless, each study included men with diverse causes of erectile dysfunction, and in each study erectile function improved more in the men in the treatment group than in those in the placebo group. How do these treatments differ, apart from the obvious one of route of administration? Although both promote the inflow and retention of blood within the corpora cavernosa of the penis, they do so in different ways.
Normal penile erections occur as a result of a series of neurally mediated alterations in blood flow in the two corpora cavernosa that constitute most of the mass of the penis. (7) The initiating events include tactile, visual, auditory, and imaginative stimuli that act centrally, primarily to increase parasympathetic outflow but also to inhibit sympathetic outflow, and local tactile stimuli that activate a penis-spinal cord-penis parasympathetic reflex arc. This nervous system activation results in the dilatation of small tortuous branches of the main cavernosal arteries, called helicine arteries, and then relaxation of the smooth muscle of the trabeculae of the corpora cavernosa. The resulting inflow of blood engorges the sinusoidal spaces of the corpora cavernosa, so that the trabecular tissue compresses small cavernosal veins against the thick fibrous tissue that surrounds the corpora, thereby maintaining the erection.
These changes in blood flow are mediated by the release of nitric oxide from postsynaptic parasympathetic neurons and, to a lesser extent, endothelial cells, (8) and also by the inhibition of (alpha)-adrenergic neurons in the arterial and trabecular smooth muscle. The readily diffusible nitric oxide stimulates guanylate cyclase in the trabecular and arterial smooth-muscle cells, increasing their content of cyclic guanosine monophosphate (GMP), which relaxes the cells.
Sildenafil acts by inhibiting the breakdown of cyclic GMP by a specific cyclic-GMP phosphodiesterase. Cyclic GMP is involved in other signaling pathways -- for example, those for atrial natriuretic hormone in the blood vessels and kidneys and color vision in the retina, and therefore inhibition of its breakdown might be expected to have effects other than maintaining smooth-muscle relaxation in the penis. More important, nitric oxide is formed in other peripheral nerves and endothelial cells, the brain, and platelets. (9) In these tissues it also activates guanylate cyclase, resulting in vasodilatation, increased synaptic transmission, and inhibition of platelet adhesion and aggregation. Sildenafil might therefore be expected to have rather widespread effects, but seemingly does not, at least when taken intermittently to improve erectile function.
Alprostadil relaxes smooth muscle directly and would be expected to have widespread vasodilatory effects if given systemically. Local injection or urethral application obviates most of these effects, but either is at best awkward and at worst traumatic and painful.
The two treatments differ in another important way. Because sildenafil potentiates the action of cyclic GMP rather than stimulating its production, it is effective only when cyclic-GMP production in penile tissue is increased by central or reflex sexual arousal. Thus, sildenafil will be ineffective if there is no arousal, enhancing the role of the man's partner. In contrast, administration of alprostadil can result in erections in the absence of sexual arousal, thus minimizing the participation of the partner. Neither treatment would probably be effective in men with erectile dysfunction caused by severe arterial insufficiency, loss of trabecular smooth muscle, or incompressible cavernosal veins.
Many disorders are associated with erectile dysfunction, including hypertension, diabetes mellitus, hypercholesterolemia, renal insufficiency, hypogonadism, neurologic and psychiatric disorders, and indeed any chronic illness. (10) So are genitourinary surgery and many drugs, particularly antihypertensive and psychotropic drugs. A causative role for many of these disorders and drugs is not established, but some may impair neural or endothelial production of nitric oxide or cause loss of trabecular smooth muscle. When men present with erectile dysfunction, doctors should consider these disorders and ask about drugs, but it is also important to ask about erectile function even when men do not volunteer that there is a problem.
The availability of sildenafil as an effective and safe oral therapy for men with erectile dysfunction means that many more men will seek help for the condition and that primary care physicians will be increasingly involved in making decisions about the evaluation and treatment of these men. There are pitfalls. First, men with erectile dysfunction may undergo little or no evaluation before treatment is initiated. Second, men with no erectile dysfunction at all may seek treatment in the hope that it will enhance their sexual performance. Yet, unanswered questions remain. Can the drug be abused? Should insurers pay for it in unlimited amounts?
The results of this study are promising, and the drug has been widely hailed in the media since its approval by the Food and Drug Administration on March 27. Anecdotes of nearly miraculous restoration of sexual function have fueled the excitement.
Whether the promise of sildenafil will be realized after many more men have been treated and the drug has been taken repeatedly for prolonged periods remains to be seen.