Sexual Dysfunction in Men

Dr. Munarriz and Dr. Ducharme lectured on January 27, addressing the topic of Sexual Dysfunction in Men. Dr. Munarriz spoke on general aspects of sexual dysfunction in men. Erectile dysfunction (ED) affects an estimated 30 million men in the United States, and over 617,000 new cases are expected annually in men between the ages of 40 and 69. Detailed summaries of this and other sexual medicine information sessions are available on our website,

Dr. Munarriz spoke of premature or early ejaculation and delayed ejaculation. For more information on that topic, please refer to an earlier information session on our website. During the discussion of erectile dysfunction, Dr. Munarriz talked about modifiable risk factors which can affect sexual function positively, such as cessation of smoking, exercise, and switching medications under a physician’s care, treating depression and anxiety, losing weight, lowering cholesterol and bike riding on a safe, two cheeked seat. There is information about bike riding on our website from a previous information session.

There are first, second and third line therapies to treat ED. First line therapies include the use of phosphodiesterase type 5 (PDE5) inhibitors sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis), and the use of androgen therapy, in particular DHEA, testosterone gels and testosterone patches, often in conjunction with the PDE5 inhibitor. A second line therapy used often at the Center for Sexual Medicine is intracavernosal injection therapy. There will be more information on this topic at a future information session, although you may read about it on our website under therapies. Third line treatments encompass surgery, either implantation of a penile prosthesis, to be discussed at an upcoming information session, or penile revascularization surgery.

Erectile dysfunction (ED) is a common and increasingly prevalent disorder. It affects an estimated 30 million men in the United States, and over 617,000 new cases are expected annually in men between the ages of 40 and 69. The availability of sildenafil citrate, the first effective oral agent for ED, has dramatically increased the number of men seeking treatment for this disorder and shifted much of the management of ED to primary care physicians. Two other oral erectogenic agents are now available. Vardenafil is a phosphodiesterase type 5 (PDE5) inhibitor with a pharmacokinetic profile and molecular configuration nearly identical to that of sildenafil. Vardenafil has a higher biochemical potency than sildenafil or the other new PDE5 inhibitor, tadalafil. Tadalafil has a unique chemical structure and a pharmacokinetic and pharmacodynamic profile that differs from both sildenafil and vardenafil.

The availability of these three PDE5 inhibitors will greatly expand our treatment armamentarium for ED but also raises important questions for patients and physicians. First, how do we choose among the 3 drugs? And, second, how do the new drugs differ from sildenafil, the established benchmark in ED treatment? Over 11,000 patient-years of experience with sildenafil exist as well as a tremendous amount of reassuring safety and efficacy data. This makes most physicians feel comfortable prescribing sildenafil as first-line therapy for ED. However, for many patients who do not have a reasonable response to sildenafil, the opportunity to try a different oral agent will be a welcome option and an alternative to second-line therapy with a vacuum constriction device, an injected agent, or intraurethral alprostadil.

To help select the most appropriate PDE5 inhibitor for patients with ED, and in the absence of carefully controlled, published head-to-head trials, it is important to examine some of the distinguishing characteristics of these agents, including selectivity, onset and duration of action, and safety and efficacy.

Selectivity is an important issue, because there are as yet no pure PDE5 inhibitors. There are 11 PDE enzymes in the body. In addition to inhibiting PDE5, both sildenafil and vardenafil also produce modest PDE6 effects at the upper limits of the dosage range, whereas these effects are absent with tadalafil. In contrast, only tadalafil has definite PDE11 effects at therapeutic doses, although the significance of this is not yet clear. We know that PDE6 inhibition affects the cones in the retina and results in the “blue” vision experienced by some patients taking sildenafil and less in patients with vardenafil. However, no adverse visual effects have been reported with sildenafil, and vardenafil. PDE11 has only recently been described and is present in the pituitary, pancreas, skeletal muscle, heart, testes, and corpus cavernosum. However, the effects on these tissues of chronic or intermittent PDE11 inhibition are not known and require further study.

Onset of Action
None of the PDE5 inhibitors works immediately. Most studies indicate that sildenafil and vardenafil have an average onset of action of about 30 to 60 minutes. Controlled studies show that sildenafil and vardenafil can result in erections satisfactory for sexual intercourse in as short as 15 minutes. Tadalafil may be effective in as little as 15 or 16 minutes however, the rapid onset of effect occurred in less than 20% of patients. In general, the speed of onset of a drug varies from person to person and will be determined by an individual’s internal chemistry. If, however, onset of action becomes a critical concern for any individual patient, the patient should be advised to avoid taking the drug on a full stomach and particularly after a fatty meal, which further delays gastric emptying and drug absorption. This is certainly true for patients taking sildenafil and vardenafil, although it may not be the case for tadalafil. Tadalafil has a reported lack of a food effect as a result, slow gastric emptying has less effect on the time to maximum concentration (Tmax).

Duration of Action
The duration of action is an exciting area of comparison among the oral agents because it is where the most significant differences are found. The reported duration of action ( HALF-LIFE (T1/2) of sildenafil is approximately 4 to 5 hours, for vardenafil is 4.8 – 6.0 hours whereas for tadalafil it is between 17 and 21 hours. There is no doubt that an oral erectogenic agent with a long duration of action provides some men with additional confidence, allowing them to take the drug long before they anticipate having sexual relations. However, on the downside, taking a drug long before sexual relations are to occur may result in some waste as well as some blunting of response over time.

Patterns of Sexual Behavior
When evaluating the onset and duration of action of the PDE5 inhibitors it is also important to consider how these features conform to the normal sexual patterns of patients. In a recent study of sexually active men aged 40 to 69 years both with and without ED, investigators found that the average frequency of sexual intercourse was 1 episode per week and that the average time for foreplay was approximately 14 minutes; the vast majority (> 70%) of men studied reported that they had sex only once in a 24-hour period. Based on these statistics, it will be relatively easy to select a drug with onset and duration of action that satisfies patients’ needs.

The safety of PDE5 inhibitors is an important concern, since many men with ED also have cardiovascular disease. A careful assessment of cardiovascular status before prescribing treatments for ED and/or advising the patient to resume sexual activity is recommended. To date, there is no evidence that any of the PDE5 inhibitors has any direct adverse cardiovascular effects. In fact, the reverse may be true, as recent studies suggest that sildenafil may delay exercise-induced ischemia and angina. Other safety issues specific to tadalafil also need to be considered. Because of the drug’s prolonged duration of action (ie, approximately 17 hours in a healthy man and up to 21 hours in an elderly patient), it will take up to 48 hours for tadalafil to delay intervention with nitroglycerin during a cardiac event. In addition, because tadalafil inhibits PDE11, additional studies examining the effects of tadalafil on spermatogenesis as well as on pituitary and cardiac function are also needed. These studies are expected to be forthcoming. Studies to date have demonstrated no long-term effects of sildenafil on sperm function.

Adverse Effects
In general, the PDE5 inhibitors are well tolerated and have similar mild to moderate adverse effects profiles. In clinical trials, the most commonly reported adverse events were vasodilation, resulting in headache, nasal congestion, facial flushing, and dyspepsia. There appears to be a greater incidence of myalgia and low back pain with tadalafil, although the etiology of the myalgia remains unclear. None of the PDE5 inhibitors has any significant drug interactions except for an absolute contraindication for the concomitant use of organic nitrates. Sildenafil and all agents in this class potentiate nitrate-induced vasodilation. In addition, they are all metabolized by the cytochrome P450 3A4 isoenzyme system, and concomitant administration of inhibitors of this pathway (eg, cimetidine, ketoconazole, erythromycin, and protease inhibitors) will prolong duration of action and raise serum concentrations of the drugs.

Clinical Efficacy
Once the safety of the drug has been established, clinical efficacy is clearly a most important factor for the clinician to consider when selecting a drug. Evidence suggests that all 3 PDE5 inhibitors improve the quality of erections and enable successful intercourse in men with ED of all etiologies, even those with severe ED. The question as to whether men with certain comorbidities (eg, diabetes, post-radical prostatectomy, and hypertension) would be more successfully treated with one particular agent awaits further study and experience. To clearly define one drug’s benefit or superiority over another requires carefully designed, head-to-head studies with well-defined efficacy measures.

Three oral treatments for ED are now available. How physicians will choose which drug to prescribe will be much the same as electing among other classes of drugs with multiple options, such as NSAIDs, alpha-blockers, or SSRIs. The selection process will take into account physicians’ previous experiences with the agents and patient satisfaction and preferences as well as the recognition that similar drugs may have significantly different effects in the same individual.

Dr. Ducharme closed the educational portion of the information session with a discussion of the biopsychosocial model of sexual dysfunction. The partner is affected by the sexual dysfunction and should be included in the therapy and education.

Primary teaching affiliate
of BU School of Medicine