Historically, androgens were thought to enhance male sexual function. However, androgen therapy should be used only in hypogonadal men. Testosterone therapy in men with normal hormonal levels may temporarily increase libido and desire but does not affect ED (33).

Furthermore, due to uncertainty regarding the risks/benefits of testosterone treatment, e.g., stimulation of prostate growth and activation of occult prostate cancer growth, testosterone should be avoided in men with normal hormonal levels. In hypogonadal men suffering from ED, transdermal and intramuscular testosterone therapy are considered more efficacious than oral testosterone preparations (34, 35). In elderly men, however, androgens do not seem to improve erectile function. Testosterone cypionate and enanthate are often used for replacement therapy; the usual dosage is 200 mg intramuscularly every 2 to 3 weeks. Their major drawbacks are the marked peaks and troughs in serum testosterone, with high levels in the first week after injection and a decrease thereafter. Several transdermal testosterone preparations (testosterone patches or gels) are now available.

Daily application of these preparations raises serum testosterone concentrations to within the normal range in over 90 percent of men. The most common adverse effects of testosterone patches have been skin irritation and contact dermatitis. These therapies are contraindicated in men with prostate cancer and BPH causing obstructive symptoms due concern about stimulating growth of the prostate. Additionally, testosterone treatment may cause polycythemia and worse obstructive sleep apnea, and so men receiving androgen replacement therapy require biannual checks with measurement of hematocrit, serum testosterone, and PSA.

Oral therapy with a type 5 phosphodiesterase inhibitor (PDE-5 inhibitors) (sildenafil, vardenafil and tadalafil) is considered first line therapy in men with ED (36) . PDE-5 inhibitors block the inactivation of cyclic GMP and result in increased smooth muscle relaxation and better erections. In the absence of sexual stimulation these medications have no effect on the penis. Numerous placebo controlled studies have been conducted on the safety and efficacy of sildenafil as it has been in clinical use for close to five years. The results have shown that the number of erections and rates of penile rigidity, orgasmic function, and overall satisfaction were significantly higher with sildenafil than placebo (37, 38). In terms of safety, most clinical trials published show only mild to moderate adverse events associated with all of the PDE-5 inhibitors and these events are usually self limited in duration.(30, 39) The most common complaints are of headache (16 percent), flushing (10 percent), dyspepsia (7 percent), nasal congestion (4 percent), and visual disturbances/ color sensitivity (3 percent). Tadalafil distinguishes itself from vardenafil and sildenafil by the relative lack of visual side effects. It does however have an additional possible adverse effect which is back pain and/or myalgia (31, 40) There is no difference in terms of adverse or serious cardiovascular events between PDE-5 inhibitors and the placebo-controlled groups (38). To date, over 20 million men in over 100 countries have used sildenafil.(30, 39) Since the release of the drug, over 200 deaths temporally associated with sildenafil therapy were reported to the Food and Drug Administration in the United States of America. Sexual activity was thought to be a likely contributor to myocardial infarction, with sildenafil acting to enable men not previously active to partake in sexual activity (31, 32). Therefore, it appears that PDE-5 inhibitor therapy is safe for most men. Men with cardiovascular disease should seek a cardiologist consultation prior to using PDE-5 inhibitors. The combination of nitrates and PDE-5 inhibitors has resulted in severe hypotension and deaths. Therefore, nitrate therapy is a contraindication for PDE-5 inhibitor therapy. The American Heart Association has published a guideline for sildenafil therapy (Table 4.) (43). This includes pre-therapy evaluation of cardiac status for men on multiple antihypertensive medications, pre-existing cardiac disease, and men using nitrite medications (44). These guidelines may be extrapolated to be used for all PDE-5 inhibitors.

A lower starting dose (25 mg of sildenafil, 5 mg of vardenafil or tadalafil) should be used in patients who may attain and maintain higher plasma levels. These include patients who are older than 65, have severe renal impairment or take potent CYP450 3A4 inhibitors. Patients who take ritonavir should not take more than 25 mg of Sildenafil in a 48-hour period . To avoid symptomatic hypotension, PDE5 inhibitors should not be taken within 4 hours of an alpha-blocker . One study found a significant rate of hypotension (28% versus 6% with placebo) in patients taking concomitant doxazosin and tadalafil; however, the rate of hypotension matched that seen in placebo-treated patients in patients taking tamsulosin and tadalafil , and some studies suggest that the interaction has less clinical relevance in patients who have undergone long-term alpha blocker therapy . The position of the American Urological Association is that all three PDE5 inhibitors interact to some degree with alpha-blockers and that concurrent use of alpha-blockers and PDE5 inhibitors may cause patients to develop orthostatic hypotension. In hemodynamically stable patients treated with alpha blockers, PDE5 inhibitors should be used with caution and initiated at the lowest recommended starting dose. Similarly, patients using PDE5 inhibitors and requiring alpha-blocker therapy should start at low doses, and be titrated gradually to effect. Other antihypertensive agents, such as calcium channel blockers, are well-tolerated by men concurrently taking any of the three PDE5 inhibitors. Concomitant administration of these drugs appears to cause no or only small additive drops in blood pressure.

Non-arteritic ischemic optic neuropathy (NAION) and PDE5 inhibitor use has garnered a great deal of attention in both scientific and lay publications. Spontaneous NAION is the most common acute optic neuropathy and ranks second only to glaucoma as a cause of acquired optic neuropathy for men aged 50 and older . Estimated annual incidence is 2.3 to 10.3 per 100 000 and is more common in Caucasians than African Americans, Asians, or Hispanics. Most patients do not become legally blind, but the degree of visual acuity and visual field loss is usually significant. Risk factors common to NAION and ED include hypertension, diabetes mellitus, hypercholesterolemia, age over 50 years, coronary artery disease, and smoking Given that an estimated 27 million men worldwide that have used sildenafil (up to 1 billion doses), not counting tadalafil or vardenafil users, the expected incidence of NAION in this group should be many-fold higher than the 43 cases reported to the FDA as of June 2005. If one bases calculations on the most conservative incidence of NAION in the general population (2.3 cases per 100,000) and the fact that there are at least 27 million users of PDE5 inhibtors, one would expect at least 621 cases in this population. This comparison therefore begs the question of whether PDE5 inhibitors exert a protective influence on the evolution of NAION. To date, the FDA maintains that a causal relationship between NAION and PDE5is has not been established. Review of safety data from over 100 clinical studies of sildenafil (>13 000 men) did not identify any cases of NAION, with similar findings for vardenafil and tadalafil. Given current evidence, it is not possible to determine whether these events are directly related to use of PDE5 inhibitors or to other factors; however, men are instructed to stop taking these medications immediately and contact their physician should visual changes or loss occur . Men with a history of NAION should not use PDE5 inhibitors.

Sildenafil (Viagra, Pfizer)works best when taken on an empty stomach and reaches maximum plasma concentrations within 30 to 120 minutes (mean 60 minutes). It is eliminated predominantly by hepatic metabolism, and the terminal half-life is about 4 hours. The recommended starting dose is 50 mg taken 1 hour before sexual activity. The maximal recommended frequency is once per day. The efficacy of sildenafil has been extensively studied in patients with other coexisting diseases. No significant difference in response rate was noted comparing a normal cohort of patients with patients with hypertension (57), spinal cord injury, depression(58), prostate surgery(59) , diabetes (60) and the elderly(61) . Patients who have undergone non-nerving sparing radical prostatectomy have a lower response rate to sildenafil compared to a normal cohort of patients (59) (Table 5.).

Vardenafil (Levitra, Bayer/GSK) is a potent and highly selective PDE-5 inhibitor. Its chemical structure is quite similar to sildenafil however in in-vitro studies the selectivity and potency of vardenafil are superior. The medication can be given in either 10 or 20 mg dosage. The time to peak plasma concentration is 40-55 minutes. Vardenafil has been shown to be highly efficacious in a wide range of clinical indications. In one multicenter phase III trial patients with diabetes (type I and II) were found to respond to 20 mg dosage of vardenafil significantly better then a similar control group. The effect also seemed to improve after 12 weeks of treatment. (62). Although similar in chemical structure, the in vitro potency and selectivity of vardenafil are superior to that of sildenafil.  Several newer studies have demonstrated vardenafil to have a faster onset of action then seen with other medications of the same class.  In particular one study (ONTIME) found that 21% of men with moderate to severe erectile dysfunction obtained erections of sufficient firmness for sexual intercourse at 11 minutes using 20 mg of Vardenafil.  At 25 minutes 53% of patients obtained erections sufficient enough for penetration as compared to placebo (26%).  The statistically superior response to vardenafil versus placebo was observed in all times from 11-25 minutes             The side effects most frequently seen are flushing, dyspepsia, headache and visual disturbances. (66-68) Adverse events reported in men taking vardenafil closely resemble those in men taking sildenafil and tadalafil.  Headache(21%), flushing (13%), dyspepsia (6%) are seem at various frequencies depending on dosages used. 

Tadalafil (Cialis, Eli Lilly, USA) is another PDE-5 inhibitor which has a distinctly different chemical structure from vardenafil and sildenafil. Because tadalafil has less of an inhibitory effect on PDE-6 it lacks the visual side effects that sildenafil and vardenfil may cause. It also comes in a 10 and 20 mg dosage. Tadalafil’s effect may be initiated as early as 30-45 minutes however it may last as long as 24-48 hours (70). As with the other PDE-5 inhibitors the side effect profile of this medication is quite mild. In addition to the lack of visual side effects, it also tends to have a reduced incidence of facial flushing compared to the other PDE-5 inhibitors. Back pain however has been noted in several studies (45) . Another distinguishing factor of this new PDE-5 inhibitor is that there is no effect on the absorption of tadalafil by alcohol or food.   An integrated analysis from five randomized control double blind placebo trials revealed that men with varying severities of ED significantly improved with Tadalafil therapy at 10 and 20 mg dosages.  The mean IIEF score (international index of erectile dysfunction score) increased by 6.5 and 7.9 at the 10 and 20 mg dosage of tadalafil.  This increase was statistically significant compared to placebo. (71)      In pharmacological studies tadalafil appears to be rapidly absorbed and reaches a peak serum concentration by 2 hours.  The uniqueness of tadalafil appears to be in that its half life is approximately 17.5 hours.  As well, the absorption and excretion of tadalafil does not appear to be affected by food or alcohol.  With a 17.5 hour half life tadalafil has period of responsiveness of up to 36 hours. 59% of patients who were administered a SEP questionnaire 24 hours after dosing (20 mg of tadalafil) responded positively to having successful intercourse as compared to 7% of placebo patients.       Like sildanafil and vardenafil, tadalafil potentiates the hypotensive effects of nitric oxide and it is therefore contraindicated in patients taking nitric oxide compounds.  Tadalafil appears to be very well tolerated in most studies.  The most frequently reported adverse events are headache and dyspepsia.  Back pain, nasal congestion, myalgia and nasal congestion appear to be more transient and decrease in frequency with future treatments.  Unique to tadalafil is the lack of visual side effects seen with sildenafil.  The rate of treatment discontinuation as with sildenafil and vardenafil is similarily quite low at 2.2% compared with the placebo discontinuation rate of 1.3%. 

PDE-5 Inhibitors and Cardiovascular Safety.Controlled and post-marketing studies of the three FDA-approved PDE-5 inhibitors demonstrated no increase in myocardial infarction or death rates in either double-blind, placebo-controlled trials or open-label studies when compared with expected rates in the study populations . Patients with known coronary artery disease or heart failure receiving PDE-5 inhibitors did not exhibit worsening ischemia, coronary vasoconstriction, or worsening hemodynamics on exercise testing or cardiac catheterization. PDE-5 inhibitors have a minimal effect on QTc interval. However, vardenafil is the only one not recommended in patients who take type-1A antiarrhythmics (such as quinidine or procainamide) or type-3 antiarrhythmics (such as sotalol or amiodarone) or in patients with congenital prolonged QT syndrome.

The vasodilator effects of sildenafil, vardenafil, and tadalafil may be more marked in patients with hypertension or coronary artery disease.  As with all vasodilators, caution is advised in certain conditions: aortic stenosis, left ventricular outflow obstruction, hypotension and hypovolemia. Caution is advised when an alpha-blocker and a PDE-5 inhibitor are given together, as interaction can lead to excessive vasodilation and hypotension.

Nitrates are absolutely contraindicated in patients taking PDE-5 inhibitors. These include organic nitrates, including sublingual nitroglycerin, isosorbide mononitrate, isosorbide dinitrate and other nitrate preparations used to treat angina, as well as amyl nitrite or amyl nitrate (so-called “poppers,” a recreational drug). Past use of nitrates, e.g. more than two weeks before the use of PDE-5 inhibitors, is not considered a contraindication. Patients who develop angina during sexual activity with a PDE-5 inhibitor should be instructed to discontinue sexual activity, relax for 5-10 minutes and, if the pain persists, seek emergency care and inform emergency medical personnel that a PDE-5 inhibitor was taken.

PDE5i ‘failures’: Prior to moving on to 2nd line treatments, several strategies may be taken when a patient complains that their new medication is not having the desired effect. An important first step is re-education on the correct use of the medications. Many patients need to be reminded that these medications are reliant on central mechanisms and that they will not work well without erotic stimulation. Up to 55% of sildenafil initial non-responders will respond after education (74.1,74.2). Dose titration may be necessary. Additionally, sildenafil may not work as well after a high fat meal, although vardenafil and tadalafil seem to be less dependent on timing with regard to meals . Another step that can be taken is to check hormonal levels, as these medications are at least partially androgen-dependent . There is also evidence that function may improve with chronic use , at least in animal models.

Yohimbine is an alpha 2-adrenergic receptor antagonist produced from the bark of the yohim tree. Its effect on erectile function is at best marginal and is therefore not recommended in patients with organic ED. A meta-analysis of several placebo-controlled studies of 419 men with predominantly non-organic ED has shown some benefit over placebo (75). Frequent side effects include palpitation, fine tremor, elevation of blood pressure, and anxiety.

Oral phentolamine (Vasomax®) has been reported to improve erectile function compared to placebo (76, 77). Side effects of the medication include headache, facial flushing, and nasal congestion. Oral phentolamine has not been approved by the FDA, but it is available in several South American countries.

Apomorphine (Uprima®), a dopaminergic agonist, is a sublingual medication that is available for use in Europe. Apomorphine is a potent emetic that acts on central dopaminergic (D1/D2) receptors. When injected subcutaneously, it induces erections in rats and humans, but the side effects, notably nausea, seriously limited its clinical usefulness (78). Sublingual apomorphine has not received FDA approval.

Bremelanotide is a melanocortin analog that acts centrally and has been investigated in subcutaneous and intranasal administration. These studies reported statistically significant improvements in erections compared to placebo in both healthy men and those who did not respond well to sildenafil. Common side effects include flushing and nausea. The medication has not been approved by the FDA, as phase 3 trials are not yet completed.

Second line therapy includes vacuum constriction device (VCD), trans-urethral suppositories and intra-cavernous injection (ICI) therapy. VCD is the least expensive. It is cumbersome and gives an unnatural erection. The erection is attained via vacuum suctioning of blood that is trapped in the penis with a constriction device. This type of therapy is preferred for older patients in stable relationships. Its side effects include petechiae, numbness and a trapped ejaculate.

Transurethral alprostadil (MUSE®) has many advantages including local application, minimal systemic effects, and the rarity of drug interaction. However, this type of secondary treatment has failed to gain popularity due to its major drawbacks including moderate to severe penile pain, low response rate and inconsistent efficacy (81, 82). It has been extensively studied in Europe and the United States and was found to be effective in 43 percent of men with erectile dysfunction of various organic causes. The most common side effects were penile pain (32 percent) and urethral pain or burning (12 percent) (83, 84). Using an adjustable constriction device (Actis®) placed at the base of the penis after MUSE administration resulted in an increase in successful sexual intercourse in 69 percent of men (85) . Patients are initially started with a test dose of 500-μg in the office. Depending on the patient's response, this dose can be titrated from 250-1000 μg. It is important to administer the test dose in the office due to the risks of urethral bleeding, vasovagal reflex, hypotension, and priapism that can occur with this medication.

Intracavernous injection therapy: There are several medications available including papaverine, alprostadil, phentolamine, VIP (vasoactive intestinal polypeptide), and ketanserin. Men must receive appropriate training and education by medical personnel before beginning home injections. The goal is to achieve an erection that is adequate for sexual intercourse but does not last for more than one hour. The two major side effects of intracavernous injection are priapism and fibrosis (penile deviation, nodules or plaque). Priapism is preventable through careful titration. To prevent fibrosis, we routinely instruct men to compress the injection site for 5 minutes (up to 10 minutes in men taking anticoagulants). Intracavernous injection therapy is contraindicated in men with sickle-cell anemia, schizophrenia or other severe psychiatric disorder due to the risk of priapism associated with intracavernous injection.

In the U.S., the most commonly used intracavernous drugs are alprostadil alone or in combination with papaverine and phentolamine (Trimix). Alprostadil's efficacy is superior to papaverine alone and it results in erections in more than 70 percent of treated men (86). The usual dose ranges from 5 to 20 μg. The most frequent side effect is painful erections that occur in 17 to 34 percent of men (86, 81). This hyperalgesic effect is most prominent in men with partial nerve injury, such as those with diabetic neuropathy and those who have undergone radical pelvic surgery. Alprostadil has a relatively low incidence of priapism (0.35 to 4 percent) and fibrosis (1 to 23 percent) (51, 87, 88). Papaverine is a non-specific phosphodiesterase inhibitor that increases cyclic AMP and cyclic GMP concentrations in penile erectile tissue (89) Its usual dose ranges from 15 to 60 mg. It is more effective in psychogenic and neurogenic erectile dysfunction (up to 80 per cent) compared to vasculogenic (36-50 per cent). Its advantages include low cost and stability at room temperature. Its major disadvantages are priapism (up to 35 percent), corporal fibrosis (up to 33 percent) and occasional increases in liver function tests.

Phentolamine is a competitive alpha-adrenergic receptor antagonist. It must be used in combination with papaverine to produce rigid erections (63-87% success rates) (90, 91). Most urologists use a combination of 30 mg papaverine and 0.5 to 1 mg phentolamine. The side effects of phentolamine include hypotension and reflex tachycardia.

Vasoactive intestinal polypeptide (VIP) is a potent smooth muscle relaxant originally isolated from the small intestine. This medication is only available in Europe. Injection of vasoactive intestinal polypeptide alone does not produce a rigid erection, (92) but when combined with phentolamine, it produces erections sufficient for sexual intercourse in up to 67 percent of men (93). Common side effects include transient facial flushing (53 percent), bruising (20 percent), pain at the injection site (11 percent), and truncal flushing (9 percent).

Combinations of medications such as papaverine and alprostadil (94), ketanserin and alprostadil,(95) and phentolamine and alprostadil(96) have been proven to be superior single medications in efficacy of response. The most effective intracavernous therapy used in the U.S. is a three-drug mixture containing papaverine, phentolamine and alprostadil (Trimix). The usual dose of Trimix solution ranges from 0.1 to 0.5 ml. The response rate to this solution is reportedly as high as 90 percent (97) . Although widely used in the U.S., it is not approved by the FDA.

Although the response rate to injection therapy is high, in long-term studies 38 to 80 percent of men dropped out (98, 99). To avoid the cumbersome nature of injection therapy, some men alternate injection therapy with sildenafil or MUSE®, preferring injection in circumstances when an erection of longer duration is desired. Alternatively, in men whom injection therapy alone fails or is insufficient, we recommend the use of injection therapy in combination with a vacuum constriction device.

No transdermal medication has been approved by the FDA for erectile dysfunction and none is available for clinical use. Nitroglycerine cream or paste, alprostadil cream, and a cream containing aminophylline, isosorbide dinitrate, and codergocrine mesylate have been used in pilot studies in men with erectile dysfunction with varing results (100).