Sexual activity, as assessed by subjective measures, is increased by T therapy.109 Treatment of six hypogonadal men with parenteral TE (400 mg every 4 weeks) increased their total erections, nocturnal erections, and coital attempts as compared with placebo treatment. Similarly, hypogonadal men given oral testosterone undecanoate experienced an increase in the number of sexual acts per week, number of ejaculations per week, frequency of sexual thought, and sexual excitement, compared with men receiving a placebo.110

T treatment of men with low total T levels can improve daytime erectile rigidity and SREs. One group of investigators reported that untreated hypogonadal men had erections while observing erotic films. They had circumference changes similar to those of controls, but diminished maximum rigidity. The penile rigidity of erections stimulated by visual erotic material improved significantly after T therapy.111 In a group of six severely hypogonadal men (aged 25 to 40 years) who had not previously received androgen replacement therapy, nocturnal erections were absent or severely impaired. SREs increased progressively into the normal range with androgen replacement therapy over 6 to 12 months.112 The authors studied six hypogonadal men who received 200-mg injections of testosterone cypionate.113 SRE studies were conducted during the week after an injection and again after 7 to 8 weeks without further replacement therapy. Androgen withdrawal was associated with a significant reduction in the number of erections, total tumescence time, penile circumference changes during erections, and penile rigidity. In 20 hypogonadal men, the duration and rigidity of nocturnal erections, as measured by RigiScan, were greater during transdermal T replacement therapy than at the end of 8 weeks of androgen withdrawal.114

The contraindications to and complications of androgen replacement therapy must be considered carefully before treatment is recommended. Men older than 50 years must be evaluated for benign prostatic hyperplasia and prostate cancer before and during androgen therapy. Sleep apnea or polycythemia may worsen with androgen therapy. Careful history-taking and periodic assessment of hematocrit, serum PSA, and the prostate are essential.

The normalization of hyperprolactinemia by the surgical removal of a prolactinoma or by administration of dopamine agonists may increase serum T levels and restore potency. Eight patients with prolactinomas were studied using nonpolysomnographic SRE monitoring before and after therapy.115 Before treatment, circumference increases during tumescence episodes were smaller and total tumescence time was lower in the patients with prolactinomas than in age-matched control subjects. Treatment was associated with a greater penile circumference increase during SREs. One study reported a 17% incidence of mild hyperprolactinemia (16–22 ng/mL) in 47 men with ED.89 The patients were randomly assigned to bromocriptine or placebo treatment groups. Clinical response did not differ between the two groups; thus, the normalization of mild hyperprolactinemia in the presence of normal T levels is unlikely to restore potency. Normalization of more marked hyperprolactinemia (>50 ng/mL), however, even in the presence of normal T levels, improves libido and potency.

Dopamine agonists may exert erectogenic effects by acting on D2 receptors and oxytocin neurons.116 Apomorphine tablets (3 or 4 mg) caused erections in 8 of 12 men with ED. Seven of the 11 men who used apomorphine at home reported successful erections.117 This agent currently is undergoing clinical trials. Melatonin II, a synthetic α-melanocyte-stimulating hormone analog, seems to work downstream from the dopamine receptor. This peptide, when administered subcutaneously, initiated erections in men with psychogenic ED.118 Its role as a therapeutic agent is not defined.

Orally administered agents to treat ED have long been sought. Sildenafil is a selective inhibitor of cGMP-specific phosphodiesterase type 5. Cyclic GMP phosphodiesterase type 5 is the predominant isozyme found in corporal smooth muscle involved in the breakdown of cGMP. Smooth muscle relaxation in cavernosal bodies is triggered by sexual stimuli. This leads to nitric oxide release from nonadren-ergic noncholinergic nerves that, in turn, innervate the cavernosal smooth muscle. Sildenafil, therefore, appears to potentiate erections induced by physiologic mechanisms. Unlike PGE₁, it does not independently evoke penile erections. Furthermore, oral L-arginine, a substrate for NO synthase, is not an effective treatment for ED.118a

In a placebo-controlled, double-blind, randomized parallel group study, use of sildenafil improved vaginal penetration (93% versus 10%) and ability to maintain erections (140% versus 13%) compared to placebo.119 The ability to achieve erections, maintain erections, or both during intercourse improved
in groups with presumed organic, psychogenic, or mixed etiologies. A dose-escalation study revealed the following adverse events for sildenafil compared to placebo: headaches (18% vs. 4%), flushing (18% vs. 1%), dyspepsia (6% vs. 2%), rhinitis (5% vs. 1%), and visual disturbances (2% vs. 1%). No patient had priapism. Initially, several deaths occurred that were attributed to sildenafil among patients taking nitrates for angina pectoris, and the FDA issued an advisory warning. In a subsequent report of 123 deaths possibly related to sildenafil use,120 details were available for 69 men, including 46 who experienced cardiovascular events, 2 who had strokes, and 21 for whom the cause of death was unknown. The mean age was 64 years (range, 29–87 years). At least 36% of these men began experiencing symptoms within 4 to 5 hours of ingestion of the drug, and 18 died during or soon after sexual intercourse. The vast majority of these men had one or more cardiovascular risk factors in addition to age and sex. Most deaths probably occurred in men with greater cardiovascular risk than those participating in the clinical trials, because the studies restricted enrollment of men using nitrates, those with comorbid systemic disease, and those who had had myocardial infarcts or strokes within the previous 6 months.

Animal studies provide insight into the mechanism of action of sildenafil. For example, in dogs N omega-nitro-L-arginine, a nitric oxide synthesis inhibitor, blocks the usual increased blood flow and intracavernosal pressure induced by pelvic nerve stimulation.121 By contrast, sildenafil (1–100 μg/kg) increases these parameters. Thus, inhibition of cGMP-specific phosphodiesterase type 5 augments the neuronal mechanisms of erection in dogs. In a study of rabbits, corpus cavernosum strips were stimulated with phenylephrine. Sildenafil reduced spontaneous tone in unstimulated tissue; the drug sensitized tissue to sodium nitroprusside but had little effect in the absence of sodium nitroprusside.122