Erectile Dysfunction Treatment & Management

After all the information regarding the patient’s status has been gathered, the various options for management of erectile dysfunction (ED) can be discussed. It is best to include the patient’s partner in this discussion. ^[1] One of the most difficult aspects of treatment is teaching men that sex entails more than simply achieving an erection.

The task of the physician is to identify which treatment would be most appropriate and most likely to have long-term success. To do that, the physician must take the time to understand the patient’s problem and be knowledgeable about the available options. Enough options are available that every man who wants to be sexually active can be, regardless of the etiology of the problem. These include the following:

• Sexual counseling if no organic causes can be found for the dysfunction
• Oral medications - Typically, phosphodiesterase type 5 (PDE5) inhibitors
• External vacuum devices
• Invasive therapy (eg, revascularization, penile implant)

Where possible, drugs that may be contributing to ED should be discontinued. However, ED as a manifestation of hypogonadism from abuse of anabolic steroids can persist for months to years after cessation of steroid use. Interim treatment for hypogonadism in such patients, while hypothalamic-pituitary-gonadal function recovers, has included judicious use of testosterone replacement therapy, human chorionic gonadotropin (hCG), and selective estrogen receptor modulators (eg, clomiphene). ^[74]

Hyperprolactinemia from antipsychotic medication, especially risperidone, has been associated with sexual dysfunction. Treatment has included dose reduction, drug holidays, adjunctive medication, and switching to another drug (eg, olanzapine); however, data to support any of those strategies are limited. ^[75] A small open-label study by Fujioi et al of adjunctive aripiprazole for patients with antipsychotic-induced hyperprolactinemia and sexual dysfunction reported a significant decrease in erectile dysfunction at week 24. ^[76]

The use of methadone for opioid replacement therapy has been associated with increased rates of ED. ^[77] Treatment with sustained-release bupropion proved effective in a phase II, randomized, double-blind, parallel-group, placebo-controlled trial involving 80 men with sexual dysfunction that emerged during methadone maintenance therapy. Of the patients receiving bupropion, 58.3% reported that their sexual function was "much/very much improved" compared with 27.7% of those receiving placebo. ^[78]

Treatment in men with cardiovascular disease

Many patients with ED also have cardiovascular disease—not surprisingly, given that the two disorders have a common etiology. Treatment of ED in these patients must take cardiovascular risks into account.

Sexual activity, in and of itself, increases the chances of ischemic events and myocardial infarction (MI) because of the exertion and sympathetic activation that may accompany it. The absolute risk of MI during sexual activity and for 2 hours afterward is only 20 chances per million per hour in post-MI patients and is even lower in men without a history of MI. ^[1]

The Princeton Consensus Panel has produced guidelines for managing ED in patients with cardiovascular disease. ^{[79, 8]} The panel advises that a man with ED and no cardiac symptoms should be considered to have cardiac or vascular disease until proven otherwise. ED patients should be assessed and categorized as high-, intermediate-, or low-risk. This stratification can guide management.

Risk-factor modification, including lifestyle interventions (eg, exercise and weight loss) is strongly encouraged for ED patients with cardiovascular disease. A study by Gupta et al supports the view that for men with cardiovascular risk factors, modifications in lifestyle along with pharmacotherapy are helpful in improving sexual function. ^[80]

Patients who have serious cardiac disease or exertional angina or are taking multiple antihypertensive medications should seek the advice of a cardiologist before beginning therapy with a PDE5 inhibitor. Nevertheless, several studies examining the cardiac effects of sildenafil and tadalafil have demonstrated that there is no increased risk of cardiovascular events in comparison with placebo. ^{[81, 82]} No significant differences in the incidence of MI, myocardial ischemia, or postural hypotension has been reported.

Angioplasty

Balloon angioplasty has been studied as treatment for erectile dysfunction in men with focal atherosclerotic narrowing of the penile artery. In a prospective study in 22 men with 34 isolated penile artery stenoses, Wang et al reported achieving procedural success with balloon angioplasty in 31 cases. At 8 months, however, CT angiography showed binary restenosis in 14 of 34 lesions in 13 patients, and at 1 year, clinical success had been sustained in only 11 of the 22 patients. ^[83]

An increasing array of medications is available to assist in the management of ED. New agents are still undergoing clinical testing, and more are in the early phases of development. Medications currently being developed include dopaminergic and melanocortin receptor agonists, second-generation phosphodiesterase 5 (PDE5) inhibitors, rho-kinase inhibitors, soluble guanylate cyclases, and maxi-k channel activators. ^[84]  

For any medication to be effective, the physiologic components involved in the erectile process must be functional. Serious impairments render the medication either completely or partially ineffective.

Phosphodiesterase-5 inhibitors

In current practice, PDE5 inhibitors are the most commonly used treatment for ED. ^[85] This drug class consists of sildenafil, vardenafil, tadalafil, and avanafil. Sildenafil was the first in this series of PDE inhibitors; avanafil is the newest, having been approved by the US Food and Drug Administration (FDA) in 2012. In a study of 390 men with diabetes and erectile dysfunction, avanafil was found to be a safe and effective treatment as early as 15 minutes and more than 6 hours after dosing. ^[86]

Guidelines from the American Urological Association (AUA) recommend offering PDE5 inhibitors as first-line therapy for ED unless the patient has contraindications to their use (eg, concurrent organic nitrate therapy). The AUA notes that insufficient evidence exists to support the superiority of any one of these agents over the others. ^[1]  European guidelines suggest that the choice of drug (short- versus long-acting) depend on the frequency of intercourse (occasional use or regular therapy, 3-4 times weekly) and the patient’s personal experience. ^[87]

The AUA warns that PDE5 inhibitors can cause mild transient systemic vasodilation, which may be aggravated by alpha-blocking agents. Consequently, the guidelines advise that vardenafil and tadalafil, at any dose, and sildenafil at 50 mg and 100 mg doses should be administered with caution in patients who are taking alpha blockers. ^[1]

In patients with ED that is refractory to therapy with oral PDE5 inhibitors, one of these agents can be combined with an injection of prostaglandin E1 (PGE1; alprostadil). ^[3] Gutierrez et al demonstrated that this combination was more effective than either one alone. ^[88] The combination of a PDE5 inhibitor with intraurethral PGE1 has also proved successful.

Androgens

Men who present with diminished libido and ED may be found to have low serum testosterone levels (hypogonadism). Hormone replacement may benefit men with severe hypogonadism and may be useful as adjunctive therapy when other treatments are unsuccessful by themselves. Libido and an overall sense of well-being are likely to improve when serum testosterone levels are restored to the reference range. ^{[89, 90, 91, 92, 93, 94]} However, a meta-analysis by Corona et al found that the positive effect of testosterone therapy on erectile function and libido was significance only in randomized controlled trials partially or completely supported by pharmaceutical companies. ^[95]

Meta-analyses suggest that the combination of testosterone and PDE5 inhibitors yields more effective results, but in noncontrolled versus controlled studies. However, adverse effects, especially in older frail men, require consideration. ^[96]

Replacement androgens are available in the following four forms:

• Oral
• Injectable
• Gel
• Transdermal

Oral therapy is rarely used; of the available approaches, it is the least effective and the most likely to be associated with hepatotoxicity, even though the risk is relatively small.

Parenteral therapy is the approach most likely to restore androgen levels to the reference range, but it requires periodic injections (usually every 2 weeks) to sustain an effective level. Measurement of peak and trough levels can help avoid symptomatic troughs and supernormal peak levels, though such measurement is rarely done in clinical practice. Typically, a level is obtained 1 week after an injection. Weekly injections using lower doses can be used to minimize the wide swings in blood levels noted with less frequent dosing.

Skin patches deliver a sustained dose and are generally accepted by patients. Testosterone gels are available for daily topical use to treat male hypogonadism and have the advantage of minimizing the peaks and troughs associated with the use of injectable agents. However, these gels require daily application and are relatively expensive.

Implantation of longer-acting testosterone pellets has become increasingly popular. The pellet is placed during an office visit. The advantage of this approach is the infrequency of pellet placement (only every 3-6 months).

The use of exogenous androgens suppresses natural androgen production. Elevation of serum androgen levels has the potential to stimulate prostate growth and may increase the risk of activating a latent cancer. Periodic prostate examinations, including digital rectal examinations, prostate-specific antigen (PSA) determinations, and blood counts (ie, complete blood count [CBC]), are recommended in all patients receiving supplemental androgens. Obtaining a testosterone level during therapy is necessary for optimizing the dosage.

Intracavernosal injection of vasodilators

The modern age of pharmacotherapy for ED began in 1993, when papaverine, an alpha-receptor blocker that produces vasodilatation, was shown to produce erections when injected directly into the corpora cavernosa. Soon afterward, other vasodilators, such as alprostadil (ie, synthetic PGE1) and phentolamine, ^[44] were demonstrated to be effective either as single agents or in combination. ^{[97, 98]}

Alprostadil is the single agent most commonly used for intracavernosal injections. In a study of 683 men, 94% reported having erections suitable for penetration after alprostadil injections. ^[99] Self-injection of this and similar agents has been of enormous benefit because they represent an effective way to achieve adequately rigid erections for a wide variety of men who otherwise would be unable to do so.

If the vasculature within the corpora cavernosa is healthy, intracavernosal injection therapy is almost always effective. However, careful instruction in how to perform the injections is essential. The dosage is adjusted so as to achieve an erection with adequate rigidity for no more than 90 minutes. Alprostadil doses as high as 40 µg can be used. An abnormal finding after biothesiometry testing has been suggested as an indicator of possible heightened sensitivity to intracavernosal injections, but this suggestion remains unproven.

The main adverse effects of intracavernosal injection are as follows ^{[99, 100, 101]} :

• Painful erection
• Priapism
• Development of scarring at the injection site

Intraurethral prostaglandin E1 pellets

Another option for ED is the Medicated Urethral System for Erections (MUSE). MUSE involves the formulation of alprostadil (PGE1) into a small intraurethral suppository that can be inserted into the urethra (see the image below). In one study, the agent was effective in 65% of a selected group of men. ^[102] Widespread application of MUSE has been limited by the system’s cost and its inability to provide rigid erections consistently.

MUSE may be effective in men who have vascular disease or diabetes or have undergone prostate surgery. Intraurethral alprostadil is a useful agent for men who do not want to use self-injections or for men in whom oral medications have failed. It has been successfully used together with sildenafil in cases in which each agent alone failed.

Few adverse effects occur. The most common is a painful erection and urethral burning, which occurs in fewer than 10% of patients.

A topical gel formulation of alprostadil for treatment of ED has been developed. ^[103] However, it has not been approved for use by the FDA.

Vascular endothelial growth factor

One area of research has involved the use of vascular endothelial growth factor (VEGF), an angiogenic growth factor and endothelial cell mitogen. VEGF is produced by vascular smooth muscle, endothelial, and inflammatory cells. It increases production of nitric oxide (NO), which results in improves endothelial function and blood flow in chronic ischemic disorders. ^{[104, 105]}

Direct intracavernosal injection of recombinant VEGF protein or adenoviral VEGF that contains plasmids has shown dramatic results on cavernosography in animal models with arteriogenic, venogenic, and neural forms of ED. Burchardt et al identified VEGF 165 as the predominant isoform in the corpora cavernosa, as well as a novel splice variant. ^[82]

Although VEGF is a potent and important vascular regulator, it probably acts in conjunction with other vascular factors. Although a single-agent VEGF is unlikely to ever be used as monotherapy for ED, the research done into its actions represents an important step in understanding the normal and abnormal vascular physiology associated with ED.

Other oral agents

Before the advent of oral PDE5 inhibitors, various other oral medications were investigated for treatment of ED, including the following ^[85] :

• Adrenergic receptor antagonists (eg, phentolamine, yohimbine, and delequamine)
• Dopamine receptor antagonists (eg, apomorphine and bromocriptine)
• Serotoninergic receptor activators (eg, trazodone)
• Xanthine derivatives (eg, pentoxifylline)
• Oxytocinergic receptor stimulators (eg, oxytocin)

Although the AUA does not recommend the use of any of these agents, ^[1]  several are worth reviewing briefly.

Yohimbine

Yohimbine, a bark extract, has been available for many years. It has both a central and a peripheral effect. Even in properly conducted, well-controlled studies, it is only slightly more effective than placebo, and AUA guidelines do not recommend its use. ^[1] Nevertheless, there has been a renewed interest in this agent, particularly when it is combined with an oral PDE5 inhibitor. ^[106] Yohimbine is a safe agent with few known adverse effects. It is administered in a dosage of 5.4 mg (1 tablet) 3 times daily

Apomorphine

A sublingual formulation of apomorphine has demonstrated some benefit in ED. Apomorphine is not approved by the FDA for this indication.

Phentolamine

Phentolamine is an alpha-receptor blocker that has not been approved by the FDA for the treatment of ED but has undergone limited clinical testing. Two placebo-controlled trials reported effectiveness in 42% and 32% of patients taking 50 mg, compared with 9% and 13% of control subjects, respectively. The erections occurred in 20-30 minutes. The drug was well tolerated, with mild-to-moderate adverse effects (usually headaches or light-headedness) occurring in less than 10% of patients.

Constriction devices

Men who have a vascular (venous) leak phenomenon may need a constriction device placed at the base of the penis to maintain their erection (see the image below). Such a device may be effective by itself or in combination with a PDE5 inhibitor. In selected cases, combination therapy with one of the PDE5 inhibitors plus an intraurethral or intracavernosal agent may be tried.

Vacuum devices

Vacuum devices for drawing blood into the penis are a relatively inexpensive method for producing an erection that has been used for many years. These devices are plastic cylinders that are placed over the penis. Air is pumped out, causing a partial vacuum. Releasing the vacuum after a few minutes and then reapplying the vacuum sometimes gives a better result. After an erection is obtained, a constricting band is placed at the base of the penis (see the images below). ^[107]

This technique is effective in 60-90% of patients and maintains the erection for up to 30 minutes. (In fact, the erection would last until the constricting band is released, but keeping the band in place for longer than 30 minutes is not recommended.) The devices are very reliable and seem to work better with increased use and practice. They can be operated and used quickly with experience but still tend to be less “romantic” than other therapeutic options.

Although vacuum devices are generally safe, hematomas, petechia, and ecchymosis have been reported. Other adverse effects include pain, lower penile temperature, numbness, absent or painful ejaculation, and pulling of scrotal tissue into the cylinder, where it becomes trapped under the ring. Many of these problems can be alleviated by proper selection of the tension rings and cylinders.

Drawbacks to the use of external vacuum devices include the need to assemble the equipment and the difficulty of transporting it. Many patients lose interest in using the device because of the preparations that are necessary, the lack of easy transportability, the inability to hide the tension ring, and the relative lack of spontaneity. Approximately half the men who use a vacuum device obtain very good erections, but only half of these men consistently use the device for a prolonged period.

Selected patients with ED are candidates for surgical treatment.

Surgical revascularization

A small number of healthy young men have developed ED as a result of trauma to the pelvic arteries. Revascularization procedures such as rotating the epigastric artery (or even smaller vessels) into the corpora have been attempted. Long-term results have been marginal. AUA guidelines recommend arterial reconstructive surgery as a treatment option only in healthy patients who have recently acquired ED as the result of a focal arterial occlusion and who have no evidence of generalized vascular disease. ^[1]

Surgical elimination of venous outflow

On occasion, men who have difficulty maintaining erections as a result of venous leaks may benefit from undergoing a surgical procedure designed to eliminate much of the venous outflow. Although there was considerable initial enthusiasm for this and other surgical approaches was significant, this type of surgery has become rare because of a lack of long-term efficacy. AUA guidelines recommend against the use of such procedures. ^[1]

Placement of penile implant

In the past, the placement of prosthetic devices within the corpora was the only effective therapy for men with organic ED. At present, however, it is the last option considered, even though more than 90% of men with an implant would recommend the procedure to their friends and relatives. Before selecting this form of management, the patient and his sexual partner should be counseled regarding the benefits and risks of this procedure (see Table 2 below). ^{[108, 109]}

Table 2. Advantages and Disadvantages of Different Types of Penile Implants for Erectile Dysfunction (Open Table in a new window)

Implants are usually used for men who have not experienced success with other therapies or who require penile reconstructions. Men who have undergone a radical prostatectomy for prostate cancer and in whom a nerve-sparing procedure was not performed or was not successful often do not respond to oral PDE5 inhibitors, and these men are good candidates for a penile implant. The same is true for men treated with radiation therapy, though more of these men tend to respond to oral agents.

Daily use of a vacuum erection device for a month before implantation of a penile prosthesis may prove beneficial. A randomized controlled trial by Canguven et al found that this strategy was associated with a significantly greater mean stretched penile length on the day of surgery; in addition, surgeons reported easier corporal dilatation intraoperatively. ^[110]

There is some evidence to suggest that an additional benefit may be gained by some men who have an implant but also take an oral PDE5 inhibitor. Sexual stimulation and sensation are enhanced.

Penile prostheses can be divided into the following 2 broad categories:

• Semirigid
• Inflatable

With the semirigid prosthesis, 2 matching cylinders are implanted into the corpora cavernosa (see the image below). These devices provide enough rigidity for penetration and rarely break. The major drawbacks are the cosmetic appearance of the penis (which remains semierect at all times), the need for surgery, and the destruction of the natural erectile mechanism when the prosthesis is implanted.

The inflatable devices consist of 2 Silastic or Bioflex cylinders inserted into the corpora cavernosa, a pump placed in the scrotum to inflate the cylinders, and a reservoir that is contained either within the cylinders or in a separate reservoir placed beneath the fascia of the lower abdomen (see the images below). The inflatable prosthesis generally remains functional for 7-10 years before a replacement may be necessary. Improvements in these devices have resulted in a failure rate lower than 10%.

Patient acceptance of these devices is very high, with nearly 100% of recipients expressing satisfaction. Part of this enthusiasm is related to the failure of other therapies and the highly motivated patient population.

Rajpurkar and Dhabuwala reported significantly better erectile function and satisfaction with a penile implant than with sildenafil or intracavernosal alprostadil (PGE1). ^[111] This was a nonrandomized study in which all 138 subjects were initially offered sildenafil. The mean follow-up was 19.54 months, and questionnaires were used to obtain the data.

Complications include infections (occurring in 2% of patients), erosion of the device through the urethra or skin (2%), and painful erections (1%). The development of an antibiotic-coated device has further reduced the infection rate. Patients should also be counseled that the penis does not lengthen as much as with normal erections.

Sexual counseling is the most important part of treatment for patients with sexual problems. Many professional sexual counselors are skilled in working with patients, but the primary care physician, the urologist, and the gynecologist also serve in this capacity to some degree. These are usually the first professionals to learn about the problem, and they often have to extract the information about the sexual problem from the patient.

Men are frequently reluctant to discuss their sexual problems and must be specifically asked. Opening a dialogue allows the clinician to begin the investigation or to refer the patient to a consultant. Regardless of any subsequent therapy, the emotional aspects of the disorder must be addressed. Ideally, the patient’s partner should be involved in counseling, but even if this is not possible, the time spent may help resolve or at least clarify the problem and certainly helps determine which of the other options would be most beneficial and appropriate.

Regardless of the etiology of ED, a psychological component is frequently associated with the disorder. The ability to achieve erection is intimately connected to a man’s self-esteem and sense of worth. Pure psychogenic ED is generally evident when a man reports that he has normal erections some of the time but is unable to achieve or to maintain a full erection at other times. Once the man has doubt regarding sexual performance, he loses confidence; thus, future attempts to have sexual relations provoke anxiety.

In many instances, the couple must work together to resolve the problem, although in some cases, the relationship itself may be responsible for the problem. Referral to a sex therapist may be helpful.

A study of 31 newly diagnosed men with ED (aged 20-55 years) who were treated with either tadalafil (n = 12) or tadalafil plus 8 weeks of stress management (n = 19) found that both groups showed significant improvement in perceived stress and erectile function scores but that the reduction in perceived stress was greater in the latter group. ^[112] This result suggests that stress reduction may be a useful component of ED treatment. Further research, involving randomized, controlled trials with larger samples and longer follow-up time, is needed.

Men with organic ED can be treated with one or more of the various available therapies (see above). However, if they have lost confidence in their ability to obtain and maintain an erection suitable for penetration, a few words of encouragement from their physician can be of great help.

The AUA observes that because diabetes, heart disease, and hypertension increase the risk of developing ED, optimal management of these diseases may prevent the development of ED. ^[1] Similarly, because attaining and maintaining a firm erection requires good vascular function, it is reasonable to assume that lifestyle modifications to improve vascular function (eg, smoking cessation, maintenance of ideal body weight, and regular exercise) may prevent or reverse ED. At present, however, only minimal data support these suppositions. ^[1]

In a clinical trial that included 106 men with newly diagnosed type 2 diabetes, Maiorino et al reported that men randomized to a Mediterranean diet demonstrated a significantly lesser decrease in erectile function, compared with men randomized to a low-fat diet (P=0.024). Total follow-up in the trial was 8.1 years. ^[113]

A systematic review and meta-analysis by Silva et al suggested that physical activity and exercise—particularly aerobic exercise of moderate-to-vigorous intensity—improve patient-reported ED.  lthough the risk of bias in the trials was deemed moderate to high, principally because of difficulties with blinding, pooled data showed a statistically significant improvement in erectile function scores. Benefit was detected with both short-term and long-term interventions as well as with physical activity and exercise alone or as an adjunct to usual care. ^[114]

One direction of research into treatment of ED focuses on restoration of the structure and function of dysfunctional erectile tissue, rather than simply relief of symptoms. These techniques, termed regenerative therapy, include the following ^[115] :

• Low-intensity extracorporeal shockwave therapy (LiESWT)
• Stem cell therapy
• Intracavernous injection of platelet-rich plasma (PRP)
• Amniotic fluid matrices (wrapping of dehydrated human amnion/chorion membranes around the neurovascular bundle during radical prostatectomy)

A consensus statement from the Sexual Medicine Society of North America recommends that these novel technologies are experimental and should be used only in the context of clinical trials. ^[116] Nevertheless, men’s health clinics are increasingly offering such treatments, often at exorbitant cost. ^[115]

Low-intensity extracorporeal shock wave therapy

Although not approved for this indication in the United States, LiESWT has proved effective in European patients with severe ED that is unresponsive to treatment with PDE5 inhibitors. ^[117] In a prospective nonrandomized study from China that compared a 9 week LiESWT treatment with 100 mg on-demand sildenafil in a group of 78 men, the two treatments had similar efficacy and safety at baseline and 3-month follow-up. ^[118] However, evaluation of LiESWT trials is complicated by their heterogeneity; they have used a variety of devices and a wide range of applied energies, number of shocks per session, and frequency and total number of sessions. ^[119]

LiESWT may have immediate effects, presumably from activation of nitric oxide–mediated vasodilation and increased arterial inflow. Mid- and long-term effects appear to involve penile revascularization, recovery/regeneration of penile nerves, and improvement in cavernosal tissue structure and function. ^[119]

Stem cell therapy

Phase I and II clinical trials of stem cell therapy for ED have for the most part shown promising results, with positive effects on erectile function and no serious adverse effects. ^{[120, 121]} However, several aspects of this approach remain unsettled: The choice between autologous or allogeneic cells remains uncertain, as does dosing, and although intracavernous injection is the administration route most used, intravenous injection causes less morbidity and is less invasive. ^[115]

A study in 48 men (half with diabetes) whose ED was unresponsive to PDE5 inhibitors found that after PRP injections, 33% of the patients with diabetes and 50% of those without diabetes were satisfied with on-demand PDE5 inhibitors. ^[122] A systematic review of PRP injections for the treatment of ED found three studies in humans with positive results and no major complications reported. The authors concluded that although this treatment appears promising, more evidence is needed from clinical trials. ^[123]