Erectile Dysfunction 

Updated: Nov 02, 2020
Author: Edward David Kim, MD, FACS; Chief Editor: Edward David Kim, MD, FACS 

Overview

Practice Essentials

Erectile dysfunction (ED), formerly termed impotence, is defined as "the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance" or "the consistent or recurrent inability to attain and/or maintain penile erection sufficient for sexual satisfaction".[1] Although some cases, particularly in younger men, may primarily reflect psychological concerns, in many cases ED results from organic disease—notably, cardiovascular disease, diabetes mellitus, hyperlipidemia, and hypertension.[2] Thus, ED may serve as a marker for medical conditions in need of treatment.[1] Regardless of the cause, however, ED can have negative effects on patients' self-esteem, relationships, and overall quality of life.[1, 2]

Signs and symptoms

The first step in the management of ED is a thorough history that includes the following:

  • Sexual history
  • Medical history
  • Psychosocial history

A physical examination is necessary for every patient, emphasizing the genitourinary, vascular, and neurologic systems. A focused examination entails evaluation of the following:

  • Blood pressure
  • Peripheral pulses
  • Sensation
  • Status of the genitalia and prostate
  • Size and texture of the testes
  • Presence of the epididymis and vas deferens
  • Abnormalities of the penis (eg, hypospadias, Peyronie plaques)

There is a strong correlation between hypertension and ED. There is also a correlation between benign prostatic hyperplasia and ED, though the causality is unclear.

See Presentation for more detail.

Diagnosis

Laboratory testing for ED depends on information gathered during the interview; it is necessary for most patients, although not for all. Such testing may include the following:

  • Evaluation of hormonal status (testosterone, serum hormone–binding globulin, luteinizing hormone [LH], prolactin, thyroid-stimulating hormone [TSH]) – Note that the American College of Physicians (ACP) does not recommend for or against routine use of hormonal blood tests or hormonal treatment in ED patients

  • Screening blood studies (hemoglobin A1c, serum chemistry panel, lipid profile)

  • Prostate-specific antigen levels, if the patient is a candidate for prostate cancer screening (controversial)

  • Urinalysis

Functional tests that may be helpful include the following:

  • Direct injection of prostaglandin E1 (PGE1; alprostadil) into the corpora cavernosa (see the image below)

    A vasodilator such as prostaglandin E1 can be inje A vasodilator such as prostaglandin E1 can be injected into one of the corpora cavernosa. If the blood vessels are capable of dilating, a strong erection should develop within 5 minutes.
  • Biothesiometry – Infrequently indicated

  • Nocturnal penile tumescence testing – Once frequently performed, this is rarely used in current practice, though it can be helpful when the diagnosis is in doubt

  • Formal neurologic testing – Not needed in the vast majority of ED patients, though it may offer some benefit to patients with a history of central nervous system problems, peripheral neuropathy, diabetes, or penile sensory deficit

Imaging studies are not commonly warranted, except in situations where pelvic trauma has been sustained or surgery performed. Modalities that may be considered include the following:

  • Ultrasonography of the penis (to assess vascular function within the penis)

  • Ultrasonography of the testes (to help disclose abnormalities in the testes and epididymides; rarely indicated)

  • Transrectal ultrasonography (to disclose abnormalities in the prostate and pelvis that may interfere with erectile function)

  • Angiography (in patients who are potential candidates for vascular surgery)

See Workup for more detail.

Management

Treatment options for ED include the following:

  • Sexual counseling, if no organic causes can be found for the dysfunction
  • Oral medications
  • Injected, implanted, or topically applied medications
  • External vacuum and constriction devices
  • Surgery

Many patients with ED also have cardiovascular disease; thus, treatment of ED in these patients must take cardiovascular risks into account.

According to American Urological Association (AUA) guidelines, oral phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy unless contraindicated.[1] Agents include the following:

  • Sildenafil
  • Vardenafil
  • Tadalafil
  • Avanafil

In patients with ED refractory to oral PDE5 inhibitors, one of these agents can be combined with an injection of PGE1.[3]

In a prospective, multicenter, single-armed study of ED patients who exhibited a suboptimal response to PDE5 inhibitors, the investigators found that percutaneous implantation of zotarolimus-eluting stents in focal atherosclerotic lesions was both safe and feasible and was associated with clinically meaningful improvement on subjective and objective measures of erectile function.[4]

Hormone replacement may benefit men with severe hypogonadism and may possibly be useful as adjunctive therapy when other treatments are unsuccessful. Replacement androgens are available in oral (rarely used), injectable, gel, and transdermal preparations.

Intracavernosal injection therapy may be considered and is almost always effective if the vasculature within the corpora cavernosa is healthy. Agents used include the following:

  • Alprostadil (most common)
  • Phentolamine
  • Papaverine

The Medicated Urethral System for Erections (MUSE) involves the formulation of alprostadil (PGE1) into a small intraurethral suppository that can be inserted into the urethra. This may be useful for men who do not want to use self-injections or those in whom oral medications have failed.

External devices that may be used include the following:

  • Vacuum devices to draw blood into the penis
  • Constriction devices placed at the base of the penis to maintain erection

Selected patients with ED are candidates for surgical treatment. Procedures to be considered include the following:

  • Revascularization (rarely indicated)

  • Surgical elimination of venous outflow (rarely indicated)

  • Placement of penile implant (semirigid or malleable rod implant, fully inflatable implant, or self-contained inflatable unitary implant) – Once the only effective therapy for men with organic ED, this is the last option considered in current practice

Suggested measures for preventing ED include the following:

  • Optimal management of diabetes, heart disease, and hypertension

  • Lifestyle modifications to improve vascular function (eg, not smoking, maintaining ideal body weight, and engaging in regular exercise)

See Treatment and Medication for more detail.

Background

Erectile dysfunction (ED) affects 50% of men older than 40 years,[5] exerting substantial effects on quality of life.[6] This common problem is complex and involves multiple pathways. Penile erections are produced by an integration of physiologic processes involving the central nervous, peripheral nervous, hormonal, and vascular systems. Any abnormality in these systems, whether from medication or disease, has a significant impact on the ability to develop and sustain an erection, ejaculate, and experience orgasm.

A common and important cause of ED is vasculogenic. Many men with ED have comorbid conditions such as hyperlipidemia, hypercholesterolemia, tobacco abuse, diabetes mellitus, or coronary artery disease (CAD).[7] The Princeton III Consensus recommends screening men who present with ED for cardiovascular risk factors; ED may be the earliest presentation of atherosclerosis and vascular disease.[8]

Additionally, the physiologic processes involving erections begin at the genetic level. Certain genes become activated at critical times to produce proteins vital to sustaining this pathway. Some researchers have focused on identifying particular genes that place men at risk for ED. At present, these studies are limited to animal models, and little success has been reported to date.[5] Nevertheless, this research has given rise to many new treatment targets and a better understanding of the entire process.

The first step in treating the patient with ED is to take a thorough sexual, medical, and psychosocial history. Questionnaires are available to assist clinicians in obtaining important patient data. (See Presentation.) Successful treatment of sexual dysfunction has been demonstrated to improve sexual intimacy and satisfaction, improve sexual aspects of quality of life, improve overall quality of life, and relieve symptoms of depression. (See Treatment.)

The availability of phosphodiesterase-5 (PDE5) inhibitors—sildenafil, vardenafil, tadalafil, and avanafil—has fundamentally altered the medical management of ED. In addition, direct-to-consumer marketing of these agents over the last 15 years has increased the general public’s awareness of ED as a medical condition with underlying causes and effective treatments.

Unfortunately, some patients may have an overly simplified understanding of the role of PDE5 inhibitors in ED management. Such patients may not expect or be willing to undergo a long evaluation and testing process to obtain a better understanding of their sexual problem, and they may be less likely to involve their partner in discussing their sexual relationship with the physician. They may expect to obtain medications through a phone call to their doctor or even over the Internet, with minimal or no physician contact at all.

In such cases, the physician’s role may have to include efforts to educate patients about realistic sexual expectations (see Patient Education). These efforts can help prevent the misuse or overuse of these remarkable medications.

Although this article focuses primarily on the male with ED, it is essential to remember that the sexual partner plays an integral role in treatment. If successful and effective management is to be achieved, evaluation and discussion of any intervention must include both partners.

Diagnostic criteria (DSM-5) for erectile disorder

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), classifies erectile disorder as belonging to a group of sexual dysfunction disorders typically characterized by a clinically significant inability to respond sexually or to experience sexual pleasure.[9]

Sexual functioning involves a complex interaction among biologic, sociocultural, and psychological factors, and the complexity of this interaction makes it difficult to ascertain the clinical etiology of sexual dysfunction. Before any diagnosis of sexual dysfunction is made, problems that are explained by a nonsexual mental disorder or other stressors must first be addressed. Thus, in addition to the criteria for erectile disorder, the following must be considered:

  • Partner factors (eg, partner sexual problems or health issues)

  • Relationship factors (eg, communication problems, differing levels of desire for sexual activity, or partner violence)

  • Individual vulnerability factors (eg, history of sexual or emotional abuse, existing psychiatric conditions such as depression, or stressors such as job loss)

  • Cultural or religious factors (eg, inhibitions or conflicted attitudes regarding sexuality)

  • Medical factors (eg, an existing medical condition or the effects of drugs or medications)

The specific DSM-5 criteria for erectile disorder are as follows[9] :

  • In almost all or all (75-100%) sexual activity, the experience of at least one of the following three symptoms: (1) marked difficulty in obtaining an erection during sexual activity, (2) marked difficulty in maintaining an erection until the completion of sexual activity, or (3) marked decrease in erectile rigidity

  • The symptoms above have persisted for approximately 6 months

  • The symptoms above cause significant distress to the individual

  • The dysfunction cannot be better explained by nonsexual mental disorder, a medical condition, the effects of a drug or medication, or severe relationship distress or other significant stressors

The severity of delayed ejaculation is classified as mild, moderate, or severe on the basis of the level of distress the patient exhibits over the symptoms. The duration of the dysfunction is specified as follows:

  • Lifelong (present since first sexual experience)

  • Acquired (developing after a period of relative normal sexual functioning)

In addition, the context in which the dysfunction occurs is specified as follows:

  • Generalized (not limited to certain types of stimulation, situations, or partners)

  • Situational (limited to specific types of stimulation, situations, or partners)

Lifelong erectile disorder is associated with psychological factors, whereas acquired erectile disorder is more often related to biologic factors. Distress associated with erectile disorder is lower among older men than among younger men.

Anatomy

An understanding of penile anatomy is fundamental to management of ED.[3] The common penile artery, which derives from the internal pudendal artery, branches into the dorsal, bulbourethral, and cavernous arteries (see the image below).

Vascular anatomy of the penis. Vascular anatomy of the penis.

The dorsal artery provides for engorgement of the glans during erection, whereas the bulbourethral artery supplies the bulb and the corpus spongiosum. The cavernous artery effects tumescence of the corpus cavernosum and thus is principally responsible for erection. The cavernous artery gives off many helicine arteries, which supply the trabecular erectile tissue and the sinusoids. These helicine arteries are contracted and tortuous in the flaccid state and become dilated and straight during erection.[10]

Venous drainage of the corpora originates in tiny venules that lead from the peripheral sinusoids immediately beneath the tunica albuginea. These venules travel in the trabeculae between the tunica and the peripheral sinusoids to form the subtunical venous plexus before exiting as the emissary veins (see the image below).[10]

These images depict penile anatomy. Note the sinus These images depict penile anatomy. Note the sinusoidal makeup of the corpora and thick fascia (ie, Buck fascia) that covers the corpora cavernosa. The major blood vessels to the corpora cavernosa enter through tributaries from the main vessels running along the dorsum of the penis.

Sexual behavior involves the participation of autonomic and somatic nerves and the integration of numerous spinal and supraspinal sites in the central nervous system (CNS). The penile portion of the process that leads to erections represents only a single component.

The hypothalamic and limbic pathways play an important role in the integration and control of reproductive and sexual functions. The medial preoptic center, paraventricular nucleus, and anterior hypothalamic regions modulate erections and coordinate autonomic events associated with sexual responses.

Afferent information is assessed in the forebrain and relayed to the hypothalamus. The efferent pathways from the hypothalamus enter the medial forebrain bundle and project caudally near the lateral part of the substantia nigra into the midbrain tegmental region.

Several pathways have been described to explain how information travels from the hypothalamus to the sacral autonomic centers. One pathway travels from the dorsomedial hypothalamus through the dorsal and central gray matter, descends to the locus ceruleus, and projects ventrally in the mesencephalic reticular formation. Input from the brain is conveyed through the dorsal spinal columns to the thoracolumbar and sacral autonomic nuclei.

The primary nerve fibers to the penis are from the dorsal nerve of the penis, a branch of the pudendal nerve. The cavernosal nerves are a part of the autonomic nervous system and incorporate both sympathetic and parasympathetic fibers. They travel posterolaterally along the prostate and enter the corpora cavernosa and corpus spongiosum to regulate blood flow during erection and detumescence. The dorsal somatic nerves are also branches of the pudendal nerves. They are primarily responsible for penile sensation.[11]

Pathophysiology

Factors mediating contraction and relaxation

The degree of contraction of cavernosal smooth muscle determines the functional state of the penis.[12] The balance between contraction and relaxation is controlled by central and peripheral factors that involve many transmitters and transmitter systems.

The nerves and endothelium of sinusoids and vessels in the penis produce and release transmitters and modulators that control the contractile state of corporal smooth muscles. Although the membrane receptors play an important role, downstream signaling pathways are also important. The RhoA–Rho kinase pathway is involved in the regulation of cavernosal smooth muscle contraction.[13]

Factors that mediate contraction in the penis include noradrenaline, endothelin-1, neuropeptide Y, prostanoids, angiotensin II, and others not yet identified. Factors that mediate relaxation include acetylcholine, nitric oxide (NO), vasoactive intestinal polypeptide, pituitary adenylyl cyclase–activating peptide, calcitonin gene–related peptide, adrenomedullin, adenosine triphosphate, and adenosine prostanoids.

Nitric oxide pathway

The NO pathway is of critical importance in the physiologic induction of erections. The drugs currently used to treat ED were developed as a result of experimental and clinical work showing that NO released from nerve endings relaxes the vascular and corporal smooth muscle cells of the penile arteries and trabeculae, resulting in an erection.

NO is produced by the enzyme NO synthase (NOS).[14] NOS plays many roles, ranging from homeostasis to immune system regulation. To date, 3 subtypes have been identified: nNOS, iNOS, and eNOS, which are produced by the genes NOS1, NOS2, and NOS3, respectively. This nomenclature is derived from the sources of the original isolates: neuronal tissue (nNOS), immunoactivated macrophage cell lines (iNOS), and vascular endothelium (eNOS). The subtypes are not, however, limited to the tissues from which they were first isolated.

All NOS subtypes produce NO, but each may play a different biologic role in various tissues. nNOS and eNOS are considered constitutive forms because they share biochemical features: They are calcium-dependent, they require calmodulin and reduced nicotinamide adenine dinucleotide phosphate for catalytic activity, and they are competitively inhibited by arginine derivatives. nNOS is involved in the regulation of neurotransmission, and eNOS is involved in the regulation of blood flow.

iNOS is considered an inducible form because it is calcium-independent. iNOS is induced by the inflammatory process, in which it participates in the production of nitrogenous amines. This subtype has been shown to be involved in carcinogenesis, leading to transitional cell carcinoma.

Inside the cell, NOS catalyzes the oxidation of L-arginine to NO and L-citrulline. Endogenous blockers of this pathway have been identified. The gaseous NO that is produced acts as a neurotransmitter or paracrine messenger. Its biologic half-life is only 5 seconds. NO may act within the cell or diffuse and interact with nearby target cells. In the corpora cavernosa, NO activates guanylate cyclase, which in turn increases cyclic guanosine monophosphate (cGMP). Relaxation of vascular smooth muscles by cGMP leads to vasodilation and increased blood flow.

Alteration of NO levels is the focus of several approaches to the treatment of ED. Inhibitors of phosphodiesterase, which primarily hydrolyze cGMP type 5, provided the basis for the development of the PDE5 inhibitors. Chen et al administered oral L-arginine and reported subjective improvement in 50 men with ED.[15] These supplements are readily available commercially. Reported adverse effects include nausea, diarrhea, headache, flushing, numbness, and hypotension.

Increasing evidence indicates that NO acts centrally to modulate sexual behavior and to exert its effects on the penis. NO is thought to act in the medial preoptic area and the paraventricular nucleus. Injection of NOS inhibitors prevents the erectile response in rats that have been given erectogenic agents.

Normal erectile process

Erections occur in response to tactile, olfactory, and visual stimuli. The ability to achieve and maintain a full erection depends not only on the penile portion of the process but also on the status of the peripheral nerves, the integrity of the vascular supply, and biochemical events within the corpora. The autonomic nervous system is involved in erection, orgasm, and tumescence. The parasympathetic nervous system is primarily involved in sustaining and maintaining an erection, which is derived from S2-S4 nerve roots.

Sexual stimulation causes the release of neurotransmitters from cavernosal nerve endings and relaxation factors from endothelial cells lining the sinusoids. NOS produces NO from L-arginine, and this, in turn, produces other muscle-relaxing chemicals, such as cGMP and cyclic adenosine monophosphate (cAMP), which work via calcium channel and protein kinase mechanisms (see the image below). This results in the relaxation of smooth muscle in the arteries and arterioles that supply the erectile tissue, producing a dramatic increase in penile blood flow.

Relaxation of the sinusoidal smooth muscle increases its compliance, facilitating rapid filling and expansion. The venules beneath the rigid tunica albuginea are compressed, resulting in near-total occlusion of venous outflow. These events produce an erection with an intracavernosal pressure of 100 mm Hg.

Additional sexual stimulation initiates the bulbocavernous reflex. The ischiocavernous muscles forcefully compress the base of the blood-filled corpora cavernosa, and the penis reaches full erection and hardness when intracavernosal pressure reaches 200 mm Hg or more. At this pressure, both inflow and outflow of blood temporarily cease.

Detumescence results from cessation of neurotransmitter release, breakdown of second messengers by phosphodiesterase, and sympathetic nerve excitation during ejaculation. Contraction of the trabecular smooth muscle reopens the venous channels, allowing the blood to be expelled and thereby resulting in flaccidity.

Role of testosterone

Both ED and low testosterone (hypogonadism) increase with age. The incidence of the latter is 40% in men aged 45 years and older.[16] Testosterone is known to be important in mood, cognition, vitality, bone health, and muscle and fat composition. It also plays a key role in sexual dysfunction (eg, low libido, poor erection quality, ejaculatory or orgasmic dysfunction, reduced spontaneous erections, or reduced sexual activity).[17]

The association between low testosterone and ED is not entirely clear. Although these 2 processes certainly overlap in some instances, they are distinct entities. Some 2-21% of men have both hypogonadism and ED; however, it is unclear to what degree treating the former will improve erectile function.[18] About 35-40% of men with low testosterone see an improvement in their erections with testosterone replacement; however, almost 65% of these men see no improvement.[16]

One study examined the role of testosterone supplementation in hypogonadal men with ED. These men were considered nonresponders to sildenafil, and their erections were monitored by assessing nocturnal penile tumescence (NPT). After these men were given testosterone transdermally for 6 months, the number of NPTs increased, as did the maximum rigidity with sildenafil.[19] This study suggests that a certain level of testosterone may be necessary for PDE5 inhibitors to function properly.

In a randomized double-blind, parallel, placebo-controlled trial, sildenafil plus testosterone was not superior to sildenafil plus placebo in improving erectile function in men with ED and low testosterone levels.[20] The objective of the study was to determine whether the addition of testosterone to sildenafil therapy improves erectile response in men with ED and low testosterone levels.

However, in contrast, a recent systematic review of published studies, the authors concluded that overall, the addition of testosterone to PDE-5 inhibitors might benefit patients with ED associated with testosterone levels of less than 300 ng/dL (10.4 nmol/L) who failed monotherapy.[21] A limitation of existing studies are their heterogeneous nature and methodological drawbacks.

The mechanisms by which testosterone plays a role in erectile function are not completely understood. A study evaluating the effect of testosterone on erections in surgically castrated rabbits and control animals, in which the rabbits’ intracavernosal pressures were compared after cavernosal nerve stimulation, determined that castrated rabbits had much lower pressures after stimulation than control rabbits did.[22] Notably, the pressures increased when castrated rabbits received exogenous testosterone replacement.

Another study compared the response of surgically and medically castrated rabbits to vardenafil with that of control rabbits.[23] Castrated rabbits did not respond to vardenafil, whereas noncastrated rabbits did respond appropriately. This result suggests that a minimum amount of testosterone is necessary for PDE5 inhibitors to produce an erection.

Another study found that castrated rats had erections if given testosterone alone or dihydrotestosterone (DHT) and 5-alpha reductase inhibitors but not if given testosterone and 5-alpha reductase inhibitors.[24] This finding suggests that DHT is the active component and is necessary at a certain level for rats to have an erection.

This study also measured intracavernosal pressure to monitor erections and NOS activity in the penile cytosol.[24] NO levels correlated with intracavernosal pressure, which suggests that testosterone and DHT act through NOS. Testosterone and DHT may act at the genomic level to stimulate production of NOS.

It appears that testosterone has NOS-independent pathways as well. In one study, castrated rats were implanted with testosterone pellets and then divided into a group that received an NOS inhibitor (L-nitro-L-arginine methyl ester [L-NAME]) and a control group that received no enzyme.[25] The castrated rats that were given testosterone pellets and L-NAME still had partial erections, a result suggesting the presence of a pathway independent of NOS activity.

Etiology

ED usually has a multifactorial etiology. Organic, physiologic, endocrine, and psychogenic factors are involved in the ability to obtain and maintain erections. In general, ED is divided into 2 broad categories, organic and psychogenic. Although most ED was once attributed to psychological factors, pure psychogenic ED is in fact uncommon; however, many men with organic etiologies may also have an associated psychogenic component.

Conditions that may be associated with ED include diabetes,[26, 27, 28] hypertension,[29] , atrial fibrillation,[30] and CAD, as well as neurologic disorders, endocrinopathies, benign prostatic hyperplasia,[31] , sleep apnea[32] , chronic obstructive pulmonary disease (COPD),[33] and depression (see Table 1 below).[34, 35, 36, 37] In fact, almost any disease may affect erectile function by altering the nervous, vascular, or hormonal systems. Various diseases may produce changes in the smooth muscle tissue of the corpora cavernosa or influence the patient’s psychological mood and behavior.

Table 1. Diseases and Conditions Associated With Erectile Dysfunction (Open Table in a new window)

Vascular causes

Atherosclerosis

Peripheral vascular disease

Myocardial infarction

Arterial hypertension

Vascular injury from radiation therapy

Vascular injury from prostate cancer treatment

Blood vessel and nerve trauma (eg, from long-distance bicycle riding)

Medications for treatment of vascular disease

Systemic diseases

Diabetes mellitus

Scleroderma

Renal failure

Liver cirrhosis

Idiopathic hemochromatosis

Cancer and cancer treatment

Dyslipidemia

Hypertension

Neurologic causes

Epilepsy

Stroke

Multiple sclerosis

Guillain-Barré syndrome

Alzheimer disease

Trauma

Respiratory disease

Chronic obstructive pulmonary disease

Sleep apnea

Endocrine conditions

Hyperthyroidism

Hypothyroidism

Hypogonadism

Diabetes

Penile conditions

Peyronie disease

Epispadias

Priapism

Psychiatric conditions

Depression

Widower syndrome

Performance anxiety

Posttraumatic stress disorder

Nutritional states

Malnutrition

Zinc deficiency

Hematologic diseases

Sickle cell anemia

Leukemias

Surgical procedures

Brain and spinal cord procedures

Retroperitoneal or pelvic lymph node dissection

Aortoiliac or aortofemoral bypass

Abdominal perineal resection

Proctocolectomy

Transurethral resection of the prostate

Radical prostatectomy

Cryosurgery of the prostate

Cystectomy

Medications

Antihypertensives

Antidepressants

Antipsychotics

Antiulcer agents (eg, cimetidine)

5-Alpha reductase inhibitors (eg, finasteride and dutasteride)

Cholesterol-lowering agents

Methadone

Conditions associated with reduced nerve and endothelium function (eg, aging, hypertension, smoking, hypercholesterolemia, and diabetes) alter the balance between contraction and relaxation factors (see Pathophysiology). These conditions cause circulatory and structural changes in penile tissues, resulting in arterial insufficiency and defective smooth muscle relaxation. In some patients, sexual dysfunction may be the presenting symptom of these disorders.

Given the multiplicity of possible etiologic factors, it may be difficult to determine how much any given factor is contributing to the problem. A thorough evaluation is necessary for correct identification of the specific cause or causes in any given individual.

Vascular diseases

Vascular diseases account for nearly 50% of all cases of ED in men older than 50 years. These diseases include atherosclerosis, peripheral vascular disease, myocardial infarction (MI), and arterial hypertension.

Vascular damage may result from radiation therapy to the pelvis and prostate in the treatment of prostate cancer.[38] Both the blood vessels and the nerves to the penis may be affected. Radiation damage to the crura of the penis, which are highly susceptible to radiation damage, can induce ED. Data indicate that 50% of men undergoing radiation therapy lose erectile function within 5 years after completing therapy; fortunately, some respond to one of the PDE5 inhibitors.

Trauma

Trauma to the pelvic blood vessels or nerves can also lead result in ED. Bicycle riding for long periods has been implicated as an etiologic factor; direct compression of the perineum by the bicycle seat may cause vascular and nerve injury.[39] On the other hand, bicycling for less than 3 hours per week may be somewhat protective against ED.[39] Some of the newer bicycle seats have been designed to diminish pressure on the perineum.[39, 40]

Diabetes mellitus

Diabetes is a well-recognized risk factor for ED. A systematic review and meta-analysis found that the prevalence of ED was 37.5% in type 1 diabetes, 66.3% in type 2 diabetes, and 52.5% in diabetes overall—a rate approximately 3.5 times higher than that in controls.[41]  The etiology of ED in diabetic men probably involves both vascular and neurogenic mechanisms. Evidence indicates that establishing good glycemic control can minimize this risk.

Abnormal cholesterol levels

The Massachusetts Male Aging Study (MMAS) documented an inverse correlation between ED risk and high-density lipoprotein (HDL) cholesterol levels but did not identify any effect from elevated total cholesterol levels.[16] Another study involving male subjects aged 45-54 years found a correlation with abnormal HDL cholesterol levels but also found a correlation with elevated total cholesterol levels. The MMAS included a preponderance of older men.

Respiratory diseases

Men with sleep disorders commonly experience ED.[42] Heruti et al recommended that in adult male patients, ED should be considered when a sleep disorder—especially sleep apnea syndrome—is suspected, and vice versa.[43]

Endocrine disorders

Hypogonadism that results in low testosterone levels adversely affects libido and erectile function. Hypothyroidism is a very rare cause of ED.

Penile conditions

Peyronie disease may result in fibrosis and curvature of the penis. Men with severe Peyronie disease may have enough scar tissue in the corpora to impede blood flow.

Mental health disorders

Mental health disorders, particularly depression, are likely to affect sexual performance. The MMAS data indicate an odds ratio of 1.82 for men with depression. Other associated factors, both cognitive and behavioral, may contribute. In addition, ED alone can induce depression.

Cosgrove et al reported a higher rate of sexual dysfunction in veterans with posttraumatic stress disorder (PTSD) than in veterans who did not develop this problem.[44] The domains on the International Index of Erectile Function (IIEF) questionnaire that demonstrated the most change included overall sexual satisfaction and erectile function.[45, 46] Men with PTSD should be evaluated and treated if they have sexual dysfunction.

Prostate surgery

Prostate surgery for benign prostatic hyperplasia has been documented to be associated with ED in 10-20% of men. This association is thought to be related to nerve damage from cauterization. Newer procedures (eg, microwave, laser, or radiofrequency ablation) have rarely been associated with ED.

Radical prostatectomy for the treatment of prostate cancer poses a significant risk of ED. A number of factors are associated with the chance of preserving erectile function. If both nerves that course on the lateral edges of the prostate can be saved, the chance of maintaining erectile function is reasonable. The odds depend on the age of the patient. Men younger than 60 years have a 75-80% chance of preserving potency, but men older than 70 years have only a 10-15% chance.

The Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) study, designed to determine whether an individual man’s sexual outcomes after most common treatments for early-stage prostate cancer could be accurately predicted on the basis of baseline characteristics and treatment plans, found that 2 years after treatment, 177 (35%) of 511 men who underwent prostatectomy reported the ability to attain functional erections suitable for intercourse.[47]

In comparison, 37% of men who had received external radiotherapy as their primary therapy reported the ability to attain functional erections suitable for intercourse, along with 43% of men who had received brachytherapy as primary treatment. Pretreatment sexual health-related quality of life score, age, serum prostate-specific antigen (PSA) level, race or ethnicity, body mass index, and intended treatment details were associated with functional erections 2 years after treatment.[47]

After surgery, one of the oral PDE5 inhibitors (sildenafil, vardenafil, or tadalafil) is frequently used to assist in the recovery of erectile function. The benefit of penile rehabilitation therapy is under investigation, but results have been mixed.[48, 49]

Medications

ED is an adverse effect of many commonly prescribed medications. For example, some psychotropic drugs and antihypertensive agents are associated with ED. Persistent posttreatment ED is a listed adverse effect of the 5-alpha reductase inhibitors finasteride and dutasteride and of alpha blockers.

However, a review of a United Kingdom medical record database found no evidence that the use of 5-alpha reductase inhibitors independently increase the risk for ED. In 71,849 men with benign prostatic hyperplasia (BPH), the risk of ED was not increased with the use of finasteride or dutasteride only (odds ratio [OR] 0.94), or a 5-alpha reductase inhibitor plus an alpha blocker (OR 0.92) compared with an alpha blocker only. In addition, the risk of ED was not increase in 12 346 men prescribed finasteride 1 mg for alopecia, compared with unexposed men with alopecia (OR 0.95). The risk of ED did increase with longer duration of BPH, regardless of drug exposure.[50]

Lifestyle

Exercise and lifestyle modifications may improve erectile function. Weight loss may help by decreasing inflammation, increasing testosterone, and improving self-esteem. Patients should be educated to increase activity, reduce weight, and stop smoking, as these efforts can improve or restore erectile function in men without comorbidities. Precise glycemic control in diabetic patients and pharmacologic treatment of hypertension may be important in preventing or reducing sexual dysfunction.[51]

Smoking

Cigarette smoking has been shown to be an independent risk factor. In studies evaluating more than 6000 men, the risk of developing ED increased by a factor of 1.5.

Epidemiology

United States and international statistics

Sexual dysfunction is highly prevalent in men and women. In the MMAS, 52% of the respondents reported some degree of erectile difficulty. Complete ED, defined as (1) the total inability to obtain or maintain an erection during sexual stimulation and (2) the absence of nocturnal erections, occurred in 10% of the respondents. Mild and moderate ED occurred in 17% and 25% of responders, respectively.[16]

Although the rate of mild ED in the MMAS remained constant (17%) in men aged 40-70 years, the number of men reporting moderate ED doubled (17-34%) and the number of men reporting complete ED tripled (5-15%). If the MMAS data are extrapolated to the US population, an estimated 18-30 million men are affected by ED.[52]

In the National Health and Social Life Survey (NHSLS), a nationally representative probability sample of men and women aged 18-59 years, 10.4% of men reported being unable to achieve or maintain an erection during the past year.[53] There is a striking correlation with the proportion of men in the MMAS who reported complete ED.

Studies conducted around the world report similar risk factors and similar prevalence rates for ED.[54, 55]

Age-related demographics

All studies demonstrate a strong association with age, even when data are adjusted for the confounding effects of other risk factors. The independent association with aging suggests that vascular changes in the arteries and sinusoids of the corpora cavernosa, similar to those found elsewhere in the body, are contributing factors. Other risk factors associated with aging include depression, sleep apnea, and low HDL levels.

Long-term predictions based on an aging population and an increase in risk factors (eg, hypertension, diabetes, vascular disease, pelvic and prostate surgery, benign prostatic hyperplasia, and lower urinary tract symptoms) suggest a large increase in the number of men with ED. In addition, the prevalence of ED is underestimated because physicians frequently do not question their patients about this disorder.

Prognosis

In a prospective population-based study of 1709 men aged 40-70 years, Araujo et al found that ED was significantly associated with increased all-cause mortality.[56] The increase primarily resulted from cardiovascular mortality.

In a prospective study from the Prostate Cancer Prevention Trial database, Thompson et al reported that men presenting with ED had a significantly higher chance of developing a cardiovascular event over a 7-year follow-up period.[57] The hazard ratio was 1.45, which is in the range of risk associated with current smoking or a family history of MI.

An analysis of 14 studies involving more than 90,000 patients with ED confirmed the relation between ED and an increased risk of cardiovascular events and mortality.[58] Compared with patients without ED, those with ED had a 44% increased risk of cardiovascular events, a 25% increased risk of all-cause mortality, a 62% increased risk of MI, and a 39% increased risk of cerebrovascular events. Treatment of ED, either through lifestyle interventions or by pharmacologic means, may improve prognosis and reduce risk.

Associated morbidity may include various other male sexual dysfunctions, such as premature (early) ejaculation and male hypoactive sexual desire disorder. The NHSLS found that 28.5% of men aged 18-59 years reported premature ejaculation, and 15.8% lacked sexual interest during the past year. An additional 17% reported anxiety about sexual performance, and 8.1% had a lack of pleasure in sex.[53]

Men with ED may also experience anxiety or depression[59] . Erectile disorder is common in men with lower urinary tract symptoms related to BPH.

Patient Education

The laboratory results should be discussed with the patient and, if possible, with his sexual partner. This educational process allows a review of the basic aspects of the anatomy and physiology of the sexual response and an explanation of the possible etiology and associated risk factors (eg, smoking and the use of various medications). Treatment options and their benefits and risks should be discussed. This type of dialogue allows the patient and physician to cooperate in developing an optimal management strategy.

Patients with both ED and cardiovascular disease who receive treatment with an oral PDE5 inhibitor require education regarding what to do if anginal episodes develop while the drug is in their system. Such education includes stressing the importance of alerting emergency care providers to the presence of the drug so that nitrate treatment is avoided.

Patients receiving penile prostheses should be instructed in the operation of the prosthesis before surgery and again in the postoperative period. The prosthesis usually is not activated until approximately 6 weeks after surgery, so as to allow the edema and pain to subside. The prosthesis is checked in the office before the patient begins to use it.

For patient education information, see the Erectile Dysfunction Health Center

 

Presentation

History

In assessing a patient with erectile dysfunction (ED), the first step is to gather the following information:

  • Sexual history

  • Medical and surgical history

  • Medication and nonprescription drug history

  • Psychological history

ED is a sensitive topic, and the clinician must be aware of the patient’s comfort level. Taking the history provides an opportunity for the physician to initiate patient and partner education about ED and its treatments and to facilitate communication. It also allows the physician to establish a rapport with the couple, which assists in treatment. Formal questionnaires may be valuable in this setting.

Sexual history

Even clinicians who are not comfortable dealing with ED should inquire into the sexual aspect of the patient’s health. A simple way to do this is simply to ask, “How’s your sex life? Everything working all right?” This type of inquiry should elicit a clear, quick, direct “Everything’s fine” from the patient. Any other response or even just a delay in answering should suggest potential ED in that patient.

If ED is a possibility, questioning should be aimed at determining which part of the sexual response is abnormal. A clear description of the problem is vital. The following information should be elicited:

  • Whether the patient has difficulty obtaining an erection

  • Whether the erection is suitable for penetration

  • Whether the erection can be maintained until the partner has achieved orgasm

  • Whether ejaculation occurs

  • Whether both partners experience sexual satisfaction

Taking the sexual history also allows the clinician to begin forming an objective opinion regarding the interpersonal relationship between the patient and his sexual partner.

Premature (early) ejaculation generally occurs in men younger than 40 years. This problem can place a great deal of stress on the couple’s relationship. A history of premature ejaculation can be obtained from many men who present in later years with erectile difficulty. Effective treatments, including selective serotonin reuptake inhibitor (SSRI) medications and sex therapy, are available to remedy this condition. (See Premature Ejaculation.)

The sexual history may include specific questions such as the following:

  • Are you ever able to obtain an erection suitable for penetration, even momentarily?

  • Is your ED getting worse or stable?

  • How long have you had trouble attaining or maintaining an erection?

  • How hard is the erection, on a scale of 0-100?

  • Is maintaining the erection a problem?

  • Have you ever had a traumatic sexual experience?

  • Are you able to achieve orgasm and ejaculation?

  • Approximately how long are able to have intercourse before ejaculating?

  • Do you use any type of contraceptives, such as condoms?

  • Do you experience nocturnal or morning erections?

  • Does pain or discomfort occur with ejaculation?

  • Do you have premature (early) ejaculation?

  • Is penile curvature (Peyronie disease) a problem?

  • How frequently do you have sexual activity? Is it typically spontaneous or planned?

  • If your erections were functional, what would be your preferred frequency of intercourse? Do you and your sexual partner agree on this issue?

  • Is adequate foreplay occurring? Is your sexual partner satisfied with the sexual experience?

  • Have you already tried any treatments? If so, what were they? Are you interested in trying a particular treatment first? Are you opposed to trying a particular type of therapy?

  • To what degree do you wish to proceed in determining the cause of the ED? How important is this to you?

Medical and surgical history

Information should be obtained about any previous surgical procedures or other medical disorders. In particular, in addition to general medical information, any history of pelvic surgery, trauma, previous prostate surgery, or irradiation of the prostate should be elicited.

Inquiries should be made regarding cardiovascular risk factors, such as hypertension, diabetes, obesity, dyslipidemia, and family history of cardiac disease. For example, there is an established link between obesity and ED in men.[60]

The Princeton Consensus Conference is a multispecialty collaborative tradition dedicated to optimizing sexual function and preserving cardiovascular health. It has the following two primary objectives:

  • To focus on evaluating and managing cardiovascular risk in men with ED and no known cardiovascular disease (CVD), with a particular emphasis on identifying those who may require additional cardiologic workup

  • To focus is on reevaluating and modifying previous recommendations for evaluation of cardiac risk associated with sexual activity in men with known CVD

The Second Princeton Consensus suggests that men with ED and no obvious cause are at high risk for subclinical coronary artery disease (CAD) and should undergo, at the least, screening for blood glucose and lipids and blood pressure measurement.[61]

The Third Princeton Consensus focuses on (1) emphasizing the use of exercise ability and stress testing to ensure that each man’s cardiovascular health is consistent with the physical demands of sexual activity before prescribing treatment for ED and (2) highlighting the link between ED and CVD, which may be asymptomatic and may benefit from cardiovascular risk reduction.[8]

ED has been demonstrated to be a harbinger of potential future cardiovascular events.[57] The development of ED has proved to be a precursor to symptomatic CAD in men, with an average lead-time of 38.8 months.[62] Since 2005, several observational studies have shown a strong correlation between ED and CAD, and subsequent large longitudinal studies have demonstrated that men with ED have a 65-85% increased risk of subsequent CAD.[63]

Medication and nonprescription drug history

It is important to obtain a detailed list of all medications taken during the past year, including all vitamins and other dietary supplements. (Patients often neglect to list dietary supplements they have tried in an effort to improve their sexual function.) Numerous prescription medications have been associated with ED, including the following:

  • Antihypertensive drugs

  • Antiulcer drugs (eg, proton pump inhibitors [PPIs] and cimetidine)

  • Lipid-lowering (eg, statins and fibrates)[64]

  • 5-Alpha reductase inhibitors (eg, finasteride and dutasteride)[65]

  • Antidepressants

  • Antipsychotic drugs (especially risperidone)[66]

  • Testosterone and anabolic steroids

In addition to prescription drug use, tobacco use, alcohol intake, caffeine intake, and illicit drug use should be documented. A smoking history is particularly important, in view of the contribution of smoking to vascular disease.

Psychological history

Factors that give rise to stress factors and tension, whether at work or at home, should be explored. The patient’s psychological state should be assessed, with particular attention to the following:

  • Indications of depression

  • Loss of libido

  • Problems and tension in the sexual relationship

  • Insomnia

  • Lethargy

  • Moodiness

  • Stress from work or other sources

It is especially important to have the patient explain his own interpretation of the problem. To this end, questions such as the following may be asked:

  • Did the onset of ED coincide with a specific event, such as a major operation or a divorce? Have you experienced the death of a spouse or family member?

  • Do you have diminished sexual desire? If so, how long have you had this? Is your diminished sexual desire a primary symptom, or is it a reaction to poor sexual performance?

  • Do you have any feelings of performance anxiety?

Pure psychogenic impotence is relatively uncommon. It is characterized objectively by the presence of good nocturnal and morning erections and negative findings on all other tests. However, a psychogenic component often is present in men with organic ED. A history of highly variable erections that can be totally absent one day but virtually normal the next suggests a psychogenic cause. Virtually 100% of men with severe depression have ED.

Use of formal questionnaires

Various formal questionnaires have been developed to gather objective data regarding ED and to assist clinicians in the evaluation of their patients,[67, 68] including the following:

  • International Index of Erectile Function (IIEF)
  • Sexual Encounter Profile (SEP)
  • Global Assessment Question (GAQ)
  • Psychological and Interpersonal Relationship Scales (PAIRS)
  • Self-Esteem and Relationship (SEAR) questionnaire
  • Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS)

The IIEF is a sensitive, specific, and standardized tool that has been validated in several languages.[46] This 15-question instrument evaluates 5 domains: erectile function, orgasmic function, sexual desire, intercourse satisfaction, and global satisfaction. It is used to evaluate pharmacologic and other therapies for the treatment of ED.

A shorter version of the IIEF, termed the IIEF-5, has been developed as a sexual health inventory for men.[45] This tool is helpful in screening patients for ED, a problem that many men are hesitant to discuss. In the IIEF-5, the patient is asked the following 5 questions with respect to the preceding 6 months:

  • How do you rate your confidence that you could achieve and maintain an erection?

  • When you had erections with sexual stimulation, how often were your erections hard enough for penetration?

  • During sexual intercourse, how often were you able to maintain your erection after you had penetrated your partner?

  • During sexual intercourse, how difficult was it to maintain your erection to the completion of intercourse?

  • When you attempted sexual intercourse, how often was it satisfactory for you?

The answers to these 5 questions are each scored on a scale of 0-5. A score of 25 is typical for a healthy man; scores of 11 or lower indicate moderate-to-severe ED. After completion of the IIEF or the IIEF-5 and a discussion with the patient, the physician should have a good understanding of the nature and scope of the patient’s problem.

The SEP is commonly used in clinical trials involving pharmacologic therapies for ED. It is a diary maintained by men after each sexual attempt, consisting of a series of yes/no questions regarding specific aspects of each encounter, as follows[69] :

  • Were you able to insert your penis into your partner’s vagina?

  • Did your erection last long enough for you to complete intercourse with ejaculation?

The GAQ has also been used in clinical trials. The questions are as follows:

  • Has the treatment you have been taking improved your erectile function?

  • If yes, has the treatment improved your ability to engage in sexual activity?

Psychosocial questionnaires have been developed, but they are infrequently used in clinical practice. They have been employed in clinical trials for product development.

The PAIRS is a self-administered questionnaire containing 3 domains (sexual self-confidence, time concerns, and spontaneity) related to the broader psychological and interpersonal outcomes associated with ED and its treatment. Patients rate their agreement or disagreement with a specific statement on a scale of 1 (“strongly disagree”) to 4 (“strongly agree”). If more than 50% of data are missing from a domain for any patient at any given visit, then that domain is considered missing for that patient at that visit.[70]

The SEAR questionnaire[71] is a subject-reported measure of psychosocial outcomes in men with ED. It consists of 14 items assessing two domains, as follows:

  • Sexual relationship (items 1-8)

  • Confidence (items 9-14)

The confidence domain consists of two subscales, as follows:

  • Self-esteem (items 9-12)

  • Overall relationship (items 13 and 14)

The EDITS is a reliable and validated questionnaire used to assess patients’ satisfaction with their ED treatment. For each question, satisfaction is rated on a scale of 0 (“extremely low treatment satisfaction”) to 4 (“extremely high treatment satisfaction”).[67]

Physical Examination

A physical examination is necessary for every patient, with particular emphasis on the genitourinary, vascular, and neurologic systems. A focused physical examination entails evaluation of the following:

  • Blood pressure

  • Peripheral pulses

  • Sensation

  • Status of the genitalia and prostate

  • Size and texture of the testes

  • Presence of the epididymis and vas deferens

  • Any penile abnormalities, such as hypospadias and Peyronie plaques

The physical examination may corroborate history findings or may reveal unsuspected physical findings, such as penile plaques, small testes, evidence of possible prostate cancer, prostate infections, or hypertension.

Several studies have found a strong correlation between hypertension and ED—not surprisingly, given that both are manifestations of a vascular disorder. In a large hypertension clinic, men who also demonstrated ED had a much higher prevalence of complications related to high blood pressure. It has been suggested that hypertensive patients with ED and poor cavernosal artery blood flow as measured during duplex ultrasonography studies should proceed to a full cardiac evaluation because of the high prevalence of associated problems.

A number of studies have shown a correlation between benign prostatic hyperplasia and ED. The cause of this correlation is not yet clear.

 

DDx

Diagnostic Considerations

In addition to the conditions listed in the differential diagnosis, the following conditions should be taken into consideration:

  • Cancer and cancer treatment

  • Epilepsy

  • Multiple sclerosis

  • Guillain-Barré syndrome

  • Alzheimer disease

  • Epispadias

  • Widower syndrome

  • Performance anxiety

  • Malnutrition

  • Leukemias

  • Medications (eg, antidepressants, antipsychotics, antihypertensives, antiulcer drugs, hyperlipidemia medications)

Excessive expectations on the part of men who actually have normal erectile function should also be considered in the differential diagnosis.

General models for diagnosis and management

The Process of Care Model for the Evaluation and Treatment of Erectile Dysfunction was developed to advance new guidelines for the diagnosis and management of ED in primary care and multidisciplinary settings.[72] The key components of this model are the following:

  • A rational approach to diagnosis and treatment

  • Emphasis on clinical history taking and a focused examination

  • Specialized testing and referral in predefined situations

  • A stepwise management approach with ranking of treatment options

  • Incorporation of patient and partner needs and preferences in the decision-making process

An alternative model was developed that included algorithms and consensus guidelines.[73] This approach is oriented toward patient goals and involves a minimum of testing. The patient and his partner express a preference for reasonable and appropriate treatment options and work with the physician to implement this plan.

Differential Diagnoses

 

Workup

Approach Considerations

The laboratory investigation for erectile dysfunction (ED) depends on information gathered during the interview. Laboratory testing is necessary for most patients, though not for all. On the basis of these study results, the physician should be able to determine the medical status of the patient, to identify and characterize the type of dysfunction, and to determine the need for additional testing (eg, penile or pelvic blood flow studies, nocturnal penile tumescence testing, or other blood tests).

Imaging studies are rarely performed, except in situations involving pelvic trauma or surgery.

In making any decisions about further management or referral, the patient’s needs, expectations, and priorities should be discussed and taken into account.

Laboratory Studies

Hormonal blood tests

According to an American College of Physicians (ACP) guideline, the evidence for the utility of hormonal blood tests in identifying and affecting therapeutic outcomes for treatable causes of ED is inconclusive. The ACP makes no recommendations either for or against routine use of hormonal blood tests or hormonal treatment in the management of patients with ED. Clinicians should make decisions to measure hormone levels on a case-by-case basis, in accordance with the patient’s clinical presentation.

Patients who express a loss of libido, depression, or any signs of diminished secondary sexual characteristics should undergo an endocrine evaluation. At a minimum, this should consist of measuring morning serum testosterone levels.

The relative merits of measuring total, free, and bioavailable testosterone levels and serum hormone–binding globulin are controversial. In screening for hypogonadism, total and free testosterone levels should be measured to investigate the hypothalamic-pituitary-gonadal axis. Testosterone levels peak at about 8 AM; thus, a morning level should be checked whenever possible. Free or bioavailable testosterone is important because it is the testosterone that is usable; the rest is attached mainly to serum hormone–binding globulin.

Measurement of luteinizing hormone (LH) may be helpful. LH levels vary according to the body’s need for testosterone. The hypothalamus regulates testosterone levels by releasing or inhibiting LH-releasing hormone (LHRH), which acts in the pituitary to produce LH. A high LH level associated with a low testosterone level implies primary testicular (Leydig cell) failure. Conversely, a low LH level associated with a low testosterone level suggests a central defect.

In some instances, prolactin levels may be helpful as well. A serum prolactin level is obtained if the patient has evidence of pituitary hyperfunction (eg, from a pituitary tumor) or if low serum testosterone levels have been documented.

A serum thyroid-stimulating hormone (TSH) evaluation is appropriate in selected patients.

Other blood tests

Additional useful screening studies include the following:

  • Hemoglobin A1c

  • Serum chemistry panel

  • Lipid profile

These studies should be considered unless the patient has had them performed recently and the results are available.

Measurement of prostate-specific antigen (PSA) levels may be appropriate if the patient is a candidate for prostate cancer screening. Such screening is controversial, however, and should be performed only after its risks and benefits have been reviewed with the patient (see Prostate Cancer).

Urinalysis

Performing a urinalysis is recommended. The presence of red blood cells (RBCs), white blood cells (WBCs), protein, or glucose can be important clues to a genitourinary disorder.

Injection of Prostaglandin E1

A test used to evaluate penile function is the direct injection of prostaglandin E1 (PGE1; alprostadil) into one of the corpora cavernosa (see the images below). If the penile vasculature is normal or at least adequate, an erection should develop within several minutes. The patient and the clinician can judge the quality of the erection. If successful, this test also establishes penile injections as a possible therapy.

A vasodilator such as prostaglandin E1 can be inje A vasodilator such as prostaglandin E1 can be injected into one of the corpora cavernosa. If the blood vessels are capable of dilating, a strong erection should develop within 5 minutes.
Erectile dysfunction. This diagram depicts a cross Erectile dysfunction. This diagram depicts a cross-section of penile anatomy and is used to instruct patients in the technique of administering intracorporeal medications.

Biothesiometry

The sensitivity of the skin of the penis to detect vibrational stimuli (ie, biothesiometry) can be employed as a simple nerve function office screening test, but it is infrequently indicated. In this test, a small electromagnetic test probe is placed on the right and left sides of the penile shaft and on the glans. The vibrational amplitude is adjusted until the subjective sensory threshold is reached, which is determined by questioning the patient (see the image below).

The presence of normal skin sensation adequate to The presence of normal skin sensation adequate to produce an erection is measured with this device.

A series of these tests determines the average vibrational sensory threshold in each location; these thresholds are then compared with reference range standards for the patient’s age group. Although this test does not directly measure erectile nerve function, it serves as a reasonable means of screening for possible sensory deficit and is simple to perform. Formal nerve conduction studies (eg, bulbocavernosus reflex latency time) are reserved for very specific situations.

Ultrasonography

Vascular function within the penis can be evaluated by means of duplex ultrasonography. In this procedure, blood flow in the cavernosal arteries within the corpora cavernosa is measured before and after the intracavernosal injection of a test dose of a standard vasodilator (eg, 20 µg of PGE1).

Criteria for evaluating the study results vary to some degree. A peak systolic velocity lower than 25 cm/sec is generally agreed to indicate arterial insufficiency. The proposed value for the lower limit of normal ranges from 25-35 cm/sec, but a peak systolic velocity of 35 cm/sec or higher clearly rules out arterial insufficiency. End-diastolic velocity serves as a proxy for venous outflow; a velocity of 5 cm/sec or lower when the penis is at full rigidity indicates the absence of abnormal venous leakage.

Nocturnal Penile Tumescence Testing

Nocturnal penile tumescence testing involves placing several bands around the penis, connected to a device such as the Rigiscan monitor, and instructing the patient to wear the assembly for 2 or 3 successive nights. If an erection occurs, which is expected during rapid eye movement sleep, its force and duration are measured on a graph (see the image below). Inadequate or absent nocturnal erections suggest organic dysfunction, whereas a normal result indicates a high likelihood of a psychogenic etiology.

This penile tumescence monitor is placed at the ba This penile tumescence monitor is placed at the base and near the corona of the penis. It is connected to a monitor that records a continuous graph depicting the force and duration of erections that occur during sleep. The monitor is strapped to the leg. The nocturnal penile tumescence test is conducted on several nights to obtain an accurate indication of erections that normally occur during the alpha phase of sleep.

Nocturnal penile tumescence testing was once frequently performed; it was thought to be useful in distinguishing psychogenic from organic impotence. Currently, other devices are available that provide similar information. Some are also able to measure rigidity (resistance to mild compression) and tumescence (size). Nocturnal penile tumescence testing is rarely used in current practice, but it can be helpful in situations where the diagnosis is in doubt.

Other Studies

Angiography is useful if the patient is a potential candidate for some type of vascular surgery. Young men with traumatic vascular injuries resulting in ED are candidates for this angiography because they may qualify for a vascular reconstruction.

In the vast majority of patients with ED, formal neurologic testing is unnecessary. However, those with a history of central nervous system (CNS) problems, peripheral neuropathy, diabetes, or penile sensory deficit may benefit from some level of neurologic testing.

 

Treatment

Approach Considerations

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]

Pharmacologic Therapy

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.

The Medicated Urethral System for Erections (MUSE) The Medicated Urethral System for Erections (MUSE) is a small suppository placed into the urethra with this device.

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.

External Erection-Facilitating Devices

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.

This is one of many types of constricting devices This is one of many types of constricting devices placed at the base of the penis to diminish venous outflow and improve the quality and duration of the erection. This is particularly useful in men who have a venous leak and are only able to obtain partial erections that they are unable to maintain. These constricting devices may be used in conjunction with oral agents, injection therapy, and vacuum devices.

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 image depicts a vacuum device used to produce This image depicts a vacuum device used to produce an erection (also see next image). In this image, the elements are shown. They include the cylinder, a pump to create a vacuum, and a constriction ring to be placed at the base of the penis after an erection has been obtained in order to maintain the erection.
This image demonstrates the vacuum device in place This image demonstrates the vacuum device in place (see previous image). Note the presence of the constricting ring at the base of the penis.

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.

Surgical Care

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)

Treatment

Advantages

Disadvantages

Semirigid or malleable rod implants

Simple surgery

Relatively few complications

No moving parts

Least expensive implant

Success rate of 70-80%

Highly effective

Constant erection at all times

May be difficult to conceal

Does not increase width of penis

Risk of infection

Permanently alters or may injure erection bodies

Most likely implant to cause pain or erode through skin

If unsuccessful, interferes with other treatments

Fully inflatable implants

Mimics natural process of rigidity-flaccidity

Patient controls state of erection

Natural appearance

No concealment problems

Increases width of penis when activated

Success rate of 70-80%

Highly effective

Relatively high rate of mechanical failure

Risk of infection

Most expensive implant

Permanently alters or may injure erection bodies

If unsuccessful, interferes with other treatments

Self-contained inflatable unitary implants

Mimics natural process of rigidity-flaccidity

Patient controls state of erection

Natural appearance

No concealment problems

Simpler surgical procedure than that required for fully inflatable prosthesis

Success rate of 70-80%

Highly effective

Sometimes difficult to activate the inflatable device

Does not increase width of penis

Mechanical breakdowns possible

Long-term results not available

Risk of infection

Relatively expensive

Permanently alters or may injure erection bodies

If unsuccessful, interferes with other treatments

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.

Two rigid cylinders have been placed into the corp Two rigid cylinders have been placed into the corpora cavernosa. This type of implant has no inflation mechanism but provides adequate rigidity to the penis to allow penetration.

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%.

This inflatable penile prosthesis has 3 major comp This inflatable penile prosthesis has 3 major components. The 2 cylinders are placed within the corpora cavernosa, a reservoir is placed beneath the rectus muscle, and the pump is placed in the scrotum. When the pump is squeezed, fluid from the reservoir is transferred into the 2 cylinders, producing a firm erection. The deflation mechanism is also located on the pump and differs by manufacturer.

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.

Counseling and Psychological Care

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.

Prevention

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]

Activity

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]

Restorative Therapy

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
  • Stem cell therapy
  • Intracavernous injection of platelet-rich plasma
  • 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, low-intensity extracorporeal shock wave therapy (LiESWT) has proved effective in European patients with severe ED that is unresponsive to treatment with PDE5 inhibitors.[117] 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.[118]

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.[118]

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.[119, 120] 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]

 

Guidelines

Guidelines Summary

American Urological Association (AUA) guidelines on erectile dysfunction (ED) contain the following recommendations on evaluation and diagnosis[1] :

  • Men presenting with symptoms of ED should undergo a thorough medical, sexual, and psychosocial history; a physical examination; and selective laboratory testing. (Clinical Principle)
  • For the man with ED, validated questionnaires are recommended to assess the severity of ED, to measure treatment effectiveness, and to guide future management. (Expert Opinion)
  • Men should be counseled that ED is a risk marker for underlying cardiovascular disease (CVD) and other health conditions that may warrant evaluation and treatment. (Clinical Principle)
  • In men with ED, morning serum total testosterone levels should be measured. (Moderate Recommendation; Evidence Level: Grade C)
  • For some men with ED, specialized testing and evaluation may be necessary to guide treatment. (Expert Opinion) 

AUA recommendations for treatment of ED are as follows:

  • Referral to a mental health professional should be considered to promote treatment adherence, reduce performance anxiety, and integrate treatments into a sexual relationship. (Moderate Recommendation; Evidence Level: Grade C)
  • Men with ED who have comorbidities known to negatively affect erectile function should be counseled that lifestyle modifications, including changes in diet and increased physical activity, improve overall health and may improve erectile function. (Moderate Recommendation; Evidence Level: Grade C)
  • Men with ED should be informed regarding the treatment option of an FDA-approved oral phosphodiesterase type 5 inhibitor (PDE5i), including discussion of benefits and risks/burdens, unless contraindicated. (Strong Recommendation; Evidence Level: Grade B)
  • When men are prescribed an oral PDE5i for the treatment of ED, instructions should be provided to maximize benefit/efficacy. (Strong Recommendation; Evidence Level: Grade C)
  • For men who are prescribed PDE5i, the dose should be titrated to provide optimal efficacy. (Strong Recommendation; Evidence Level: Grade B)
  • Men who desire preservation of erectile function after treatment for prostate cancer by radical prostatectomy (RP) or radiotherapy (RT) should be informed that early use of PDE5i post-treatment may not improve spontaneous, unassisted erectile function. (Moderate Recommendation; Evidence Level: Grade C)
  • Men with ED and testosterone deficiency (TD) who are considering ED treatment with a PDE5i should be informed that PDE5i may be more effective if combined with testosterone therapy. (Moderate Recommendation; Evidence Level: Grade C)
  • Men with ED should be informed regarding the treatment option of a vacuum erection device (VED), including discussion of benefits and risks/burdens. (Moderate Recommendation; Evidence Level: Grade C
  • Men with ED should be informed regarding the treatment option of intraurethral (IU) alprostadil, including discussion of benefits and risks/burdens. (Conditional Recommendation; Evidence Level: Grade C) For men with ED who are considering the use of IU alprostadil, an in-office test should be performed. (Clinical Principle)
  • Men with ED should be informed regarding the treatment option of intracavernosal injections (ICI), including discussion of benefits and risks/burdens. (Moderate Recommendation; Evidence Level: Grade C)
  • For men with ED who are considering ICI therapy, an in-office injection test should be performed. (Clinical Principle)
  • Men with ED should be informed regarding the treatment option of penile prosthesis implantation, including discussion of benefits and risks/burdens. (Strong Recommendation; Evidence Level: Grade C)
  • Men with ED who have decided on penile implantation surgery should be counseled regarding postoperative expectations. (Clinical Principle)
  • Penile prosthetic surgery should not be performed in the presence of systemic, cutaneous, or urinary tract infection. (Clinical Principle)
  • For young men with ED and focal pelvic/penile arterial occlusion and without documented generalized vascular disease or veno-occlusive dysfunction, penile arterial reconstruction may be considered. (Conditional Recommendation; Evidence Level: Grade C)
  • Penile venous surgery is not recommended for men with ED. (Moderate Recommendation; Evidence Level: Grade C)
  • Low-intensity extracorporeal shock wave therapy (ESWT) should be considered investigational for ED. (Conditional Recommendation; Evidence Level: Grade C)
  • Intracavernosal stem cell therapy should be considered investigational for ED. (Conditional Recommendation; Evidence Level: Grade C)
  • Platelet-rich plasma (PRP) therapy should be considered experimental for ED. (Expert Opinion)
 

Medication

Medication Summary

A growing array of medications is available to assist in the management of erectile dysfunction (ED). An ideal agent would be rapidly effective, easy to administer, affordable, applicable to a wide range of patients, and minimally toxic. The types of medications can be divided into oral, topical, injectable, and intraurethrally inserted. Phosphodiesterase type 5 (PDE5) inhibitors are the principal oral agents used in ED.

Phosphodiesterase-5 Enzyme Inhibitors

Class Summary

At least seven phosphodiesterase (PDE) classes are known, many with subtypes identified by structure and function. PDEs are a diverse family of enzymes that have different tissue distributions and functions but that all exert their effect by lowering intracellular levels of cyclic nucleotides, such as cyclic guanosine monophosphate (cGMP).

PDE5 is cGMP-specific and is a major cGMP-hydrolyzing enzyme in the vascular smooth muscle of the penis. PDE5 inhibitors rely on the role of nitric oxide (NO) in inducing vasodilatation. NO relaxes the smooth muscle of the corpora cavernosa peripherally by stimulating guanylyl cyclase activity, which results in increased cGMP levels; inhibition of PDE5 increases intracellular concentrations of cGMP, which, in turn, induces vasodilation.

Available PDE5 inhibitors include sildenafil, vardenafil, tadalafil, and avanafil. These agents do not directly cause penile erections but affect instead the response to sexual stimulation. Sildenafil was the first to be approved, avanafil the most recent. Although all of these agents inhibit PDE5, the newer drugs in the class are significantly more selective in their inhibition.

Sildenafil (Viagra)

Sildenafil is most effective in men with mild-to-moderate ED. It is to be taken on an empty stomach approximately 1 hour before sexual activity. Sexual stimulation is necessary to activate response. Sildenafil is available as 25-, 50-, and 100-mg tablets.

Vardenafil (Levitra, Staxyn)

Vardenafil is most effective in men with mild-to-moderate ED. It is to be taken on an empty stomach approximately 1 hour before sexual activity. Sexual stimulation is necessary to activate response. Vardenafil is available as 2.5-, 5-, 10-, and 20-mg tablets.

Tadalafil (Cialis)

Tadalafil is a PDE5-selective inhibitor that is chemically unrelated to sildenafil and vardenafil. It is most effective for mild-to-moderate ED of varying etiologies, including both organic and psychogenic causes. May take 30 min prior to sexual activity.

Increased sensitivity for erections may last 36 hours with intermittent dosing. Low-dose daily dosing may be recommended for more frequent sexual activity (eg, twice weekly); men can attempt sexual activity at any time between daily doses. In 2011, tadalafil was also FDA approved for daily use for the treatment of men with BPH, as well as ED.

Tadalafil is available as 2.5-, 5-, 10-, and 20-mg tablets. In patients who respond, coitus has been recorded from 30 minutes to 36 hours after administration.

Avanafil (Stendra)

Avanafil is a PDE5 inhibitor that inhibits cGMP degradation and thereby enhances the effects of NO in smooth muscle relaxation of the corpus cavernosum. May take 30 min prior to sexual activity.

Vasodilators

Class Summary

Some agents injected directly into the penis exert their relaxant effect directly on the smooth muscle of the corpora cavernosa. They can be used alone or in combination with other medications. The most commonly used agents are alprostadil (prostaglandin E1 [PGE1]), papaverine, and phentolamine. The optimal dosages and the most effective combination of these agents must be determined on a case-by-case basis.

These medications can be obtained as commercial preparations or can be formulated according to the physician’s request by compounding pharmacies. Patients can be supplied with vials of a single agent or a combination of agents mixed in a single vial. Patients must be instructed in the proper technique for administration.

A single intraurethral agent, PGE1, which has been formulated into a small suppository, is commercially available as a component of the Medicated Urethral System for Erections (MUSE). This agent was available before the introduction of sildenafil and is still used by a select group of men.

Alprostadil (Caverject, Caverject Impulse, Edex, Muse)

Alprostadil is identical to naturally occurring PGE1 and has various pharmacologic effects, including vasodilation and inhibition of platelet aggregation. When injected into the penile shaft, it relaxes trabecular smooth muscle and dilates cavernosal arteries, thereby, in turn, promoting blood flow and entrapment in the lacunar spaces of the penis, causing penile erection. Various doses have been employed.

Papaverine

Papaverine is a benzylisoquinoline derivative with a direct nonspecific relaxant effect on vascular, cardiac, and other smooth muscles. In the treatment of erectile dysfunction, it is injected intracavernosally into the penis to increase blood flow to the penis and produce an erection.

Phentolamine

Phentolamine is an alpha1- and alpha2-adrenergic blocking agent that blocks circulating epinephrine and norepinephrine, reducing the hypertension that results from catecholamine effects on the alpha-receptors. Injected into the penis, it causes an erection.

Androgens

Class Summary

Androgens are primarily of benefit in men with low levels of serum testosterone (hypogonadism). Men with hypogonadism who desire a restoration of libido and who wish to become sexually active usually benefit from exogenous supplementation of androgens. This can be accomplished with injections, cutaneous application via gel or skin patches, or oral administration.

Testosterone (AndroGel, Axiron, Depo-Testosterone, Testopel, Testim, Androderm, Striant, Fortesta, Natesto, Aveed)

Testosterone promotes and maintains secondary sex characteristics in androgen-deficient males. Depot injections can produce high levels of serum testosterone when administered in adequate doses. Because of its adverse effects, the use of testosterone replacement therapy is limited to men with testosterone levels less than 300 ng/dL.

 

Questions & Answers

Overview

How is erectile dysfunction (ED) defined?

What is included in the initial evaluation of patients with erectile dysfunction (ED)?

How is erectile dysfunction (ED) diagnosed?

What are the treatment options for erectile dysfunction (ED)?

What is erectile dysfunction (ED)?

How is erectile dysfunction (ED) treated?

What are the DSM-5 criteria for diagnosis of erectile dysfunction (ED)?

What is the anatomy relevant to erectile dysfunction (ED)?

What factors are involved in contraction and relaxation of the penis in erectile dysfunction (ED)?

What is the role of the nitric oxide pathway in the pathophysiology of erectile dysfunction (ED)?

What is the normal erectile process relative to erectile dysfunction (ED)?

What is the role of testosterone in the pathogenesis of erectile dysfunction (ED)?

What causes erectile dysfunction (ED)?

What is the role of vascular diseases in the etiology of erectile dysfunction (ED)?

What is the role of trauma in the etiology of erectile dysfunction (ED)?

What is the role of diabetes mellitus (DM) in the etiology of erectile dysfunction (ED)?

What is the role of elevated cholesterol levels in the etiology of erectile dysfunction (ED)?

What is the role of respiratory diseases in the etiology of erectile dysfunction (ED)?

What is the role of endocrine disorders in the etiology of erectile dysfunction (ED)?

What is the role of Peyronie disease in the etiology of erectile dysfunction (ED)?

What is the role of mental health disorders in the etiology of erectile dysfunction (ED)?

What is the role of prostate surgery in the etiology of erectile dysfunction (ED)?

What is the role of medications in the etiology of erectile dysfunction (ED)?

Which lifestyle modifications are beneficial in the treatment of erectile dysfunction (ED)?

What is the role of smoking in the etiology of erectile dysfunction (ED)?

What is the prevalence of erectile dysfunction (ED)?

How does the prevalence of erectile dysfunction (ED) vary by age?

What is the prognosis of erectile dysfunction (ED)?

What should be included in patient education about erectile dysfunction (ED) cases?

Presentation

Which histories are needed for the evaluation of erectile dysfunction (ED)?

What should be included in a sexual history for the evaluation of erectile dysfunction (ED)?

What should be the focus of the medical and surgical history in the evaluation of erectile dysfunction (ED)?

Why is a detailed medication history needed for the evaluation of erectile dysfunction (ED)?

What should be included in the psychological history for evaluation of erectile dysfunction (ED)?

Which formal questionnaires may be used in the evaluation of erectile dysfunction (ED)?

What should be included in the physical exam to evaluate erectile dysfunction (ED)?

DDX

Which conditions should be included in the differential diagnosis of erectile dysfunction (ED)?

What is the Process of Care Model for the Evaluation and Treatment of Erectile Dysfunction and how is it used?

What are the differential diagnoses for Erectile Dysfunction?

Workup

What is the role of lab studies in the workup of erectile dysfunction (ED)?

What are the American College of Physicians (ACP) guideline for lab testing in the diagnosis and management of erectile dysfunction (ED)?

What is the role of blood tests in the workup of erectile dysfunction (ED)?

How is a urinalysis used in the workup of erectile dysfunction (ED)?

What is the role of prostaglandin E1 injection in the diagnosis and treatment of erectile dysfunction (ED)?

What is the role of biothesiometry in the evaluation of erectile dysfunction (ED)?

What is the role of ultrasonography in the evaluation of erectile dysfunction (ED)?

What is the role of nocturnal penile tumescence testing in the workup of erectile dysfunction (ED)?

When are angiography and neurologic testing indicated for the evaluation of erectile dysfunction (ED)?

Treatment

What is the basis for treatment selection in erectile dysfunction (ED)?

How is erectile dysfunction managed in patients with hypogonadism?

What is the treatment for medication-related erectile dysfunction?

How is comorbid cardiovascular disease treated in men with erectile dysfunction (ED)?

What is the role of angioplasty in the treatment of erectile dysfunction (ED)?

What is the role of pharmacologic therapy in the treatment of erectile dysfunction (ED)?

What are the guidelines for use of PDE5 inhibitors in the treatment of erectile dysfunction (ED)?

What is the role of androgens in the treatment of erectile dysfunction (ED)?

What is the role of intracavernosal injections in the treatment of erectile dysfunction (ED)?

What is the role of Medicated Urethral System for Erections (MUSE) in the treatment of erectile dysfunction (ED)?

What is the role of vascular endothelial growth factor (VEGF) in the treatment of erectile dysfunction (ED)?

Which medications have been investigated for the treatment of erectile dysfunction (ED)?

What is the role of yohimbine in the treatment of erectile dysfunction (ED)?

What is the role of apomorphine in the treatment of erectile dysfunction (ED)?

What is the role of phentolamine in the treatment of erectile dysfunction (ED)?

What is the role of constriction devices in the treatment of erectile dysfunction (ED)?

What is the role of vacuum devices in the treatment of erectile dysfunction (ED)?

When is surgery indicated in the treatment of erectile dysfunction (ED)?

What is the role of surgery to eliminate venous outflow in the treatment of erectile dysfunction (ED)?

What is the role of prosthetic devices in the treatment of erectile dysfunction (ED)?

What is the role sexual counseling and psychotherapy in the treatment of erectile dysfunction (ED)?

How is erectile dysfunction (ED) prevented?

How does increased physical activity affect the treatment of erectile dysfunction (ED)?

What is the role of restorative therapies in the treatment of erectile dysfunction (ED)?

Guidelines

What are the AUA guidelines on the evaluation and diagnosis of erectile dysfunction (ED)?

What are the AUA guidelines on the treatment of erectile dysfunction (ED)?

Medications

Which medications are used in the management of erectile dysfunction (ED)?

Which medications in the drug class Androgens are used in the treatment of Erectile Dysfunction?

Which medications in the drug class Vasodilators are used in the treatment of Erectile Dysfunction?

Which medications in the drug class Phosphodiesterase-5 Enzyme Inhibitors are used in the treatment of Erectile Dysfunction?