Medical Evaluation and Management of Erectile Dysfunction

Erectile dysfunction (ED) has been defined as the inability to achieve or maintain a penile erection sufficient for satisfactory sexual intercourse. A survey among American men of age 40 to 70 years found some degree of self-reported ED in 52% and complete ED in 9.6%. Age matters. There is a 5% prevalence of complete ED in men 40 years old and a 25% prevalence in men 75 years old. Similar prevalences have been found in other countries. Other forms of male sexual dysfunction, including premature ejaculation, which is more common among younger men, are addressed in Chapter 229.

Recent years have seen a revolution in the evaluation and management of ED. Greater understanding of erectile pathophysiology led to the development and unprecedented promotion of inhibitors of phosphodiesterase type 5 (PDE-5). The availability of these drugs has affected approaches to diagnosis and treatment. The effectiveness and safety of PDE-5 inhibitors have made a therapeutic trial a reasonable approach for many men with ED. Recent commercial promotion of transdermal testosterone therapy has raised the question in the minds of many men of its role in treatment of ED and stimulated requests for serum testing. All of this has placed the primary care physician at the center of management decisionsfully, patient education and counseling.

NORMAL AND PATHOLOGIC PHYSIOLOGY AND CLINICAL PRESENTATIONS (1, 2, 3, 4, 5, 6, 7, 8, 9 and 10)

Normal Physiology

Penile erection is a hemodynamic process mediated by the integration of highly specialized neural and vascular mechanisms that control the rate of blood flow into and out of the highly vascular corpora cavernosa, which constitute the bulk of the penile shaft. Blood flow is modulated by changes in the contractile state of the trabecular smooth muscle lining the corporal arterioles and sinusoids. In the flaccid state, trabecular smooth muscle tone is high, and arterial flow into the penis is minimal. Venous outflow is facilitated by copious arteriovenous shunts. With sexual stimulation, the smooth muscle relaxes, arterioles dilate, and blood flows in, engorging the corporal sinusoidal spaces. This engorgement compresses the arteriovenous shunts and venular plexuses between the trabeculae and the fibrous tunica albuginea, markedly impairing venous outflow. The result is an intracavernosal pressure of 100 mm Hg and what is termed a full erection. Intercourse or masturbation elicits the bulbocavernosus reflex, with the ischiocavernous muscles compressing the base of the engorged corpora cavernosa, driving intracavernous pressure to several hundred millimeters of mercury. During this phase of rigid erection, the penis is at its hardest as the flow of blood comes to a temporary standstill. When ejaculation occurs, a sympathetic discharge leads to contraction of the trabecular smooth muscle, reopening the venous channels and releasing the trapped blood, rendering the penis flaccid. Both autonomic and somatic nerves control this sequence of events. Sympathetic and parasympathetic nerves merge in the pelvis to form the cavernous nerves, which regulate blood flow. Somatic innervation of the dorsal nerves, which derive from the pudendal nerve, is responsible for penile sensation and for the functioning of the bulbocavernosus and ischiocavernous muscles.

Control Centers and Mechanisms

There are two spinal erection centers. The sympathetic reflex center is situated in the thoracolumbar (T-12 to L-2) region. It controls adrenergic tone and sustains the vasoconstriction of the flaccid state. The parasympathetic reflex center occupies the midsacral (S-2 to S-4) region. The vascular changes responsible for erections can be triggered by one or more of three mechanisms, referred to as psychogenic, reflexogenic, and centrally originated. Psychogenic erections occur in response to erotic sensations and the related stimulatory pathways (e.g., sight, touch, smell, sound) that travel from the spinal erection centers and induce dopaminergic initiation of the erection sequence from the medial preoptic area. Reflexogenic erections are produced by direct tactile stimulation of the penis. In most instances, these two mechanisms are synergistic. Centrally originated erections, also referred to as nocturnal erections, are seen during rapid eye movement (REM) sleep and reflect a decrease in baseline sympathetic inhibition.

Mediators

Mediators of erection and the erection pathway at the cellular level are illustrated in Fig. 132-1. In the flaccid state, penile vascular smooth muscle is maintained in a semicontracted state by baseline myogenic tone, adrenergic stimulation, and endothelium-derived relaxing factors. Parasympathetic stimulation associated with sexual stimulation increases the concentration of nitric oxide in smooth muscle cells, thereby mediating the vasodilation of penile erection. High concentrations of nitric oxide are delivered to the trabecular smooth muscle by the cavernous nerves. In addition, cholinergic output stimulates endothelial nitric oxide synthase, causing an increased production of nitric oxide. The nitric oxide diffuses across the smooth muscle membrane, where it activates guanylate cyclase, stimulating the production of cyclic guanosine monophosphate (cGMP), which ultimately reduces cytosolic calcium concentration, causing cavernosal smooth muscle relaxation. The pathway is regulated by phosphodiesterase enzymes that inactivate cGMP. PDE-5 is the most important isozyme in the corpora cavernosa. A separate mechanism mediated by cyclic adenosine monophosphate (cAMP) also decreases intracellular calcium levels.

The balance between parasympathetic and adrenergic stimulation necessary for normal erectile function offers insight regarding some of the common correlates of dysfunction. Patients with diabetes, depression, and central and peripheral neuropathic diseases have impaired parasympathetic output. Men who smoke have an increase in outflow from the sympathetic nervous system that inhibits the relaxation necessary for erection. It is believed that adrenergic output is impaired in men with lower urinary tract symptoms of benign prostatic hyperplasia (BPH).

Hormonal influences include the role of testosterone as a stimulant of sexual activity and a regulator of penile erectile physiology, manifesting influences on penile nitric acid synthesis, venous occlusion, penile blood flow, and smooth muscle mass. Unappreciated are the wide variations in the amount of
testosterone needed to sustain sexual function in men and the important role of testosterone-derived estrogen.

Figure 132-1 Mediators of erection at the cellular level. Outflow from the parasympathetic nervous system relaxes the cavernous sinusoids by increasing the concentration of nitric oxide (NO) in smooth muscle cells. NO is the neurotransmitter in nonadrenergic, noncholinergic (NANC) fibers, and stimulation of endothelial nitric oxide synthase (eNOS) through cholinergic output causes increased production of NO. With increase in NO content, the smooth muscle cell decreases its intracellular calcium concentration through a pathway mediated by cyclic guanosine monophosphate (cGMP), which leads to relaxation. A separate mechanism that decreases the intracellular calcium level is mediated by cyclic adenosine monophosphate (cAMP). With increased cavernosal blood flow, as well as increased levels of vascular endothelial growth factor (VEGF), the endothelial release of NO is further sustained through the phosphatidylinositol 3 (PI3) kinase pathway. Active treatments include drugs that affect the cGMP pathway (phosphodiesterase type 5 [PDE5] inhibitors and guanylyl cyclase agonists), the cAMP pathway (alprostadil), or both pathways (papaverine), along with neural-tone mediators (phentolamine and Rho kinase inhibitors). α1, α-adrenergic receptor; GPCR, G-protein-coupled receptor; GTP, guanosine triphosphate; PGE, prostaglandin E; PGF, prostaglandin F. (From McVary K. Erectile dysfunction. N Engl J Med 2007;357:2472, with permission. Copyright © 2007, Massachusetts Medical Society.)

Pathophysiology and Clinical Presentations

Impairment of any element of the erectile apparatus or its control can lead to ED. Obvious organic causes are injury to the reflex centers in the spinal cord, severance of cortical input, and injury to the peripheral nerves and/or vascular apparatus through trauma or surgery. Less obvious and much more common are multifactorial explanations related to aging and the common agerelated chronic diseases. It has been estimated that among men older than 50 years with ED, at least 40% of cases were attributable to atherosclerosis. One attempt to categorize organic causes of ED concluded that 40% were due to atherosclerosis separate from diabetes, 30% to diabetes, 15% to medication, 6% to pelvic surgery or trauma, 5% to neurogenic causes, 3% to endocrine disease, and 1% to other conditions. Psychological factors and the effects of drugs are also frequently involved.

The Aging Male

ED is strongly associated with age. Roughly 20% of men in their early 40s report moderate or complete ED. By the early 70s, that number has grown to 50% (Fig. 132-2). Serum testosterone declines gradually with age. Reductions associated with reduced sexual function (e.g., < 200 ng/dL) can be found in 20% of men by age 60 years and in 50% of men by age 80 years. (What happens to estrogen levels, which may also be important, remains to be established). In addition, there are concentrations of elastic fibers and smooth muscle fibers decrease as a man grows older. Sensitivity of the penis decreases with age as do levels of penile nitric oxide. However, it is not clear how much ED is attributable to normal aging in the absence of disease. Cardiovascular disease, diabetes, submissive personality, obesity, and lower educational attainment are all associated with higher risk.

Figure 132-2 The probability of minimal, moderate, and complete ED is strongly associated with age. (From Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151:54, with permission. Published by Elsevier, Inc. All rights reserved.)

Vascular Disease

Arterial insufficiency is usually listed as a leading cause of ED in older men. Unexplained, progressive slowing of erection followed by decreased rigidity can be among the first symptoms of aortoiliac vascular disease when plaque obstructs the iliac arteries immediately distal to the aortic bifurcation. ED develops in almost 40% of men with stenosis and nearly 75% of those with occlusion. Symptoms of claudication in association with ED, aortic or femoral bruits, and diminished peripheral pulses describe Leriche syndrome. In some cases, the patient has the ability to initiate an erection but cannot maintain it. Patients with hypertension, diabetes, and hypercholesterolemia or who smoke are at increased risk for the compromise of penile perfusion by atheromatous disease. Radiation therapy and pelvic trauma are other risk factors for vascular injury. Venous dysfunction can be equally important and result from age- or lipid-induced loss of venous fibroelastic compressibility. Several authorities argue that venous dysfunction may be more important than previously suspected.

Diabetes Mellitus

ED may be the presenting symptom of diabetes and is reported in up to 50% of men with the disease. Autonomic neuropathy resulting in failure of the pathways leading to vasodilation is the principal problem. In addition, endothelium-derived relaxing factor becomes deficient. Occlusive disease of larger vessels plays a much less important role than was previously believed, although it does play an important role in some cases. The risk for ED appears to parallel the duration and severity of diabetes. With conventional means of achieving glucose control, the majority of diabetic men experience some degree of ED, with fewer than 10% achieving restoration of normal function. Aggressive control of type 1 diabetes has effected a marked reduction in the risk for the development of autonomic neuropathy. The forerunner of ED in the diabetic is often retrograde ejaculation. The presence of dry orgasm or milky postcoital urine augurs a loss of erectile function within 1 year.

Drugs

Although it is a common observation that drugs can interfere with sexual functioning, the precise mechanisms for the effects of particular drugs are incompletely understood. These effects are often unpredictable and may vary from patient to patient and with dose and duration. Most are reversible by reducing or discontinuing the medication.

As noted, androgen deprivation therapy in the treatment of prostate cancer is now a common cause of low testosterone and resulting loss of libido. Androgen suppression with gonadotropin-releasing hormone agonists (e.g., leuprolide or goserelin) is the usual approach. Antiandrogens may also be used (e.g., flutamide, bicalutamide, nilutamide).

Antihypertensives are frequently to blame (see Chapter 26), although less so than in the past with the decline in the use of centrally acting agents like methyldopa, clonidine, and reserpine, and diuretics leading the list. ED has also been observed in patients taking antihypertensives with peripheral activity (e.g., hydralazine, thiazides, prazosin) and with beta-blockers. In patients with underlying vascular insufficiency, antihypertensives may contribute to ED by lowering perfusion pressure. Ganglionic blockers may inhibit parasympathetic activity from the sacral segments of the cord or sympathetic activity from the sympathetic chain. Although most antihypertensives have been implicated, the calcium channel blockers and angiotensin-converting enzyme inhibitors appear to interfere least with sexual function.

Psychotropic agents may also be responsible for unpredictable forms of sexual dysfunction. The phenothiazines suppress central sympathetic activity. They are capable of producing such side effects as decreased libido, impaired ejaculation, ED, and retrograde ejaculation. The anticholinergic effects of tricyclic antidepressants may interfere with erection, although sexual function often improves after drug treatment of depression (see Chapter 227). The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline have also been found to impair sexual functioning. Large doses of alcohol can acutely depress the sexual reflexes to the point of abolishing them. Chronic alcoholism leads to nerve damage, liver failure, and high levels of circulating estrogens (see Chapter 71). Exogenous estrogen therapy may have a similar effect of diminishing the libido.

Drug abuse involving barbiturates, heroin, morphine, or methadone can result in major disturbances of sexual potency. Most cases are reversible. Marijuana, amyl nitrite, hashish, and lysergic acid diethylamide may heighten the perception of the sexual experience but do not specifically increase or decrease potency. Amphetamines, in moderate users, may increase libido and delay orgasm, thus prolonging the sexual act; however, ED often occurs with long-term, heavy use. Cocaine increases both male and female sexual excitability, but side reactions, including a flight of ideas, may interfere with sustained sexual performance. Episodes of painful priapism may develop in chronic abusers.

Pelvic Surgery or Trauma and Other Neurogenic Causes

Damage to either central or peripheral nerves can cause ED. Stroke, Alzheimer disease, and Parkinson disease cause a decrease in libido and an overinhibition of spinal centers. Radical prostate, bladder, or colorectal surgery can produce ED as a result of surgical damage to the pelvic autonomic nerves. The incidence of radical prostate surgery has increased dramatically in recent decades due to increased clinical detection of prostate cancer. Improved understanding of the course of these autonomic fibers has led to revised surgical techniques, such as nerve-sparing radical prostatectomy to lower the risk for ED. Some surgeons have reported good results, but the procedure cannot be performed in all cases (see Chapter 143.). Neurogenic ED can also be caused by radiation therapy, which is also increasingly used for prostate cancer.

After radical retroperitoneal lymph node dissection for testicular tumors, ejaculatory failure may develop in young men as a result
of bilateral resection of the paraaortic sympathetic ganglia, but ED rarely develops. Bilateral sympathectomy of lumbar ganglia at L-1 will inhibit ejaculatory capacity, but not orgasmic sensation, in more than half of cases. More than 75% of all men with spinal cord injuries demonstrate some erectile capacity, but only 25% are able to engage successfully in intercourse. The erection is reflexogenic, requiring continued penile stimulation to be maintained. Erections are totally abolished when local destruction of spinal segments S-2 to S-4 or their roots is complete. Again, the higher the location of the lesion, the better are the chances of a good erection. Ejaculation is rare when the lower thoracic and upper lumbar segments (approximately to L-3) of the cord are so extensively damaged that the nearby sympathetic components are destroyed. Sexual sensation is abolished with transection anywhere above the sacral level. Herniated intervertebral disks and metastatic cancer of the vertebral column, especially between T-10 and L-5, which cause local swelling and destruction of spinal cord tissue, may produce a similar clinical picture.

Endocrine Diseases

Testosterone deficiency can contribute to male sexual dysfunction, predominantly by decreasing interest in sexual activity and perhaps by impairing normal erectile physiology. Results from studies of replacement therapy in men with testosterone deficiency are equivocal with regard to improvement in erectile function; sexual activity scores rise, but effect on erectile function per se is less definitive. Such findings raise the question of testosterone’s specific relevance to ED and the need for attention to its treatment in men with ED (see later discussion). Causes of testosterone deficiency include advancing age; chromosomal, pituitary, and testicular disorders; and antiandrogen therapy. Manifestations include regression of secondary male sex characteristics, along with feeble libido and waning potency. When the cause is testicular failure, gonadotropin levels will be very high; when a pituitary or hypothalamic cause is present, gonadotropin levels will be low.

Hyperprolactinemia is an important source of pituitaryderived ED. Serum testosterone levels fall as gonadotropins decline, although ED seems to be more closely related to the degree of prolactin elevation. A reduction in prolactin restores erectile function. Hyperprolactinemia may be idiopathic, the result of a functioning pituitary adenoma, or a consequence of hypothyroidism (stimulated by high levels of thyroid-stimulating hormone; see Chapter 100).

Addison disease tends to lead to loss of libido and ED. Cushing syndrome, except when associated with adrenal carcinoma, impairs libido and potency after an initial period (weeks or months) of marked increase. Acromegaly leads to an early impairment of potency and a premature extinction of function. The decline in function is frequently preceded by a hyperlibidinal period.

Prostatic Disease

BPH and resulting lower urinary tract symptoms are very common among men in age groups most at risk for ED. A number of recent studies suggested an association between BPH and ED, but the pathophysiologic relationship between the two is unclear. Increased sympathetic outflow and impaired nitric oxide content in the penis, prostate, and bladder have been described as possible explanations. Early evidence suggests that PDE-5 inhibitor therapy may improve urinary function, as well as erectile function.

ED may be the first symptom of prostate cancer. Advancing centrifugal growth of neoplastic tissue in the posterior lobe of the prostate may induce local swelling and destruction of the parasympathetic fibers that run along the posterolateral aspect of the prostate. Prostatitis may cause painful ejaculations and even hematospermia. Premature ejaculation and postcoital fatigue occur, but ED is not characteristic.

Other Causes

Pelvic fracture, resulting from a crash injury in which the posterior urethra is ruptured, causes ED in 25% to 30% of cases. Nonperformance may result from painful intromission associated with Peyronie disease, balanitis, acute gonorrhea, herpes genitalis, or phimosis. Hypospadias with a chordee of the shaft can preclude intercourse. With priapism, erection may be only partial and insufficient for intercourse because irreversible fibrosis of the corpora cavernosa has occurred. A large hernia or hydrocele may mechanically interfere with coitus, although potency should remain intact.

Psychogenic Conditions

Anxiety and depression are potent precipitants of ED. The marked sympathetic outflow that accompanies anxiety increases alpha-adrenergic tone and impedes trabecular smooth muscle relaxation. In addition, cortical influences may inhibit sacral cord reflexes that would normally trigger erection by way of parasympathetic stimulation (see Chapter 229). Performance anxiety, relationship problems, and stress are often contributors.

DIFFERENTIAL DIAGNOSIS (4,8)

The differential diagnosis of ED is broad, as reflected in the listed description of clinical presentations. In many patients, especially the elderly, sexual dysfunction is multifactorial in origin. Both psychological and organic factors are often present, and in many instances, more than one medical condition is involved. Etiologies and contributing factors are summarized in Table 132-1.

WORKUP (3,4,6,8,11, 12 and 13)

Advances in the pathophysiologic understanding of ED and the availability of safe and effective treatment in the form of PDE-5 inhibitors have dramatically altered the approach to workup. Before PDE-5 inhibitors, patients were often subjected to extensive laboratory investigation either before or after referral to a specialist. Now, however, a therapeutic trial of a PDE-5 inhibitor usually follows a workup that includes little more than a careful history and physical examination. It is important to distinguish ED from other dysfunctions such as premature ejaculation or loss of libido. The severity of ED can be assessed using a validated questionnaire such as the International Index of Erectile Function (IIEF). Once the presence of ED has been confirmed and the degree of dysfunction assessed, the evaluation can shift to a comprehensive multidimensional assessment (see details of the medical component next and those of the psychosocial evaluation in Chapter 229).

History

Differentiating Organic from Psychogenic Disease

The onset of the condition, its clinical course, and its effect on morning erections help to differentiate psychogenic from organic mechanisms. A sudden onset and the preservation of erections on awakening or with masturbation are suggestive of psychogenic disease. A gradual onset and the progressive loss in duration and strength of morning erections and erections associated with masturbation and coitus are more consistent with organic disease. These distinctions are not absolute. For example, depression may be associated with a temporary loss of morning erections, mimicking organic disease. Inquiry into libido is also important. Other forms of sexual dysfunction,
such as premature ejaculation, may evoke performance anxiety, which in turn may lead to ED.

TABLE 132-1 Causes of Erectile Dysfunction

Aging
	Structural changes
	Physiologic changes
Cardiovascular Disease
	Peripheral vascular disease
	Radiation injury
	Venous dysfunction
Diabetes
	Autonomic neuropathy
	Vascular disease
Drugs
	Gonadotropin-releasing hormone agonists
	Antiandrogens
	Antihypertensives (especially beta-blockers and diuretics)
	Phenothiazines
	Tricyclic antidepressants
	Selective serotonin reuptake inhibitors
	Protease inhibitors
	H₂ antagonists
	Cytotoxic agents
	Exogenous estrogens
	Illicit drugs
Neurogenic
	Stroke
	Alzheimer disease, Parkinson disease
	Surgical injury to nerves
	Spinal cord injuries
	Autonomic neuropathy
Endocrine Diseases
	Androgen deprivation therapy
	Hypogonadism
	Hyperprolactinemia
	Hypothyroidism
	Addison disease
	Cushing syndrome
	Acromegaly
Psychogenic
	Anxiety
	Depression
	Relationship issues
Other
	Prostate disease
	Injury to penis