Chapter 39. Male Sexual Dysfunction

Innervation of the Penis

The autonomic spinal erection center is located in the intermediolateral nuclei of the spinal cord at levels S2–S4 and T12–L2. Nerve fibers from the thoracolumbar (sympathetic) and sacral (parasympathetic) spinal segments join to form inferior hypogastric and pelvic plexuses, which send branches to the pelvic organs. The fibers innervating the penis (cavernous nerves) travel along the posterolateral aspect of the seminal vesicles and prostate and then accompany the membranous urethra through the genitourinary diaphragm (Figure 39–1). Some of these fibers enter the corpora cavernosa and corpus spongiosum with the cavernous and bulbourethral arteries. Others travel distally with the dorsal nerve and enter the corpus cavernosum and corpus spongiosum in various locations to supply the mid- and distal portions of the penis. The terminal branches of the cavernous nerves innervate the helicine arteries and trabecular smooth muscle, and are responsible for vascular events during tumescence and detumescence.

Figure 39–1.

Location of cavernous nerves in relation to urethra.

The center for somatic motor nerves is located at the ventral horn of the S2–S4 segments (Onuf's nucleus). The motor fibers join the pudendal nerve to innervate the bulbocavernosus and ischiocavernosus muscles. The somatic sensory nerves originate at receptors in the penis to transmit pain, temperature, touch, and vibratory sensations. The brain has a modulatory effect on the spinal pathways of erection, specifically the medial preoptic area and paraventricular nucleus of the hypothalamus, periaqueductal gray of the midbrain, and the nucleus paragigantocellularis of the medulla. Positron emission tomography and functional magnetic resonance imaging have allowed for greater understanding of brain activation during sexual arousal and orgasm by measuring regional cerebral blood flow or activity. These powerful tools, used in the study of higher brain function and central activation of sexual arousal, may better define pathophysiology associated with varied conditions including psychogenic ED, premature ejaculation, and orgasmic dysfunction (Georgiadis and Holstege, 2005).

Three types of erections are noted in humans: genital stimulated (contact or reflexogenic), central stimulated (noncontact or psychogenic), and central originated (nocturnal). Genital-stimulated erection is induced by tactile stimulation of the genital area. This kind of erection can be preserved in upper spinal cord lesions, although erections are usually short in duration and poorly controlled by the individual. Central-stimulated erection is more complex, resulting from memory, fantasy, visual, or auditory stimuli. Centrally originated erections can occur spontaneously without stimulation or during sleep; most sleep erections occur during rapid eye movement (REM) sleep. During REM sleep, the cholinergic neurons in the lateral pontine tegmentum are activated while the adrenergic neurons in the locus coeruleus and the serotonergic neurons in the midbrain raphe are silent. This differential activation may be responsible for the nocturnal erections during REM sleep. Of note, the number and duration of erections for men with hypogonadism or receiving antiandrogen therapy is markedly reduced (Granata et al, 1997).

Anatomy and Hemodynamics of Penile Erection

The tunica of the corpora cavernosa is a bilayered structure with multiple sublayers. The inner circular bundles support and contain the cavernous tissue. From this inner layer, intracavernosal pillars that act as struts radiate to augment the septum; both structures provide structural support to the corpus cavernosum. The outer-layer bundles are oriented longitudinally and extend from the glans penis to the proximal crura. These fibers insert into the inferior pubic ramus but are absent between the 5- and 7-o'clock positions. In contrast, the corpus spongiosum lacks an outer layer or intracorporeal struts, ensuring a lower pressure structure during erection. The tunica is composed of elastic fibers forming a network on which the collagen fibers rest. Emissary veins run between the inner and outer layers for a short distance, often piercing the outer bundles obliquely. Branches of the dorsal artery take a more direct perpendicular route and are surrounded by a periarterial fibrous sheath (Hsu et al, 2004).

The paired internal pudendal artery is the major carrier of the blood supply to the penis, dividing into three branches: the bulbourethral artery, dorsal artery, and the cavernous artery (deep artery). The cavernous artery supplies the corpora cavernosa; the dorsal artery, the skin, subcutaneous tissue, and the glans penis; and the bulbourethral artery, the corpus spongiosum. In some cases, accessory pudendal arteries from external iliac or obturator arteries may supply a major portion of the penis, with collaterals among the three branches often observed. The venous drainage of the glans is mainly through the deep dorsal vein. The corpus spongiosum is drained via the circumflex, urethral, and bulbar veins, but the drainage of the corpora cavernosa is more complex: the mid- and distal shaft are drained by the deep dorsal and periarterial veins to the preprostatic plexus while the proximal portion is drained by the cavernous and crural veins to the preprostatic plexus and internal pudendal vein. The drainage of all three corpora originates in the subtunical venules, which unite to form emissary veins. The glans penis possesses numerous large and small veins that communicate freely with the dorsal veins. The penile skin and subcutaneous tissue are drained by superficial dorsal veins, which then empty into the saphenous veins.

Activation of the autonomic nerves produces a full erection secondary to filling and trapping of blood in the cavernous bodies. After full erection is achieved, contraction of the ischiocavernosus muscle (from activation of the somatic nerves) compresses the proximal corpora and raises the intracorporal pressure well above the systolic blood pressure, resulting in rigid erection (Table 39–1). This rigid phase occurs naturally during masturbation or sexual intercourse but can also occur from slight bending of the penis, without muscular action. The erection process can be divided into phases as shown in Table 39–1 and Figure 39–2. The hemodynamics of the penile glans is somewhat different. Arterial flow increases in a manner similar to that in the shaft. Because it lacks the tunica albuginea, however, the glans functions as an arteriovenous fistula during the full erection phase. Nevertheless, during rigid erection, most of the venous channels are temporarily compressed, and further engorgement of the glans can be observed (Lue, 2000).

Figure 39–2.

Phases of penile erection (induced in monkeys via neurostimulation). Numbers correspond to phases outlined in Table 39–1. (Lower tracing = intracavernous pressure; upper tracing = flow within the internal pudendal artery.)

Table 39–1. Phases of the Erection Process.a

Table 39–1. Phases of the Erection Process.a

Flaccid phase (1)

Minimal arterial and venous flow; blood gas values equal those of venous blood.

Latent (filling) phase (2)

Increased flow in the internal pudendal artery during both systolic and diastolic phases. Decreased pressure in the internal pudendal artery; unchanged intracavernous pressure. Some elongation of the penis.

Tumescent phase (3)

Rising intracavernous pressure until full erection is achieved. Penis shows more expansion and elongation with pulsation. The arterial flow decreases as the pressure rises. When intracavernous pressure rises above diastolic pressure, flow occurs only in the systolic phases.

Full erection phase (4)

Intracavernous pressure can rise to as much as 90–100% of the systolic pressure. Arterial flow is less than that in the initial filling phase but is still higher than in the flaccid phase. Although the venous channels are mostly compressed except the proximal ones, the total venous flow is slightly higher than venous flow in the flaccid phase. Blood gas values approach those of arterial blood.

Rigid erection phase (5)

As a result of contraction of the ischiocavernous muscle, the intracavernous pressure rises well above the systolic pressure, resulting in rigid erection. During this phase, no blood enters the corpus cavernosum. The duration of this phase is short and does not cause ischemia or tissue damage.

Detumescent phase (6)

After ejaculation or cessation of erotic stimuli, sympathetic tonic discharge resumes, resulting in contraction of the smooth muscles around the sinusoids and arterioles. This diminishes the arterial flow to flaccid level, reopens the venous channels, and expels blood from the sinusoidal spaces. The penis returns to its flaccid length and girth.

aNumbers 1–6 correspond to phases shown in Figure 39–2.

Mechanism of Penile Erection

The penile erectile tissue, specifically cavernous, arteriolar, and arterial wall smooth musculature, is key to the erectile process. In the flaccid state, these smooth muscles are tonically contracted due to intrinsic smooth-muscle tone and possibly tonic adrenergic discharge, allowing only a small amount of arterial flow for nutritional purposes. The blood partial pressure of oxygen (PO2) is about 35 mm Hg. When smooth muscles relax due to the release of neurotransmitters, resistance to incoming flow drops to a minimum. Arterial and arteriolar vasodilatation occurs, and sinusoids expand to receive a large increase of flow. Trapping of blood causes the penis to lengthen and widen rapidly until the capacity of the tunica albuginea is reached. Expansion of the sinusoidal walls against one another and the tunica albuginea results in compression of the subtunical venous plexus. As well, uneven stretching of the layers of the tunica albuginea compresses the emissary veins and effectively reduces the venous flow to a minimum (Lue, 2000; Figures 39–3A and B). Intracavernous pressure (ICP) and PO2 increase to about 100 and 90 mm Hg, respectively, raising the penis from a dependent position to the erect state; further pressure increases (to several hundred millimeters of mercury) due to contraction of the ischiocavernosus muscles result in the rigid-erection phase (Dean and Lue, 2005; Gratzke et al, 2010).

Figure 39–3.

The mechanism of penile erection. In the flaccid state (A), the arteries, arterioles, and sinusoids are contracted. The intersinusoidal and subtunical venular plexuses are wide open, with free flow to the emissary veins. In the erect state (B), the muscles of the sinusoidal wall and the arterioles relax, allowing maximal flow to the compliant sinusoidal spaces. Most of the venules are compressed between the expanding sinusoids. Even the larger intermediary venules are sandwiched and flattened by distended sinusoids and the noncompliant tunica albuginea. This effectively reduces the venous capacity to a minimum.

Hormones and Sexual Function

Androgens are essential for male sexual maturity. Testosterone (T) regulates gonadotropin secretion and muscle development; dihydrotestosterone mediates male sexual maturation, including hair growth, acne, male pattern baldness, and spermatogenesis. In adults, androgen deficiency results in decreased libido (sexual interest) and impaired seminal emission. Aging is associated with a progressive decline of testosterone, dehydroepiandrosterone, thyroxine, melatonin, and growth hormone and increased levels of sex hormone-binding globulin, pituitary gonadotropins, and prolactin (Morales, 2005). In a longitudinal study of middle-aged men for 7–10 years, total T levels declined at 0.8%/year of age, whereas both free and albumin-bound T declined at about 2%/year. Sex hormone-binding globulin increased at 1.6%/year (Feldman et al, 2002). Testosterone levels do not correspond to severity of ED; however, lower levels are observed in men with reduced libido. Although frequency, magnitude, and latency of nocturnal penile erections are reduced with decreased T, erectile response to visual sexual stimulation is preserved in men with hypogonadism, suggesting that androgen is not essential for erection. Due to the inhibitory action of prolactin on central dopaminergic activity and resultant decreases in gonadotropin-releasing hormone secretion, hyperprolactinemia of any cause results in both reproductive and sexual dysfunction (Corona et al, 2004).

Neurotransmitters and Pharmacology of Erection

Neural control of penile erection involves adrenergic, cholinergic, and nonadrenergic–noncholinergic (NANC) neuroeffector systems. Adrenergic nerves mediate intracavernous smooth-muscle contraction, maintaining the penis in a nonerect state. Currently, it is suggested that sympathetic contraction is mediated by activation of postsynaptic alpha-1a- and alpha-1d-adrenergic receptors and modulated by presynaptic alpha-2-adrenergic receptors (Giuliano et al, 2004). Cholinergic nerves may contribute to smooth-muscle relaxation and penile erection through inhibition of adrenergic nerves via inhibitory interneurons and the release of nitric oxide (NO) from the endothelium by acetylcholine (Saenz de Tejada et al, 2004).

The principal neurotransmitter for penile erection is NO from parasympathetic, NANC nerve terminals. Once blood rushes into the sinusoids, shear stress can also release NO from endothelium to augment smooth-muscle relaxation and erection. In addition, oxygen tension and substances secreted by endothelial cells lining the sinusoidal spaces, prostaglandins, endothelins, and angiotensin may also be involved in penile erection and detumescence (Musicki and Burnett, 2006). The agents capable of inducing erection and causing detumescence are summarized in Table 39–2. Although mechanisms of action vary, erection-inducing substances cause smooth muscle to relax and detumescing agents cause them to contract.

Table 39–2. Agents that Have Been Reported to Induce or Inhibit Penile Erection.

Table 39–2. Agents that Have Been Reported to Induce or Inhibit Penile Erection.

Inducers

Inhibitors

Thymoxamine

Metaraminol

Alprostadil (prostaglandin E1)

Ephedrine

Vasoactive intestinal polypeptide (VIP)

Prostaglandin I 2

Calcitonin gene-related peptide (CGRP)

Prostaglandin F 2α

Nitric oxide donor

Thromboxane A 2 (TXA2)

Guanylate cyclase activator

Endothelin

Dopamine receptor agonist

Angiotensin II

Phosphodiesterase inhibitors

Rho-kinase inhibitors

Melanocortin receptors agonist

Molecular Mechanism of Smooth-Muscle Contraction and Relaxation

Smooth-muscle contraction is regulated by Ca2+. As cytosolic free Ca2+ increases from resting levels of 120–270 to 500–700 nM, calmodulin-4 Ca2+ complex binds to myosin light-chain kinase. The activated kinase then phosphorylates the light chain and initiates a contraction cycle (Gratzke et al, 2010). Once cytosolic Ca2+ returns to basal levels, calcium-sensitizing pathways take over. Activation of excitatory receptors coupled to G proteins causes contraction by increasing calcium sensitivity without changes in cytosolic Ca2+ levels. This pathway involves RhoA, a small monomeric G protein that activates Rho-kinase. Activated Rho-kinase phosphorylates, and thereby inhibits, the regulatory subunit of smooth-muscle myosin phosphatase, preventing dephosphorylation of myofilaments and maintaining contractile tone (Jin and Burnett, 2006). The emerging consensus is that phasic contraction of penile smooth muscle is regulated by increased cytosolic Ca2+ and tonic contraction is governed by calcium-sensitizing pathways.

Signal Transduction in Penile Erection

During sexual stimulation, NO released from nerve endings and endothelium diffuses into the trabecular and arterial smooth-muscle cells to activate guanylyl cyclase, catalyzing the formation of second messenger cyclic guanosine monophosphate (cGMP). cGMP in turn activates protein kinase G, phosphorylating potassium and calcium channels; the end result is hyperpolarization, reduced intracytosolic calcium, and dissociation of the myosin head from actin as smooth muscle relaxes. Cyclic adenosine monophosphate (cAMP) is another second messenger involved in smooth-muscle relaxation and is activated by cAMP-signaling molecules including adenosine, calcitonin gene-related peptides, and prostaglandins (Lin et al, 2005).

Both of these second messengers activate cAMP- and cGMP-dependent protein kinases, resulting in a drop of cytosolic free calcium and smooth-muscle relaxation via the (1) opening of the potassium channels and hyperpolarization, (2) sequestration of intracellular calcium by the endoplasmic reticulum, and (3) blockage of calcium influx through inhibition of voltage-dependent calcium channels (Dean and Lue, 2005). On the other hand, norepinephrine, phenylephrine, and endothelin appear to activate phospholipase C, leading to the formation of inositol triphosphate and diacylglycerol. The net result is increased cytoplasmic calcium and subsequent smooth-muscle contraction. Detumescence occurs following degradation of cGMP and cAMP to GMP and AMP, respectively, by specific phosphodiesterases. Eleven classes of phosphodiesterases have been identified. The penis is rich in PDE-5 (GMP specific), and therefore, the selective PDE-5Is (sildenafil, vardenafil, and tadalafil) are able to improve penile erections in patients with ED.

Intercellular Communication

Gap junctions are aqueous intercellular channels that have been demonstrated to interconnect the cytoplasm of adjacent cells in many tissues. In the penis, smooth-muscle cells are sparsely innervated by the terminal branches of the cavernous nerves. Therefore, gap junctions play a vital role in the intercellular communication within the corpus cavernosum, enabling the penis to function as a unit (Melman et al, 2007).

Male Sexual Dysfunction

Male sexual dysfunction, denoting the inability to achieve a satisfactory sexual relationship, may involve inadequacy of erection or problems with emission, ejaculation, or orgasm.

Premature (rapid) ejaculation refers to persistent or recurrent occurrence of ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it.

Retarded ejaculation is undue delay in reaching a climax during sexual activity.

Retrograde ejaculation denotes backflow of semen into the bladder during ejaculation owing to an incompetent bladder neck mechanism.

Anorgasmia is the inability to achieve an orgasm during conscious sexual activity, although nocturnal emission may occur.

Epidemiology

In the Massachusetts Male Aging Study, a community-based survey of men between 40 and 70 years of age, 52% of respondents reported some degree of ED: 17% mild, 25% moderate, and 10% complete. Although the prevalence of mild ED remained constant (17%) between the age of 40 and 70, there was a doubling in the number of men reporting moderate ED (from 17% to 34%) and a tripling in the number of men reporting complete ED (from 5% to 15%) (Feldman et al, 1994). More than 70% of men older than 65 years report that they are sexually active; however, 40% are dissatisfied with their sexual function (Braun et al, 2000). Among the major predictors of ED are hypertension, hyperlipidemia, diabetes mellitus, and heart disease. Risk of ED appears to increase with smoking, and may occur in a dose-dependent manner (Polsky et al, 2005). There is a higher prevalence of ED in men who have undergone radiation or surgery for prostate cancer or other pelvic malignancies. The psychological correlates of ED include decreased self-esteem, depression, anxiety, anger, and relationship dissatisfaction (Althof et al, 2006). Other male sexual dysfunctions have also been found to be highly prevalent: premature ejaculation and decreased libido (lack of sexual interest) are common patients' concerns.

Classification and Pathogenesis

The classification system of ED most commonly used encompasses organic, psychogenic, and mixed etiologies of ED and is endorsed by the International Society of Impotence Research (Table 39–3). In the 1950s, 90% of cases of ED were believed to be psychogenic. Most authors now believe that mixed organic and psychogenic ED is the most common.

Table 39–3. New Classification of ED Recommended by the International Society for Sexual Medicine.

Table 39–3. New Classification of ED Recommended by the International Society for Sexual Medicine.

Psychogenic
Organic
Mixed organic/psychogenic (most common type)

Psychological Disorders

Many psychologic conditions (performance anxiety, strained relationship, lack of sexual arousal, depression, and schizophrenia) can either cause or aggravate ED. Sexual behavior and penile erection are controlled by the hypothalamus, cerebral cortex, and limbic systems. Given the number and complexity of known and as yet unidentified factors involved, it is not surprising that the pathogenesis of psychogenic ED is still speculative. Possible mechanisms proposed include an imbalance of central neurotransmitters, overinhibition of spinal erection center by the brain, inadequate NO release, and sympathetic overactivity (Bodie et al, 2003).

Neurogenic Disorders

It has been estimated that up to 20% of all ED is neurogenic in origin, resulting from peripheral (cavernous and pudendal nerve) or central pathologies. In men with spinal cord injury, the degree of erectile function depends on the nature, location, and the extent of the lesion. Brain lesions associated with ED include dementias, Parkinson's disease, stroke, tumors, trauma, and Shy-Drager syndrome (Papatsoris et al, 2006). Peripheral neuropathy due to diabetes mellitus, chronic alcohol abuse, or vitamin deficiency may affect the nerve endings and result in a deficiency of neurotransmitters. Direct injury to the cavernous or pudendal nerves from trauma, radical pelvic surgeries for malignancy, or pelvic irradiation can also cause ED. It is important to note that even with nerve-sparing approaches to prostatic and rectal surgery, erectile recovery can take up to 24 months or longer.

Hormonal Disorders

Historically, hypogonadism as a cause of ED was thought to be rare, but recent data support a significant increase of hypogonadism with age. Hypogonadism due to hypothalamic or pituitary tumors, estrogen or antiandrogen therapy, or orchiectomy can suppress sexual interest and nocturnal erections. As mentioned earlier, erections are usually preserved to some extent. Hyperprolactinemia, Cushing's syndrome, and Addison's disease can cause decreased libido and ED. Hyperthyroidism is commonly associated with decreased libido, likely due to elevated estrogen levels, while hypothyroidism can contribute to ED through diminished testosterone secretion and elevated prolactin levels (Veronelli et al, 2006).

Arterial Disorders

Although arteriogenic ED may be congenital or posttraumatic, more often it is part of a generalized systemic arterial disease. Traumatic arterial occlusive or atherosclerotic disease of the hypogastric (iliac)–pudendal–cavernous arterial tree can decrease flow to the sinusoidal spaces and perfusion pressure, thus decreasing the rigidity or prolonging time to maximal erection. Some patients with severe arterial disease may retain erectile function as long as arterial flow exceeds venous flow; conversely, some patients with minimal arterial disease may develop partial or complete ED because of large venous outflow, cavernous smooth-muscle dysfunction, or inadequate neurotransmitter release (Dean and Lue, 2005).

High prevalence of ED has been reported in men with coronary, cerebral, and peripheral vascular diseases (Chai et al, 2009; Kloner et al, 2003). Among men with coronary arterial disease, the prevalence of ED increases as the severity of coronary arterial lesions increase. In patients with chronic coronary disease who also had ED, onset of sexual dysfunction occurred before coronary artery disease (CAD) onset in 93%, with a mean time interval of 24 [12–36] months (Montorsi et al, 2006). When ED occurs in a younger man, it is associated with a marked increase in the risk of future cardiac events, whereas in older men, ED appears to be of little prognostic importance (Inman et al, 2009).

Common risk factors associated with arterial insufficiency include hypertension, hyperlipidemia, diabetes mellitus, and metabolic syndrome. Long-distance cycling is also a likely risk factor for vasculogenic and neurogenic ED (Huang et al, 2005). Several modifiable life style factors such as physical inability, smoking, and alcohol consumption may also contribute to ED (Kupelian et al, 2009).

Arterial disease is classified as extra- or intrapenile arterial insufficiency. Extrapenile disease may be amenable to surgical repair in selected patients, and comprises diseases of the internal pudendal artery, internal and common iliac arteries, aorta, the pelvic steal syndrome, and pelvic trauma. Intrapenile arterial disease secondary to aging, arteriosclerosis, or diabetes mellitus does not respond well to currently available surgical techniques.

Cavernosal Disorders

Cavernous veno-occlusive dysfunction (CVOD) may result from a variety of pathophysiologic processes. Degenerative changes (Peyronie's disease, aging, and diabetes) and traumatic injury to the tunica albuginea (penile fracture) can impair the compression of the subtunical and emissary veins. Fibroelastic alteration of the trabeculae, cavernous smooth muscle, and endothelium may result in venous leakage (Deveci et al, 2006). Men with diabetes mellitus and atherosclerosis are at increased risk of smooth-muscle atrophy, fibrous replacement, and endothelial disruption. In men with no symptoms of coronary disease, the presence of CVOD was reported to have the greatest chance of predicting abnormal exercise stress echocardiography (Mulhall et al, 2009).

CVOD can be divided into five types according to cause: In type 1, large veins exit the corpus cavernosum (etiology is likely congenital); in type 2, venous channels are enlarged as a result of distortion of the tunica albuginea (secondary to Peyronie's disease or weakening associated with aging); in type 3, the cavernous smooth muscle is unable to relax because of fibrosis, degeneration; in type 4, there is inadequate neurotransmitter release (neurologic or psychologic impotence, or endothelial dysfunction) (Watts et al, 2007); and in type 5, there is abnormal communication between the corpus cavernosum and the spongiosum or glans (congenital, traumatic, or secondary to shunt procedures for priapism) (Dean and Lue, 2005).

Medication-Induced Erectile Dysfunction

Many drugs have been reported to cause ED, although the mechanism of action is often unknown and there are few controlled studies on the sexual side effects of a particular agent. As ED is common among older men, it will coexist with other conditions that are themselves risk factors for ED, such as cardiovascular disease, diabetes, or depression. Sexual symptoms related to medications can also involve a combination of complaints concerning desire, arousal, and orgasm rather than being limited to impaired erection.

In general, drugs that interfere with central neuroendocrine or local neurovascular control of penile smooth muscle have the potential to cause ED. Central neurotransmitter pathways, including serotonergic, noradrenergic, and dopaminergic pathways involved in sexual function, may be disturbed by antipsychotics, antidepressants, and centrally acting antihypertensive drugs (Balon, 2005). Selective serotonin reuptake inhibitors are the most common class of drugs currently used to treat depression; it is estimated that up to 50% of patients using these agents experience a change in sexual function. Nonspecific beta-adrenergic blocking drugs may cause ED by potentiating alpha-1 adrenergic activity in the penis. Conversely, alpha-1 blockers and angiotensin-II-receptor blockers both tend to improve sexual function during treatment and may therefore be useful when commencing antihypertensive therapy in men with preexisting ED. Thiazide diuretics have been reported to cause ED; spironolactone can also cause a decrease in libido and gynecomastia. Alpha-adrenergic blocking drugs, such as doxazosin, terazosin, and tamsulosin, may cause retrograde ejaculation owing to relaxation of the bladder neck (Guiliano, 2006). Other drugs thought to cause ED include opiates, antiretroviral agents, and histamine H2-receptor antagonists (cimetidine).

Antiandrogens modify sexual behavior by varying degrees, ranging from complete loss to normal function, chiefly by modulating sexual desire via central nervous system androgen receptors. Finasteride, a 5-alpha-reductase inhibitor commonly used to treat benign prostatic hypertrophy, is the antiandrogen with the least effect on circulating testosterone and sexual function. Sexual symptoms are reported in approximately 5% of men treated with a 5-mg dose (Miner et al, 2006). Estrogens and drugs with antiandrogenic action such as ketoconazole, luteinizing hormone-releasing hormone (LHRH) agonists, nonsteroidal (bicalutamide), and steroidal (cyproterone acetate) acetate can diminish sexual function. The near-complete androgen deprivation achieved by medical castration with LHRH agonists results in a profound loss of sexual desire, which is usually accompanied by ED.

Cigarette smoking may induce vasoconstriction and penile venous leakage because of its contractile effect on the cavernous smooth muscle and is seen to approximately double the rate of ED in coronary artery disease, hypertension, and atherosclerosis (Korenman, 2004). Alcohol in small amounts improves erection and increases libido because of its vasodilatory effect and the suppression of anxiety; however, large amounts can cause central sedation, decreased libido, and transient ED. Chronic alcoholism may cause hypogonadism and polyneuropathy, which may affect penile nerve function.

Aging and Systemic Disease

Sexual function progressively declines in “healthy” aging men. Longitudinal studies demonstrate a nonlinear decline for most aspects of sexual function as age increases, with a more pronounced decline in older groups (Araujo et al, 2004). The latent period between sexual stimulation and erection increases, erections are less turgid, ejaculation is less forceful, ejaculatory volume decreases, and the refractory period between erections lengthens. There is also a decrease in penile sensitivity to tactile stimulation, a decrease in serum testosterone concentration, and an increase in cavernous muscle tone. While psychologic and organic factors are important contributors to ED across age groups, organic issues tend to play a more profound role as men age.

ED in men with diabetes mellitus occurs approximately threefold that of the general population, and can be the presenting symptom for diabetes mellitus and/or predict later neurologic sequelae (Fonseca and Java, 2005). Diabetes may affect small vessels, cavernous nerve terminals, smooth muscle, and endothelial cells; neurovascular sequelae of long-term diabetes results in decreased responsiveness to oral PDE-5 inhibitor therapy. Obesity, a component of metabolic syndrome, has been linked to endothelial dysfunction, androgen deficiency, and ED (Traish et al, 2009). Alteration of protein levels in the corpus cavernousum has also been proposed as a cause of ED (Chiou et al, 2010).

Men with severe pulmonary disease may have ED because of fear of aggravating dyspnea during sexual intercourse (Koseoglu et al, 2005) Patients with angina, myocardial infarction (MI), or heart failure may have ED from anxiety, depression, or concomitant penile arterial insufficiency, which is quite common in these patients. Chronic renal failure has frequently been associated with diminished erectile function, impaired libido, and infertility (Shamsa et al, 2005). In men with chronic renal failure and ED, many were found to have cavernous artery occlusive disease and veno-occlusive dysfunction. The mechanism is likely multifactorial: low serum testosterone concentration, diabetes mellitus, vascular insufficiency, multiple medications, autonomic and somatic neuropathy, and psychological stress. Other systemic disorders such as cirrhosis, chronic debilitation, and cachexia can cause ED due to loss of libido or neurovascular dysfunction.

Diagnosis and Treatment

The management of ED is built on a patient-centered and evidence-based principle. A detailed medical, sexual, and psychosocial history and a thorough physical examination are the most important steps in the differential diagnosis of sexual dysfunction. Interviewing the partner, if available, is helpful in eliciting a reliable history, planning treatment, and obtaining a successful outcome.

Medical, Sexual, and Psychosocial History

The goals of the medical history are to evaluate the potential role of underlying medical conditions, differentiate between organic and psychogenic causes, and to assess the role of medication(s), both causative and therapeutic. The patient's past surgical history may similarly yield insights. A sexual history confirms the diagnosis, and should ascertain the severity, onset, and duration of the problem, as well as the presence of concomitant medical or psychosocial factors. It is necessary to determine whether the presenting complaint (eg, ED, premature ejaculation) is the primary sexual problem or if some other aspects of the sexual response cycle (desire, ejaculation, orgasm) are involved. Psychosocial assessment of past and present partner relationships is essential given the interpersonal context of sexual problems. Sexual dysfunction may affect the patient's self-esteem and coping ability, as well as social relationships and occupational performance.

Physical and Laboratory Examination

A focused physical examination is performed on each patient, assessing the genitourinary, endocrine, neurologic, and vascular systems, and includes a complete genital examination including digital rectal and measurement of blood pressure and heart rate. Examination may yield a diagnosis of Peyronie's disease, prostatic enlargement, malignancy, or evidence of hypogonadism (decreased testes size, altered secondary sex characteristics).

Recommended tests include fasting glucose, lipid profile, and morning testosterone (calculated free testosterone is more reliable to establish hypogonadism). Diabetic patients should have hemoglobin A1C measured and additional hormonal testing (prolactin, follicle-stimulating hormone [FSH], and luteinizing hormone [LH]) is required when low testosterone levels are noted or for clinical suspicion of abnormality. Optional tests, including prostate-specific antigen (PSA), thyroid-stimulating hormone (TSH), complete blood cell count, and creatinine, must be tailored to the patient's complaints and risk factors.

Self-Reported Questionnaires and Laboratory Investigations

The most commonly used validated questionnaires are the 15-item International Index of Erectile Function (IIEF) or an abridged 5-item version (IIEF-5) more suited for office use. Sexual domain functions measured by the IIEF include erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. These tools are useful to determine baseline erectile function and to assess the impact of a specific treatment modality. ED severity is classified into five categories based on the IIEF-5: severe (5–7), moderate (8–11), mild to moderate (12–16), mild (17–21), no ED (22–25) (Rosen, 2004).

The physician should review the findings, inquire about the goals and preferences of the man (and his partner), and discuss further diagnostic and therapeutic options such that his (or their) participation in the decision-making process is well informed. For a minority of patients, referral for further testing and/or assessment may be appropriate. Indications for referral include patient request, treatment failure, complex gonadal or other endocrine disorders, neurologic deficits suggestive of brain or spinal cord disease, deep-seated psychologic or psychiatric problems, and active cardiovascular disease. Patients deemed to be at intermediate or higher cardiac risk (cardiac status uncertain, moderate-to-severe symptoms, or unable to perform exercise of modest intensity) should be assessed by a cardiologist/internist and sexual activity deferred until cardiac condition is stabilized or resumption of sexual activity is deemed safe by the consultant. Low-risk patients, those able to perform exercise of modest intensity (six or more metabolic equivalents) without symptoms, do not generally require cardiologic assessment (Jackson et al, 2006).

Follow-Up Strategy

Regardless of the treatment regimen chosen, follow-up is essential to ensure optimal outcomes. Modification of life style, diet change, regular exercise, and smoking cessation should be reassessed and encouraged at each clinic visit. Monitoring adverse events, assessing satisfaction or failure with a given treatment, identifying a partner's sexual dysfunction, and assessing overall health and psychosocial function are key considerations. In patients who do not respond to first-line therapy (oral PDE-5 inhibitor therapy), consideration should also be given to whether an alteration in dose or treatment might be of value, as most second- and third-line options have demonstrated reasonable response and satisfaction rates in controlled studies (Lue et al, 2004).

Advanced Testing for Erectile Dysfunction

For patients with more complex problems, including penile deformity, history of pelvic or perineal trauma, ED of unknown etiology, cases requiring vascular or neurosurgical intervention, complicated endocrinopathy, complicated psychiatric disorder, complex relationship problems, and medicolegal concerns or at the patient's request, a variety of vascular and neurologic diagnostic tests are available to identify the cause of ED or plan treatment (Table 39–4).

Table 39–4. Tests Suggested for Various Treatment Options.a

Table 39–4. Tests Suggested for Various Treatment Options.a

Oral medication, transurethral therapy, or vacuum constriction device
No further testing
Intracavernous injection therapy
CIS test
Penile prosthesis
CIS test or NPT test or duplex scanning
Venous surgery
CIS test
Duplex scanning or cavernous arterial occlusion pressure test
Cavernosometry and cavernosography
Arterial surgery (or combined arterial and venous surgery)
CIS test
Duplex scanning or cavernous arterial occlusion pressure
Cavernosometry and cavernosography
Pharmacologic arteriography

CIS, combined injection and stimulation; NPT, nocturnal peniletumescence.

aRegardless of desired treatment, all patients must undergo his-tory, physical examination, and basic laboratory testing.

Tests for Penile Vascular Function

The goal of vascular evaluation is to identify and evaluate arterial and veno-occlusive dysfunction. The most commonly utilized tests include combined intracavernous injection and stimulation (CIS), duplex ultrasound, dynamic infusion cavernosometry and cavernosography (DICC), and selective penile angiography. A test for endothelium dependent flow-mediated dilation of the brachial artery has been proposed but will not be discussed here because it is not specific for penile function (Yavuzgil et al, 2005).

Combined Intracavernous Injection and Stimulation Test

This is a commonly performed diagnostic procedure for ED. It consists of an ICI, visual or manual sexual stimulation, and a rating of the subsequent erection. Before injection, the patient should be informed about the purpose, alternatives, risks, and benefits of the test. Neurogenic and hormonal influences are bypassed, as the vascular status of the penis is assessed by direct injection of medication into the corpus cavernosum. The most commonly used vasodilator is 10 μg of alprostadil or 0.3 mL of a mixture of papaverine and phentolamine. A rigid erection lasting >10 minutes is indicative of normal venous function. However, the same conclusion cannot be made for arterial function, as some men with mild arterial insufficiency can also have the same response. Although some researchers have modified this test by using an oral PDE-5 inhibitor and audiovisual sexual stimulation, the normal criteria have not been established.

Color Duplex Ultrasonography

Color duplex ultrasound, the most popular vascular assessment of ED, is utilized when accurate vascular diagnostic testing is indicated. It consists of an intracavernous pharmaco-test and measurement of blood flow by color duplex ultrasound (Aversa and Sarteschi, 2007; Figure 39–4). High-resolution (7–12 MHz) real-time ultrasonography and color pulsed Doppler enable the ultrasonographer to visualize the dorsal and cavernous arteries selectively, perform dynamic blood flow analysis, and is the best tool available for the diagnosis of high-flow priapism and localization of a ruptured artery. Normal arterial response is a peak flow velocity measured at the base of penis of >30 cm/s, a sharp upstroke of the waveform and absence of diastolic flow after sexual stimulation. Ultrasound can also be used to detect penile abnormalities such as Peyronie's plaque, calcifications, thickened vessel walls, and intracavernous fibrosis. When the Doppler waveform exhibits high systolic flow (>30 cm/s peak systolic velocity [PSV]) and persistent end-diastolic flow velocity (EDV) >5 cm/s accompanied by quick detumescence after self-stimulation, the patient is considered to have venogenic impotence. The parameters useful in diagnosing venous leakage include a diastolic venous flow velocity of >5 cm/s and/or a resistive index (RI) of <0.75. RI = PSV−EDV/PSV.

Figure 39–4.

Color duplex ultrasonography analysis of the arterial response to intracavernous vasodilator injection. In a man with normal vascular response (A), the peak flow velocity of the cavernous artery is 89.69 cm/s with negative diastolic wave indicating that his intracavernous pressure is higher than his diastolic blood pressure. In another man with arterial disease (B), the peak flow velocity is 21.94 cm/s with positive diastolic wave.

The Pulsed Doppler Study is performed using the Midus portable unit, which is specifically designed for use in the urologist's office. Penile blood flow is evaluated in a fashion similar to duplex ultrasound by recording the waveform of the cavernous arteries without providing a real-time ultrasound image (UroMetrics, Anoka, MN).

Cavernosometry and Cavernosography

Pharmacologic cavernosometry involves ICI of a potent vasodilator combination (papaverine + phentolamine + alprostadil) followed by saline infusion and simultaneous monitoring of ICP to assess the penile outflow system. In men with normal venous function, the maintenance flow should be <10 mL/min at an ICP of 100 mm Hg and the rate ICP drops after infusion ceases should be <50 mm Hg in 30 seconds. Veno-occlusive dysfunction is indicated by either the inability to increase ICP to the level of the mean systolic blood pressure with saline infusion or a rapid drop of ICP after cessation of infusion.

Cavernosography is used to visualize the site of venous leakage. Following the induction of an artificial erection by ICI of vasodilators (activation of the veno-occlusive mechanism), diluted radiocontrast solution is infused into the corpora cavernosa (Mulhall et al, 2004). Minimal or no contrast is seen outside the corpora cavernosa with normal veno-occlusive function. In patients with venous leakage of congenital or traumatic origin, the leakage is seen most often in the crura or at the site of injury, respectively (Figure 39–5). Leakage sites to the glans, corpus spongiosum, superficial dorsal veins, and cavernous and crural veins can be detected. In the majority of patients, more than one site is visualized. The typical finding in men with intrinsic disease of the corpus cavernosum or the tunica albuginea is a diffuse leakage through all penile venous channels.

Figure 39–5.

Cavernosography after intracavernous injection of papaverine. In a normal man (A), the cavernosogram shows opacification of the erect corpora cavernosa and nonvisualization of penile veins. In (B), the patient has a large leak through both superficial dorsal veins (arrows) to the saphenous veins (arrowheads). Film (C) shows abnormal venous drainage via the cavernous veins (solid arrow) into the preprostatic plexus (open arrow) and the internal pudendal veins (arrowhead). (Reproduced, with permission, from Lue TF, Tanagho EA: Physiology of erection and pharmacological management of impotence. J Urol 1987;137:829. By Williams & Wilkins, 1987.)

Cavernous Arterial Occlusion Pressure

Cavernous arterial occlusion pressure, a variation of penile blood pressure measurement, involves infusing saline solution into the corpora after ICI of vasodilators to raise the ICP above the systolic blood pressure. A pencil Doppler transducer is then applied to the side of the penile base, saline infusion is stopped, and the ICP is allowed to fall. The pressure at which the cavernous arterial flow becomes detectable is defined as the cavernous artery systolic occlusion pressure (CASOP). A gradient between the cavernous and brachial artery pressures of <35 mm Hg and equal pressure between the right and left cavernous arteries are defined as normal.

Arteriography

Arteriography is reserved for the evaluation of the complex patient for whom revascularization surgery is contemplated; indications include the young patient with ED secondary to a traumatic arterial disruption or a patient with a history of perineal compression injury. The study is performed by ICI of a vasodilating agent (papaverine, papaverine + phentolamine, or alprostadil) followed by selective cannulation of the internal pudendal artery and injection of a diluted contrast solution of low osmolarity. The anatomy and radiographic appearance of the cavernous arteries is then evaluated (Figure 39–6), as are the iliac vessels, dorsal penile arteries, and the size and length of the inferior epigastric arteries.

Figure 39–6.

Internal iliac arteriogram in the flaccid penis (A) shows poor visualization of penile arteries, simulating occlusion (arrow). After intracavernous injection of 60 mg of papaverine (B), all the branches of the penile artery are well visualized.

Neurologic Tests

The effect of a neurologic deficit on penile erection is a complicated phenomenon and with few exceptions, neurologic testing rarely changes management. Testing is recommended for specific research protocols or medicolegal investigations, including cases of trauma or surgical complications, or can be used in selected cases to (1) uncover reversible neurologic disease such as dorsal nerve neuropathy secondary to long-distance bicycling, (2) assess the extent of neurologic deficit from a known neurologic disease such as diabetes mellitus or pelvic injury, and (3) determine whether a referral to a neurologist is necessary (eg, workup for possible spinal cord tumor). Based on best-available evidence, neurologic tests lack adequate sensitivity and reliability for routine clinical diagnosis.

Somatic nerves are evaluated by testing nerve conduction velocities and evoked potentials, and these tests have well-known reproducibility and validity. Autonomic function tests are less reliable because they simultaneously measure a chain of events or reactions involving receptors, small fibers, and target organs. The complex interactions among central and peripheral sympathetic and parasympathetic nerve systems make autonomic testing difficult. Currently available tests are not well standardized and lack validity, reproducibility, and comparability.

Biothesiometry

This test is designed to measure the sensory perception threshold to various amplitudes of vibratory stimulation produced by a hand-held electromagnetic device (biothesiometer) placed on the pulp of the index fingers, big toes, both sides of the penile shaft, and the glans penis.

Bulbocavernosus Reflex Latency

This test is performed by placing two stimulating ring electrodes around the penis, one near the corona and the other 3 cm proximal. Concentric needle electrodes are placed in the right and left bulbocavernous muscles to record the response to square-wave impulses delivered via a direct current stimulator. The latency period for each stimulus response is measured from the onset of the stimulus to the beginning of the response. An abnormal bulbocavernosus reflex (BCR) latency time, defined as a value >3 standard deviations above the mean (30–40 ms), carries a high probability of neuropathology.

Penile Thermal Sensory Testing

Thermal threshold measurements quantify conductance of small sensory nerve fibers, which can indirectly reflect autonomic disturbances in the context of diffuse neuropathies, such as diabetic polyneuropathy.

Nocturnal Penile Tumescence Test

Nocturnal erections, 80% of which occur during REM sleep, occur in healthy males of all ages and are relatively free of psychologically mediated effects. The average man has three to five episodes of nocturnal penile tumescence (NPT) each night, with episodes ranging from 30 to 60 minutes. Total NPT time declines with increasing age. Classically, NPT has been measured by several methods including the stamp test, snap or strain gauges, and sleep lab nocturnal penile tumescence rigidity (NPTR). Contemporary NPT testing is performed with simpler outpatient devices such as Rigiscan NPTR (Rigiscan; Timm Medical Technologies, Inc., Eden Prairie, MN). These newer devices electronically record the number, duration, rigidity, and circumference of penile erections: although sleep lab NPTR concurrently records nasal air flow; oxygen saturation; and electroencephalographic, -myographic, and -oculographic data to document REM sleep, hypoxia, and/or abnormal limb movement, it has been replaced by outpatient Rigiscan due to prohibitive expense.

NPT was originally designed to differentiate psychogenic from organic ED, as a full erection indicates a functionally intact neurovascular axis. In the United States, it is now mostly used in medicolegal or complicated cases, as well as for research purposes.

Psychological Evaluation

Psychogenic ED is defined as the persistent inability to achieve or maintain an erection satisfactory for sexual performance, which is due predominantly or exclusively to psychological or interpersonal factors. Clinical subtypes of psychogenic ED include generalized versus situational and lifelong (primary) versus acquired (secondary, including substance abuse or major psychiatric illness). The psychological and interpersonal dimensions of sexual function and dysfunction are complex; therefore, a skillful diagnostic interview is the mainstay of a good psychological evaluation. A suggestive history of psychogenic ED includes sudden onset, selective dysfunction (eg, rigid erection with one partner and poor erection with others, or normal erection during masturbation or fantasy but not during intercourse), and a normal pattern of nocturnal erections coupled with an abnormal pattern during waking hours. This is often associated with anxiety, guilt, fear, emotional stress, religious, or parental inhibition. If the medical and sexual histories suggest a combination of organic and psychological risk factors, these patients should be diagnosed as having mixed organic/psychogenic ED; successful treatment must address both components.

Although psychological consultation is not indicated for most patients, it is very useful in evaluating and treating men with deep-seated psychological problems. Three groups of psychometric instruments are commonly used: (1) personality questionnaires, (2) the depression inventory, and (3) questionnaires for sexual dysfunction and relationship factors. The Minnesota Multiphasic Personality Inventory (MMPI)-2 is a valuable tool for evaluating the patient's personality and its relevance to sexual dysfunction. The self-reported Beck Depression Inventory is a validated test for which a score exceeding 18 is considered indicative of significant clinical depression. Overall quality of relationships can be assessed using the Short Marital Adjustment Test (married couples) and the Dyadic Adjustment Inventory (unmarried individuals) (Mallis et al, 2005).

Nonsurgical Treatment of Erectile Dysfunction

Advances in pharmacologic therapy for ED have resulted in greater numbers of patients seeking primary and specialty care for sexual concerns. Oral PDE-5Is have emerged as the preferred first-line treatment of ED worldwide due to their efficacy, ease of use, and patient safety. Prior to their release, efficacious oral therapies for ED were unavailable and patient options were limited to nonspecific modalities including lifestyle modification, medication changes, vacuum devices, intraurethral agents, intracavernosal injection therapy, or penile prosthesis insertion. Over the last decade, nonsurgical approaches have replaced prosthetic surgery as the preferred choice of management. In most cases, nonspecific therapies appear to be more effective for ED; however, the patient should also be aware of specific therapies so that an informed treatment decision can be made.

Lifestyle Changes

The beneficial effect of lifestyle change (total body weight loss of 10% or more by reducing caloric intake and increasing physical activity) was demonstrated in a randomized, single-blinded trial of 110 obese men (body mass index ≥30) aged 35–55 years, without diabetes, hypertension, or hyperlipidemia, but with ED (a score of 21 or less on the IIEF). The mean IIEF score improved in the intervention group (from 13.9 ± 4.0 to 17 ± 5; p< .001), but remained stable in the control group who were given general information about healthy food choices and exercise (Esposito et al, 2004). The beneficial effect was reproduced in a larger study of 209 nonobese men randomly assigned to interventional versus control group (Esposito et al, 2009).

It is well known that ED is intimately related to the atherosclerotic coronary and peripheral vascular diseases, as well as the metabolic syndrome, characterized by central obesity, abnormal lipids, insulin dysregulation, and borderline hypertension. Regular exercise, a healthy diet, smoking cessation, and limiting use of alcohol can reduce the risk of ED or improve underlying dysfunction. A Mediterranean-style diet (fruits, vegetables, nuts, whole grain, olive oil, and decreased saturated lipids) has recently been shown to improve endothelial function scores and inflammatory markers (C-reactive protein) when compared with men on a control diet (Esposito et al, 2010). Obesity and smoking have been prospectively identified as risk factors for ED, while physical activity is inversely associated with the development of ED.

Perineal compression on penile arteries from long-distance cycling may also represent a modifiable risk factor for ED. Changing the bicycle seat or riding practices will often improve erectile function if penile vascular compromise is identified; specific strategies include replacing a protruding nose with a noseless seat, changing posture to a more upright/reclining position, using a gel saddle, and tilting the seat downward (Huang et al, 2005).

Changing Medications

When a patient complains of sexual dysfunction after taking a particular medication, it is important to determine whether the problem is related to loss of sexual drive, impaired erection, or rapid/delayed ejaculation. In many situations, changing the medication to a different class of agents is a feasible first step. Antihypertensive agents therapeutically lower blood pressure; this primary effect has long been thought the mechanism of their adverse actions on erection. Switching patients to agents including alpha-adrenoceptor antagonists, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors may reverse ED in some patients. Patients complaining of sexual dysfunction while taking antidepressants may benefit from substitution (bupropion, nefazodone, buspirone, mirtazapine), drug holidays, selective serotonin reuptake inhibitor (SSRI) dosage reduction, and/or PDE-5 inhibitors.

Psychosexual Therapy

Therapies such as PDE-5Is or ICIs may provide more rapid relief for patients with ED compared with a prolonged course of psychosexual therapy. However, in patients with evidence of psychological problems, referral to a psychologist or sex therapist is highly recommended because the elimination of a specific underlying cause may result in a cure. Recent approaches to sex therapy have included cognitive-behavioral interventions focused on challenging or correcting maladaptive cognitions, behavioral techniques (desensitization and assertiveness exercises), exploration of past developmental experiences on present behavior, and couples' therapy. Moreover, in some patients with mixed psychogenic and organic ED, psychosexual therapy may help relieve the anxiety and remove unrealistic expectations associated with medical or surgical therapy.

Hormonal Therapy

Referral to an endocrinologist is recommended for patients with thyroid, adrenal, pituitary, or hypothalamic dysfunction. Aging men with ED may show a variety of symptoms when hypogonadism coexists: low libido, depression, decreased intellectual abilities, lean body mass, bone mineral density, or skin turgor, changes in body hair distribution, changes in sleep patterns, and increased visceral fat. In the patient with documented hypogonadism and ED, it is reasonable to initiate androgen therapy; for hypogonadal patients unresponsive to PDE-5 inhibitor therapy alone, the addition of testosterone may enhance the treatment effect and improve erectile function (Morales, 2005). This discussion is limited to treatment of hypogonadism and hyperprolactinemia as they relate to ED.

Parenteral depo-preparations of testosterone (T), such as testosterone cypionate and enanthate, are the least expensive form of androgen supplementation and are effective in restoring serum levels to normal. A normal circadian rhythm is not replicated by these agents. Rather, they are administered through deep intramuscular injection (200–250 mg every 2 weeks) and result in supraphysiologic levels of T for 72 hours with steady exponential decline to subphysiologic levels in 10–12 days; the initial supraphysiologic “rush” may be disconcerting to some patients, but others enjoy an improved sense of well-being, aggression, and libido.

Transdermal delivery more closely simulates normal circadian levels of testosterone if patients apply a patch in the morning, as the higher initial absorption mimics normal diurnal variations. Several U.S. Food and Drug Administration (FDA)-approved preparations are available in the United States. Testoderm TTS, which has largely replaced the Testoderm scrotal patch, is convenient to use, as it is applied daily to the arm, back, or upper buttocks as a 5-mg patch. Another product, Androderm, comes as a patch that delivers 2.5 or 5 mg T per day. The most common adverse reactions to both are itching, chronic skin irritation, and allergic contact dermatitis. Patients should alternate application sites and avoid sun-exposed areas. Local application of cortisone cream may relieve irritated skin. AndroGel is a 1% gel pack (containing 50 mg, 75 mg, or 100 mg of T), which is also applied daily in the morning to clean, dry skin over the shoulders, upper arms, or abdomen. Hands should be washed thoroughly after application, as skin contact can transmit testosterone. Testim topical gel also contains 1% T, providing continuous transdermal delivery for 24 hours after a single application to intact, clean, dry skin of the shoulders and upper arms. One 5-g tube of Testim contains 50 mg of testosterone.

When taken orally, methyl testosterone preparations are largely rendered metabolically inactive during “first pass” circulation through the liver. The large dosages (exceeding 200 mg/d) required to achieve therapeutic levels can be hepatotoxic, leading to hepatitis, cholestatic jaundice, hepatomas, hemorrhagic liver cysts, and hepatocarcinoma. Although unavailable in the United States, the only orally active and safe form of T is Andriol (testosterone undecanoate [TU] in oleic acid), which, owing to its lipophilic side chain, is partly taken up by the lymph and partially escapes hepatic inactivation. The maximal plasma concentration is generally observed within 2–3 hours, but after 6–8 hours, levels have returned to pretreatment values. A dosage of 40 mg three times a day generally provides adequate androgen replacement, yielding T levels within the (low) normal range, whereas dihydrotestosterone (DHT) levels are moderately increased (2–4 nmol/L). Absorption varies with food consumption and the dose required should be based upon plasma levels and clinical effects. Other FDA-approved delivery systems include Testopel subcutaneous pellets (dosage of 2–6 pellets [150–450 mg T]), which lasts for 4–6 months, and Striant, a tablet-like mucoadhesive buccal system used to deliver 30 mg of T twice daily.

In patients with hyperprolactinemia with or without hypogonadism, androgen therapy does not improve sexual function. Treatment should first be aimed at eliminating the offending drugs, such as estrogens, sedatives, neuroleptics, or morphine. Bromocriptine, a dopamine agonist that lowers prolactin levels and restores T to normal, is used to reduce the size of prolactin-secreting adenomas. Surgical ablation may occasionally be required if the bromocriptine response is unsatisfactory or if visual field changes secondary to optic nerve compression occur.

Potential Adverse Effects of Testosterone Replacement

Testosterone replacement is clearly the treatment of choice for young hypogonadal men without contraindications. However, the potential risks of androgen therapy may outweigh the benefits for some patients. Supraphysiologic levels of T suppress LH and FSH production and can lead to infertility, breast tenderness, and gynecomastia. Erythrocytosis is the most common laboratory alteration noted with long-term therapy; increases in red cell mass, thromboxane A2, and platelet aggregation may increase cardiovascular risk. Androgens may also induce or worsen sleep apnea. Long-term therapy requires a commitment from the patient and the specialist for continued follow-up, as outlined in the following.

Regarding prostate safety, a number of studies in the literature suggest that androgen replacement does not induce prostate cancer in men with normal prostates, and placebo-controlled studies show little difference in prostate volume, PSA, and obstructive symptoms. No increased risk of prostate cancer has been noted in (1) clinical trials of T supplementation, (2) longitudinal population-based studies, or (3) in a high-risk population of hypogonadal men receiving T treatment (Morgentaler, 2006). Although the fear of exacerbating an occult cancer of the prostate remains a concern, many older hypogonadal patients whose libido and erectile function can be restored by T therapy likely should not be denied this treatment option. When a patient desires T replacement, a digital rectal examination and a serum PSA level should be obtained. When in doubt, ultrasound-guided biopsy is performed before T therapy is given. The presence of prostate or breast cancer is an absolute contraindication to androgen supplementation. Patients are followed every 6 months with a rectal examination and serum PSA indefinitely while on therapy. Laboratory surveillance should also include hemoglobin/hematocrit levels, liver function tests, and cholesterol and lipid profile. The efficacy of supplementation is determined by clinical response rather than blood levels of testosterone.

Oral Pharmacologic Therapy

Phosphodiesterase Inhibitors

Sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis), the three selective PDE-5Is currently approved for clinical use in the United States, have become the preferred first-line therapy for most men with ED due to their efficacy, safety, and ease of use. All are highly effective in enhancing erectile function across a wide range of outcome measures, causes of ED, patient subgroups, and regional populations. The three PDE-5Is appear to have equivalent efficacy in the treatment of ED, are generally well tolerated, and have similar contraindications and warnings (Carson and Lue, 2005).

Mechanism of Action

Sexual stimulation results in the release of NO from nerve endings and vascular endothelial cells in the penis, which then diffuses into vascular and cavernous smooth-muscle cells of the corpus cavernosum. Stimulation of guanylyl cyclase by NO elevates levels of cGMP, lowering cytoplasmic calcium and resulting in smooth-muscle relaxation and subsequent penile erection. PDE-5Is amplify the NO-cyclic cGMP pathway through competitive inhibition of cGMP degradation by type 5 phosphodiesterase. Without sexual stimulation and resultant NO release, however, these inhibitors are ineffective.

Clinical Efficacy

The clinical efficacy and safety of sildenafil, vardenafil, and tadalafil has been evaluated in many placebo-controlled, double-blinded trials and open label studies (Brock et al, 2002; Carson and Lue, 2005; Goldstein et al, 1998; Porst et al, 2003). Treatment effect was principally assessed by items 3 and 4 of the IIEF-15 questionnaire (ability to attain and maintain erection, respectively). For sildenafil, improvements in erectile function were reported by 56–84% of subjects taking 25–100 mg of sildenafil versus 25% in the placebo group. Little ED benefit and considerably more side effects were noted above 100 mg. For specific etiologies, sildenafil was effective in 70% of hypertensive patients, 57% of diabetic patients, 43% of radical prostatectomy patients, and 80% of spinal cord injury patients. The efficacy of vardenafil was similarly evaluated with 10-mg and 20-mg dose. Mean IIEF scores increased from 12.8 at baseline to 21 at week 12 of treatment (compared with 13.6 to 15.0 for placebo). Similarly, integrated phase III studies of tadalafil involving 1112 patients demonstrated IIEF erectile domain scores of 24 in men receiving a 20-mg dose versus 15 for placebo. More than 70% of intercourse attempts were successfully completed from >30 minutes to 36 hours after dosing. For difficult to treat groups, including diabetics, severe ED, and postradical prostatectomy, the three PDE-5Is represent effective therapies for many men.

Time of Onset

The onset of activity, in reports with similar methods, is 14 minutes with sildenafil, 10 minutes with vardenafil, and 16 minutes with tadalafil. However, success rates after 20 minutes are much less than after 1 hour; therefore, if patients do not experience a rapid beneficial effect, they should be advised to delay sexual intercourse for one (sildenafil or vardenafil) or 2 hours (tadalafil)—when serum concentrations have peaked. High-fat meal intake has been shown to delay absorption of vardenafil and sildenafil; this effect is not seen with tadalafil (Carson and Lue, 2005).

Period of Efficacy

Tadalafil therapy has a broader window of clinical responsiveness than either sildenafil or vardenafil because of its longer half-life (17.5 vs 4–5 hours for sildenafil or vardenafil). Tadalafil enhances erectile function in men with ED for up to 36 hours and may mean less planning and pressure to have sexual intercourse according to a schedule.

Adverse Events

Eleven distinct families (PDE-1–PDE-11) are known to have or are implicated in a broad range of cellular functions. PDE-5 is present in high concentrations in the smooth muscle of the penile corpora cavernosa. Sildenafil and vardenafil cross-react slightly with PDE-6, that is, the IC50s for PDE-5 are only four- to tenfold lower than those for PDE-6. This may explain why some patients using sildenafil complain of visual disturbances. Tadalafil minimally cross-reacts with PDE-11. Most side effects associated with PDE-5Is result from inhibition of PDE-5 in other tissue or organs. In randomized controlled trials, flushing (10%) and visual side effects were more common in patients receiving sildenafil or vardenafil, and back pain/myalgia (1–4%) was more common for tadalafil users. These events were mostly mild, abated with time (within 2–4 weeks), and prompted treatment discontinuation in only a small number of patients (Brock et al, 2002; Goldstein et al, 1998; Porst et al, 2003). Except for visual disturbances, the other reported side effects of PDE-5Is (headaches 15%, flushing, rhinitis 5–10% for vardenafil and sildenafil, slight lowering of blood pressure, dyspepsia, etc.) are likely caused by PDE-5 inhibition in vascular or gastrointestinal smooth muscle.

ED is common among men who have atherosclerotic coronary artery disease. With regard to overall cardiac safety, controlled and postmarketing studies of the three FDA-approved PDE-5Is demonstrated no increase in MI or death rates in double-blinded, placebo-controlled, or open-label studies when compared with expected study population rates. Patients who develop angina during sexual activity with a PDE-5I should discontinue sexual activity, relax for 5–10 minutes and if pain persists, seek emergency care and inform emergency medical personnel that a PDE-5I was taken. Patients who have an acute MI after a PDE-5I may be given standard therapies (except for organic nitrates). Nitroglycerin should not be given with 24 hours of sildenafil or vardenafil use, or 48 hours for tadalafil. Patients who develop hypotension after organic nitrates and PDE-5Is should be placed in the Trendelenburg position and given IV fluids, with alpha-agonists (such as phenylephrine) added as needed. In patients with refractory hypotension, intra-aortic balloon counterpulsation should be administered, as suggested by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines. At present, there is no pharmacologic antidote to the PDE-5 inhibitor/nitrate interaction (Kostis et al, 2005).

Because of its effect on QTc interval, vardenafil is not recommended for patients who take type-1A antiarrhythmics (such as quinidine or procainamide), type-3 antiarrhythmics (such as sotalol or amiodarone), or with congenital prolonged QT syndrome.

Finally, there have been reports of the development of nonarteritic anterior ischemic optic neuropathy (NAION) in men using PDE-5Is. Epidemiologically, NAION is the second most common acquired optic neuropathy in men aged 50 years and older. Risk factors for NAION, cardiovascular disease, and ED are shared and include age, dyslipidemia, diabetes, hypertension, and cigarette smoking. Given the large number of men safely using these agents and a limited number of events, it is not possible to determine whether NAION is directly linked to the use of PDE-5Is. Nevertheless, physicians should continue to advise patients to stop use of a PDE-5 inhibitor and seek immediate medical attention in the event of a sudden loss of vision as a safety measure (Laties, 2009).

Warnings and Drug Interaction

PDE-5Is are contraindicated for patients using nitrates, as a precipitous and potentially life-threatening hypotensive episode may occur with concurrent use. PDE-5Is are either not recommended or are to be used with caution in men with unstable angina, cardiac failure, recent MI, uncontrolled or life-threatening arrhythmia, or poorly controlled blood pressure (resting BP <90/50 mm Hg or >170/100–110 mm Hg). Caution is also advised when an alpha-blocker and a PDE-5 inhibitor are given together, as interaction can lead to excessive vasodilation and hypotension.

Starting Doses

The recommended starting doses are 50 mg for sildenafil and 10 mg for vardenafil and tadalafil. The dose may be increased to 100 mg (sildenafil) or 20 mg (vardenafil and tadalafil) or decreased to 25 mg or 5 mg, respectively, based on individual efficacy and tolerability. Several reports have shown that daily dose of 5 mg of tadalafil was able to reduce side effects while matching the effectiveness of 20 mg of tadalafil taken as needed (Seftel et al, 2009). Patients should also be counseled to trial a PDE-5I several times before declaring it “ineffective”; for instance, the cumulative probability of success with sildenafil increases with the first nine to ten attempts, after which it stabilizes (McCullough et al, 2002).

Centrally Acting Oral Agents

Apomorphine is a proerectile D1/D2 dopamine receptor agonist, but it may also stimulate 5-HT(2C) receptor to enhance penile erection (Kimura et al, 2008). Uprima, a sublingual form designed for buccal absorption, has been approved for ED in Europe (but not in the United States) and reported to induce erection in 67% of men with psychogenic ED. Apomorphine has a rapid onset of action, with a window of sexual opportunity of approximately 2 hours from ingestion. Maximal plasma concentrations are reached in 50 minutes. In a double-blind placebo-controlled study of 2- and 4-mg dosages, erections firm enough for intercourse were reported by 45% and 55% of patients, respectively, with placebo responses of 35% and 36%. Adverse events included nausea 16.9%, dizziness 8.3%, sweating 5%, somnolence 5.8%, yawning 7.9%, and emesis 3.7%. There were no documented food/drug interactions in clinical trials (with the exception of ethanol) and, specifically, no documented pharmacologic interactions for subjects using nitrate drugs.

Yohimbine is a centrally acting alpha-2-adrenergic antagonist that is not recommended for use in the treatment of ED by the 2005 American Urological Association (AUA) guidelines. Side effects include gastrointestinal intolerance, palpitations, headache, agitation, anxiety, and increased blood pressure (precautions are advised in men with cardiovascular disease). Trazodone is also not recommended; efficacy in pooled analyses was statistically equivalent to placebo. Side effects include drowsiness, nausea, emesis, blood pressure changes (both hypotension and hypertension are reported), urinary retention, and priapism (especially at therapeutic antidepressant levels) (Montague et al, 2005).

Transurethral Therapy

Alprostadil, a synthetic formulation of prostaglandin E-1, is the only FDA-approved pharmacologic agent approved for the management of ED via intracavernous and transurethral routes. After absorption from the urethra to the corpus spongiosum and then corpus cavernosum, alprostadil stimulates adenyl cyclase to increase intracellular levels of cAMP and lower levels of intracellular calcium, thereby relaxing arterial and trabecular smooth muscle. MUSE (medicated urethral system for erection) consists of a small semisolid pellet (3 × 1 mm) administered into the distal urethra (2–3 cm) by a proprietary applicator (MUSE; VIVUS Inc., Menlo Park, CA). Clinical studies showed that 66% of men responded to in-office trials; however, postmarketing studies have produced less successful results of about 50% (Mulhall et al, 2001). Penile rigidity can be enhanced by placing an elastic ring at the base of the penis (ACTIS, VIVUS Inc.) to mechanically assist veno-occlusion. Penile and/or scrotal pain or discomfort is a ubiquitous side effect of alprostadil-based therapies and is clearly dosage related and was reported in 33% of men in MUSE trials. Hypotension and syncope have been noted in 1–5.8% of patients, thus mandating initial trial dose administration in the office setting. Some female partners also report vaginal discomfort (about 10%) after ejaculation by a man using MUSE.

Intracavernous Injection

ICI of vasoactive drugs is considered the most effective nonsurgical therapy for ED. It remains the first-line therapy for select patients and a valuable treatment option for PDE-5I nonresponders or those that cannot tolerate side effects of oral agents. ICI treatment offers several potential advantages to the patient, including a rapid onset of action, essentially no systemic side effects and drug interactions, and dependable efficacy for all forms of ED. Men who have failed first-line oral pharmacotherapy constitute the largest group of ICI-treated patients, with a significant erectile response rate of >80% demonstrated among PDE-5I nonresponders indicating that progression to second-line injection therapy is appropriate. A list of drugs that have been used clinically is presented in Table 39–5, and the most commonly used agents and combinations are discussed later.

Table 39–5. Intracavernous Vasodilator Injection Therapy.a

Table 39–5. Intracavernous Vasodilator Injection Therapy.a

Drug

Test dose

Therapeutic dose

Papaverine

15–30 mg

15–60 mg

Alprostadil

5–10 μg

5–60 μg

Papaverine (30 mg) + phentolamine (1 mg)

0.1–0.3 mL

0.1–1 mL

Papaverine (30 mg) + phentolamine (1 mg) + alprostadil (10 μg)

0.1–0.3 mL

0.1–1 mL

aLower doses for management of neurogenic and psychogenic impotence.

Papaverine

Papaverine, an alkaloid isolated from the opium poppy, induces relaxation of cavernous smooth muscle and penile vessels via nonspecific inhibition of phosphodiesterase. It is metabolized by the liver, with a plasma half-life of 1–2 hours. Monotherapy doses range from 15 to 60 mg. Advantages include low cost and stability at room temperature, while adverse effects include priapism (up to 6%), corporal fibrosis (6–30%; thought to be associated with poor technique, minimal injection site compression time, >1 cc injection volume, pH 3–4), and occasional elevation of liver enzymes (Bella and Brock, 2004).

Alprostadil (Prostaglandin E1)

Alprostadil causes smooth-muscle relaxation, vasodilation, and inhibition of platelet aggregation through elevation of intracellular cAMP. It is metabolized by the enzyme prostaglandin 15-hydroxydehydrogenase, which has been shown to be active in human corpus cavernosum. After ICI, 96% of alprostadil is locally metabolized within 60 minutes and no change in peripheral blood levels is observed. Alprostadil have been approved by the FDA for intracavernous therapy as Caverject (Pfizer, NYC) and Edex (Schwarz Pharma, Milwaukee, WI). Cumulative data yield a success rate of 70–75% across ED etiologies, utilizing a median dose of 12–15 mg. Common adverse effects include pain at the injection site or during erection (11–15%), small hematoma or bruising, penile fibrosis (1–3%), and burning sensation at the time of injection. Rates of priapism are low (1–3%) and systemic side effects are rare (Bella and Brock, 2004).

Drug Combinations

The most commonly used drug combinations for ICI in the United States are bimix (papaverine/phentolamine) and trimix (papaverine/phentolamine/alprostadil) in various concentrations (Montorsi et al, 2010). A combination of vasoactive intestinal polypeptide and phentolamine has also been used in other countries. Multiple series have demonstrated patient satisfaction rates of >75% and low rates of priapism or fibrosis. Side effects are reduced, as smaller amounts of each agent are required, and the targeting of multiple pathways increases therapeutic efficacy.

Adverse Effects

Priapism and fibrosis are the two serious side effects associated with ICI therapy. Priapism occurred in 1.3% of 8090 patients in 48 studies with alprostadil, which is about five times lower than with papaverine or bimix (Linet and Ogrinc, 1996). Fibrosis can occur as a nodule, diffuse scarring, plaque or curvature. Scar tissue can be prevented by >5 minutes compression of the injection site to reduce bleeding and trauma. Priapism is best prevented by careful dosage titration.

Dosage and Administration

Patients must have the first injection performed by medical personnel and receive appropriate training and education before home injection. An initial dose of 2.5 μg for alprostadil is recommended. If the response is inadequate, increases in 2.5-μg increments can be given until a full erection is achieved or a maximum of 60 μg is reached. For drug combinations, treatment is initiated with a small dose (eg, 0.1 mL) and titrated according to erectile response. The goal is to achieve a full erection of <1-hour duration to avoid priapism.

Treatment of Prolonged Erection or Priapism

The best treatment is prevention; prolonged erections, a potentially devastating adverse effect of ICI, are often secondary to rapid dose escalation by the patient, missed initial injection with second attempt, or use among neurogenic and/or young patients. It is imperative that the clinician prescribing intracavernous therapies emphasizes to the patient that priapism represents a urologic emergency, and any erection lasting >4 hours necessitates urgent medical evaluation. The best regimen for averting priapism is ICI of diluted phenylephrine 250–500 μg every 3–5 minutes until detumescence. In patients with cardiovascular disease, monitoring of blood pressure and pulse is recommended (Montague et al, 2003). If the priapism lasts for more than 2–3 days, T-shunt with intracavernous tunneling may be required (Brant et al, 2009).

Contraindications

ICI is contraindicated in patients with sickle cell anemia, schizophrenia, or a severe psychiatric disorder. Because monoamine oxidase (MAO) in involved in catecholamine (including phenylephrine) metabolism, if a man on an MAO inhibitor developed prolonged erection/priapism after ICI, a simple T-shunt might be a better treatment than ICI of phenylephrine. For patients using an anticoagulant or aspirin, compressing the injection site for 7–10 minutes after injection is recommended. In patients with poor manual dexterity, the sexual partner can be instructed to perform the injection.

Vacuum Constriction Device

The vacuum constriction device consists of a plastic cylinder connected directly or by tubing to a vacuum-generating source (manual or battery-operated pump). Only devices containing a vacuum limiter should be used, as injury to the penis may occur with extremely high negative pressures (Montague et al, 2005). After the penis is engorged, a constricting ring is applied to the base to maintain the erection. The ring may be uncomfortable or painful; to avoid injury, it should not be left in place for <30 minutes. The erection produced differs from a physiologic or ICI-induced erection as the portion of the penis proximal to the ring is not rigid, which may result in a pivoting effect. The penile skin may be cold and dusky, and ejaculation may be trapped by the constricting ring. Complications include penile pain and numbness, difficult ejaculation, ecchymosis, and petechiae. Patients taking aspirin or Coumadin should exercise caution when using these devices.

In some patients, the device can produce an erection that is of sufficient rigidity for coitus or engorge the glans for men with glanular insufficiency. In patients with severe vascular insufficiency, the device may not produce adequate erection. Although it is a safe and less costly means of treating ED when used properly, low patient acceptability limits the application or use of this therapy.

Penile Vascular Surgery

Isolated stenosis or occlusion of extrapenile arteries may be amenable to surgical repair. Arterial reconstructive surgery is a treatment option for healthy men, usually aged 55 or younger, with acquired ED secondary to focal arterial occlusion and the absence of severe veno-occlusive disorder or generalized vascular disease secondary to hyperlipidemia, diabetes mellitus, chronic hypertension (Montague et al, 2005). The most commonly used technique for penile revascularization is a bypass from the inferior epigastric artery to the dorsal artery or deep dorsal vein of the penis.

Penile venous surgery is also indicated only in young men with congenital or traumatic venous leakage. In congenital venous leakage, the venous insufficiency is typically through abnormal crural veins or superficial dorsal vein and is amendable to surgical cure. Traumatic venous leak is usually due to localized damage to the tunica albuginea or formation of a “fistula” between the corpus cavernosum and corpus spongiosum. Repair of the tunica or closure of the fistula can result in significant improvement of erectile function. In older men with chronic systemic diseases, venous leakage is usually caused by atrophy of the cavernous smooth muscle and degeneration of tunica albuginea; ligation of penile vein will only produce transient improvement and is not recommended.

Penile Prosthesis

Patients considered for prosthesis implantation should be made aware of types of prosthesis available, efficacy, and potential complications including infection, mechanical failures, cylinder or tubing leaks, perforation, persistent pain, penile shortening, and autoinflation. Penile prostheses are divided into three general types: malleable (semirigid), mechanical, and inflatable devices. The malleable devices are made of silicone rubber, and several models contain a central intertwined metallic core. The mechanical device is also made of silicone rubber but contains polytetrafluoroethylene-coated interlocking polysulfone rings in a rod column, which provides rigidity when the rings are lined up in a straight line and flaccidity when the penis is bent. Inflatable (hydraulic) devices are further divided into two-piece and three-piece devices. Two-piece inflatable prostheses consist of a pair of cylinders attached to a scrotal pump reservoir. The most commonly used device, the three-piece inflatable penile prostheses, consists of paired penile cylinders, a scrotal pump, and a retropubic fluid reservoir (Table 39–6).

Table 39–6. Types of Penile Protheses.

Table 39–6. Types of Penile Protheses.

Semirigid

American Medical System (AMS) Spectra

Coloplast genesis

Two-piece inflatable

AMS Ambicor, Coloplast Excel

Three-piece inflatable

Coloplast Titan and Titan OTR

AMS 700 MS series: CX, CXR, LGX

In general, the malleable devices last longer than the inflatable ones. Modern three-piece prostheses are extremely durable and reliable. However, patients should be informed that a 5–15% failure rate is expected within the first 5 years for inflatable implants, and the majority of devices will fail in 10–15 years and need replacement. Patient satisfaction with the three-piece device is high, exceeding 85–90% in appropriately selected patients. Recent innovations in penile prosthetics include antibiotic- and hydrophilic-coated devices (infection rate <1%), lockout valves to prevent autoinflation, and a more patient-friendly pump (Knoll et al, 2009; Wolter and Hellstrom, 2004).

Male Sexual Dysfunction Involving Emission, Ejaculation, and Orgasm

Physiology of Emission, Ejaculation, and Orgasm

Different mechanisms are involved in erection, emission, ejaculation, and orgasm, and these events can be dissociated from one another (eg, a frequent complaint of men with ED is ejaculating through a “limp penis”). Except for nocturnal emissions, or “wet dreams,” emission and ejaculation require stimulation of the external genitalia. Impulses traveling from the pudendal nerves reach the upper lumbar spinal sympathetic nuclei. Efferent signals traveling in the hypogastric nerve activate secretions and transport sperm from the distal epididymis, vasa deferentia, seminal vesicles, and prostate to the prostatic urethra. Coordinated closing of the internal urethral sphincter and relaxation of the external sphincter direct the semen into the bulbous urethra (emission). Subsequent rhythmic contractions of the bulbocavernosus muscles force the semen through a pressurized conduit—the constricted urethral lumen compressed by the engorged corpus spongiosum—to produce the 2–5-mL ejaculate. The external ejaculation process involves the somatomotor efferent of the pudendal nerve to contract the bulbocavernosus muscle. Since this action is involuntary, however, integrated autonomic and somatic action is required.

The mechanism of orgasm is the least understood of the sexual processes. It probably involves cerebral interpretation and response to sexual stimulation. Along with emission and ejaculation, several nongenital responses also occur. These include involuntary rhythmic contractions of the anal sphincter, hyperventilation, tachycardia, and elevation of blood pressure.

Disorders Affecting Ejaculation, Emission, and Orgasm

Premature or rapid ejaculation, a persistent or recurrent occurrence of ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it, is reported by up to 20–30% of men (Althof, 2006). Some propose that the definition of premature ejaculation should include rapidity of ejaculation, lack of control, and negative consequences (McMahon et al, 2008). In addition to psychotherapy or behavioral therapy, current guidelines suggest an SSRI, such as paroxetine (10–40 mg daily or 20 mg 3–4 hours before intercourse), may be used as pharmacotherapy for premature ejaculation, although this indication is not FDA approved (Montague et al, 2004). Penile sensitivity may be reduced with use of a condom or topical anesthetizing cream (lidocaine–prilocaine). Although time to ejaculation is prolonged, a significant percentage of men experience decreased pleasure (penile numbness) or loss of erection. A short acting SSRI, dapoxetine hydrochloride, has been developed for on-demand use in premature ejaculation but has not been approved by FDA. Its pharmacokinetic profile is characterized by rapid absorption, a short initial half-life of 1.3–1.4 hours and rapid elimination with minimal accumulation even after multiple dosing. Several large phase III studies have demonstrated that dapoxetine can increase intravaginal ejaculatory latency time and improve several patient-reported outcomes relevant to control of ejaculation and satisfaction with intercourse. The most common adverse events were nausea, dizziness, diarrhea, and headache. There were no signals for treatment-emergent anxiety or SSRI discontinuation syndrome after abrupt withdrawal (Owen, 2009).

Successful emission and ejaculation without orgasm occur in some patients with spinal cord injury. A history of disease or surgery is helpful in differentiating emission failure from retrograde ejaculation. If microscopic examination confirms the presence of sperm in bladder urine after a dry ejaculation, retrograde ejaculation can be diagnosed. If no sperm is found, emission failure is the cause. Bilateral sympathectomy at the L2 level may result in ejaculatory dysfunction in about 40% of patients while high bilateral retroperitoneal lymphadenectomy causes an even higher percentage of emission failures. Retrograde ejaculation is usually the result of dysfunction of the internal sphincter or the bladder neck, as seen after prostatectomy, with alpha-blocker therapy, and in autonomic neuropathy due to diabetes.

Elimination of alpha-adrenergic blockers may cure some patients with emission failure or retrograde ejaculation. Alpha-sympathomimetics, such as ephedrine or a combination of chlorpheniramine maleate and phenylpropanolamine hydrochloride (Ornade), have been used successfully in patients with retrograde ejaculation (McMahon et al, 2008). Electroejaculation via a rectal probe has been applied in patients suffering from spinal cord injury with some success. Psychosexual counseling is appropriate for patients who have normal wet dreams but cannot achieve orgasm and ejaculation.

Bibliography