Since the introduction of oral therapy, erectile dysfunction (ED) has become a widely publicized disease. These agents have revolutionized the management of ED and helped identify patients at risk for developing ED and other associated medical conditions. Since the erectile bodies of the penis are nothing more than a complex vascular structure, it has become evident that ED dysfunction may represent a local manifestation of widely systemic disease. Evaluation and management of the patient with ED may have a global impact on the overall health. With that in mind, this chapter represents a review of the current status of ED diagnosis, evaluation, and management.
The penis is composed of three main functional structures; two dorsal erectile bodies and one ventral urethra. The urethra functions to allow for the egress of urine and ejaculate. Whereas erectile bodies are vital biologic functions, they are not required for erectile functioning. Despite the anatomic association and proximity of the erectile bodies, urination, orgasm, emission, and erectile function can occur independently.
The corporal bodies are the functional units for penile tumescence. These two parallel structures are anchored proximally at the inferior puboischial rami. Initially, they are separate but fuse in the midline as the penis extends from the perineum. This proximal separation allows for the urethra to assume its position in the ventral midline by passing beneath the crus of the proximal corporal bodies. As the penis extends from the body, it is supported by the suspensory ligament of the penis. This ligament offers erectile support and facilitates directed penetration. The erectile bodies terminate distally beneath the glans penis which acts as a cap over the distal end. The glans penis is contiguous with the corpus spongiosum or spongy sinusoids that surround the penile urethra.
Another important and underestimated anatomic component for erectile function is the tunica albuginea of the cavernous body. This bilaminar casing has functionality based on its elasticity and pliability. In the flaccid state, the tunica albuginea is soft and relaxed. This allows for open venous drainage to the cavernous sinusoids. In contrast, during tumescence the longitudinal and circular fibers of the tunica albuginea occlude of the emissary veins restricting venous outflow. This leads to corporal filling during the erectile response and ultimately penile rigidity. If the tunica albuginea loses its elasticity, the occlusive process fails and venous leak ED ensues.
The primary arterial supply originates from the terminal branch of the internal iliac artery. This vessel, the internal pudendal artery, passes through Alcock’s canal and divides to give rise to the penile artery. The penile artery branches into the bulbar, urethral, and cavernous arteries. The cavernous artery provides the main arterial inflow to the corporal body. However, perforating branches of the dorsal artery can provide additional blood flow. This artery arises from the superficial branch of the inferior external pudendal artery.
Venous drainage of the erectile bodies originates from the emissary veins that perforate the tunica albuginea of the corporal bodies. These veins drain to the deep dorsal vein of the penis, which passes through the pelvic floor and into the prostatic venous plexus. This plexus will drain into the internal iliac venous system bilaterally.
Neurologic control of vascular inflow is heavily mediated by nonadrenergic noncholinergic (NANC) nerves from the cavernous nerves. These nerves supply the nitric oxide (NO) that leads to the profound vasodilation resulting in tumescence. The cavernous nerves arise from the pelvic plexus on the lateral aspect of the rectum. This plexus is a consolidation of the cholinergic, adrenergic, and NANC nerves supplying the pelvic and genital organs. The cavernous nerve arises from this plexus to penetrate the pelvic floor that is posterolateral to the urethra. It terminates in the corporal body. Injury to this nerve during pelvic surgery leads to ED.
Penile development requires two separate but overlapping organ systems to develop simultaneously. Both systems, genital and urinary, are needed for a fully functional male penis. Penile development is orchestrated by a complex interplay of developmental timing, hormonal regulation, and tissue interactions. The initiation of development of the external genitalia is the same in both males and females. During the fifth week of development, a pair of swellings develops on either side of the cloacal membrane. The cloacal folds meet just anterior to the cloacal membrane and form a midline swelling called the genital tubercle. In the seventh week, there is fusion of the urorectal septum with the cloacal membrane creating the primitive perineum. This divides the posterior anal membrane to form the urogenital membrane anteriorly. The cloacal fold flanking the urogenital membrane is now called the urethral fold (also known as the genital or urogenital fold). The new labioscrotal swellings appear after the urethral fold. During the sixth week, the cavity of the urogenital sinus extends onto the enlarging genital tubercle and becomes the urethral groove. This groove is temporarily filled by the urethral plate, which as the phallus grows recanalizes to form an even deeper urethral groove. The urogenital membrane ruptures during the seventh week opening the cavity of the urogenital sinus to the amniotic fluid. The genital tubercle elongates to form the penis. The coronary sulcus on the genital tubercle demarcates the primordial glans penis from the phallic shaft. The adult derivatives of these embryonic structures are listed in Table 44-1.1,2
The most popular hypothesis of external genital and urethral development was proposed by Glenister3 in 1954. At the start of the fourth month, the effects of androgens (especially dihydrotestosterone [DHT]) on the male external genitalia become apparent. The perineum elongates and the labioscrotal folds fuse in the midline to form the scrotum. As the penis elongates, the urethral folds grow toward the midline and enclose the penile urethra by 14-week gestation.3 The penile urethra is initially blind ending as the urethral groove that does not extend onto the glans penis which originated from the distal part of the genital tubercle. There is an ectodermal invagination from the tip of the glans that then completes the terminal portion of the penile urethra.
In the flaccid penis, the smooth musculature of the arterial and arteriolar walls of the corpora cavernosa is tonically contracted, allowing only a small amount of arterial flow for nutritional purposes.4,5 This state of moderate contraction is maintained by a combination of three main factors: intrinsic myogenic activity; endothelium-derived contracting factors such as prostaglandin I2, prostaglandin F2α, thromboxane A2, and endothelins; and α-adrenergic receptors on the arteries, arterioles, and cavernous trabeculae are stimulated by norepinephrine (NE) from sympathetic nerve endings.5,6,7,8,9
Sexual stimulation triggers release of neurotransmitters, principally NO, from the cavernous nerve terminals. NO released from NANC nerve endings and from the endothelium diffuses into smooth muscle cells activating guanylyl cyclase. This increases the production of intracellular cyclic guanosine monophosphate (cGMP) causes increased phosphorylation of myosin light-chain kinase resulting in dissociation of myosin and actin, which in turn results in relaxation of cavernous smooth muscle. Potassium influx is also induced through cGMP depended potassium channels and NO simulation of the Na-K ATPase. This increased potassium influx causes hyperpolarization, which leads to closure of voltage depended calcium channels and a decrease in intracellular calcium. Acetylcholine and vasointestinal peptide (VIP) likely play some role in cavernous smooth muscle relaxation during erections, but this seems to be secondary to the role of NO.8,10,11,12,13,14
The development and maintenance of erection is a complex mechanism dependent on smooth muscle relaxation involving both arterial dilation and sinusoidal relaxation causing venous compression.15,16 Dilation of the cavernous smooth muscle increases blood flow to the corporal bodies which initiates a well-studied cascade of events resulting in an erection.
The initial event is dilation of the arteries and arterioles increasing blood flow to the cavernous sinusoids. The resultant expansion of the cavernous sinusoids traps the incoming blood. Compression of the subtunical venous plexuses, peripheral sinusoids, and emissary veins from tunical stretching increases the intracavernous pressure to approximately 100 mm Hg and establishing a full erection. Contraction of the ischiocavernosus muscles leads to a further increase in pressure.
Detumescence after erection is likely is in part because of a combination of cessation of NO release and the breakdown on cGMP by phosphodiesterases. However, the sympathetic discharge during ejaculation is extremely important for return to the flaccid state. Norepinepherine’s action on α-receptors in the cavernous trabeculae and arteries seems to be the principal neurotransmitter in detumescence. Three hemodynamic phases of detumescence have been reported.17 First, a smooth muscle contraction initiated by norepinephrine against a closed venous system causes a transient intracorporeal pressure increase. Second, the resumption of basal arterial flow and a slow reopening of the venous channels result in a slow pressure decrease. Finally, a fully restored venous outflow capacity results in a fast pressure decrease and return of the penis to the flaccid state.
The prevalence of ED increases with age. The Massachusetts Male Aging Study (MMAS) is the only longitudinal study conducted in the United States. This study reports that the overall prevalence increases from about 40% of men in their forties to about 70% of men aging 70 years.18 The National Health and Social Life Survey (NHSLS) also estimated the prevalence of ED in men. This study reported dysfunction in 7% of men aging from 18 to 29 years, 9% for ages 30 to 39 years, 11% for ages 40 to 49 years, and 18% for ages 50 to 59 years.19 There were 24 international studies looking at the prevalence of ED between 1993 and 2003. All showed a rising prevalence when stratified by age, but the absolute prevalence varied widely. Almost all of the studies reported rates of less than 10% for men younger than 40 years and rates of 50% to 75% or higher for men older than 70 years.
The crude incidence rate in the United States was estimated by the Massachusetts Male Aging Study to be 25.9 cases per 1000 man-years. Incidence was also shown to be a function of age with the annual incidence rate increasing with each decade. Using these data, it is estimated that there would be over 600 000 new cases of ED in white men between the ages of 40 and 69 each year in the United States.20 Studies in South America and Europe also suggest incidence rates between 25 and 30 per 1000 man- years.21,22
The risk factors of ED are varied and include age, general health status, diabetes mellitus, cardiovascular disease, genitourinary disease, psychiatric or psychologic disorders, sociodemographic conditions, smoking, medications, hormonal factors, neurologic diseases, and other chronic diseases. Diabetes is associated with decreased libido, orgasmic dysfunction, and ED. Endothelial dysfunction is a common pathway for many cases of ED and is a manifestation of many of the above conditions.
Many classifications have been proposed based on the cause (diabetic, traumatic, iatrogenic, etc.) or mechanism (neurogenic, arterial, venous, etc.). The International Society of Impotence Research recommended a classification system in 1999 that is the most widely used classification scheme (Table 44-2).23 It is unlikely that any individual patient’s impotence is derived from a single source, and many cases have a significant psychologic component (Figure 44-1).
In the 1970s, this was believed to be the most common cause of ED and was thought to affect 90% of impotent men;24 however, it is now understood that ED is typically a mixed condition that is predominantly function or physical.
Centrally, erections are controlled by the hypothalamus, limbic system, and cerebral cortex. The spinal erection centers are controlled by these higher centers. The proposed mechanisms for psychogenic ED involve excessive direct inhibition of the spinal erection center by the higher centers and or excessive sympathetic outflow mediating an increase in penile smooth muscle tone.25,26,27,28
The medial preoptic area, paraventricular nucleus, and hippocampus are important integration centers for both sex drive and erection. Any pathologic state in these areas, such as Parkinson disease, stroke, encephalitis, epilepsy, trauma, or dementia, is frequently associated with ED.29,30
The innervation to the penis is both autonomic and somatic. The somatic nerves are primarily responsible for sensation and contraction of the bulbocavernosus and ischiocavernosus muscles. The parasympathetic innervation arises from the intermediolateral cell columns in the second, third, and fourth sacral cord segments and travels into the pelvic plexus. The sympathetic innervation originates from the 11th thoracic to 2nd lumbar spinal segments and passes to the sympathetic chain ganglia through the lumbar splanchnic nerves, inferior mesenteric, and superior mesenteric plexus to the hypogastric plexus. From there they travel to the pelvic plexus where they join the parasympathetic fibers and form the cavernous nerves.31 The location and extent of a spinal cord injury will largely determine the degree of the resultant erectile function. Although the thoracolumbar pathway may be compensatory, the sacral parasympathetic neurons mediate reflexogenic erections. Reflex erections are preserved in 95% of men with complete upper cord lesions, but only 25% of men with complete lower cord injuries.32,33
The cavernous nerves arise from the pelvic plexus and travel to innervate the penis. These nerves can be easily damaged during pelvic surgery, and a clear understanding of the course of these nerves is essential in order to preserve their function and prevent neurogenic ED after pelvic surgery.34,35 A more complete understanding of these pathways has resulted in a dramatically decreased incidence of ED following radical pelvic surgery for cancer.4
Any resistance to blood flow through the hypogastric-cavernosal arterial tree can decrease perfusion pressure and blood flow into the sinusoidal spaces. This leads to increased time to maximal erection and decreased rigidity. In the majority of patients, this is a single component of a more generalized atherosclerotic process. Vascular disease of penis is a local manifestation of more systemic disease. Common risk factors for penile arterial insufficiency and ED include hypertension, hyperlipidemia, cigarette smoking, diabetes mellitus, pelvic irradiation, and pelvic or perineal trauma. Many studies have shown that the patient age and incidence of ED parallel other arterial and atherosclerotic disease processes, especially coronary artery disease.18,36,37,38 In vasculogenic ED, corporal oxygen tension is decreased from baseline, and decreased from that seen in psychogenic ED.39 Formation of PGE2 is oxygen dependent, and chronic decreases in oxygen tension leads to lower levels of PGE2, and may diminish the corporal trabecular smooth muscle content and induce collagen synthesis leading to diffuse venous leakage.40,41,42,43 Endothelium-dependent release of NO and resultant smooth muscular vasodilatation has been shown to be further suppressed in patients with endothelial dysfunction due essential hypertension, elevated low-density lipoproteins, or diabetes.16,44 This leads to further suppression of penile blood flow with erectile stimulation independent of structural vascular changes.
Traumatic injury to the hypogastric, penile, or cavernosal arteries can result in chronic focal stenosis of the injured vessel. This is most commonly associated with young patients who have sustained blunt pelvic or perineal trauma, however, it has also been reported in long-distance cycling, through the pressure placed on the hypogastric and common penile artery traversing Alcock’s canal from the bicycle seat.45,46
Failure of adequate venous occlusion to develop and maintain an erection is a common cause of ED and results from a variety of processes. Degenerative changes of the tunica albuginea or subtunical architecture can impair compression of the subtunical and emissary veins. This can be as a result of a diffused process throughout the corpora, as seen with aging or diabetes, or can be caused by focal areas of inelasticity such as prior penile trauma or Peyronie disease.47,48,49,50 ED can also result from the creation of cavernosal spongiosal shunts formed after traumatic injuries or surgical manipulation for urethral stricture disease.51
Furthermore, structural or functional abnormalities in the fibroelastic, smooth muscle, or endothelium of the trabeculae of the corpora may result in venous leakage. This may occur as a result of systemic disease, resultant chronic changes, or excessive androgen tone in anxious individuals or patients with psychogenic ED. This is frequently associated with a relative decrease in corporal NO and an increase in α-adenoreceptor tone, and it can be modified by increasing corporal NO.6 It has been shown that stripping the deep dorsal vein, thereby dramatically reducing the vascular outflow, that venogenic ED can be partially corrected.52
Hypogonadism is a prevalent finding in men with ED. Mulligan and Schmitt performed a review of articles on male hypogonadism from 1975 until 1992 and concluded that androgens are important for sexual interest, increase the frequency of sexual acts, and increase the frequency of nocturnal erections. However, testosterone has little if any effect on fantasy or visually stimulated erections.53 In multiple animal models, castration has been shown to decrease arterial flow and induce venous leakage and reduce the erectile response to stimulation of the cavernous nerve, as well as decreasing nitric oxide synthase (NOS) activity and increasing cavernosal cellular apoptosis in these animals.4 It is clinically well established that men who are castrated or receive androgen ablative therapy for prostate cancer report poor libido and ED. Also any disruption of the hypothalamic-pituitary-gonadal axis, such as hyperprolactinemia, hyper- or hypothyroidism, mumps orchitis, surgery, tumor, or trauma can result in decrease circulating levels of testosterone and ED. Diabetes mellitus is the most common endocrine disorder associated with ED, but its mechanism is though a combination of vascular, endothelial, and neurogenic mechanism, and will be discussed further in those sections.
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