Atlas of Clinical Andrology

Chapter 7. Erectile dysfunction

Erectile dysfunction (ED) is the persistent inability to achieve and maintain an erection sufficient for satisfactory sexual intercourse, and has a reported prevalence of about 50% in men aged 40-70 years. The penis might be erect, but the erection may not last long enough before it fades away. Extensive investigations have been conducted into the etiology of ED, its endocrine profile, the effects of testosterone and prostate cancer, and the application of animal models (reviewed by Hafez and Hafez, 2004). ED may lead to depressive symptoms, low self-esteem, other signs of psychological distress and decreased quality of life. ED can be due to organic and psychological mechanisms associated with psychological, neurological, endocrinological, vascular (venous or arterial), traumatic or iatrogenic factors (drugs and surgery).

PREVALENCE OF ERECTILE DYSFUNCTION

ED is a common problem in general medical practice affecting especially the elderly and those with hypertension, ischemic heart disease, peripheral vascular disease and diabetes mellitus (Jaffe et al., 1996; Panser et al., 1995). ED is manifested in 10-60% of men depending on the demography of the population (Table 7.1).

Some 40% of diabetic men > 60 years of age have ED all the time (complete ED). Men with ischemic heart disease are 1.9 times more likely to have complete ED than those who do not have ischemic heart disease.

PATHOPHYSIOLOGY AND PSYCHOPATHOLOGY OF ERECTILE DYSFUNCTION

Two major psychopathological/emotional factors play a significant role in the etiology of ED: performance anxiety and relationship discord. Changes associated with ED are shown in Tables 7.2 and 7.3.

Pathophysiology of erectile dysfunction

Vascular dysfunction results from arterial insufficiency and/or incompetence of the veno-occlusive mechanism (venous leak) (Brow et al., 2000). Differentiating between the two has prognostic and therapeutic implications (Table 7.4). Corporal fibrosis, which causes venogenic (venous leak) impotence, develops secondary to abnormalities in the regulation of collagen synthesis and degradation, probably related to chronic ischemia (Nehra et al., 1996). Erectile and sexual functions are regulated by dopamine and oxytocin release by the neurons of the hypothalamus. However, hypogonadism does not seem to contribute to the impaired penile reflex, as testosterone replacement does not cause the centrally mediated penile reflexes to recover (Sarapura and Schlaff, 1993; Sobrinho, 1993). Potassium (K) channels are key regulators of membrane potential and, therefore, of transmembrane Ca²⁺ flux, and, subsequently, the degree of contraction of many types of smooth muscle, including human corporal smooth muscle (Christ etal., 1995). Corporal smooth muscle tone, in turn, modulates penile blood flow and intracavernous pressure and, as such, affects both penile rigidity and erectile capacity. At least four subtypes of K channels are present in human corporal myocytes, with the high conductance calcium-sensitive potassium channel (maxi-K or K_Ca channel) and the metabolically regulated potassium channel (K_ATP) being the most physiologically relevant. The low pO₂ in patients with arteriogenic impotence, and the subset of men with severe venous leak impotence, support a concept of low cavernosal pO₂ as a mechanism for both arteriogenic and venogenic impotence (Brow et al., 2000).

Reproductive function is suppressed by hyperprolactinemia, but little is known about its effect on penile erection. Hyperprolactinemic men exhibit decreased libido and an inability to either obtain or maintain a rigid erection. Monga et al. (2001) evaluated the long-term efficacy of testosterone supplementation for ED, using parenteral Depo- testosterone, Testoderm scrotal patches as compared to Testoderm-transdermal therapeutic system (TTS) non-scrotal patches. They reported a better response with Depo-testosterone and Testoderm-TTS non- scrotal patches as compared to Testoderm scrotal patches. Testoderm-TTS non-scrotal patches were significantly better than Depo-testosterone with regard to satisfaction with sexual intercourse.

Devices used to treat ED include those which are malleable, mechanical, inflatable (self-contained) and inflatable (multicomponent). These devices are inserted in the corpora cavernosa through an incision between the penis and scrotum. The inside of each chamber in the penis is stretched open to allow placement of the device. The chambers are then closed and the skin is stitched closed (Figure 7.1).

Biochemical parameters

ED can be due to organic and psychological mechanisms associated with psychological, neurological, endocrinological, vascular (venous or arterial), traumatic or iatrogenic factors (drugs and surgery).

Selective inhibition of the enzyme phosphodiesterase (PDE) type 5, the enzyme responsible for the breakdown of cyclic guanosine monophosphate (cGMP) in the corpora cavernosa, has been used to treat ED. Persistence of cGMP leads to smooth muscle relaxation, resulting in erection. Extensive studies have been conducted on the etiology, pathophysiology, pharmacokinetics and therapy of ED (Chew et al., 2000; Christ, 1995; Christ et al., 1995; Fabbri and Aversa, 1997; Govier et al., 1997; Jaffe et al., 1996; Lee et al., 2000; Sarteschi et al., 1998).

Nitric oxide (NO)-mediated smooth muscle relaxation is a critical event during sexually stimulated penile erection. Subsequent to activation of neuronal and endothelial NO synthases, NO diffuses into penile vascular smooth muscle cells and binds the heme moiety of soluble guanylyl cyclase to stimulate the synthesis of cGMP, an important intracellular messenger that transduces extracellular signals in cavernosal smooth muscle cells. These events result in smooth muscle relaxation within the resistance arteries and cavernosal trabeculae, enabling exposure to systemic arterial blood pressure and corporal volume expansion.

Table 7.5 Clinical manifestation/psychophysiological mechanism and management of different types of erectile dysfunction (ED) and related phenomena

Little is known about the effect of stress-related hormone changes on the neurobiological correlates of psychogenic impotence. future research is needed to evaluate parameters of blood biochemistry, hormone profile and the corpora cavernosa associated with ED. Patterns of ED have been examined using frequency distributions and contingency tables generated with Microsoft Graph software. Statistical associations were assessed using the x2 test. The relationships between various grades of ED and self-reported comorbidity were examined using logistic regression and EGRET software, with the final multivariate model being derived using backwards stepwise elimination (Chew et al., 2000). Color power Doppler sonography is a valuable technique in the initial evaluation of penile circulation in ED (Aversa et al., 2000). This procedure is employed to achieve a full penile erection and complete smooth muscle relaxation by an intracavernous injection (ICI) of several vasoactive drugs to evaluate fully both the morphodynamic features of the cavernous arteries and to obtain information about the corpora cavernosa (Table 7.5).

Neurological mechanisms

Penile erection (PE), a psychoneuroendocrine vascular phenomenon, involves three simultaneous steps: arterial dilatation with subsequent increase in flow; lucunar space dilatation with filling of the corpora cavernosa; and, decreased venous outflow (Fabri and Aversa, 1997). PE is associated with increased arterial flow, smooth muscle relaxation and increased venous outflow resistance. Psychological distress can have a grave detrimental effect on sexual function. However, psychiatric disease does not predispose or protect against the development of cardiac, diabetic or endocrine conditions (Blazer et al., 1994; Feldman et al., 1994; Helmchen et al., 1996). There is concern about the possible negative effects of psychiatric medications on erectile function and libido. The increased size of the cavernosal bodies creates stretching and compression of the subtunical venules, leading to functionally rigid penile erections.

Figure 7.1 Schematic illustration of the human penis. (a) Lateral aspect.The penis leans on and is supported by a suspensory ligament, which is an extension of the linea alba. It is capped by the glans penis. Proximally, the corpus spongiosum is held by the bulbospongiosus muscle in which the fibers are mostly transverse.The corpora cavernosa are surrounded by the tunica albuginea, which is a bilayered structure (an inner circular and an outer longitudinal layer with multiple sublayers).The intracavernosal pillars, which may be considerably larger distally, are a continuation of the inner circular layer. Each corpus cavernosum is entrapped in the ischiocavernosus muscle with the muscle fibers aligned in the longitudinal direction. (b) Medial aspect.The distal ligament is aggregated from the collagen bundles of the outer longitudinal layer of the tunica albuginea. It is a non-elastic fibrous structure that forms the trunk of the glans penis. The incomplete septum is dorsally fenestrated.The corpus spongiosum contains the urethra. (c) Ventral aspect. The three-dimensional structure of the human penis is evident.The ischiocavernosus muscle is paired with and situated at the lateral boundary of the perineum. Each segment covers its ipsilateral penile crus. Meanwhile, the anterior fibers of the bulbospongiosus muscle partly radiate to encircle the corpus cavernosum and insert mainly into the ventral thickening of the tunica. From Hsu et al. (2004), with permission

CLINICAL PARAMETERS

Clinical testing

A simple, inexpensive test is to provide the patient with test strips to determine nocturnal erections and the rigidity of the erection. This can be accomplished with commercially prepared strips or even with postage stamps placed on the penis at bedtime. Dorsal nerve conduction studies may be obtained if neural origin is suspected and the patient wishes to pursue nerve grafting. Doppler color flow studies can help to assess the arterial flow to the cavernosa. This may be of benefit to those who are seeking surgical revisualization (Basson, 2001; Baum and Spiefer, 2001; Colpo, 1988; Lue, 1992; Rendell et al., 1999).

Priapism (Table 7.6)

Priapism, prolonged erection unaccompanied by sexual desire or stimulation, is manifested in two categories: high flow (non-ischemic) and low flow (ischemic) depending upon the veins involved, severity of the disease and duration of venous occlusion (Ramos et al., 1995; Seftel et al., 1998). High-flow priapism is characterized by adequate (or increased) arterial inflow with normal venous outflow, but helicine arteriolar bypass, or a defect in regulation, prevents detumescence (Sartenshi et al., 1998). Causes of low- flow priapism include sickle cell anemia, leukemia, secondary penile cancer, prostatitis, urethritis, prolonged sexual intercourse/erection, pelvic thromboses, congenital neonatal priapism, spinal stenosis, spinal cord injury, antipsychotic drugs, clozapine, chlorpromazine, antihypertensives, hydralazine, guanethidine, antidepressants, marijuana, alcohol, cocaine, heparin and testosterone (Hoffman et al., 2000).

THERAPY (TABLES 7.7-7.9)

Factors that affect erections can be of five different etiologies or any combination of these causes. Psychogenic and organic are the major classifications of etiology for erectile dysfunction. Organic origin is further designated as neurological, hormonal, vascular, cavernosal and mixed etiologies. Treatment could include:

(1) Oral medication - Viagra®, Vasomax, apomorphine, pentoxifylline, yohimbine and other oral agents, including testosterone replacement;

(2) Mechanical devices - vacuum erection devices (VED);

(3) Injection therapy - including Caverject®, Edex, alprostadil, papaverine and Regitine^®;

(4) Surgical treatment - penile implants, vascular surgery to improve blood flow, treatment for Peyronie’s disease, plication or plaque removal.

Intracavernous vasoactive injections

Several intracavernous vasoactive injections have been used alone or in combination for the evaluation and diagnosis of ED: papaverine, phentolamine, prostaglandin E1 (PGE1), vasointestinal peptide and moxysilite (Costa et al., 1996; Govier et al., 1997). High levels of state-anxiety, measured by psychological tests, are often present in newly diagnosed impotent patients and may lead to an incomplete pharmaco- induced erection with vasoactive agents (Aversa et al., 2000). Since the veno-occlusive mechanism is highly susceptible to psychological factors and to the type and dosage of the vasoactive agent, some authors used to combine intracavernous injection with audiovisual sexual stimulation (AVSS) (Costa et al., 1996). Treatment of ‘phallodynamically’ challenged individuals without adequately addressing the possible presence of psychopathology accounts for treatment failures and has the potential for leaving untreated serious emotional problems.

Table 7.8 Some medication side-effects

Sildenafil (Viagra®)

Sildenafil (Viagra) helps 70% of those treated to achieve sexual function. It was originally developed for heart disease, but was found to have a unique mechanism of action that blocks the enzyme phosphodiestgerase-5, thus maintaining persistent levels of cGMP, which is produced in the penis during sexual arousal and relaxes smooth muscle and increases blood flow. Viagra is effective within 20-40 min without risk of priapism (Tissot and Johnson, 2001).

Alprostadil

Medicated urethral system for erection (MUSE®) (Vivus; Merck) is the intraurethral administration of alprostadil (prostaglandin E₁ (PGE₁) suppository). Absorption of PGE₁ across the tunica albuginea to reach corporal bodies is limited, with systemic absorption through well vascularized corpus spongiosum. High concentrations of PGE₁ are used to maintain efficacy: a significant burning sensation can occur in up to 30% of patients. Sixty-five per cent (65%) success rates are reported, as determined by one successful sexual intercourse; in significant organic disease only 7% sustained rigid erections and 63% erections inadequate for sexual intercourse are reported.

MUSE is most effective in conjunction with use of an Actus Ring to restrict the venous flow. The most commonly used dose for patients at the Charleston V.A. Hospital is 500 μg, with a range of 125-1000 μg. MUSE should be inserted, after urinating, by pushing the button to completely insert the alprostadil into the urethra. Gently massaging or rolling the penis in the hand helps absorb the medication into the tissues. The effect is enhanced with standing for approximately 10 min and sexual stimulation. Sexual positions can affect the erect penis. Standing or being on top help keep the penis erect.

Testosterone supplement

Monga et al. (2003) evaluated the effect of various testosterone supplements on improved libido, improved energy and improved erection (Table 7.10).

Devices used to treat ED (Figure 7.2)

Devices and techniques used to treat ED include:

(1) Penile implants:

(a) malleable implant in normal or

(b) erect position;

(c) inflatable implant (Bostwick et al., 1999).

Table 7.10 Comparative effects of various testosterone supplements on patients with erectile dysfunction (Monga et al., 2002)

DPT, Depo-testosterone;TSD,Testoderm scrotal patches;TTS, transdermal testosterone system non-scrotal patches

Figure 7.2 Penile implants used for erectile dysfunction. (a) Malleable penile implant: a bendable prosthesis placed into both of the corpora can be bent in any direction.There are no moving parts, so problems with malfunction and breakage are rare. Courtesy of Mentor Urology, Inc. (b) Multicomponent inflatable penile implant uses a separate pump placed in the scrotum to inflate and deflate separate cylinders in the corpora. A separate reservoir may be used to hold fluid.This device allows for the most natural results. Courtesy of American Medical Systems, Inc. (c) Inflatable penile implant with scrotal pump, which is also the reservoir.This is squeezed to pump fluid into the device and results in increased rigidity. From Marks (1999), with permission. (d) One-handed unit, including cylinder and pump combined with thick ring and two-handed unit, including clear cylinder, vacuum pump and thin rings

(2) Penile anatomy and self-injection: normal erection develops when blood flows into both corpora cavernosa within the penis. Penile self-injection is an effective technique to produce an erection by stimulating blood flow with medication injected directly into one of the corpora. After the medication is injected through a tiny needle, blood flow increases and an erection develops.

(3) Mechanical penile implant: this movable device, placed into the corpora, is easier to bend and stays in position better than the malleable penile implant.

(4) Malleable penile implant: a bendable prosthesis placed into both of the corpora bent in any direction. There are no moving parts, so problems with malfunction and breakage are rare.

(5) Multicomponent inflatable penile implant: inflatable penile implant uses a separate pump placed in the scrotum to inflate and deflate separate cylinders in the corpora. A separate reservoir may be used to hold fluid. This device allows for the most natural results.

(6) Inflatable penile implant: inflatable penile implant with scrotal pump, which is also the reservoir. This is squeezed to pump fluid into the device and results in increased rigidity.

(7) Penile clamp: penile clamp squeezes urethra shut to prevent urine from leaking.

(8) Artificial sphincter: placed surgically, the artificial sphincter provides relief from severe urinary incontinence. Cuff surrounds bladder neck and urethra and squeezes shut, blocking any urine leakage. Device is activated and deactivated by a pump placed in the scrotum.

(9) Vacuum erection device: uses a pump attached to a plastic cylinder. The cylinder is placed over the lubricated penis, and a vacuum is created by the pump. This results in blood flowing into the two chambers in the penis to create an erection. An elastic ring is then slipped off of the cylinder onto the base of the penis to keep the blood in place and the erection intact.