Erectile Dysfunction (ED) is defined as the consistent inability to achieve and maintain an erection of the penis sufficient to permit satisfactory sexual intercourse. The word “consistent” is included in the definition because an occasional episode of ED occurs in many men as a normal phenomenon. Additionally, the use of “impotence” as a synonym for ED has been virtually abandoned because of its inherent implications of weakness and lack of power.
Studies in the United States indicate that at least thirty million American men (and their sexual partners) are affected by ED. Of these, ten to twenty million have a severe degree of involvement resulting in complete inability to maintain a penile erection, while 25% have moderate and 17% minimal degrees of involvement. Difficulty in ejaculation and attaining orgasm as well as the inability to penetrate the sexual partner and produce sexual satisfaction are associated with ED. As with other chronic conditions such as diabetes, hypertension and heart disease, the prevalence of erectile dysfunction increases with advancing age. While there is an estimated 39% prevalence at age 40, this will rise to 67% at age 70. As our longevity increases, so will the incidence of ED so that the number of projected victims will increase by nearly ten million by the year 2025.
Effect of ED on Quality of Life
The above figures may actually underestimate the true dimensions of the problem since the incidence of ED is notoriously under-reported or remains undiagnosed. In a survey of general medical practice, less than 12% of men with ED reported having received treatment for it. This has occurred despite the fact that adults of all ages view sex as an important issue in their Quality of Life (QOL) and that the imposition of ED usually results in detrimental effects on the QOL not only of the victims, but of their sexual partners as well.
The last decade, however, has witnessed a remarkable increase in public awareness and acceptance of ED as an important and very common medical problem. This has been the result of a combination of several important factors. First, there has been a marked increase in our knowledge and understanding of the normal physiological processes involved in penile erection and the disturbances that can result in ED. Through public awareness campaigns, the clinical benefits of the foregoing advances are now being realized. However, because of embarrassment or even shame about ED, many, or perhaps even most men would rather remain celibate than seek treatment. Secondly, this increase in knowledge and understanding has resulted in new safe and effective therapeutic modalities for the treatment of ED that have allowed entrance of the primary care physician into the therapeutic area of ED. Finally, it has been recognized that the vast majority (at least 80%) of cases of ED have a physiological rather than a psychological basis. This has resulted in greater acceptance of ED into the public arena as well as the elimination of the perceived stigma formerly associated with the diagnosis of ED.
he Pathophysiology of Erectile Dysfunction
The Anatomy of the Penis
The penis is composed of three principal structures that extend longitudinally along the shaft, including a pair of parallel columns termed the corpora cavernosa that are composed of spongy tissue containing smooth muscle, fibrous tissue, nerves, sinuses, arteries and veins. A third longitudinal compartment, the corpus spongiosum, located under the corpora cavernosa, contains the urethra. All three compartments are rich in tiny, pearl-shaped blood vessels called cavernous sinuses; these are, in turn, surrounded by smooth muscle and supported by elastic collagenous tissue.
Physiology of Penile Erection
Penile erection results from enhancement of blood flow into the penis as a consequence of penile arteriolar vasodilation and cavernosal and muscular relaxation. The train of events leading to this is complex, involving the brain, circulation, peripheral nervous system and various body chemicals and hormones. Although some events in the cascade resulting in penile erection await clarification, it appears that NO, a gas with intrinsic vasodilator properties, activates guanylate cyclase and, in turn, stimulates the formation of cGMP. This substance then acts as a second messenger, playing a pivotal role in vasodilation and relaxation of corporal smooth muscle, the structural changes responsible for penile erection.
Three major steps have been identified as the predominant factors in the process: The first step is sexual arousal. This is initiated in the brain or spinal cord and perpetuated by a variety of stimuli that may involve any (or a combination) of the senses: visual, auditory or olfactory. In addition, cognitive and erotic images are potent stimuli in effecting sexual arousal. Tactile sensory stimulation arises in the spinal cord. Sexual arousal results in the release of the chemical nitrous oxide (NO) from the specialized cells in the brain.
The second step is communication of the sexual arousal by the brain to the spinal and peripheral nervous site maps. Neuroanatomic targets include the thoracolumbar ganglia. Their stimulation causes activation of nerve fibers, primarily by NO (originally termed endothelium-derived relaxing factor). This process is also under parasympathetic control through the pudendal nerve.
The third step in this cascade occurs when nitrous oxide penetrates the spinal cord and nerves causing the release of another chemical, cyclic glutamine monophosphate (cyclic GMP or cGMP). Among other functions, cGMP is responsible for dilating the blood vessels and relaxing the muscles of the penis, thus allowing for an increase in blood flow to the penis and resultant rigidity. Parasympathetic fibers and their neurotransmitter, acetylcholine, are also stimulated by tactile sensations in the penile shaft, further enhancing relaxation of cavernous smooth muscle and increasing blood flow to the penis. The aging process is characterized by an increasing dependence on the latter process, emphasizing the importance of foreplay in the sexual function of older men.
The effects of cGMP are relatively short-acting. A specialized chemical, phosphodiesterase 5 (PDE-5), causes the breakdown of cGMP and, with the help of the nervous system, allows the penis to return to its normal flaccid, relaxed state. Thus, in most circumstances of impaired erectile dysfunction, inhibition of PDE-5 would serve to amplify and perpetuate penile erection. It was this hypothesis that formed the basis for recent therapeutic breakthroughs in therapy for ED. A new series of drugs, exemplified by sildenafil (Viagra, Pfizer), vardenafil (Levitra, Bayer) and tadalafil (Cialis, Lilly) block the action of PDE-5, thus allowing unblocked initiation and persistence of the erectile action of cGMP.
Phosphodiesterases (PDEs) play key roles in the regulation of cGMP activity, producing degradation of cGMP and thus ending its function as a second messenger in many vital processes. Multiple PDEs exist throughout the body, their isoforms varying with the specific functions they perform. The PDE-5 isoform, which is responsible for terminating cGMP-induced penile vasodilation and smooth muscle relaxation plays a relatively minor role in certain physiologic activities within the heart and eye.
Prostaglandin E1 (PGE1) is produced by penile musculature during erection. PGE1 activates an enzyme that results in calcium release by the smooth muscle cells enhancing their relaxation and promoting increased blood flow. Dynamic vascular studies have demonstrated that venous outflow production and the resultant entrapment of arterial blood in the penis are essential in the initiation and maintenance of rigid penile erection. The intrapenile pressure rises to several hundred millimeters of mercury. The venous entrapment is supplemented by the restraining capacity of the tunica albuginea, the fibrous peripheral tissue of the penis. Failure of these vascular phenomena such as occurs with venous leakage results in ED.
Causes of Erectile Dysfunction
Because penile erection requires a sequence of events, ED can occur when any step is disrupted. About 85% of the causes of ED are organic in nature and the balance of cases are psychogenic. Both mechanisms are important and often “mixed” in the same patient; consequently, psychogenic aspects cannot be ignored. In many instances, psychological issues may arise as causes and/or consequences of ED. Every patient with ED has an almost unavoidable component of performance anxiety, and the determination of whether psychological factors are the main problem or a secondary accompaniment may be difficult.
Organic Causes of ED
Organic causes of erectile dysfunction include those of vascular, neurological, hormonal, surgical and traumatic, disease-related or drug-related origins. Because of the complex and complicated nature of the human sexual response, it is often impossible to identify a single entity as the etiology. Because of the multiplicity of factors, the etiology of ED is often multifactorial.
Sources of ED may be grouped into those factors that are endogenous, or inherent in the individual, and exogenous, or arising from sources outside the body. Endogenous factors include endocrine imbalances, concomitant medical conditions and disorders, and psychological causes. Included among exogenous factors are medications, surgery, trauma and irradiation, and substance abuse.
Psychological Causes of Erectile Dysfunction
Psychological factors can precipitate ED either in the presence of absence of substantial organic causes. Stress, fatigue, depression, guilt, low self-esteem and negative feelings for or by a sexual partner are significant psychogenic etiological factors.6 Depressive symptoms and/or difficulty coping with anger may be particularly influential, and longitudinal data from the Massachusetts Maile Aging Study (MMAS) have indicated that incident ED was related to a ?submissive personality.
Comorbid Conditions Associated with ED
The frequent association between ED and a number of cardiovascular conditions such as hypertension and coronary artery heart disease (CHD) has raised the valid assumption that ED may serve as an important marker for the detection of these disorders. A significant positive correlation has been noted between ED and diabetes, hypertension, hypercholesterolemia, peripheral vascular disease, lung diseases, rheumatism and allergy. These relationships were unrelated to other factors such as the use of alcohol and tobacco and were age-controlled. The demonstration of the co-morbidity of ED with other disorders may provide an important aid to the diagnosis of these conditions.
Additionally, an increased incidence of depression has been noted in men with ED that is believed to be distinct from the reactive type of depression that might occur secondary to ED. This has led to the recognition of a possible syndrome linking depression and ED.
Risk Factors for Erectile Dysfunction
Erectile dysfunction is clearly a manifestation of many conditions and certain factors have been identified as risk factors associated with ED. These risk factors can be subdivided into those that are modifiable and those that are unmodifiable. In the initial approach to the patient with ED, an analysis of risk factors should be done and emphasis placed to correct or improve those factors that are modifiable. Most amenable to correction are those risk factors that are considered to be exogenous in origin. These include provocation or exacerbation of ED by such factors as medications, obesity, physical inactivity, smoking, alcohol and drug abuse. Sexual anxiety and other stressful psychological parameters such as guilt as well as psychosocial factors such as marital discord and lack of partner support should be confronted and, if possible, resolved. Gratifying improvement may result from elimination or improvement in these potentially remedial factors.
Attempts should also be made to improve the status of endogenous risk factors such as diabetes mellitus, hypertension and coronary heart disease, although data are inadequate to substantiate subsequent improvement in ED from such measures. Thus, although these conditions are modifiable to improvement, it does not follow that the associated ED will also improve.
The identification of risk factors for ED has an important impact on the prevention of ED, and knowledge of the risk factors can be a useful guide for prevention strategies. For example, certain medications such as those used for hypertension, depression and psychotic conditions can be selected that have no associated risk for ED.
Obesity, alcohol and tobacco use are among the exogenous risk factors that lend themselves more ready to respond to corrective changes compared with those endogenous factors that are associated with comorbid conditions. Overweight men are more likely to suffer from ED than are their slimmer counterparts. Results of studies related the effects of obesity on ED are controversial. In one study of 1,981 men between the ages of 51 and 88, 34% reported moderate to severe ED. The incidences of hypertension, older age and obesity were significantly greater in the ED group than in those without ED. Men with a waistline of 42 inches or more were nearly twice as likely to have ED compared to men whose girth measured 32 inches or less even after adjusting for other factors such as age, hypertension and smoking.
Limited observations have been made on the effect of correction of some of the above potentially modifiable risk factors on ED. In one study, a significant decrease in residual erectile function was reported in obese men compared to lean controls. However, this difference existed only in the presence of other vascular risk factors and the investigators concluded that obesity in itself did not pose a significant risk factor. In an additional study20, there was a significant association of ED with obesity (p = 0.0006) with baseline obesity predicting a higher risk regardless of weight loss.
Case and retrospective studies have shown an association of smoking with ED. The study revealed that the association of ED with risk factors such as coronary heart disease and hypertension was amplified by cigarette smoking. Smoking appeared to increase the likelihood of moderate or complete ED two-fold. The prevalence for ED in former smokers was no different from that of individuals who had never smoked, implying that cessation of smoking decreases the risk of ED.
Reports differ on the effects of alcohol on the incidence of ED. A positive relationship between the two has been postulated on the basis that alcohol-induced liver disease and a change in the androgen/estrogen ratio may have an effect. Others, however, have failed to find an association of alcohol with alcohol intake.
Physical activity status has been reported to be associated with ED, with the highest risk among men who remained sedentary and the lowest risk among those who remained active or initiated physical activity (p = 0.01). The findings suggested that physical activity might reduce the risk of ED even if initiated in midlife.
The Diagnosis of Erectile Dysfunction
As a central physiologic, psychological, emotional and social process, sexual function merits the clinician’s attention during routine well visits. Previous experience with the patient and his sexual partner often affords the primary care physician an opportunity to explore highly delicate and personal problems in an objective, but compassionate manner. Ideally and if possible, the sexual partner should be present when the sexual history is taken. Ende and associates used a short list of relatively simple, direct and straightforward questions to enhance recognition and treatment of ED. They found that the use of the questionnaire resulted in significant (p < 0.001) improvement in therapeutic success compared to a control group in which the questionnaire was not employed.
Several self-administered patient questionnaires assist in the evaluation of sexual function. One instrument in wide use is the International Index of Erectile Function (IIEF). A 15-item questionnaire, the IIEF addresses the five relevant issues of male sexual function: erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction. The IIEF is considered brief, reliable, psychometrically sound and easy to administer in both research and clinical settings. Variants of the IIEF include a 5-question abridged version, the Erectile Dysfunction Inventory for Treatment Satisfaction (EDITS) and the Brief Male Sexual Function Inventory (BMSFI). Other instruments include the Sexual Encounter Profile (SEP), a diary evaluating sexual encounters, and a Global Assessment Question (GAQ).
The history often provides valuable clues concerning evaluation of the psychogenic versus the organic components of ED.
A comprehensive physical examination enables evaluation of blood pressure (BP), secondary sex characteristics, femoral pulses, scrotal formation, and urethral position, as well as determination of any gynecomastia or thyroid abnormalities. The penile shaft should be examined for fibrous plaques and the testes palpated for size and consistency while ruling out nodules. Sensitivity of the shaft and perineum to touch or pinprick can be evaluated. A rectal examination should be performed to determine the status of the prostate. During the rectal examination rectal sphincter tone may be assessed and the bulbocavernosus reflex checked. Laboratory and Special Studies
Basic laboratory tests should be obtained in patients with ED to investigate the existence of comorbid conditions such as diabetes mellitus. Blood tests should include hemoglobin and hematocrit, leucocyte count, electrolyte status and baseline renal and hepatic function. If clinically indicated, tests of thyroid function should be done. In cases where hypogonadism is suspected, levels of testosterone (total and free) prolactin and gonadotrophins should be obtained. More refined, sophisticated tests may require the instrumentation and expertise of a consultant.
Nocturnal studies present perhaps a truer picture of ED due to organic causes. The most comprehensive evaluation of nocturnal erectile function is obtained in a sleep laboratory, where patients are monitored for rapid eye movement (REM) sleep. Under normal conditions, an erection is more likely to occur in REM sleep. Nocturnal erections can be characterized in terms of tumescence and buckling force (a measure of rigidity). Various techniques have been used to measure penile tumescence, including mercury strain gauges. Available for home use are Velcro snap gauges consisting of three plastic bands which break at distinct tensile strengths (80-160 mm Hg) and respond to increasing penile tumescence, but impart no or negligible information on penile rigidity or duration of erection. The Rig Scan monitor, a recording unit, can be set up in the physician’s office. It is inserted into a Velcro thigh holster, and disposable strain gauge loops are placed on the base and tip of the penis, where tumescence and rigidity are measured. The data are recorded and stored on a computer chip within the device for later downloading and generation of a graph for analysis by the physician.
Duplex Doppler ultrasonography has also been used extensively in evaluating erectile function. Doppler ultrasound enables determination of peak cavernosal arterial flow, direct visualization of the vasculature, and insight into penile fibrosis and other pathologies. Dynamic infusion pharmacocavernosometry and pharmacocavernosography are important tests for detection of veno-occlusive dysfunction.
Pharmacological testing involves intracavernosal injection of a small amount of an active agent, such as alprostadil or prostaglandin E1 (PGE1) that, theoretically, would produce a normal or priapic erection in a patient with normal erectile function but would produce a poor response in a patient with ED. One pitfall of this test is that, unless the patient’s sympathetic nerve impulses are completely overcome by the injected agent, he may have a poor erection even though his overall erectile function is normal.
Treatment of Erectile Dysfunction
Even if the origin of ED is purely organic, psychological counseling can reinforce or potentiate the effects of either medical or surgical approaches. It is important that sexual partners be equally willing to participate and cooperate with therapy. If deemed necessary and where possible, the clinician should arrange for a consultation with a psychotherapist or marital counselor to explore key relationship issues, including major life stressors associated with work, finances and family. Performance anxiety as it relates to fear of sexual failure and its attendant frustration or embarrassment should be evaluated and addressed by a qualified sex therapist, either a psychologist or psychiatrist. Sexual partners of older men should be advised that increased foreplay may be necessary for male sexual arousal and overall function.
In addition, even otherwise healthy men should become acquainted with a number of prevention and self-care measures to avoid ED, including the following:
- limitation or avoidance of alcohol and other drugs
- smoking cessation
- regular exercise
- stress reduction
- adequate sleep
- seeking psychological counseling as needed
- regular medical checkups and screening tests
Both the patient and his sexual partner should be reassured that episodic ED is normal and no indication of permanent or irreversible loss of sexual function or desire. Open communication with both the patient and sexual partner is important and should be maintained throughout the diagnosis and treatment process, which is often more successful if couples work together as a team.
Definitive therapy for ED is usually subdivided into pharmacological and nonpharmacological or mechanical groups of agents. Pharmacological therapy may be further subdivided into oral, topical or injectable modalities. A priority classification has also developed resulting in therapies being considered as first-line, second-line or third-line.
First Line Therapy
- Psychosexual counseling and therapy
o Oral erectogenic medications
+ PDE-5 inhibitors: Since the approval by the FDA of sildenafil citrate (Viagra, Pfizer) in 1998, two additional PDE-5 inhibitors have been approved for clinical use – vardenafil (Levitra, Bayer) and tadalafil (Cialis, Lilly). As inhibitors of the PDE normally responsible for the breakdown of corporal cGMP, the second messenger in penile erection, these oral agents exert no erectogenic effect in the absence of sexual stimulation. These agents are highly selective for PDE-5. There are individual claims involving these agents for greater specificity and safety, early onset of desired effects and longer duration of actions, but there are favorable reports of safety and efficacy for all three preparations.
+ Yohimbine: The availability of the safe and effective PDE-5 inhibitors in the treatment of ED has resulted in a sharp decrease in the use of this time-honored aphrodisiac. Derived from the bark of a tropical tree, yohimbine is reported to have both central and peripheral mechanisms acting peripherally as a cholinergic stimulant and an adrenergic depressant, thereby increasing penile blood flow. It also appears to have central nervous activity.
+ Apomorphine: This dopamine agonist administered sublingually has been reported as effective in the treatment of erectile dysfunction. Its emetic action limited its use and with the introduction of the PDE-5 inhibitors, its use is negligible.
+ Phentolamine: This peripheral a1/a2 blocker is said to work through the sympathetic nervous system and have both central and peripheral effects in producing an erection.31
o Non Pharmacological First Line Therapy
+ Vacuum devices: Prior to the advent of the PDE-5 oral erectogenic agents, vacuum erection devices (e.g., ErecAid, Post-T-Vac, VED) were an excellent option for many patients. A vacuum tube placed around the penis enhanced the erectile effects of the inherent pressure within the penis, causing it to become larger and thicker. Some passive dilation of the intracavernosal spaces also occurred. A band was then placed around the base of the penis to maintain the erection.
Second Line Therapy
- Intracavernous and intraurethral injection therapy (ICIT)
o Penile alprostadil (PGE1) may be administered via one of two routes: intracavernosal injections (Caverject, Pharmacia & Upjohn; and Edex, Schwarz Pharma) or by transurethral suppository (MUSE, Vivus).
Alprostadil, a synthetic PGE1 enzyme, assists in causing relaxation of cavernosal smooth muscle and dilation of cavernosal arterioles. These actions permit increased penile blood flow and address secondary veno-occlusive mechanism by compression of the venules against the surrounding tunica albuginea. Both administration routes result in dose-response improvements in frequency of erection sufficient for intercourse.
Side effects with PGE1 have been minimal, although about one third of patients receiving intercavernosal alprostadil noticed mild to moderate penile pain at some point, which was ascribed to the injection per se and there was interference with sexual activity in about 10% of men. Double-blind, placebo-controlled, randomized clinical trials in men with mild to moderate ED as indicated by the International Index of Erectile Function (IIEF) revealed significant benefits of penile alprostadil compared with placebo.
Third Line Therapy
- Surgical Therapy
o Penile prosthesis. The use of penile prostheses has decreased significantly since the advent of safe and effective oral erectogenic agents. Semirigid, malleable and inflatable devices are available. Use in patients with diabetes, urinary tract infections and spinal cord injuries are prone to infectious complications. Dissatisfaction of the sexual partner may pose a problem.
o Surgery. In the past, surgery for cavernous veno-occlusive dysfunction was considered appropriate therapy for ED. However, revascularization of the corpus cavernosa to provide improved blood flow does not address the fundamental basis for ED and results vary widely among medical centers. Vascular surgery seems most successful in young patients who have had pelvic or perineal trauma and have few vascular risk factors.
Hormone Replacement Therapy
Hypogonadism is an uncommon cause of ED, but should be suspected in the presence of suggestive physical findings and blood levels of free and total testosterone, prolactin and gonadotrophins should be obtained. Thyroid status should also be obtained. Patients with low serum testosterone levels should undergo evaluation for the cause. Exogenous testosterone therapy, either by injection or transdermal patch may be helpful in some patients. If the decrease in testosterone is associated with hyperprolactinaemia, treatment with bromocriptine mesylate is warranted.
First-line therapies may be used as single interventions or in combinations. Second- and third-line therapies are generally reserved for those patients who manifest insufficient response to or adverse effects from one or more first-line therapies. Whatever therapy is decided upon, follow-up at regular intervals is essential for every patient. The physician should be alert for adverse reactions and drug interactions. Priapism is a rare adverse effect requiring prompt treatment, which might include aspiration detumescence, corporal irrigation, and/or injection of vasoconstrictors at low concentrations.
Dosage titration or the substitution or addition of another therapeutic agent should be considered in patients who have an unsatisfactory response. The physician should ascertain that the patient and his cooperative sexual partner are knowledgeable concerning his condition and whether there is need for further education.
The past decade has witnessed major developments in our basic understanding of the physiology of normal penile erection and the pathophysiology of erectile dysfunction. The demonstration that the vast majority of cases of ED are organic and not psychogenic in origin has helped to eliminate the taboos that previously characterized ED and has brought the disorder into the public arena.
At the same time, the increase in knowledge concerning the basic mechanisms and risk factors responsible for ED has resulted in the dramatic introduction of safe and effective therapeutic agents, particularly in the area of phosphodiesterase-5 (PDE-5) inhibitors. The result has been a tremendous expansion of the ED patient base entering the practice of the primary physician. Guidelines for the diagnosis and treatment of erectile dysfunction have been developed.
These recent developments have raised some challenging issues for the future. These include societal changes regarding ED, definition of the ED patient, expansion of clinical and basic research, definition of the role of the Internet, increased awareness and interest in female sexual dysfunction, all accompanies by a large economic impact.