Jennifer Willis MD

CASE

DF is a 50 yo white male that presents to the clinic with the chief complaint of inability to achieve an erection. This problem has been occurring for months. He stated he could achieve semifirm erections but never erections firm enough to complete successful sex. He denied any physical or mental trauma and complained of no other medical problems. He denied any urinary difficulties or bowel problems. He claimed he desired sex "but just couldn’t seem to do it".

PMH: no chronic medical conditions

no medications

no past surgeries

SH: married - no marital problems

no extramarital relations

no tobacco

social alcohol

FH: positive for hypertension

PE: BP 140/80

Abd +BS soft NTND no bruits

Femoral and distal pulses 2+

Uncircumcised penis

Testicles normal size/ left epididymal mass

No herniations

Rectal exam - normal tone, prostate mildly enlarged without nodules, no mass or tenderness

A/P: Impotence with an epididymal mass

Testicular sonogram to define mass - cystic/solid

Testosterone level

Return in 2 weeks to follow up and discuss results

11/97 Returns to clinic

Ultrasound showed left epididymal cyst / testosterone normal

Further sexual history - had morning erections but not as firm as previously. No recent major stressors or depression, but fears the effects of this on his marriage

Placed on Yohimbine tid

Return in 1 month / consider urology referral

12/97 Returns to clinic

No improvement with Yohimbine

Discontinued Yohimbine and placed on Trazodone 50 mg tid

Referred to Urology

Impotence is the inability to achieve and/or maintain a penile erection of sufficient rigidity to permit satisfactory sexual relations(4). It is a common disorder, with greater than 10 million men suffering from some degree of impotence (6).

In the absence of a more descriptive term, it is more appropriately referred to as erectile dysfunction secondary to the negative connotation the word impotence implies (6). Erectile dysfunction can be divided into primary or secondary dysfunction (7). Those suffering from primary erectile dysfunction have never been able to have sexual intercourse (7). Secondary erectile dysfunction is much more common, occurring in men who have previously maintained sufficient erectile capacity to achieve intercourse (7). Most men have at some time or another had transient episodes of erectile failure. If it continues to occur, help should be sought. The longer the problem exists, the more difficult it is to treat (6). This is a result of the psychological component that accompanies repeated episodes (7). Erectile dysfunction has a prevalence of about 5% at age 40, increasing to 25% from age 65 years onwards in the USA (6). Organic disease should be ruled out since 2⁰ ED may very well be the first sign of an underlying organic problem. It has been shown that approximately 90% of men presenting to a urologist with erectile dysfunction have a physiologic cause for their problem (1). Furthermore, it accounts for more than 500,000 ambulatory primary care visits annually (4).

The erection process is an interplay of a combination of vascular, nervous, and hormonal events (12). In order for a man to have an erection, he must have: an intact penile vascular tree, normal innervation of the vascular tree, and a normal libido which is in part androgen mediated (1).

Review of Anatomy and Physiology

The cavernous bodies are the major erectile organs of the penis consisting of paired dorsal corpora cavernosa and a ventral corpus spongiosum. The cavernous bodies are enclosed in a thick, dense, fibrous capsule called the tunica albuginea. The corpus spongiosum ,which surrounds the urethra, forms the glans penis distally and the bulbis penis proximally which is covered by the bulbocavernosus muscle. The corpora cavernosa communicate distally in the pendulous penis and proximally form the crura, which attach to the ischiopubic ramus and are covered by the ischiocavernosus muscles. The corpora consist of spongy tissue with multiple interlacing and intercommunicating cavernous spaces. These spaces are separated by fibrous trabecula which are composed of smooth muscle and a fibroelastic frame of fibroblasts, collagen, and elastin. The cavernous spaces are lined by a vascular endothelium. The penis is flaccid when the spaces are empty and erect when filled with blood (11).

Arterial Supply

Erection depends upon intact arterial blood flow. The abdominal aorta divides into the two common iliac arteries from which the internal iliac (hypogastric) artery derives. The internal iliac, after giving off large branches to the gluteal muscles, continues as the internal pudendal artery. After the internal pudendal artery gives off the perineal artery, it is called the penile artery which runs horizontally piercing the urogenital diaphragm. There are 3 branches of the penile artery - the urethral artery (bulbosa), deep artery, and dorsal artery. There is individual variation, but for the most part, the deep arteries of the penis are the principal vessels that supply the cavernous spaces and are involved in an erection. They give off numerous branches which open directly into the cavernous spaces called helicine arteries secondary to there spiral course. Blood from the cavernous spaces is drained by a venous plexus that joins the deep dorsal vein located in the tunica albuginea (11).

Nerve Supply

Both autonomic (sympathetic/parasympathetic) and somatic nerves supply the penis (3). Penile erection is triggered by either of two mechanisms: a reflexogenic pathway or a central/psychogenic pathway (3). Full erection requires input form both centers (12). The reflexogenic pathway is initiated by direct stimulation of the genitalia (12). Sensory receptors are stimulated and afferent fibers via the dorsal nerve join the pudendal nerve to reach the sacral spinal cord at S2-S4 (9). In the sacral parasympathetic center, efferent fibers travel via the pelvic nerve to the cavernosa nerve leading to the erectile tissue which it innervates (9). The psychogenic pathway is less understood. Centers in the brain, namely the thalamus, rhinencephalon, and limbic structures exert control over spinal sympathetic (T11-L2) and parasympathic (S2-S4) centers (9). The psychogenic pathway is initiated by auditory, visual , tactile, and imaginative stimuli (9). Both systems work in concert in the initiation and maintenance of penile erections (12).

Mediators

Different neuroeffector systems control penile tone (9). In the flaccid state, penile vascular smooth muscle contraction is maintained by sympathetic tone (13). This is mediated by norepinephrine release acting on alpha 1 and to a lesser extent alpha 2 receptors (13). The erect state is secondary to parasympathetic activation medicated by cholingeric and noncholingeric-nonadrenergic/nitric oxide release causing smooth muscle relaxation (13). Local mediators produced by vascular endothelial cells contribute to relaxation including prostaglandins and nitric oxide (9). Androgens also play a role especially with development and libido, however, the role played in erectile function is poorly understood (9).

Mechanism of erection

An erection is a hemodynamic event induced by smooth muscle relaxation of both the cavernosa and the arterial vessels which deliver blood to them (1). This is mediated by nitric oxide synthesized in the nerve terminals of these muscles released in response to parasympathetic activity (1). The smooth muscle relaxation in the cavernosa creates increased storage space in the trabecular spaces of the corpora allowing pooling of blood from the increased flow (1). The blood engorges and dilates the cavernous spaces causing an increase in the intracavernosal pressure (1). This , in turn, occludes veins that exit the cavernosa through the tunica albuginea of the corpora (1). In order to achieve an erection, an equilibrium must exist between adequate filling of the corpora via the cavernosa arteries and adequate retention of blood (7). The key feature is smooth muscle relaxation which allows adequate blood flow and, in turn, creates a pressure high enough to cause the tissue to expand and occlude the veins (1). The corpora then become rigid and enlarged (6). Contraction of the superficial perineal muscles also increase penile rigidity (6). The ischiocaverinous and bulbocavernous muscles force blood from the cavernous spaces into distal parts of the corpora cavernosa (7). They also compress the deep dorsal vein of the penis with contraction helping to maintain erection (7). The erection ensues until ejaculation occurs, resulting from a sympathetic neural impulse from the hypogastric plexus (6). Following ejaculation, increasing sympathetic tone causes constriction of smooth muscle and the helicine cavernosal arteries contract such that the lacuna no longer compress the venules (6). Parasympathetic tone is reduced and blood is drained from the cavernous spaces into the deep dorsal vein at which time detumescene is complete (6).

Erectile dysfunction may be secondary to one cause or may be multifactorial. It is commonly classified into organic, nonorganic/psychogenic, or mixed disorders (50). The etiologies of organic erectile dysfunction can be divided into 5 broad categories: vascular, endocrine, penile disease, neurologic and drug related (50). In most cases, erectile dysfunction has an organic etiology with vascular disease the most common cause (9).

Vascular Erectile Dysfunction

Arterial or venous abnormalities account for about 70% of cases of organic erectile dysfunction (8). The vascular causes include: 1. arterial insufficiency of the vessels supplying the penis 2. venous leakage 3. disease of the sinusoidal spaces and 4. aortic occlusion or large vessel disease (Leriche syndrome) (50). Erectile dysfunction occurs if arterial inflow is insufficient or if corporal veno-occlusive dysfunction, also known as venous leakage, occurs through outflow veins which are normally blocked by corporeal engorgement (1).

Arterial Insufficiency

Insufficiency of the arterial blood supply during sexual stimulation resulting in erectile dysfunction is most often seen with increasing age (>40 yo) (2). Atherosclerosis is the predominant cause of occlusions to the arteries (6). Furthermore, arterial occlusions may occur after pelvic fractures, arteriovenous anastamosis in the pelvic area, dysplasia of the arteries and reconstructive surgery of the arteries in the legs (9). Atherosclerotic changes that may influence erection are disease in the distal aorta, common and internal iliacs, internal pudendal artery and/or penile arteries (7). Atherosclerotic disease of the vasculature supplying the penis decreases perfusion pressure and arterial flow to the lacunar spaces (9). This results in a decrease in the rigidity of the penis and also increases the time for maximum erection to occur (9). The risk factors for arterial insufficiency are those for atherosclerosis including hypertension, , cigarette smoking, hypercholesterolemia, diabetes, trauma (including blunt perineal or pelvic trauma) and pelvic irradiation (9).

Pelvic/external iliac steal syndrome is a vascular condition that can cause erectile dysfunction. It is characterized by the ability to achieve erection but inability to maintain it once coitus is started (18). Patients complain of loss of erection immediately following the initiation of coital moments (10). It is also accompanied by gluteal pain (10). Modifying coital position from a prone to lateral or supine position, which decreases muscle activity of the hip extensors, corrects the problem to some extent (10). It occurs when there is a stenosis or occlusion in the common iliac artery (10). Blood flowing through the internal iliac artery , therefore may reserve (10). Blood to the lower extremity is supplied by collaterals (10). Blood flow may be sufficient in a resting state to allow a normal erection, however, dilation of the arteries in the legs and gluteal muscles occur with movement and blood flow to the pelvic area including the cavernosa stops causing the erection to be lost (10). Similarly, occlusion of the distal aorta can cause erectile problems. The French surgeon Leriche in the 1940's described the occurrence of erectile dysfunction in men with arterial thrombosis and occlusion of the aortic bifurcation, hence the name Leriche syndrome describing aortic occlusion (7).

Venous Leakage

In other patients, adequate arterial blood flow into the penis may be present but venous leakage may occur from faulty veno-occlusive mechanisms (9). Excessive outflow through the subtunical venules occur leading to erectile failure or decreased rigidity (9). Sometimes men with venous leakage may be able to have a normal erection if inflow can overcome the exaggerated outflow (1). Conversely, a man with a low inflow may be able to have a normal erection if complete corporeal occlusion occurs (1). Veno-occlusive dysfunction is secondary to inadequate relaxation of trabecular smooth muscle or structural alterations in the fibroelastic components of the trabecula (9). Situations which cause inadequate relaxation of the cavernosal muscle include excessive adrenergic constrictor tone (e.g. anxiety) or damage to the parasympathetic dilator nerves (9). Structural alterations in the fibroelastic components of the trabecula result from altered synthesis of collagen, increased cross linking of collagen fibers (non-enzymatic glycogatin), surgery, or trauma (9). These may be secondary to age or systemic disease (vascular disease, hypercholesterolemia, diabetes) (9). The fibroelastic framework loses compliance with the resultant inability to expand the trabecula against the tunica albuginea such that it fails to compress the subtunical venules (9).

Neurologic Erectile Dysfunction

Many neurologic disorders cause erectile dysfunction. The most common include: 1. spinal cord injury and disease, 2. neuropathies including alcoholic and diabetic autonomic neuropathy, 3. surgical procedures which disrupt the autonomic nerve supply to the erectile tissues including radial prostatectomy, cystectomy, and rectosigmoid operations and 4. demylenating diseases such as multiple sclerosis (50). Neurologic impotence can occur from any disorder affecting either the parasympathetic sacral spinal cord or the peripheral efferent autonomic fibers (9). Since these nerves cause relaxation of smooth muscle in both the cavernosa and the arteries supplying the cavernosa, complete or partial erectile dysfunction will result if their function is disrupted (9).

Spinal cord lesions/injuries cause a variable degree of erectile difficulties depending on both the completeness and level of the lesion (9). Cord lesions above T12-L1 cause erectile dysfunction secondary to lack of control from higher centers, even though the reflexogenic erectile mechanism is intact (14). This may be overcome , however by constant tactile stimulation even though sensation may not be present (14). If the cord lesion is below the thoracic center (T12-L1) but above the sacral center (S2-S4), psychogenic erections are capable via impulses from higher centers exiting the cord at T12-L1 (14). Patients with incomplete lesions or injury to the upper cord have greater erectile capacities than their counterparts (9).

Drugs

It has been estimated that drugs play a role in one-fourth of patients seeking help for erectile dysfunction (2). This is especially true in the younger patient population (21). This greatly effects patient compliance and is an important question to ask patients after starting a new drug or with patients taking multiple medications. Many drugs have been implicated as offenders. It is, however, at times unclear whether the erectile difficulties that appear to coincide with commencement of the medications are in fact a result of the treatment or from the underlying pathology itself (HTN, depression, etc) (5). The drug classes commonly known to impair erection are the antihypertensives, antiandrogens, anticholigeries, antidepressants, CNS depressants, and drugs of habituation such as alcohol, heroine, methadone, etc, (50). Of the antihypertensive agents, beta blocking agents, central and peripheral acting sympatholytics, and thiazides are well known for their negative effects on erectile function (50). Alternatives for treating hypertension in the case of drug induced erectile dysfunction include alpha blocking agents, calcium channel blockers and ace inhibitors (13). Digoxin is also a big offender, the mechanism of which is believed to be secondary to inhibition of the NA/K-ATPase pump (13). Surprisingly, H-2 blockers , spironolactone, and ketoconazole all have anti-androgen effects that can cause erectile dysfunction (13). Antidepressant and antipsychotic drugs commonly have side effects on sexual performance. This is thought to be secondary to dopaminergic and serotinergic effects of the central nervous system (13). Lastly, chronic alcohol abuse is associated with erectile dysfunction, primarily because of liver involvement and failure to detoxify estrogen (13).

Endocrinologic Erectile Dysfunction

Endocrinologic disease can cause erectile dysfunction, however, it is relatively infrequent (46). Disorders include primary testicular failure/ hypergonadotrophic hypogonadism, secondary testicular failure/ hypogonadtrophic hypogonadism, hyperprolactinemia and hypo or hyperthyroidism (50). Any disturbance in the hypothalamic-pituitary-gonadal axis can cause erectile dysfunction. Androgens, in which testosterone is the major player, influence development of libido (9). The most common endocrine abnormality detected in erectile dysfunction is a low or borderline testosterone level (7). In cases of hypogonadism, androgen deficiency in young males with delayed puberty is clinically apparent. However, less severe deficiencies in adult men can be clinically difficult to recognize (15).

Testosterone is secreted by the Leydig cells in the testicles in response to luteinizing hormone (15). Episodic secretion of testosterone follows a diurnal pattern with higher levels occurring in the early morning and nadir in the late afternoon (15). Similar to other hormones, testosterone is highly protein bound so levels are affected by the availability of binding proteins (15). The active form of testosterone is the free unbound form, making up a mere 2% of total body stores (15). The free portion exerts its effects in the target organ by binding to a receptor protein in the cell cytosol or is first converted to dihydrotestosterone by 5-alpha reductase which then binds to the receptor protein (15). The remaining 98% of testosterone is bound to sex hormone binding globulin (SHBG) and albumin (15). The amount of free testosterone is dependant on the amount of plasma protein (15). There are many conditions associated with alterations in serum SHBG levels or reduction of SHBG binding sites (50). Conditions associated with an increased level of SHBG include cirrhosis, hyperthyroidism, estrogen, aging (>50 yr) and a low fat diet (<20g/day) (50). Conditions associated with a decreased level of SHBG include nephrotic syndrome, androgens, obesity, growth hormone and glucocorticoids (50). Furthermore, some drugs compete with androgens (testosterone and dihydrotestosterone) for binding sites including spironolactone, danazol, and progestins (13).

After the diagnosis of androgen deficiency is established, determination of the cause is in order. It may be secondary to testicular, pituitary or hypothalamic disease. Measurement of luteinizing hormone distinguishes testicular disease from pituitary or hypothalamic disease (50). In patients with primary testicular dysfunction, LH levels are increased, unless pituitary or hypothalamic disease is also present (50). If LH is low or normal, serum prolactin should be measured (50). Hyperprolactinemia can be secondary to a pituitary adenoma, medications, chronic renal failure, or idiopathic and is associated with low levels of testosterone and gonadotropin releasing hormone (9). Prolactin also has antagonistic effects on the peripheral action of testosterone (9).

Penile Disease

Diseases of the penis can also cause erectile dysfunction including Peyronie’s disease, priapism, and trauma. Priapism is an involuntary, persistent, painful erection of the penis, not associated with sexual excitement and not subsiding after ejaculation (16). It may begin de novo, occur after intercourse, or follow a prolonged nocturnal erection (16). If untreated, it leads to fibrosis of the erectile tissue (16). Priapism can be classified as primary or secondary (16). Primary priapism is most common and includes cases in which no etiologic factors can be identified (16). Secondary priapism occurs from a number of causes including hematologic, neoplastic, traumatic, neurogenic, and pharmacologic (16). Depending on the underlying hemodynamic pathology, priapism can also be classified as high flow (nonischemic) or low flow (ischemic) also known as arterial priapism or veno-occlusive priapism respectively (17). Most etiologic factors cause a low flow veno-occlusive type of priapism while high flow priapism is usually traumatic in nature with rupture of the cavernous artery (17). A significant number of patients will suffer from erectile dysfunction following priapism owing to destruction and fibrosis of the corpora cavernosa (17).

Peyronie’s disease is a nonmalignant idiopathic disorder characterized by formation of inelastic scars or plagues located within the tunica albuginea of the corpora cavernosa. The disease causes variable degrees of penile curvature, decreased penile rigidity, and painful erections. Although the exact etiology and pathogenesis is poorly understood, it tends to have a genetic predisposition commonly affecting men of Northern European decent in the fifth and sixth decades of life. The natural progression of the disease is variable. The active phase lasts between six to eighteen months. Thereafter, approximately 10% will experience complete remission with disease regression and resolution of symptoms, 50% will remain with little or no change, and the remaining 40% will have progressive disease with larger plague formations and further deformity (18).

Lastly, penile trauma with resultant injury can cause erectile dysfunction. Traumatic rupture of the urethra in association with pelvic fracture can cause urethral stricture formation and erectile difficulties (7). Any disruption in the vascular or neural tissue supplying the erectile tissue can cause erectile failure, including traumatic or iatrogenic. Furthermore, radiation therapy to the pelvis can cause late arterial inflow restriction which in turn causes venous leakage (46).

Nonorganic/Psychogenic Erectile Dysfunction

Most patients with erectile dysfunction exhibit both organic and psychogenic factors (21). The profound effect of the inability to perform sex, from whatever etiology, causes significant psychic stress (23). Sexual dysfunction can be exacerbated by failures and fears (23). Men are particularly worried about fears concerning performance, termed performance anxiety (23). Fear of rejection and humiliation interferes with performance (23). Proper treatment requires attention to both organic and the psychological factors contributing to the dysfunction.

The etiology of psychogenic erectile dysfunction can be divided into earlier causes and more immediate causes (21). The two causes often unite to produce overt dysfunction (21). Sexual dysfunction based upon earlier/deeper factors develop in response to misconceptions concerning human sexual expression (22). Our culture discourages sexual curiosity and exploration. The search for sexual pleasure is frowned upon. Children and adolescents are frequently taught that sex is bad. They are punished if they touch their genitals or display sexual interest. This indoctrination during development causes many people as adults to feel sexual conflict and guilt (22). Furthermore, society instills the ideals of strength and independence in males leaving some men inable to permit their own needs for affection to be met (22).

Immediate causes of sexual dysfunction include life stressors such as divorce/break up of a relationship, illness, death of a spouse/significant other, loss of a job, change in social status or family problems (5). The loss of erectile capacity or decline in vigor produces conflict impacting sexual activity (5). One of the most common immediate causes of sexual failure is spectatoring (23). This is the act of critically watching one’s own performance while engaged in sexual activity (23). Anxiety concerning the ability to achieve and maintain erection, achieve orgasm, as well as concern with partner satisfaction, are questioned during sexual act (23). In many cases spectatoring is related to a fear of repeating previous sexual failure (23). Such over concern prevents one from spontaneously enjoying sex (23). Another immediate cause for sexual dysfunction is an antierotic environment created by the inability to do things the person finds exciting (22). Fear of failure plays a role in producing an inhibitory anxiety coupled with fear of rejection and an exaggerated sense of pressure to perform (22).

Other causes of sexual dysfunction are related to interactions between couples. Successful sex requires mutual trust and abandonment to pleasure. Of course, infidelity, martial dissatisfaction, and rejection can cause psychological trauma. Couples must make compromises and communicate openly with each other. Lack of either can cause frustration and disappointment which can lead to anger or rebellion which may be expressed primarily as sexual dysfunction. Another factor that can lead to sexual difficulty is a struggle for power. The need to control people in ones environment is usually unconscious. It is often related to fear of losing control and underlying anger. If each partner fights for domination, a destructive struggle occurs which is often manifested by sexual dysfunction (22).

Depression is often accompanied by loss of sexual interest and ability to perform sexually (16). It is important to consider whenever a sexual complaint is made. Other symptoms of depression such as sleep/appetite disturbances, interpersonal withdrawal, and loss of ability to experience pleasure should be sought. In some circumstances, erectile dysfunction will begin as a manifestation of depression. The depression may later get better, but the erectile dysfunction remains (60). The original stress is replaced by the stress of the erectile dysfunction and is associated with loss of self worth and performance anxiety (6). Furthermore, men who have been sexually inactive for sometime secondary to loss of a partner or illness, may experience erectile difficulties upon resumption of sexual activity (6). Erectile function usually returns with psychotherapy and/or antidepressant medications (6). However, care must be taken in choice of antidepressant therapy since many effective antidepressants are burdened by sexual side effects that stifle libido and erectile function (13).

There are several forms of psychotherapy for erectile dysfunction embellishing the concepts of psychoanalysis, behavior modification, and symptom-oriented sex therapy involving both the individual and couple (23). Referral to a psychiatrist or therapist with expertise in sexual dysfunction should be offered to all patients with nonorganic erectile dysfunction. Counselling can also be beneficial to all patients with erectile dysfunction in helping to find ways to reduce psychosocial stressors and in dealing with anxiety experienced with sexual encounters.

Work Up

A thorough sexual history should be obtained including factors such as the onset and duration of erectile dysfunction, a complete list of medications taken, other medical conditions present, and trauma or past surgeries (8). Also questions inquiring about libido and impaired ejaculation should be asked. Distinguishing whether there is difficulty obtaining erection, maintaining erection, or both is important. For example, patients with veno-occlusive disease complain of difficulty maintaining erections while those with arterial disease have little or no spontaneous or nocturnal erections (8). Distinguishing between organic and nonorganic erectile dysfunction can be challenging. Typically, the onset of organic impotence is gradual while psychogenic causes are abrupt in onset (20). Organic impotence tends to be progressive and constant (20). In contrast, psychogenic impotence is intermittent and situational, perhaps with an identifiable stressor (20). Nocturnal and early morning erections can also give a clue to etiology (20). They are typically present with nonorganic causes and absent with organic causes (20).

The physical exam should include a thorough assessment of the vascular, neurologic and hormonal systems. It should begin with inspection , noting general habitus, degree of masculination , and testicle size and consistency. The penis should be elevated looking for lesions or fibrotic plaques (8). The neck is palpated for thyroidomegaly. The vascular system is evaluated by measuring blood pressure, palpating pulses, and auscultation of the great vessels for bruits (8). A rectal exam is performed to evaluated sphincter tone, the prostate gland and the bulbocavernous reflex (8). A complete neurologic exam with sensory and reflex testing should be performed (12). The bulbocavernous reflex gives a crude measurement of sacral root function (7). The cremasteric reflex and discrimination between pin prick and light touch can also be beneficial (9). If hormonal dysfunction is suspected, a free or total testosterone level should be measured (12). These patients may complain of decreased libido and/or have testicular atrophy on exam (15). If the testosterone level is low, a prolactin level is indicated (12). If diabetes or thyroid disease is suspected, fasting blood sugar and thyroid function testing/screening TSH are in order (12). In the patient with a suspected nonorganic cause, nocturnal penile tumescence testing may be helpful (12). If the patient admits to abnormal morning erections, intracavernosal injection therapy is warranted (12). If this is successful, the patient can be educated on self administration (12). Patients with severe arteriolar insufficiency, veno-occlusive disease, and at times psychogenic erectile dysfunction, will not respond to injections (12). Conversely, a positive response to drug injection therapy cannot distinguish between organic and nonorganic erectile dysfunction (12). If injection is not successful or the patient is uncomfortable with injections, a trial with a vacuum constriction device can be attempted (12). If none of these help, referral to a urologist for further studies is in order (12).

Studies involved in evaluating erectile dysfunction include nocturnal penile tumenscence testing, duplex doppler ultrasonography and cavernosometry with cavernosography. Nocturnal penile tumenscense testing (NPT) is based on the fact that during sleep, involuntary erections occur associated with REM sleep (46). An organic etiology is suspected without evidence of these erections (46). Formal testing takes place in a sleep laboratory with three nights of monitoring (46). The frequency and quality of erection is measured (46). There is, however, debate on what exactly is a normal response (1). Other simpler screening test exist including at home SNAP-gauge test, where three bands of increasing strength are placed around the penis at night (46). The bands may or may not be broken in the morning depending upon the presence and strength of erection (46).

Penile blood pressures can be measured noninvasively by a Doppler flow probe placed distal to an inflated small cuff to assess for arteriosclerosis causing penile arterial insufficiency. Penile systolic blood pressures can then be compared with brachial pressures expressed as the penile branchial index (PBI). A PBI of .75 is normal, suggesting no major occlusion exists between the aorta and the measurement point. A PBI of <.60 suggest an arterial abnormally such as aortoiliac occlusion. If the PBI drops dramatically with exercise, pelvic steal syndrome may be present (46).

Duplex doppler ultrasonography (DDU) is more sophisticated, evaluating penile corporal arterial blood flow in conjunction with vasodilation stimulation (46). This provides information about penile anatomy assessing such factors as penile arterial pliability, compliance, calcification, and possible fibrosis (46). The change in blood flow through penile vessels before and after vasodilator injections is measured. This is useful in determining the adequacy of penile arterial inflow and venous abnormalities (8). Vessels with arteriosclerosis show minimal changes in diameter and decreased flow velocity (20). When venous leak is suspected as a consequence, cavernosometry with cavernosography may be helpful if surgical repair is contemplated (8). Dynamic infusion cavernosometry measures the rate of leakage of blood out of the corpora (1). If abnormal, cavernosography is done (1). This is an x-ray localizing where the leakage occurs (1). These tests are usually done only after diagnostic intracorporeal injection failed to produce an adequate erection (1).

Treatment

Disease Specific

If a patient is on a medication believed to be contributing to erectile difficulties, then a trial off medication can be tried. Both the doctor and patient should discuss alternate medications and whether the benefits of treatment outweigh this side effect.

If hyperprolactinemia is the cause of erectile dysfunction, then medications associated with overproduction of prolactin should be stopped (estrogen, methyldopa, reserpine, or phenothiazine) (7). In patients with prolactinomas, referral to a specialist is indicated. Micoradenomas are treated with bromocriptine, a dopamine agonist, which is effective in restoring potency (20). Large tumors may not respond however, and may require surgical ablation (20). Testosterone should not be given secondary to its ability to stimulate growth of the pituitary adenoma (20). Furthermore, testosterone has not been effective in restoring potency in these patients (9).

Testosterone may be used to treat hypogonadism after documenting low levels, mainly for the benefit of increasing libido (12). It may occasionally be successful in treating erectile dysfunction, however, its use is not well supported (20). Physicians must remember testosterone can stimulate the growth of prostate cancer as well as cause prostatic hypertrophy (12). Testosterone is administered via intramuscular injection or transdermally. Oral testosterone is avoided secondary to its high frequency of hepatitis and hyperlipidemia (20).

Nondisease Specific

There are a number of medical and surgical options for the treatment of erectile dysfunction. Five basic types of therapy for organic erectile dysfunction include 1. Oral/transurethral drug therapy 2. Intercavernous vasoactive drug therapy 2. Vacuum constriction device 4. Penile prothesis implantation 5. Vascular surgery.

Oral Agents

Oral medications may be tried in some patients. Yohimbine hydrochloride (Yucon, Yohimex) has become a popular agent. It is available without a prescription and can be found at health food stores with a cost of about $25.00 per month . Yohimbine is an idolalkylamine alkaloid in Rubaceae and related trees (Rauwolfiia serpentia) chemically similar to reserpine although its effects are weaker and of shorter duration (25). Its mechanism of action involves blockade of alpha 2 adrenergic receptors (25). Its effects on the peripheral autonomic nervous system include increasing parasympathetic (cholinergic) tone and decreasing sympathetic (adrenergic) tone, exerting effects on intracavernosal blood flow by increasing penile inflow while decreasing outflow (25). It also has a central effect, exerting a stimulatory action on mood (25). Side effects include irritability, nausea, and hypertension although it reportedly has no significant influence on cardiac stimulation and other beta adrenergic effects (25). It has a modest value in men with psychogenic or early vasculogenic dysfunction, results slightly better than placebo in a few controlled trials (27-30). A double blind placebo controlled study evaluating 100 men with psychogenic impotence showed erectile function resuming in 37% of men treated with 5.4 mg of Yohimbine po tid within three weeks of therapy while only 15% of placebo treated men responded (27). Other studies show no significant improvement over placebo (26). The American Urological Association (AUA) guidelines discourage its use stating that it is not effective and the subpopulation of patients most likely to benefit has not been accurately identified (31).

Sildenafil is an oral agent that is a potent, competitive inhibitor of the cGMP phosphodiesterase enzyme, the predominant isoenzyme in the human corpus cavernosum. Inhibition on cGMP phosphodiesterase inhibits the breakdown of intracellular cGMP, resulting in the efflux of Ca++ from the cell with consequent smooth muscle relaxation. Treatment with Sildenafil, therefore, is expected to enhance relaxation of the corpus cavernosal smooth muscles increasing blood flow into the cavernosa thereby increasing intracavernosal pressure. Preliminary studies report a well tolerated and effective therapy for erectile dysfunction in men with an established organic cause (32). It is currently in phase III multi-institutional trials (32).

The antidepressant Trazodone (Desyerel) is also used empirically to treat erectile dysfunction. Its mechanism of action in promoting erection is multifold, exerting a primary effect via stimulation of 5-HT_1C receptors through serotonin inhibition and secondarily as an alpha blocking agent (33). Its side effects are few, however, it infrequently causes priapism (33). When Trazodone was administered to patients with erectile dysfunction at the dose of 50mg, qd - tid, positive responses were observed in more than 60% of patients, significantly superior to placebo (34-35). Furthermore, synergism between Yohimbine and Trazodone has been demonstrated (36). Trazodone is an inexpensive treatment with the generic formulation costing 4-12 cents per day (33).

Pentoxifylline (Trental) is an agent used in intermittent claudication, also used in patients with erectile dysfunction secondary to mild penile vascular disease. It exerts its effects on red blood cells, rendering them more deformable ,aiding in passage through partially obstructed arterial channels. It also has direct vasodilatory properties. Its onset of action is delayed since the red cell membrane is altered at the time of formation. A placebo controlled study showed a significant improvement in erectile dysfunction and the penile-branchial index with a 400 mg dose given tid (37). It did not , however, have any effect in patients with diabetes (37).

L-Arginine has shown promising results in patients with psychogenic or mild vasculogenic erectile dysfunction (38). Oral administration of 1400 mg bid for two weeks in a placebo controlled trial improved erectile dysfunction in 40% of men (38). The responders where younger with nearly normal vascular indices while the nonresponders where older and tended to have more significant vascular insufficiency (38). L-arginine is an amino acid that is a precursor to nitric oxide (38). Nitric oxide is one of the main neurotransmitters involved in penile erection and is found in endothelial cells of the corpus cavernosa (38).

Apomorphine is a derivative of morphine that has direct central dopamine stimulation effects lowering response thresholds for erections (39). Its use has been limited by side effects including nausea, hypertension, and addiction (39). A new sublingual formulation has been invented without these side effects (39). It appears to be useful in patients with minimal vasculogenic and psychogenic impotence with a 60% response rate after a 3 mg dosage (39). Advantages of its use include the administration of the drug on an as needed basis (39).

Phentolamine is an alpha 1 and 2 adrenergic blocking agent used orally, via buccal preparation, or by intracavernosal injection in the treatment of erectile dysfunction. Gwinup (40), reported that 68% of patients with erectile dysfunction of various etiologies were able to achieve erection after 50 mg of phentolamine taken orally. It has a direct effect on the corpus cavernosum via relaxation of its blood vessels as well as antiserotonin action promoting a central antianxiety effect (40). The most common side effect observed was orthostatic hypotension (40).

Intracavernosal Injection Therapy

Intracavernosal injection therapy is used for both diagnostic and therapeutic purposes. It is now considered to be the treatment of choice in most patients (48). Successful treatment , defined as the production of a functional erection, has been achieved in more than 75% of patients (49). Intracavernosal application of vasoactive substances influence penile hemodynamics locally allowing high drug concentrations with a lower incidence of systemic side effects (48). Vasoactive agents are injected directly into one of corporeal bodies using a 26-30 gauge needle (8). Cross circulation allows the medication injected into one corpora to diffuse over to the contralateral side (8). A full erection can be produced within a few minutes after administration (8). The duration of action is dose dependent, the goal being 30-60 minutes (8).

Intracavernosal vasoactive agents can be classified into four main groups: (1) alpha adrenoceptor blocking agents (2) phosphodiesterase inhibitors (3) adenylate cyclase activators and (4) mixtures of the three.

The alpha adrenoceptor antagonists include phentolamine, phenoxybenzamine, and moxisylyte. Phentolamine, as mentioned earlier, is a competitive alpha 1 and 2 antagonist that directly relaxes smooth muscles (40). Its plasma half life is about 30 minutes (40). Its action tends to be weak in the corporeal smooth muscle therefore, it is usually combined with papervine or alprostadil (48). Phenoxybenzamine is rarely used secondary to its long half life of 24 hours (48). Moxisylyte is a newer alpha blocker currently under investigation (48).

The phosphodiesterase inhibitors include papaverine. It exerts an effect intra- cellularly on cAMP and cGMP leading to activation of protein kinases (48). Through a complex regulation cascade, membrane proteins are phosphorylated causing decreasing levels of intracellular calcium with smooth muscle relaxation (48). Its corporal clearance is relatively slow, resulting in the potential for priapism (48). It is, therefore, usually used in combination in order to reduce its dosage (48).

The adenylate cyclase activators include alprostadil, colforsin, and vasoactive intestinal peptide (48). The best studied is alprostadil/PGE1, which relaxes corporal smooth muscle by activating adenylate cyclase via G protein cleavage (49). It is the safest of the substances used, with less fibrotic, hepatic, and cardiovascular side effects (49). Besides its low incidence of side effects, its efficacy is high (49). Alprostadil is the only intracavernous medication reviewed and approved by the FDA (8).

Side effects for penile self injection therapy include pain with injection, priapism, and penile scarring (8). Despite the relatively high success rate, the attrition rate is fairly high (8). The cost is between $15-40 per dose depending on the agent (8). Contraindications include sickle cell anemia, unstable angina, bleeding disorders, and poor vision / manual dexterity (8). The AUA approves of penile injection therapy (31). Therapy should be initiated with alprostadil first, but may be changed to another agent if it fails (31). Patient education and a discussion of complications including prolonged erection and fibrosis is mandatory (37).

Topical Drug Therapy

The use of topically acting vasodilating drugs have been used with limited success. There are three main agents that can be applied topically to promote erection. Condoms must be worn to prevent adverse effects to the partner (43). These include papervine, nitroglycerin, and minoxidil (20). Papervine gel is dispensed in 7.5, 15, and 20% formulas which when applied to the penis, scrotum, and perineum increases penile blood flow(41). A phase I-placebo controlled study using the 20% gel in patients with erectile dysfunction, most of whom had neurogenic erectile dysfunction secondary to spinal cord injury, showed increases in peak systolic flow velocity and cavernous artery diameter (41). Although papaverine, may augment reflex erections, only 15% had functional erections (41). Also of note, functional erections were obtained in the placebo group (41). Another agent, nitroglycerin, is a well known vasodilator and smooth muscle relaxer. Its uses topically include treatment of Raynaud’s disease, heart disease, and erectile dysfunction (42). The dose for erectile dysfunction is 2 cm of a 2% ointment applied 30-60 minutes before intercourse (42). Placebo controlled studies have shown the occurrence of partial and full erections in patients with mixed impotence (42). Neurogenic erectile dysfunction responded most often (42). More often than not, nitroglycerin use increased penile rigidity, but not enough to permit penetration (43). Side effects include headache and hypotension (42). The last agent, minoxidil, is used topically in a 2% solution with a suggested dose of 1 ml (.28 mg) (44). It is best known for its use in alopecia and hypertension. It is a vasodilator acting on arterial smooth muscle by opening potassium channels (44). In a direct comparison with nitroglycerin, minoxidil was more effective in producing functional erections (45). Side effects are few and include burning at the application site (44).

Transurethral Drug Therapy

In lieu of the relatively poor results with topical medications, systemic side effects with oral therapy and to avoid injection therapy, the transurethral route of delivery was discovered. The urethral mucosa is lined by complex columnar cells which are more suitable for absorption when compared with stratified squamou . The drug is delivered to the erectile tissue through small collateral veins. A sterile packaged inserter containing the medication is placed in the urethra after urination such that the mucosa is moist allowing absorption of the water soluble drug (24). Two drugs are used via this route: Alprpstadil/PGE₁ and dinoprostone/PGE₂. The mechanisms of the prostaglandins include increasing intracellular concentrations of cAMP and alpha blocking properties causing cavernous and arterial smooth muscle relaxation while causing restriction of venous outflow (47). The results of a double blind, placebo controlled multicenter phase III study showed 62% of patients responded with an erection suitable for intercourse compared to 10% of patients receiving placebo after using intraurethral alprostadil in doses ranging from 125-250-500 to 1000 ug (47). Approximately 1500 men were involved with erectile dysfunction of various etiologies (47). It, furthermore, was well tolerated with the main compliant of penile pain on administration but less than 1% discontinued the treatment because of this (47). The cost is approximately $20.00 per dose (24). Contraindications include urethritis or urethral strictures, sickle cell anemia, thrombocytopenia, polycythemia, or multiple myeloma (24).

Vacuum Constriction Devices

Vacuum constriction devices are safe, easy to use, and can be useful for treatment of erectile dysfunction despite the etiology (12). The device consists of a hollow cylinder placed over the penis, a manual vacuum pump to generate a vacuum within the cylinder, and a constriction ring which is placed over the cylinder and rolled to the base of the penis (8). The vacuum created with the pump increases arterial inflow by creating a negative pressure around the penis engorging it with blood and erection is achieved (20). The constriction ring acts as a tourniquet trapping blood in the corporeal bodies reducing venous outflow (8). The cylinder is then removed and the constriction ring remains in place (12). The erection is maintained until removal of the ring which may be worn for 60 minutes (12). This device provides an immediate solution to erectile dysfunction, but has some disadvantages. Side effects include limited spontaneity, impaired ejaculation secondary to urethral blockage, and discomfort and/or bruising (20). Contraindications include sickle cell anemia and bleeding diathesis, including patients on anticoagulation therapy (20). It should be used with caution in patients with diabetes, severe vascular disease, and unreliable patients since leaving the device intact for prolonged periods can damage the urethra and corpora (24). These devices are available by prescription at a cost of $200-500 (12). Satisfaction rates are high in patients with organic erectile dysfunction, especially those with venous leaks and neurologic etiologies (20). The AUA approves of the use of vacuum constriction devices but states careful patient education in their use is mandatory to optimize efficiency and safety (19).

Different types of constriction rings also are available designed to enhance erections. The venous flow controller is one such device. It consists of elastic tubing held together by an adjustable ring. It is placed over the penis and slid to the base where the ring is adjusted for a snug fit. It slows venous outflow helping maintain penile rigidity. It is indicated for venous leak/veno-occlusive disease and in pelvic steal syndrome (25).

Surgical Options

Surgical interventions in the treatment of erectile dysfunction include penile augmentation and vascular surgery (12). The use of penile implants allow sufficient penile rigidity for intercourse (20). There are three basic types of prostheses: a semirigid rod, malleable/positional rod, and inflatable prothesis (12). The semirigid rod maintains a constant shape and size but may be bent up or down (12). It is usually composed of silicone with either a central stainless steel or silver wire core (12). The malleable rod maintains a constant size but the shape can be manipulated allowing it to be curved or straightened as desired (20). The inflatable protheses has a pumping mechanism placed in the scrotum which allows it to remain flaccid until fluid from a retropubic reservoir moves into the penile prosthesis causing it to enlarge (12). The overall effectiveness of implants is high as well as patient satisfaction rates (8). The inflatable devices are more cosmetically appealing but can be prone to mechanical failure (8). All implants fail with time, but should last ten years (12). The most common complications include postoperative infection, urethral and/or corporal perforation, implant extrusion, and mechanical problems (20). Cost is related to surgical implantation and hospital stay ranging form $10,000 to $25,000 (8). A screening process takes place before surgery taking into consideration the etiology of the patients erectile dysfunction, motivation, general medical condition, as well as psychological screening (31). The AUA approves of the use of penile prosthetic implants as long as informed consent is obtained and all risks, benefits, and treatment options are made available (31).

Vascular surgery involves either arterial revascularization or correction of abnormal drainage conditions with venous ligation or embolization of deep veins (12). Arterial revasuclarization procedures include anastomosis of the inferior epigastric artery to either the corpus cavernosum directly or to the dorsal penile artery in an attempt to increase blood supply (9). Bypass grafting is also used (9). To correct rapid venous outflow in patients with venous leakage, veins are ligated or embolized (9). Most of the surgical attempts thus far have been disappointing (12). For this reason, the AUA concluded that vascular surgery for erectile dysfunction in men with atherosclerosis be viewed as investigational (31). Patients who are interested should be referred to investigational medical centers (12). In the young patients with arteriogenic erectile dysfunction secondary to trauma, arterial revasculazation may be considered an option (31).

Conclusion

Erectile dysfunction is experienced by 20-30 million men in the United States and accounts for thousands of outpatient visits each year (7). Sexuality is an important issue often overlooked by primary care physicians which has a tremendous impact on a persons well-being. Most patients will not discuss their sexual problems unless the physician asks. It is therefore, important for us as physicians to become comfortable discussing sexual dysfunction and executing the appropriate work up. There are advantages to including the diagnosis and treatment of erectile dysfunction in the primary care visit. First, most men will have other medical problems that will need evaluation and treatment as well as the need for screening for prostatic and colorectal cancer (24). Second, treatment for erectile dysfunction is promising, having progressed rapidly over the past decade with may finding treatment that is successful.