I know that many on this forum have ED, and that diagnosing and treating its causes and effects are exceedingly difficult. I wanted to post this article so that you can read about the current, and standard medical and surgical treatment for ED.
http://www.endotext.org/male/male8/maleframe8.htm
"Chapter 8 - Medical and Surgical Therapy of Erectile Dysfunction
Alan Shindel, MD, Clinical Instructor, Department of Urology, UCSF, San Francisco, CA, USA
Derek Bochinski, MD, Attending Urologist, Alberta Urology Institute, Edmonton, Alberta, Canada
William O Brant, MD, Assistant Professor, Division of Urology, University of Utah, Salt Lake City, UT, USA
Anthony J Bella,MD, Assistant Professor, Division of Urology, Ottawa Hospital, Ottawa, ON, Canada
Tom Lue, MD, Professor and Vice Chair, Department of Urology, UCSF, San Francisco, CA, USA
Updated March 30, 2010
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Erectile dysfunction (ED) is defined as the inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse (1). ED may result from psychological, neurologic, hormonal, arterial, and penile states. As many as 30 million men in the United States have varying degrees of erectile dysfunction and the rate of ED increases as men age (2, 3). In this chapter, we will discuss the physiology of penile erection and pathophysiology of ED. We will review contemporary medical treatments for ED as well as surgical options for patients that fail medical management. Finally, we will detail treatment options that may become available in the near future.
8.1. PHYSIOLOGY OF ERECTIONS
Penile erection is a neurovascular event modulated by psychological and hormonal status. The penis is innervated by autonomic and somatic nerves. The somatic component is controlled by the pudendal nerve, which is responsible for penile sensation and the contraction and relaxation of the bulbocavernosus and ischiocavernosus striated muscles. The cavernous nerves regulate the blood flow during erection and detumescence. The sympathetic and parasympathetic nerves merge to form the cavernous nerves in the pelvis.
Sexual stimulation leads to a release of neurotransmitters (most importantly nitric oxide NO) from the nonadrenergic-noncholinergic cavernous nerve terminals and endothelial cells in the corpora cavernosa. NO activates a soluble guanylyl cyclase raising intracellular concentrations of cyclic guanosine monophosphate (cGMP). cGMP in turn activates a cGMP-specific protein kinase, which phosphorylates certain proteins and ion channels, resulting in: opening of the potassium channels and hyperpolarization; sequestration of intracellular calcium by the endoplasmic reticulum; and inhibition of calcium channels, blocking calcium influx. The consequence is a drop in cytosolic calcium content (4). Decline in calcium content results in smooth muscle relaxation and vasodilation in the arteries and arterioles supplying the erectile tissue. A several-fold increase in blood flow occurs, with a concomitant increase in compliance of the corporeal sinusoids from relaxed cavernous smooth muscle. This facilitates rapid filling and expansion of the sinusoidal system against the tunica albuginea. The subtunical venular plexuses are thus compressed between the corporeal sinusoids and the tunica albuginea, resulting in almost total occlusion of venous outflow (5, 6). With trapping of blood within the corpora cavernosa the flaccid penis becomes erect, with intracavernous pressures increasing to approximately 100 mm Hg (full erection phase). During sexual activity and with increasing arousal, the bulbocavernosus reflex is triggered, causing the ischiocavernosus muscles to forcefully compress the base of the blood-filled corpora cavernosa and the penis. During this phase the penis (including the glans) becomes very rigid, with an intracavernous pressure reaching several hundred mm Hg (the rigid erection phase). During this phase, inflow and outflow temporarily cease (7).
With sexual climax or cessation of arousal, the penis returns to the flaccid state. Flaccidity is initiated in large part by hydrolysis of cGMP to guanosine monophosphate by phosphodiesterase type 5. Other phosphodiesterases are also found in the corpus cavernosum, but they do not appear to play an important role in detumescence. Detumescence is also mediated in part by sympathetic discharge during ejaculation, leading to vasoconstriction and cessation of NO release from the cavernous nerves and corporal endothelium. The sub-tunical venous channels open with contraction of the trabecular smooth muscle, permitting egress of trapped blood and restoring flaccidity.
8.2. CLASSIFICATION OF ERECTILE DYSFUNCTION
ED may be classified as psychogenic, organic (neurogenic, hormonal, arterial, cavernosal and drug-induced), and mixed. Mixed ED is the most common encountered having both a psychogenic and organic component (Table 1).
Table 1. Classification and Common Causes of Erectile Dysfunction
Category of Erectile dysfunction
Common disorders
Pathophysiology
Neurogenic
Stroke or Alzheimer’s disease
Spinal cord injury
Radical pelvic surgeries
Diabetic neuropathy
Pelvic injury
Interrupted neuronal transmission
Failure to initiate nerve impulse
Psychogenic
Depression
Psychological stress
Performance anxiety
Relationship problems
Impaired nitric oxide (NO) release
Over-inhibition of NO release
Loss of libido
Hormonal
Hypogonadism
Hyperprolactinemia
Loss of libido
Inadequate NO release
Vasculogenic (arterial and cavernosal)
Hypertension Atherosclerosis
Diabetes mellitus
Trauma/ Bicycling accident
Peyronie’s disease
Impaired veno-occlusion
Inadequate arterial inflow
Drug-induced
Antihypertensives
Antiandrogen
Antidepressants
Alcohol abuse
Cigarette smoking
Central suppression
Decreased libido
Alcoholic neuropathy
Vascular insufficiency
Systemic diseases
Old age
Diabetes mellitus
Chronic renal failure
Coronary heart disease
Multifactorial
Neuronal and vascular dysfunction
Sexual function progressively declines as men age, although this decline need not be considered any more “normal” or “natural” than the development of diabetes, hypercholesterolemia, hypertension, or any other disease state more common in the aged. With age, the latent period between sexual stimulation and erection increases, erections are less turgid, ejaculation is less forceful, ejaculatory volume decreases, and the refractory period between erections lengthens (8). There is also a decrease in penile sensitivity to tactile stimulation, a decrease in serum testosterone concentration, and an increase in cavernous muscle tone (9-11).
Erectile dysfunction is more common in patients with neurologic disorders such as Parkinson's and Alzheimer's diseases, stroke, and cerebral trauma. This may be due to both a decrease in libido and/or inability to initiate the erectile process. Spinal cord injury patients have varying degrees of erectile dysfunction largely dependent on the location and extent of the lesion. Sensory input from the genitalia is essential to achieve and maintain reflexogenic erection, and this input becomes more important as the effect of psychological stimuli abates with age.
About 50 percent of men with chronic diabetes mellitus are reported to have erectile dysfunction. In addition to the disease's effect on small vessels, it may also affect the cavernous nerve terminals and endothelial cells, resulting in deficiency of neurotransmitters (4). Additionally, in diabetics, corporal smooth muscle relaxation in response to neuronal- and endothelial-derived nitric oxide (NO) is impaired, possibly due to the accumulation of glycosylation products .
Chronic renal failure has frequently been associated with diminished erectile function, impaired libido, and infertility. The mechanism is probably multifactorial: low serum testosterone concentrations, diabetes mellitus, vascular insufficiency, multiple medications, autonomic and somatic neuropathy (16), and psychological stress.
Psychogenic ED can be caused by performance anxiety, strained relationship, lack of sexual arousability, and overt psychiatric disorders such as depression and schizophrenia. Several studies have confirmed the strong relationship between depression and sexual dysfunction (17, 18).
Androgen deficiency results in a decrease in nocturnal erections and decreases libido. However, erection in response to visual sexual stimulation is preserved in men with hypogonadism, suggesting that androgen is not essential for erection (19). Prolactin has inhibitory activity on central dopaminergic activity and gonadotropin-releasing hormone secretion; ergo, hyperprolactinemia of any cause often results in reproductive and sexual dysfunction from secondary hypogonadotropic hypogonadism.
Vascular disease is another common cause of ED. Common vascular risk factors associated with generalized penile arterial insufficiency include hypertension, hyperlipidemia, cigarette smoking, diabetes mellitus, and pelvic irradiation (22, 23). Focal stenosis of the common penile artery most often occurs in men who have sustained blunt pelvic or perineal trauma (e.g., biking accidents, pelvic fractures) (22). Patients with hypertension may develop erectile dysfunction from the associated arterial stenotic lesions associated with elevated blood pressure (24).
Veno-occlusive dysfunction (VOD) may result from the formation of large venous channels draining the corpora cavernosa. In this situation there may be inadequate compression of the subtunical venules during the full erection phase (25). Venous leak impotence may also be the result of degenerative changes that affect the penis including Peyronie's disease, penile scarring, , and diabetes mellitus. A patient may develop VOD from traumatic injury to the tunica albuginea such as a penile fracture. Venous leak can also be seen in anxious men with excessive adrenergic tone causing structural alterations of the cavernous smooth muscle and endothelium and insufficient trabecular smooth muscle relaxation (10). Finally, VOD can be seen in patients with acquired shunts that result from the operative correction of priapism.
Many drugs have been reported to cause erectile dysfunction. Central neurotransmitter pathways, including serotonergic, noradrenergic, and dopaminergic pathways involved in sexual function, may be disturbed by antipsychotics, antidepressants and centrally acting antihypertensive drugs. Although any antihypertensive agent could theoretically cause ED by decreasing the availability of blood to the corporal arteries (i.e. a pressure-head phenomenon), differences are noted between various classes of medications, with le angiotensin converting enzyme inhibitors and angiotensein receptor blockers less likely to cause ED. Beta-adrenergic blocking drugs may lead to erectile dysfunction by potentiating a-1 adrenergic activity in the penis, although more modern beta blockers with eNOS activity (such as nebivolol) may help minimize this effect. Thiazide diuretics have been reported to cause erectile dysfunction by an unknown mechanism. Spironolactone, acting as an anti-androgen, can cause a decrease in libido and gynecomastia as well as causing ED. Cimetidine, a histamine-H2 receptor antagonist, has been reported to decrease libido and cause ED; it acts as an anti-androgen and can cause hyperprolactinemia(30). Other drugs known to cause erectile dysfunction are estrogens and drugs with anti-androgenic action such as ketoconazole and cyproterone acetate.
Social drugs including cigarettes and alcohol also affect erectile function. Cigarette smoking may induce vasoconstriction and penile venous leakage because of its contractile effect on the cavernous smooth muscle (31); more importantly, chronic use may accelerate atherosclerotic changes in penile microvaculature. Alcohol in small amounts may improve erections and increases libido because of its vasodilatory effect and the suppression of anxiety; however, large amounts can cause central sedation, decreased libido and transient erectile dysfunction. Chronic alcoholism may cause hypogonadism and polyneuropathy, which may affect penile nerve function (32).
8.3. EVALUATION OF ERECTILE DYSFUNCTION
Erectile dysfunction may be the first manifestation of many disease states, including diabetes mellitus, coronary artery disease, hyperlipidemia, hypertension, spinal-cord compression, pituitary tumors, and pelvic malignancies (Figure 1). In fact, ED has been proven to be a sentinel event for future cardiac disease and should therefore be taken as an indication that formal cardiovascular evaluation is indicated. The evaluation of a patient with ED requires a thorough history (medical, sexual and psycho-social), physical examination and appropriate laboratory tests (creatinine, fasting glucose, lipid profile, and testosterone) aimed at detecting these diseases. If the man's total testosterone concentration is low, serum free (or bioavailable) testosterone, prolactin, and lutenizing hormone should be assayed.
After assessing the therapeutic needs and goals of the patient and his partner, further diagnostic and treatment options should be contemplated. Consideration should be given to the patient's physical and mental health as well as his motivation and sexual needs. The patient's performance status and cardiovascular health need to be evaluated, if necessary in consultation with a cardiologist, in order to assess the patient's ability to tolerate sexual activity. Occasionally, a change in life-style or medications may be all that is needed to restore potency.
Some men may benefit from a referral for further testing and treatment (Table 2). The indications for specialty referral include: complex gonadal or other endocrine disorders, neurologic deficit suggestive of brain or spinal cord disease, deep-seated psychologic or psychiatric problems, Peyronie's disease, post-traumatic or primary erectile dysfunction, and active cardiovascular disease.
Table 2. Medical Workup of Erectile Dysfunction.
Test
Indications
Combined injection and stimulation (CIS) test
Injection of intracavernous medication Followed by penile stimulation
Assess penile vascular function.
Therapeutic test in men who choose intracavernous therapy
Duplex (color) ultrasonography
Assess penile hemodynamics and presence of Peyronie’s disease
Cavernosography
Assess for congenital or traumatic venous leakage, most useful in young men contemplating venous surgery for ED
Pelvic arteriography
Assess for correctable lesions in young men with traumatic arterial insufficiency
Ambulatory nocturnal penile tumescence and Rigidity (Rigiscan®)
Differentiate psychogenic from organic erectile dysfunction
8.4. MEDICAL MANAGEMENT OF ERECTILE DYSFUNCTION (Table 3.)
Table 3. Various Treatments of Erectile Dysfunction.
Treatment
Cost
Advantage
Disadvantage
Rcommendation
Psychosexual Therapy
$50- 150 /session
Non-invasive. Partner involved. Potentially curative for Psychogenic ED
Time consuming
Patient resistance to medication
First-line treatment. May be combined with other treatments
Oral: PDE 5 inhibitor (sildenafil, tadalafil, vardenafil)
$10-20 /dose Oral
Effective 1-hour wait
Up to 24 hour action (tadalifil)
May be taken on-demand or as daily supplement (tadalafil only)
Contraindicated in:- Men with severe cardiovascular disease- Men on nitrates
Potential for side effects
First-line treatment
Vacuum Constriction Device
$150- 450 /device
No systemic side effects
May compromise ejaculation
May be uncomfortable and/or cause numbness for some men
2nd-line treatment
Transurethral: MUSE®1
$25 /dose
Local therapy. Few systemic side effects
Moderately effective. Requires raining. May cause penile pain
2nd-line treatment
Penile injection (Caverject®, Edex®, or compounded drugs) 3,4
$5-25 /dose
Highly effective (up to 90%) Few systemic side effects
Requires injection. May cause penile pain. High dropout rate. Risk of priapism or fibrosis
2nd-line treatment
Penile Prosthesis (all types)
$8,000- 15,000
Very Successful
Unnatural erection. Risk of device infection. Requires surgery. Requires replacement after mechanical failure (typically 5-15 years
Men dissatisfied with medical management
Vascular Surgery
$10,000- 15,000
Potentially curative
Requires surgery. Poor results in older men with generalized disease
Young men with congenital or traumatic ED
1. MUSE signifies Medicated Urethral System for Erection. It contains alprostadil pellet. 2. Caverject and Edex both contain injectable alprostadil.4. Drug mixtures contain two or three of the following drugs: papaverine, phentolamine and prostaglandin, atropine.
Historically, androgens were thought to enhance male sexual function. However, androgen therapy has only been shown to be of benefit in hypogonadal men; this benefit primarily pertains to libido but some improvements in erectile function and response to PDE5 inhibitors have been reported after testosterone supplementation in select populations. Testosterone therapy in men with normal hormonal levels may temporarily increase libido and desire but does not affect ED in this population (33).
Transdermal and intramuscular testosterone therapy are generally more efficacious than oral testosterone preparations (34, 35). Testosterone cypionate and enanthate are often used for intramuscular replacement therapy; the usual dosage is 200 mg intramuscularly every 2 to 3 weeks. Their major drawbacks are the marked peaks and troughs in serum testosterone, with high levels in the first week after injection and a decrease thereafter.
Several transdermal testosterone preparations (testosterone patches or gels) as well as an implantable subcutaneous testosterone pellet are now available. Daily application of these preparations raises serum testosterone concentrations to within the normal range in over 90 percent of men. The most common adverse effects of testosterone patches have been skin irritation and contact dermatitis.
The safety profile of testosterone remains somewhat controversial but it the most recent data suggest that testosterone supplementation appears to be safe with respect to risk of prostate cancer development. However, extreme caution with respect to testosterone supplementation should exercised in men with untreated prostate cancer. Additionally, testosterone treatment may cause polycythemia and worse obstructive sleep apnea, and so men receiving androgen replacement therapy require biannual checks with measurementof hematocrit, serum testosterone, liver function tests, and PSA. More frequent checks in the early phase after initiation of therapy are often prudent.
Oral therapy with a type 5 phosphodiesterase inhibitor (PDE-5 inhibitors, sildenafil, vardenafil and tadalafil) is considered first line therapy in men with ED (36) . PDE-5 inhibitors block the inactivation of cyclic GMP and result in increased smooth muscle relaxation and better erections. In the absence of sexual stimulation these medications have no effect on the penis. Numerous placebo controlled studies have been conducted on the safety and efficacy of sildenafil as it has been in clinical use for over a decade. The results have shown that the number of erections and rates of penile rigidity, orgasmic function, and overall satisfaction were significantly higher with sildenafil than placebo (37, 38).
In terms of safety, most clinical trials published show only mild to moderate adverse events associated with all of the PDE-5 inhibitors, and these events are usually self limited in duration.(30, 39) The most common complaints are of headache (16 percent), flushing (10 percent), dyspepsia (7 percent), nasal congestion (4 percent), and visual disturbances/ color sensitivity (3 percent). Tadalafil distinguishes itself from vardenafil and sildenafil by the relative lack of visual side effects. It does however have an additional possible adverse effect which is back pain and/or myalgia (31, 40)
There is no difference in terms of adverse or serious cardiovascular events between PDE-5 inhibitors and the placebo-controlled groups (38). To date, well over 20 million men in over 100 countries have used sildenafil.(30, 39) Since the release of the drug, over 200 deaths temporally associated with sildenafil therapy were reported to the Food and Drug Administration in the United States of America. Sexual activity was thought to be a likely contributor to myocardial infarction, with sildenafil acting to enable men not previously active to partake in sexual activity (31, 32). Therefore, it appears that PDE-5 inhibitor therapy is safe for most men. Men with cardiovascular disease should however seek a cardiologist consultation prior to using PDE-5 inhibitors to insure that their heart is able to tolerate the physical exertion of sexual activity. The American Heart Association has published a guideline for sildenafil therapy (Table 4.) (43).This includes pre-therapy evaluation of cardiac status for men on multiple antihypertensive medications, pre-existing cardiac disease, and men using nitrite medications (44). These guidelines may be extrapolated for use with all PDE-5 inhibitors.
A lower starting dose (25 mg of sildenafil, 5 mg of vardenafil or tadalafil) should be used in patients who may attain and maintain higher plasma levels. These include patients who are older than 65, have severe renal impairment, or take potent CYP450 3A4 inhibitors. Patients who take ritonavir should not take more than 25 mg of Sildenafil in a 48-hour period.
Patients using PDE5 inhibitors and requiring alpha-blocker therapy should start at low doses, and be titrated gradually to effect. To avoid symptomatic hypotension, PDE5 inhibitors should not be taken within 4 hours of an alpha-blocker. One study found a significant rate of hypotension (28% versus 6% with placebo) in patients taking concomitant doxazosin and tadalafil; however, the rate of hypotension matched that seen in placebo-treated patients in patients taking tamsulosin and tadalafil, and some studies suggest that the interaction has less clinical relevance in patients who have undergone long-term alpha blocker therapy. The position of the American Urological Association is that all three PDE5 inhibitors interact to some degree with alpha-blockers and that concurrent use of alpha-blockers and PDE5 inhibitors may cause patients to develop orthostatic hypotension. Other antihypertensive agents, such as calcium channel blockers, are well-tolerated by men concurrently taking any of the three PDE5 inhibitors. Concomitant administration of these drugs appears to cause no or only small additive drops in blood pressure.
Non-arteritic ischemic optic neuropathy (NAION) and PDE5 inhibitor use has garnered a great deal of attention in both scientific and lay publications. Spontaneous NAION is the most common acute optic neuropathy and ranks second only to glaucoma as a cause of acquired optic neuropathy for men aged 50 and older. Estimated annual incidence is 2.3 to 10.3 per 100 000 and is more common in Caucasians than African Americans, Asians, or Hispanics. Most patients do not become legally blind, but the degree of visual acuity and visual field loss is usually significant. Risk factors common to NAION and ED include hypertension, diabetes mellitus, hypercholesterolemia, age over 50 years, coronary artery disease, and smoking. Given that an estimated 27 million men worldwide that have used sildenafil (up to 1 billion doses), not counting tadalafil or vardenafil users, the expected incidence of NAION in this group should be many-fold higher than the 43 cases reported to the FDA as of June 2005. If one bases calculations on the most conservative incidence of NAION in the general population (2.3 cases per 100,000) and the fact that there are at least 27 million users of PDE5 inhibitors, one would expect at least 621 cases in this population. This comparison therefore begs the question of whether PDE5 inhibitors exert a protective influence on the evolution of NAION. To date, the FDA maintains that a causal relationship between NAION and PDE use has not been established. Review of safety data from over 100 clinical studies of sildenafil (>13 000 men) did not identify any cases of NAION, with similar findings for vardenafil and tadalafil. Given current evidence, it is not possible to determine whether these events are directly related to use of PDE5 inhibitors or to other factors; however, men are instructed to stop taking these medications immediately and contact their physician should visual changes or loss occur. Men with a history of NAION should not use PDE5 inhibitors.
There has also been some recent concern regarding the potential of PDE5 inhibitors to interfere with hearing. Several dozen cases of PDE5 inhibitor associated hearing loss have been reported and some research has indicated mechanisms by which hearing loss may be attributable to action of these drugs. Men who experience hearing impairment while using PDE5 inhibitors should halt treatment until they are able to speak with their doctors regarding long term risk of hearing loss.
Table 4. Recommendations for Sildenafil in Men With Cardiac Disease
1. Sildenafil is contraindicated in men taking long-acting or short-acting nitrate drugs.
2. Men with stable coronary disease not needing nitrates on a consistent basis may take sildenafil if the risks of the medication have been carefully discussed with the patients by their physician. If the patient requires nitrates for mild or moderate exercise induced angina, sildenafil should not be given.
3. All men taking an organic nitrate (including recreational amyl nitrate) should be informed about the nitrate/sildenafil hypotensive interaction.
4. Men must be warned of the danger of taking sildenafil in the 24-hour period before or after taking a nitrate preparation.
5. Pre-sildenafil treadmill testing may be indicated in some men with cardiac disease to assess the risk of cardiac ischemia during sexual intercourse.
6. Initial monitoring of blood pressure after taking sildenafil may be indicated in: men with congestive heart failure who have borderline low blood pressure and low volume status; and men being treated with a complicated, multidrug antihypertensive regimen.
*Prepared by the American Heart Association (31)
Sildenafil (Viagra, Pfizer) works best when taken on an empty stomach and reaches maximum plasma concentrations within 30 to 120 minutes (mean 60 minutes). It is eliminated predominantly by hepatic metabolism, and the terminal half-life is about 4 hours. The recommended starting dose is 50 mg taken 1 hour before sexual activity. The maximal recommended frequency is once per day. The efficacy of sildenafil has been extensively studied in patients with other coexisting diseases. No significant difference in response rate was noted comparing a normal cohort of patients with patients with hypertension (57), spinal cord injury, depression (58), prostate surgery (59) , diabetes (60) and the elderly(61) . Patients who have undergone non-nerving sparing radical prostatectomy have a lower response rate to sildenafil compared to a normal cohort of patients (59) (Table 5.).
Table 5. Success of Sildenafil in Men with Erectile Dysfunction
Response
Cause of Erectile Dysfunction
Diabetes Mellitus
Spinal Cord Injury
Radical Prostatectomy
Psychogenic
Depression
(N = 268)
(N = 178)
(N = 107)
(N = 179)
(N = 151)
Improved erection
Placebo
10%
12%
15%
26%
18%
Sildenafil
57%
83%
43%
84%
76%
uccessful intercourse
Placebo
12%
13%
N/A
29%
NA
Sildenafil
48%
59%
43%
70%
N/A
Sildenafil dosage 50 to 100 mg (source:Sildenafil package insert [Pfizer Inc. New York, NY., 1998])
Vardenafil (Levitra, Bayer/GSK) is a potent and highly selective PDE-5 inhibitor. Its chemical structure is quite similar to sildenafil however in in-vitro studies the selectivity and potency of vardenafil are superior. The medication can be given in either 10 or 20 mg dosage. The time to peak plasma concentration is 40-55 minutes. Vardenafil has been shown to be highly efficacious in a wide range of clinical indications. In one multicenter phase III trial patients with diabetes (type I and II) were found to respond to 20 mg dosage of vardenafil significantly better then a similar control group. The effect also seemed to improve after 12 weeks of treatment. (62). Although similar in chemical structure, the in vitro potency and selectivity of vardenafil are superior to that of sildenafil. There has not, however, been any convincing evidence that this translates to superior results in vivo.
Several newer studies have demonstrated vardenafil to have a faster onset of action then seen with other medications of the same class. In particular one study (ONTIME) found that 21% of men with moderate to severe erectile dysfunction obtained erections of sufficient firmness for sexual intercourse at 11 minutes after using 20 mg of Vardenafil. At 25 minutes 53% of patients obtained erections sufficient enough for penetration as compared to placebo (26%). The statistically superior response to vardenafil versus placebo was observed in all times from 11-25 minutes. The side effects most frequently seen with vardenafil include flushing, dyspepsia, headache and visual disturbances. (66-68) Adverse events reported in men taking vardenafil closely resemble those in men taking sildenafil and tadalafil. Headache (21%), flushing (13%), dyspepsia (6%) are seem at various frequencies depending on dosages used.
Tadalafil (Cialis, Eli Lilly, USA) is a PDE-5 inhibitor which has a distinctly different chemical structure from vardenafil and sildenafil. Because tadalafil has less of an inhibitory effect on PDE-6 it lacks the visual side effects that sildenafil and vardenfil may cause. Tadalafil is dosed at 5, 10,and 20 mg on demand and is also available as a daily dose medication at 2,5 and 5 mg. Tadalafil’s erection potentiating effect may onset within 30-45 minutes of dosing but may last as long as 24-48 hours (70). As with the other PDE-5 inhibitors the side effect profile of this medication is quite mild. In addition to the lack of visual side effects, it also tends to have a reduced incidence of facial flushing compared to the other PDE-5 inhibitors. Back pain however has been noted in several studies (45). Another distinguishing factor of this new PDE-5 inhibitor is that there is no effect on the absorption of tadalafil by alcohol or food. An integrated analysis from five randomized control double blind placebo trials revealed that men with varying severities of ED significantly improved with Tadalafil therapy at 10 and 20 mg dosages. The mean IIEF score (international index of erectile dysfunction score) increased by 6.5 and 7.9 at the 10 and 20 mg dosage of tadalafil. This increase was statistically significant compared to placebo. (71) In pharmacological studies tadalafil appears to be rapidly absorbed and reaches a peak serum concentration by 2 hours. The uniqueness of tadalafil appears to be in that its half life is approximately 17.5 hours. As well, the absorption and excretion of tadalafil does not appear to be affected by food or alcohol. With a 17.5 hour half life tadalafil has period of responsiveness of up to 36 hours. 59% of patients who were administered a SEP questionnaire 24 hours after dosing (20 mg of tadalafil) responded positively to having successful intercourse as compared to 7% of placebo patients.
Like sildanafil and vardenafil, tadalafil potentiates the hypotensive effects of nitric oxide and it is therefore contraindicated in patients taking nitric oxide compounds. Tadalafil appears to be very well tolerated in most studies. The most frequently reported adverse events are headache and dyspepsia. Back pain, nasal congestion, myalgia and nasal congestion appear to be more transient and decrease in frequency with future treatments. The rate of treatment discontinuation as with sildenafil and vardenafil is similarly quite low at 2.2% compared with the placebo discontinuation rate of 1.3%.
PDE-5 Inhibitors and Cardiovascular Safety.
Controlled and post-marketing studies of the three FDA-approved PDE-5 inhibitors demonstrated no increase in myocardial infarction or death rates in either double-blind, placebo-controlled trials or open-label studies when compared with expected rates in the study populations . Patients with known coronary artery disease or heart failure receiving PDE-5 inhibitors did not exhibit worsening ischemia, coronary vasoconstriction, or worsening hemodynamics on exercise testing or cardiac catheterization. PDE-5 inhibitors have a minimal effect on QTc interval. However, vardenafil is not recommended in patients who take type-1A antiarrhythmics (such as quinidine or procainamide) or type-3 antiarrhythmics (such as sotalol or amiodarone) or in patients with congenital prolonged QT syndrome.
The vasodilator effects of sildenafil, vardenafil, and tadalafil may be more marked in patients with hypertension or coronary artery disease. As with all vasodilators, caution is advised in certain conditions: aortic stenosis, left ventricular outflow obstruction, hypotension and hypovolemia. Caution is advised when an alpha-blocker and a PDE-5 inhibitor are given together, as interaction can lead to excessive vasodilation and hypotension.
Nitrates are absolutely contraindicated in patients taking PDE-5 inhibitors. These include organic nitrates, including sublingual nitroglycerin, isosorbide mononitrate, isosorbide dinitrate and other nitrate preparations used to treat angina, as well as amyl nitrite or amyl nitrate (so-called “poppers,” a recreational drug). Past use of nitrates, e.g. more than two weeks before the use of PDE-5 inhibitors, is not considered a contraindication. Patients who develop angina during sexual activity with a PDE-5 inhibitor should be instructed to discontinue sexual activity, relax for 5-10 minutes and, if the pain persists, seek emergency care and inform emergency medical personnel that a PDE-5 inhibitor was taken.
PDE5i ‘failures’: Prior to moving on to 2nd line treatments, several strategies may be taken when a patient complains that medication prescribed PDE5 inhibitor is not having the desired effect. An important first step is re-education on the correct use of the medications. Many patients need to be reminded that these medications are reliant on central mechanisms and that they will not work well without erotic stimulation. Up to 55% of sildenafil initial non-responders will respond after education (74.1,74.2). Dose titration may be necessary. Additionally, sildenafil may not work as well after a high fat meal, although tadalafil seem to be less dependent on timing with regard to meals. Another step that can be taken is to check hormonal levels, as these medications are at least partially androgen-dependent and improved efficacy after testosterone replacement in hypogonadal men has been observed. There is also evidence that efficacy may improve with chronic use, at least in animal models.
Yohimbine is an alpha 2-adrenergic receptor antagonist produced from the bark of the yohim tree. Its effect on erectile function is at best marginal and is therefore not recommended in patients with organic ED. A meta-analysis of several placebo-controlled studies of 419 men with predominantly non-organic ED has shown some benefit over placebo (75). Frequent side effects include palpitation, fine tremor, elevation of blood pressure, and anxiety.
Oral phentolamine (Vasomax®) has been reported to improve erectile function compared to placebo (76, 77). Side effects of the medication include headache, facial flushing, and nasal congestion. Oral phentolamine has not been approved by the FDA, but it is available in several South American countries.
Apomorphine (Uprima®), a dopaminergic agonist, is a sublingual medication that is available for use in Europe. Apomorphine is a potent emetic that acts on central dopaminergic (D1/D2) receptors. When injected subcutaneously, it induces erections in rats and humans, but the side effects, notably nausea, seriously limited its clinical usefulness (78). Sublingual apomorphine has not received FDA approval.
Bremelanotide is a melanocortin analog that acts centrally and has been investigated in subcutaneous and intranasal administration. These studies reported statistically significant improvements in erections compared to placebo in both healthy men and those who did not respond well to sildenafil. Common side effects include flushing and nausea. The medication has not been approved by the FDA due to concerning elevations in blood pressure which were noted during phase III studies.
Second line therapy for ED includes the vacuum constriction device (VCD), trans-urethral suppositories (MUSE®) and intra-cavernous injection (ICI) therapy. VCD produces erection via vacuum suctioning of blood into the corporal spaces. Blood is subsequently trapped in the penis with a constriction device Placed at the base of the phallus. This type of therapy is preferred for older patients in stable relationships. Its potential side effects include discomfort, petechiae, numbness, and a interference with ejaculation.
The Medicated Urethral Suppository for Erections (MUSE®) is a transurethral prostaglandin suppository that has several advantages including local application, minimal systemic effects, and the rarity of drug interaction. However, this type of secondary treatment has failed to gain popularity due to its major drawbacks including moderate to severe penile pain, low response rate, and inconsistent efficacy (81, 82). It has been extensively studied in Europe and the United States and was found to be effective in 43 percent of men with erectile dysfunction of various organic causes. The most common side effects were penile pain (32 percent) and urethral pain or burning (12 percent) (83, 84). Using an adjustable constriction device (Actis®) placed at the base of the penis after MUSE administration resulted in an increase in successful sexual intercourse in 69 percent of men (85). Unfortunately the Actis® ring is no longer commercially available but alternative constrictive devices may be obtained from adult stores, with the important caveat that no constrictive device should be left on for more than 30 minutes and the device should be promptly removed if there are signs of numbness or ischemia. Patients are initially started with a test dose of 500-?g of MUSE® in the office. Depending on the patient's response, this dose can be titrated from 250-1000 ?g. It is important to administer the test dose in the office due to the risks of urethral bleeding, vasovagal reflex, hypotension, and priapism that can occur with this medication.
There are several intracavernous medications available for the treatment of ED including papaverine, alprostadil, phentolamine, VIP (vasoactive intestinal polypeptide), and ketanserin. Men must receive appropriate training and education by medical personnel before beginning home injections. The goal is to achieve an erection that is adequate for sexual intercourse but does not last for more than one hour. The two major side effects of intracavernous injection are priapism and fibrosis (penile deviation, nodules or plaque). Priapism is preventable through careful titration. To prevent eccchymosis, we routinely instruct men to compress the injection site for 5 minutes (up to 10 minutes in men taking anticoagulants). Intracavernous injection therapy is contraindicated in men with sickle-cell anemia, schizophrenia or other severe psychiatric disorder due to the risk of priapism associated with intracavernous injection.
In the U.S., the most commonly used (and only FDA approved) intracavernous drug isalprostadil.Alprostadil's efficacy is superior to papaverine alone and it results in erections in more than 70 percent of treated men (86). The usual dose ranges from 5 to 20 ?g. The most frequent side effect is painful erections that occur in 17 to 34 percent of men (86, 81). This hyperalgesic effect is most prominent in men with partial nerve injury, such as those with diabetic neuropathy and those who have undergone radical pelvic surgery. Alprostadil has a relatively low incidence of priapism (0.35 to 4 percent) and fibrosis (1 to 23 percent) (51, 87, 88).
Papaverine is a non-specific phosphodiesterase inhibitor that increases cyclic AMP and cyclic GMP concentrations in penile erectile tissue (89) Its usual dose ranges from 15 to 60 mg. It is more effective in psychogenic and neurogenic erectile dysfunction (up to 80 per cent) compared to vasculogenic (36-50 per cent). Its advantages include low cost and stability at room temperature. Its major disadvantages are priapism (up to 35 percent when taken in large doses), corporal fibrosis (up to 33 percent although the clinical relevance of mild fibrosis is debatable) and occasional perturbations in serum liver enzyme levels.
Phentolamine is a competitive alpha-adrenergic receptor antagonist. It is most often used in combination with papaverine (Bimix) to produce rigid erections (63-87% success rates) (90, 91). Most urologists use a combination of 30 mg papaverine and 0.5 to 1 mg phentolamine. The potential side effects of phentolamine include hypotension and reflex tachycardia.
Vasoactive intestinal polypeptide (VIP) is a potent smooth muscle relaxant originally isolated from the small intestine. This medication is only available in Europe. Injection of vasoactive intestinal polypeptide alone does not produce a rigid erection, (92) but when combined with phentolamine it produces erections sufficient for sexual intercourse in up to 67 percent of men (93). Common side effects include transient facial flushing (53 percent), bruising (20 percent), pain at the injection site (11 percent), and truncal flushing (9 percent).
Combinations of medications such as papaverine and alprostadil (94), ketanserin and alprostadil,(95) and phentolamine and alprostadil(96) have been proven to be superior single medications in efficacy of response. The most effective intracavernous therapy used in the U.S. is a three-drug mixture containing papaverine, phentolamine and alprostadil (Trimix). The usual dose of Trimix solution ranges from 0.1 to 0.5 ml. The response rate to this solution is reportedly as high as 90 percent (97). Although widely used in the U.S., trimix is not approved by the FDA.
Although the response rate to injection therapy is high, in long-term studies 38 to 80 percent of men cease to use the treatment over time (98, 99). To avoid the cumbersome nature of injection therapy, some men alternate injection therapy with sildenafil or MUSE®, preferring injection in circumstances when an erection of longer duration is desired. Alternatively, in men whom injection therapy alone fails or is insufficient, we recommend the use of injection therapy in combination with a vacuum constriction device.
No transdermal medication has been approved by the FDA for erectile dysfunction although some such preparations are available through compounding pharmacies. Nitroglycerine cream or paste, alprostadil cream, and a cream containing aminophylline, isosorbide dinitrate, and codergocrine mesylate have been used in pilot studies in men with erectile dysfunction with variable results (100).
8.5. PRIAPISM
Priapism is defined as a painful prolonged penile erection in the absence of sexual stimulation. Two subtypes of priapism have been described.
NON-ISCHEMIC PRIAPISM
Non-ischemic (or high-flow) priapism, is relatively rare. In this scenario, injury to a cavernosal artery, usually after perineal or direct penile trauma, results in uncontrolled high arterial inflow within the corpora cavernosa. Patients with arterial priapism typically seek medical attention later than those with ischemic priapism, due to the fact that non-ischemic priapism causes less pain and discomfort.
Non-ischemic priapism is not considered a medical emergency. Treatment is tailored to the circumstance that induced this condition. In some cases conservative therapy will allow the injured cavernous artery to seal off and restore normal blood flow to the corporal bodies. In other more established cases embolization or even open repair of the cavernous vessels might be needed. Use of super selective arteriography allow for the exact determination of the site of injury and treatment through embolization. There remains a low risk of impotence associated with high flow priapism. This must be considered in treating these individuals.
ISCHEMIC PRIAPISM
Ischemic (or low-flow) priapism is much more common and is characterized by a veno-occlusive state in which inadequate venous outflow creates an acidotic hypoxic environment leading to a painful prolonged erection. This more common type of priapism has become a well-recognized clinical entity because of the widespread use of intracavernous agents for erections.
Ischemic priapism should be considered a serious medical condition as it can lead to permanent penile fibrosis and erectile dysfunction. When effectively treated early (within 6-12 hours) little risk of permanent injury exists. Tissue injury is visible after 12 hours of ischemia, characterized as interstitial edema. Within 24 hours, there is destruction of the sinusoidal endothelium and adherence. All men using vasoactive drugs for penile self-injection should be instructed to seek medical attention if their erection persists longer than 3-4 hours. Other causes of ischemic priapism include sickle cell anemia, medication induced, and pelvic malignancy.
The agent of choice for the treatment of ischemic priapism is phenylephrine at a dosage of 100-250 ug injected into the cavernous body each 2 minutes until the penis is no longer rigid. At this concentration, little impact on the systemic BP is seen in most men although blood pressure and heart rate should be monitored in men with cardiac disease. Detumescence is often seen by 2-5 minutes and will first be noted with return of the arterial pulsations of the penis. In some cases, aspiration of blood of the fully rigid penis may be needed to attain detumescence. Once the rigidity is decreased a more effective delivery of the alpha-agonist is possible. However, it is important to understand that even in most cases when a fully rigid erection is present simply injecting phenylephrine will succeed in reversing the condition. Cases refractory to conservative management may require surgical shunting procedures to return the penis to a flaccid state. One exception is with sickle cell anemia. Priapism in these patients should be initially treated with oxygenation, hydration, analgesia and transfusions to reduce the concentration of hemoglobin S below 30%.
The long-term sequelae of ischemic priapism may include penile scarring and fibrosis, penile deformity and ED. Strategies to avoid these complications include education of the patient on an injection program and rapid treatment of priapism as it occurs.
8.6. SURGICAL MANAGEMENT OF ERECTILE DYSFUNCTION
With advances in basic science research, newer pharmacological therapies have decreased the indications of surgical therapy of ED. Nevertheless, surgical therapy remains an important part of the urologists' arsenal in the treatment of medically refractory ED. One of the earliest contemporary surgical approaches to ED was described by Wooten in 1902, who recommended ligation of the dorsal vein of the penis as a means for restoring erections (101). Penile prosthesis surgery was described in the early 1930s. (102) The superficially placed rigid prosthesis made from synthetic material soon followed.(103) These early prostheses tended to shift under the penile skin and were generally unsatisfactory.
It was not until the early seventies that satisfactory results were seen with the introduction of modern prosthetic devices which fit into the corpora cavernosa and provided both good functional as well as cosmetic results(102, 104, 105). At around the same time,
penile arterial bypass surgery was reported i as a treatment for erectile dysfunction from arterial insufficiency. Finally, venous surgery for ED was re-introduced with modifications in the early eighties to treat corporal veno-occlusive dysfunction. While penile prosthetic devices have generally been successful for a wide range of patients, vascular surgery (both arterial and venous) for ED has been effective only in very select patients, typically healthy young men with either congenital or traumatic ED;for this reason penile prosthesis surgery is considered the standard surgical treatment of erectile dysfunction.
8.7. ARTERIAL REVASCULARIZATION
Arterial revascularization offers patients the possibility of restoration of normal erectile function without the necessity of medications, injections, or devices. Penile arterial bypass surgery was first described in the early 1970s (106, 107) and has undergone many modifications since its early description. Penile arterial insufficiency is most frequently the result of general arteriosclerosis as seen in other medical conditions with similar risk factors of hypercholesterolemia, hypertension, cigarette smoking, and diabetes mellitus. In patients with arterial insufficiency from these entities, penile revascularization is unlikely to be of benefit. Rather, this surgery may be of use in young healthy men with traumatic disruption of a discrete segment of the penile vasculature.
Penile arterial insufficiency is diagnosed by performing an intracavernous injection test followed by self stimulation (audiovisual or manual) (108). Duplex ultrasonography of the penis performed during injection and stimulation test can help delineate echogenicity of corporal tissues, peak flow velocity of cavernosal arteries, thickness of tunica albuginea and cavernosal arteries, diameter and wave form of arteries. Once the diagnosis of pure arterial insufficiency has been confirmed, selective penile/pudendal arteriogram is necessary to identify penile vascular anatomy, demonstrate communication between cavernosal and dorsal arteries, confirm location of obstructive/traumatized arterial lesion, and plan surgical reconstruction.
Several techniques of revascularization have been described (109-112). Current approaches use a technique whereby the epigastric artery is anastomosed to the dorsal penile artery (revascularization) or the deep dorsal vein (arterialization). Long term results of these patients have been disappointing with an efficacy of 30-50% in well selected patients, but, with increasing accuracy of diagnostic modalities, improved operative techniques, and a narrowed selection criteria, long term results have significantly improved to greater than 60% (109, 113, 114). Young men with arterial insufficiency secondary to pelvic trauma are the ideal patients for this procedure (115). Recently, laparoscopy has been used to minimize the morbidity of the procedure (116). Overall long-term success in appropriately selected patients range from 34-80% spontaneous erections (109, 117). The most frequent side effect with penile arterialization has been hyperemia of the glans. This can occur in up to 13% of patients who have undergone epigastric artery-deep dorsal vein anastomosis. Other complications include infection, hematoma, and thrombosis of anastomosis.
8.8. VENOUS SURGERY
Venogenic dysfunction is often suspected during evaluation by the finding of a sub-optimal erectile response to intracavernosal injection despite a normal arterial response on duplex Doppler sonography. The presence of persistent end-diastolic flow of greater than 5 cm/sec on duplex sonography has also been shown in some studies to correlate with the finding of venous leakage (118, 119). The gold standard test for the diagnosis of venogenic erectile dysfunction remains the dynamic infusion cavernosometry and cavernosography (DICC). Cavernosometry and cavernosography can be used to document the severity of venous leakage as well as visualize the sites of leakage (120-123). An abnormal cavernosometry result (after injection of vasodilators to completely relax the penile smooth muscles) is 1) an intracavernosal infusion rate of greater than 10cc/minute of saline to maintain the erection or 2) a drop of intracavernosal pressure of greater than 50 mmHg within 30 seconds of terminating the saline infusion (124, 125). An abnormal cavernosogram (performed immediately after cavernosometry) shows visualization of penile veins or venous leakage from the crura on films taken immediately after intracavernous injection of diluted contrast.
Only patients with clearly defined and visualized venous leakage on cavernosogram should be offered venous surgery for ED. Patients with generalized penile venous disease should be offered penile prostheses as it is unlikely that adequate ligation can be accomplished in these men without obliterating arterial inflow. Penile venous surgery should be limited to men under age 50 because the high incidence of combined arteriogenic and venogenic impotence in older men leads to an unacceptably high failure rate in this age group. Other relative contraindications to the procedure are: diabetes mellitus, generalized arterial disease, and unwillingness or inability to quit smoking. Informed consent should include the risks of possible numbness of the penile skin, shortening of penile length, penile curvature and hematoma. Some investigators also advocate concomitant deep dorsal vein arterialization in order to increase venous resistance (126, 127.
The historical lack of long-term success of venous ligation procedures can be partially explained by the complexity of venous drainage of the penis. In the majority of patients, multiple venous leak sites can be visualized on cavernosography. Common leak sites include the superficial and deep dorsal vein, crural veins, corpus spongiosum, and glans penis. The deep dorsal, cavernosal and crural veins are the main venous drainage of the corpora cavernosa and are the most common sites for ligation procedures. Another possible explanation in the widely varied results of venous surgery in the literature may be due to the many variations of surgical techniques developed to treat patients with veno-occlusive erectile dysfunction.
The reasons for failure of the procedure will vary, but include improper diagnosis, incomplete surgical resection of abnormal venous channels, the presence of an arteriogenic component, and the formation of collateral vessels. In a retrospective review of 50 patients (25 successful and 25 failures) who underwent penile venous surgery the most important factors affecting surgical outcome were the findings on cavernosography and the consequent ease of identification and suture-ligation of the abnormal leak(128, 129) . Those patients with leak into unusual sites, such as the glans, corpus spongiosum, crura in combination with a large amount of drainage to the deep dorsal or cavernous vein had the highest rate of failure. If the venous leak could be easily identified on the cavernosogram and could be suture ligated at the tunica albuginea, success was more likely. Development of venous collaterals and persistent venous leakage appears to be a contributing factor in many patients who fail to improve following venous surgery. Factors that predict a poor prognosis include increasing patient age, duration of impotence, multiple leak sites, proximal (crural) venous leak site, and concomitant arteriogenic insufficiency (102, 130).
At present, in our hands approximately 61% of patients with veno-occlusive dysfunction treated with venous surgery are improved after surgical correction. The etiology of veno-occlusive incompetence remains incompletely understood. As our understanding of the cavernosal and sinusoidal function of the penis improves treatment, both medical and surgical, of venous leakage can be directed towards treating the underlying cause rather than a symptom of the disease.
8.9. PROSTHETIC SURGERY
When there is lack of efficacy or dissatisfaction with other modalities, penile prostheses are often the best alternative for erectile dysfunction. Unlike the other modalities, prosthesis surgery is irreversible in that the corporal tissue is permanently altered such that physiologic erections are no longer possible. If the prosthesis has to be removed, there will be complete ED, although devices are readily replaced should mechanical failure occur. While a variety of exotic materials, flaps, and grafts have been used historically, most contemporary prostheses are hydraulic pumps or semi-rigid/malleable rods. The malleable prostheses are made of silicone rubber with a central intertwined metallic core. Mechanical devices are also made of silicone rubber with interlocking segments in a column, which provide rigidity when the rings are lined up in a straight line and flaccidity when the penis is bent (similar to a gooseneck lamp). The advantages of semi-rigid devices are that they are easy to implant, have few mechanical parts with minimal mechanical failure, and generally last longer than inflatable devices. The major disadvantage of the semi-rigid devices is that the penis is never fully rigid nor fully flaccid. These devices may interfere with urination, are difficult to conceal, and have a higher likelihood of device erosion. About 15% of patients choose semi-rigid rod implants, and those with limited mental or manual dexterity are encouraged to receive this type of device.
Inflatable prostheses come in two or three-component designs. Two-piece inflatable prostheses consist of a pair of cylinders attached to a scrotal pump. The prosthesis can be deflated by bending the penis at midshaft. While these devices permit some appearance of flaccidity, the lack or a reservoir does limit the amount of detumescence that can be attained,
Three-piece inflatable prostheses are the current gold standard for treatment of medically refractory ED and consist of a pair of penile cylinders, a scrotal pump, and a supra-pubic reservoir. They provide excellent rigidity when erect and a more natural appearance when flaccid. When fully erect, they are as rigid as the two-piece device. In the flaccid state, they surpass flaccidity of two-piece prostheses. Of all the prosthesis types, hydraulic three-piece implants have been the most popular, accounting for 85% of the US market. Most inflatable devices will need replacement after 10-15 years. Repair or replacement rates of 5%-20% in the first five years are realistic.
Of all modalities for management of ED, prostheses have the highest satisfaction rates, with 2 large studies demonstrating greater than 95% satisfaction for men and similar satisfaction rates for partners. This extremely high satisfaction rate is likely due to the capacity of prostheses to allow for spontaneous and repeated reliable erections without external medications or devices. However, it must be considered that men willing to undergo implantation of a penile prosthetic are a self-selecting group and may not be representative of the general male population with ED.
Infection remains the most devastating and feared complication of penile implant surgery. Modern prostheses allow for antibiotic impregnation and elution, and infection rates are approximately 3% for a first-time prosthesis. Although some studies suggest that elevated HbA1c levels may predict a higher rate of infections in diabetics having penile prosthesis surgery, more recent studies refute this. A large study from Wilson, et al demonstrated that neither diabetic status nor preoperative HgA1c were risk factors for prosthesis infection. A more recent study also finds that elevated HbA1c is not a risk factor for infection but notes that short-term sugar control is (as defined by morning fasting glucose levels >200 ng/ml), although data is hampered by very low numbers of patients within that cohort. Penile shortening and eventual mechanical failure of the device are other common side effects.
8.10. CONCLUSIONS
As our understanding of the basic mechanisms of erectile function continues to grow, new and improved therapies for the management of ED will continue to emerge. We have witnessed a dramatic change in the treatment of men with erectile dysfunction over the past 30 years. Treatment options have progressed from psychosexual therapy and penile prostheses in the seventies, through arterial revascularization, vacuum constriction devices, and intracavernous injection therapy in the eighties, to transurethral and oral drug therapy in the nineties and the new millennium. Future interventions in development for ED include new and improved drug therapy. Attention and interest has also been directed to gene and stem cell therapy for this condition. Regardless of modality utilized, restoration of erectile capacity and facilitation of satisfying sexuality will remain an important goal for men and their sexual partners in the future."
http://www.endotext.org/male/male8/maleframe8.htm
"Chapter 8 - Medical and Surgical Therapy of Erectile Dysfunction
Alan Shindel, MD, Clinical Instructor, Department of Urology, UCSF, San Francisco, CA, USA
Derek Bochinski, MD, Attending Urologist, Alberta Urology Institute, Edmonton, Alberta, Canada
William O Brant, MD, Assistant Professor, Division of Urology, University of Utah, Salt Lake City, UT, USA
Anthony J Bella,MD, Assistant Professor, Division of Urology, Ottawa Hospital, Ottawa, ON, Canada
Tom Lue, MD, Professor and Vice Chair, Department of Urology, UCSF, San Francisco, CA, USA
Updated March 30, 2010
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Erectile dysfunction (ED) is defined as the inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse (1). ED may result from psychological, neurologic, hormonal, arterial, and penile states. As many as 30 million men in the United States have varying degrees of erectile dysfunction and the rate of ED increases as men age (2, 3). In this chapter, we will discuss the physiology of penile erection and pathophysiology of ED. We will review contemporary medical treatments for ED as well as surgical options for patients that fail medical management. Finally, we will detail treatment options that may become available in the near future.
8.1. PHYSIOLOGY OF ERECTIONS
Penile erection is a neurovascular event modulated by psychological and hormonal status. The penis is innervated by autonomic and somatic nerves. The somatic component is controlled by the pudendal nerve, which is responsible for penile sensation and the contraction and relaxation of the bulbocavernosus and ischiocavernosus striated muscles. The cavernous nerves regulate the blood flow during erection and detumescence. The sympathetic and parasympathetic nerves merge to form the cavernous nerves in the pelvis.
Sexual stimulation leads to a release of neurotransmitters (most importantly nitric oxide NO) from the nonadrenergic-noncholinergic cavernous nerve terminals and endothelial cells in the corpora cavernosa. NO activates a soluble guanylyl cyclase raising intracellular concentrations of cyclic guanosine monophosphate (cGMP). cGMP in turn activates a cGMP-specific protein kinase, which phosphorylates certain proteins and ion channels, resulting in: opening of the potassium channels and hyperpolarization; sequestration of intracellular calcium by the endoplasmic reticulum; and inhibition of calcium channels, blocking calcium influx. The consequence is a drop in cytosolic calcium content (4). Decline in calcium content results in smooth muscle relaxation and vasodilation in the arteries and arterioles supplying the erectile tissue. A several-fold increase in blood flow occurs, with a concomitant increase in compliance of the corporeal sinusoids from relaxed cavernous smooth muscle. This facilitates rapid filling and expansion of the sinusoidal system against the tunica albuginea. The subtunical venular plexuses are thus compressed between the corporeal sinusoids and the tunica albuginea, resulting in almost total occlusion of venous outflow (5, 6). With trapping of blood within the corpora cavernosa the flaccid penis becomes erect, with intracavernous pressures increasing to approximately 100 mm Hg (full erection phase). During sexual activity and with increasing arousal, the bulbocavernosus reflex is triggered, causing the ischiocavernosus muscles to forcefully compress the base of the blood-filled corpora cavernosa and the penis. During this phase the penis (including the glans) becomes very rigid, with an intracavernous pressure reaching several hundred mm Hg (the rigid erection phase). During this phase, inflow and outflow temporarily cease (7).
With sexual climax or cessation of arousal, the penis returns to the flaccid state. Flaccidity is initiated in large part by hydrolysis of cGMP to guanosine monophosphate by phosphodiesterase type 5. Other phosphodiesterases are also found in the corpus cavernosum, but they do not appear to play an important role in detumescence. Detumescence is also mediated in part by sympathetic discharge during ejaculation, leading to vasoconstriction and cessation of NO release from the cavernous nerves and corporal endothelium. The sub-tunical venous channels open with contraction of the trabecular smooth muscle, permitting egress of trapped blood and restoring flaccidity.
8.2. CLASSIFICATION OF ERECTILE DYSFUNCTION
ED may be classified as psychogenic, organic (neurogenic, hormonal, arterial, cavernosal and drug-induced), and mixed. Mixed ED is the most common encountered having both a psychogenic and organic component (Table 1).
Table 1. Classification and Common Causes of Erectile Dysfunction
Category of Erectile dysfunction
Common disorders
Pathophysiology
Neurogenic
Stroke or Alzheimer’s disease
Spinal cord injury
Radical pelvic surgeries
Diabetic neuropathy
Pelvic injury
Interrupted neuronal transmission
Failure to initiate nerve impulse
Psychogenic
Depression
Psychological stress
Performance anxiety
Relationship problems
Impaired nitric oxide (NO) release
Over-inhibition of NO release
Loss of libido
Hormonal
Hypogonadism
Hyperprolactinemia
Loss of libido
Inadequate NO release
Vasculogenic (arterial and cavernosal)
Hypertension Atherosclerosis
Diabetes mellitus
Trauma/ Bicycling accident
Peyronie’s disease
Impaired veno-occlusion
Inadequate arterial inflow
Drug-induced
Antihypertensives
Antiandrogen
Antidepressants
Alcohol abuse
Cigarette smoking
Central suppression
Decreased libido
Alcoholic neuropathy
Vascular insufficiency
Systemic diseases
Old age
Diabetes mellitus
Chronic renal failure
Coronary heart disease
Multifactorial
Neuronal and vascular dysfunction
Sexual function progressively declines as men age, although this decline need not be considered any more “normal” or “natural” than the development of diabetes, hypercholesterolemia, hypertension, or any other disease state more common in the aged. With age, the latent period between sexual stimulation and erection increases, erections are less turgid, ejaculation is less forceful, ejaculatory volume decreases, and the refractory period between erections lengthens (8). There is also a decrease in penile sensitivity to tactile stimulation, a decrease in serum testosterone concentration, and an increase in cavernous muscle tone (9-11).
Erectile dysfunction is more common in patients with neurologic disorders such as Parkinson's and Alzheimer's diseases, stroke, and cerebral trauma. This may be due to both a decrease in libido and/or inability to initiate the erectile process. Spinal cord injury patients have varying degrees of erectile dysfunction largely dependent on the location and extent of the lesion. Sensory input from the genitalia is essential to achieve and maintain reflexogenic erection, and this input becomes more important as the effect of psychological stimuli abates with age.
About 50 percent of men with chronic diabetes mellitus are reported to have erectile dysfunction. In addition to the disease's effect on small vessels, it may also affect the cavernous nerve terminals and endothelial cells, resulting in deficiency of neurotransmitters (4). Additionally, in diabetics, corporal smooth muscle relaxation in response to neuronal- and endothelial-derived nitric oxide (NO) is impaired, possibly due to the accumulation of glycosylation products .
Chronic renal failure has frequently been associated with diminished erectile function, impaired libido, and infertility. The mechanism is probably multifactorial: low serum testosterone concentrations, diabetes mellitus, vascular insufficiency, multiple medications, autonomic and somatic neuropathy (16), and psychological stress.
Psychogenic ED can be caused by performance anxiety, strained relationship, lack of sexual arousability, and overt psychiatric disorders such as depression and schizophrenia. Several studies have confirmed the strong relationship between depression and sexual dysfunction (17, 18).
Androgen deficiency results in a decrease in nocturnal erections and decreases libido. However, erection in response to visual sexual stimulation is preserved in men with hypogonadism, suggesting that androgen is not essential for erection (19). Prolactin has inhibitory activity on central dopaminergic activity and gonadotropin-releasing hormone secretion; ergo, hyperprolactinemia of any cause often results in reproductive and sexual dysfunction from secondary hypogonadotropic hypogonadism.
Vascular disease is another common cause of ED. Common vascular risk factors associated with generalized penile arterial insufficiency include hypertension, hyperlipidemia, cigarette smoking, diabetes mellitus, and pelvic irradiation (22, 23). Focal stenosis of the common penile artery most often occurs in men who have sustained blunt pelvic or perineal trauma (e.g., biking accidents, pelvic fractures) (22). Patients with hypertension may develop erectile dysfunction from the associated arterial stenotic lesions associated with elevated blood pressure (24).
Veno-occlusive dysfunction (VOD) may result from the formation of large venous channels draining the corpora cavernosa. In this situation there may be inadequate compression of the subtunical venules during the full erection phase (25). Venous leak impotence may also be the result of degenerative changes that affect the penis including Peyronie's disease, penile scarring, , and diabetes mellitus. A patient may develop VOD from traumatic injury to the tunica albuginea such as a penile fracture. Venous leak can also be seen in anxious men with excessive adrenergic tone causing structural alterations of the cavernous smooth muscle and endothelium and insufficient trabecular smooth muscle relaxation (10). Finally, VOD can be seen in patients with acquired shunts that result from the operative correction of priapism.
Many drugs have been reported to cause erectile dysfunction. Central neurotransmitter pathways, including serotonergic, noradrenergic, and dopaminergic pathways involved in sexual function, may be disturbed by antipsychotics, antidepressants and centrally acting antihypertensive drugs. Although any antihypertensive agent could theoretically cause ED by decreasing the availability of blood to the corporal arteries (i.e. a pressure-head phenomenon), differences are noted between various classes of medications, with le angiotensin converting enzyme inhibitors and angiotensein receptor blockers less likely to cause ED. Beta-adrenergic blocking drugs may lead to erectile dysfunction by potentiating a-1 adrenergic activity in the penis, although more modern beta blockers with eNOS activity (such as nebivolol) may help minimize this effect. Thiazide diuretics have been reported to cause erectile dysfunction by an unknown mechanism. Spironolactone, acting as an anti-androgen, can cause a decrease in libido and gynecomastia as well as causing ED. Cimetidine, a histamine-H2 receptor antagonist, has been reported to decrease libido and cause ED; it acts as an anti-androgen and can cause hyperprolactinemia(30). Other drugs known to cause erectile dysfunction are estrogens and drugs with anti-androgenic action such as ketoconazole and cyproterone acetate.
Social drugs including cigarettes and alcohol also affect erectile function. Cigarette smoking may induce vasoconstriction and penile venous leakage because of its contractile effect on the cavernous smooth muscle (31); more importantly, chronic use may accelerate atherosclerotic changes in penile microvaculature. Alcohol in small amounts may improve erections and increases libido because of its vasodilatory effect and the suppression of anxiety; however, large amounts can cause central sedation, decreased libido and transient erectile dysfunction. Chronic alcoholism may cause hypogonadism and polyneuropathy, which may affect penile nerve function (32).
8.3. EVALUATION OF ERECTILE DYSFUNCTION
Erectile dysfunction may be the first manifestation of many disease states, including diabetes mellitus, coronary artery disease, hyperlipidemia, hypertension, spinal-cord compression, pituitary tumors, and pelvic malignancies (Figure 1). In fact, ED has been proven to be a sentinel event for future cardiac disease and should therefore be taken as an indication that formal cardiovascular evaluation is indicated. The evaluation of a patient with ED requires a thorough history (medical, sexual and psycho-social), physical examination and appropriate laboratory tests (creatinine, fasting glucose, lipid profile, and testosterone) aimed at detecting these diseases. If the man's total testosterone concentration is low, serum free (or bioavailable) testosterone, prolactin, and lutenizing hormone should be assayed.
After assessing the therapeutic needs and goals of the patient and his partner, further diagnostic and treatment options should be contemplated. Consideration should be given to the patient's physical and mental health as well as his motivation and sexual needs. The patient's performance status and cardiovascular health need to be evaluated, if necessary in consultation with a cardiologist, in order to assess the patient's ability to tolerate sexual activity. Occasionally, a change in life-style or medications may be all that is needed to restore potency.
Some men may benefit from a referral for further testing and treatment (Table 2). The indications for specialty referral include: complex gonadal or other endocrine disorders, neurologic deficit suggestive of brain or spinal cord disease, deep-seated psychologic or psychiatric problems, Peyronie's disease, post-traumatic or primary erectile dysfunction, and active cardiovascular disease.
Table 2. Medical Workup of Erectile Dysfunction.
Test
Indications
Combined injection and stimulation (CIS) test
Injection of intracavernous medication Followed by penile stimulation
Assess penile vascular function.
Therapeutic test in men who choose intracavernous therapy
Duplex (color) ultrasonography
Assess penile hemodynamics and presence of Peyronie’s disease
Cavernosography
Assess for congenital or traumatic venous leakage, most useful in young men contemplating venous surgery for ED
Pelvic arteriography
Assess for correctable lesions in young men with traumatic arterial insufficiency
Ambulatory nocturnal penile tumescence and Rigidity (Rigiscan®)
Differentiate psychogenic from organic erectile dysfunction
8.4. MEDICAL MANAGEMENT OF ERECTILE DYSFUNCTION (Table 3.)
Table 3. Various Treatments of Erectile Dysfunction.
Treatment
Cost
Advantage
Disadvantage
Rcommendation
Psychosexual Therapy
$50- 150 /session
Non-invasive. Partner involved. Potentially curative for Psychogenic ED
Time consuming
Patient resistance to medication
First-line treatment. May be combined with other treatments
Oral: PDE 5 inhibitor (sildenafil, tadalafil, vardenafil)
$10-20 /dose Oral
Effective 1-hour wait
Up to 24 hour action (tadalifil)
May be taken on-demand or as daily supplement (tadalafil only)
Contraindicated in:- Men with severe cardiovascular disease- Men on nitrates
Potential for side effects
First-line treatment
Vacuum Constriction Device
$150- 450 /device
No systemic side effects
May compromise ejaculation
May be uncomfortable and/or cause numbness for some men
2nd-line treatment
Transurethral: MUSE®1
$25 /dose
Local therapy. Few systemic side effects
Moderately effective. Requires raining. May cause penile pain
2nd-line treatment
Penile injection (Caverject®, Edex®, or compounded drugs) 3,4
$5-25 /dose
Highly effective (up to 90%) Few systemic side effects
Requires injection. May cause penile pain. High dropout rate. Risk of priapism or fibrosis
2nd-line treatment
Penile Prosthesis (all types)
$8,000- 15,000
Very Successful
Unnatural erection. Risk of device infection. Requires surgery. Requires replacement after mechanical failure (typically 5-15 years
Men dissatisfied with medical management
Vascular Surgery
$10,000- 15,000
Potentially curative
Requires surgery. Poor results in older men with generalized disease
Young men with congenital or traumatic ED
1. MUSE signifies Medicated Urethral System for Erection. It contains alprostadil pellet. 2. Caverject and Edex both contain injectable alprostadil.4. Drug mixtures contain two or three of the following drugs: papaverine, phentolamine and prostaglandin, atropine.
Historically, androgens were thought to enhance male sexual function. However, androgen therapy has only been shown to be of benefit in hypogonadal men; this benefit primarily pertains to libido but some improvements in erectile function and response to PDE5 inhibitors have been reported after testosterone supplementation in select populations. Testosterone therapy in men with normal hormonal levels may temporarily increase libido and desire but does not affect ED in this population (33).
Transdermal and intramuscular testosterone therapy are generally more efficacious than oral testosterone preparations (34, 35). Testosterone cypionate and enanthate are often used for intramuscular replacement therapy; the usual dosage is 200 mg intramuscularly every 2 to 3 weeks. Their major drawbacks are the marked peaks and troughs in serum testosterone, with high levels in the first week after injection and a decrease thereafter.
Several transdermal testosterone preparations (testosterone patches or gels) as well as an implantable subcutaneous testosterone pellet are now available. Daily application of these preparations raises serum testosterone concentrations to within the normal range in over 90 percent of men. The most common adverse effects of testosterone patches have been skin irritation and contact dermatitis.
The safety profile of testosterone remains somewhat controversial but it the most recent data suggest that testosterone supplementation appears to be safe with respect to risk of prostate cancer development. However, extreme caution with respect to testosterone supplementation should exercised in men with untreated prostate cancer. Additionally, testosterone treatment may cause polycythemia and worse obstructive sleep apnea, and so men receiving androgen replacement therapy require biannual checks with measurementof hematocrit, serum testosterone, liver function tests, and PSA. More frequent checks in the early phase after initiation of therapy are often prudent.
Oral therapy with a type 5 phosphodiesterase inhibitor (PDE-5 inhibitors, sildenafil, vardenafil and tadalafil) is considered first line therapy in men with ED (36) . PDE-5 inhibitors block the inactivation of cyclic GMP and result in increased smooth muscle relaxation and better erections. In the absence of sexual stimulation these medications have no effect on the penis. Numerous placebo controlled studies have been conducted on the safety and efficacy of sildenafil as it has been in clinical use for over a decade. The results have shown that the number of erections and rates of penile rigidity, orgasmic function, and overall satisfaction were significantly higher with sildenafil than placebo (37, 38).
In terms of safety, most clinical trials published show only mild to moderate adverse events associated with all of the PDE-5 inhibitors, and these events are usually self limited in duration.(30, 39) The most common complaints are of headache (16 percent), flushing (10 percent), dyspepsia (7 percent), nasal congestion (4 percent), and visual disturbances/ color sensitivity (3 percent). Tadalafil distinguishes itself from vardenafil and sildenafil by the relative lack of visual side effects. It does however have an additional possible adverse effect which is back pain and/or myalgia (31, 40)
There is no difference in terms of adverse or serious cardiovascular events between PDE-5 inhibitors and the placebo-controlled groups (38). To date, well over 20 million men in over 100 countries have used sildenafil.(30, 39) Since the release of the drug, over 200 deaths temporally associated with sildenafil therapy were reported to the Food and Drug Administration in the United States of America. Sexual activity was thought to be a likely contributor to myocardial infarction, with sildenafil acting to enable men not previously active to partake in sexual activity (31, 32). Therefore, it appears that PDE-5 inhibitor therapy is safe for most men. Men with cardiovascular disease should however seek a cardiologist consultation prior to using PDE-5 inhibitors to insure that their heart is able to tolerate the physical exertion of sexual activity. The American Heart Association has published a guideline for sildenafil therapy (Table 4.) (43).This includes pre-therapy evaluation of cardiac status for men on multiple antihypertensive medications, pre-existing cardiac disease, and men using nitrite medications (44). These guidelines may be extrapolated for use with all PDE-5 inhibitors.
A lower starting dose (25 mg of sildenafil, 5 mg of vardenafil or tadalafil) should be used in patients who may attain and maintain higher plasma levels. These include patients who are older than 65, have severe renal impairment, or take potent CYP450 3A4 inhibitors. Patients who take ritonavir should not take more than 25 mg of Sildenafil in a 48-hour period.
Patients using PDE5 inhibitors and requiring alpha-blocker therapy should start at low doses, and be titrated gradually to effect. To avoid symptomatic hypotension, PDE5 inhibitors should not be taken within 4 hours of an alpha-blocker. One study found a significant rate of hypotension (28% versus 6% with placebo) in patients taking concomitant doxazosin and tadalafil; however, the rate of hypotension matched that seen in placebo-treated patients in patients taking tamsulosin and tadalafil, and some studies suggest that the interaction has less clinical relevance in patients who have undergone long-term alpha blocker therapy. The position of the American Urological Association is that all three PDE5 inhibitors interact to some degree with alpha-blockers and that concurrent use of alpha-blockers and PDE5 inhibitors may cause patients to develop orthostatic hypotension. Other antihypertensive agents, such as calcium channel blockers, are well-tolerated by men concurrently taking any of the three PDE5 inhibitors. Concomitant administration of these drugs appears to cause no or only small additive drops in blood pressure.
Non-arteritic ischemic optic neuropathy (NAION) and PDE5 inhibitor use has garnered a great deal of attention in both scientific and lay publications. Spontaneous NAION is the most common acute optic neuropathy and ranks second only to glaucoma as a cause of acquired optic neuropathy for men aged 50 and older. Estimated annual incidence is 2.3 to 10.3 per 100 000 and is more common in Caucasians than African Americans, Asians, or Hispanics. Most patients do not become legally blind, but the degree of visual acuity and visual field loss is usually significant. Risk factors common to NAION and ED include hypertension, diabetes mellitus, hypercholesterolemia, age over 50 years, coronary artery disease, and smoking. Given that an estimated 27 million men worldwide that have used sildenafil (up to 1 billion doses), not counting tadalafil or vardenafil users, the expected incidence of NAION in this group should be many-fold higher than the 43 cases reported to the FDA as of June 2005. If one bases calculations on the most conservative incidence of NAION in the general population (2.3 cases per 100,000) and the fact that there are at least 27 million users of PDE5 inhibitors, one would expect at least 621 cases in this population. This comparison therefore begs the question of whether PDE5 inhibitors exert a protective influence on the evolution of NAION. To date, the FDA maintains that a causal relationship between NAION and PDE use has not been established. Review of safety data from over 100 clinical studies of sildenafil (>13 000 men) did not identify any cases of NAION, with similar findings for vardenafil and tadalafil. Given current evidence, it is not possible to determine whether these events are directly related to use of PDE5 inhibitors or to other factors; however, men are instructed to stop taking these medications immediately and contact their physician should visual changes or loss occur. Men with a history of NAION should not use PDE5 inhibitors.
There has also been some recent concern regarding the potential of PDE5 inhibitors to interfere with hearing. Several dozen cases of PDE5 inhibitor associated hearing loss have been reported and some research has indicated mechanisms by which hearing loss may be attributable to action of these drugs. Men who experience hearing impairment while using PDE5 inhibitors should halt treatment until they are able to speak with their doctors regarding long term risk of hearing loss.
Table 4. Recommendations for Sildenafil in Men With Cardiac Disease
1. Sildenafil is contraindicated in men taking long-acting or short-acting nitrate drugs.
2. Men with stable coronary disease not needing nitrates on a consistent basis may take sildenafil if the risks of the medication have been carefully discussed with the patients by their physician. If the patient requires nitrates for mild or moderate exercise induced angina, sildenafil should not be given.
3. All men taking an organic nitrate (including recreational amyl nitrate) should be informed about the nitrate/sildenafil hypotensive interaction.
4. Men must be warned of the danger of taking sildenafil in the 24-hour period before or after taking a nitrate preparation.
5. Pre-sildenafil treadmill testing may be indicated in some men with cardiac disease to assess the risk of cardiac ischemia during sexual intercourse.
6. Initial monitoring of blood pressure after taking sildenafil may be indicated in: men with congestive heart failure who have borderline low blood pressure and low volume status; and men being treated with a complicated, multidrug antihypertensive regimen.
*Prepared by the American Heart Association (31)
Sildenafil (Viagra, Pfizer) works best when taken on an empty stomach and reaches maximum plasma concentrations within 30 to 120 minutes (mean 60 minutes). It is eliminated predominantly by hepatic metabolism, and the terminal half-life is about 4 hours. The recommended starting dose is 50 mg taken 1 hour before sexual activity. The maximal recommended frequency is once per day. The efficacy of sildenafil has been extensively studied in patients with other coexisting diseases. No significant difference in response rate was noted comparing a normal cohort of patients with patients with hypertension (57), spinal cord injury, depression (58), prostate surgery (59) , diabetes (60) and the elderly(61) . Patients who have undergone non-nerving sparing radical prostatectomy have a lower response rate to sildenafil compared to a normal cohort of patients (59) (Table 5.).
Table 5. Success of Sildenafil in Men with Erectile Dysfunction
Response
Cause of Erectile Dysfunction
Diabetes Mellitus
Spinal Cord Injury
Radical Prostatectomy
Psychogenic
Depression
(N = 268)
(N = 178)
(N = 107)
(N = 179)
(N = 151)
Improved erection
Placebo
10%
12%
15%
26%
18%
Sildenafil
57%
83%
43%
84%
76%
uccessful intercourse
Placebo
12%
13%
N/A
29%
NA
Sildenafil
48%
59%
43%
70%
N/A
Sildenafil dosage 50 to 100 mg (source:Sildenafil package insert [Pfizer Inc. New York, NY., 1998])
Vardenafil (Levitra, Bayer/GSK) is a potent and highly selective PDE-5 inhibitor. Its chemical structure is quite similar to sildenafil however in in-vitro studies the selectivity and potency of vardenafil are superior. The medication can be given in either 10 or 20 mg dosage. The time to peak plasma concentration is 40-55 minutes. Vardenafil has been shown to be highly efficacious in a wide range of clinical indications. In one multicenter phase III trial patients with diabetes (type I and II) were found to respond to 20 mg dosage of vardenafil significantly better then a similar control group. The effect also seemed to improve after 12 weeks of treatment. (62). Although similar in chemical structure, the in vitro potency and selectivity of vardenafil are superior to that of sildenafil. There has not, however, been any convincing evidence that this translates to superior results in vivo.
Several newer studies have demonstrated vardenafil to have a faster onset of action then seen with other medications of the same class. In particular one study (ONTIME) found that 21% of men with moderate to severe erectile dysfunction obtained erections of sufficient firmness for sexual intercourse at 11 minutes after using 20 mg of Vardenafil. At 25 minutes 53% of patients obtained erections sufficient enough for penetration as compared to placebo (26%). The statistically superior response to vardenafil versus placebo was observed in all times from 11-25 minutes. The side effects most frequently seen with vardenafil include flushing, dyspepsia, headache and visual disturbances. (66-68) Adverse events reported in men taking vardenafil closely resemble those in men taking sildenafil and tadalafil. Headache (21%), flushing (13%), dyspepsia (6%) are seem at various frequencies depending on dosages used.
Tadalafil (Cialis, Eli Lilly, USA) is a PDE-5 inhibitor which has a distinctly different chemical structure from vardenafil and sildenafil. Because tadalafil has less of an inhibitory effect on PDE-6 it lacks the visual side effects that sildenafil and vardenfil may cause. Tadalafil is dosed at 5, 10,and 20 mg on demand and is also available as a daily dose medication at 2,5 and 5 mg. Tadalafil’s erection potentiating effect may onset within 30-45 minutes of dosing but may last as long as 24-48 hours (70). As with the other PDE-5 inhibitors the side effect profile of this medication is quite mild. In addition to the lack of visual side effects, it also tends to have a reduced incidence of facial flushing compared to the other PDE-5 inhibitors. Back pain however has been noted in several studies (45). Another distinguishing factor of this new PDE-5 inhibitor is that there is no effect on the absorption of tadalafil by alcohol or food. An integrated analysis from five randomized control double blind placebo trials revealed that men with varying severities of ED significantly improved with Tadalafil therapy at 10 and 20 mg dosages. The mean IIEF score (international index of erectile dysfunction score) increased by 6.5 and 7.9 at the 10 and 20 mg dosage of tadalafil. This increase was statistically significant compared to placebo. (71) In pharmacological studies tadalafil appears to be rapidly absorbed and reaches a peak serum concentration by 2 hours. The uniqueness of tadalafil appears to be in that its half life is approximately 17.5 hours. As well, the absorption and excretion of tadalafil does not appear to be affected by food or alcohol. With a 17.5 hour half life tadalafil has period of responsiveness of up to 36 hours. 59% of patients who were administered a SEP questionnaire 24 hours after dosing (20 mg of tadalafil) responded positively to having successful intercourse as compared to 7% of placebo patients.
Like sildanafil and vardenafil, tadalafil potentiates the hypotensive effects of nitric oxide and it is therefore contraindicated in patients taking nitric oxide compounds. Tadalafil appears to be very well tolerated in most studies. The most frequently reported adverse events are headache and dyspepsia. Back pain, nasal congestion, myalgia and nasal congestion appear to be more transient and decrease in frequency with future treatments. The rate of treatment discontinuation as with sildenafil and vardenafil is similarly quite low at 2.2% compared with the placebo discontinuation rate of 1.3%.
PDE-5 Inhibitors and Cardiovascular Safety.
Controlled and post-marketing studies of the three FDA-approved PDE-5 inhibitors demonstrated no increase in myocardial infarction or death rates in either double-blind, placebo-controlled trials or open-label studies when compared with expected rates in the study populations . Patients with known coronary artery disease or heart failure receiving PDE-5 inhibitors did not exhibit worsening ischemia, coronary vasoconstriction, or worsening hemodynamics on exercise testing or cardiac catheterization. PDE-5 inhibitors have a minimal effect on QTc interval. However, vardenafil is not recommended in patients who take type-1A antiarrhythmics (such as quinidine or procainamide) or type-3 antiarrhythmics (such as sotalol or amiodarone) or in patients with congenital prolonged QT syndrome.
The vasodilator effects of sildenafil, vardenafil, and tadalafil may be more marked in patients with hypertension or coronary artery disease. As with all vasodilators, caution is advised in certain conditions: aortic stenosis, left ventricular outflow obstruction, hypotension and hypovolemia. Caution is advised when an alpha-blocker and a PDE-5 inhibitor are given together, as interaction can lead to excessive vasodilation and hypotension.
Nitrates are absolutely contraindicated in patients taking PDE-5 inhibitors. These include organic nitrates, including sublingual nitroglycerin, isosorbide mononitrate, isosorbide dinitrate and other nitrate preparations used to treat angina, as well as amyl nitrite or amyl nitrate (so-called “poppers,” a recreational drug). Past use of nitrates, e.g. more than two weeks before the use of PDE-5 inhibitors, is not considered a contraindication. Patients who develop angina during sexual activity with a PDE-5 inhibitor should be instructed to discontinue sexual activity, relax for 5-10 minutes and, if the pain persists, seek emergency care and inform emergency medical personnel that a PDE-5 inhibitor was taken.
PDE5i ‘failures’: Prior to moving on to 2nd line treatments, several strategies may be taken when a patient complains that medication prescribed PDE5 inhibitor is not having the desired effect. An important first step is re-education on the correct use of the medications. Many patients need to be reminded that these medications are reliant on central mechanisms and that they will not work well without erotic stimulation. Up to 55% of sildenafil initial non-responders will respond after education (74.1,74.2). Dose titration may be necessary. Additionally, sildenafil may not work as well after a high fat meal, although tadalafil seem to be less dependent on timing with regard to meals. Another step that can be taken is to check hormonal levels, as these medications are at least partially androgen-dependent and improved efficacy after testosterone replacement in hypogonadal men has been observed. There is also evidence that efficacy may improve with chronic use, at least in animal models.
Yohimbine is an alpha 2-adrenergic receptor antagonist produced from the bark of the yohim tree. Its effect on erectile function is at best marginal and is therefore not recommended in patients with organic ED. A meta-analysis of several placebo-controlled studies of 419 men with predominantly non-organic ED has shown some benefit over placebo (75). Frequent side effects include palpitation, fine tremor, elevation of blood pressure, and anxiety.
Oral phentolamine (Vasomax®) has been reported to improve erectile function compared to placebo (76, 77). Side effects of the medication include headache, facial flushing, and nasal congestion. Oral phentolamine has not been approved by the FDA, but it is available in several South American countries.
Apomorphine (Uprima®), a dopaminergic agonist, is a sublingual medication that is available for use in Europe. Apomorphine is a potent emetic that acts on central dopaminergic (D1/D2) receptors. When injected subcutaneously, it induces erections in rats and humans, but the side effects, notably nausea, seriously limited its clinical usefulness (78). Sublingual apomorphine has not received FDA approval.
Bremelanotide is a melanocortin analog that acts centrally and has been investigated in subcutaneous and intranasal administration. These studies reported statistically significant improvements in erections compared to placebo in both healthy men and those who did not respond well to sildenafil. Common side effects include flushing and nausea. The medication has not been approved by the FDA due to concerning elevations in blood pressure which were noted during phase III studies.
Second line therapy for ED includes the vacuum constriction device (VCD), trans-urethral suppositories (MUSE®) and intra-cavernous injection (ICI) therapy. VCD produces erection via vacuum suctioning of blood into the corporal spaces. Blood is subsequently trapped in the penis with a constriction device Placed at the base of the phallus. This type of therapy is preferred for older patients in stable relationships. Its potential side effects include discomfort, petechiae, numbness, and a interference with ejaculation.
The Medicated Urethral Suppository for Erections (MUSE®) is a transurethral prostaglandin suppository that has several advantages including local application, minimal systemic effects, and the rarity of drug interaction. However, this type of secondary treatment has failed to gain popularity due to its major drawbacks including moderate to severe penile pain, low response rate, and inconsistent efficacy (81, 82). It has been extensively studied in Europe and the United States and was found to be effective in 43 percent of men with erectile dysfunction of various organic causes. The most common side effects were penile pain (32 percent) and urethral pain or burning (12 percent) (83, 84). Using an adjustable constriction device (Actis®) placed at the base of the penis after MUSE administration resulted in an increase in successful sexual intercourse in 69 percent of men (85). Unfortunately the Actis® ring is no longer commercially available but alternative constrictive devices may be obtained from adult stores, with the important caveat that no constrictive device should be left on for more than 30 minutes and the device should be promptly removed if there are signs of numbness or ischemia. Patients are initially started with a test dose of 500-?g of MUSE® in the office. Depending on the patient's response, this dose can be titrated from 250-1000 ?g. It is important to administer the test dose in the office due to the risks of urethral bleeding, vasovagal reflex, hypotension, and priapism that can occur with this medication.
There are several intracavernous medications available for the treatment of ED including papaverine, alprostadil, phentolamine, VIP (vasoactive intestinal polypeptide), and ketanserin. Men must receive appropriate training and education by medical personnel before beginning home injections. The goal is to achieve an erection that is adequate for sexual intercourse but does not last for more than one hour. The two major side effects of intracavernous injection are priapism and fibrosis (penile deviation, nodules or plaque). Priapism is preventable through careful titration. To prevent eccchymosis, we routinely instruct men to compress the injection site for 5 minutes (up to 10 minutes in men taking anticoagulants). Intracavernous injection therapy is contraindicated in men with sickle-cell anemia, schizophrenia or other severe psychiatric disorder due to the risk of priapism associated with intracavernous injection.
In the U.S., the most commonly used (and only FDA approved) intracavernous drug isalprostadil.Alprostadil's efficacy is superior to papaverine alone and it results in erections in more than 70 percent of treated men (86). The usual dose ranges from 5 to 20 ?g. The most frequent side effect is painful erections that occur in 17 to 34 percent of men (86, 81). This hyperalgesic effect is most prominent in men with partial nerve injury, such as those with diabetic neuropathy and those who have undergone radical pelvic surgery. Alprostadil has a relatively low incidence of priapism (0.35 to 4 percent) and fibrosis (1 to 23 percent) (51, 87, 88).
Papaverine is a non-specific phosphodiesterase inhibitor that increases cyclic AMP and cyclic GMP concentrations in penile erectile tissue (89) Its usual dose ranges from 15 to 60 mg. It is more effective in psychogenic and neurogenic erectile dysfunction (up to 80 per cent) compared to vasculogenic (36-50 per cent). Its advantages include low cost and stability at room temperature. Its major disadvantages are priapism (up to 35 percent when taken in large doses), corporal fibrosis (up to 33 percent although the clinical relevance of mild fibrosis is debatable) and occasional perturbations in serum liver enzyme levels.
Phentolamine is a competitive alpha-adrenergic receptor antagonist. It is most often used in combination with papaverine (Bimix) to produce rigid erections (63-87% success rates) (90, 91). Most urologists use a combination of 30 mg papaverine and 0.5 to 1 mg phentolamine. The potential side effects of phentolamine include hypotension and reflex tachycardia.
Vasoactive intestinal polypeptide (VIP) is a potent smooth muscle relaxant originally isolated from the small intestine. This medication is only available in Europe. Injection of vasoactive intestinal polypeptide alone does not produce a rigid erection, (92) but when combined with phentolamine it produces erections sufficient for sexual intercourse in up to 67 percent of men (93). Common side effects include transient facial flushing (53 percent), bruising (20 percent), pain at the injection site (11 percent), and truncal flushing (9 percent).
Combinations of medications such as papaverine and alprostadil (94), ketanserin and alprostadil,(95) and phentolamine and alprostadil(96) have been proven to be superior single medications in efficacy of response. The most effective intracavernous therapy used in the U.S. is a three-drug mixture containing papaverine, phentolamine and alprostadil (Trimix). The usual dose of Trimix solution ranges from 0.1 to 0.5 ml. The response rate to this solution is reportedly as high as 90 percent (97). Although widely used in the U.S., trimix is not approved by the FDA.
Although the response rate to injection therapy is high, in long-term studies 38 to 80 percent of men cease to use the treatment over time (98, 99). To avoid the cumbersome nature of injection therapy, some men alternate injection therapy with sildenafil or MUSE®, preferring injection in circumstances when an erection of longer duration is desired. Alternatively, in men whom injection therapy alone fails or is insufficient, we recommend the use of injection therapy in combination with a vacuum constriction device.
No transdermal medication has been approved by the FDA for erectile dysfunction although some such preparations are available through compounding pharmacies. Nitroglycerine cream or paste, alprostadil cream, and a cream containing aminophylline, isosorbide dinitrate, and codergocrine mesylate have been used in pilot studies in men with erectile dysfunction with variable results (100).
8.5. PRIAPISM
Priapism is defined as a painful prolonged penile erection in the absence of sexual stimulation. Two subtypes of priapism have been described.
NON-ISCHEMIC PRIAPISM
Non-ischemic (or high-flow) priapism, is relatively rare. In this scenario, injury to a cavernosal artery, usually after perineal or direct penile trauma, results in uncontrolled high arterial inflow within the corpora cavernosa. Patients with arterial priapism typically seek medical attention later than those with ischemic priapism, due to the fact that non-ischemic priapism causes less pain and discomfort.
Non-ischemic priapism is not considered a medical emergency. Treatment is tailored to the circumstance that induced this condition. In some cases conservative therapy will allow the injured cavernous artery to seal off and restore normal blood flow to the corporal bodies. In other more established cases embolization or even open repair of the cavernous vessels might be needed. Use of super selective arteriography allow for the exact determination of the site of injury and treatment through embolization. There remains a low risk of impotence associated with high flow priapism. This must be considered in treating these individuals.
ISCHEMIC PRIAPISM
Ischemic (or low-flow) priapism is much more common and is characterized by a veno-occlusive state in which inadequate venous outflow creates an acidotic hypoxic environment leading to a painful prolonged erection. This more common type of priapism has become a well-recognized clinical entity because of the widespread use of intracavernous agents for erections.
Ischemic priapism should be considered a serious medical condition as it can lead to permanent penile fibrosis and erectile dysfunction. When effectively treated early (within 6-12 hours) little risk of permanent injury exists. Tissue injury is visible after 12 hours of ischemia, characterized as interstitial edema. Within 24 hours, there is destruction of the sinusoidal endothelium and adherence. All men using vasoactive drugs for penile self-injection should be instructed to seek medical attention if their erection persists longer than 3-4 hours. Other causes of ischemic priapism include sickle cell anemia, medication induced, and pelvic malignancy.
The agent of choice for the treatment of ischemic priapism is phenylephrine at a dosage of 100-250 ug injected into the cavernous body each 2 minutes until the penis is no longer rigid. At this concentration, little impact on the systemic BP is seen in most men although blood pressure and heart rate should be monitored in men with cardiac disease. Detumescence is often seen by 2-5 minutes and will first be noted with return of the arterial pulsations of the penis. In some cases, aspiration of blood of the fully rigid penis may be needed to attain detumescence. Once the rigidity is decreased a more effective delivery of the alpha-agonist is possible. However, it is important to understand that even in most cases when a fully rigid erection is present simply injecting phenylephrine will succeed in reversing the condition. Cases refractory to conservative management may require surgical shunting procedures to return the penis to a flaccid state. One exception is with sickle cell anemia. Priapism in these patients should be initially treated with oxygenation, hydration, analgesia and transfusions to reduce the concentration of hemoglobin S below 30%.
The long-term sequelae of ischemic priapism may include penile scarring and fibrosis, penile deformity and ED. Strategies to avoid these complications include education of the patient on an injection program and rapid treatment of priapism as it occurs.
8.6. SURGICAL MANAGEMENT OF ERECTILE DYSFUNCTION
With advances in basic science research, newer pharmacological therapies have decreased the indications of surgical therapy of ED. Nevertheless, surgical therapy remains an important part of the urologists' arsenal in the treatment of medically refractory ED. One of the earliest contemporary surgical approaches to ED was described by Wooten in 1902, who recommended ligation of the dorsal vein of the penis as a means for restoring erections (101). Penile prosthesis surgery was described in the early 1930s. (102) The superficially placed rigid prosthesis made from synthetic material soon followed.(103) These early prostheses tended to shift under the penile skin and were generally unsatisfactory.
It was not until the early seventies that satisfactory results were seen with the introduction of modern prosthetic devices which fit into the corpora cavernosa and provided both good functional as well as cosmetic results(102, 104, 105). At around the same time,
penile arterial bypass surgery was reported i as a treatment for erectile dysfunction from arterial insufficiency. Finally, venous surgery for ED was re-introduced with modifications in the early eighties to treat corporal veno-occlusive dysfunction. While penile prosthetic devices have generally been successful for a wide range of patients, vascular surgery (both arterial and venous) for ED has been effective only in very select patients, typically healthy young men with either congenital or traumatic ED;for this reason penile prosthesis surgery is considered the standard surgical treatment of erectile dysfunction.
8.7. ARTERIAL REVASCULARIZATION
Arterial revascularization offers patients the possibility of restoration of normal erectile function without the necessity of medications, injections, or devices. Penile arterial bypass surgery was first described in the early 1970s (106, 107) and has undergone many modifications since its early description. Penile arterial insufficiency is most frequently the result of general arteriosclerosis as seen in other medical conditions with similar risk factors of hypercholesterolemia, hypertension, cigarette smoking, and diabetes mellitus. In patients with arterial insufficiency from these entities, penile revascularization is unlikely to be of benefit. Rather, this surgery may be of use in young healthy men with traumatic disruption of a discrete segment of the penile vasculature.
Penile arterial insufficiency is diagnosed by performing an intracavernous injection test followed by self stimulation (audiovisual or manual) (108). Duplex ultrasonography of the penis performed during injection and stimulation test can help delineate echogenicity of corporal tissues, peak flow velocity of cavernosal arteries, thickness of tunica albuginea and cavernosal arteries, diameter and wave form of arteries. Once the diagnosis of pure arterial insufficiency has been confirmed, selective penile/pudendal arteriogram is necessary to identify penile vascular anatomy, demonstrate communication between cavernosal and dorsal arteries, confirm location of obstructive/traumatized arterial lesion, and plan surgical reconstruction.
Several techniques of revascularization have been described (109-112). Current approaches use a technique whereby the epigastric artery is anastomosed to the dorsal penile artery (revascularization) or the deep dorsal vein (arterialization). Long term results of these patients have been disappointing with an efficacy of 30-50% in well selected patients, but, with increasing accuracy of diagnostic modalities, improved operative techniques, and a narrowed selection criteria, long term results have significantly improved to greater than 60% (109, 113, 114). Young men with arterial insufficiency secondary to pelvic trauma are the ideal patients for this procedure (115). Recently, laparoscopy has been used to minimize the morbidity of the procedure (116). Overall long-term success in appropriately selected patients range from 34-80% spontaneous erections (109, 117). The most frequent side effect with penile arterialization has been hyperemia of the glans. This can occur in up to 13% of patients who have undergone epigastric artery-deep dorsal vein anastomosis. Other complications include infection, hematoma, and thrombosis of anastomosis.
8.8. VENOUS SURGERY
Venogenic dysfunction is often suspected during evaluation by the finding of a sub-optimal erectile response to intracavernosal injection despite a normal arterial response on duplex Doppler sonography. The presence of persistent end-diastolic flow of greater than 5 cm/sec on duplex sonography has also been shown in some studies to correlate with the finding of venous leakage (118, 119). The gold standard test for the diagnosis of venogenic erectile dysfunction remains the dynamic infusion cavernosometry and cavernosography (DICC). Cavernosometry and cavernosography can be used to document the severity of venous leakage as well as visualize the sites of leakage (120-123). An abnormal cavernosometry result (after injection of vasodilators to completely relax the penile smooth muscles) is 1) an intracavernosal infusion rate of greater than 10cc/minute of saline to maintain the erection or 2) a drop of intracavernosal pressure of greater than 50 mmHg within 30 seconds of terminating the saline infusion (124, 125). An abnormal cavernosogram (performed immediately after cavernosometry) shows visualization of penile veins or venous leakage from the crura on films taken immediately after intracavernous injection of diluted contrast.
Only patients with clearly defined and visualized venous leakage on cavernosogram should be offered venous surgery for ED. Patients with generalized penile venous disease should be offered penile prostheses as it is unlikely that adequate ligation can be accomplished in these men without obliterating arterial inflow. Penile venous surgery should be limited to men under age 50 because the high incidence of combined arteriogenic and venogenic impotence in older men leads to an unacceptably high failure rate in this age group. Other relative contraindications to the procedure are: diabetes mellitus, generalized arterial disease, and unwillingness or inability to quit smoking. Informed consent should include the risks of possible numbness of the penile skin, shortening of penile length, penile curvature and hematoma. Some investigators also advocate concomitant deep dorsal vein arterialization in order to increase venous resistance (126, 127.
The historical lack of long-term success of venous ligation procedures can be partially explained by the complexity of venous drainage of the penis. In the majority of patients, multiple venous leak sites can be visualized on cavernosography. Common leak sites include the superficial and deep dorsal vein, crural veins, corpus spongiosum, and glans penis. The deep dorsal, cavernosal and crural veins are the main venous drainage of the corpora cavernosa and are the most common sites for ligation procedures. Another possible explanation in the widely varied results of venous surgery in the literature may be due to the many variations of surgical techniques developed to treat patients with veno-occlusive erectile dysfunction.
The reasons for failure of the procedure will vary, but include improper diagnosis, incomplete surgical resection of abnormal venous channels, the presence of an arteriogenic component, and the formation of collateral vessels. In a retrospective review of 50 patients (25 successful and 25 failures) who underwent penile venous surgery the most important factors affecting surgical outcome were the findings on cavernosography and the consequent ease of identification and suture-ligation of the abnormal leak(128, 129) . Those patients with leak into unusual sites, such as the glans, corpus spongiosum, crura in combination with a large amount of drainage to the deep dorsal or cavernous vein had the highest rate of failure. If the venous leak could be easily identified on the cavernosogram and could be suture ligated at the tunica albuginea, success was more likely. Development of venous collaterals and persistent venous leakage appears to be a contributing factor in many patients who fail to improve following venous surgery. Factors that predict a poor prognosis include increasing patient age, duration of impotence, multiple leak sites, proximal (crural) venous leak site, and concomitant arteriogenic insufficiency (102, 130).
At present, in our hands approximately 61% of patients with veno-occlusive dysfunction treated with venous surgery are improved after surgical correction. The etiology of veno-occlusive incompetence remains incompletely understood. As our understanding of the cavernosal and sinusoidal function of the penis improves treatment, both medical and surgical, of venous leakage can be directed towards treating the underlying cause rather than a symptom of the disease.
8.9. PROSTHETIC SURGERY
When there is lack of efficacy or dissatisfaction with other modalities, penile prostheses are often the best alternative for erectile dysfunction. Unlike the other modalities, prosthesis surgery is irreversible in that the corporal tissue is permanently altered such that physiologic erections are no longer possible. If the prosthesis has to be removed, there will be complete ED, although devices are readily replaced should mechanical failure occur. While a variety of exotic materials, flaps, and grafts have been used historically, most contemporary prostheses are hydraulic pumps or semi-rigid/malleable rods. The malleable prostheses are made of silicone rubber with a central intertwined metallic core. Mechanical devices are also made of silicone rubber with interlocking segments in a column, which provide rigidity when the rings are lined up in a straight line and flaccidity when the penis is bent (similar to a gooseneck lamp). The advantages of semi-rigid devices are that they are easy to implant, have few mechanical parts with minimal mechanical failure, and generally last longer than inflatable devices. The major disadvantage of the semi-rigid devices is that the penis is never fully rigid nor fully flaccid. These devices may interfere with urination, are difficult to conceal, and have a higher likelihood of device erosion. About 15% of patients choose semi-rigid rod implants, and those with limited mental or manual dexterity are encouraged to receive this type of device.
Inflatable prostheses come in two or three-component designs. Two-piece inflatable prostheses consist of a pair of cylinders attached to a scrotal pump. The prosthesis can be deflated by bending the penis at midshaft. While these devices permit some appearance of flaccidity, the lack or a reservoir does limit the amount of detumescence that can be attained,
Three-piece inflatable prostheses are the current gold standard for treatment of medically refractory ED and consist of a pair of penile cylinders, a scrotal pump, and a supra-pubic reservoir. They provide excellent rigidity when erect and a more natural appearance when flaccid. When fully erect, they are as rigid as the two-piece device. In the flaccid state, they surpass flaccidity of two-piece prostheses. Of all the prosthesis types, hydraulic three-piece implants have been the most popular, accounting for 85% of the US market. Most inflatable devices will need replacement after 10-15 years. Repair or replacement rates of 5%-20% in the first five years are realistic.
Of all modalities for management of ED, prostheses have the highest satisfaction rates, with 2 large studies demonstrating greater than 95% satisfaction for men and similar satisfaction rates for partners. This extremely high satisfaction rate is likely due to the capacity of prostheses to allow for spontaneous and repeated reliable erections without external medications or devices. However, it must be considered that men willing to undergo implantation of a penile prosthetic are a self-selecting group and may not be representative of the general male population with ED.
Infection remains the most devastating and feared complication of penile implant surgery. Modern prostheses allow for antibiotic impregnation and elution, and infection rates are approximately 3% for a first-time prosthesis. Although some studies suggest that elevated HbA1c levels may predict a higher rate of infections in diabetics having penile prosthesis surgery, more recent studies refute this. A large study from Wilson, et al demonstrated that neither diabetic status nor preoperative HgA1c were risk factors for prosthesis infection. A more recent study also finds that elevated HbA1c is not a risk factor for infection but notes that short-term sugar control is (as defined by morning fasting glucose levels >200 ng/ml), although data is hampered by very low numbers of patients within that cohort. Penile shortening and eventual mechanical failure of the device are other common side effects.
8.10. CONCLUSIONS
As our understanding of the basic mechanisms of erectile function continues to grow, new and improved therapies for the management of ED will continue to emerge. We have witnessed a dramatic change in the treatment of men with erectile dysfunction over the past 30 years. Treatment options have progressed from psychosexual therapy and penile prostheses in the seventies, through arterial revascularization, vacuum constriction devices, and intracavernous injection therapy in the eighties, to transurethral and oral drug therapy in the nineties and the new millennium. Future interventions in development for ED include new and improved drug therapy. Attention and interest has also been directed to gene and stem cell therapy for this condition. Regardless of modality utilized, restoration of erectile capacity and facilitation of satisfying sexuality will remain an important goal for men and their sexual partners in the future."
