Review Articles

Erectile Dysfunction: Clinical Guidelines (2)

SAFARINEJAD MR*, HOSSEINI SY

Urology/Nephrology Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, Iran

ABSTRACT

Purpose: According to a survey, the Massachusetts Male Aging Study, 52% of men

beyond 40 years of age may have some degrees of erectile failure, and it is projected

to affect 322 million men worldwide by 2025. We present a framework for the evalu-

ation, treatment, and follow-up of the male patient who presents with erectile dysfunc-

tion.

Materials and Methods: A comprehensive review of the literature was conducted

using the MEDLINE database for all articles from 1975 through 2004 on male sexual

dysfunction and the most pertinent articles are discussed. 

Results: Remarkable progress has been made in the treatment of erectile dysfunc-

tion (ED). Erectile dysfunction is a common condition associated with aging, chronic

illnesses and various modifiable risk factors. Erectile dysfunction can be due to vascu-

logenic, neurogenic, hormonal, and/or psychogenic factors as well as alterations in the

nitric oxide/cyclic guanosine monophosphate pathway or other regulatory mecha-

nisms. The number of consultations from new patients presenting with erectile dys-

function and resulting costs for health care systems are increasing. Urologist should

be the evaluating physician who supervises the surgical, medical, and hormonal treat-

ment and who refers the patient, as necessary, to other members of the multidiscipli-

nary team.

Conclusion: Erectile dysfunction has a significant negative impact on quality of life.

Male sexual dysfunction, especially erectile dysfunction, necessitates a comprehensive

medical and psychologic evaluation involving both partners. All possible risk factors

should be outlined and corrected, when feasible.

KEY WORDS: impotence, pathology, treatment outcome, penile erection, physiology

227

Urology Journal

UNRC/IUA

Vol. 1, No. 4, 227-239 Autumn 2004

Printed in IRAN

Treatment of Erectile Dysfunction

The first step in the management of a patient

with ED is to facilitate the patient's and his part-

ner's (if available) understanding of the condi-

tion, the results of the diagnostic assessment and

to identify the patient's and his partner's needs,

expectations, priorities, and preferences. The

identification and recognition of associated med-

ical and psychological factors in the individual

patient must be emphasized. Clearly, the selection

of therapy is strongly influenced by personal, cul-

tural, ethnic, religious, and economic (affordabili-

ty) factors. The presentation and stratification of

therapies may therefore vary from individual to

individual, culture-to-culture, religious persuasion

to religious persuasion, and from one economic

tier to another. Sensitivity to these factors is

important in determining the long-term success

of any selected therapeutic course. Prior to direct

intervention, good medical practice recognizes

the value of altering modifiable risk factors, and

this step alone may be of some value in selected

patients. 

The patient and his partner (if available) should
*Corresponding author: P.O. Box: 19395-1849,

Tel: +98 912 109 5200, E-mail: safarinejad@unrc.ir



Erectile Dysfunction

be informed of all of the available and acceptable

treatment options applicable to his clinical condi-

tion and the related benefits, risks, and costs of

each modality. The development of ED can signif-

icantly affect the quality of life, but it is not a life-

threatening disease. Consequently, it is reason-

able to discuss the benefits, risks, and costs of

the available treatment strategies with the

patient and have the patient actively participate

in the choice of therapy (shared decision making).

An important issue prior to the institution of any

therapy and the subsequent resumption of sexual

activity is the overall cardiovascular condition of

the patient. Is this patient able to resume the

exercise of sexual activity? If not, priority cardio-

vascular assessment and intervention may be

appropriate. The partner's sexual function, if pos-

sible, should be considered prior to initiating

therapy. The vast majority of patients will need to

consider direct treatment options for ED. Only

those pharmacological treatments that have been

thoroughly tested in randomized clinical trials,

with subsequent publication of results in peer-

reviewed literature, should be considered for gen-

eral use. Long-term follow-up of all treatment

options must be performed to demonstrate dura-

bility and continuous efficacy and safety as well

as patient and partner acceptability. Additionally,

new treatment options that enter the arena not

only will need to meet the above efficacy and safe-

ty criteria, but also should be compared to avail-

able therapies for cost-effectiveness. The treat-

ment selected by a patient, will be influenced not

only by issues such as efficacy and safety, but

also by the patient's cultural, religious, and eco-

nomic background. Additionally, such factors as

1. ease of administration, 2. invasiveness, 3.

reversibility, 4. cost and 5. the mechanism of

action (peripheral vs. central, inducer vs.

enhancer), and 6. availability, may critically influ-

ence the individual patient's selection of therapy.

As previously mentioned, affordability is a prime

factor in influencing patient acceptance and uti-

lization of a specific therapy for ED.(1)

Any drugs that might be contributing to ED

should be discontinued. In the case of antihyper-

tensive agents, other drugs with a different mech-

anism of action should be considered. 

Five basic types of therapy reported in the lit-

erature are potential options for treating organic

erectile dysfunction:

1. Oral drug therapy,

2. Vacuum constriction device therapy,

3. Intracavernous vasoactive drug injection and

topical therapy,

4. Penile prosthesis implantation,

5. Venous and arterial surgery. 

Oral Drug Therapy

There is a wide range of treatments for erectile

dysfunction. If organic problems seem to be dom-

inant, the first step is to identify the medical risk

factors and correct them, if possible. Plasma glu-

cose must be regulated in men with poorly con-

trolled diabetes. Medications for hypertension

must be optimized. Cessation of tobacco abuse is

important. Hyperlipidemia must be treated

aggressively. Intake of alcohol and illicit drugs

should be discontinued. The central issue in

understanding the patient with ED is not only

understanding ED as a medical condition, but

also understanding patient behavior and atti-

tudes. It is important to remember that there is

a broader context for treating ED. Physicians

need to avoid over-focusing on the genital

response and consider the psychosocial conse-

quences and obstacles of ED. 

A wide range of oral treatments have been used

in men with erectile dysfunction, including silde-

nafil, apomorphine, oral phentolamine, isox-

suprine, trazodone, and yohimbine.(2) New drugs

include several new phosphodiesterase type 5

inhibitors and agents with other mechanisms of

action.(3,4)

Sildenafil (Viagra) is now the first choice for

treating erectile dysfunction and has helped men

with a wide range of conditions. 

Pharmacology: Sildenafil facilitates erections

associated with sexual stimulation. It will not act

if the man is not sufficiently mentally aroused or

his peripheral autonomic nerves are absent (e.g.

radical prostatectomy). It acts by inhibiting phos-

phodiesterase isoenzyme 5 (PDE-5), thus prolong-

ing cyclic guanosine monophosphate (cGMP)

activity in erectile tissue, and enhancing the

vasodilating actions of nitric oxide, which is

released in response to sexual stimulation.

Sildenafil is rapidly absorbed from the gut peak-

ing 30 to 120 minutes after an oral dose. At peak

effect, it lowers mean systolic supine blood pres-

sure (8 mmHg) in healthy volunteers. The drug is

eliminated by liver metabolism (CYP3A4) with a

half-life of 3 to 5 hours. Half-life is prolonged in

patients over 65 years and in patients with renal

or hepatic impairment. 

Adverse effects: The most common adverse

228



Safarinejad and Hosseini

effects, as absolute risk increase over placebo,

were headache at 14%, flushing at 17%, dyspepsia

at 4%, rhinitis at 4%, and visual disturbance at

1%. None of the studies assessed the effects of

long-term sildenafil use. Such studies are needed,

particularly in patients with a history of retinal

and cardiovascular disorders. Serious rare side

effects include priapism, severe hypotension,

heart attack, stroke and death. 

Contraindications:  Sildenafil is contraindicated

in patients taking or at risk of requiring nitrates

in any form, patients, in whom sexual activity is

inadvisable because of their cardiovascular status

(e.g. myocardial infarction or cerebrovascular

accident within 6 months, heart failure, unstable

angina, hypotension, uncontrolled hypertension,

aortic stenosis, etc.), and patients with retinitis

pigmentosa, anatomical deformities of the penis,

conditions predisposing to priapism (e.g. sickle

cell anemia, multiple myeloma), or receiving mul-

tiple antihypertensive drugs. 

Precautions: There is no safety information on

patients excluded from the trials (e.g. patients

with alcoholism, active peptic ulcer, proliferative

diabetic retinopathy, etc.). Inhibitors of CYP3A4

such as erythromycin, ketoconazole, grapefruit

juice, and others would be expected to increase

the magnitude and duration of response to

sildenafil.

A relatively small number of deaths have been

reported in association with sildenafil usage, but

the specific relationship to the drug is uncertain.

This underscores the need for cardiovascular

assessment prior to the treatment of ED and reg-

ular follow-up. A small percentage of these deaths

occurred with concomitant use of nitrates and

are presumed to be due to severe hypotension

that may ensue, following this combination.(5) In

addition, patients with possible or active coro-

nary heart disease or other significant cardiovas-

cular diseases such as aortic stenosis should

undergo cardiac evaluation and management

prior to considering sildenafil usage.(5) To date,

there is no physiological reason to indicate silde-

nafil exerts a direct effect on the myocardium. In

general, sildenafil when prescribed appropriately

has demonstrated broad efficacy and an accept-

able safety profile. 

Dosage and cost: The drug should be taken on

an empty stomach 1 hour before intended sexual

activity and no more than once daily. Dose range

is 25 to 100 mg. As with most drugs start with

the lowest dose, 25 mg, and increase only if nec-

essary. Since the cost of each tablet is similar

($10 to $12), prescribing the higher dose tablets

and dividing them can substantially reduce the

cost. 

Although sildenafil is currently the most wide-

ly used approach and has an excellent overall suc-

cess rate (60% to 85%), a substantial portion of

patients continue to have an inadequate

response.(6) Martinez-Jabaloyas et al(7) recently

evaluated risk factors for treatment failure with

sildenafil and noted that diabetes, non-nerve

sparing radical prostatectomy and high baseline

disease severity, as reflected by Sexual Health

Inventory for Men scores, were all predictors of

a lower success rate for sildenafil therapy. Oral

sildenafil is a moderately effective treatment for

erectile dysfunction in men with diabetes. The

response rate was lower and cardiovascular

events were higher than previously reported in

nondiabetic patients.(8)

Currently, two other phosphodiesterase-5

inhibitors are available: tadalafil and vardenafil.

Early data indicate that there are differences

among sildenafil, tadalafil, and vardenafil in

pharmacokinetic properties, efficacy, potency,

half-life, and adverse effect profiles.(9)

Tadalafil (Cialis) is the latest of the three to be

approved by the Food and Drug Administration

(FDA).(10) This medication is a highly selective,

potent, reversible inhibitor of phosphodiesterase

type 5 (PDE5).(11, 12) Tadalafil differs from the

other two products in that it stays in the body for

a longer time, which is an advantage for men

with ED.(10) Compared with sildenafil, tadalafil

has an extended terminal half life, 17.5 hours(13)

versus 3.7 hours,(14) suggesting a lengthened peri-

od of responsiveness compared with sildenafil.

The same cautions apply for these agents as they

do for sildenafil. Common side effects of this

agent are similar to those of sildenafil and

include flushing, dizziness, nasal congestion,

upset stomach, and vision abnormalities. Success

rates have been significant in men suffering from

erectile dysfunction of varying severity and from

many causes. One study suggested, however, that,

as with sildenafil, it may interact with nitrates. 

An assessment of the safety and effectiveness

of tadalafil in patients older than 65 years of age

versus younger patients indicated that it was safe

and effective in both groups, with improved

erections in up to 81% of men in the combined

population.(15)

Simultaneous administration of tadalafil and

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Erectile Dysfunction

the alpha-adrenergic antagonists, except for 0.4

mg once-daily tamsulosin, is contraindicated. In a

study of drug-drug interactions, 20 mg of

tadalafil was administered to healthy subjects tak-

ing 8 mg of doxazosin mesylate daily. A signifi-

cant increase in the blood pressure-lowering

effect of doxazosin was observed.(16)

The recommended starting dose for most

patients is 10 mg, to be taken before anticipated

sexual activity. The dose may be increased to 20

mg or decreased to 5 mg, depending on the

agent's efficacy and patient's tolerability. For

most patients, the maximum dosing frequency is

once daily. Unlike other available treatments,

tadalafil may enable a patient to take a pill on a

Wednesday evening and have intercourse with his

partner on a Thursday night or a Friday morn-

ing. This extended period of responsiveness

afforded by tadalafil may lead to a new treatment

paradigm for men with ED.(16,17)

Vardenafil (Levitra), another novel selective

phosphodiesterase type 5 inhibitor, has also been

shown to be safe and effective for the treatment

of erectile dysfunction in a 12-week, multicenter,

randomized, double-blind, placebo-controlled trial

that included 601 men with mild to severe erec-

tile dysfunction.(18) For most patients, the recom-

mended starting dose of vardenafil is 10 mg,

taken orally approximately 60 minutes before sex-

ual activity. The dose may be increased to a max-

imum recommended dose of 20 mg or decreased

to 5 mg based on efficacy and side effects. The

maximum recommended dosing frequency is once

per day. Vardenafil can be taken with or without

food. Sexual stimulation is required for response

to treatment. 

Studies evaluating vardenafil have determined

it to be safe and effective at doses of 5 mg to 40

mg, including subjects with diabetes mellitus and

subjects who have undergone radical prostatecto-

my. Vardenafil has a pharmacokinetic profile sim-

ilar to that of sildenafil, with an onset of action

and half-life of 0.7 hours and 5 hours, respective-

ly. Vardenafil, like other PDE5 inhibitors, is

metabolized hepatically via the cytochrome P-450

system. The drug appears to be well tolerated. In

clinical trials, headache, dyspepsia, and flushing

were the most common adverse effects reported

by subjects taking vardenafil. No adverse hemody-

namic or visual effects have been reported during

clinical trials of vardenafil; however, further

investigation, including post-marketing surveil-

lance, will be required to determine whether var-

denafil will cause these adverse effects. In vivo,

vardenafil has been found not to interact with

nifedipine, nitroglycerin, digoxin, magnesium

hydroxide/aluminum oxide, or ranitidine. Only a

small, clinically insignificant interaction was

observed when vardenafil was given concurrently

with cimetidine.

Further research and clinical experience with

the newer PDE-5 inhibitors (vardenafil and

tadalafil) will be needed before their roles in the

treatment of ED can be determined. 

Patients taking nitrate drugs (used to treat

chest pain) and those taking alpha-blockers (used

to treat high blood pressure and benign prostatic

hyperplasia) should not take selective enzyme

inhibitors. 

Common side effects of selective enzyme

inhibitors include headache, reddening of the face

and neck (flushing), indigestion, and nasal con-

gestion. Tadalafil may cause muscle aches and

back pain, which usually resolve on their own

within 48 hours. 

Oral Phentolamine. Phentolamine is an agent

that has been used in injections for achieving

erection. Phentolamine is an α-adrenergic block-
ing agent with both central and peripheral activ-

ity. An oral form of phentolamine (Vasomax) has

been developed that may be of some benefit for

men with mild impotence. The drug is not as

effective as sildenafil and it has more side effects.

However, Vasomax works faster and it does not

interact with nitrates. Studies suggest that it pro-

duces erections within 20 to 40 minutes in 40%

to 50% of men with mild to moderate erectile dys-

function. Side effects include nasal congestion,

headache, light-headedness, low blood pressure,

tachycardia and nausea. These events are mini-

mal at the usual dose of 40 mg.(1)

Apomorphine (Spontane, Uprima), which is

taken as a tablet under the tongue, causes a sex-

ual signal in the brain to trigger an erection,

although it is not an aphrodisiac. Apomorphine is

a dopaminergic agonist acting at the central

nervous system level. It was initially adminis-

tered subcutaneously. However intolerable

adverse events prompted the development of a

sublingual pill. 

Apomorphine has shown efficacy in placebo-

controlled fixed and dose escalation studies.(19) In

responders, erection usually begins within 20

minutes. Its principal adverse effect is nausea,

which is usually minimal at lower dosages (2 mg

and 4 mg). Other adverse effects are dizziness,

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Safarinejad and Hosseini

sweating, somnolence and yawning as well as

rarely, syncope.(1)

Studies report improved erectile function in

40% to 60% of men, with the better results occur-

ring at the higher doses. High doses, however,

also cause severe side effects, including nausea

(in between 15% to a third of patients), yawning,

fatigue, dizziness, sweating, excitability, and

aggression. Apomorphine appears to be safe for

men with diabetes or stable heart disease, and is

well tolerated by men with high blood pressure. 

Opioid Antagonists. Opioid antagonists, such

naltrexone (ReVia), are used to help maintain

abstinence in alcoholism. Naltrexone may be help-

ful for erectile dysfunction in men with inhibited

sexual desire. The most common side effect of

naltrexone is nausea, which is usually mild and

temporary. High doses can cause liver damage.

The drug should not be administered to anyone

who has used narcotics within a week to 10 days. 

Angiotensin-receptor blockers. Recent drugs

known as angiotensin-receptor blockers (ARBs),

also known as angiotensin II receptor antagonists

are being used to lower blood pressure in men

with hypertension. In one study, after 12 weeks

of treatment with an ARB called losartan

(Cozaar), 88% of hypertensive males with sexual

dysfunction reported improvement in at least one

area of sexuality. The number of men reporting

impotence declined from 75.3% to 11.8%. Other

ARBs include candesartan (Atacand), telmisartan

(Micardis), and valsartan (Diovan). 

Trazadone, a widely used antidepressant, has

been associated with the development of

priapism.

Trazodone, a serotonin antagonist and reuptake

inhibitor, improved premature ejaculation and

erectile function in men with psychogenic ED but

had a marginal effect in men with organic ED.(20)

This side effect has created interest for its poten-

tial use in men with impotence. Doses of 150 mg

per day have been used in most studies and case

reports. The mechanism by which trazodone may

help patients with impotence is unclear but is

most likely a result of the drug's ability to block

both serotonin and α2-adrenorceptors. Whatever
the mode of action, recent clinical studies seem

to indicate that if trazodone does have a role in

the treatment of erectile dysfunction, then its

benefit may only be marginal.

Yohimbine, an alkaloid derived from the bark of

the Central African yohimbine tree, has been

used as folk medicine for many years. The alka-

loid has α2-adrenoreceptor blocking activity and
produces a rise in sympathetic drive. Yohimbine

has no effect on erectile function when adminis-

tered by intracavernous injection, and its action

in relation to erectile dysfunction is thought to be

almost entirely central. Traditionally, extracts

from the yohimbine bark have been used to treat

all forms of impotence.

Most information available on the use of yohim-

bine comes from isolated reports and uncon-

trolled trials. Only in the last 15 years have for-

mal clinical studies been undertaken. A review of

recent clinical trials indicates that the response

rate to yohimbine is only 30-40%. The difference

between responders to yohimbine and to placebo

has not been clinically significant in many cases.

It is clear that some patients, especially those

without serious medical problems, demonstrate

improvement in the quality, frequency or rigidity

of erections but not always enough to restore sat-

isfactory sexual function. Side effects associated

with the use of the drug include nausea, insom-

nia, nervousness, headache, and dizziness. Large

doses can increase blood pressure and heart rate

but rarely do patients have to discontinue thera-

py subsequent to adverse effects. Questions about

the drugs long-term safety still remain. The most

commonly used dose is 5.4 mg three times

daily.(21,22)

Isoxsuprine is a vasodilator, acting by direct

relaxation of vascular smooth muscle. Its primary

mechanism of action is by stimulation of Beta-

adrenergic receptors. The commercially available

form is a 10mg tablet. Isoxsuprine is no better

than placebo as a first line treatment for mixed

type erectile dysfunction.(23)

Hormonal Treatment

Endocrine disorders, such as hypogonadism,

androgen abnormalities, growth hormone defects,

thyroid disease and lipid disorders also play a sig-

nificant role in ED physiology.(10)

Castration reduces intracavernous pressure

following intracavernosal administration of

adrenomedullin, calcitonin gene-related peptide,

vasoactive intestinal polypeptide or nociceptin.

All of these compounds lead to increases in

cAMP. Moreover, testosterone regulates the

expression and activity of NOS in some species.

Castration also inhibits the increase in intracav-

ernous pressure following a nitric oxide (NO)

donor. These findings suggest that androgens

influence the cAMP and cGMP pathways in addi-

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Erectile Dysfunction

tion to NOS. Although androgens may not direct-

ly augment the effects of cyclic nucleotides, these

data argue that androgen replacement may be a

prerequisite for pharmacological therapy to

improve ED if an androgen deficiency exists.

Thus, in hypoandrogenic patients the combina-

tion of testosterone and PDE-5 inhibition or

intracavernous activation of adenylate cyclase

may be indicated.(24)

The hypothalamic-pituitary-gonadal axis has

been shown to decrease functioning temporarily

after acute medical events or surgical procedures;

such an occurrence can cause low gonadotropin

and testosterone levels. Similarly, a temporary

decrease in testosterone levels may occur as a

result of less serious circumstances, such as anx-

iety, excessive intake of alcohol, use of multiple

medications, or uncontrolled diabetes. Patients

with these causes are less likely to respond to

testosterone replacement. Stimulation of

gonadotropins with clomiphene citrate and the

subsequent increase in testosterone levels empha-

size the functional and reversible nature of this

phenomenon; short-term therapy with

clomiphene citrate may help some patients. If the

testicles are intact, testosterone can be stimulat-

ed by injections of human chorionic

gonadotropin, but this technique is cumbersome

and rarely used. Hypogonadism is common in

patients with diabetes, many of whom may

respond to testosterone treatment.(25)

Appropriate therapy in the presence of a docu-

mented deficiency (e.g. androgen deficiency and

hypogonadism), may not necessarily improve ED

and thus one may need to consider direct inter-

vention therapy even in this patient population.

The issue of androgen replacement therapy is

complicated. There is a statistical decline of

testosterone levels, particularly free testosterone,

in aging men. While this fall is only moderate,

aging men show clinical signs of hypogonadism

(loss of muscle mass/strength, reduction in bone

mass and an increase in visceral fat).

Testosterone replacement or supplement therapy

may improve bone mass, muscle mass, strength

and frequently nocturnal erections as well in this

age group. However, the effects on sexual func-

tion, mood and cognition are less clear but may

be meaningful in certain men. The identification

of that segment of the aging male population that

might possibly benefit from androgen supplemen-

tation remains difficult. Questions still remain

regarding the magnitude and longevity of these

potential beneficial effects. More importantly, the

long-term risks of androgen therapy in this age

group really are now known, especially in the

areas of cardiovascular and prostate diseases.(26)

Despite increasing evidence that patients with

subnormal or borderline normal levels of testos-

terone could be considered as candidates for

testosterone treatment, until more information is

available, testosterone and androgens in general

should not be recommended as supplemental

therapy.(1)

Testosterone replacement for hypogonadism

may also correct sexual dysfunction, unless the

patient has other comorbid illnesses. For decades,

the standard has been a depot intramuscular

injection of testosterone enanthate or cypionate

every 2 or 3 weeks (200 mg or 300 mg, respec-

tively). Smaller doses and more frequent injec-

tions, however, are better at maintaining circulat-

ing testosterone levels of testosterone enanthate

or cypionate intramuscularly at 7- to 14-day inter-

vals. An alternative approach is to administer 100

mg on days 1, 11, and 21 of each month, while

allowing some flexibility of injection days. If

testosterone levels are measured, they should be

in the normal range just before the next injection.

Other forms of intramuscular testosterone prepa-

rations are also being evaluated. Implantable

testosterone pellets are now, but they are infre-

quently prescribed. Oral forms of testosterone

are not recommended because of the risk for liver

damage when taken for long periods of time. 

The US Food and Drug Administration (FDA)

have now approved testosterone scrotal and non-

scrotal dermal patches. Testosterone absorption

is greater through scrotal skin. The scrotal patch

was the first to be introduced. These patches are

placed on the scrotal skin and are changed daily,

in the morning. For many patients, weekly shav-

ing of the scrotum is necessary. The patch

increases testosterone levels to the low-normal

range, with peak levels achieved 3 to 5 hours

after application of the patch. Because 5-a-reduc-

tase in scrotal skin is high, the dihydrotestos-

terone (DHT) level in serum becomes quite high.

The role of DHT is currently being investigated.

The nonscrotal patch (Androderm), applied daily

in the evening, may be worn in various sites on

the skin. The manufacturer recommends that it

not be used over bony prominences. The levels

remain stable in the middle of the normal range,

and the DHT levels remain normal. Skin irrita-

tion may develop and often responds to applica-

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Safarinejad and Hosseini

tion of corticosteroid cream. In a certain small

percentage of patients, therapeutic blood levels of

testosterone may not be achieved. Another non-

scrotal patch, Testoderm, was associated with

less skin irritation but was more likely to fall off;

it has recently been withdrawn from the market.

The FDA for use in the United States has recent-

ly approved a 1% testosterone gel. It is more

expensive than the testosterone patches. The

blood levels of testosterone associated with use of

the gel are dose dependent and vary less than

with the testosterone patches. Care must be exer-

cised because the testosterone can be transferred

to another person if skin-to-skin contact occurs. 

With any form of testosterone treatment, the

patient may have a slow but steady increase in

libido and erectile ability during a course of

months. If no improvement is noted after three

months, the hormone deficiency is probably not

the only cause of the sexual dysfunction. A

comorbid medical illness might be present, or

perhaps performance anxiety is dominant. 

Any patient treated with replacement andro-

gens should be reassessed within 1 to 3 months

after initiation of therapy and then at 6- to 12-

month intervals to ensure that clinical problems

have not developed or worsened during such

treatment. Prostate cancer and breast cancer are

contraindications to androgen therapy, whereas

sleep apnea, peripheral edema, erythrocytosis

(hematocrit >52%), and benign prostatic

Hyperplasia are relative contraindications that

may respond to adjustments in the medication or

specific treatments (for example, use of

continuous positive airway pressure or weight

reduction).(27)

Intracavernous vasoactive drug injection

and topical therapies

Intracavernosal Injections. Drugs for ED vary

by not only class, but also route of administra-

tion. Penile injections have now largely been

replaced by oral medications, specifically silde-

nafil. Nevertheless, injection and topical (skin)

therapies employ various agents that have prop-

erties that help achieve erection, even in many

men who do not succeed with sildenafil. 

Alprostadil (Caverject). This is the most widely

used agent. Alprostadil is derived from a natural

substance, prostaglandin E1, and acts by opening

blood vessels. It is an effective treatment for

some men. It can be administered in three ways:

by injection into the erectile tissue of the penis

(Caverject, Edex), by a device that administers

the drug through the urethra (MUSE system),

and in a topical cream (Topiglan, Alprox-TD)

applied directly to the penis. Regardless of how it

is administered, alprostadil works in many men

with a wide range of medical disorders related to

erectile dysfunction, including the following: dia-

betes, prostate cancer treatments (early use of

alprostadil injections after treatment, particularly

when followed by oral sildenafil, may be very

helpful for men being treated for prostate can-

cer), men who are taking nitrates and injury.

Alprostadil is not an appropriate choice for the

following individuals: men with severe circulatory

or nerve damage, men with bleeding abnormali-

ties or men who are taking medications that thin

the blood, such as heparin or warfarin and men

with penile implants. The drug may have toxic

effects if it reaches the fetus in pregnant women,

so men should not use alprostadil for intercourse

with pregnant women without the use of a con-

dom or other barrier contraceptive device.

It is effective in 70% to 80% of patients and has

a low incidence of side effects. Penile pain occurs

in 15% to 50% of patients but is often not trou-

blesome. The dose range is 5 to 20 mcg but some

physicians will increase it further or use a combi-

nation with papaverine and phentolamine.

Priapism occurred in about 1% of patients and

the incidence of penile fibrosis was 10% in a peri-

od of 3 years. About half of the cases with fibro-

sis resolved spontaneously.

Thymoxamine (moxisylyte hydrochloride)

(Erecnos, Icavex). This agent, a selective α1 adren-
ergic receptor antagonist, has been licensed for

use in erectile dysfunction and is used in a

dosage of 10-20 mg. It is less effective in initiat-

ing erection but with sexual stimulation gives suf-

ficient rigidity in some patients. It has a lower

incidence of side effects such as penile pain and

prolonged erection. 

Papaverine (Pavabid, Cerespan). This was the

first agent in general use and had the advantage

of being cheap. It is not licensed for the treat-

ment of ED and is not recommended because of

the relatively high risk of priapism and penile

fibrosis.

Papaverine and Phentolamine Mixtures

(Androskat). This is still used in some countries

because of its efficacy and relatively low cost. It

is more effective than papaverine alone.

Trimix (Papaverine, Phentolamine and

Alprostadil). This combination was introduced to

233



Erectile Dysfunction

treat those patients who responded poorly to the

papaverine/phentolamine mixture or alprostadil.

It is unlicensed and is prepared by specialized

pharmacies.

Vasointestinal Polypeptide (VIP) and phento-

lamine (Invicorp). This is another preparation in

an advanced phase of clinical development

although it is not yet licensed except recently in

Denmark. The main side effect is facial flushing

and tachycardia but it has the advantage over

alprostadil of a lower incidence of pain. Its effec-

tiveness, compared to alprostadil has yet to be

determined.(28)

While intercavernosal injection therapy consis-

tently produces erections in up to 87% of

patients, there is a dropout rate of about 50%.(29)

Intraurethral Suppository. Prostaglandin E1

(alprostadil) (MUSE system), is also available as

an intraurethral suppository. Padma-Nathan et

al35 reported an at home successful sexual inter-

course rate of approximately 60% in a large series

of men, 20% of whom had diabetes. Although

PGE1 is less invasive and easier to use than

intracavernosal injection, it may reduce sexual

spontaneity. Men must remain standing after the

pellet has been inserted to increase penile blood

flow, and the time to erection is 15 to 30 min-

utes. Patients may complain of penile pain (12%),

minor urethral bleeding (5%), testicular pain, and

dizziness. Female partners may report vaginal

burning or itching (6%) with use of the supposi-

tory. Prostaglandin E1 is contraindicated in men

with abnormal penile anatomy and those with

hyperviscosity syndromes; men cannot take

PGE1 if they have intercourse with pregnant

women who are not using barrier contracep-

tives.(30)

Reported success rates with intraurethral

alprostadil have been around 50% but range

widely.

Venous and arterial surgery

Impaired arterial inflow has been addressed in

select cases by various penile revascularization

procedures and attempts to induce neovascular-

ization. Of course, known risk factors, such as

smoking, hyperlipidemia, diabetes, hypertension

and obesity, should be controlled.

Penile Revascularization. For men whose impo-

tence is caused by damage to the arteries or

blood vessels, vascular surgery might be an

option. The best candidates for such surgery are

young men with discrete blockage of an artery

because of an injury to the crotch or fracture of

the pelvis. The procedure is almost never success-

ful in older men with widespread blockage. 

Penile revascularization represents the only cur-

rently feasible cure of arteriogenic ED.(31,32) The

revascularization procedure usually involves tak-

ing an artery from a leg and then surgically con-

necting it to the arteries at the back of the penis,

bypassing the blockages and restoring blood flow.

In a related procedure called deep dorsal vein

arterialization, a penile vein is used for the

bypass. Young men with local sites of arterial

blockage or those with pelvic injuries generally

achieve the best results. In studies of selected

patients there was improvement in erectile dys-

function in 50% to 75% of men after five years.

In the Virag type of procedures the epigastric

artery is anastomosed to the deep dorsal vein at

the base of the penis. Blood flows retrograde

through the veins and enters the corpora through

the connecting posterior emissary veins.(33)

Direct anastomosis of the epigastric artery to the

cavernosal artery is feasible but technically chal-

lenging.(34) Direct epigastric artery to dorsal

penile artery anastomosis in various modifica-

tions has also been described.(32,35)

Neovascularization. Neovascularization is anoth-

er emerging approach to reversal of impaired cav-

ernosal artery flow. Tissue hypoxia and the

inflammatory response are major physiological

stimuli to angiogenesis. The process is under the

control of angiogenic growth factors, small pro-

teins that induce proliferation and migration of

endothelial and smooth muscle cells, and branch-

ing of the vascular tree. All growth factors are

mitogens to endothelial cells and include basic

fibroblast growth factor, vascular endothelial

growth factor (VEGF) and hypoxia inducible fac-

tor. In addition to direct stimulation of endothe-

lial cell growth, some growth factors such as

VEGF possess the ability to stimulate production

of NO. Intracavernosal injection of VEGF in an

ischemic rat model has recently been shown to

stimulate endothelial nitric oxide synthase (NOS)

and inducible NOS expression.(36) Several recent

animal studies have shown the feasibility of using

local intracavernosal VEGF injection. In vitro

VEGF treatment has been shown to ameliorate

the effects of hypercholesterolemia on rabbit cav-

ernosal smooth muscle.(37) In a rat model using

acute arterial ligation, a single intracavernosal

bolus of VEGF improved penile erection.(38)

Regeneration of nerves and endothelial cells

234



Safarinejad and Hosseini

lining the cavernous spaces was seen.(38)

Venous ligation. Venous leak has been termed

an "epiphenomenon" of cavernosal smooth muscle

dysfunction.(15) Thus, it does not appear to offer

curative potential when addressed as an isolated

phenomenon. Venous ligation is performed when

the penis is unable to store a sufficient amount

of blood to maintain an erection. This operation

ties off or removes veins that are causing an

excessive amount of blood to drain from the erec-

tion chambers. The success rate is estimated at

between 40% and 50% initially, but drops to 15%

over the long term. It is important to find a sur-

geon experienced in this surgery. In a variation

of this technique called venous ablation, ethanol

is injected into the deep dorsal vein, the main

vein that drains blood from the penis. The

ethanol causes scarring that closes off smaller

veins and prevents blood leakage, thereby bolster-

ing erectile function. In a small trial in 10 men

with severe impotence, half maintained erectile

function two to three years after the procedure. 

Recently, improved results were reported when

patients were selected according to the presence

of mild cavernous leak, more than 30% cavernous

smooth muscle content, normal cavernosal elec-

tromyography results, and oxygen tension of

more than 65 mm Hg during erection, and age

younger than 50 years. In this series of 23 men

treated with venous ligation 74% had normal erec-

tions at 1 year and 50% beyond 1 year. Venous lig-

ation appears to have a role only in highly select-

ed men with minimal cavernosal dysfunction.(34)

The American Urologic Association stresses

that vascular surgery is still investigative.

Vacuum constriction device therapy 

Vacuum constrictor device. Any system encour-

aging blood to flow into and be captured in the

penis should produce an erection. This is the

principle behind the vacuum constrictor device

(VCD) now offered as a noninvasive means of

restoring erections for some impotent men.

Vacuum devices, or external management sys-

tems, are effective, safe, and simple to use for all

forms of impotence except when severe scarring

has occurred from Peyronie's disease. Vacuum

devices rely on first drawing blood into the penis,

by means of an externally applied suction pump,

and then retaining the resultant erection by

means of an elastic ring applied to the base of the

penis. Provided it is used properly, the failure

rate is very low and serious adverse effects are

rare, although many patients find the method

cumbersome. The band may only be kept on for

30 minutes and ejaculation may be obstructed.

One small retrospective study shows that 81% of

men stopped using the device over a one-year

period.(39) A second study of 50 men suggested

that only 27% preferred the vacuum device to

intracavernosal injection therapy.(40)

Not only does vacuum-induced pressure in the

VCD cause most men to experience penile dis-

comfort, but the erection achieved by this means

is inferior to a spontaneous erection in three sig-

nificant aspects. Once the vacuum has induced

the erection, the rubber bands in place at the

base of the penis choke off blood flow into the

penis. This causes penile skin temperatures to

fall to 35.5-centigrade degree. One-third of the

female partners of men using VCDs found the

chilled penis displeasing during intercourse.

Another drawback is that as the penis becomes

engorged and congested by the VCD-induced suc-

tion and inhibition of venous outflow, penile cir-

cumference increases more than it would during

a normal erection. This gives the penis a sausage

like appearance. Third, the erection created by

the VCD is rigid only from the point at which the

rubber bands are affixed. This means that it is

not fully upright and rigid like a normal erection,

but flexible and capable of swiveling or pivoting

at its base. The VCD also does not permit normal

ejaculation. Because the rubber bands remain in

place throughout the sexual act, semen is trapped

in the urethra and can be released only after the

bands are removed. 

Venous flow controllers. Vacuum-less devices

that trap blood within the penis are also avail-

able. They are called venous flow controllers or

simple constricting devices. These devices are

typically rubber or silicone rings or tubes (e.g.,

Actis) that are placed at the base of the erect

penis to trap the erection. Men who can achieve

erections but lose them easily can use them.

These devices should not be used for longer than

30 minutes or lack of oxygen can damage the

penis, and patients who have bleeding problems

or are taking anticoagulants should not use them. 

Penile prosthesis implantation

Implanted devices, known as prostheses, can

restore erection in many men with ED. Possible

problems with implants include mechanical break-

down and infection, although mechanical prob-

lems have diminished in recent years because of

235



Erectile Dysfunction

technological advances.

Malleable implants usually consist of paired

rods, which are inserted surgically into the corpo-

ra cavernosa. The user manually adjusts the posi-

tion of the penis and, therefore, the rods.

Adjustment does not affect the width or length of

the penis.

Inflatable implants consist of paired cylinders,

which are surgically inserted inside the penis and

can be expanded using pressurized fluid. Tubes

connect the cylinders to a fluid reservoir and a

pump, which are also surgically implanted. The

patient inflates the cylinders by pressing on the

small pump, located under the skin in the

scrotum. Inflatable implants can expand the

length and width of the penis somewhat. They

also leave the penis in a more natural state when

not inflated.

There appear to be no long-term immune prob-

lems related to the silicon or other materials in

the devices. 

There are potential limitations with these

devices. Erectile tissue is permanently damaged

when these devices are implanted and procedures

are irreversible. Although uncommon, mechanical

breakdown can occur, or the device can slip or

bulge, especially if the patient coughs or vomits

vigorously after the operation. In addition, a less

than optimal quality of erection may result.

(Using the MUSE system may restore or improve

the function of a penile prosthesis in patients

with a failed device.)

Infection is the major concern with these

devices. Redness and fever often accompany a

full-blown

infection. Any intermittent pain that continues

to occur after an implant may be an indicator of

a low-grade infection. If the infection can be

caught early enough, implant failure can be pre-

vented. Most infections are treated with antibi-

otics for at least 10 to 12 weeks. If antibiotics fail,

a surgical exchange, in which the infected implant

is simultaneously replaced with a new one, should

be considered. This is a complex procedure, but

some surgeons have reported a 90% success rate.

Coatings with specific antibiotics are being inves-

tigated and studies are reporting very low infec-

tion rates.

Miscellaneous Therapy

Psychosexual counseling

Although widely recommended, there have been

no controlled studies of the use of psychosexual

counseling in erectile dysfunction. One question-

naire survey of 289 sex therapists suggested that

they achieved a successful outcome in 25% of

patients treated for impotence, although the

nature of the patients referred is unclear.(41) In

another study, 20 consecutive diabetic men with

erectile dysfunction were referred for psychosex-

ual assessment and treatment.(42) Three of these

achieved long-term improvement in sexual func-

tion, although it proved impossible to identify

these responders from their pretreatment charac-

teristics. A third study looked at a combination of

treatment strategies in 145 men.(43) Twenty-one

per cent of those studied were able to have inter-

course after psychotherapy alone. Interestingly,

those with clearly organic impotence benefited

almost as much as those with psychogenic impo-

tence (21% versus 32%).

Psychological counseling for patients with or

without their partners are helpful in addressing

the psychogenic and interpersonal factors associ-

ated with erectile dysfunction.(44) Approaches

include techniques to reduce anxiety and to

enhance sexual stimulation, desensitization proce-

dures, cognitive-behavioral interventions, and tra-

ditional counseling. These approaches may be

used alone or in addition to other treatment

interventions such as oral medication or the vac-

uum pump. Such combination therapy may be

particularly useful in situations of low sexual

desire, problems of sexual initiation, other sexual

dysfunction, and significant relationship prob-

lems.(45) Psychosocial factors that contribute to

men discontinuing therapy, despite its effective-

ness, also can be addressed in psychological coun-

seling or sex therapy sessions.(46) These factors

include emotional readiness of each partner to

resume sexual activity, the attitude of each part-

ner toward using a medical intervention, the

quality of the sexual relationship, unconventional

arousal patterns, and the quality of the couple's

sexual life before erectile dysfunction. 

Sex Therapy

A significant number of men develop impotence

from psychological causes that can be overcome.

When a physiological cause is treated, subsequent

self-esteem problems may continue to impair nor-

mal function and performance. Qualified thera-

pists (e.g. sex counselors, psychotherapists) work

with couples to reduce tension, improve sexual

communication, and create realistic expectations

for sex, all of which can improve erectile function. 

236



Safarinejad and Hosseini

Psychological therapy may be effective in con-

junction with medical or surgical treatment. Sex

therapists emphasize the need for men and their

partners to be motivated and willing to adapt to

psychological and behavioral modifications,

including those that result from medical or surgi-

cal treatment.

Lifestyles changes

Staying sexually active can help prevent impo-

tence. Frequent erections stimulate blood flow to

the penis. It may be helpful to note that erections

are firmest during deep sleep right before waking

up. Autumn is the time of the year when male

hormone levels are highest and sexual activity is

most frequent. 

Cigarette smoking has been shown to be an

independent risk factor for ED.(47) In one study

the relative risk of developing internal pudendal

artery atherosclerosis for each 10 pack-year

smoked was 1.(48) The evidence linking smoking

with ED is complex and it has been concluded

that an association between smoking and ED is

likely.(49) This finding is supported by some ani-

mal(50) and human(51) studies, which demonstrat-

ed a direct inhibitory effect of smoking on erec-

tion. However, direct evidence of restoration of

erectile ability with smoking cessation is

sparse(52,53) and there may be a point of no return

after years of cigarette smoking. 

Everyone should eat a diet rich in fresh fruits

and vegetables, whole grains, and fiber and low

in saturated fats and sodium. Because erectile

dysfunction is often related to circulation prob-

lems, diets that benefit the heart are especially

important. Foods that some people claim to have

qualities that enhance sexual drive include

chilies, chocolate, licorice, lard, scallops, oysters,

olives, and anchovies. No evidence exists for

these claims, and eating large amounts of some

of these foods, such as licorice and lard, can be

dangerous. 

Nevertheless, as with hypercholesterolemia,

advising our patients who are seeking improve-

ment of erectile function to cease smoking is

strongly recommended. Obesity and sedentary

lifestyle are also well-recognized risk factors that

can be modified in an attempt to improve erectile

ability.(52) A regular exercise program is extreme-

ly important. One study reported that older men

who ran 40 miles a week boosted their testos-

terone levels by 25% compared to their inactive

peers. Another study found that men who burned

200 calories or more a day in physical activity

(which can be achieved by two miles of brisk

walking) cut their risk of erectile dysfunction by

half compared to men who did not exercise. 

Gene therapy

Defective smooth muscle is seen in the rat

model of aging, when the corporal tissue becomes

more fibrotic as the animal ages. What has also

been shown in this aged animal model is a reduc-

tion in NOS activity in the corporal tissue. In an

attempt to overcome this dual hit to aged tissue,

investigators have searched for ways to either

regenerate the relatively noncompliant corporal

tissue or to up-regulate the factors that promote

smooth muscle relaxation. One of the ways to

accomplish this is via the Ca2+ sensitive K+

channel (maxi-K+) that regulates smooth muscle

relaxation. Christ et al used naked DNA that

encodes the maxi-K+ channel for injection into the

penises of aged animals and was able to augment

their erectile response in this manner. This gene

therapy approach to overcome the processes that

fail with certain disease states highlights what

can be expected in the future for the treatment of

patients who have erectile dysfunction that is

refractory to medical therapy.(54)

Conclusion

Major advances have been made in the under-

standing of the pathophysiology of impotence and

erectile dysfunction. The ability to relax and con-

tract corporal smooth muscle with pharmacologic

agents has led to the development of several new

treatment options for men with impotence. The

demand for safer and more effective treatments

for erectile dysfunction will continue to foster

research in this field. Men with erectile dysfunc-

tion should be encouraged to overcome their

reluctance to seek advice. The standard diagnos-

tic assessment should include a detailed medical

and sexual history and clinical examination of the

patient. 

There are various treatment options available

for the management of erectile dysfunction and

each is associated with a different profile of effi-

cacy, safety and patient satisfaction. Most

patients would prefer to regain their ability to

have a normal spontaneous erection. This is how-

ever only possible when the problem is mainly

psychological, hormonal, drug-dependent or in

the rare men where arterial reconstruction is pos-

sible. All patients benefit from some psychosexu-

237



Erectile Dysfunction

al counseling and it is important to remember

that some patients prefer the option of having a

satisfactory, non-penetrative, sexual relationship.

It is customary to start with a non-invasive type

of therapy and limit more invasive treatments to

those patients with a special indication, for exam-

ple arterial reconstruction, or those who do not

respond to non-invasive methods by implanting a

penile prosthesis.

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