| c palmer 2004-08-21, 2:11 am |
| Erectile function and dysfunction
How it works and what can be done when it doesn't
Gerald H. Jordan, MD
Preview: The advent of "the pill" for erectile dysfunction has prompted
discussion in the news as well as jokes on late-night talk shows.
However, the underlying causes of the condition are complex, and no
single treatment is right for all patients. To select the best therapy
for each patient, it is important to understand how an erection works
and how the available treatments address the various causes of
dysfunction. Dr Jordan presents a comprehensive, straightforward
(sometimes humorous) look at the mechanisms involved in erectile
function and offers an approach to management of dysfunction.
An erection is a complex, involuntary, neuropsychological,
hormone-mediated vascular event that occurs when blood rapidly flows
into the penis and becomes trapped in its spongy chambers (1-6).
Erectile dysfunction, the preferred term for impotence, was defined at
the National Institutes of Health Consensus Conference, December 1992,
as "the inability to achieve or maintain an erection satisfactory for
sexual intercourse." Satisfaction is determined by both patient and
partner, making erectile dysfunction a "couple's disease."
Understanding the mechanisms involved in erectile function is helpful in
treatment of dysfunction.
Anatomy of the penis
The anatomy of the male genitalia is very complex; however, for the
purposes of discussion of erectile function, the corpora cavernosa are
"where the action is" (figure 1: not shown). These two columns of
erectile tissue in the shaft of the penis are surrounded by the tunica
albuginea and separated by an incompetent septum composed of fibers. The
fibers interweave with the inner layer of the tunica albuginea (7,8). A
third erectile body, the corpus spongiosum, is located on the ventrum of
the corpora cavernosa and contains the urethra. Although this body
becomes tumescent, it does not contribute to rigidity and may, in fact,
serve only to make the urethra an efficient conduit for the ejaculate.
The sensation of the glans penis is mediated via the dorsal nerves of
the penis, which are branches of the pudendal nerve. Erectile function
is controlled both parasympathetically and sympathetically. The
parasympathetic input is excitatory in function (3,7). The
parasympathetic nerves adjacent to the prostate gland (nervi erigentes)
coalesce in the hilum of the penis and penetrate into the corpora
cavernosa (3,7-9). The sympathetic input is an extension of the
thoracolumbar plexus and is inhibitory in function (3,7).
Arterial inflow to the deep structures of the penis is dependent on the
deep internal pudendal vessels via the common penile arteries (figure 2:
not shown). These branches provide vascularity to the deep structures as
well as the glans penis. The venous outflow from the penis is a bit more
complex and has been divided into three separate systems: (1)
superficial, consisting of the superficial veins, (2) intermediate,
consisting of the emissary, circumflex, and deep dorsal veins, and (3)
deep, consisting of the hilar and cavernosal veins (1,7,8,10-12) (figure
3: not shown).
Physiology of an erection
The basic physiology of an erection can be described by a simplistic
model that presumes a single lacunar space as the entire corpora (figure
4: not shown). The helicine artery drains into the lacunar space. The
lacunar space is bounded by the intracavernosal smooth musculature and
lined with endothelial cells. Exiting from the lacunar space are one or
more venules that coalesce to become a subtunical venule, which then
drains through the tunica albuginea as the emissary vein.
When the penis is flaccid (figure 4a: not shown), the intralacunar
smooth muscle is in a contracted state; the tonus is maintained by
norepinephrine (alpha stimulation). With stimulation of the cavernous
nerve (alpha blockade), active relaxation of the cavernosal smooth
muscle occurs. The lacunar space and the helicine arteries dilate, the
subtunical venules are compressed physically and possibly
neurologically, and the emissary veins are constricted physically
(figure 4b: not shown). In short, the lacunar space becomes a large
vascular "sink" into which blood rapidly flows and becomes trapped,
thereby elevating the pressure within the lacunar space to that of mean
arterial pressure (2,13-17).
Relaxation of cavernosal smooth muscle is initiated by the following
neurotransmitters: (1) acetylcholine, (2) vasoactive intestinal
polypeptide (VIP) via the VIP-ergic system, (3) prostaglandin via the
prostacyclin system, and (4) nitric oxide via the nitrergic system
(5,6,14,15,18-20) (figure 5: not shown).
Causes of erectile dysfunction
Erectile dysfunction can be categorized as either functional
(psychological) or organic (physical). Although erectile failure of a
purely functional or organic origin is rare, analysis of the two as
independent entities sheds light on some of the characteristic features.
Functional origin
Episodic erectile dysfunction is usually indicative of a functional
cause. Affected patients have normal nocturnal or morning erections and
can often have erections with fantasizing or masturbation. The classic
presentation includes sudden onset often preceded by a period of high
stress. The patient usually firmly maintains that he has a "physical
problem."
Organic origin
Erectile dysfunction of organic origin is characterized by gradual onset
of deterioration of function. The patient first notices diminishing
firmness and a decrease in the frequency of erections. Often, attempts
at intercourse are unsuccessful during periods of fatigue or stress.
Loss of nocturnal erections, poor morning erections, and no improvement
in erections with masturbation are also noted. The patient often has
reactive psychological concerns and is more than willing to assume that
he has a "psychological problem." His libido is usually normal, but it
is not uncommon for libido to diminish with any kind of erectile
dysfunction. Avoidance of intercourse after failed attempts is also a
contributing factor.
The many organic causes of erectile dysfunction include:
Inflammatory conditions of the prostate (eg, prostatitis), urethra, or
seminal vesicles
Surgical procedures (eg, perineal surgery, radical prostatectomy,
cystoprostatectomy, abdominal-perineal resection, vascular surgery)
Pelvic fractures with or without urethral distraction injuries
Lumbar neurologic injuries
Vascular disease affecting large or small vessels
Neurologic conditions (eg, Parkinson's disease, amyotrophic lateral
sclerosis, multiple sclerosis, tabes, peripheral neuropathies)
Endocrine disorders (eg, pituitary problems, gonadal failure, adrenal
disorders, thyroid disorders, diabetes mellitus)
Local factors (eg, cavernous veno-occlusive dysfunction)
Poor overall health (eg, severe angina or shortness of breath that
limits or prevents the physical act of intercourse)
Smoking and consumption of alcohol
Medication use
Erectile dysfunction is a side effect of many common medications,
including antidepressants, inotropic agents, cytotoxic agents,
histamine2 agonists, lipid-lowering drugs, opiates, antihypertensives,
diuretics, hormones, and nonsteroidal anti-inflammatory drugs. However,
not all agents within each drug class produce the same effects. For
example, the antidepressant trazodone hydrochloride (Desyrel) has been
used in small institutional studies (albeit with limited success) as a
treatment for erectile dysfunction, whereas sertraline hydrochloride
(Zoloft) and fluoxetine hydrochloride (Prozac) can adversely affect
erectile function. In short, if a patient is having problems with one
medication, it is reasonable to substitute another medication that may
have fewer ill effects.
Evaluation
When erectile function is viewed as a brain-mediated event, the
influence of central factors as well as local factors becomes evident
(1,6,13,16). In the simplistic analogy illustrated in figure 6 (now
shown), the brain is the "boss" that controls the master switch. An
"off" switch represents functional erectile dysfunction (figure 6a: not
shown). An "on" switch but broken "machinery" (eg, plugged arteries,
broken nerves) is the sine qua non of organic erectile dysfunction
(figure 6b: not shown). Interestingly, when the boss is asleep, the
master switch is always left on (figure 6c: not shown), hence
urologists' interest in nocturnal studies.
Nocturnal studies
Nocturnal studies present a true picture of erectile dysfunction due to
organic causes. The most complete evaluation of nocturnal erectile
function is obtained in a sleep laboratory, where patients are monitored
for rapid eye movement (REM) sleep. Under normal conditions, an erection
would be expected to occur with each REM episode. The erection can be
described in terms of tumescence and buckling force (a measure of
rigidity).
Vascular erectile testing
Duplex Doppler ultrasonography has been used extensively, and likely
overused, in evaluation of erectile function. It provides information
about both arterial and venous flow. The value of the test is
questionable unless the information obtained is needed for treatment
selection (16). Dynamic infusion pharmacocavernosometry and
pharmacocavernosography (DICC) also provides detailed data about
pressure related to erectile function, but this information often is
more extensive than is required for treatment of erectile dysfunction
(6).
Pharmacologic testing
Office pharmacologic testing is used by some physicians. The test
involves intracavernosal injection of a small amount of an active agent
(eg, 10 micrograms of alprostadil [prostaglandin E1]) that,
theoretically, would produce a normal or priapic erection in a patient
with normal erectile function but a poor response in a patient with
erectile dysfunction. The problem with this test is that unless the
patient's sympathetic nerve impulses are completely overcome by the
injected agent, he may have a poor erection even though his erectile
function is normal.
Hormone testing
Measuring serum levels of testosterone (both total and free),
gonadotropins, and gonadotropin-releasing hormone may be helpful in a
patient in whom history taking or physical examination suggests lack of
androgen stimulation. Clues to low androgen levels include poor libido,
a disproportionately small prostate gland relative to the patient's age,
small or soft testicles, and noticeable thinning or diminished growth of
the beard. If the patient's total testosterone level is low, the
prolactin level should be checked, because hyperprolactinemia alone may
be the cause.
Treatment
Not long ago, penile prostheses were the only option for the treatment
of erectile dysfunction. However, many new treatments are currently
available.
Vacuum erection devices
The vacuum erection device (eg, ErecAid, Post-T-Vac, VED) is an
excellent option for many patients. A vacuum tube placed around the
penis enhances the effects of the inherent pressure within the penis,
causing it to become longer and thicker. Some passive dilation of the
intracavernosal spaces also occurs. A band is then placed around the
base of the penis to maintain the erection.
Oral therapy
A number of oral drugs for treating erectile dysfunction are being used
experimentally, and a few are now available for clinical use. All of the
agents have indications for both organic and functional erectile
dysfunction.
Yohimbine is a naturally-occurring alpha blocker. Its efficacy in
erectile dysfunction is questionable. In my experience, yohimbine
therapy is most successful in patients who have very minimal organic
dysfunction with a large functional overlay. The newer oral alpha
blockers will likely replace use of this agent.
As mentioned, trazodone has been used clinically in small institutional
settings as therapy for erectile dysfunction. The usual dosage is 50 mg
taken 2 hours before coitus. However, a more realistic approach may be
50 or 100 mg nightly for a couple of weeks to allow evaluation of the
effects.
Sildenafil citrate (Viagra) inhibits phosphodiesterase type V, the
enzyme that converts cyclic guanosine monophosphate (GMP) to inactive
5-GMP. When this chemical action is blocked, the levels of cyclic GMP
increase and smooth-muscle relaxation is enhanced, thereby increasing
and maintaining relaxation of the lacunar spaces (14).
Two other agents, sublingual apomorphine hydrochloride (Zydis), a
central dopamine stimulant, and oral phentolamine (Vasomax), an
alpha-adrenergic blocker, are undergoing clinical trials. The chief
adverse effect of apomorphine is nausea, sometimes accompanied by
vomiting. The agent is indicated specifically for patients with
functional erectile dysfunction.
Hormone treatment
Patients with low testosterone levels should undergo evaluation to
determine the cause. Exogenous testosterone therapy may be helpful in
some patients. Testosterone transdermal systems (Androderm, Testoderm)
are available. Oral testosterone (ie, methyltestosterone) generally is
not indicated. If the decrease in testosterone is associated with
hyperprolactinemia, treatment with bromocriptine mesylate (Parlodel) is
warranted.
Injection and intraurethral therapy
Intracavernosal injection therapy involves three drugs given alone or in
combination ("tri-mix"): alprostadil (Caverject, Edex), the alpha
blocker phentolamine (Regitine), and papaverine hydrochloride (6,16).
Another injectable agent, vasoactive intestinal polypeptide, is
currently undergoing clinical trials.
An intraurethral suppository form of alprostadil (Muse) is also
available (21,22). This delivery method is based on the theory that the
venous connections between the corpus spongiosum and corpora cavernosa
allow for absorption via the urethral epithelium and immediate transport
to the corpora cavernosa. In fact, the systemic absorption is
substantial, and intraurethral alprostadil therapy can have systemic
side effects. Up to 50% of patients have a measurable drop in blood
pressure, although only about 3% are aware of it. Some patients have
significant symptoms of hypotension. With both intraurethral and
intracavernosal injection therapy, dose levels should be tested and
adjusted under supervision by a physician.
A study by the MUSE Study Group (21) showed that few patients responded
to doses below 500 micrograms. Therefore, in my practice, all patients
are given a 500-micrograms challenge in the office. "Super responders"
are switched to a lower dose; "under responders" are rechallenged at
1,000 micrograms.
Surgery
At one time, surgery for cavernous veno-occlusive dysfunction (23) was
thought to be "the answer" to erectile dysfunction. However, the vast
majority of patients with cavernous veno-occlusive dysfunction are not
candidates for surgery. The best candidates should (1) be less than 50
years of age, (2) have minimal or no inflow abnormalities, (3) have no
Peyronie's disease or other abnormalities of the tunica albuginea, and
(4) probably have a relatively insignificant smoking history.
Revascularization of the corpora cavernosa does not address the
pathologic cause of erectile dysfunction (1,12,24,25). Instead, it is
based on a premise similar to that of coronary artery bypass grafting:
When vessels are blocked, new vessels are brought to the area to provide
better inflow. Although the results vary widely among medical centers,
vascular surgery is most successful in young patients who have had
pelvic or perineal trauma and have few vascular risk factors.(26-28)
Penile implants
Since the development of other options, prostheses have assumed a much
smaller role in the treatment of erectile dysfunction. However, various
types of prostheses are still marketed: (1) simple rod, (2) malleable
rod, (3) self-contained hydraulic, (4) multiple-component hydraulic, and
(5) articulated prostheses. Each type has advantages and disadvantages,
which should be matched to the patient's individual preferences.
Although implantation is not without complications, the complication
rate is quite acceptable. The infection rate is slightly less than 3%.
Mechanical failure rates are now within very acceptable ranges, and most
prostheses are extremely reliable (29,30).
Approach to management
In initial management of erectile dysfunction, it is imperative to
determine whether the dysfunction is primarily organic with a small
overlay of functional "baggage" or predominantly functional with only a
small component of organic dysfunction.
In patients with functional erectile dysfunction, counseling by a
skilled sex therapist is usually successful. A trial of yohimbine,
intraurethral alprostadil, or testosterone is not indicated, and in some
cases, it may be dangerous. Yohimbine may cause hypotension in some
patients, and alprostadil can cause hypotension as well as priapism.
Testosterone therapy is not indicated in any patient who has not been
proven to be hypogonadal. Cases have been described of patients with
occult carcinoma of the prostate who had an apparent flare after
administration of exogenous testosterone. However, yohimbine may have a
role in selected patients (31). If clinical trials of sublingual
apomorphine confirm the efficacy seen in pilot studies, this agent may
be another first-line option.
In management of organic erectile dysfunction, the first decision point
is whether the patient is a surgical candidate. If he is, referral to a
urologic surgeon for evaluation (eg, sleep laboratory testing, duplex
ultrasonography) is warranted. For most patients, however, search for an
effective nonsurgical treatment is indicated.
Sildenafil is a safe drug but not the panacea that media reports have
suggested. Great caution must be taken with patients who have coronary
artery disease or, in my estimation, any type of vascular disease.
However, in other patients, sildenafil is an excellent choice. Patients
should be instructed in proper use of the medication (ie, take while
fasting, 30 to 60 minutes before intercourse) and counseled regarding
the side effects (ie, facial flushing, headache, "blueing out").
If sildenafil therapy is unsuccessful and the patient has no medical
problems that would be adversely affected by hypotension (eg, carotid
stenosis, angina), intraurethral alprostadil therapy is a logical next
step. This option is effective in 35% to 40% of patients (21). When it
is unsuccessful, the next step in patients who remain motivated to find
an effective treatment is intracavernosal injection therapy. In my
opinion, unless the primary care physician is prepared to provide proper
in-office instruction and to treat priapism that can arise with use of
this method, the patient should be referred to a urologist.
The available oral medications have acceptable side-effect profiles and
are an appropriate option for many patients. Therapy with trazodone or
yohimbine in the vast majority of patients appears to be effective
primarily as a placebo. However, sildenafil (and possibly oral
phentolamine, when it becomes available) would definitely be worth a try
in patients with mild erectile dysfunction. It must be kept in mind that
sildenafil is a facilitator, not an initiator. The patient must,
therefore, have some erectile function to facilitate.
When other therapies are unsuccessful, patients may consider a vacuum
erection device, which can be highly effective in motivated patients.
Proper instruction and counseling from a device manufacturer's
representative, if available, are important. For many patients, however,
the vacuum erection device seems cumbersome or unnatural and is a
barrier to spontaneity.
Conclusion
The management of erectile dysfunction has come a long way in the last
15 years. The medical profession has gone from a total lack of
understanding of how an erection occurs to a very sophisticated
understanding. Whereas physicians once thought there was only one
"solution" for erectile dysfunction--that is, acceptance of the
condition--they now can offer a host of options, all of which can be
individualized to the patient's needs and wants. In spite of the range
of current options, the fact remains that outcome studies have shown a
high dropout rate with all therapies (23). Thus, the search for a
"miracle cure" likely will continue.
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Dr Jordan is professor of urology, Eastern Virginia Medical School of
the Medical college of Hampton Roads, and director, Devine Center for
Genitourinary Reconstruction at Sentara Norfolk General Hospital,
Norfolk, Virginia. Correspondence: Gerald H. Jordan, MD, Devine-Fiveash
Urology, 400 W Brambleton Ave, Suite 100, Norfolk, VA 23510-1196.
E-mail: ghjordan@sentara.com.
knowledge is power - growing old is mandatory - growing wise is optional
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