Erectile Dysfunction

Prevalence
Epidemiologic studies demonstrated that 35% of men aged 40 to 70 years suffer from
moderate or severe ED, and an additional 25% have milder forms of ED (Feldman,
Goldstein, Hatzichristou, Krane, & McKinlay, 1994). ED affects ap proximately 1 in 10
men worldwide (Benet & Melman, 1995). The risk of erectile dysfunction in creases
with age. As the population continues to grow and age, the prevalence is expected
to continue to increase, with an estimate that there will be 322 million men worldwide
with ED by the year 2025 (Ayta, McKinlay, & Krane, 1999). Al though awareness of
erectile dysfunction has in creased with the advent of oral therapies, a significant
number of men remain undiagnosed and untreated.

Etiology of Erectile Dysfunction
Historically, ED was believed to primarily have a psychogenic origin; however, the
majority of individuals are currently identified to have organic ED due to an underlying
physiologic cause. The most common cause of ED is atherosclerosis and is associated
with disease states such as diabetes mellitus, hypertension, smoking, and
dyslipidemia. These risk factors cause oxidative stress and damage to the endothelial
cells (Azadzoi et al., 1998; Saenz de Tajada, Goldstein, Azadzoi, Krane, & Cohen,
1989; Sullivan et al., 1999). Endothelial cell dysfunction results in a decrease in nitric
oxide production, the key neurotransmitter in the normal erectile process.
The presence of ED is a good predictor of occult coronary artery disease, particularly if
the erectile dysfunction is severe. ED in men with coronary artery disease is a
predictor of occult peripheral vascular disease (Solomon, Martin, & Jackson, 2002). In
a study assessing cardio vascular disease in 50 men aged 40 to 60 years with
organic ED and who were asymptomatic for coronary artery disease, up to 40% had
significant coronary artery disease on cardiac evaluation (Pritzer, 1999). Peripheral
vascular disease elsewhere in the body also correlates with the severity of ED
(Gensini, 1983; Greenstein et al., 1997; Kawanishi et al., 2001; Solomon et al., 2002;
Solomon, Man, Wierzbicki, & Jackson, 2003).

The normal erectile process is a neurovascular event that is triggered by cognitive or
tactile stimulation. Psychogenic and hormonal factors may also play a role in the
erectile process (Meredith, 1995). Disease states and medications that can affect
arousal, hormones, and the normal function of nerves, arteries, and veins may have
an impact on erectile function.

Physiology of Erection
Sexual stimulation is required for an erection. As a result of sexual stimulation, neural
impulses are conveyed through the spinal cord to the pelvic parasympathetic
preganglionic nerves, which form the pelvic plexus. Acetycholine released from the
pelvic nerve terminals stimulates the cavernosal nerves, which enter the cavernosal
bodies within the penis. Stimulation of the cavernosal nerves leads to the release of
the neurotransmitter, nitric oxide. Nitric oxide activates the enzyme guanyl cyclase,
which catalyzes the formation of cyclic guanosine monophosphate (cGMP) from
guanosine triphosphate (GTP). cGMP stimulates cGMP-specific protein kinase, which
blocks calcium influx by inhibiting calcium channels. The decreased cytosolic calcium
concentration leads to relaxation of the cavernosal smooth muscle, and a resultant
inflow of blood into the cavernosal bodies and rapid distention of the sinusoids. The
distended sinusoids compress peripheral venules against the tunica albuginea, a
fibroelastic covering that surrounds the corporal bodies, thus preventing venous
outflow. The combination of increased arterial inflow and diminished venous outflow
yields intracavernosal pressures that approximate systolic pressure, and the penis
achieves sufficient rigidity for vaginal penetration (Vickers & Wright, 2004).
Cavernosal smooth muscle relaxation is also regulated by cyclic adenosine
monophosphate, which causes relaxation of the trabecular smooth muscle in the
corpus cavernosa (Walsh, Retik, Vaughan, & Wein, 2002).

Evaluation of Erectile Dysfunction
In 1996, the American Urological Association (AUA) Erectile Dysfunction Clinical Guide
line Panel published the Report on the Treatment of Organic Erectile Dysfunction, an
evidence-based guideline for the diagnosis and treatment of erectile dysfunction
(Montague et al., 1996). Since that time, an Erectile Dysfunction Guideline Update
Panel (the Panel) was appointed by the AUA Practice Guidelines Committee in 2000 to
update the 1996 guidelines. The following recommendations are in accordance with
these guidelines (Montague et al., 2005). The male presenting with a complaint of ED
should be evaluated with sexual, medical-surgical, and psychosocial histories; a
focused physical examination; and laboratory tests thorough enough to identify
co-morbid conditions that may predispose the individual to ED and may have an
impact on the treatment choice.

Diagnosing Androgen Deficiency in the Aging Male
The diagnosis of hypogonadism is by hormonal evaluation. It is rarely identified by
history and physical examination. Al though testosterone positively affects libido,
decreased libido may be related to other causes, such as depression and lack of
interest due to underlying ED. Similarly, the presence of normal secondary sex
characteristics on physical examination does not rule out a low testosterone level. In
most men, a morning total testosterone level is all that is necessary. In older and
obese males, increased SHBG levels may aberrantly raise total serum testosterone
levels; therefore, measurement of bioavailable testosterone, ideally via equilibrium
dialysis assay, is more accurate. Although there are no clear-cut testosterone levels
that define hyoponadism, it is believed that levels less than 250ng/dL are low, levels
greater than 350 ng/dL are normal, and levels between 250 ng/dL and 350 ng/dL are
indeterminate. If the testosterone level is low, then it is appropriate to check LH, FSH,
and serum prolactin levels. Medications that may affect gonadal function include
thiazide diuretics, long-acting oral opiates, antiepileptics, corticosteroids, and atypical
antipsychotic (such as risperidone and olanzapine) (Lunenfeld, 2003). If the prolactin
level is elevated, then further evaluation with an MRI is indicated to rule out a
pituitary adenoma.

What Level of Serum Testosterone Level Warrants Treatment?
Current consensus recommendations suggest limiting use of TRT to men with a serum
testosterone level of less than 200 ng/dL and symptoms of hypogonadism, although
evidence supporting this recommendation is lacking (The Practice Committee of the
American Society for Reproductive Medicine, 2004). Studies have demonstrated that
in individuals with low normal testosterone levels who have failed oral PDE-5 inhibitor
therapy, an improvement in response to PDE-5 inhibitors with testosterone
supplementation exists (Shabsigh et al., 2004). The use of TRT for other factors, such
as bone density and body fat mass, remains controversial.

What Types of TRT Are Available?
The ideal testosterone preparation is that which allows for normalization of serum
testosterone levels, mimics the normal circadian pattern of testosterone production,
produces normal levels of testosterone metabolites, and minimizes side effects.
Therapies currently used in the United States include injectable, topical, and
transbuccal testosterone. Oral testosterone therapy is not used in the United States
due to the inability to achieve adequate systemic levels and the higher risk of
adverse effects.

What Are the Potential Adverse Effects of TRT?
TRT may increase prostate size and cause lower urinary tract symptoms. In males on
testosterone supplementation, the PSA may increase by 0.3ng/ml/year, whereas
older men may experience up to a 0.43 ng/ml/yr change in PSA when on TRT (Bhasin
& Buckwalter, 2001). A baseline PSA should be obtained before starting TRT and a
repeat PSA obtained 6 to 12 weeks after starting therapy and semi-annually
thereafter. Polycythemia and sleep apnea are more commonly associated with the
parenteral testosterone, and a baseline hematocrit is recommended in individuals
starting TRT and periodically thereafter.

The impact of TRT on cardiovascular morbidity remains poorly defined. Physiologic
doses of testosterone have either no effect or potentially beneficial effects on the
cardiovascular system. Caution should be used in men with congestive heart failure,
since testosterone therapy may lead to an increase in hematocrit levels (Kostis et al.,
2005; Swerdloff & Wang, 2003). From a cardiovascular standpoint, higher-serum
testosterone levels may be cardioprotective, and changes in lipid profile are less
relevant when the testosterone level is restored to physiologic levels (Liu et al.,
2003).

Changes in anticoagulant activity may be seen with androgen use, and thus,
individuals on anticoagulants should have regular laboratory testing. Concurrent use
of oxyphenbutazone and androgens may lead to increased levels of
oxyphenbutazone. In diabetic patients, the metabolic effects of androgens may lower
the blood glucose and insulin requirements. Concurrent administration of
testosterone with adrenocorticotrophic hormone (ACTH) may enhance edema
formation, and the combination should be used with caution, especially in patients
with cardiovascular or hepatic disease.

Assessment of Cardiovascular Risk
Cardiovascular risk stratification has become an essential component of the
evaluation of men presenting with ED. Questions pertaining to exercise capabilities,
history of cardiovascular disease, and current/past medications can help assess
whether or not an individual is at risk for cardiovascular disease. Guidelines have
been established to assist in stratification of an individual's cardiovascular risk.
Concerns regarding cardiovascular safety and the risk of drug-drug interactions have
led to two Princeton Consensus conferences, one in 1999 and the other in 2004, that
focused on sexual dysfunction and cardiac risk. A risk stratification algorithm was
developed by the First Princeton Consensus Panel to evaluate the degree of
cardiovascular risk associated with sexual activity in men with varying degrees of
cardiovascular disease (DeBusk et al., 2000). The consensus study from the Second
Princeton Consensus Conference corroborated and clarified the algorithm and
emphasized the importance of risk factor evaluation and management for all patients
with ED.

Cardiovascular risk was divided into 3 groups: patients who were considered at low
risk, intermediate or indeterminant risk, and high risk. Patients who are at
intermediate or indeterminant risk are those with uncertain cardiac conditions and
who may also have multiple risk factors. It is recommended that these individuals
undergo further evaluation/testing before resuming sexual activity. Based on results
of further evaluation, these individuals may be re-stratified as high or low risk for
cardiovascular complications related to sexual activity. Patients in the high-risk group
are deemed to have a potentially significant risk associated with sexual activity, and
thus, sexual activity should be deferred until the patient's cardiologist and/or primary
care provider indicates that it is safe to participate in sexual activity.
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