Testicular size decreases with age; however, the testicular degeneration is sporadic,
thereby allowing most elderly men to maintain a normal or slightly decreased sperm
200 Overall, spermatogenesis decreases and is accompanied by an increase in
serum concentration of FSH. FSH elevation correlates well with a decline in the
number of Sertoli cells that secrete inhibin. Inhibin normally decreases FSH.
As a result of primary or secondary hypogonadism in the elderly male, available
testosterone declines. Approximately 60% to 75% of circulating serum testosterone
albumin, and 1% to 2% is unbound, or free. The unbound portion of testosterone is
the only active portion of the total serum testosterone concentration. Testosterone
serum concentrations are 20% higher in the morning than in the evening, and this
should be taken into consideration when evaluating laboratory results. In virtually all
cases of ED, the serum concentration of testosterone should be measured in the
Testosterone production is regulated by feedback with the hypothalamus and
pituitary. The hypothalamus produces gonadotropin-releasing hormone (GnRH) in
response to low testosterone levels. GnRH induces the pituitary to secrete LH and
FSH, which in turn stimulates the Leydig cells of the testes to secrete testosterone.
Less than 10% of cases of ED studied are caused strictly by hypogonadism.
role of testosterone in ED is complex. After testosterone production decreases,
libido eventually declines and precedes the decrease in frequency of erections.
Men given antiandrogens maintain their erectile capacity but have a decreased
205 On the other hand, high dosages of androgens given to hypogonadal men
increase both the frequency of erections and libido.
postulate that at physiologic levels, testosterone modulates the cognitive processes
associated with sexual arousal more than it contributes to erectile capability.
Many endocrine disorders can result in ED. Patients with prolactinomas commonly
have ED, but prolactinomas account for less than 1% of ED cases.
inhibits the release of testosterone, resulting in secondary hypogonadism.
Hyperprolactinemia may be more prevalent in diabetic patients.
however, hyperprolactinemia often is secondary to the use of medications. F.M.’s
serum prolactin level is elevated, most likely because of his diabetes mellitus.
In summary, aged men have a decrease in testosterone because of defects in
testicular and hypothalamic–pituitary function. Secondary hypogonadism in elderly
men is common, and the point at which this becomes pathologic has not yet been
established. Correspondingly, the use of hormonal therapy to treat physiologic
secondary hypogonadism is extremely controversial. Therefore, the gonadal function
tests for F.M. are normal for his age and do not provide an explanation for his ED.
MEDICATIONS THAT CAUSE ERECTILE DYSFUNCTION
CASE 109-4, QUESTION 5: Is it likely that a medication is causing F.M.’s ED?
Several general statements can be made regarding sexual function and medications.
Drugs that affect libido generally have a central mode of action. For example,
medications that block central dopamine transmission can decrease libido, and
opiates have an antiandrogen effect.
176 Drugs that alter hemodynamics may interfere
with erection. Excessive sympathetic tone is thought to cause the “steal syndrome,”
which increases blood flow to muscles, drawing blood away from the erectile
165 Drugs that block the peripheral sympathetic system can cause retrograde
ejaculation or no ejaculation at all. Numerous drugs have been associated with
altered sexual function (Table 109-6).
Few studies exist in the literature solely devoted to drug-induced ED or sexual
187,188 A few studies and review articles, however, list medications as
one of many potential causes for ED.
Most studies documenting drug-induced ED have been subjective and based on
case reports, uncontrolled studies, and clinical impressions. The MMAS reported
that ED was statistically correlated with antihypertensive, vasodilator, cardiac, and
hypoglycemic drugs. The probability of moderate as well as complete ED was
particularly high for vasodilator drugs.
136 Although the MMAS is one of the most
well-designed studies to date, the medications reported are not considered to be the
universe of all medications associated with ED. Diagnosis of drug-induced sexual
dysfunction should be restricted to a reproducible dose-related effect that disappears
on discontinuation of the drug.
146 A much larger survey of a controlled study in a
clinical population would be required to establish any suspect medication as
causative, rather than temporal.
F.M.’s sexual dysfunction (e.g., loss of interest in sexual activity and ED) is not
caused by his current drug regimen, ramipril, and glipizide. Although the MMAS
reported a correlation between the use of antihypertensives and hypoglycemic drugs
with ED, clinicians must look at the individual drugs themselves and the conditions
for which they are prescribed. Sexual dysfunction is not likely to occur with ramipril,
or any of the other angiotensin-converting enzyme inhibitors, or with the
hypoglycemic agent glyburide. Although ramipril is an antihypertensive, its
pharmacologic effects do not contribute to a decline in libido or cause ED (an
advantage that angiotensin-converting enzyme inhibitors have compared with other
antihypertensive medications). Similarly, the pharmacologic action of glipizide does
not contribute to F.M.’s decreased libido or ED. In most sexual dysfunction cases, it
is less likely that the medication is the direct cause of the problem; rather, it is the
medical condition for which the drugs were prescribed. The ability of a drug to
induce sexual dysfunction simply is an extension of its pharmacologic actions. As a
general rule, drugs that manipulate the sympathetic or the parasympathetic system,
both centrally and peripherally, are associated with sexual dysfunction.
CASE 109-4, QUESTION 6: What factors most likely are contributing to F.M.’s ED?
F.M. is a patient with hypertension and diabetes who smokes cigarettes. Those
three factors are more likely to be the cause of F.M.’s sexual dysfunction than are his
medications. Diabetes mellitus is the most common hormonal disorder associated
with ED in the elderly population.
195 The continued loss of interest in sexual activity
experienced by F.M. most likely is the result of having experienced ED during past
F.M.’s subjective and objective findings are common among elderly men. His
sexual dysfunction is caused by atherosclerosis and possible neuropathy secondary to
diabetes mellitus. Because cigarette smoking is no doubt contributing to F.M.’s ED,
cessation should be encouraged; some improvement can be expected.
need to alter F.M.’s drug regimen.
CASE 109-4, QUESTION 7: What are the primary therapeutic considerations for F.M.?
Essentially, there are three levels to the management of ED. Level 1 includes
lifestyle and drug therapy modifications. Specifically, the patient should be instructed
to modify smoking and alcohol use. The patient’s drug regimen should be checked
periodically to ensure that drugs associated with ED are not being prescribed. If
necessary, psychosocial counseling should be provided. After careful consideration,
oral medications for management of ED should be instituted. If level 1 therapies have
failed or are not acceptable to the patient, then level 2 therapy is instituted. These
interventions include a vacuum constriction device to elicit an erection,
intracavernosal injections, or transurethral inserts. Level 3 management involves
placement of a penile prosthesis.
Any therapy directed at male sexual dysfunction must include the elimination of drugs
causing adverse sexual effects. Drug therapy is directed primarily toward treatment
of ED and includes hormonal therapy, bromocriptine, prostaglandin E1
tadalafil, vardenafil, avanafil, and apomorphine.
Phosphodiesterase-5 inhibitors
CASE 109-4, QUESTION 8: Would phosphodiesterase-5 inhibitor therapy be appropriate for F.M.? What
are its side effects and contraindications? Does it interact with other drugs?
F.M. has diabetes mellitus and atherosclerosis and therefore is a candidate for
treatment with a phosphodiesterase-5 (PDE-5) inhibitor.
active and selective inhibitors of cyclic guanosine monophosphate-specific PDE-5,
the predominant phosphodiesterase isoenzyme metabolizing cyclic guanosine
monophosphate in the corpus cavernosum. They facilitate an erection in response to
sexual stimulation by enhancing the nitric oxide-induced relaxation of corpus
cavernosal smooth muscle. The results of double-blind, placebo-controlled clinical
trials in men with ED of various causes have demonstrated that PDE-5 inhibitors
significantly improve erectile function and the rate of successful sexual intercourse,
with therapeutic outcomes approaching those of normal men of the same age.
F.M. should be counseled on the adverse effects of PDE-5 inhibitors. The
vasodilating action of PDE-5 inhibitors affects both the arteries and the veins, so the
most common side effects are headache and facial flushing.
a small decrease in both systolic and diastolic blood pressures, but clinically
significant hypotension is rare. Studies of PDE-5 inhibitors and nitrates taken
together show much greater drops in blood pressure. For that reason, PDE-5
inhibitors are contraindicated in patients taking long-acting nitrates or short-acting
nitrate-containing medications.
In phase II/III studies before US Food and Drug
Administration (FDA) approval, more than 3,700 patients received sildenafil and
almost 2,000 received placebo in double-blind and open-label studies.
Approximately 25% of patients had hypertension and were taking antihypertensive
medications, and 17% were diabetic. In these studies, the incidence of serious
cardiovascular adverse effects was similar in the double-blind sildenafil group, the
double-blind placebo group, and the open-label group. Twenty-eight patients had
experienced a myocardial infarction. When adjusted for patient-years of exposure, no
significant differences were seen in the myocardial infarction rates between the
sildenafil and the placebo group, and no deaths were attributed to sildenafil.
an analysis of 67 double-blind, placebo-controlled trials of sildenafil, the overall
frequency of death was comparable between the sildenafil-treated patients (13 of
8,691; 0.15%) and placebo group (7 of 6,602; 0.11%).
deaths caused by myocardial infarction or arrhythmia have been associated with the
218 Deaths associated with sildenafil (and presumably other PDE-5
inhibitors) are most likely caused by increased cardiac workload in patients with
Transient visual anomalies (mostly blue-green color-tinged objects, increased
sensitivity to light, and blurred vision) have been reported in patients taking PDE-5
inhibitors, especially at higher dosages. These visual effects appear to be related to
the weaker inhibiting action of PDE-5 inhibitors on the enzyme phosphodiesterase-6,
which regulates signal transduction pathways
in the retinal photoreceptors. In patients with inherited disorders of retinal
phosphodiesterase-6, such as retinitis pigmentosa, PDE-5 inhibitors should be
administered with extreme caution. In 2005, the FDA recommended that all PDE-5
inhibitors include a precaution in their labeling regarding the risk of nonarteritic
anterior ischemic optic neuropathy as a cause of decreased vision including
permanent vision loss. There have been only a handful of reports of nonarteritic
anterior ischemic optic neuropathy in postmarketing surveillance, and most patients
220 Clinicians should advise patients to discontinue the use
of all PDE-5 inhibitors and seek medical attention in the event of sudden vision loss
The vasodilator actions of nitrates are profoundly amplified with concomitant use
of PDE-5 inhibitors. This interaction likely applies to all nitrates and nitric oxide
donors, regardless of their predominant hemodynamic site of action. They also may
potentiate the inhaled form of nitrate, such as amyl nitrite, and therefore are
contraindicated in patients using this product. Dietary sources of nitrates, nitrites, and
L-arginine (the substrate from which nitric oxide is synthesized) do not contribute to
the circulating levels of nitric oxide in humans and, therefore, are unlikely to interact
with PDE-5 inhibitors. The anesthetic agent, nitrous oxide, is eliminated unchanged
from the body, mostly via the lungs, within minutes of inhalation. It does not form
nitric oxide in the human body and does not itself activate guanylate cyclase. As such,
no contraindication exists to its use after administration of PDE-5 inhibitors. The
concomitant use of nitrates and the PDE-5 inhibitors is contraindicated although some
differences in the nitrate-free period do exist based on the pharmacokinetic profile of
the PDE-5 inhibitor. After 24 hours, the administration of nitrates can once again be
considered in patients using vardenafil and sildenafil; however, this should be
extended to 48 hours in patients using tadalafil and can be shortened to 12 hours with
CASE 109-4, QUESTION 9: Which PDE-5 inhibitor should be recommended for F.M.?
The typical dose of sildenafil is 50 mg orally, taken 1 hour before sexual activity.
However, it may be taken anywhere from 4 hours to 30 minutes before sexual
activity. The maximal recommended dosing frequency is once per day. The following
factors are associated with increased plasma levels of sildenafil: age older than 65
years (40% increase in area under the curve), hepatic impairment (e.g., cirrhosis,
80% increase), severe renal impairment (creatinine clearance <30 mL/minute, 100%
increase), and concomitant use of potent CYP3A4 inhibitors (e.g., erythromycin,
ketoconazole, itraconazole, 200% increase). Because higher plasma levels may
increase both the efficacy and the incidence of adverse events, a starting dose of 25
mg should be considered in these patients. The dose may be increased to 100 mg.
Because F.M. is older than 65 years of age, he should be started on 25-mg tablets of
sildenafil. The dose may be increased under strict supervision.
Sildenafil is metabolized by both the CYP2C9 pathway and the CYP3A4 pathway.
Thus, inhibitors of the CYP3A4 isoenzyme, such as erythromycin or cimetidine, may
physiologic effects of sildenafil are not known, but clinicians should be warned
about the potential interaction.
Inadequate physical sexual stimulation while using any of the PDE-5 inhibitors can
lead to treatment failure. Adequate sexual stimulation is needed to trigger the events
221 PDE-5 inhibitors cannot initiate an erection; they can only
assist in the process. Some patients may need several attempts at sexual stimulation
before they are successful with intercourse.
Similar to sildenafil, tadalafil is a selective inhibitor of PDE-5. Tadalafil has several
times more affinity for PDE-5 than sildenafil.
222 Tadalafil and vardenafil, however,
have minimal or no effect on visual disturbance (impairment of blue-green color
discrimination), which is a well-recognized side effect of sildenafil.
extended half-life of 17.5 hours relative to sildenafil most likely precludes its use in
patients with angina or hypertension. Tadalafil is metabolized by the hepatic
CYP3A4 isozyme. Food has no effect on the oral absorption of tadalafil in contrast to
sildenafil (bioavailability decreased by 29%). Tadalafil may be advantageous in a
subset of patients, based on its shorter onset of action (16 minutes) and 24-hour
224 Specifically, patients with psychogenic or neurogenic ED and
those with stable cardiovascular systems may prefer tadalafil because it offers the
potential for multiple sessions of intercourse with a single daily dose.
Vardenafil is the third FDA-approved oral PDE-5 inhibitor for treatment of ED. The
warnings regarding the use of nitrates while taking vardenafil are similar to the
warnings for sildenafil. Patients using vardenafil may experience headache, flushing,
or rhinitis; the incidence of these side effects is dose related.
metabolized by the hepatic CYP3A4 isozyme and has a reported half-life of 5
226 Thus, drugs known to inhibit the CYP3A4 isozyme have the potential to
prolong its half-life. Vardenafil 10 mg does not impair the ability of patients with
stable coronary artery disease to exercise at levels equivalent to or greater than that
attained during sexual intercourse.
Avanafil is a new PDE-5 inhibitor with enhanced PDE-5 selectivity which may
translate to fewer side effects due to less selectivity for non-PDE-5 isoenzymes,
found in the heart, retina, and skeletal muscle. The starting dose is 50 mg and should
be taken 30 minutes before sexual activity whereas the 100- to 200-mg doses can be
taken 15 minutes before. It has a similar half-life to sildenafil and vardenafil and is
rapidly absorbed following administration. Side effects and contraindications for
avanafil are similar to the other PDE-5 inhibitors.
F.M. has hypertension that most likely would be affected by tadalafil; therefore,
extreme caution is advised. Perhaps, the shorter-acting sildenafil, vardenafil, or
avanafil would be the PDE-5 inhibitor drug of choice for F.M.
CASE 109-4, QUESTION 10: Should F.M. be treated with testosterone?
Primary hypogonadism with severely deficient serum levels of bioavailable
testosterone is the only appropriate indication for the use of androgen hormone
169 The goal of androgen-replacement therapy is to restore potency and libido
by maintaining normal serum levels of testosterone.
229 Testosterone has no benefit in
the treatment of eugonadal or mildly hypogonadal elderly men and actually may
enhance the growth of undiagnosed adenocarcinoma of the prostate or cause further
In eugonadal men, testosterone enhances the rigidity of the erection, but does
not change the penile circumference.
230 F.M. would not be a candidate for
CASE 109-4, QUESTION 11: Which type of patient would benefit from testosterone therapy?
Unless testosterone deficiency is severe, (free testosterone serum levels less than
7 to 8 pg/mL) testosterone replacement therapy will not improve the success rate of
231 Testosterone replacement in patients with primary hypogonadism
generally restores libido and potency. In some patients with secondary hypogonadism
caused by disorders of the hypothalamus or pituitary, GnRH analogs can be
administered to differentiate between hypothalamic and pituitary abnormalities and to
correct testosterone deficiency.
229 Libido and potency then are restored.
CASE 109-4, QUESTION 12: How should testosterone be used as a treatment for ED?
Testosterone-replacement therapy is available in several formulations, including
gels, transdermal patches, and intramuscular injection. Because of poor drug
bioavailability, oral testosterone-replacement therapy is less effective than
parenteral testosterone in achieving normal serum testosterone levels. Oral
administration also is associated with a higher incidence of hepatotoxicity and
143,174 A long-acting testosterone intramuscular
formulation, such as the enanthate or cypionate ester, is still considered the regimen
of choice for the treatment of primary hypogonadism. A dose of 50 to 400 mg should
be administered intramuscularly every 2 to 4 weeks. Side effects of testosterone
therapy include early gynecomastia, increases in hematocrit (sometimes to the point
of polycythemia), and fluid retention that may worsen hypertension or heart failure.
Results of several studies have demonstrated that serum testosterone levels are
normalized while using transdermal testosterone applications.
normalizes DHT to testosterone ratios and reduces LH levels toward the normal
range. The transdermal testosterone is well tolerated, with application site reactions
such as pruritus, burn-like blisters, and erythema being the most commonly reported
event. The adhesive side of the patch should be applied to a clean, dry area of the
skin on the back, abdomen, upper arms, or thighs. The patient should be instructed to
avoid application over bony prominences or on a part of the body that may be subject
to prolonged pressure during sleep or sitting (e.g., the deltoid region of the upper
arm, the greater trochanter of the femur, and the ischial tuberosity); do not apply to
the scrotum. The sites of application should be rotated, with an interval of 7 days
between applications to the same site. The area selected should not be oily, damaged,
Topical testosterone gel should be applied once daily in the morning to clean, dry
skin. Depending on the specific product, it can be applied to the upper arms,
shoulders, thighs, or abdomen. A topical solution for application to the axilla is also
available. The dose can be as high as 100 mg/24 hours. After the gel or solution has
dried on the site of application, it should be protected with clothing to prevent
transfer to a nonuser. The patient should wash his hands after application.
Commonly reported adverse effects in chronic users include acne, edema,
gynecomastia, and dermatologic reactions to injections or transdermal applications
of testosterone. The most serious risk of prolonged testosterone use is prostate
carcinoma, although the association between high concentrations of testosterone and
the risk of prostate carcinoma is controversial.
235–237 Three studies suggest that
testosterone-replacement therapy is relatively safe in hypogonadism.
assessment of the prostate should be done before starting testosterone-replacement
therapy. This should consist of a TRUS, digital palpation of the prostate gland, and
analysis of the PSA, hemoglobin, and hematocrit levels.
CASE 109-4, QUESTION 13: Because F.M.’s prolactin serum concentration is 28 ng/mL, should
bromocriptine be prescribed to decrease his hyperprolactinemia and treat his ED?
Hyperprolactinemia may be treated with the ergot alkaloid bromocriptine, which
works as a dopamine agonist to inhibit prolactin secretion. Even with normalization
of prolactin levels, approximately 50% of elderly male patients are unable to achieve
doses may be increased weekly, at a rate of no more than 2.5 mg/day. Adverse events
associated with bromocriptine are nausea, dizziness, drowsiness, hypotension, and
143,229 For those who fail bromocriptine, cabergoline is a
reasonable alternative given once or twice a week with good efficacy and a lower
F.M. is not a candidate for treatment with bromocriptine because he does not have
secondary hypogonadism, and his ED probably is secondary to atherosclerosis
associated with his hypertension, diabetes, and cigarette smoking. Furthermore, the
elevation of F.M.’s serum prolactin concentration is not significant enough to warrant
drug therapy. Medication-induced hyperprolactinemia is usually associated with
prolactin levels ranging from 25 to 100 μg/L, but metoclopramide, risperidone, and
phenothiazines can lead to prolactin levels exceeding 200 μg/L by way of dopamine
241 Verapamil can cause hyperprolactinemia presumably by blocking
hypothalamic dopamine, and opiates and cocaine can induce it through the μreceptor.
241 Usually prolactin will normalize 3 days following discontinuation of the
offending medication, however this patient is not on any medications that can induce
hyperprolactinemia. Because the response rate to bromocriptine in elderly men is
50% (or less), the risk of adverse reactions (e.g., dyskinesia, dizziness,
hallucinations, dystonia, confusion, cerebrovascular accidents) outweighs the benefit
of this dopamine agonist therapy.
CASE 109-4, QUESTION 14: What other drug therapy is available for F.M.?
Before the advent of the PDE-5 inhibitors, intracavernosal and intraurethral
(alprostadil) administration was the only nonsurgical option for ED.
Alprostadil causes direct vascular smooth muscle relaxation allowing blood flow
and entrapment in penis. Less invasive than intracavernosal injections, alprostadil
intraurethral pellet is inserted, as semisolid gel form, through the urethral opening of
the penis 5 to 10 minutes before sex and works for up to one hour. However, it is less
effective and not recommended with pregnant partners.
are given at the base of the penis 10 to 20 minutes before sex and were effective in
87 percent of cases in one clinical trial.
243 Phentolamine, papaverine, and vasoactive
the injection site, and penile fibrosis after long-term use. Topical alprostadil cream
has also shown efficacy in 74% of patients but is not currently available in the US.
A full list of references for this chapter can be found at
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chapter, with the corresponding reference number in this chapter found in parentheses
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http://effectivehealthcare.ahrq.gov/ehc/index.cfm/search-for-guides-reviews-and-reports/?
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National Association for Continence. http://www.nafc.org.
Simon Foundation for Continence. http://www.simonfoundation.org.
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