Alfuzosin is another quinazoline α1
-adrenergic receptor antagonist. It displays a
lower rate of hypotensive effects than doxazosin and terazosin. A lack of penetration
of alfuzosin into the brain has been hypothesized to contribute to the decreased CNS
effects such as somnolence. Unlike tamsulosin, alfuzosin will not cause ejaculatory
dysfunction; the incidence is comparable to placebo.
86 Alfuzosin is available as an
extended-release tablet that has a recommended daily dose of 10 mg given after the
and is 20 times more “uroselective” than tamsulosin.
comparing silodosin with tamsulosin was a noninferiority trial which found silodosin
to be as effective as tamsulosin in controlling lower urinary tract symptoms in men
89 The most common side effect with silodosin is retrograde ejaculation,
reported in 21% of patients in an open-label extension study.
as 4- and 8-mg capsules, and the recommended dose is 8 mg once daily. In patients
with a creatinine clearance of less than 50 mL/minute, the dose should be decreased
PHOSPHODIESTERASE-5 INHIBITORS
Tadalafil is a selective inhibitor of phosphodiesterase-5 and has indications for
erectile dysfunction and use as monotherapy or combination therapy in BPH. Its
mechanism in BPH is unclear; however, compared to placebo, tadalafil 5 mg once
daily was shown to improve BPH symptoms compared to placebo. Combining
tadalafil with α-adrenergic receptor antagonists is not recommended because it has
not been adequately studied and may increase the risk of low blood pressure.
Similarly, patients on antihypertensives, nitrates, or drinking 5 or more units of
alcohol are also at increased risk of hypotension with tadalafil. Tadalafil should be
taken at the same time every day without regard to meals. Additional information on
tadalafil can be found under pharmacotherapy for erectile dysfunction later in this
Maintenance of morphology and functional activity of the adult human prostate is
controlled by, and dependent on, androgens. Prostatic regression after androgen
deprivation is an active process that requires the synthesis of macromolecules.
result of androgen deprivation, the loss of stromal and epithelial prostate cells is
disproportionate, with 4 times greater loss of epithelial cells. Testosterone serves as
the prohormone for the two active metabolites, DHT and 17-β-estradiol.
Testosterone is metabolized to DHT by the enzyme 5α-reductase (types 1 and 2).
Thus, conversion of testosterone to DHT precludes its conversion to estrogen by the
aromatase enzyme, and the relative activity of these two enzymes is of paramount
importance in prostate homeostasis.
Although the mean plasma testosterone level in men falls after the age of 60, the
level of testosterone in subjects with BPH and age-matched control subjects is not
93 Moreover, the onset of BPH starts some 10 to 20 years before the plasma
testosterone levels decrease. The serum concentration of DHT is increased,
91,94,95 The mechanism responsible for accumulation of
DHT has not been established, but a significant increase in 5α-reductase activity
occurs, which is known to produce DHT.
One other major hormonal change associated with aging is the increased formation
of estrogen from circulating androgens in both the testes and the peripheral adipose
tissue. Androgen conversion to estrogen via aromatase begins in men at
approximately the third decade of life and increases with age,
estrogen concentration is the same in men with BPH and age-matched control
94 Estrogen receptors are abundant in stroma cells,
in patients with prostatic carcinoma than in patients with BPH.
stimulation of stromal tissue was once believed to explain the prostatic growth that
continued with age despite the decline in testosterone secretion by the testes.
Progesterone receptors, however, appear to be more abundant than estrogen
receptors in the stromal and epithelial cells of prostate tissue of patients with BPH.
Thus, progesterone may play a more important role in the pathogenesis of BPH than
estrogen. The known effect of DHT in initiating the BPH process is believed to be
102 The number of prostate androgen receptors can be
increased by estrogens and can be reversed by the administration of antiestrogens.
The increase in androgen receptors induced by estrogens may allow for continued
androgen-mediated growth despite the declining amount of testosterone produced
Finasteride, a competitive inhibitor of 5α-reductase (type 2), decreases the
conversion of testosterone to DHT, the principal androgen responsible for
stimulation of prostatic growth. After 7 days of treatment with all doses of
finasteride, prostatic tissue DHT declined to 15% or less of control levels, and the
testosterone concentration increased in a reciprocal manner.
administered in 1- and 5-mg doses to men with BPH for a total of 12 months, the
symptom score and urinary flow improved significantly. Finasteride 5 mg daily
decreased the median prostate volume by 24% and improved the maximal urinary
104 Adverse effects in the finasteride groups occurred in
less than 5%, and side effects, such as decreased libido and ejaculatory dysfunction,
105 The efficacy of daily finasteride 5 mg was evaluated in 298
men for 24 months and found a slight improvement compared with the results
reported at the end of the 12-month period.
106 The median DHT levels had declined
by 74.5% compared with 69.3% at 12 months, and prostate volume declined by
25.2% compared with 21.2% at 12 months. Patient symptom scores indicated slightly
more improvement at 24 months compared with 12 months. Obstructive symptom
scores were responsible for most of the improved symptoms reported. The
prevalence of sexual adverse experiences at 24 months was similar to that at 12
months. In those men who experienced finasteride-induced sexual dysfunction, 50%
will experience resolution after discontinuing the medication.
5α-reductase inhibitors does not affect testosterone-mediated functions on muscle
mass, libido, or spermatogenesis. Thus, finasteride has an acceptable safety profile,
halts disease progression, and improves the quality of life in patients with moderate
BPH disease (i.e., enlarged prostate with symptoms of urinary obstruction, but not
acute urinary retention). Finasteride improves objective pressure flow parameters
after 1 year of therapy, and efficacy appears to be greatest in patients with large
108 For those who do respond, the drug must be continued
indefinitely because DHT serum concentrations return to pretreatment levels within
14 days of discontinuing finasteride, and prostate size returns to pretreatment levels
Unlike leuprolide, finasteride does not affect the histologic features of BPH and
111 Morphologic evaluation of patients treated with finasteride with
symptomatic BPH having adenectomy showed a reduction in the size of the prostate
and an increase in the stroma to epithelial and stroma to lumen ratios.
Dutasteride is a competitive inhibitor of both types 1 and 2 5α-reductase isoenzymes.
An advantage of dutasteride compared with finasteride is the additional inhibition of
5α-reductase (type 1) in the peripheral tissues, which produces a further decline in
serum DHT. In a prospective study of 2,951 men with moderate-to-severe BPH,
dutasteride 0.5 mg/day decreased DHT serum levels by 90% at 1 month in 58% of
patients. At 24 months, 85% of those treated with dutasteride were noted to have a
113 Correspondingly, the patients noted reduction in
urinary symptoms as early as 3 months after treatment initiation
and a significant (p < 0.001) reduction in symptoms by the sixth month when
compared with those treated with placebo. Common side effects of dutasteride are
similar to those of finasteride: impotence (4.7%), decreased libido (3.0%),
ejaculation disorder (1.4%), and gynecomastia (1.0%).
Owing to different mechanisms of action, it is a reasonable strategy to combine an α1
adrenergic receptor antagonist that will work quickly to provide symptomatic relief
with a 5α-reductase inhibitor that will take 6 to 12 months to reduce prostate size.
This strategy has been supported by the Medical Therapy of Prostate Symptoms
(MTOPS) and Combination of Avodart and Tamsulosin (CombAT) trials. The
MTOPS trial studied 3,047 men with moderate-to-severe BPH and demonstrated that
progression of BPH was reduced by 39% in patients treated with doxazosin alone, by
34% in patients treated with finasteride alone, and by 66% in patients treated with
114 The CombAT trial studied 4,844 men with risk factors for
BPH progression such as larger prostates (>30 g) and higher serum PSA
concentrations (1.5–10 mcg/L). Combination therapy reduced the relative risk of
acute urinary retention or BPH-related surgery by 65.8% compared with tamsulosin
and by 19.6% compared with dutasteride. In addition, for those patients who
completed the study, the mean change in the International Prostate Symptom Score
from baseline to year 4 was significantly higher for the combination therapy
compared with tamsulosin or dutasteride alone.
115 Adverse drug events are more
common with combination therapy, but study withdrawal rates are less than 5% and
similar among treatment groups. A combination product of dutasteride 0.5 mg and
tamsulosin hydrochloride 0.4 mg is commercially available.
Effect of Androgen Suppression on Prostate-Specific
CASE 109-3, QUESTION 5: G.M. has an annual PSA test. Will androgen suppression alter his results?
Antiandrogen treatment of BPH could possibly adversely affect the interpretation
of the PSA screening test for prostate cancer. For example, androgen suppression
with leuprolide acetate reduces prostate volume primarily by inducing involution of
the epithelial elements of the prostate.
116 Because PSA primarily is produced by the
epithelial cells of the prostate, these drugs can alter serum and prostate
117 Finasteride 5 mg/day also can reduce the serum PSA level
118 Dutasteride reduces total serum PSA by approximately 40% after 3
months of treatment and by approximately 50% after 24 months.
level reduction is predictable, however, and serum PSA levels can be recalculated
during hormonal treatment for BPH. Nevertheless, patients receiving a 5α-reductase
inhibitor should have (a) a digital rectal examination of their prostate periodically,
(b) a PSA level measured, and (c) any suspicious findings investigated
106 Androgen suppression therapy is not contraindicated in BPH solely
on the basis of its effect on serum PSA levels.
CASE 109-3, QUESTION 6: G.M asks whether there are nonprescription treatments available that are
effective for BPH. What over-the-counter medications are available for prostate disorders?
Two agents, saw palmetto and pygeum, have been promoted for the treatment of
BPH. Saw palmetto is an herbal product obtained from the fruit of the Serenoa repens
tree with antiandrogen activity. The active ingredients are phytosterols; β-sitosterol
and β-sitosterol-3-O-glucosides are the most abundant. Several trials have shown
that it significantly improves BPH symptoms
123 However, a 2012 meta-analysis of 32 randomized trials failed to
detect a difference in urinary symptom improvement even with triple the usual dose
of saw palmetto compared to placebo.
124 The dose most often studied is 320 mg a day
in one or two divided doses. Pygeum (Pygeum africanum bark extract) has been
observed to moderately reduce urinary symptoms associated with enlargement of the
prostate gland at a dose of 75 to 200 mg/day.
125 Pygeum has been well tolerated in
most studies; however, the safety has not been extensively or systematically studied.
Herbal products may be tried by men with mild symptoms that would usually be
managed by watchful waiting; however, the use of complementary and alternative
medicines for BPH is not currently recommended by the AUA guidelines.
TRANSURETHRAL RESECTION OF THE PROSTATE
CASE 109-3, QUESTION 7: What are the options if drug therapy does not work for G.M.? When should
prostate surgery be undertaken in general?
G.M.’s subjective and objective findings, particularly the acute urinary retention
and hydronephrosis, collectively indicate the need for a TURP. G.M. has been
advised by his urologist that a TURP is the treatment of choice given the severity of
his presentation (e.g., large prostate gland with acute urinary retention) and that the
procedure will relieve his symptoms, allow him to lead a relatively normal life, and
avoid sequelae of prolonged obstruction.
TURP provides significant relief of BPH symptoms in 86%, 83%, 75%, and 75%
of patients at 3 months, 1 year, 3 years, and 7 years, respectively.
severe BPH, 93% report reduced symptoms 1 year after a TURP.
considered the gold standard for the treatment of BPH and is used in 90% of patients
with symptoms of residual urine or acute urinary retention.
alternatives are always compared with the outcome studies of TURP.
The need for a TURP in G.M.’s situation is fairly clear. In most cases, however,
the need for a TURP is less clear because the symptoms do not inevitably worsen and
men often are willing to live with their symptoms. Therefore, clinicians need to talk
with patients and help them answer the question of whether the discomfort, risk, and
problems during the postsurgical recovery period are outweighed by the high
probability that surgery will relieve symptoms.
As individuals are living longer, there is a growing interest in maintaining one’s
sexual health throughout later life. Nearly 39% of men and 17% of women between
the ages of 75 and 85 reported being sexually active in a cross-sectional study
129 A nationally representative study concluded that the majority of
older adults are engaged in sexual activity and regard sex as an important part of
130 Poor health often is cited by elderly women as a reason for not participating in
sexual activity, and among men, erectile dysfunction (ED) is the leading cause
131,132 The major factors that correlate with reduced sexual
activity include an older spouse, poor mental or physical health, marital difficulties,
previous negative sexual experiences, and negative attitudes toward sexuality in the
133 During the postmenopausal years, women undergo substantial physiologic
changes (see Chapter 51, The Transition Through Menopause).
The major physiologic event of natural menopause is a decrease in estrogen
production. Little doubt exists that a decline in estrogen production is associated with
many of the physiologic changes causing elderly women to report a low interest in
sexual activity. The medical literature is replete with research and data on elderly
male sexual dysfunction, but little, if any, data exist on female sexual dysfunction.
Aging men may experience andropause, a syndrome consisting of weakness, fatigue,
reduced muscle and bone mass, impaired hematopoiesis, oligospermia, sexual
dysfunction, and psychiatric symptoms.
134 The relationship between declining
testosterone and andropause is not firmly established. Free testosterone levels begin
to decline at the rate of 1% per year after age 40 years. By the age of 60 years, 20%
of men have levels below the lower limit of normal.
psychological effects of declining hormone levels in men are less dramatic than those
Sexual function is considered an interaction between motivation, drive, desires,
thoughts, fantasies, pleasures, experiences (referred to as the libido), penile
vasocongestion, erection, orgasmic contractions, and ejaculations (referred to as
136,137 Testosterone plays an important role in male libido and sexual
behavior and may play some role in penile erection. Elderly men show a strong
correlation between advancing age and diminishing bioavailable serum testosterone
138 Testosterone progressively declines after the seventh decade, partly
because of testicular and hypothalamic–pituitary dysfunction.
Male sexual dysfunction, denoting the inability to achieve a satisfactory sexual
relationship, may involve inadequacy of erection or problems with emission,
ejaculation, or orgasm. Erectile dysfunction is the inability to achieve and maintain a
firm erection sufficient for satisfactory sexual performance.
refers to uncontrolled ejaculation before or shortly after entering the vagina.
Retarded ejaculation usually is synonymous with delayed ejaculation. Retrograde
ejaculation denotes backflow of semen into the bladder during ejaculation caused by
an incompetent bladder neck mechanism.
ED, once regarded as a psychosocial disorder, today is regarded as caused by a
variety of medical, psychological, and lifestyle factors. It is an age-related condition,
with about 30% of US men older than 40 years of age self-reporting some degree of
141 Because the population ages, it is estimated that the worldwide
prevalence of ED will be approximately 322 million in 2025.
Approximately 80% of all cases of ED now are thought to be related to organic
disease and subject to numerous influences.
vascular disorders were the primary causes of ED among elderly men, and
psychogenic factors were the cause in less than 10%.
etiology for erectile failure in the elderly is severe atherosclerosis (e.g., vascular
disease and diabetes mellitus).
138 Cardiovascular disease, hypertension, diabetes
mellitus, elevated low-density lipoprotein cholesterol, and cigarette smoking are
associated with a greater probability of complete ED in men.
Because ED is more likely in male patients with coronary artery disease, the
understanding of the cardiovascular stresses involved with sexual intercourse can aid
in patient management. Cardiac and metabolic expenditures during sexual intercourse
vary depending on the type of sexual activity. Healthy males with their usual female
partners generally achieve a peak heart rate of 110 beats/minute with woman-on-top
coitus and an average peak heart rate of 127 beats/minute with man-on-top coitus.
There is significant individual variation in cardiovascular response, when measured
as oxygen uptake and metabolic expenditures, for man-on-top coitus.
In a study of medication-free patients with coronary artery disease who were in
New York Heart Association functional class I or II, sexual activity was compared
with near-maximal exercise treadmill test.
148 Electrocardiographic changes
representing ischemia during intercourse were found in one-third of the patients;
however, two-thirds of these patients remained asymptomatic. All patients with
ischemia during coitus also demonstrated ischemia during exercise treadmill testing.
The average heart rate during coitus was 118 beats/minute, with some patients
attaining a heart rate of 185 beats/minute at orgasm. Intercourse in patients with
coronary artery disease may provoke increased ventricular ectopic activity that is not
necessarily elicited by other stimuli.
149 These electrocardiographic changes and
associated symptoms can be abolished with the use of β-blockers.
is a likely contributor to the onset of myocardial infarction only 0.9% of the time.
Coital death is rare, accounting for 0.6% of sudden death cases.
changes associated with sexual activity may be far greater with an unfamiliar partner,
in unfamiliar settings, and after excessive eating and alcohol consumption.
Erection involves the neurologic, psychological, hormonal, arterial, and venous
systems. Evidence indicates that more than 80% of the cases of ED are because of
organic causes, of which vascular disease is the most common.
male sexual dysfunction studies, 50% involve vascular problems, and 30% relate to
ED can be caused by damage to the brain, spinal cord, cavernous or pudendal nerves,
terminal nerve endings, and the receptors. Approximately 95% of patients with upper
motor neuron lesions resulting from spinal injury are capable of erection through the
155 whereas only 25% of patients with complete lower motor
neuron lesions can have erections through the psychogenic mechanism.
incomplete lesions, up to 90% of patients in both groups retain erectile ability.
Patients who have a cerebrovascular accident, dementia, epilepsy, Parkinson
disease, or a brain tumor most likely experience erectile failure through loss of
sexual interest or overinhibition of the spinal erection centers.
The incidence of ED with a hormonal cause has been estimated to be 5% to 35%,
depending on which medical specialty is reporting the finding.
hormonal disorder associated with ED in the elderly is diabetes mellitus. Depending
on the severity and duration of diabetes, the prevalence of ED ranges from 20% to
Other hormonal disorders, such as hypothyroidism, hyperthyroidism, Addison
disease, and Cushing syndrome, are associated
with ED. Patients with hypogonadism caused by pituitary or hypothalamic tumors,
antiandrogen therapy, or orchiectomy experience ED. These patients can have a
normal erection from visual stimulation, however, indicating that the erectile
Atherosclerosis is the leading vascular disease associated with male ED. The age of
onset of coronary artery disease parallels the onset of ED, indicating a generalized
atherosclerotic etiology for the ED.
160 The degree of arteriolar narrowing and
clinical presentation, however, differ from patient to patient. Some patients can have
severe coronary artery disease but retain the capability of a full erection. As long as
the arterial flow into the penis exceeds the venous outflow, the patient can be potent.
Narrowing of the arterial lumen lowers pressure in the cavernous arteries, and poor
arterial flow can only partially fill the sinusoidal system. Overall, the partial filling
of the sinusoidal system causes inadequate expansion of the sinusoidal wall, resulting
in partial compression of the venules. The net effect is a partial erection, difficulty in
maintaining an erection, or the most common complaint, early detumescence.
enlarged prostate gland and evidence of pubic and axillary hair loss. Vitalsigns were as follows:
Respirations, 14 breaths/minute
Free testosterone level, 30 pg/mL (normal, 52–280 pg/mL)
Luteinizing hormone (LH), 4 milliunits/mL (normal, 1–8 milliunits/mL)
Serum prolactin level, 28 ng/mL (normal, <20 ng/mL)
What signs and symptoms does F.M. have that would suggest the need for a complete medical workup for
F.M. presents with the complaint of loss of interest in sexual activity and the
inability to maintain a full erection during greater than 75% of sexual encounters with
his partner. On physical examination, F.M. is found to have a noticeable loss of pubic
and axillary body hair. With long-standing androgen deficiency, there may be loss of
hair in the androgen-dependent areas of the body, fine wrinkling of the skin around
the mouth and eyes, noticeable loss of muscle mass and strength, altered body-fat
distribution, and osteoporosis. In contrast, overt hypogonadism results in a change in
the pattern of pubic hair from the male diamond shape to the female-inverted triangle
appearance. At this point, it appears that F.M.’s loss of pubic and axillary hair is the
result of androgen deficiency, with the cause yet to be determined. The laboratory
results for gonadal function coincide with what is expected in an elderly man with
ED (see Case 109-4, Question 4).
workup of F.M. to determine the cause of his ED?
A detailed medical and sexual history and thorough physical examination are
essential in the evaluation of sexual dysfunction. General medical history and
physical examination should consider drug-induced ED (Table 109-6).
Although laboratory-based diagnostic procedures are available, sexual function
may be best assessed in a naturalistic setting with patient self-report techniques. A
psychometrically sound self-reporting tool is the International Index of Erectile
Function (IIEF), which addresses the relevant domains of male sexual function
(erectile function, orgasmic function, sexual desire, intercourse satisfaction, and
overall satisfaction) and has been linguistically validated in 10 languages.
simplified version, the IIEF-5, is a five-item questionnaire that is also popular.
F.M.’s endocrine status should include assessment of his diabetes, thyroid function
tests, and a serum lipid profile. Neuropathy and atherosclerosis are common findings
among male patients with diabetes mellitus, and both are potential causes of ED.
Patients experiencing hypothyroidism may have decreased libido, and
hypothyroidism is associated with hyperprolactinemia, which can result in an
inhibition in the release of testosterone. Elevated serum lipids (e.g., total cholesterol,
triglycerides) may be associated with significant vascular damage that could
contribute to erectile dysfunction. Diabetes mellitus is best evaluated with
hemoglobin-A1c and fasting blood glucose tests.
The serum concentrations of free testosterone, prolactin, and LH should be
evaluated. Testosterone, as with all other hormones secreted into the plasma, is
available to tissues only in the free form (i.e., unbound to serum proteins, particularly
the sex hormone-binding globulin). Only 1% to 2% of testosterone is free and
physiologically active; therefore, measurement of the unbound serum testosterone
provides the best estimate of biologically available testosterone. Low testosterone
serum concentrations are associated with primary and secondary hypogonadism.
Primary hypogonadism is associated with testicular disease (e.g., Leydig cell
tumors), whereas secondary hypogonadism is the result of pituitary or hypothalamic
The serum prolactin concentration should be determined because a high serum
concentration of prolactin inhibits release of testosterone from the testes. Therefore,
a low serum testosterone concentration may be caused by hyperprolactinemia.
Hyperprolactinemia may be caused by prolactin adenomas, diabetes mellitus, or drug
therapy (e.g., neuroleptics, metoclopramide).
LH stimulates testicular steroidogenesis and secretion of testosterone. LH
increases the conversion of cholesterol to pregnenolone, a precursor of testosterone.
FSH is required for spermatogenesis in early puberty, but is not a required
gonadotropin for the maintenance of spermatogenesis in adult men. Normal testicular
function depends on stimulation by the gonadotropin LH, which is secreted by the
anterior pituitary gland. Consequently, a low normal serum concentration of LH is
associated with secondary hypogonadism.
In patients with symptoms of prostatic disease, expressed prostatic secretions
(EPS) should be examined because prostate inflammation has been associated with
ejaculatory dysfunction. During prostatic inflammation, the EPS contains leukocytes
and macrophages, and microscopic examination of the EPS can determine the degree
prostatitis can be attributed to a bacterial infection; the remaining 95% is caused by
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