Download Benign Prostatic Hyperplasia

Benign Prostatic Hyperplasia
Epidemiology
Definition
Although understanding of BPH has grown substantially over the past few years, its
true epidemiology remains unclear because there is a lack of consensus about a working
epidemiologic definition of the condition. Clinical BPH generally has been identified as
the combination of lower urinary tract symptoms of a certain severity, a peak uroflow rate
of <15 mL/sec without evidence of cancer, and a prostate size of >20 g. Further
complicating the search for a definitive description is the fact that some men may have
histologic evidence of disease with few symptoms while others have varying degrees of
symptomatology. Members of the Epidemiology and Natural History of BPH Committee
of the 3rd International Consultation on BPH have proposed a more precise descriptive
definition of disease. They suggest the terms "benign prostatic hyperplasia" (BPH) for
purely histologic disease, which may be asymptomatic; "bladder outlet obstruction" for
those cases in which there are both traditional symptoms of BPH and a high probability of
physiologic obstruction based on clinical and laboratory findings; and "lower urinary tract
dysfunction" for those instances in which clinical symptoms exist but there is a low
probability of bladder outlet obstruction. These recommendations require further
discussion and agreement, but they set the stage for more precise definition of the
condition, more exact determination of its epidemiology, and potentially more specific
diagnostic and treatment approaches.
Prevalence
In general, it has been estimated that approximately 50% of men have histologic
evidence of BPH by the time they reach their 60s, with the prevalence increasing to 70%
in the 70s, and 90% in the 90s. Further, it is estimated that 50% of men older than 60 years
have symptoms of BPH. With more men living longer, it has been suggested that by the
year 2000, every other man will reach an age at which he has an 88% chance of
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developing histologic disease and more than a 50% chance of developing symptoms.
Taking into consideration the previously mentioned limitations to an epidemiologic
definition of BPH, several studies have documented the increasing prevalence of BPH
with age. For example, a 1991 Scottish study showed the prevalence increasing from 14%
in men in their 40s to 43% in those in their 60s and 40% in men aged 70 to 79 years. Other
studies in Olmsted County, Minnesota and Shimamki-Mura, Japan showed similar
increases with age, although the overall incidence was lower than that seen in the Scottish
study. Finally, investigations of men who had moderate-to-severe disease based on scores
from the International Prostate Symptom Score (IPSS) showed differing prevalence in the
United States, France, Netherlands, and Japan, but an overall increase with age.
The impact of BPH is illustrated by several facts:
• Symptoms of BPH form the basis for an estimated 1.7 million annual
physicians office visits in the United States
• Prostatectomy is the most common form of major surgery in men more than 55
years of age in the United States at an approximate rate of 379,000 procedures
annually
• BPH has been estimated to cost £62 to £91 million in the United Kingdom
Further, estimated surgical costs for BPH in 1990 ranged from $0.70 per person of
population in France to $8.90 per person in the United States.
Risk Factors
The primary risk factors for the development of BPH, as documented in epidemiologic
studies, are age and circulating androgens (functioning testes). Other factors that have
been suggested, but not proved, as increasing the risk include ethnicity, environment, and
heredity. Clinical BPH has been reported as more common among blacks than whites and
more common among whites than Asians, but these data require further evaluation and
confirmation. Additionally, it appears that Asians who migrate to Western countries may
have a greater incidence of clinical disease than those who remain in Asia, which suggests
an environmental component that may overcome any ethnic predisposition. Finally, there
appears to be a familial propensity toward BPH.
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Natural History
The primary symptom of BPH is a declining peak urine flow rate, which decreases
with age at an average of about 0.2 ml/sec/year. However, community studies of untreated
BPH have shown that the rate of decrease may not be constant with age. Further, the
associated symptomatology and degree of "bother" in lifestyle created by these changes
vary substantially among individual men.
The bladder obstruction that occurs with BPH has both static and dynamic
components. In the early stages of disease, normal prostatic tissue is compressed by
hyperplastic tissue, which impinges on the prostatic urethra, creating the static component.
The bladder detrusor muscle responds to this obstruction of urine flow with smooth
muscle hypertrophy and changes in the composition of the extracellular matrix. This
results in the increased voiding pressure, decreased bladder compliance, and involuntary
bladder contractions that comprise the dynamic component of obstruction. Untreated,
advanced disease that involves prolonged obstruction may cause chronic urinary retention.
The classic obstructive symptoms include hesitancy, weak urine stream, straining, prolonged micturition, feeling of incomplete bladder emptying, urgency, frequency, nicturia,
and urge incontinence.
The potential complications of untreated BPH, although uncommon, include
deteriorating renal function, bladder diverticula, urinary tract infection, bladder stones, and
pyelonephritis.
Pathology and Pathophysiology
Macroscopic changes of BPH begin at about age 35, are evident in approximately 50%
of men at age 60, and can be seen in nearly 100% of men aged 80 to 85 years. Although
50% of those who have macroscopic disease develop symptoms that require surgery, this
is not a predictable development; both the presence of symptoms and the speed with which
they develop varies considerably among individuals. BPH is characterized by the
relationship between symptoms (prostatism), hyperplasia (prostate enlargement), and
intravesical obstruction. Although all three are related and often overlap, they remain
independent variables in determining the nature of the clinical disease. For example, some
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men who have hyperplasia may have minimal symptomatology and obstruction, while
others may have severe symptoms and obstruction. It has not yet been determined whether
intravesical obstruction, response of the detrusor muscle to the obstruction, abnormal
inputs from the prostate, a deficient central mechanism, or a combination of these factors
causes the classic symptoms of BPH.
Anatomy
BPH primarily affects three anatomic structures: the prostate, urethra, and bladder (Fig.
1). Of the three zones that comprise the prostate-peripheral, transition, and central-the
transition zone in the central part of the organ is the area affected in BPH. Stromal
nodules appear in the periurethral area of that zone as glandular hyperplasia develops. In
contrast, prostate cancer generally develops in the peripheral zone of the organ.
In the normal prostate, cell growth is regulated by a balance between cell death (apoptosis)
and cell growth (proliferation). Investigators examining prostate tissue at the cellular level
have found a substantial decrease in the total number of both glandular and basal epithelial
cells dying in hyperplastic tissue compared with normal tissue. This suggests a
deregulation of apoptotic cell death mechanisms in prostate tissue that results in a growth
imbalance in favor of cell proliferation in the presence of BPH. The implications of these
findings for clinical treatment are under investigation.
Obstruction
Urethral obstruction in BPH results both from the enlarged prostate, as hyperplastic
tissue impinges on and narrows the urethral tract, and the tonus exerted by the smooth
muscle in both the prostate and the bladder neck. As noted previously, the obstruction has
a mechanical component, which is relatively stable, and a dynamic component, which can
be extremely variable. The bladder detrusor muscle thickens in response to prolonged
obstruction and becomes less compliant. The overall contractile force of the bladder
usually does not increase as compliance decreases, resulting in the mechanical obstruction.
The dynamic component of obstruction originates primarily from activity of smooth
muscle cells in the bladder neck, urethra, and prostate. Innervation of these tissues is
predominantly sympathetic, and stimulation of alpha adrenoceptors, which are especially
dense in these tissues, can cause contraction and increase outlet resistance. The variation
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in muscle activity may account for differences in the degree of symptomatology among
men who suffer BPH and even changes in symptoms in the same man over time.
Diagnosis
The primary signs of BPH include prostatism, hyperplasia, weak urinary stream, and
subvesical obstruction. All of these areas should be covered in the evaluation of a man in
whom BPH is suspected. Findings not only can help to categorize the degree of disease,
but can have an impact on the choice of treatment. For example, the man who has
prostatism and an enlarged prostate without a weak urine stream or the man who has
prostatism and a weak stream without evidence of hyperplasia may be a more appropriate
candidate for medical management than surgical treatment.
A general description of prostatism consists of two categories of symptoms voiding
and storage or irritative. It is important to note that these symptoms are not exclusive to
BPH. Further, they may be present in varying combinations and to different degrees in the
man who does have BPH. Finally, the relationship of these symptoms to the presence or
degree of obstruction has not yet been established. Therefore, evaluation of suspected
BPH must extend far beyond documentation of prostatism.
Baseline Evaluation
The 3rd International Consultation on Benign Prostatic Hyperplasia has recommended
certain tests for a baseline evaluation of the man suspected of having BPH. By addressing
the primary aspects of BPH, findings from these examinations can provide the clinician
with a clearer picture of the clinical situation, suggest appropriate avenues of treatment,
and serve as monitoring tools during treatment.
The initial evaluative step is to quantify symptoms and quality of life to establish a
baseline for severity and frequency of symptoms and to employ as a monitor of progress
with or without treatment. The American Urological Association (AUA) has developed,
tested, and validated a four-part index that rates symptoms of urinary problems (eg,
urgency, frequency, nicturia), the degree to which these symptoms are a problem to the
patient, the impact of the symptoms on the patient's life (eg, physical discomfort, worry,
bother), and the overall quality of the patient's life. A more widely used evaluation based
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on that developed by the AUA is the International Prostate Symptom Score (IPSS). This
simplified, easily administered form assesses symptoms and general quality of life.
The patient should be asked to keep a voiding diary that documents the time of each
urination during the day and night, the volume of urine, and whether there is leakage.
Assessing the patterns in the diary can help the clinician to differentiate BPH from other
causes of nicturia, which are common in the elderly.
The medical history should focus on several areas:
• Diseases of and previous surgery or trauma to the genital and urinary tracts
• Family history of prostate diseases and general health
• Smoking and recreational drug use history
• Current medications (especially those that may increase detrusor relaxation or
improve detrusor contraction, increase or decrease outlet resistance, and decrease prostatic
volume)
• Fitness for possible surgical procedures Trauma, surgery, or disease of the genital and
urinary tracts can provide important information for the differential diagnosis. Positive
findings of a family history of prostate diseases can aid in making the diagnosis; there is a
tendency toward a familial occurrence of BPH. Finally, use of medications that adversely
affect the bladder or prostate may provide a better explanation for symptoms than BPH.
The physical examination should focus on two specific tests: the digital rectal
examination (DRE) and a neurologic examination. The DRE is especially important in
assessing the size, consistency, and anatomic limits of the prostate; findings may be
especially helpful in differentiating BPH from prostatic cancer. The normal prostate
weighs approximately 20 g; in BPH it may be greater than 50 g. The prostate that contains
a nodule or that is diffusely hardened and asymmetric may indicate cancer in contrast to
the smooth, symmetric, and elastic consistency of a benign gland. The neurologic
examination should assess rectal sphincter tone, the bulbocavernosus reflex, and general
motor and sensory function of the lower extremities.
Urinalysis via dipstick testing or microscopic examination of sediment is employed
both to differentiate BPH from urinary tract infection or bladder cancer and to prompt the
use of additional tests if findings are pathologic. Such optional tests might include upper
urinary tract imaging or endoscopy.
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Renal function is assessed via measurement of serum creatinine. If the creatinine is
elevated, indicating compromised renal function, ultrasonography is the appropriate
follow-up study.
There is continuing discussion of the value of measuring prostatic specific antigen
(PSA) in the population in general and in the specific population of men suspected of
having BPH. PSA has been suggested as a screening tool for prostatic cancer, but the
antigen is produced by normal, hyperplastic, and cancerous tissue, which can limit its
diagnostic usefulness as a single test. However, in combination with a careful DRE, it can
have an increased positive predictive value. The 3rd International Consultation on BPH
recommends measuring serum PSA in men who have lower urinary tract symptoms and a
life expectancy of more than 10 years. These are the men in whom a diagnosis of prostatic
cancer could change the treatment plan for BPH. However, the patient should be told that
there is a good possibility of a false-positive or false-negative result that might require the
use oftransrectal ultrasonographic (TRUS)-guided biopsy to confirm or refute the
diagnosis of malignancy.
Urodynamic studies are a vital part of the initial patient evaluation to diagnose bladder
outlet obstruction and as monitoring tools to assess treatment. The preferred approach for
measuring postvoid residual urine is transabdominal ultrasonography, a noninvasive
methodology. If the first measurement documents significant volume (>50 to 100 mL),
serial measurements should be obtained because there can be significant variation in
individual patients. Elevated levels of postvoid residual urine suggest detrusor
decompensation following long-term obstruction, but they cannot be used to deduce the
presence of obstruction with certainty. However, elevated levels can identify those
patients who would respond less well to the watchful waiting treatment option (ie, those
volumes are >200 to 300 mL).
Uroflowmetry provides an objective "visualization" of micturition by measuring the
interaction between the expelling force of the detrusor muscle and the resistance of the
urethra. Although a peak flow rate (Qmax) of less than 10 ml/sec has a 90% positive
predictive value for bladder outlet obstruction, results of uroflowmetry are considered
nonspecific because they cannot distinguish between subvesical obstruction and decreased
bladder contractility. Also, because of large intraindividual variability, at least two
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independent flows rate recordings of > 150 ml volume should be obtained before any
treatment decision is made. (It should be noted that a learning effect has been documented
with uroflowmetry that suggests a greater likelihood for an increased Qmax than a
decreased one with subsequent recordings.) Investigational studies have shown a poor
correlation between Qmax and presence, severity, and bother of symptoms. Uroflowmetry
should be obtained routinely if invasive treatment modalities are planned or if results of
other basic evaluations show discrepancies (eg, symptoms present, but DRE results are
negative).
Optional Studies
Numerous optional studies may be undertaken based on their availability, findings from
baseline evaluations, and clinician familiarity.
Prostate size can be assessed by transrectal ultrasonography, which is preferred over
computed topography or magnetic resonance imaging because of its accuracy, availability,
and lower cost. Investigational studies have suggested that the volume of the transition
zone or the ratio of the transition zone to total prostate volume may be especially helpful
because they appear to correlate with symptoms, Qmax, and urodynamic parameters.
Urethrocystoscopy may be appropriate as a guideline when surgical treatment is
planned to rule out pathology and to assess the size and shape of the prostate. This form of
endoscopy can provide visual documentation of an enlarged prostate that is obstructing the
urethra and bladder neck, obstruction of the bladder neck by a high posterior lip, muscular
hypertrophy of the detrusor muscle (indicated by muscular trabeculation and formation of
cellules and diverticula), formation of bladder stones, and retention of urine in the bladder.
Pressure flow studies can provide a precise diagnosis of obstruction. They should be
considered as optional for the routine symptomatic patient, but they may be appropriate if
results of the standard evaluation, flow rate recording, and residual urine measurements
are not highly suggestive of obstruction. Therefore, a careful history, free uroflowmetry
recording, and postvoid residual urine volume must be obtained before undertaking
pressure flow studies. These examinations should be performed on men whose flow rates
are at least 10 ml/sec before undertaking surgery because those who have both a low Q max
and low pressure will not benefit greatly from surgical intervention.
Pressure flow studies measure the flow rate, detrusor pressure, abdominal pressure, and
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intravesical pressure. There are three general interpretations of the studies:
Low detrusor pressure + high flow rate = no obstruction
High detrusor pressure + low flow rate = obstruction
Low detrusor pressure + low flow rate = weak detrusor contraction Applying the
Abrams/Griffith nomogram for analysis of results can diagnose the presence of
obstruction, and applying the linearized passive urethral resistance relation can grade the
severity of obstruction.
Filling cystometry records bladder pressure during continuous, slow filling. It can
diagnose detrusor instability and reduced bladder compliance, but it is not highly specific
for obstruction. It is not recommended for routine evaluation.
A urethral pressure profile, electromyography, and video urodynamics may be
appropriate further tests if pressure flow studies are inconclusive, but they are not
recommended for routine patients.
Urinary tract imaging is not recommended in otherwise healthy patients whose
evaluation results are consistent with uncomplicated BPH. However, it may be
appropriate if there is a history of or current urinary tract infection, urinary retention,
history of urolithiasis, history of urinary tract surgery, renal insufficiency, or if results of
DRE and PSA evaluations suggest prostatic cancer. In these situations, ultrasonography is
preferred over intravenous urography.
Evaluation of Symptoms, Quality of Life, and Sexuality
A variety of evaluative tools are available to assess a patient's symptoms, quality of
life, and sexuality. These can be used alone or in combination, depending on availability,
time, and clinician comfort with their use.
As noted previously, the AUA Symptom Index and the IPSS are valuable in assessing
incomplete bladder emptying, increased frequency, intermittence, urgency, weak stream,
hesitancy, and nicturia. Investigational studies have shown that the IPSS correlates poorly
with age, total prostate volume, transition zone volume, maximum flow rate, postvoid
residual urine volume, and pressure flow parameters, but it correlates well with the AUA
bother score and with the single disease-specific quality of life question. Clinical
application of the IPSS has shown that a subjective perception of improvement depended
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on the baseline symptom score. These findings suggest that the IPSS can be a valuable
part of the initial evaluation and can help in monitoring patients who are receiving medical
or surgical treatment or undergoing watchful waiting.
The BPH Impact Index measures the degree to which lower urinary tract symptoms
affect various domains of health, including physical discomfort, general worry about
health, bother with urination, and prevention from regular activities. It can serve as a
bridge between measures of symptoms and overall health status. It has been shown to
correlate moderately well with IPSS scores.
The
BPH-specific
Health-related
Quality
of
Life
Questionnaire
assesses
physical/functional, mental health, social life, and overall health status. Testing of this
instrument showed that improvement in quality of life continued beyond the initial period
in which symptoms improved.
A Brief Sexual Function Inventory assesses sexual drive, erectly function, ejaculation,
patient perception of problems, and overall satisfaction with sexual function.
Conclusion
BPH is a growing medical problem that affects a large portion of the elderly male
population. Because this population cohort is growing, it is anticipated that primary care
physicians and urologists will be encountering an increasing number of cases of BPH.
Although understanding of this complex disease process is expanding, the fact that its
natural history and effects on patients are characterized by substantial variation presents a
diagnostic and therapeutic dilemma. The primary symptoms of prostatism, which usually
are the impetus for a physician visit, can be vague and can be attributed to other conditions
beyond BPH. Additionally, the severity of the symptoms and the bother that patients
associate with them varies. Finally, the relationship between prostatism, prostatic
hyperplasia, and intravesical obstruction varies significantly.
In general, BPH develops in the transition zone of the prostate, and urethral obstruction
is due to a combination of the enlarged prostate and the tonus exerted by smooth muscle in
the prostate and bladder neck. Obstruction has both a mechanical and dynamic component,
which form the basis for various avenues for treatment.
Numerous tests are available for diagnosing BPH, but the primary ones evaluate the
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symptoms of prostatism, the degree of hyperplasia, and the effect on urinary stream and
attempt to determine the presence and degree of subvesical obstruction. These tests can be
very helpful in the differential diagnosis of urinary tract infection and prostatic cancer.
Finally, these evaluations can provide valuable information to guide choice of treatment,
offer ongoing information in terms of patient monitoring, and suggest the need for further
testing.
Treatment
Treatment Algorithm
As the treatment options for BPH increase, so can confusion about what approach is
most appropriate for individual patients. The World Health Organization-endorsed
International Consultation on BPH has created treatment guidelines based on those created
by the American Health Care Policy and Research Guidelines. The guidelines are based on
a comprehensive initial diagnostic evaluation, including a careful history, scoring of
symptoms on the IPSS, physical examination that includes digital rectal examination
(DRE), urinalysis, and renal function assessment. Based on results of these studies, clinicians may opt for further tests, adopt watchful waiting, prepare the patient for surgery, or
undertake medical therapies.
As noted previously, the incidence of surgical treatment has decreased as the range of
medical treatments has grown. In general, the only absolute indication for transurethral
resection of the prostate (TURP) today is BPH that has led to bladder stones obstruction of
the upper urinary tract with uremia, or formation of diverticula. A prostate that is larger
than 70 g often requires open Prostatectomy for treatment. Urine retention or recurrent
urinary tract infections strongly suggest the need for treatment, but surgery is not
necessarily the answer.
Several findings on diagnostic tests should steer the clinician away from particular
treatment options. For example, a large middle lobe or urine retention are
contraindications to transurethral thermotherapy.
The treatment of choice for a man who has a medium-sized prostate without
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obstruction-related complications often is medical therapy, primarily with alpha-blockers.
However, it is vitally important to involve the patient intimately in the treatment decision
process. He should be informed of both the positive and negative aspects of suggested
treatment options and weigh them against the degree of discomfort, worry, and disruption
of lifestyle he is experiencing with BPH.
Medical Management
Medical management often is the preference of physicians for the treatment of men
who have bothersome symptoms. Men who have severe symptoms also may be candidates
for medical therapy. Contraindications to medical therapy include urine retention, renal
insufficiency, bladder stones, and gross recurrent hematuria. No matter which medical
therapy is chosen, patients should be re-evaluated every 3 to 6 months to determine
whether therapy can be continued unchanged or whether other treatment options should be
considered. With the agents currently available, neither patient nor clinician need consider
medical therapy to be only a holding action until surgery is undertaken; symptoms can be
controlled quite effectively and the patient's lifestyle affected positively. Clinical studies
have shown that responses to medical therapy may be maintained for up to 5 years.
5-alpha Reductase Inhibitors
These agents inhibit 5-alpha reductase, the enzyme that converts testosterone to
dihydrotesterone (DHT). DHT is a key component involved in control of prostate growth,
so inhibition of its formation can limit prostate hyperplasia and, in fact, reverse its
development. Thus, these drugs address the mechanical component of obstruction in
BPH.
The primary agent in this class is finasteride. Clinical studies have shown that it can
reduce the volume of the prostate by about 20%. Relative to placebo, symptom scores
have been shown to improve about 1 symptom unit in the first year of use and the Q max to
increase 1.3 to 1.8 ml/sec over 12 months. Although these treatment effects were
statistically significant, the clinical significance of a 1-unit symptom score change is
questionable. Clinical improvements become apparent after 3 to 6 months of treatment. A
recent study sponsored by the VA Cooperative Studies Program demonstrated that
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finasteride was no better than placebo. In the subset of patients who had very large
prostates (>50 cm3), the therapeutic effect of finasteride was similar to that reported in
initial studies.
The primary adverse effects of finasteride are reduced libido, decrease in volume of
ejaculate, and erectly impotence in 3% to 5% of patients. These effects reverse when
treatment is stopped. It also has been suggested that there is a potential for contamination
in expectant women via drug penetration in semen; such an occurrence may lead to fetal
deformity. Finally, finasteride appears to lower serum PSA concentrations on average by
nearly half after 6 to 12 months of treatment. There is no unequivocal evidence that such
reduced levels limit the effectiveness of PSA as a cancer detection tool. To date, there is
no clear evidencing that treatment with finasteride prevents complications of BPH from
occurring or reduces the need for subsequent surgery.
Alpha Blockers
The use of alpha-blockers in treatment of BPH is based on the finding of a high density
of adrenergic nerves in the urogenital system and, particularly, a high density of alpha 1
adrenoceptors in the smooth muscle cells of the prostate, urethra, and bladder neck. The
alpha, adrenoceptors is activated when an agonists such as norepinephrine attaches to it;
such activation can cause smooth muscle contraction. Alpha-blockers compete with the
agonists in occupying the adrenoreceptor and, thus, prevent smooth muscle contraction in
the prostate. Thus, these agents address the dynamic component of obstruction in BPH.
Because alpha adrenoceptors are located throughout the body, use of non-selective
alpha-blockers can result in adverse effects at sites other than the prostate and bladder,
such as the central nervous system. Selective alpha-blockers can provide clinical
effectiveness in BPH with fewer adverse effects than nonselective blockers.
At least three subtypes of alpha1 receptors have been identified in research
investigations, and it has been reported that the alpha1A subtype mediates prostate smooth
muscle tension. However, an in vitro study of binding affinities at cloned human alpha 1adrenoceptors showed that the contractile response did not appear to be mediated by
alpha1A-, alpha1B-, or alpha1D-adrenoceptors. A very selective alpha-blocker, such as
tamsulosin, which exhibits a partial selectivity for the alpha1A subtype, has the potential to
be effective in the treatment of BPH and limit adverse effects, but until the exact role of
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other alpha1 receptors in the prostatic smooth muscle have been determined, the clinical
significance of such focused uroselectivity remains unknown.
The currently available alpha1 blockers include afluzosin, doxazosin, prazosin,
tamsulosin, and terazosin. Their primary differences are related to the pharmacokinetic
profiles, with prazosin and afluzosin having half-lives of only 3 and 5 hours, respectively,
compared with 10 and 12 hours for tamsulosin and terazosin and 22 hours for doxazosin.
With the longest half-life of any of the alpha-blockers, doxazosin not only can be
administered once daily, but it is associated with minimal variations between peak and
trough plasma concentrations. An additional difference is the suggested time of drug
administration. Doxazosin can be administered in the moaning or evening. In contrast, it is
recommended that terazosin be administered in the evening, and tamsulosin is
recommended for administration after breakfast. The longer half-lives of these three
alpha-blockers result in a more gradual onset of action and improves their safety profile.
The much shorter half-lives of afluzosin and prazosin necessitate twice- and thrice-daily
dosing.
Clinical trials have shown that alpha-blockers increase the Qmax by 1.5 to 3.5 ml/sec
and significantly improve symptoms in more than 60% of patients who have symptomatic
clinical BPH. A statistically significant reduction in maximum voiding pressures and
improvement in uroflow has been documented, as has a modest improvement in residual
volume. Unlike the 5-alpha reductase inhibitors, clinical improvements with alphablockers are evident after only 1 to 3 weeks of treatment. The clinical response should be
evaluated after 4 to 6 weeks of therapy. Long-term studies suggest that alpha-blockers
have a well-maintained duration of response.
The primary adverse effects of alpha-blockers are related to their mode of action on
adrenoceptors at sites other than the prostate. Central and peripheral nervous system
effects include headache, dizziness, fatigue, a flu-like malaise, and postural hypotension.
These adverse effects can be minimized by careful titration of the dose and usually are
less common with the longer-acting agents. Also, these effects tend to diminish over time.
As with the 5-alpha reductase inhibitors, alpha-blockers have not been shown to prevent
the development of BPH complications or reduce the need for eventual surgery.
The VA Cooperative study is the only investigation to compare the safety and efficacy
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of 5-alpha-reductase inhibitors and alpha-blockers. In men who had prostate volumes less
than 50 cm3, the 5-alpha-reductase inhibitor was no better than placebo. The treatmentrelated effect of an alpha1- blockers on symptoms was threefold greater than that of the 5alpha-reductase inhibitor in men who had large prostates.
Phytotherapeutic Agents
Natural compounds have been used for many years in Europe in the treatment of BPH.
Many of these compounds are undergoing critical clinical evaluation in an effort to
determine their mechanism of action and efficacy. Four compounds have received the
most intensive in vitro and clinical examination: pollen extract, Sabal Serrulata, Serenoa
Repens, and Pygeum Africanum. In vitro studies have suggested various mechanisms of
action, ranging from relaxant and antiproliferative tissue effects to inhibition of
androgenic effects, although no definitive findings have been published. Clinical trials
suggest some symptomatic improvement with the use of phytotherapeutic agents, but only
a few placebo-controlled investigations have been undertaken. Results from many of the
placebo-controlled trials with pollen extract showed similar symptomatic improvement in
both the treated and placebo groups. Those involving Serenoa Repens and Sabal Serrulata
showed varying results; in one study there was no difference between treated and placebo
patients and in two others, those treated its the plant extract had better symptomatic
improvement. However, evaluation in these studies was at 30 days and 3 months, and
longer follow-up is required.
Hormonal Therapy
As an androgen-dependent process, BPH theoretically should respond to withdrawal of
hormones. A critical level of prostatic androgen is necessary to maintain hyperplasia of
the tissue, and withdrawal of androgen can cause the tissue to involute. However, when
hormonal therapy is withdrawn, the tissue returns to the enlarged size.
The attendant medical and psychological risks of surgical castration preclude its use,
but several agents have been investigated for medical castration. GnRH analogues, which
inhibit the release of gonadotropins by the pituitary, have been effective in reducing
hyperplastic prostate tissue, but such treatment is costly and has been associated with
sexual dysfunction and hot flashes in many treated patients. Therefore, it is not
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recommended for routine treatment of BPH.
Hydroprogesterone caproate, cyproterone acetate, and chlormadinone acetate are the
primary progestational agents that have been examined in the treatment of BPH. These
agents inhibit androgen production through decreased GnRH secretion and block
androgen receptors in the prostate. Although they have been shown to be clinically
effective, associated side effects of androgen withdrawal, such as impotence, have limited
their widespread use.
Androgen receptor antagonists, which block activation of androgen in prostate and
other tissue, also have been examined. Among the agents being investigated are
flutamide, bicalutamide, and zanoterone. They have shown varying degrees of efficacy in
terms of symptomatic improvement, but all were associated with breast tenderness and
some degree of sexual dysfunction that resulted in a high incidence of study drop-out.
Therefore, it would appear that the side effects associated with androgen receptor
antagonists outweigh their clinical benefits.
Estrogen withdrawal also has been studied as a treatment alternative in BPH based on
some evidence that these hormones play a role in the disease. Aromatase inhibition
appeared to be an effective treatment in animal studies, but clinical studies failed to
confirm that potential.
Surgical Treatment
Surgical treatment may be required in patients who have advanced BPH that has
resulted in complications or in those for whom medical therapy proved not to be effective
in controlling symptoms.
Transurethral Prostatectomy (TURP) is the most commonly performed surgical
approach to BPH, although, as noted earlier, the frequency with which this procedure is
performed has decreased in the past few years as less invasive medical therapies have
become more available. Absolute indications for the procedure include BPH leading to
bladder stones or obstruction of the upper urinary tract with uremia. Because of their
potential for serious consequences, recurrent urinary retention or urinary tract infections
suggest the need for surgical treatment. Investigative studies have shown that symptoms
improve in 70% to 90% of patients, with a Qmax of >15 to 20 ml/sec achieved. However,
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the surgery also can be associated with significant adverse effects, including impotence
(15% to 20% of patients), retrograde ejaculation due to loss of bladder neck sphincter
mechanism, hemorrhage, and incontinence (<1% of patients). Additionally, approximately
20% of patients require reoperation over 8 years of follow-up.
Transurethral incision of the prostate (TUIP) has been suggested as a viable alternative
to the more invasive TURP in men whose prostates are <30 g resectable weight with a
high bladder neck and no middle lobe hyperplasia. Its efficacy is considered to be almost
equivalent to that of TURP and its complication rate lower, particularly in terms of
retrograde ejaculation.
Open Prostatectomy is the most invasive of the surgical procedures and is indicated
when the prostate is >70 g resectable weight. Symptomatic improvement has been seen in
98% of treated patients, with Qmax often increasing to >20 ml/sec. However, a longer
hospital stay and a higher rate of complications are seen with this procedure than with
TURP or TUIP. The need for further surgery is less than with the other two operative
options.
Laser Prostatectomy can be performed at low-power density, which results in tissue
coagulation, or high-power density, which causes vaporization of tissue. Many variables
contribute to the success or limitations of laser prostatectomies, including time, power,
and wave length of laser; beam angle, divergence, power density, and method of beam
deflection in delivering the laser; and tissue absorption and changes. Although results of
laser Prostatectomy have been encouraging, the unpredictable postoperative course of
urinary retention, the necessary prolonged catheterization, and the protracted irritative
symptoms are limitations to its use. Additionally, it is not yet known how long the
changes created by lasers will endure and what the need for retreatment will be.
Transurethral electrovaporization of the prostate (TVP) is a modification of TURP that
combines electrosurgical vaporization with desiccation to remove hyperplastic tissue.
Initial studies have shown it to be similar in efficacy to TURP, although longer follow-up
with more patients is required to determine its exact role in the therapeutic
armamentarium. Its primary potential advantage is the lower cost in hospital days and
potential morbidity compared with traditional surgery and laser treatment.
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Other Nonmedical Therapies
A variety of other procedures have been investigated for the treatment of BPH, ranging
from balloon dilatation and stents to thermotherapy, radiofrequency, and high-intensity
focused ultrasonography. In most cases, these procedures are considered experimental or
are not recommended for routine treatment.
Balloon dilatation of the prostatic urethra and the prostatic capsule has been used for
many years, but the results generally are not long-lasting. The only controlled study
demonstrated that balloon dilatation and a sham cystoscopy provided equivalent efficacy.
Several new approaches to this older technique are being examined, but require more
experience and clinical trials before they can be recommended. These include balloon
incision of the prostate, transurethral heat-delivering balloons that ablate central prostatic
tissue, transurethral balloon laser thermography that compresses the lateral lobes of the
prostate, and water-induced thermotherapy. Although there is an overall low incidence of
complications with these variations, the observed beneficial effects are not maintained for
a significant period of time.
Stents are used to maintain expansion of the prostatic urethra and generally are
employed in patients who have outflow obstruction but whose illness precludes
Prostatectomy or in those who require but refuse long-term catheterization. They produce
only modest improvements in symptoms and urine flow rate in those who do not have
urinary retention. They are contraindicated in men who have severe mental impairment,
urinary incontinence, limited mobility or manual dexterity, untreated urinary tract
infections, and bladder stones or tumors. There are two categories of stents: temporary
and permanent. The temporary stents may be biodegradable or nonabsorbable, and the
nonabsorbable ones must be changed every 6 to 36 months. The permanent stent is a
mesh-like tubular device that is intended to be covered by urethral epithelium and
incorporated into the urethral wall. Numerous potential problems limit the usefulness of
stents, including migration, encrustation with calcium salts, incontinence, prolonged
urethral discomfort and irritation, obstruction, and stone formation.
Thermotherapy may be considered as an alternative to TURP when BPH is
characterized by moderate symptoms and mild obstruction. Contraindications include the
presence of a large middle lobe, urinary retention, and severe obstruction. Transurethral
19
microwave thermotherapy (TUMT) induces tissue necrosis in the prostate and may
damage intraprostatic nerves and alpha adrenoceptors. Studies have shown that the Qmax
increases approximately 3 ml/sec. Sham controlled studies demonstrated initial treatmentrelated efficacy comparable to alpha1- blocker therapy. Lower energy treatment appears
to provide symptomatic improvement in most patients; higher energy should be reserved
for patients who have moderate-to-severe bladder obstruction and larger prostates. Not
surprisingly, there is increased morbidity with the higher-energy approach. The most
serious complication of TUMT is temporary urine retention after treatment, which occurs,
in approximately 25% of treated patients. Additionally, long-term results are uncertain;
there is an approximately 10% retreatment rate with the lower-energy therapy.
Transurethral needle ablation (TUNA) is an outpatient procedure that employs lowlevel radiofrequency through a catheter device to target specific sites in the prostate for
tissue ablation. The resultant decreases in symptoms are similar to those seen with TURP.
Some bleeding and the need for catheterization are the primary drawbacks. This therapy is
still very much in the investigational stage and requires more clinical studies of longer
duration before definitive recommendations can be made.
Laser ablation of hyperplastic prostatic tissue also has been investigated. Transurethral
laser incision of the prostate (TULIP) involves use of a laser that has been positioned via
ultrasonography while endoscopic laser ablation of the prostate (ELAP) is undertaken
with a probe that is inserted into the prostate via a cystoscope. Preliminary studies have
shown an improvement in symptom scores of >50%, with an increased Qmax of 3 to 6
mL/sec. Potential complications include minimal blood loss, postoperative pain and
difficulty in passing urine, and the possible need for catheterization.
High-intensity focused ultrasonography (HIFU) employs an ultrasonographic beam
aimed transrectally in tight focus at a selected depth in the prostate. A temperature above a
specific level produces necrosis while that below the level produces cavitation. Few data
are available on this procedure, which is in the process of phase II trials.
Overall, many of the nonmedical therapies (excluding surgery) remain in experimental
stages. Some have been essentially discarded as not providing substantial improvement of
sufficient duration (balloon dilatation), while others have potentials that have encouraged
greater investigation (TUNA and TVP). In general, these approaches are not yet
20
appropriate for the routine management of BPH.
Summary
There is no standard treatment of BPH that is appropriate for all patients. Thus,
clinicians must evaluate each patient carefully to determine the extent of symptoms,
degree of obstruction, and effect of these conditions on the individual's lifestyle. All of
these factors must enter into the decision of the treatment path to take. Generally, mild
symptoms that are not causing the patient undue stress or discomfort can be addressed
with watchful waiting that involves some lifestyle changes and annual evaluation of
symptoms, signs, and laboratory tests. Medical management alternatives have increased
the treatment possibilities for patients whose symptoms are moderate to severe and who
have no potentially life-threatening complications of BPH. In these instances, weighing
the efficacies and potential adverse effects of the therapies in conjunction with the
patient's desires can result in efficacious treatment that minimizes interference with the
patient's lifestyle. Surgical management should be reserved for patients who have
evidence of potentially life-threatening consequences of BPH because although their
efficacy has been proven, they also are associated with substantial potential adverse
effects that can have a significant impact on the patient's life.
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21
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