1. health and fitness
2. disease
3. cancer

PROCEEDINGS
SERUM PROSTATE-SPECIFIC ANTIGEN AS A BIOMARKER FOR
DISEASE PROGRESSION IN BENIGN PROSTATIC HYPERPLASIA*
—
Alan W. Partin, MD, PhD,† Michael M. Lieber, MD,‡ Leonard S. Marks, MD,§ Claus G. Roehrborn, MD||
ABSTRACT
Recent advances in understanding of the natural history of benign prostatic hyperplasia (BPH)
and the development of new treatment options
are enabling a shift in approach to treatment
from palliative to preventive strategies. Studies of
the natural history of BPH reveal that it is a progressive condition with a predictable course.
Furthermore, with the introduction of 5α-reductase inhibitor pharmacotherapy, it may be possible to prevent progression of BPH and to reduce
the risk of serious sequelae. Symptomatic BPH
does not progress in all patients; therefore, progression-modifying intervention is not always
warranted. To tailor therapeutic and/or preventive approaches appropriately, it is valuable to
*This article is based on a roundtable symposium held
in Baltimore, Maryland, February 5, 2003.
†Professor of Urologic Oncology, Brady Urological
Institute, Department of Urology, The Johns Hopkins Medical
Institutions, Baltimore, Maryland
‡Professor of Urology, Vice Chair for Research,
Department of Urology, Mayo Clinic and Mayo Foundation,
Rochester, Minnesota.
§Clinical Associate Professor, Department of Surgery/
Oncology, University of California at Los Angeles School of
Medicine, and Founding Medical Director, Urological Sciences
Research Foundation, Los Angeles, California.
||Professor and Chairman, Department of Urology, The
University of Texas Southwestern Medical Center, Dallas, Texas.
Address correspondence to: Alan W. Partin, MD, Brady
Urological Institute, The Johns Hopkins Hospital, 600 North
Wolfe Street, Baltimore, MD 21287.
Advanced Studies in Medicine
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differentiate patients at high risk of progression
from those at low risk of progression. A considerable body of evidence shows that serum
prostate-specific antigen (PSA), a commonly used
screening test for prostate cancer, can also be
useful in predicting disease progression in BPH
when considered in conjunction with other clinical indicators. Specifically, patients with PSA of at
least 1.5 ng/mL, in the presence of an enlarged
prostate and lower urinary tract symptoms, are at
increased risk of disease progression. These
patients may benefit from close monitoring and
may be good candidates for pharmacotherapy to
arrest the disease process. On the other hand,
patients with a small prostate gland, low serum
PSA, and bothersome lower urinary tract symptoms might benefit most from symptomatic treatment but should be periodically monitored to
assess changes in clinical status. The strong predictive utility of PSA—combined with the fact that
it, unlike other clinical markers of BPH status, can
be accurately and easily measured—renders it
an important tool for the clinician seeking to optimize outcomes for patients with BPH.
(Adv Stud Med. 2002;3(4D):S347-S355)
enign prostatic hyperplasia (BPH)
affects nearly all men reaching normal
life expectancy. Among men 60 years
and older, the prevalence of clinical BPH
is approximately 70%—substantially
greater than that of other common diseases such as
diabetes (which affects ~20% of those older than 65
B
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years) or asthma (which affects ~6% of the US populaoptimize patient care, it is valuable to differentiate
tion at large).1-3 The prevalence of BPH increases with
patients at high risk of progression from those at low
age. By the time men are 80 years old, 90% have historisk of progression so that treatment can be cuslogically verifiable BPH.4 As life expectancy continues to
tomized appropriately. A considerable body of eviincrease and the US population continues to age, BPH
dence shows that serum prostate-specific antigen
will affect a growing proportion of the population. BPH
(PSA), a commonly used screening test for prostate
is a chronic condition characterized by gradually
cancer, is also useful in predicting disease progression
increasing prostate volume, decreasing urinary flow
in BPH when considered in conjunction with other
rate, and worsening of lower urinary tract symptoms
clinical indicators. Specifically, data suggest that
(LUTS) such as urgency, frequency, and nocturia.5 The
patients with PSA of at least 1.5 ng/mL, in the preseffects of BPH symptoms on the patient range from
ence of an enlarged prostate and LUTS, may be at
mild discomfort and embarrassment to significant
increased risk of disease progression. These patients
impairment in activity and quality of life.6 Serious
may benefit from close monitoring and may be good
sequelae of BPH include acute urinary retention—a
candidates for pharmacotherapy to arrest the disease
painful event necessitating emergency care and
process (Figure 1). This monograph discusses the evicatheterization—and ultimately surgery. These sequedence regarding serum PSA as a biomarker for disease
lae, which are costly from both humanistic and ecoprogression in BPH and considers how serum PSA can
nomic perspectives, are not uncommon. For a
be used to facilitate therapeutic decision making.
60-year-old man, for example, the 10-year cumulative
incidence of acute urinary retention (14%) exceeds
BPH AS A PROGRESSIVE DISEASE
that of myocardial infarction (5%), a new diagnosis of
The utility of PSA as a biomarker for BPH progresdiabetes (5%), or stroke (7%).7 Because of its high
prevalence and its potential functional and economic
sion can be understood in the context of the natural
impacts, BPH is a significant men’s health concern.
history of BPH, which has been assessed in clinic- and
Medical and surgical intervention for
BPH has historically focused on relieving
symptoms.8 However, recent advances in
understanding of the natural history of BPH
and the development of new treatment
Figure 1. The therapeutic strategy for preventive management of
options enable a more proactive, compreBPH depends on whether or not the patient is at high risk of
hensive approach to BPH management.
disease progression.
Studies of the natural history of BPH reveal
that it is a progressive condition with a predictable course. Furthermore, with the
introduction of 5α-reductase inhibitor pharmacotherapy, it may be possible to prevent
progression of BPH and to reduce the risks of
acute urinary retention and prostate surgery.
These developments are facilitating a shift
from palliative to preventive strategies for
managing BPH.
BPH does not progress in all patients, and
progression-modifying intervention is not
always warranted. The treatment of a patient
with mild bothersome LUTS who is unlikeOn the basis of the literature reviewed in this paper, patients with PSA of at least 1.5 ng/mL
ly to have progressive disease differs from the
and prostate volume of at least 30 cc may be at increased risk of disease progression. These
patients may benefit from close monitoring and may be good candidates for pharmacotherapy
treatment for a patient with moderate to
to arrest the disease process. Patients with serum PSA below 1.5 ng/mL and smaller prostates
severe LUTS who is at high risk of disease
are unlikely to have progressive disease. If experiencing bothersome symptoms, patients meetprogression and BPH-associated sequelae. To
ing the latter criteria may benefit most from symptomatic treatment.
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community-based studies as well as among men treated with placebo in long-term clinical trials. These
studies show that, while the course of BPH varies from
patient to patient, in many men it is a progressive condition characterized by:
• Increasing prostate volume;
• Worsening lower urinary tract symptoms;
• Decreased urinary flow rate; and
• Increased risk of acute urinary retention and
BPH-associated surgery.1
PROSTATE VOLUME
Prostate volume increases over time and is directly
related to age in patients with BPH.7,9,10 For example,
in the community-based Olmsted County
(Minnesota) study, which followed approximately
2100 randomly selected men, prostate volume was
measured by transrectal ultrasound up to 4 times over
a 7-year follow-up period in a subset of 631 white
men ages 40 to 79 years who had not previously
undergone prostate surgery or had prostate cancer.9
The results show that, although prostate growth rates
were variable between patients, prostate volume
increased with age across the population. Across all
age groups, the average annual change in prostate volume (estimated by a mixed-effects regression model)
was 1.6% (Figure 2).9 The mean overall annual
growth was 0.6 cc and ranged from 0.4 cc in men ages
40 to 59 years to 1.2 cc in men ages 60 to 79 years.
Higher baseline prostate volumes were associated with
higher rates of prostate growth over the follow-up
period. A similar pattern of results was observed
among 164 placebo-treated patients in the PLESS
(Proscar Long-Term Efficacy and Safety Study) clinical trial, which followed men with BPH for 4
years.11 Mean annual prostate growth was 1.8 cc and
ranged from 1.5 cc in men ages 50 to 59 years to 2.4
cc in men ages 70 to 79 years.
example, in the Forth Valley Study, which followed a
community-based cohort of 217 Scottish men with
untreated BPH for 3 years, prevalence of symptoms,
symptom bothersomeness, and symptom-related interference in daily activities increased over the study period.14 It is estimated, on the basis of data from several
studies, that symptoms worsen over years in approximately 55% of patients with untreated BPH; remain stable in 30% of patients; and improve in 15%.15
URINARY FLOW RATE
Data from the Olmsted County study also demonstrate that maximum urinary flow rate (Qmax) and
voided volume progressively decrease over time and as
a function of age.16 In this analysis, Qmax and voided
volume were assessed in a sample of 492 men over a 6year follow-up period. The median decrease in peak
urinary flow rate was 2.1% per year. Rapid decrease in
peak urinary flow rate (ie, at least 4.5% decrease per
year) was most likely to occur in men at least 70 years
Figure 2. Predicted longitudinal changes in prostate volume as a function of age in the Olmsted County study.9
SYMPTOMS
Consistent with the progressive nature of BPH,
community- and clinic-based studies generally show a
gradual, age-related worsening of irritative and
obstructive symptoms. The deterioration in symptoms parallels the progressive increase in prostate volume and decrement in urinary flow rate.12-14 For
Advanced Studies in Medicine
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Each black line on the graph represents the predicted prostate growth data for
1 patient. Across all age groups, the average annual change in prostate volume (estimated by a mixed-effects regression model) was 1.6%, indicated by the line marked with *.
Adapted with permission from Lippincott Williams & Wilkins, publisher of The
Journal of Urology.
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PROCEEDINGS
of age. Similar results have been observed in other
studies of BPH and LUTS.17,18
SEQUELAE OF BPH
Like the signs and symptoms of BPH, the incidence of serious sequelae of BPH increases over time
and is directly related to age as well as to other parameters such as prostate volume and symptom severity.1,19 In the Olmsted County study, for example, the
incidence of acute urinary retention over a 4-year period was directly related to severity of symptoms measured using the American Urological Association
Symptom Index.19 This effect was particularly marked
in older individuals. Among those ages 70 to 79 years,
the frequency of acute urinary retention per 1000
patient-years increased from 9.3 in the presence of
mild to moderate symptoms to 34.7 in the presence of
moderate to severe symptoms.19
The likelihood of needing BPH-related prostate
surgery also increases over time. In the Baltimore
Longitudinal Study of Aging, which prospectively
followed 1057 men for up to 30 years, the 10-year
probability of prostate surgery for BPH was directly
related to age among both those with prostatic
enlargement and obstructive symptoms and among
those without prostatic enlargement and obstructive symptoms.20 The risk of surgery was particularly high for older men with prostatic enlargement
and obstructive symptoms. The 10-year probability
of BPH-related prostate surgery among 60- to 69year olds with prostate enlargement and obstructive
symptoms was 16%. For 70- to 79-year olds with
prostate enlargement and obstructive symptoms,
the 10-year probability of BPH-related prostate
surgery was 34% (Figure 3).20
sistently show BPH to be a progressive condition renders the evidence compelling. While the studies show
that signs and symptoms of BPH gradually worsen
and the risk of sequelae increases across groups of
men, they also show considerable variability between
individuals in the rate and extent to which BPH progresses. Research to be reviewed in the following sections shows that serum PSA is useful in gauging risk
of progression in the individual patient.
PSA
PSA, a single-chain glycoprotein with a molecular
weight of 34 kilodaltons, is produced by all prostatic
epithelial cells whether benign or malignant.21 In men
with enlarged prostates associated with BPH, prostate
cancer, or prostatitis, serum PSA levels are believed to
be elevated through leakage of intraprostatic PSA into
the systemic circulation.7 In the systemic circulation,
PSA occurs in both a free form (free PSA) and a form
complexed to endogenous protease inhibitors such as
alpha-1-antichymotrypsin. A common, reliable, reproducible test that is easy to obtain in nearly any clinical
setting, serum PSA is the best biomarker available for
prostate cancer. However, it is not cancer specific in
Figure 3. 10-year probability of BPH-related surgery as
a function of age in patients with or without prostatic
enlargement and obstructive symptoms in the Baltimore
Longitudinal Study of Aging.20
CONCLUSIONS: BPH AS A PROGRESSIVE DISEASE
These data show that BPH is progressive. Over
time, prostate volume increases while urinary flow
rate decreases and symptoms worsen. Moreover, the
risk of serious BPH sequelae such as acute urinary
retention and prostate surgery increases over time.
The progressive nature of BPH is supported by the
results of several studies ranging from clinical trials
following patients for up to 4 years to cross-sectional and longitudinal community-based studies following individuals for up to 7 years.9-17,19,20 That
these varying approaches, each associated with
unique advantages and disadvantages (Table), con-
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PROCEEDINGS
that it is elevated in the presence of both benign and
malignant prostate disease.
SERUM PSA: A BIOMARKER FOR BPH PROGRESSION
ship; that is, the logarithms of the 2 variables are linearly related, and that relationship depends on age.
That serum PSA and prostate volume are closely related is not surprising given that the age-related increase
in serum PSA is most likely attributed to the increase
in prostate volume (arising from increased epithelial
mass) that occurs as men age.23
The direct relationship between age and serum
PSA as well as between age and prostate volume is
illustrated by the results of an analysis of data from
The utility of serum PSA as a biomarker for disease
progression arises from the ability to use serum PSA
values as a proxy for prostate volume, which is well
established as a primary predictor of progression and
outcomes in BPH. While PSA and total prostate volume are both strong predictors
of disease progression in BPH,
PSA may be more useful in the
clinical setting than is total
prostate volume. PSA can be
Table. Advantages and Disadvantages of the Primary Study Designs Employed
accurately measured with a
in Assessing the Predictive Value of Serum PSA in BPH
simple clinical test whereas
total prostate volume is generally difficult to estimate accuStudy Design
Advantages
Disadvantages
rately without sophisticated
Clinical trial
Follow-up is consistent from
• Inclusion and exclusion critetechniques such as trans-rectal
patient to patient so that influria may render sample
ultrasound or magnetic resoence of extraneous variables is
unrepresentative
nance imaging. Digital rectal
minimized
• Placebo effect
examination, the most com• Hawthorne effect (i.e.,
behaviors change as a consemon means of assessing
quence of being studied)
prostate volume in the clinic,
• Volunteer bias
often underestimates prostate
• Significant numbers of particiLongitudinal, community-based Sample is representative of
volume.22 Given that PSA prepants are often lost to followcohort study
reference
population
so
“real
dicts outcomes in BPH at least
up in studies employing
world” meaningfulness of data
as robustly as does prostate
prolonged observation periods
is enhanced
volume, that it can be more
Can establish timing and direc- • Data may not be generalizable to samples from comtionality of events
easily and accurately meamunities with other
sured, and that it is available in
demographic and clinical
the medical records of any
characteristics
patient screened for prostate
• Selection bias (i.e., sample
cancer, it constitutes an impordiffers from population in
measured or unmeasured
tant tool to use alone or in
baseline characteristics
conjunction with other clinical
because of the way particiassessments in managing the
pants were selected or
patient with BPH.
assigned)
• Volunteer bias
RELATIONSHIPS AMONG
SERUM PSA, AGE,
AND PROSTATE VOLUME
Both PSA and total
prostate volume increase with
advancing age. PSA and total
prostate volume have an agedependent, log-linear relation-
Advanced Studies in Medicine
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Cross-sectional communitybased study
Sample is representative of
reference population so “real
world” meaningfulness of data
is enhanced
• Data may not be generalizable to samples from communities with other
demographic and clinical
characteristics
• Selection bias
• Volunteer bias
• Cannot establish timing and
directionality of events
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PROCEEDINGS
clinical trials in which baseline prostate volume was
measured by either transrectal ultrasound or magnetic resonance imaging in 4627 men with no prostate
cancer.23 Both the log of baseline serum PSA and the
log of baseline prostate volume were directly related to
age throughout the adult life span (Figure 4).23 Data
from this analysis show that PSA cut-off values for
detecting men with prostate volume exceeding 30 mL
were PSA >1.3 ng/mL, >1.5 ng/mL, and >1.7 ng/mL
for men with BPH in their 50s, 60s, and 70s, respectively. These criteria had 70% specificity and 65% to
70% sensitivity for detecting men with prostate volume exceeding 35 mL. These findings show that
serum PSA values were closely related to current
prostate volume in men enrolled in clinical trials.
Whether or not serum PSA predicted future prostate
volume changes associated with disease progression
was not assessed in this analysis.
SERUM PSA PREDICTS PROSTATE GROWTH
That serum PSA values can indeed predict future
prostate growth was established in subsequent
analyses of clinical trials data and in a communitybased study. In the PLESS clinical trial, 164 men in
the placebo group had yearly evaluations of prostate
volume via pelvic magnetic resonance imaging over
a period of 4 years.11 Baseline PSA values more
strongly predicted prostate growth than either age
or baseline prostate volume (both of which also predict prostate growth). Annualized growth rates in
mL/year were 0.7 for those with baseline PSA of 0.2
to 1.3 ng/mL (low tertile), 2.1 for those with baseline serum PSA of 1.4 to 3.2 ng/mL (middle tertile), and 3.3 for those with baseline serum PSA of
3.3 to 9.9 ng/mL (high tertile) (Figure 5).11
Baseline PSA values also predicted subsequent
prostate enlargement in the community-based
Baltimore Longitudinal Study of Aging.24 Over a 30year period, the long-term risk of prostate enlargement among men ages 40 to 49.9 years (n=194), 50
to 59.9 years (n=191), and 60 to 69.9 years (n=144)
was predicted by serum PSA quartile at baseline.
The relationship was particularly strong for those
ages 50 and older:
Figure 4. Baseline prostate volume as a function of
baseline serum PSA in patients of different ages in the
PLESS study23
Copyright © 2000 American Diabetes Association from Diabetes Care. 2000;23:11031107. Reprinted with permission from The American Diabetes Association.
Figure 5. Baseline serum PSA values predicted prostate
growth over a 4-year period in patients treated with
placebo in the PLESS trial11
• Among those ages 50 to 59.9 years, the risk of an
enlarged prostate was 8.6 times higher when
serum PSA level exceeded 1.4 ng/mL than when
serum PSA was 0.5 ng/mL or below (Figure 6).24
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PROCEEDINGS
• Among those ages 60 to 69.9 years, the risk of an
enlarged prostate was 11.1 times higher when
serum PSA level exceeded 1.7 ng/mL than when
serum PSA was 0.5 ng/mL or below (Figure 6).24
Figure 6. The relative risk of prostate enlargement over
a 30-year period increased with increasing serum PSA
values24
The authors concluded that “risk stratification
based on PSA level may be useful to identify men at
greatest risk for adverse events due to prostate
enlargement.”24
Both the observation that PSA predicts future
prostate growth and the age-dependent, log-linear
relationship between baseline PSA and baseline
prostate volume support the use of PSA as a proxy for
prostate volume in predicting progression of BPH.
SERUM PSA PREDICTS CHANGES IN
SYMPTOMS AND URINARY FLOW RATE
Serum PSA also predicts changes in symptoms and
urinary flow rate. In the PLESS trial, mean changes in
American Urological Association Symptom Index
(AUA-SI) scores at the end of 4 years of treatment
with placebo were inversely related to baseline serum
PSA levels.25 Mean changes in AUA-SI score were -2.4,
-0.4, and -0.2 in men with BPH and baseline serum
PSA of 0 to 1.3 ng/mL, 1.4 to 3.2 ng/mL, and 3.3 to
12 ng/mL, respectively. A similar relationship was
observed between baseline serum PSA levels and
changes in maximum urinary flow rate over 4 years.
SERUM PSA PREDICTS INCIDENCE OF
SEQUELAE OF BPH
Besides predicting increases in prostate volume
and changes in symptoms and urinary flow rate,
serum PSA predicts 4-year incidences of either
acute urinary retention or BPH-related surgery at
least as well as does prostate volume. Among 312
placebo-treated patients in the 4-year PLESS study,
the incidence of acute urinary retention was directly related to both baseline prostate volume and
baseline serum PSA (Figure 7).26 Baseline prostate
volume and baseline serum PSA were more powerful predictors of the occurrence of acute urinary
retention than were symptom scores, urinary flow
rates, or residual urine volume. The need for BPHrelated surgery, like the risk of acute urinary retention, was strongly predicted by baseline prostate
volume and baseline serum PSA.
PSA also strongly predicted the incidence of
acute urinary retention in another analysis of data
Advanced Studies in Medicine
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Figure 7. Baseline serum PSA and prostate volume predicted the incidence of acute urinary retention over 4
years in the PLESS study26
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PROCEEDINGS
from clinical trials of men with LUTS and BPH.27 The
ability of 110 variables to predict acute urinary retention was assessed by logistic regression analysis and
classification and regression tree methods with data
from 5335 patients. The occurrence of acute urinary
retention was predicted by several variables including
prostate volume, serum PSA, frequency of urination,
symptom problem index, maximum urinary flow rate,
and hesitancy. Serum PSA alone was as strongly predictive of the occurrence of acute urinary retention as
was the combination of PSA, urinary frequency and
hesitancy, flow rate parameters, and symptom problem index.
CONCLUSIONS: PSA AS A BIOMARKER
OF BPH PROGRESSION
Considered in aggregate, the data on the relationships among PSA, prostate volume, and BPH
progression show that PSA is a powerful predictor of
disease progression in BPH. The strong predictive
utility of PSA—combined with the fact that it,
unlike other clinical markers of BPH status, can be
accurately and easily measured—renders it an
important tool for the clinician seeking to optimize
outcomes for patients with BPH. These conclusions
should be interpreted with the knowledge that most
of the data supporting the predictive value of serum
PSA levels are derived from retrospective analyses
rather than studies prospectively designed to examine the ability of serum PSA to predict progression
of BPH. This caveat notwithstanding, the consistency of data from various sources ranging from clinical
trials to longitudinal community-based studies lends
credence to the conclusion that serum PSA is a powerful marker of disease progression in BPH.
The precise PSA value above which risk of progression can be considered to be clinically significant
may vary from patient to patient depending on factors such as the patient’s age, individual goals, general health status, and socioeconomic circumstances.
Generally and for practical purposes, patients with
PSA values of 1.5 ng/mL or above can be considered
at high risk of disease progression. The findings
reviewed above show that, above this PSA cut-off
point, the risk of BPH-associated sequelae increases
significantly. Patients with PSA values of 1.5 ng/mL
or above may benefit from close monitoring and
may be appropriate candidates for pharmacotherapy
that can delay or prevent progression of BPH. Early
S354
pharmacotherapeutic intervention can improve
patients’ health and quality of life, decrease the risk
of serious sequelae of BPH, and reduce the economic and personal costs of surgery.
FUTURE APPLICATIONS
Understanding of the possible applications of PSA
in the management of BPH continues to evolve. Free
(noncomplexed) PSA exists in several forms in serum.
Serum levels of one of these forms, benign PSA
(BPSA), are closely associated with the transition zone
enlargement that occurs in BPH and may constitute a
specific marker for the biochemical changes associated
with BPH.28-30 BPSA can be accurately measured in
serum and may eventually prove to be a more specific
and sensitive marker for the presence of BPH than
serum PSA.
CONCLUSIONS
The data reviewed herein establish that BPH is a
progressive condition characterized by increases in
prostate volume, decreases in urinary flow rate,
worsening symptoms, and increasing risk of acute
urinary retention and BPH-related surgery. While
BPH is progressive and follows a predictable course,
the rate and extent of BPH progression vary
among patients. Progression-modifying therapy is
therefore not warranted for everyone. For optimum
management of patients with BPH, it is valuable to
predict which patients are likely to progress and
which are not likely to progress so that those at high
risk of progression can be monitored closely and/or
administered preventive therapy. A large body of
research from both clinical trials and communitybased studies demonstrates that serum PSA levels are
a useful predictor of disease progression in BPH.
Men with PSA levels above 1.5 ng/mL are particularly likely to show rapid disease progression and are
at increased risk of acute urinary retention and
BPH-related surgery. These men, more than those
whose disease is unlikely to progress rapidly or to
cause adverse sequelae, are appropriate candidates
for early intervention with pharmacotherapy that
can delay or prevent disease progression. On the
other hand, patients with a small prostate gland, low
serum PSA, and bothersome lower urinary tract
symptoms might benefit most from symptomatic
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PROCEEDINGS
treatment but should be periodically monitored to
assess for changes in clinical status. The strong predictive utility of PSA—combined with the fact that
it, unlike other clinical markers of BPH status, can
be accurately and easily measured—renders it an
important tool for the clinician seeking to optimize
outcomes for patients with BPH.
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April 2003