Full text of DOI:10.1592/phco.22.16.1426.33695

_
R EVIEW S F T H ERA PEUTIC S
The Effect of Phytosterols on Quality of Life
in the Treatment of Benign Prostatic Hyperplasia
Craig I. Coleman, Pharm.D., John H. Hebert, Pharm.D., and Prabashni Reddy, Pharm.D.
In the United States, phytosterols are available as over-the-counter dietary
supplements and are promoted as a safe and natural way to maintain a healthy
prostate. In men with benign prostatic hyperplasia (BPH), evidence suggests
that the agents improve urologic symptoms and flow measures to a greater
extent than placebo and to a similar extent as finasteride. The primary goal
for treating men with BPH is to reduce lower urinary tract symptoms and
increase quality of life (QOL). Therefore, QOL has become an increasingly
important end point in clinical trials. We reviewed all seven studies that
determined the effect of phytosterols on QOL in patients with BPH. All trials
assessed QOL with international prostate symptom score questions. Six
studies found phytosterols to have beneficial effects on QOL; however, poor
study design limits what can be learned from these evaluations. Most studies
included a limited number of patients, and many were not placebo controlled.
Since few of them evaluated the effect of phytosterols beyond 6 months, little
evidence exists of the agents’ long-term efficacy in reducing symptomatology
or increasing QOL. Finally, phytosterols have not been adequately compared
with ␣-blocking agents, one of the most widely administered and effective
pharmacologic treatments of BPH. Larger studies comparing phytosterols
with other treatments of BPH such as ␣-blockers should be conducted. In
addition, a consensus should be reached as to which questionnaires are best to
evaluate potential changes in QOL after treatment of BPH.
(
Pharmacotherapy 2002;22(11):1426–1432)
OUTLINE
States, and are promoted as a safe and natural
way for men to maintain a healthy prostate. In
1
Methods
1
999 consumers in this country spent over $1402
Instruments That Assess the Effects of Phytosterols on
Quality of Life in Benign Prostatic Hyperplasia
Clinical Trials
million on saw palmetto (Serenoa repens) alone.
Serenoa repens is a dwarf palm tree that grows in
the southwest United States. Extracts of the
plant contain a mixture of phytosterols such as
Serenoa repens
␤-Sitosterols
␤
-sitosterol, campesterol, and stigmasterol, as
Discussion
Summary
3
well as flavonoids and other compounds.
Phytosterols used to treat benign prostatic
hyperplasia (BPH) are also extracted from
Hypoxis rooperi (South African star grass). This
extract contains ␤-sitosterol, with lesser amounts
of other sterols, and is marketed in Europe under
brand names Harzol and Azuprostat. Although
both plant-derived extracts contain many
phytosterols, ␤-sitosterol often is considered the
major active component. The mechanism of
Phytosterols are readily available over the
counter as dietary supplements in the United
From Hartford Hospital, Hartford, Connecticut (Dr.
Coleman), and the School of Pharmacy, University of
Connecticut, Storrs, Connecticut (all authors).
Address reprint requests to Prabashni Reddy, Pharm.D.,
Abt Associates Clinical Trials, 55 Wheeler Street,
Cambridge, MA 02138; e-mail: prabashni_reddy@abtassoc.
com.
3
3

PHYTOSTEROLS IN TREATMENT OF BENIGN PROSTATIC HYPERPLASIA Coleman et al
1427
action of phytosterols in BPH, although not well
described, reportedly includes alterations in
cholesterol metabolism; antiestrogenic, anti-
androgenic, and antiinflammatory effects; and
with BPH is to improve QOL, the effects different
treatments have on QOL should be considered.
5, 10, 13
Randomized clinical trials were identified
through a MEDLINE search (January 1966–May
1
14
decreases in sex hormone–binding globulin.
2002). An optimally sensitive search strategy
Phytosterols improved lower urinary tract
symptoms (LUTS) and urinary flow measures in
1
, 4
numerous clinical trials.
According to a
systematic review of 18 randomized, controlled
studies of S. repens (alone or in combination with
other phytotherapeutic agents) of 4–48 weeks’
duration, compared with placebo, men treated
with S. repens had decreases in LUTS scores and
nocturia and greater improvement in peak urine
1
flow. Compared with finasteride, men treated
with S. repens had similar improvements in LUTS
1
scores and peak urine flow rates.
␤
-Sitosterols also are efficacious in the
treatment of BPH, improving urinary symptoms
and flow measures in four placebo-controlled
4
clinical trials. To date, the efficacy of phytosterols
has not been compared with that of ␣-blocking
1
, 4
agents in the treatment of BPH.
The primary goals of treating BPH are to5
reduce LUTS and improve quality of life (QOL).
Quality of life includes physical, psychologic, and
social domains and is a subjective perception of
6
how a disease or treatment affects health status.
Despite frequent reports of use of herbal products
to promote general health and well-being and to
increase QOL, studies mainly focused on clinical
outcomes, with QOL evaluated only occasionally
In 1993 the International Consensus Committee
on BPH recommended that the International
Prostate Symptom Score (IPSS) questionnaire
become the gold standard in assessing treatment
7
15
as a secondary end point. The American College
effect on LUTS. The IPSS contains the well-
of Clinical Pharmacy published a white paper
that called for additional research on herbal
products, listing QOL evaluations as an area in
validated, highly reliable (r = 0.92, Cronbach ’s ␣
= 0.86), and responsive American Urological
Association symptom index (AUASI) for BPH,
which includes seven questions covering
frequency, nocturia, weak urinary stream,
hesitancy, intermittence, incomplete emptying,
8
which further investigation is necessary.
Quality of life was evaluated as a secondary
end point in a number of clinical trials of ␣-
blockers and finasteride, the most efficacious
1
6
and urgency, scored on a 6-point scale.
9
, 10
medical treatments for BPH.
Since they
Although there are no standard recommendations
for grading patients with mild, moderate, or
severe symptoms, patients can be tentatively
classified as follows: 0–7 mildly symptomatic,
applied several QOL instruments, comparisons
9
among drugs are difficult. Evidence shows,
however, that ␣-blockers excel over finasteride,
with earlier onset of response, greater improve-
8
–19 moderately symptomatic, and 20–35
9
ments in QOL, and fewer sexual side effects.
severely symptomatic.
Whereas symptom evaluation of BPH are
standard with the IPSS, no consensus has been
The combination of finasteride with an ␣-blocker
(
terazosin, doxazosin) appears to improve QOL
to a similar extent as the ␣-blocker alone, but to
reached as to which QOL instrument is
a greater extent than finasteride alone or
10, 13, 15
preferred.
Numerous instruments are
1
1, 12
placebo.
Finasteride ’s effect on QOL was
available and can be divided into two categories,
9
most promising in patients with large prostate.
17
generic and disease specific. Generic measures
allow for broad comparisons of interventions
across a variety of health states. The best known
are the Sickness Impact Profile, the Short Form
Methods
Since one of the primary goals of treating men

1
428
PHARMACOTHERAPY Volume 22, Number 11, 2002
1
8–20
(
SF)-36, and the EuroQoL.
It is unlikely,
domains, although for general health perceptions
it was 0.32. The Mayo HRQoL has had only limited
use in clinical trials.
however, that these instruments will be sensitive
to changes after BPH treatment.
1
7
24
Disease-
specific measures are often more sensitive, but
they do not allow for cross-condition comparisons
and are limited as to interventions or populations
in which they can be used. Disease-specific
instruments for BPH are the IPSS QOL question,
International Continence Society QOL (ICS-
QoL), BPH Health-related QOL Short Form 9
Problems with internal consistency, limited
clinical use, high respondent burden, and narrow
response options hinder the use of many of these
1
7
21–24
BPH-specific measures of QOL
Inconsistent
use of any one or group of QOL measures in the
past makes comparison with today’s data
1
3
difficult.
(
BPH HRQoL-9), BPH Impact Index (BPHii), and
Mayo Clinic Health-related QOL (Mayo HRQoL)
questionnaire.
Clinical Trials
1
6, 21–24
The effects of phytosterols on QOL in patients
In addition to the AUASI, the IPSS contains the
following question: “If you were to spend the
rest of your life with your urinary condition just
the way it is now, how would you feel about
that?” Answers range from “delighted” to
2
5–31
with BPH were studied in seven clinical trials,
2
5–28
four with S. repens
sitosterols (Table 1).
and three with ␤-
2
9–31
Dosages of S. repens were 160–320 mg/day for
up to 6 months. Two trials were dose-ranging
“
terrible” (0–6). This question correlates well
1
8–19
studies,
one study compared S. repens with
with overall symptom score and summarizes the
impact of urologic symptoms.
20
21
finasteride, and only one was placebo controlled.
Trials of ␤-sitosterols used two standard
preparations, Harzol and Azuprostat, containing
0 and 130 mg/day of ␤-sitosterols, respectively.
Two studies were placebo controlled,
1
5
The ICS-QoL contains six questions, two
addressing general issues (interference of LUTS
with life, feelings about having LUTS for rest of
life), three addressing symptom-related issues
2
5–27
2
2
5–27
and the
third was an open-labeled extension of one of the
(
need to change clothes because of incontinence,
2
6
earlier studies.
need to reduce drink intake, length of time with
LUTS), and one addressing worries associated
with LUTS. Each item has anywhere from four to
seven possible responses. The results are
reported as the proportion of patients selecting
each response. The ICS-QoL has good content
and construct validity, but poor internal
Serenoa repens
In one study 305 men with untreated BPH took
2
5
S. repens 160 mg twice/day for 3 months. The
IPSS QOL score was evaluated at baseline and at
days 45 and 90. Although actual scores were not
provided, improvements were seen at both days
(p<0.0001). The QOL score after 45 days
remained unchanged in 33% of patients,
improved in 65%, and worsened in 2%. At 90
days, scores were unchanged in 19%, improved
in 78%, and worse in 3% of patients.
2
1
consistency (Cronbach ’s ␣ = 0.59).
The BPH HRQoL-9 investigates BPH-specific
social (including sexual function) and general
realms. Originally constructed as a 20-item
questionnaire, a 9-item tool was developed
consisting of 1-cm visual analog scales. The
internal consistency was 0.70 and retest
The article is limited in the amount and quality
of data reported. Whereas 65% and 78% of
patients showed improvement at 45 and 90 days,
respectively, what constituted improvement was
not defined. Lack of a placebo-control group
limits what can be learned from any clinical trial,
but it is especially difficult to draw conclusions
from a BPH clinical trial, since up to 45% of
patients will respond to placebo. As with
previous studies, this one had a limited number
of patients.
2
2
reliability was 0.7.
The BPHii was developed in conjunction with
the AUASI for men with LUTS. It contains four
items related to physical discomfort, worry,
bothersomeness, and interference with daily
activities scored on a scale from 0–4. The BPHii
has good internal consistency (Cronbach ’s ␣ =
2
3
0
.87) and retest reliability (r = 0.83).
The Mayo Clinic questionnaire contains 44
items in 6 domains: symptoms, bother, general
health perception, BPH-specific interference with
activities, worries, and concerns and sexual
satisfaction. Items are scored on a scale from
A 3-month, double-blind, randomized,
parallel-group study compared the efficacy and
tolerability of two regimens of the lipidosterolic
2
6
0
0
–6. Test-retest reliability was only moderate (r =
.41–0.43). Cronbach ’s ␣ was 0.81–0.96 for most
extract of S. repens (Permixon)
Ninety-two
men aged 50 years or older with symptomatic

PHYTOSTEROLS IN TREATMENT OF BENIGN PROSTATIC HYPERPLASIA Coleman et al
1429
Table 1. Clinical Trials Assessing Phytosterols’ Effects on Quality of Life in the Treatment of Benign Prostatic Hyperplasia
a
No. of Pts
Regimen
Serenoa repens 160 mg b.i.d.
Condition Duration
Results
2
5
3
05
BPH
90 days Improvements in QOL score (p<0.0001); after 45 days
unchanged in 33% of patients, improved in 65%,
worse in 2%; at 90 days, QOL unchanged in 19%,
improved in 78%, worse in 3%.
2
6
4
4
5
7
Serenoa repens 160 mg b.i.d.
Serenoa repens 320 mg q.d.
BPH
3 mo
QOL improved from baseline in both regimens at
3 mo, 4.0 to 2.9 (p<0.0001) and 4.0 to 2.9 (p<0.001),
respectively. Patients with at least 1 point ↓ in IPSS
QOL score: 67% b.i.d. regimen, 72.4% q.d. regimen
at 3 mo (p value not given). Regimens did not differ
significantly on any other measure at 3 mo.
2
7
5
5
53
45
Serenoa repens 320 mg/day
Finasteride 5 mg
BPH
26 wks QOL improved from baseline in patients receiving
Serenoa repens for 26 wks (3.63 to 2.25, p<0.001).
QOL improved to similar extents in Serenoa repens
and finasteride groups (p=0.14). Over 50% of
patients felt QOL was improved regardless of
whether they received Serenoa repens or finasteride.
2
2
3
8
4
4
1
4
Serenoa repens 160 mg/day
Placebo
LUTS
BPH
6 mo
6 mo
No significant improvement in QOL between
Serenoa repens and placebo (-0.7 and -0.3, p=0.20)
at 6 mo.
9
9
9
6
1
␤-Sitosterol 20 mg/day
Placebo
QOL improved at 6 mo with mean change from
baseline of -1.4 and -0.2 (p<0.01) for ␤-sitosterol
and placebo, respectively.
0
3
1
1
8
4
2
G1: ␤-sitosterol 20 mg/day x 18 mo
G2: ␤-sitosterol 20 mg/day x 6 mo
G3: ␤-sitosterol 20 mg/day x 6 mo,
then other phytotherapy
BPH
18 mo
G1 continued to have favorable outcomes achieved in
previous 6-mo trial but did not provide additional
benefit with longer treatment. G4 improved to same
extent as G1 for all end points examined. G1 and
G4 improved all end points at 18 mo compared with
those who did not receive ␤-sitosterol in open
extension trial (p<0.01).
2
7
8
G4: Placebo x 6 mo, then
␤-sitosterol 20 mg/day up to 18 mo
1
8
G5: Placebo x 6 mo
G6: Placebo x 6 mo, then other
phytotherapy
3
1
8
8
8
9
␤-Sitosterol 130 mg/day
Placebo
BPH
6 mo
QOL score improved compared with placebo at 6 mo
(-1.8 vs -0.9, p<0.01).
a
All trials used the International Prostate Symptom Score (IPSS) quality of life (QOL) questionnaire.
BPH = benign prostatic hyperplasia; LUTS= lower urinary tract symptoms.
BPH for at least 6 months were randomly
allocated to S. repens 160 mg twice/day or 320
mg once/day. Changes from baseline in IPSS
QOL score were measured after 3 months. Scores
improved from baseline in men receiving both
dosages at 3 months (4.0 ± 0.7 to 2.9 ± 1.2,
p<0.0001, 4.0 ± 1.0 to 2.9 ± 1.3, p<0.001,
respectively). The percentage of patients with at
least a one-point decrease in the score was 66.7%
with the twice-daily regimen and 72.4% with the
daily regimen at 3 months (probability not
reported).
patients receiving S. repens for 26 weeks (3.63 ±
1.28 to 2.25 ± 1.29, p< 0.001), with similar
changes in the finasteride group (3.66 ± 1.17 to
2.15 ± 1.26, p< 0.001). This improvement was
similar in both groups (p=0.14). Over 50% of
patients felt their QOL was improved (> 1-point
decrease in the 7-point scale) regardless of which
treatment they received.
After a 1-month run-in period, 85 men aged 45
years or older with LUTS and IPSS of 8 or greater,
were randomized to receive S. repens 160 mg
8
twice/day or placebo for 6 months. The IPSS
In the largest study (> 1000 patients), S. repens
20 mg (Permixon) and finasteride 5 mg were
QOL was measured at baseline and 6 months
after randomization. No improvement in scores
was noted between groups (S. repens -0.7,
placebo -0.3, p = 0.20) at 6 months.
Potential study limitations included small
sample and imperfectly matched treatment and
3
compared in a 6-month, randomized equivalence
2
7
trial in men with moderate BPH. The primary
QOL end point was the IPSS question at 26
weeks. The QOL improved from baseline in

1
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PHARMACOTHERAPY Volume 22, Number 11, 2002
placebo groups. Men receiving S. repens had a
higher (although not statistically significant)
IPSS at baseline compared with placebo
recipients, which may have resulted in the former
being more likely to show variability regarding
improvement (regression to the mean).
sitosterol group than in the placebo group (-1.8 ±
1.02 vs -0.9 ± 0.91, p<0.01).
Discussion
Based on the studies reviewed, phytosterols are
generally well tolerated and potentially effective
in treating symptoms of BPH and in improving
␤-Sitosterols
2
5–31
25–27, 29–31
QOL. Of the seven studies,
showed beneficial effects.
six
Two randomized, placebo-controlled, double-
2
9
blind trials evaluated ␤-sitosterols (Harzol).
Use of herbal supplements is clearly on the rise
3
2
The first one randomized 187 patients with
symptomatic BPH to ␤-sitosterol 20 mg 3
times/day or placebo for 6 months. The IPSS
QOL was administered at baseline and 6 months.
At 6 months, IPSS QOL scores showed improve-
ment, with a mean change from baseline of 1.4 ±
in the United States. Millions of Americans
frequently include the products as part of their
routine health regimens to prevent or treat
3
3
disease and improve QOL. Herbal supplements
have been studied in both Europe and the United
States to determine whether claims to improve
health are justified. In many cases, such as with
phytosterols for BPH, data support their
0
.8 and 0.2 ± 1.0 (p<0.01) for ␤-sitosterol and
placebo, respectively.
1
,4, 25–31
An 18-month follow-up study was an open
extension of the 6-month trial and is the only
one to examine the long-term effects of
efficacy.
However, other herbals lack the
8
support of well-conducted clinical trials.
Because most herbal supplements aim to improve
QOL, we initially planned to review the literature
that investigated the effects of the 12 most
3
0
phytosterols on QOL in patients with BPH.
Men in this phase were free to choose their
treatment, with 117 of the initial 305 patients
opting to participate. They were reevaluated
with the IPSS QOL 18 months after random-
ization for the first study. Those previously
treated with ␤-sitosterol who continued the drug
continued to have favorable QOL outcomes but
did not receive any additional benefit from longer
treatment. Men who previously received placebo
and who began therapy with ␤-sitosterol had
improvement to the same extent as the original
double-blind trial treatment group. Patients who
chose ␤-sitosterol for further therapy had
significant improvements in QOL at 18 months
compared with those who did not receive ␤-
sitosterol in the open extension trial (p<0.01).
Patients who received ␤-sitosterols in the double-
blind trial but decided not to take any
phytotherapy in the follow-up arm still had
improvement over those who had never received
phytotherapy (p<0.01). The authors concluded
that the effects on QOL of ␤-sitosterol are
maintained over at least 18 months in men with
symptomatic BPH.
3
4
commonly used herbals in the United States.
This search revealed 23 studies investigating
QOL as either a primary or secondary end point.
Phytosterols have evidence supporting their
clinical efficacy, but many herbals lacked a
suitable number of studies to draw a solid
conclusion. For this reason, we limited our
review to the effects of phytosterols on QOL in
patients with BPH.
A number of issues must be considered before
drawing conclusions. First, poor design limits
what can be learned from these studies. Most
studies had a limited number of patients and
2
5,
were not powered to detect differences in QOL.
2
6, 29, 30
Small studies often are not able to show
statistical significance even when it exists.
Lack of a control group is also a confounding
factor due to the large placebo effect (~45%
1
0
improvement) realized in BPH clinical trials.
There is little evidence of phytosterol ’s long-term
efficacy (> 6 mo) in reducing symptomatology
1
,4, 25–29, 31
and increasing QOL.
In addition, the
agents have not been adequately compared with
finasteride and lack comparison with ␣-blocking
agents, the most widely used and effective drugs
Another double-blind, placebo-controlled trial
examined a ␤-sitosterol (Azuprostat) in patients
3
1
10
with symptomatic BPH. A total of 177 patients
received ␤-sitosterol 130 mg/day or placebo
once/day. After a 4-week washout period,
patients were evaluated at baseline and 6 months
for changes in QOL using the IPSS question. The
IPSS scores improved to a greater extent in the ␤-
to treat BPH.
Next, it is difficult in the case of the IPSS QOL
question to determine what constitutes a
clinically significant change compared with a
statistically significant one. A number of studies
considered an increase in QOL score of more

PHYTOSTEROLS IN TREATMENT OF BENIGN PROSTATIC HYPERPLASIA Coleman et al
than 1 point (on a scale of 0–6) to be clinically other treatments of BPH must be
1431
2
6,27
significant.
When applied to the reviewed
conducted. In addition, consensus as to which
questionnaires should be used to evaluate
potential changes in QOL after treatment of BPH
symptoms remains to be reached.
studies, all those with statistically significant
improvements would have clinically significant
improvements in QOL.
2
5–27, 29–31
Potential
downfalls were proposed with the use of the
minimal clinically important difference (MCID)
for QOL measures due to inherent problems
related to their calculation that may result in
oversimplification of results. Several issues
should be considered when interpreting MCIDs,
including cost of therapy and baseline QOL. A
therapy that results in a statistically significant
change always should be assessed in context of
what it costs in terms of dollars and adverse
effects. In addition, the clinical significance of a
QOL change will depend on the patient ’s baseline
assessment. When applying MCIDs to study
results, these issues must be kept in mind.
References
1
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used the IPSS QOL question. It may be that
alternative questionnaires may be more accurate.
Finally, our ability to identify studies was
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1
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4
recommendations. Additional searches of other
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1
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(
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Summary
1
It appears that phytosterols improve QOL in
2
5–27, 29–31
men with BPH.
However, confirmatory
studies that are more methodologically sound
and have larger study populations are required to
support these findings. Since few studies
evaluated the effect of phytosterols beyond 6
months, there is little evidence of the compounds’
long-term efficacy in reducing symptomatology
1
2
1
, 4, 25–29, 31
or improving QOL.
not been adequately compared with ␣-blocking
Phytosterols have
1
0
agents. Larger studies comparing them with

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