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JOURNAL OF MEDICINAL FOOD
J Med Food 11 (2) 2008, 000–000
© Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition
DOI: 10.1089/jmf.2007.602
Effects of Dietary Flaxseed Lignan Extract on Symptoms of
Benign Prostatic Hyperplasia
Wei Zhang,
1
Xiaobing Wang,
1
Yi Liu,
1
Haimei Tian,
1
Brent Flickinger,
2
Mark W. Empie,
2
and Sam Z. Sun
2
ABSTRACT A flaxseed lignan extract containing 33% secoisolariciresinol diglucoside (SDG) was evaluated for its ability
to alleviate lower urinary tract symptoms (LUTS) in 87 subjects with benign prostatic hyperplasia (BPH). A randomized, dou-
ble-blind, placebo-controlled clinical trial with repeated measurements was conducted over a 4-month period using treatment
dosages of 0 (placebo), 300, or 600 mg/day SDG. After 4 months of treatment, 78 of the 87 subjects completed the study.
For the 0, 300, and 600 mg/day SDG groups, respectively, the International Prostate Symptom Score (IPSS) decreased 3.67
1.56, 7.33 1.18, and 6.88 1.43 (mean SE, P .100, .001, and .001 compared to baseline), the Quality of Life
score (QOL score) improved by 0.71 0.23, 1.48 0.24, and 1.75 0.25 (mean SE, P .163 and .012 compared
to placebo and P .103, .001, and .001 compared to baseline), and the number of subjects whose LUTS grade changed
from “moderate/severe” to “mild” increased by three, six, and 10 (P .188, .032, and .012 compared to baseline). Maximum
urinary flows insignificantly increased 0.43 1.57, 1.86 1.08, and 2.7 1.93 mL/second (mean SE, no statistical sig-
nificance reached), and postvoiding urine volume decreased insignificantly by 29.4 20.46, 19.2 16.91, and 55.62
36.45 mL (mean SE, no statistical significance reached). Plasma concentrations of secoisolariciresinol (SECO), enterodiol
(ED), and enterolactone (EL) were significantly raised after the supplementation. The observed decreases in IPSS and QOL
score were correlated with the concentrations of plasma total lignans, SECO, ED, and EL. In conclusion, dietary flaxseed lig-
nan extract appreciably improves LUTS in BPH subjects, and the therapeutic efficacy appeared comparable to that of com-
monly used intervention agents of 1A-adrenoceptor blockers and 5-reductase inhibitors.
KEY WORDS:
•
benign prostatic hyperplasia
•
enterodiol
•
enterolactone
•
flaxseed
•
lignan
•
lower urinary tract
symptoms
•
secoisolariciresinol diglucoside
1
INTRODUCTION
B
ENIGN PROSTATIC HYPERPLASIA
(BPH) is a physiological/
pathological phenomenon widely occurring in the older
male population. BPH is the most common cause of lower
urinary tract symptoms (LUTS) mainly clinically manifested
as urinary blockage and storage. BPH subjects are often
physically bothered by and psychologically burdened from
the symptoms. One commonly accepted mechanism caus-
ing BPH is an imbalance of testosterone and dihydrotestos-
terone in the circulation and/or prostate tissue. Usually, in
patients of pre-BPH or BHP, the enzyme 5-reductase (5R)
excessively catalyzes dihydrotestosterone production from
testosterone, and dihydrotestosterone stimulates prostate tis-
sue proliferation via binding with -adrenergic receptors.
This mechanism has been previously reviewed by Andriole
et al.,
1
Tahmatzopoulos et al.,
2
and Anglin et al.
3
Natural plant compounds containing estrogenic activity
have been investigated for their influence on various hor-
monally sensitive end points. The class of phytoestrogens,
consisting of hydroxylated bicyclobenzylbutane diol deriv-
atives, also known as lignans, has been observed epidemi-
ologically to be correlated with reductions in prostate can-
cer incidence.
4,5
Flaxseed and flaxseed derivatives are one
of the richest dietary sources of plant lignans, with the prin-
cipal one being secoisolariciresinol (SECO), found naturally
as the diglycoside (secoisolariciresinol diglucoside [SDG]).
Recently, flaxseed is increasingly used in the human diet be-
cause of its potential benefits, including cardiovascular pro-
tection
6–8
and prostate health enhancement.
9,10
The concen-
trations of SDG in flaxseed vary with its different cultivars.
Eliasson et al.
11
reported that SDG concentrations in 27
flaxseed species ranged from 1.19% to 2.59% for ()-SDG
and 0.22% to 0.5% (wt/wt) for its diastereoisomer, (-)-SDG.
Westcott et al.
12
presented a range of SDG concentrations
from 0.97% to 3.09% (wt/wt) in eight varieties of defatted
flaxseed meals. The SDG metabolites, enterodiol (ED) and
enterolactone (EL), can weakly bind to estrogen receptors,
1
Tumor Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing, People’s Republic of China; and
2
James R. Randall Research
Center of Archer Daniels Midland Company, Decatur, Illinois
Manuscript received 26 September 2007. Revision accepted 26 December 2007.
Address reprint requests to: Sam Z. Sun, Ph.D., James R. Randall Research Center, Archer
Daniels Midland Company, 1001 Brush College Road, Decatur, Illinois 62521,USA,
E-mail: sun@admworld.com
and isoflavones together with SDG represent commonly
consumed phytoestrogens in the human diet.
It has been documented that the SDG metabolites, ED
and EL, can inhibit 5R.
13
Thus, supplementation with a lig-
nan-rich flaxseed extract may help to relieve LUTS in BPH
subjects. Currently, there have been no peer-reviewed re-
ports describing the use of flaxseed lignan extract to treat
BPH subjects. We conducted this clinical trial using a lig-
nan-rich extract (consisting of one-third SDG) to investigate
its effects on the clinical symptoms in BPH subjects. Plasma
lignan concentrations of SECO, ED, and EL were measured
and correlated with the treatment effects on LUTS.
MATERIALS AND METHODS
Study design
Eighty-seven Chinese men diagnosed with BPH, 55–80
years old, were included in this randomized, placebo-con-
trolled, double-blind clinical study. Eligible subjects had
prostate volume of 30 cm
3
, an International Prostate
Symptom Score (IPSS) of 7 points, and a maximal uri-
nary flow rate (Q
max
) between 5 and 15 mL/second and were
not sensitive or allergic to flax. Subjects also had normal
serum -glutamyl transferase and alanine aminotransferase
values, serum creatinine 110 mol/L, and blood urea ni-
trogen 7.1 mg/dL. Subjects were not to have used any
drugs, herbs, flax-containing products, or other nonpre-
scription preparations for treating BPH-related symptoms
within 4 weeks of screening. Each subject, who met the cri-
teria and agreed to participate in the study, carefully read
and signed the consent form.
Eighty-seven subjects were randomly assigned into the 0
mg (placebo), 300 mg, or 600 mg/day SDG groups (n 29
in each). Daily dosage was delivered by administering two
tablets at breakfast and two at dinner (two tablets 2 times).
Subjects were counseled not to change their regular dietary
patterns and physical activities. All subjects were requested
to revisit the clinic monthly. At the time of each return, any
concerns and any adverse reactions were recorded, and treat-
ment tablets were refilled. At baseline and the end of months
2 and 4, a 20-mL blood sample was drawn following an
overnight fast. Compliance was evaluated by subject in-
quiry, tablet counts, and plasma lignan concentrations. The
study protocol was approved by the Clinical Trial Evalua-
tion Board of the Tumor Hospital and Institute in Beijing,
People’s Republic of China.
Study material
The flaxseed lignan extract, containing approximately
33.0% SDG, 15.1% coumaric acid glucoside, 8.1% ferulic
acid glucoside, 15.6% hydroxymethylglutaric acid, and the
rest water and other components (Beneflax™, Archer
Daniels Midland Co., Decatur, IL), was formulated to de-
liver the targeted daily SDG doses in four tablets (each tablet
contains 0, 75, or 150 mg of SDG). Placebo tablets con-
taining food-grade maltodextrin (combined with food grade
colors to approximate the color of the flaxseed extract) were
prepared to match the size, shape, and color of SDG-con-
taining tablets. In addition to flaxseed lignan extract or
placebo material, tablets were formulated with commonly
used excipient ingredients. Prepared tablets were analyzed
for SDG content and then released to the study upon con-
firmation of appropriate SDG levels.
Clinical examination and measurements
Demographic information of age, medical history, mar-
riage status, occupation, education level, and current med-
ications were noted. Biochemical measurements, including
plasma total cholesterol, triglyceride, glucose, blood urea ni-
trogen, creatinine, alanine aminotransferase, and -glutamyl
transferase, were determined using standard laboratory
methods and relevant experimental kits (Roche Diagnostics,
Indianapolis, IN). Clinical evaluations included genitouri-
nary tract physical examination, prostate digital rectal ex-
amination, urine bacterial count, urination data (such as
maximal and mean urinary flow rate using Dynamic
Uroflowometry [model ZNC-961A, Weixin Electronics,
Chengdo, People’s Republic of China]), and prostate and
bladder volume (using a Philips HDI 5000 Ultrasonic Di-
agnostic System, Bothell, WA). The residual volume of
urine was calculated by differences between initial bladder
urine volume and voided volume. Data on IPSS and Qual-
ity of Life score (QOL score) were collected using standard
questionnaire forms (2003 American Urology Association
Guideline on the Management of BPH: Diagnosis and Treat-
ment Recommendations). For the IPSS, seven questions re-
lated to urinary symptoms were asked, and scores from 0 to
5 were given for each question (the higher score, the worse
symptoms). For QOL scores, only one question was asked.
The question and its scoring are: 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? Score 0 is for “De-
lighted,” 1 for “Pleased,” 2 for “Mostly satisfied,” 3 for
“Mixed,” 4 for “Mostly dissatisfied,” 5 for “Unhappy,” and
6 for “Terrible.” Like the IPSS, the higher the score for QOL,
the worse the quality of life, and vice versa. Based on the
grading criteria of the American Urological Association for
BPH symptom, subjects with IPSS of 7 were considered
as having a mild grade of LUTS, 8–19 were considered as
having moderate grade, and 20 as having a severe grade
of LUTS. Safety evaluation for the treatment was based on
a questionnaire aimed to monitor adverse events, including
vertigo, headache, fatigue, constipation, nausea, vomiting,
abdominal pain, rashes, digestive abnormality, and sexual
dysfunction. LUTS, blood biochemistry, SECO, ED, and EL
were determined at baseline and the end of months 2 and 4.
Plasma SECO, ED, and EL measurements were deter-
mined using a liquid chromatography/tandem mass spec-
trometry method (model 1100 liquid chromatograph [Agi-
lent, Palo Alto, CA] and model 14000 mass spectrometer
[Applied Biosystems, Foster City, CA]).
14
Briefly, a 100-
2 ZHANG ET AL.
L plasma sample was mixed with 100 L of
-glu-
curonidase (containing 1,200 units of the enzyme activity),
the sample was incubated for 24 hours at 37°C, and after
400 L of ethyl acetate was added, the test tube was vor-
tex-mixed for 3 minutes. The sample mixture was further
centrifuged for 2 minutes at 170 g, and the upper ethyl ac-
etate layer was collected and dried under N
2
. One hundred
microliters of high-performance liquid chromatography sol-
vent (methanol/ammonium acetate [5 mmol/L], 70:30) was
added to dissolve the dried material. A 5-L sample was in-
jected into the liquid chromatography/tandem mass spec-
trometry system. The recovery rates of the method ranged
from 79% to 105.6% with coefficients of variations
19.4%. The lower detection limits for plasma SECO, ED,
and EL were 5, 1, and 1 ng/mL, respectively.
Statistical analysis
Some variables measured in this study were scored, or-
dinal, or non-normally distributed. Consequently, where ap-
propriate, changes from baseline values were used in statis-
tical analysis. After descriptive statistics, Mixed Model pro-
cedures were used to test the proposed treatment effects on
changes of LUTS-related measurements (including IPSS,
QOL, Q
max
, residual volume of urine, and prostate volumes)
using the data of the placebo group as reference (Dunnett
adjustment). The response variation of individual subjects
to the treatment was considered as a random factor, and the
time point by month of the measurements was regarded as
a repeated factor. General Linear Model procedures were
used to test the treatment effects within subjects, and base-
line data were used as a comparative reference. The changes
in number of subjects having mild symptom between and
within groups after treatment were compared using
2
or
Fisher’s exact statistics. Concentration changes of plasma
SECO, ED, EL, and total lignans were also compared be-
tween and within subjects. The data of plasma lignan con-
centrations were non-normally distributed (right-skewed).
The data were therefore logarithm-transformed into ap-
proximately normal distribution before analysis. Moreover,
DIETARY FLAXSEED LIGNAN EXTRACT AND BPH 3
T
ABLE
1. B
ASELINE
C
HARACTERISTICS OF
S
UBJECTS
Treatment
SDG 0 mg (n 24) SDG 300 mg (n 29) SDG 600 mg (n 25)
Age (years) 69.67 0.94 70.73 1.08 67.52 1.01
BMI (kg/m
2
) 24.05 0.43 24.12 0.44 25.37 0.63
TC (mmol/L) 4.70 0.17 4.66 0.12 4.61 0.17
TG (mmol/L) 1.65 0.18 1.54 0.12 1.64 0.26
Glucose (mmol/L) 5.11 0.23 5.13 0.25 5.86 0.63
IPSS 18.25 1.28 19.24 1.14 19.21 1.16
QOL score 3.79 0.12 4.07 0.13 4.00 0.14
Q
max
(mL/second) 11.26 1.47 11.54 1.14 10.82 1.10
Residual volume of urine (mL) 153.71 22.65 140.79 23.16 203.30 40.19
Prostate volume (mL) 41.01 2.35 42.67 2.32 46.66 3.73
ALT (U/L) 20.04 1.91 24.13 3.31 23.60 2.26
GGT (U/L) 29.83 1.82 28.30 4.71 26.60 2.31
BUN (mmol/L) 6.14 0.37 5.90 0.23 5.93 0.29
Creatinine (mol/L) 77.29 3.07 82.70 2.66 79.72 3.59
Data are mean SE values. No statistical differences were observed between groups for the parameters measured. ALT, ala-
nine aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; GGT, -glutamyl transferase; TC, total cholesterol; TG,
triacylglycerol.
T
ABLE
2. S
UMMARY OF
T
REATMENT
E
FFECTS OF
F
LAXSEED
L
IGNAN ON
LUTS
IN
BPH S
UBJECTS
0 mg SDG (n 24) 300 mg SDG (n 29) 600 mg SDG (n 25)
Variable 2 months 4 months 2 months 4 months 2 months 4 months
IPSS 6.0 1.55* 3.67 1.56 4.97 1.32** 7.33 1.18** 7.0 1.41** 6.88 1.43**
QOL score 0.91 0.23* 0.71 0.23 1.34 0.18** 1.48 0.24*** 1.79 0.23
a,
*** 1.75 0.25
b,
***
Q
max
(mL/second) 1.0 1.53 0.43 1.57 0.29 1.13 1.86 1.08** 2.0 1.17 2.7 1.93
Residual volume (mL) 48 31.39 29.4 20.46 7.1 21.07 19.2 16.91 76.1 23.68* 55.62 36.45
Prostate volume (mL) 5.65 1.05** 5.39 0.92** 3.59 1.25* 6.46 1.2** 6.26 1.54** 6.6 1.22**
Subjects with IPSS 7 4 4 4 7* 7* 10**
Data are mean SE values for the differences of data at month 2 or 4 minus baseline data. A patient with IPSS 7 is considered to have mild LUTS.
At baseline, the numbers of subjects with mild symptoms in each group were 1.
Compared to placebo,
a
P .05,
b
P .01; compared to baseline, *P .05, **P .01, ***P .001.
correlations between the changes of IPSS, QOL, and Q
max
and plasma lignan concentrations were determined. A sta-
tistical value of P .05 was considered as a statistical
threshold of significant difference. SAS software version 9.1
(SAS Institute, Cary, NC) was employed for data process
and analysis.
RESULTS
Seventy-eight of 87 subjects completed the study. Nine
subjects dropped out (four needed other treatment, two had
a heavy travel schedule, one relocated, and two did not give
a reason). The baseline demographic and clinical character-
istics of subjects are shown in Table 1. No statistical dif-
ference was noted between groups for the baseline data.
Table 2 shows the changes in IPSS, QOL, Q
max
, residual
volume, prostate volume, and the number of subjects hav-
ing mild LUTS. Plasma lignan concentrations and correla-
tions between the changes of LUTS and lignan concentra-
tions are reported in Tables 3 and 4.
As specified in Table 2, all three treatment groups had
significant IPSS decreases compared to baseline after 2
months (all P .001). However, after 4 months, only the
SDG treatment groups remained significantly different from
baseline. No statistically significant difference between
groups was obtained for IPSS decrease. For QOL score, an
overall significant treatment effect of SDG was observed
(P .007 for the model) between groups (Table 2). The ob-
served significance on QOL score mprovement was obtained
from the 600 mg SDG group (P .035 at month 2 and P
.012 at month 4 compared to the placebo, respectively). No
significant treatment effect was reached in the 300 mg SDG
group (P .175 compared to the placebo). Within both
SDG treatment groups, significant QOL score improvement
was observed at month 2 and 4 (compared to baseline, P
.01 or 0.001 either at month 2 or 4). Within the placebo
group, although QOL scores were also improved, the im-
proved values were smaller, and the statistical significance
only appeared at month 2 (P .05).
After 4 months, increases in Q
max
from baseline were
0.43 1.57, 1.86 1.08, and 2.7 1.93 mL/second
(mean SE, Table 2) in the placebo and 300 and 600 mg
SDG treatment groups, respectively. Although the Q
max
in-
creases (of 1.86 or 2.7 mL/second) would be clinically
meaningful, the large response variance and relatively small
sample size may have caused a lack of statistical signifi-
cance either between or within groups. Changes of residual
urine volume in bladder also showed no significant differ-
ence between or within groups. The variations of the data
are also large. Unexpectedly, prostate volumes were signif-
icantly reduced from baseline after 2 months of treatment
in all groups, and no statistical difference was observed be-
4 ZHANG ET AL.
T
ABLE
3. P
LASMA
L
IGNAN
C
ONCENTRATIONS
Concentration (ng/mL)
SDG Month Total lignan SECO ED EL
0 mg (n 24) 0 55.05 9.92 25.10 7.91 1.37 0.39 28.58 5.95
2 42.65 8.54 25.90 7.95 0.56 0.06 16.18 3.35
4 46.55 10.50 27.74 9.44 0.65 0.09 18.17 5.78
300 mg (n 29) 0 42.75 9.13 21.69 8.78 0.52 0.02 20.54 4.69
2 251.89 51.43 62.22 16.39 98.38 21.74 91.29 20.41
4 272.88 45.61 58.41 13.41 88.08 18.17 126.39 29.74
600 mg (n 25) 0 24.50 4.93 8.58 1.92 0.75 0.10 15.17 4.60
2 526.88 80.67 150.24 29.40 246.44 42.23 130.19 29.10
4 560.57 72.72 162.19 37.77 266.94 31.84 131.43 19.99
Data are mean SE values. Total lignan SECO ED EL. In the SDG treatment groups, all lignan concentrations significantly increased
either compared to placebo or baseline.
T
ABLE
4. S
PEARMAN
C
ORRELATIONS
B
ETWEEN
L
IGNAN
C
ONCENTRATIONS AND
LUTS R
ELIEF
Lignans SECO ED EL
IPSS
Correlation r 0.2878 0.2825 0.3266 0.1395
P value .0001 .0001 .0001 .0366
QOL score
Correlation r 0.4876 0.4187 0.5287 0.373
P value .0001 .0001 .0001 .0001
Q
max
Correlation r 0.1408 0.0639 0.1196 0.1653
P value .0424 .3592 .0854 .0171
changes from baseline values.
tween the treatment groups. And, it was noted that the SDG
treatment groups had more subjects whose LUTS grades
were reduced from moderate or severe to mild compared to
placebo at the end of 4 months (four in the placebo group,
seven in the 300 mg group, and 10 in the 600 mg group),
and only within-group statistical significances were reached
(P .05 and .01 compared to baseline, respectively) in
the SDG treatment groups (Table 2).
Table 3 gives the concentrations of plasma SECO, ED,
EL, and total lignan ( SECO ED EL) at baseline and
after 2 and 4 months of treatment. At baseline, the means
of total lignan concentrations among the three treatment
groups were relatively similar, from 24.5 to 55.05 ng/mL.
With flaxseed extract supplementation, concentrations of
SECO, ED, and EL all substantially increased compared to
placebo and baseline, and the profile of lignan distribution
changed from baseline. Among them, the increase of ED
concentration was proportionally greater than the others,
particularly with the higher dosing. The data indicate that
all three lignans can be absorbed into the circulation, and
lignan intake dose could influence the proportions of each
compound in plasma. Table 4 shows the correlations be-
DIETARY FLAXSEED LIGNAN EXTRACT AND BPH 5
FIG. 2. Comparison of treatment effect of drugs
and botanicals on maximum flow (Q
max
). Data are
from 1977 to 2007. Three classes of treatment agents
(AR blockers, 5R inhibitors, and botanicals) and two
kinds of clinical trials (placebo-controlled or non-
placebo) are included here. The Q
max
data are in-
creases from baseline. The green dots represent
non–placebo-controlled trials,
15,17–25,28–38
and the
red dots and circles represent placebo-controlled tri-
als.
42–49,51–60
The lines linking the red dots and cir-
cles indicate the treatment effects and correspond-
ing placebo effects. The data in blue are from the
current trial.
FIG. 1. Comparison of treatment effect of drugs and
botanicals on IPSS decrease. Data are from 1997 to
2007. Three classes of treatment agents (AR block-
ers, 5R inhibitors, and botanicals) and two kinds of
clinical trials (placebo-controlled or non-placebo) are
included here. The IPSS data are decreases from base-
line. The green dots represent non–placebo-controlled
trials,
15–41
and the red dots and circles represent
placebo-controlled trials.
42–60
The lines linking the
red dots and circles indicate the treatment effects and
corresponding placebo effects. The data in blue are
from the current trial.
tween plasma lignan concentrations and changes in IPSS,
QOL, and Q
max
expressed by Spearman correlation coeffi-
cients with corresponding P values. Total lignan, SECO, ED,
and EL were all significantly correlated with decreases of
IPSS and QOL score. And, only total lignan and EL were
significantly correlated with the increase of Q
max
.
No adverse effects were reported and no abnormal val-
ues of blood urea nitrogen, creatinine, alanine aminotrans-
ferase, and -glutamyl transferase were observed during the
entire study period.
DISCUSSION
LUTS is a common health problem resulting from BPH,
manifesting with daily physical and psychological burdens,
and yielding a lower QOL score. To date, considerable ef-
fort has been made on the development of effective inter-
vention agents for BPH using pharmaceutical approaches.
Currently, most commonly used noninvasive treatment
agents for BPH include 1A-adrenoceptor (AR) blockers,
5R inhibitors, and botanicals (such as saw palmetto extract).
Many clinical studies have investigated treatment effects of
these agents on BPH-linked LUTS; however, observed ef-
ficacies vary considerably. We surveyed treatment effects
on IPSS and Q
max
reported during the last 10 years and com-
pared them with the treatment result observed in this study
(Figs. 1 and 2). In general, the majority of trials were not
placebo-controlled. For those trials with placebo control, ob-
vious placebo effects exist, and in some trials, the effects of
active agent were similar to that of placebo.
Figure 1 shows the treatment effects of AR blockers, 5R
inhibitors, and botanicals on IPSS. Treatment efficacies are
expressed as IPSS decreases from baseline. For each treat-
ment agent, the IPSS decreases between placebo-controlled
and non-placebo trials are comparable. It seems that the
treatment of AR blockers could lower IPSS more efficiently
than did the other two types of agents, but it may not be true
because greater placebo effects also appeared in those AR-
blocker trials. The observed effect of the flaxseed lignan ex-
tract on improving IPSS in this study is similar to that of
AR blockers and other botanicals and appears to be more
effective than 5R inhibitors (Fig. 1). Treatment effects on
Q
max
from the surveyed clinical trials conducted during the
last 10 years are summarized in Figure 2 (also expressed as
changes from baseline). The treatment efficacies among the
three classes of agents are also comparable, although the
data from botanical trials have a much larger range. The
mean Q
max
increase from flaxseed lignan treatment in our
study is located around the median of Q
max
increases ob-
served in the surveyed drug trials (Fig. 2).
Ordinary dietary intake of SDG lignan is typically low.
Ingested SDG is broken down into SECO and ED and fur-
ther to EL in the intestine and colon. Although some publi-
cations provide EL or ED concentrations in human plasma,
few studies have reported plasma SECO concentrations and
how these three compounds are distributed in the circula-
tion. It is not clear whether the distribution of plasma lig-
nans solely depends upon absorption, further metabolism,
or a combination of both. The large SEs of mean plasma
lignan concentrations in this study may indicate that gut con-
version of dietary lignan can be considerably dissimilar be-
tween individuals. Several other studies by Nesbitt et al.,
61
Morton et al.,
62
and Kuijsten et al.
63
examined plasma ED
and EL concentrations using flaxseed or SDG supplemen-
tation. In these studies, wide ranges and large SDs for mean
ED and EL concentrations were also reported. The large
variance for plasma lignan concentrations appears to be a
common attribute in all these studies, including ours, and
likely depends on the profiles of particular gut microflora.
The mechanism by which flaxseed lignan extract could
relieve IPSS and improve QOL score remains unclear, ex-
cept for a possibility that EL and ED inhibit the activity of
5R as previously reported.
13
To our knowledge, the current
study is the first clinical trial using flaxseed lignan extract
to address LUTS in BPH subjects. Considering that SDG is
a phytoestrogen,
64
the observed treatment effects may be
linked to its potential antagonistic action on male hormone
conversion or receptor binding, such as testosterone or di-
hydrotestosterone. The significant correlation between IPSS
or QOL score improvement and plasma lignan concentra-
tions suggests that lignans may be the functional agents in
the preparation tested. However, we cannot rule out that
some other compounds in the flaxseed lignan extract may
also play a role, such as coumaric acid glucoside or ferulic
acid glucoside. The latter compounds provided approxi-
mately 15% and 8% of the composition of the extract, re-
spectively. These compounds have some antioxidant fea-
tures due to their phenolic chemical structures. Also, it
remains unclear if synergistic effects exist among the lig-
nans, coumaric acid, and ferulic acid.
There are limitations in the current study. First, the sam-
ple size is relatively small, which could create larger data
variances and weaken statistical power. This may account
for certain variables not reaching statistical significance,
even if there were substantial changes between or within
groups. Second, the study period was short, and this aspect
may impede finding the maximum treatment efficacy and
diminish time needed for placebo effect to normalize. Third,
similar to other BPH studies, an obvious placebo effect oc-
curred in our study.
In conclusion, this study indicates that dietary lignan-rich
flaxseed extract can appreciably relieve LUTS and improve
quality of life in BPH subjects. The observed plasma lignan
concentrations provide a primary determination of absorp-
tion and plasma distribution of dietary flaxseed lignans. The
correlations between the plasma lignan concentrations and
the improvements in IPSS and QOL score suggest they may
be the key functional components. The efficacy of flaxseed
lignan appeared to be comparable to that of commonly used
drugs (AR blockers or 5R inhibitors) and botanicals. Con-
sidered together with safety data and nonadverse effects, the
flaxseed lignan extract should be further evaluated as a nat-
ural alternative for LUTS management or intervention in
BPH populations.
6 ZHANG ET AL.
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8 ZHANG ET AL.
