0013-7227/02/$15.00/0
Printed in U.S.A.
The Journal of Clinical Endocrinology & Metabolism 87(4):1527–1532
Copyright © 2002 by The Endocrine Society
Flaxseed Improves Lipid Profile without Altering
Biomarkers of Bone Metabolism in
Postmenopausal Women
EDRALIN A. LUCAS, ROBERT D. WILD, LISA J. HAMMOND, DANIA A. KHALIL, SHANIL JUMA,
BRUCE P. DAGGY, BARBARA J. STOECKER, AND BAHRAM H. ARJMANDI
Department of Nutritional Sciences (E.A.L., L.J.H., D.A.K., S.J., B.P.D., B.J.S., P.H.A.), Oklahoma State University,
Stillwater, Oklahoma 74078; and Department of Obstetrics and Gynecology (R.D.W.), University of Oklahoma Health
Sciences Center, Oklahoma City, Oklahoma 73190
The risk of cardiovascular disease and osteoporosis drastically increases at the onset of menopause. Phytoestrogens
have been suggested to inhibit bone loss and protect the cardiovascular system, in part by improving lipid profiles. The
purpose of the present study was to examine the effects of
flaxseed, a rich source of the phytoestrogens called lignans, on
lipid metabolism and biomarkers of bone turnover in postmenopausal women. Postmenopausal women who were not on
hormone replacement therapy were assigned to one of two
treatment groups in a double-blind randomized study. Women
were asked to consume 40 g of either ground flaxseed or
wheat-based comparative control regimen daily for 3 months.
In addition, all subjects received 1,000 mg calcium and 400 IU
vitamin D daily. Flaxseed supplementation lowered (P < 0.05)
A
LTHOUGH HORMONE REPLACEMENT therapy is
efficacious in relieving postmenopausal symptoms
such as hot flashes and vaginal dryness and in the prevention
of bone loss, its cardiovascular protective effects are being
questioned (1). High blood cholesterol level is a major risk
factor for cardiovascular disease (2–3). In addition to existing
drug therapies, certain nutritional factors reduce serum cholesterol, including dietary fiber (4 –9), plant sterols (10 –12),
and phytoestrogens (13–18). Among food sources rich in
phytoestrogens, flaxseed has been reported to lower cholesterol in a limited number of human (19 –23) and animal (24)
studies.
Flaxseed is the richest food source of lignans, one of the
major groups of phytoestrogens (25), and is increasingly
being incorporated into human diets because of its reported
health benefits. Lignans have been implicated as having antitumorigenic (26), estrogenic and/or anti-estrogenic (27), and
antioxidant (28 –30) properties. Prasad (24) reported that rabbits receiving secoisolariciresinol diglucoside, the major lignan found in flaxseed, had reduced hypercholesterolemic
atherosclerosis that could be partly attributed to lower totaland low-density lipoprotein (LDL)-cholesterol concentrations. A recent population study also found an inverse association between serum lignan concentrations and the risk
Abbreviations: AP, Alkaline phosphatase; apo A-1, apolipoprotein
A-1; apo B, apolipoprotein B; BMI, body mass index; BSAP, bone-specific
AP; CV, coefficient of variation; Dpd, deoxypyridinoline; E1, estrone;
IGFBP, IGF binding protein; MI, maturation index; TRAP, tartrateresistant acid phosphatase.
both serum total cholesterol and non-high-density lipoprotein
cholesterol by 6%, whereas the comparative control regimen
had no such effect. Flaxseed regimen reduced serum levels of
both low-density- and high-density-lipoprotein cholesterol by
4.7% and triglyceride by 12.8%, albeit not statistically significant. Serum apolipoprotein A-1 and apolipoprotein B concentrations were significantly (P < 0.005) reduced by 6 and
7.5%, respectively, by the flaxseed regimen. Markers of bone
formation and resorption were not affected by either of the
treatments. The findings of this study indicate that flaxseed
supplementation improves lipid profiles but has no effect on
biomarkers of bone metabolism in postmenopausal women.
(J Clin Endocrinol Metab 87: 1527–1532, 2002)
of acute coronary heart disease (31). However, the hypocholesterolemic effects of whole flaxseed can also be attributed
to its ␣-linolenic acid and fiber components (20, 21, 23).
Therefore, the extent to which the individual components of
flaxseed contribute to its cholesterol-lowering properties
needs to be explored. Due to structural similarities between
lignans and estrogen, it can be postulated that lignans
present in flaxseed may also play a role in the maintenance
of skeletal health. Hence, in this 3-month clinical study, in
addition to the assessment of lipid parameters, the effects of
flaxseed supplementation on selected blood and urinary
markers of bone metabolism in postmenopausal women
were investigated.
Subjects and Methods
Subjects
Postmenopausal women younger than 65 yr old who were not on
hormone replacement therapy or any prescription medications
known to influence lipid or bone metabolism were recruited. Women
with cancer, liver disease, hypothyroidism or hyperthyroidism, gastrointestinal disorders, insulin-dependent diabetes mellitus, pelvic
inflammatory disease, and endometrial polyps were excluded from
the study. The study protocol was approved by the Institutional
Review Boards at Oklahoma State University and the University of
Oklahoma Health Sciences Center. Subjects signed a consent form
after being provided with oral and written descriptions of the study.
A complete medical history was obtained from all subjects before
initiating the treatments. Subjects were also given routine physical
and gynecological examinations including a vaginal smear, performed by an obstetrician and evaluated by a pathologist. Subjects
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Lucas et al. • Flaxseed Lowers Serum Cholesterol
lived at home, consumed their habitual diet, and maintained their
usual physical activity.
Study design
Fifty-eight postmenopausal women were randomly assigned to one
of two dietary treatments (n ⫽ 29 per treatment) in a controlled doubleblind parallel study. The dietary treatments consisted of 40 g of either
ground whole flaxseed or wheat-based comparative control regimen to
be consumed daily for a period of 3 months. The macronutrient composition and the calcium and phosphorus contents of both regimens are
shown in Table 1. To provide some protection against rapid bone loss,
all study participants were provided with 1,000 mg elemental calcium
plus 400 IU vitamin D for daily consumption. The dietary regimens and
calcium plus vitamin D supplements were distributed to the subjects on
a monthly basis. Subjects were asked to return any unused supplements
to monitor treatment compliance. The study participants were advised
by a registered dietitian to make appropriate adjustments in their daily
food consumption to account for the additional energy, fat, and protein
intakes.
One-week food frequency questionnaires were obtained via interview at the beginning and the end of the study. Nutrient analysis was
performed using food analysis software (Food Processor version 7.50,
ESHA Research, Salem, OR). Anthropometric data were collected at the
beginning and the end of the study by a single trained staff member, as
described elsewhere (19).
Physical and gynecological examinations were repeated at the end of
the study. Maturation index (MI) was calculated as the percentage of
superficial cells plus half of the percentage of intermediate cells (32).
Overnight fasting blood was obtained at baseline and at the end of
the study. Blood was centrifuged for 15 min at 1,500 ⫻ g, and serum
aliquots were stored at ⫺80 C until analyzed. Study participants were
also instructed to collect 24-h urine before initiation of treatment and at
the end of the study. Urine volume was recorded, and urine aliquots
were stored at ⫺20 C until analyzed.
Analytical methods
Serum total cholesterol and triglyceride concentrations were determined enzymatically using kits from Roche Diagnostics (Sommerville,
NJ). Serum high-density lipoprotein (HDL) cholesterol was determined
by a direct method (Unimate HDL Direct, Roche Diagnostics) that uses
the combined action of polymers, polyanions, and detergent to solubilize
cholesterol from HDL but not from very LDL, LDL, and chylomicrons.
LDL-cholesterol concentration was calculated by the Friedewald equation (33). Non-HDL-cholesterol concentration was calculated by subtracting HDL cholesterol from total cholesterol. Apolipoprotein A-1 (apo
A-1) and apolipoprotein B (apo B) were determined by immunoturbidimetry using kits from Roche Diagnostics. These tests were performed
using a Cobas-Fara II clinical analyzer (Montclair, NJ). The intra- and
interassay coefficients of variation (CVs) were 1.5 and 2.1%, 2.0 and 2.6%,
TABLE 1. Composition of flaxseed and wheat-based
control regimen
Measures
Flaxseed
(per 40 g)
Wheat
(per 40 g)
Energy (kcal)
Fat (g)
Fiber (g)
Protein (g)
Mineral (g)
Calcium (mg)
Phosphorus (mg)
237
12.6
2.1
8.6
1.5
133
0.9
202
8.9
2.0
10.6
1.3
14
1.1
Gross energy, crude protein, and fat were analyzed by bomb calorimetry (Parr Model 1261 Calorimeter, Parr Instrument Co., Moline,
IL), Association of Official Analytical Chemists Kjeldahl method (44),
and ether extraction (44), respectively. Calcium was measured using
atomic absorption spectrophotometry (Model 5100PC, PerkinElmer,
Norwalk, CT) (45). Phosphorus was measured using a kit from Roche
Diagnostics (Branchburg, NJ).
1.2 and 2.9%, 1.4 and 3.4%, and 1.4 and 5.2%, for total cholesterol,
triglycerides, HDL cholesterol, apo A-1, and apo B, respectively.
RIA kits were used to analyze serum IGF-I (Nichols Institute Diagnostics, San Juan Capistrano, CA), IGF-binding protein (IGFBP)-3, 17␤estradiol (E2), estrone (E1), FSH, and SHBG (Diagnostics Systems Laboratories, Inc., Webster, TX). Serum total alkaline phosphatase (AP) and
tartrate-resistant acid phosphatase (TRAP) activities and serum calcium
were determined colorimetrically using kits from Roche Diagnostics.
These tests were performed on a Cobas-Fara II clinical analyzer. Bonespecific AP (BSAP) activity in serum was quantified by immunoassay in
a microtiter format (Metra Biosystems, Mountain View, CA). The intraand interassay CVs were 3.0 and 8.4%, 3.0 and 1.0%, 6.5 and 9.7%,
5.6 and 11.1%, 2.7 and 6.8%, 3.4 and 8.7%, 1.9 and 2.8%, 2.7 and 8.3%,
1.2 and 2.3%, and 3.9 and 7.6% for IGF-I, IGFBP-3, E2, E1, FSH, SHBG,
AP, TRAP, calcium, and BSAP, respectively.
Urinary creatinine was measured colorimetrically with a commercially available kit from Roche Diagnostics using a Cobas Fara II clinical
analyzer. Urinary deoxypyridinoline (Dpd) was measured by competitive enzyme immunoassay in a microassay stripwell format (Metra
Biosystems, Mountain View, CA). Urinary excretion of helical peptide,
a peptide derived from the helical region of ␣1 chain of type I collagen,
was assayed using a competitive enzyme immunoassay in a microassay
stripwell format (Quidel Corporation, Mountain View, CA). The intraand interassay CVs were 1.7 and 6.3%, 4.3 and 4.6%, and 6.5 and 8.6%
for creatinine, Dpd, and helical peptide, respectively.
Statistical analyses
The data were analyzed using SAS (Version 6.11, SAS Institute, Inc.,
Cary, NC). ANOVA and least square means were calculated using
PROC MIXED. Data are reported as least square mean ⫾ se, unless
otherwise indicated; P ⬍ 0.05 was regarded as significant.
Results
Of the 58 postmenopausal women initially included in the
study, only 36 women (20 receiving the flaxseed regimen and
16 receiving the wheat-based regimen) completed the study.
Reasons for attrition included medical conditions that prevented continued inclusion into the study (one subject from the
wheat regimen), time constraints (two subjects from the wheat
regimen), gastrointestinal problems (three subjects from the
flaxseed and six subjects from the wheat regimen), lack of palatability of the dietary regimen (six subjects from the flaxseed
and three subjects from the wheat regimen), and unrelated
personal reasons (one subject from the wheat regimen).
There were no significant differences in the baseline and
final values of body weight and body mass index (BMI)
among the subjects in either treatment group (Table 2). However, body weight (P ⫽ 0.092) and BMI (P ⫽ 0.072) tended
to be higher after a 3-month supplementation with the
wheat-based regimen. This was not observed among women
in the flaxseed group.
Daily nutrient intake, excluding the supplements provided by the study, as assessed by 7-d food frequency questionnaires showed that the women in both groups had similar dietary intakes before and after the study (Table 3).
Consumption of 40 g flaxseed but not wheat-based regimen for 3 months resulted in a significant decrease (6%) in
both serum total and non-HDL cholesterol concentrations
(Table 4). Although flaxseed regimen reduced serum levels
of LDL cholesterol by 4.7% and triglyceride by 12.8%, these
decreases did not reach statistical significance. HDL-cholesterol concentrations were also somewhat (P ⫽ 0.091) lowered
by flaxseed consumption. Apo A-1 and apo B concentrations
were both significantly reduced as a result of flaxseed sup-
Lucas et al. • Flaxseed Lowers Serum Cholesterol
J Clin Endocrinol Metab, April 2002, 87(4):1527–1532 1529
TABLE 2. Subject characteristicsa
Measures
Age (yr)
Weight (kg)
BMI (kg/m2)
a
Flaxseed (n ⫽ 20)
Baseline
Final
54 ⫾ 8
78.2 ⫾ 4.3
29.1 ⫾ 1.6
Values are least square means ⫾
77.9 ⫾ 4.3
29.0 ⫾ 1.6
Wheat (n ⫽ 16)
P value
Baseline
Final
P value
0.650
0.648
55 ⫾ 5
74.2 ⫾ 4.8
28.7 ⫾ 1.8
75.1 ⫾ 4.8
29.1 ⫾ 1.8
0.092
0.072
SE.
TABLE 3. Daily energy, macronutrient, fiber, calcium, magnesium, and phosphorus intakesa,b
Daily intake
Total energy (kcal)
Nutrients (g)
Protein
Carbohydrates
Dietary fiber
Total fat
SFA
PUFA
C18:3(n-3)
C18:2(n-6)
Minerals (mg)
Calcium
Magnesium
Phosphorus
Flaxseed (n ⫽ 20)
Wheat (n ⫽ 16)
Baseline
Final
P value
Baseline
Final
P value
1619 ⫾ 137
1529 ⫾ 140
0.55
1786 ⫾ 140
1531 ⫾ 154
0.13
64 ⫾ 6
223 ⫾ 22
22 ⫾ 2
56 ⫾ 6
20 ⫾ 3
10 ⫾ 1
0.97 ⫾ 0.15
7.78 ⫾ 0.96
65 ⫾ 6
208 ⫾ 22
18 ⫾ 2
59 ⫾ 6
19 ⫾ 3
12 ⫾ 1
1.10 ⫾ 0.15
9.41 ⫾ 0.93
1.00
0.58
0.13
0.69
0.73
0.12
0.54
0.21
74 ⫾ 6
235 ⫾ 22
19 ⫾ 2
64 ⫾ 6
23 ⫾ 3
12 ⫾ 1
1.14 ⫾ 0.16
9.41 ⫾ 0.99
60 ⫾ 7
205 ⫾ 25
17 ⫾ 3
53 ⫾ 6
20 ⫾ 3
9⫾1
0.79 ⫾ 0.16
6.78 ⫾ 1.02
0.06
0.33
0.31
0.17
0.37
0.07
0.13
0.06
718 ⫾ 111
270 ⫾ 26
1038 ⫾ 115
745 ⫾ 112
255 ⫾ 26
1009 ⫾ 116
0.77
0.66
0.77
838 ⫾ 113
294 ⫾ 26
1199 ⫾ 118
740 ⫾ 121
260 ⫾ 29
954 ⫾ 126
0.34
0.34
0.03
SFA, Saturated fatty acids; PUFA, polyunsaturated fatty acids.
a
Values do not include the treatment regimen and calcium plus vitamin D supplement.
b
Values are least square means ⫾ SE.
TABLE 4. Effects of dietary regimens on lipid parametersa
Measures
TC (mmol/liter)
LDL (mmol/liter)
HDL (mmol/liter)
non-HDL (mmol/liter)
TG (mmol/liter)
Apo A-1 (g/liter)
Apo B (g/liter)
Flaxseed (n ⫽ 20)
Wheat (n ⫽ 16)
Baseline
Final
P value
Baseline
Final
P value
5.76 ⫾ 0.25
3.21 ⫾ 0.25
1.89 ⫾ 0.09
3.87 ⫾ 0.29
1.48 ⫾ 0.16
1.98 ⫾ 0.05
1.34 ⫾ 0.07
5.44 ⫾ 0.25
3.06 ⫾ 0.25
1.80 ⫾ 0.09
3.64 ⫾ 0.29
1.29 ⫾ 0.16
1.86 ⫾ 0.05
1.24 ⫾ 0.07
0.01
0.22
0.09
0.02
0.14
0.003
0.002
5.95 ⫾ 0.28
3.52 ⫾ 0.28
1.61 ⫾ 0.10
4.34 ⫾ 0.31
1.56 ⫾ 0.19
1.94 ⫾ 0.06
1.38 ⫾ 0.08
6.13 ⫾ 0.28
3.64 ⫾ 0.28
1.67 ⫾ 0.10
4.46 ⫾ 0.31
1.74 ⫾ 0.19
1.95 ⫾ 0.06
1.44 ⫾ 0.08
0.18
0.37
0.34
0.29
0.20
0.82
0.07
TC, Total cholesterol; non-HDL, TC ⫺ HDL; TG, triglycerides.
a
Values are least square means ⫾ SE.
plementation but were not affected by the wheat-based regimen. The changes from baseline values of the various serum
lipid parameters were compared between flaxseed and the
wheat-based regimens (Fig. 1). The response to treatment
was significantly different between flaxseed and wheat supplementation for total cholesterol (P ⬍ 0.01), non-HDL cholesterol (P ⬍ 0.05), apo A-1 (P ⬍ 0.05), and apo B (P ⬍ 0.001).
No significant changes were observed in the measured
parameters that are reflective of bone metabolism, including
circulating IGF-I, IGFBP-3, AP, BSAP, TRAP, calcium, urinary Dpd, and helical peptide in both treatment regimens
(Table 5). Neither the flaxseed nor the wheat-based regimen
produced estrogenic effects as assessed by serum levels of E1,
E2, FSH, and SHBG (Table 6). Women on the flaxseed regimen had slightly (P ⫽ 0.09) lower MI after 3 months,
whereas wheat-based supplement had no such effect.
Discussion
In this study, we have shown that supplementation of
flaxseed to the diets of postmenopausal women can lower
concentrations of serum total cholesterol and non-HDL cholesterol. These findings are in agreement with the findings of
our earlier study (19) in which flaxseed given in the form of
bread and muffins reduced total cholesterol in postmenopausal women. However, in the present study, LDL-cholesterol concentration was lowered by about 4.7% only vs. 14.7%
in the previous study. Feeding the subjects whole ground
flaxseed instead of its incorporation into baked products may
have contributed to this difference. It has been suggested that
the consumption of up to 50 g flaxseed in its raw form is safe
(22), but it is not clear whether the constituents of flaxseed
that influence lipid metabolism such as secoisolariciresinol
diglucoside and ␣-linolenic acid are as bioavailable when
flaxseed is consumed in its raw form. However, whether
processing or temperature will affect the bioavailability of
flaxseed components requires further investigation.
In a crossover study in which hyperlipidemic men and
postmenopausal women were fed 50 g of partially defatted
flaxseed daily for 3 weeks, Jenkins et al. (23) observed overall
reductions of 5.5 and 9.7% in serum total- and LDL-choles-
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Lucas et al. • Flaxseed Lowers Serum Cholesterol
evidence that consumption of ␣-linolenic acid-rich oils such
as flaxseed oil may offer greater protection against cardiovascular disease than linoleic acid-rich oils through their
effects on platelet functions.
Similar to the findings of Jenkins et al. (23), we observed
that flaxseed reduced serum levels of both apo B and apo A-1.
However, the magnitude of change in serum apo B (10%) was
greater than that of apo A-1 (6%), suggestive of cardioprotective properties of flaxseed. Apo B is a more sensitive
indicator of the risk of heart disease than total cholesterol
because it reflects the number of lipoproteins that are associated with the development of atherosclerosis such as LDL,
very LDL, and chylomicron remnants (36).
Whether the hypolipidemic effects of whole flaxseed are
due to a single component or the interactions among its
components remains unclear. Kuroda et al. (37) evaluated the
hypolipidemic properties of a series of diesters of arylnaphthalene lignans. They reported that these synthetic lignans
effectively lower serum total cholesterol and LDL cholesterol
while increasing HDL cholesterol. Lignans have also been
shown to modulate activities of 7 ␣-hydroxylase and acyl
CoA cholesterol transferase (38), two of the key enzymes
involved in cholesterol metabolism. Prasad et al. (39) concluded that reduction in hypercholesterolemic atherosclerosis by flaxseed is due to a decrease in serum total cholesterol
and LDL cholesterol and that the antiatherogenic activity of
flaxseed is independent of its ␣-linolenic acid content. Soluble fiber mucilage present in flaxseed may also contribute
to the observed hypocholesterolemic properties (4, 5). Hence,
the mode of action of flaxseed is unclear and needs to be
investigated in future studies.
As far as the effect of flaxseed on bone is concerned, there
is a paucity of data. The findings of a study by Babu et al. (40)
indicated that feeding whole or defatted flaxseed to weanling
terol concentrations, respectively. The investigators concluded that flaxseed gum is likely the major active ingredient
responsible for the lipid-lowering action of flaxseed. Moreover, other constituents present in flaxseed may also play an
essential role in lipid metabolism. For instance, the hypocholesterolemic effects of ␣-linolenic acid have been reported
in both animals (34) and humans (35). Garg et al. (34) demonstrated that feeding an ␣-linolenic acid-rich diet to rats
lowered serum cholesterol levels more effectively than a diet
rich in linoleic acid. Clinical trials (35) have provided further
FIG. 1. Mean changes from baseline values in serum lipid parameters after 3 months of flaxseed and wheat supplementation. Compared with wheat regimen, flaxseed supplementation significantly
reduced total cholesterol (TC; P ⬍ 0.01), non-HDL cholesterol (P ⬍
0.05), apo A-1 (P ⬍ 0.05), and apo B (P ⬍ 0.001). aUnit for TC, LDL,
HDL, non-HDL and triglycerides (TG) is mmol/liter, and unit for Apo
A-1 and Apo B is g/liter.
TABLE 5. Effects of dietary regimens on indices of bone metabolisma
Flaxseed (n ⫽ 20)
Measures
Baseline
Serum
IGF-I (nmol/liter)
IGFBP-3 (nmol/liter)
AP (U/liter)
BSAP (U/liter)
TRAP (U/liter)
Calcium (mmol/liter)
Urine
Dpd (nmol/mmol creatinine)
Helical peptide (␮g/mmol
creatinine)
a
Values are least square means ⫾
Wheat (n ⫽ 16)
Final
P value
Baseline
Final
P value
14.7 ⫾ 1.3
96.6 ⫾ 4.1
82.0 ⫾ 4.5
22.2 ⫾ 1.4
3.7 ⫾ 0.1
2.52 ⫾ 0.03
15.9 ⫾ 1.3
96.3 ⫾ 4.1
80.9 ⫾ 4.5
21.7 ⫾ 1.4
3.7 ⫾ 0.1
2.60 ⫾ 0.03
0.21
0.91
0.54
0.35
0.75
0.087
15.3 ⫾ 1.4
93.1 ⫾ 4.7
83.9 ⫾ 4.9
20.4 ⫾ 1.5
3.6 ⫾ 0.1
2.52 ⫾ 0.03
15.2 ⫾ 1.4
97.8 ⫾ 4.7
81.3 ⫾ 4.9
20.3 ⫾ 1.5
3.4 ⫾ 0.1
2.55 ⫾ 0.03
0.95
0.09
0.18
0.87
0.27
0.48
6.63 ⫾ 0.55
48.57 ⫾ 7.44
6.83 ⫾ 0.55
55.52 ⫾ 7.36
0.54
0.19
6.44 ⫾ 0.62
41.50 ⫾ 8.23
5.91 ⫾ 0.62
38.15 ⫾ 8.34
0.14
0.57
SE.
TABLE 6. The effect of dietary regimens on vaginal MI and sex hormone levelsa
Measures
MI (%)
Serum
E2 (pmol/liter)
E1 (pmol/liter)
FSH (mIU/ml)
SHBG (nmol/liter)
a
Flaxseed
Wheat
Baseline
Final
P values
42.8 ⫾ 5.8
34.8 ⫾ 5.8
0.09
37.0 ⫾ 6.6
32.5 ⫾ 6.6
0.39
34.1 ⫾ 7.4
84.7 ⫾ 6.7
44.2 ⫾ 9.1
55.8 ⫾ 9.8
33.0 ⫾ 7.4
85.8 ⫾ 6.7
47.6 ⫾ 9.0
69.8 ⫾ 9.8
0.90
0.84
0.25
0.32
28.8 ⫾ 8.4
78.9 ⫾ 7.4
63.6 ⫾ 10.1
62.6 ⫾ 11.0
20.0 ⫾ 8.4
82.1 ⫾ 7.4
60.6 ⫾ 10.1
67.6 ⫾ 11.0
0.36
0.60
0.36
0.75
Values are least square means ⫾
SE.
Baseline
Final
P values
Lucas et al. • Flaxseed Lowers Serum Cholesterol
female rats for 56 d suppressed serum total AP activity, a
nonspecific marker of bone formation. In that study (40), the
indices of bone resorption were not assessed, leading us to
speculate whether flaxseed or its lignans behave similarly to
estrogen by suppressing both bone formation and bone resorption. It is conceivable that lignanic compounds, analogous to estrogen, also directly exert effects on estrogenresponsive tissues, including bone, through ERs. This notion
is supported by more recent findings that human osteoclasts
(41) and osteoblasts (42) express ERs, including ER␤, the
receptor to which phytoestrogens preferentially bind (15, 43).
However, contrary to expectations, in the present study we
have not seen any effects of flaxseed supplementation on
indices of bone turnover.
In summary, the findings of the present study suggest that
flaxseed consumption by postmenopausal women is effective in reducing total cholesterol, non-HDL cholesterol, and
apo B, known risk factors of coronary heart disease. Additionally, flaxseed did not exert any estrogenic properties as
assessed by unaltered circulating levels of sex hormones,
SHBG, and MI. With respect to bone, the findings of this
3-month study indicate that flaxseed has no effect on bone
metabolism, as evident by its lack of effects on biomarkers of
bone turnover.
J Clin Endocrinol Metab, April 2002, 87(4):1527–1532 1531
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Acknowledgments
We thank Mr. Paul Stitt at the Natural Ovens of Manitowoc, Wisconsin, for providing the treatment regimens for this study.
Received September 25, 2001. Accepted December 21, 2001.
Address all correspondence and requests for reprints to: Bahram H.
Arjmandi, Department of Nutritional Sciences, 416 Human Environmental Sciences, Oklahoma State University, Stillwater, Oklahoma
74078-6141. E-mail: arjmand@okstate.edu.
This work was supported, in part, by NIH Grant R03-AG16487-01.
References
1. Meihan E, Thorneycroft IH 2001 Prevention of heart disease in women: is
postmenopausal therapy warranted? Menopause Management 10:16 –28
2. Kannel WB, Castelli W, Gordon T 1971 Serum cholesterol, lipoprotein, and
risk of coronary heart disease: the Framingham study. Ann Intern Med 74:1–12
3. 1978 Relationship of blood pressure, serum cholesterol, smoking habit, relative
weight and ECG abnormalities to incidence of major coronary events. Final
report of the Pooling Project Research Group. J Chronic Dis 31:201–306
4. Brown L, Rosner B, Willett WW, Sacks FM 1999 Cholesterol-lowering effects
of dietary fiber: a meta-analysis. Am J Clin Nutr 69:30 – 42
5. Chen WJL, Anderson JW 1986 Hypocholesterolemic effects of soluble fibers.
In: Kritchevsky D, Yahouny GV, eds. Dietary fiber: basic and clinical aspects.
New York: Plenum Press; 275–289
6. Saltzman E, Das SK, Lichtenstein A, Dallal GE, Corrales A, Schaefer EJ,
Greenberg AS, Roberts SB 2001 An oat-containing hypocaloric diet reduces
systolic blood pressure and improves lipid profile beyond effects of weight loss
in men and women. J Nutr 131:1465–1470
7. Frias AC, Sgarbieri VC 1998 Guar gum effects on food intake, blood serum
lipids and glucose levels of Wistar rats. Plant Foods Hum Nutr 53:15–28
8. Anderson JW, Davidson MH, Blonde L, Brown WV, Howard WJ, Ginsberg
H, Allgood LD, Weingand KW 2000 Long-term cholesterol-lowering effects
of psyllium as an adjunct to diet therapy in the treatment of hyper-cholesterolemia. Am J Clin Nutr 71:1433–1438
9. Arjmandi BH, Sohn E, Juma S, Murthy SR, Daggy BP 1997 Native and
partially hydrolyzed psyllium have comparable effects on cholesterol metabolism in rats. J Nutr 127:463– 469
10. Meguro S, Higashi K, Hase T, Honda Y, Otsuka A, Tokimitsu I, Itakura H
2001 Solubilization of phytosterols in diacylglycerol vs. triacylglycerol improves the serum cholesterol-lowering effect. Eur J Clin Nutr 55:513–517
11. Maki KC, Davidson MH, Umporowicz DM, Schaefer EJ, Dicklin MR, Ingram KA, Chen S, McNamara JR, Gebhart BW, Ribaya-Mercado JD, Perrone
G, Robins SJ, Franke WC 2001 Lipid responses to plant-sterol-enriched re-
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
duced-fat spreads incorporated into a National Cholesterol Education Program Step I diet. Am J Clin Nutr 74:33– 43
Jones PJ 1999 Cholesterol-lowering action of plant sterols. Curr Atheroscler
Rep 1:230 –235
Clifton-Bligh PB, Baber RJ, Fulcher GR, Nery ML, Moreton T 2001 The effect
of isoflavones extracted from red clover (Rimostil) on lipid and bone metabolism. Menopause 8:259 –265
Clarkson TB, Anthony MS, Morgan TM 2001 Inhibition of postmenopausal
atherosclerosis progression: a comparison of the effects of conjugated equine
estrogens and soy phytoestrogens. J Clin Endocrinol Metab 86:41– 47
van der Schouw YT, de Kleijn MJ, Peeters PH, Grobbee DE 2000 Phytooestrogens and cardiovascular disease risk. Nutr Metab Cardiovasc Dis 10:
154 –167
Potter SM, Baum JA, Teng H, Stillman RJ, Shay NF, Erdman Jr JW 1998 Soy
protein and isoflavones: their effects on blood lipids and bone density in
postmenopausal women. Am J Clin Nutr 68:1375S–1379S
2000 The role of isoflavones in menopausal health: consensus opinion of the
North American Menopause Society. Menopause 7:215–229
Baum JA, Teng H, Erdman Jr JW, Weigel RM, Klein BP, Persky VW, Freels
S, Surya P, Bakhit RM, Ramos E, Shay NF, Potter SM 1998 Long-term intake
of soy protein improves blood lipid profiles and increases mononuclear cell
low density lipoprotein receptor messenger RNA in hypercholesterolemic,
postmenopausal women. Am J Clin Nutr 68:545–551
Arjmandi BH, Khan DA, Juma S, Drum ML, Venkatesh S, Sohn E, Wei L,
Derman R 1998 Whole flaxseed consumption lowers serum LDL-cholesterol
and lipoprotein(a) concentrations in postmenopausal women. Nutr Res 18:
1203–1214
Bierenbaum ML, Reichstein R, Watkins TR 1993 Reducing atherogenic risk
in hyperlipemic humans with FS supplementation: a preliminary report. J Am
Coll Nutr 25:501–504
Cunnane SC, Hamadeh MJ, Leide AC, Thompson LU, Wolever TMS, Jenkins
DJA 1995 Nutritional attributes of traditional FS in healthy young adults. Am J
Clin Nutr 61:62– 68
Cunnane SC, Ganguli S, Menard C, Liede AC, Hamadeh MJ, Chen ZY,
Wolever TM, Jenkins DJ 1993 High ␣ linolenic acid flaxseed (Linum usitatissimum): some nutritional properties in humans. Br J Nutr 69:443– 453
Jenkins DJ, Kendall CW, Vidgen E, Agarwal S, Rao AV, Rosenberg RS,
Diamandis EP, Novokmet R, Mehling CC, Perera T, Griffin LC, Cunnane SC
1999 Health aspects of partially defatted flaxseed, including effects on serum
lipids, oxidative measures, and ex vivo androgen and progestin activity: a
controlled crossover trial. Am J Clin Nutr 69:395– 402
Prasad K 1999 Reduction of serum cholesterol and hypercholesterolemic atherosclerosis in rabbits by secoisolariciresinol diglucoside isolated from flaxseed. Circulation 99:1355–1362
Thompson LU, Robb P, Serraino M, Cheung F 1991 Mammalian lignan
production from various foods. Nutr Cancer 16:43–52
Thompson LU, Seidl M, Rickard SE, Orcheson LJ, Fong HHS 1996 Antitumorigenic effect of mammalian lignan precursor from flaxseed. Nutr Cancer
26:159 –165
Collins BM, Mclachlan JA, Arnold S 1997 The estrogenic and antiestrogenic
activities of phytochemicals with the human receptor expressed in yeast.
Steroids 62:365–372
Prasad K 1997 Hydroxyl radical-scavenging property of secoisolariciresinol
diglucoside (SDG) isolated from flax-seed. Mol Cell Biochem 168:117–123
Prasad K 2000 Antioxidant activity of secoisolariciresinol diglucoside-derived
metabolites, secoisolariciresinol, enterodiol, and enterolactone. Int J Angiol
9:220 –225
Kitts DD, Yuan YV, Wijewickreme AN, Thompson LU 1999 Antioxidant
activity of the flaxseed lignan secoisolariciresinol diglycoside and its mammalian lignan metabolites enterodiol and enterolactone. Mol Cell Biochem
202:91–100
Vanharanta M, Voutilainen S, Lakka TA, van der Lee M, Adlercreutz H,
Salonen JT 1999 Risk of acute coronary events according to serum concentrations of eneterolactone: a prospective population-based case-control study.
Lancet 354:2112–2115
Duncan AM, Underhill KEW, Xu X, Lavalleur J, Phipps WR, Kurzer MS 1999
Modest hormonal effects of soy isoflavones in postmenopausal women. J Clin
Endocrinol Metab 84:3479 –3484
Friedewald WT, Levy RI, Fredrickson DS 1972 Estimation of the concentration of low-density lipoprotein cholesterol without the use of the preparative
ultracentrifuge. Clin Chem 18:499 –502
Garg ML, Wierzbicki AA, Thomson ABR, Clandinin MT 1989 Dietary saturated fat level alters the competition between ␣-linolenic and linoleic acid.
Lipids 24:334 –339
Chan JK, Bruce VM, McDonald BE 1991 Dietary ␣-linolenic acid is as effective
as oleic acid and linoleic acid in lowering blood cholesterol in normolipidemic
men. Am J Clin Nutr 53:1230 –1240
Singer P, Berger I, Wirth M 1986 Slow desaturation and elongation of linoleic
acid and ␣-linolenic acid as a rationale of eicosapentaenoic acid-rich diet to
lower blood pressure and serum lipids in normal, hypertensive and hyperlipidemic subjects. Prostaglandins Leukot Med 24:173–193
Kuroda T, Kondo K, Iwasaki T, Ohtani A, Takashima K 1997 Synthesis and
1532
38.
39.
40.
41.
J Clin Endocrinol Metab, April 2002, 87(4):1527–1532
hypolipidemic activity of diesters of arylnaphthalene lignan and their heteroaromatic analogs. Chem Pharm Bull (Tokyo) 45:678 – 684
Sanghvi A, Divven WF, Seltman H, Warty V, Rizk M, Kritchevsky D, Setchell KDR 1984 Inhibition of rat liver cholesterol 7-␣ hydroxylase acyl CoA:
cholesterol acyltransferase activities by enterodiol and enterolactone. In: Krietchevsky D, ed. Proceedings of the Symposium on Drugs Affecting Lipid
Metabolism. New York: Plenum Press; 450 (Abstract)
Prasad K, Mantha SV, Muir AD, Westcott ND 1998 Reduction of hypercholesterolemic atherosclerosis by CDC-flaxseed with very low ␣-linolenic acid.
Atherosclerosis 136:367–375
Babu US, Mitchell GV, Wiesenfeld P, Jenkins MY, Gowda H 2000 Nutritional
and hematological impact of dietary flaxseed and defatted flaxseed meal in
rats. Int J Food Sci Nutr 51:109 –117
Mano H, Yuasa T, Kameda T, Miyazawa K, Nakamaru Y, Shiokawa M, Mori
Lucas et al. • Flaxseed Lowers Serum Cholesterol
42.
43.
44.
45.
Y, Yamada T, Miyata K, Shindo H, Azuma H, Hakeda Y, Kumegawa M 1996
Mammalian mature osteoclasts as estrogen target cells. Biochem Biophys Res
Commun 223:637– 642
Arts J, Kuiper GG, Janssen JM, Gustafsson JA, Lowik CW, Pols HA, van
Leeuwen JP 1997 Differential expression of estrogen receptors ␣ and ␤ mRNA
during differentiation of human osteoblast SV-HFO cells. Endocrinology 138:
5067–5070
Setchell KDR, Cassidy A 1999 Dietary isoflavones: biological effects and
relevance to human health. J Nutr 129:758S–767S
Williams S 1984 Official methods of analysis, 14th Ed. Arlington, VA: Association of Official Analytical Chemists
Hill AD, Patterson KY, Veillon C, Morris ER 1986 Digestion of biological
materials for mineral analysis using a combination of wet and dry ashing. Anal
Chem 58:2340 –2342