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Nutrition and Cancer, 60(5), 612–618
Copyright © 2008, Taylor & Francis Group, LLC
ISSN: 0163-5581 print / 1532-7914 online
DOI: 10.1080/01635580801971864
Effect of Dietary Flaxseed on Serum Levels of Estrogens and
Androgens in Postmenopausal Women
Susan R. Sturgeon and Joanna L. Heersink
Division of Biostatistics and Epidemiology, School of Public Health and Health Sciences,
University of Massachusetts Amherst, Amherst, Massachusetts, USA
Stella L. Volpe
Division of Biobehavioral and Health Sciences, School of Nursing, University of Pennsylvania,
Philadelphia, Pennsylvania, USA
Elizabeth R. Bertone-Johnson and Elaine Puleo
Division of Biostatistics and Epidemiology, School of Public Health and Health Sciences,
University of Massachusetts Amherst, Amherst, Massachusetts, USA
Frank Z. Stanczyk
Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California,
Los Angeles, California, USA
Sara Sabelawski
Department of Nutrition, School of Public Health and Health Sciences,
University of Massachusetts Amherst, Amherst, Massachusetts, USA
Kristina W¨
ah¨
al¨
a
Laboratory of Organic Chemistry, Department of Chemistry, University of Helsinki, Helsinki, Finland
Mindy S. Kurzer
Department of Food Science and Nutrition, University of Minnesota, Saint Paul, Minnesota, USA
Carol Bigelow
Division of Biostatistics and Epidemiology, School of Public Health and Health Sciences,
University of Massachusetts Amherst, Amherst, Massachusetts, USA
Flaxseed is a rich source of dietary lignans. Experimental stud-
ies suggest lignans may exert breast cancer preventive effects
through hormonal mechanisms. Our aim was to study the effects of
flaxseed on serum sex hormones implicated in the development of
breast cancer. Forty-eight postmenopausal women participated in
a 12-wk preintervention–postintervention study. Participants con-
sumed 7.5 g/day of ground flaxseed for the first 6 wk and 15.0
grams/day for an additional 6 wk. Nonsignificant declines were
noted over the 12 wk (95% confidence intervals) for estradiol
(pg/ml), estrone (pg/ml), and testosterone (pg/ml): –4.4 (–12.6 to
Submitted 9 July 2007; accepted in final form 13 September 2007.
Address correspondence to Susan R. Sturgeon, Dr PH, Division of
Biostatistics and Epidemiology, School of Public Health and Health
Sciences, University of Massachusetts, 715 North Pleasant Street,
Amherst, MA 01003-9304. E-mail: ssturgeon@schoolph.umass.edu
3.9), –3.3 (–7.7 to 1.2), –4.7 (–17.8 to 8.5), respectively. Changes
tended to be more pronounced in overweight/obese women, par-
ticularly for estrone (–6.5, –11.9 to –1.2; P=.02). Our results
suggest that dietary flaxseed may modestly lower serum levels of
sex steroid hormones, especially in overweight/obese women.
INTRODUCTION
Endogenous levels of estrogens and androgens are believed
to play a central role in the etiology of breast cancer (1). After
menopause, most estrogen is derived by the aromatase con-
version of plasma androstenedione to estrone in adipose tissue
(2). Some estrone is metabolized to estradiol. Free estradiol, un-
bound to sex hormone-binding globulin (SHBG) is hypothesized
to be the most biologically active fraction in the breast. Es-
trone sulfate is an abundantly circulating estrogen that serves
612
FLAXSEED AND SERUM HORMONE LEVELS 613
as a reservoir for the more biologically active estrogens. Epi-
demiologic studies have indicated that elevated serum levels of
total and free estradiol, estrone, estrone sulfate, and lower lev-
els of SHBG after menopause each substantially increase the
risk of breast cancer (1). Recent cohort studies (3,4), although
not all (5,6), also have suggested that elevated serum levels of
testosterone, free testosterone, and androstenedione may inde-
pendently increase breast cancer risk.
Lignans, naturally occurring compounds structurally simi-
lar to sex steroid hormones, are found in low levels in a wide
variety of grains, fruits, and vegetables (7). In humans, plant
lignans are converted by colonic microflora to the mammalian
lignans, enterolactone and enterodiol (8). Because breast can-
cer incidence rates are lower in Asian countries where women
typically consume diets rich in fruits and vegetables, it has
been hypothesized that lignans may have cancer preventative
properties.
Lignans have been shown to inhibit cell proliferation and
reduce mammary tumor incidence in rats (9,10). Experimen-
tal studies imply lignans exert breast cancer preventive effects
through hormonal mechanisms. Specifically, lignans may con-
tribute to decreased bioavailable estrogen in circulation through
inhibition of aromatase activity in adipose tissue (11,12) and in-
creased SHBG synthesis in the liver (9,13). Lignins, precursors
to plant lignans, may be effective in binding to testosterone (14).
Through this binding process, testosterone may be more read-
ily excreted in the bile, thereby potentially lowering circulating
levels.
There is limited information on the effect of plant lignan in-
take on serum sex hormone levels in humans. Urinary levels of
enterolactone were associated positively with serum levels of
SHBG and inversely associated with serum levels of estradiol
in one cross-sectional study (15). Another cross-sectional study
reported an inverse association between serum testosterone lev-
els and number of servings of foods rich in dietary lignans (i.e.,
dark brown bread) (16).
Dietary flaxseed is, by far, the richest dietary source of
lignans (17). To date, three intervention studies have evalu-
ated the impact of dietary flaxseed consumption on serum lev-
els of sex hormones in postmenopausal women (18–20). One
randomized cross-over study of 28 postmenopausal nuns re-
ported serum levels of estradiol and estrone sulfate decreased
significantly with flaxseed supplementation, although SHBG
and testosterone concentrations were unchanged (18). Two
other small intervention studies, each involving 20 or fewer
women in the flaxseed treatment group, reported no changes
in serum concentrations of estradiol, estrone, estrone sulfate,
or SHBG associated with a flaxseed diet (19–20). By admin-
istering a well-tolerated flaxseed dose and employing a high-
quality assay to measure hormone levels, this dietary flaxseed
preintervention–postintervention study was designed to ad-
dress potentially important methodologic limitations of prior
studies, specifically noncompliance and hormone measurement
error.
MATERIALS AND METHODS
Study Population and Experimental Design
The 48 study participants were recruited from the Amherst,
Massachusetts area using newspaper advertisements and posted
advertisements from December 2003 to June 2004. Eligible
participants were defined as women who had undergone natural
menopause (defined by cessation of menses for one or more
years); were English speaking; did not have any bowel disease,
cancer, or diabetes; had not taken antibiotics in the past 6 mo
(because antibiotics may interfere with the microbial conversion
of plant lignans to mammalian lignans); had not taken certain
medications within the past 6 mo (i.e., hormone therapy, oral
corticosteroids, anticoagulants); and were nonsmokers.
The study was explained at an in-person introductory visit,
and written informed consent was obtained. Subjects were asked
to follow certain dietary restrictions for at least 3 wk prior to
a baseline visit and throughout the follow-up period. Specifi-
cally, participants were requested to avoid flaxseed and flaxseed-
containing foods, all soy and soy products; dietary supplements,
herbs, or teas known to have phytoestrogen activity (specifically
isoflavones, natural estrogens, plant estrogens, genistein, dong
quai, ginseng, black cohosh, Vitex, chastree, wild yam, moth-
erwort, lemon balm, licorice, and red clover); and cruciferous
vegetables (specifically broccoli, broccoli sprouts, brocoflower,
brocolini, Brussels sprouts, cauliflower, cabbage, bok choy, Chi-
nese cabbage, kale, Swiss chard, kohlrabi, rutabaga, turnips,
collard greens, mustard greens, turnip greens, and watercress)
because of their potential effects on endogenous hormone lev-
els. Initially, participants were asked to refrain from alcohol
consumption because it is known to alter endogenous hormone
levels (21). However, this requirement made subject recruitment
difficult. The alcohol requirements were therefore relaxed, re-
quiring subjects to maintain their normal alcohol consumption
but consume no more than two alcoholic beverages per day
and no more than 7 alcoholic beverages per week. Study par-
ticipants were asked to maintain their usual diet and exercise
patterns throughout the study.
At the baseline visit, a 20 ml nonfasting blood specimen was
drawn by a nurse phlebotomist (between the hours of 7:00 AM
and 10:00 AM), and study participants submitted a 24-h urine
specimen that had been collected over the previous day. In addi-
tion, study participants completed a 7-day dietary recall (7DDR;
University of Massachusetts Medical School, Worcester), which
queried dietary intake of 118 food categories or individual foods
and 13 beverage items consumed over the previous week (22).
The 7DDR also evaluates recreational and exercise activities,
occupational activities, and household and childcare activities
over the prior 28-day period. The 7DDR has been validated
cross-sectionally against 24-h dietary recalls in three separate
studies in a total of 261 subjects (23). Height and body weight
was also measured at this visit, and a self-administered ques-
tionnaire was used to elicit information on sociodemographic
factors and standard breast cancer risk factors.
614 S. R. STURGEON ET AL.
At the baseline visit, study participants were instructed to
consume one tablespoon of ground flaxseed (7.5 g) per day until
the scheduled first follow-up visit, approximately 6 wk later. At
the first follow-up visit, study participants were instructed to
consume two tablespoons of ground flaxseed per day (15 g)
until the second follow-up visit, 6 wk after the first follow-up
visit. As with the baseline visit, at each of the follow-up visits, a
20 ml blood specimen was obtained, and participants provided
a 24-h urine specimen that had been collected over the previous
day. In addition, study participants completed a 7DDR and were
weighed.
Stabilized flaxseed without any additives was purchased from
the Essential Nutrient Research Corporation (ENRECO, New-
ton, WI). All of the flaxseed used in this study originated from a
single production lot and was shipped to the University of Mas-
sachusetts Amherst in two separate shipments. Whole flaxseed
was stored in cold storage and was ground immediately prior to
shipping. A 1-lb bag of ground flaxseed and a tablespoon mea-
sure with instructions for standard measurement procedures was
provided for each subject at the baseline visit, and any unused
flaxseed was returned at the first follow-up visit. Two 1-lb bags
of ground flaxseed were provided for each subject at the first
follow-up visit, and any unused flaxseed was returned at the
second follow-up visit. Study participants were instructed to
sprinkle it on any cold food of their choice, for example, cot-
tage cheese, yogurt, cereal, applesauce, pudding, or salad. They
were instructed not to cook or bake with the flaxseed. Partici-
pants were provided with already ground flaxseed to maximize
adherence, and were instructed to store the flaxseed in the refrig-
erator to prevent spoiling. The flaxseed that was returned at each
follow-up visit was weighed to determine subject compliance.
Laboratory Analyses
Blood specimens were immediately processed and frozen at
−80◦C. Hormone assays were performed at the Reproductive
Endocrine Research Laboratory at the University of Southern
California, Los Angeles, directed by one of the authors (F. Z.
Stanczyk). For each study participant, all three serum samples
were included in the same analysis batch; the order in which
samples were placed into a batch was randomized. Two repli-
cate quality control blood specimens from two postmenopausal
women were also inserted randomly into each of the 4 batches,
for a total of 16 assessments of laboratory assay quality. Labora-
tory technicians were blinded to the identification of all samples
from study and quality control subjects.
Concentrations of testosterone, estrone, and estradiol were
measured by sensitive and specific radioimmunoassays (RIAs)
after organic solvent extraction and Celite column partition chro-
matography as described previously (24,25). The sensitivities
of the testosterone, estrone, and estradiol RIAs are 1.5 ng/dl,
4 pg/ml, and 3 pg/ml, respectively. SHBG was quantified by
a solid-phase, 2-site, chemiluminescent immunoassay using the
Immulite analyzer (Diagnostic Products Corp., Inglewood, CA).
Bioavailable (non-SHBG bound) testosterone and estradiol con-
centrations were calculated using a validated algorithm on the
basis of total testosterone estradiol, and SHBG concentrations,
as well as an assumed albumin concentration (26–28). Based on
the blinded quality control serum replicates inserted from two
postmenopausal women, intra-assay coefficient of variations,
respectively, were 9.4% and 8.2% for testosterone, 11.5% and
12.9% for estrone, 15.5% and 14.3% for estradiol, and 3.9%
and 3.4% for SHBG.
Urine was collected in containers with ascorbic acid, and
after recording the weight, 0.1% sodium azide was added as a
preservative. Urine specimens were immediately processed and
frozen at −20◦C and shipped on dry ice to the Department of
Nutrition and Food Science (University of Minnesota, St. Paul).
Urinary concentrations of enterodiol, as a marker of flaxseed
compliance, were measured using a modification of standard
gas-chromatography/mass-spectrometry methods (29).
Statistical Analyses
Dietary and physical activity variables were created from
the 7DDR administered at each of the three visits. Physical
activity levels were calculated as total minutes per week and
metabolic equivalent task (MET) hours per day following the
method of Ainsworth and colleagues (30). Macronutrient and
micronutrient intake in grams per day were adjusted for total
energy intake using the residual method (31).
Repeated measures analysis of variance was performed to
assess the significance of changes over time in hormone levels.
Repeated measures analysis of covariance was used to deter-
mine changes in the hormone levels after adjustment for se-
lected dietary factors, weight, and level of physical activity. Di-
etary factors evaluated included total energy intake and energy
adjusted macronutrients and micronutrients (total fat, total sat-
urated fat, total protein, vegetable protein, animal protein total
carbohydrates, alcohol, total fiber, insoluble fiber, and linoleic
acid). The decision to retain potential confounders in the re-
peated measures analysis of covariance was based on initial
assessments of changes over time in each of the preceding co-
variates and utilized the Ftest (P≤0.05) in a repeated measures
analysis.
RESULTS
As shown in Table 1, the study population was mainly non-
Hispanic White (95%) and college educated (74%), with a mean
age of 57 ±4.8 yr. Based on an analysis of the weights of
distributed and returned flaxseed, mean daily flaxseed intake
(±SD) was 7.8 ±1.6 g/day and 15.4 ±2.8 g/day during the
first and second follow-up periods, respectively. Mean urinary
enterodiol levels at baseline, 6 wk, and 12 wk were 0.6 mg/day,
2.39 mg/day, and 5.75 mg/day, respectively, showing a rise as
expected when higher doses of flaxseed were ingested. There
were no changes in study subject weight or level of physical
activity over the intervention period (results not shown). Mean
FLAXSEED AND SERUM HORMONE LEVELS 615
TABLE 1
Baseline Characteristics of Study Participantsa
Characteristic Mean (SD) No.b%
Age (yr) 57 (4.8)
MET (h/day) 2.8 (0.5)
Minutes of activity per week 260 (47)
Total energy intake (kcal/day) 1,732 (139.1)
Race
White 46 94.8
Other 1 2.1
Education
High school or some college 13 27.1
College graduate 35 72.9
Body mass index (kg/m2)
<25 25 53.2
≥25 22 46.8
Menopausal hormone use (yr)
Never 27 56.3
<51327.1
≥5716.4
Ever smoked cigarettes
No 31 64.6
Yes 17 35.4
Family history of breast cancer
No 39 81.3
Yes 9 18.8
History of benign breast disease
No 37 77.1
Yes 11 22.9
an=48. Abbreviation is as follows: MET =metabolic task
equivalent.
bMay not add up to 48 (100%) due to missing data.
body weights (kg) were 67.5, 67.5, and 67.2 at the baseline visit,
first follow-up visit, and second follow-up visit, respectively.
There were small declines in serum levels of testosterone,
estrone, and estradiol after 6 and 12 wk of flaxseed ingestion
among all women, although these declines were not statistically
significant (Table 2). Body mass index (BMI) is a recognized
breast cancer risk factor; the elevated risk in overweight women
likely reflects higher circulating estrogens due to increased aro-
matase activity in adipose tissue (32). At baseline, circulating
levels of estradiol across 3 weight groups (<25, 25–30, >30
kg/m2) were 15.1, 11.1, and 15.6 pg/ml, respectively (P=0.86),
whereas comparable estrone levels were 24.6, 25.9, and 58.6
pg/ml (P<0.001), respectively. Because dietary lignans have
been shown to inhibit aromatase activity (11,12), we examined
the effects of flaxseed on serum sex hormone levels separately in
normal weight (BMI <25 kg/m2) and overweight/obese (BMI
≥25 kg/m2) women. Among overweight/obese women, we ob-
served a pattern of more substantial declines in serum levels of
testosterone, estrone, and estradiol associated with consuming
flaxseed. The decline among overweight/obese women was sta-
tistically significant for testosterone at 6 wk and for estrone at
6 and 12 wk. Among normal weight women, we also observed
small suggestive declines in serum sex hormone levels, but these
were not statistically significant.
A total of 6 study participants had estradiol concentrations
≥30 pg/ml at any of the 3 study visits. All study subjects
had follicle-stimulating hormone levels in the postmenopausal
range, and none reported use of hormone therapy during the
study period (results not shown). All analyses were rerun ex-
cluding these participants to determine their impact on the study
findings. Results were generally similar to those reported above.
Among overweight/obese women, for example, there continued
to be statistically significant declines in estrone from baseline to
Follow-Up 1, and from baseline to Follow-Up 2 (–5.9 pg/ml and
–3.9 pg/ml, respectively). There were also statistically signifi-
cant declines from baseline to Follow-Up 1 for testosterone (–
15.9 pg/ml) and estradiol (–1.5 pg/ml), but changes in these hor-
mones were modest and not statistically significant from base-
line to Follow-Up 2 (–6.6 pg/ml and –0.6 pg/ml, respectively).
When we further restricted the data set to 6 obese women
(≥30 kg/m2; results not shown), we observed statistically sig-
nificant declines between baseline and Follow-Up 1 for testos-
terone (–34.2 pg/ml) and estrone (–18.4 pg/ ml). Comparable
values between baseline and Follow-Up 2 were –15.6 pg/ml and
–10.9 pg/ml, respectively, although these were not statistically
significant.
Overall, there was little evidence that consuming a higher
dose of flaxseed for 12 wk resulted in a greater decline in serum
sex hormone levels than consumption of flaxseed for 6 wk in
either subgroup. Serum levels of SHBG were essentially un-
changed between the first and second follow-up visits. Although
mean intake of vegetable protein, carbohydrate, and linoleic acid
changed significantly over the intervention periods, the results
in Table 2 were essentially unchanged after adjustment for these
factors.
DISCUSSION
Consuming 7.5 g of flaxseed per day for 6 wk and 15 g of
flaxseed for an additional 6 wk resulted in modest, nonstatisti-
cally significant declines in serum levels of testosterone, estrone,
and estradiol but not SHBG in this group of postmenopausal
women. In the subset of overweight women, the mean reduc-
tion of 6.5 pg/ml for estrone was statistically significant. In
the randomized cross-over trial of 28 postmenopausal women
by Haggans and colleagues (18), 5 and 10 g/day flaxseed diets
for 7 wk reduced serum concentrations of estradiol and estrone
sulfate but not estrone. By contrast, dietary flaxseed at much
higher prescribed doses (25 g/day for 16 weeks, and 40 g/day
for 3 mo, respectively) have not been shown to alter serum levels
of estrogens or SHBG in 2 small intervention studies (19,20).
The difference between our findings and those from prior stud-
ies may reflect noncompliance to high-dose flaxseed regimens,
616 S. R. STURGEON ET AL.
TABLE 2
Serum Sex Hormone Levels at Baseline and Change Associated With Dietary Flaxseed Intervention Among Postmenopausal
Women and by Category of Body Mass Indexa
Change from Baseline to Change from Baseline to
Baseline Level Follow-Up 1 Follow-Up 2b
Mean Mean (95% CI) PValue % Mean (95% CI) PVal u e %
All women (n=48)c
Testosterone (pg/ml) 181 −9.9 (−23.8 to 4.0) 0.16 −5.5 −4.7 (−17.8 to 8.5) 0.48 −2.6
Estrone (pg/ml) 30.0−2.6 (−6.7to1.5) 0.21 −8.7 −3.3 (−7.7to1.2) 0.15 −11.0
Estradiol (pg/ml) 14.1−2.7 (−6.6to1.2) 0.17 −19.1 −4.4 (−12.6 to 3.9) 0.29 −31.2
SHBG (nmol/l) 49.10.6(−2.5to3.7) 0.71 +1.2 .04 (−2.7to2.0) 0.98 0.0
Bioavailable estradiol (pg/ml) 8.9−0.2 (−4.1to3.7) 0.92 −2.2 −2.8 (−7.5to2.0) 0.25 −31.4
Bioavailable testosterone (pg/ml) 9.1−0.7 (−1.5 to 0.14) 0.10 −7.7 −0.4 (−1.1to0.4) 0.33 −4.4
Overweight/obese (n=22)d
Testosterone (pg/ml) 180 −14.6 (−28.1 to 1.1) 0.03 −8.1 −7.0 (−18.2 to 4.2) 0.20 −3.9
Estrone (pg/ml) 36.3−7.6 (−14.2 to 0.9) 0.03 -19.4 −6.5 (−11.9 to 1.2) 0.02 −18.0
Estradiol (pg/ml) 12.5−3.6 (−9.4 to 2.2) 0.21 -20.9 −3.4 (−9.3to2.4) 0.24 −27.2
SHBG (nmol/l) 38.0−0.1 (−2.1to1.9) 0.93 -0.0 −1.1 (−3.0to0.8) 0.25 −2.9
Bioavailable estradiol (pg/ml) 8.71.1(−7.0to9.3) 0.77 +12.6 −2.2 (−5.6to1.3) 0.21 −25.3
Bioavailable testosterone (pg/ml) 10.3−1.0 (−1.7 to −0.2) 0.02 -10.9 −0.3 (−1.1to0.5) 0.38 −2.5
Normal Weight (n=25)e
Testosterone (pg/ml) 182 −6.7 (−31.6 to 18.2) 0.58 −3.7 −2.1 (−25.9 to 21.7) 0.86 −1.2
Estrone (pg/ml) 24.61.4(−3.8to6.6) 0.58 +5.7 −0.5 (−7.8to6.8) 0.88 −2.0
Estradiol (pg/ml) 15.6−2.1 (−7.9to3.7) 0.47 −13.5 −5.3 (−20.6 to 10.0) 0.48 −34.0
SHBG (nmol/l) 59.91.3(−4.5to7.2) 0.64 +2.2 1.1 (−5.7to7.9) 0.74 +1.8
Bioavailable estradiol (pg/ml) 9.2−1.4 (−4.7to1.8) 0.38 −15.2 −3.3 (−12.0 to 5.4) 0.44 −35.9
Bioavailable testosterone (pg/ml) 8.0−0.5 (−2.0to0.9) 0.47 −6.3 −0.4 (−1.7to0.9) 0.56 −5.0
aAbbreviations are as follows: SHBG, sex hormone-binding globulin; BMI, body mass index.
bExcludes 1 woman without a follow-up 2 visit.
cIncludes 1 woman with missing height.
dBMI ≥25kg/m2.
eBMI <25 kg/m2.
hormone measurement variability, or differences in body weight
across studies.
We observed a decline in testosterone after flaxseed con-
sumption, consistent with a report that plant lignins can bind
and promote excretion of testosterone in the bile (14). In con-
trast to our findings, the randomized cross-over study in post-
menopausal women by Haggans and colleagues (18) observed
no change in testosterone levels. However, in one cross-sectional
study of approximately 250 postmenopausal women in Wis-
consin (16), serum testosterone was inversely associated with
number of servings per week of whole grain products from
the dark bread group (r=–.20, P=0.01). This association
was attributed to lignan content because no overall associa-
tion between dietary fiber and testosterone concentration was
observed.
One cross-sectional study of approximately 40 women re-
ported a positive association between urinary excretion of en-
terolactone and serum SHBG, an inverse association between
enterolactone and serum testosterone levels, and an inverse as-
sociation between enterolactone and serum estradiol levels (31).
Similarly to the other intervention studies (18–20), we did not
observe an association between SHBG and flaxseed ingestion
in the present study.
Ziegler (34) highlighted the methodological challenges in
interpreting findings from observational studies on the relation-
ship between lignan exposure and risk of breast cancer. Three
case-control studies (35–37) and 6 cohort studies (38–43) have
examined the relationship between enterolactone in serum or
urine, as markers of lignan exposure, and risk of breast cancer.
The three case-control studies reported substantial reductions
in breast cancer risk after menopause associated with urinary
excretion of enterolactone (35–37). Interestingly, our data are
consistent with observational evidence that an inverse associ-
ation between urinary excretion of lignans and risk of breast
FLAXSEED AND SERUM HORMONE LEVELS 617
cancer may be more pronounced among women with a higher
BMI (35). Among overweight women, Dai and colleagues (37)
found that breast cancer risk decreased steadily with increas-
ing tertiles of urinary lignan levels (relative risk =1.0, 0.72,
and 0.27). By contrast, the comparable relative risks among
overweight women were 1.0, 1.53, and 0.70. It is possible that
changes in metabolism or in dietary intake after a breast cancer
diagnosis may account for the observed associations in case-
control studies. Of the 5 cohort studies, only one observed an
inverse association between enterolactone exposure and risk
of breast cancer (38). As noted by Ziegler (34), however, sin-
gle measures of enterolactone in biological specimens such as
those used in cohort studies, although capturing potentially im-
portant individual variation in colonic metabolism of dietary
lignans, may result in missed associations, as they do not reflect
integrated long-term exposure.
Three other case-control studies (44–46) and two cohort stud-
ies (47,48) have examined the relation between dietary lignan
intake and risk of breast cancer. Women with higher dietary
lignan intake tended to have reduced breast cancer risk in three
studies (44,45,48). Although dietary measures of lignans may be
better at integrating exposure over a long time period, databases
for lignan content of food may not be comprehensive. In addi-
tion, estimates of breast cancer risk vary depending on which
measures of lignan intake is employed: absolute quantity of
plant lignans (matairesinol and secoisolaciresinol) or estimated
bioavailable lignans (enterolactone and enterodiol) using a con-
version factor derived from an in vitro model for colonic fer-
mentation (34). Other more general limitations of research in
this field have also been noted, including that the level and vari-
ation in lignan exposure is low in most populations studied to
date, and many dietary questionnaires do not include foods that
are especially high in lignan content, including dietary flaxseed.
These limitations would tend to bias the association between
lignans and risk of breast cancer toward the null.
This study has several limitations. First, it was relatively
small and thus small changes in serum sex hormones due to
flaxseed are difficult to detect. In addition, the study lacks a
placebo control group. Nevertheless the findings suggest that
consumption of one to two tablespoons of flaxseed per day for 12
wk may favorably influence estrogen and androgen concentra-
tions, particularly in overweight/obese women. It is also impor-
tant to emphasize flaxseed is a whole food that is notably rich in
lignans, the plant-based omega-3 fatty acid (i.e., alpha-linolenic
acid) and fiber, and it cannot be assumed that a single dietary
component is responsible for observed biological effects. In
summary, additional research focused on clarifying the effects of
flaxseed on breast biology is warranted. Such research is impor-
tant because of the promotion of flaxseed as having breast cancer
preventative effects and its increasing widespread availability.
ACKNOWLEDGMENT
This research was supported by a grant from the United States
Department of Defense Breast Cancer Research Program (Grant
DAMD17–02–1–0470–1).
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