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RES E AR C H Open Access
Green tea intake is associated with urinary
estrogen profiles in Japanese-American women
Barbara J Fuhrman
1,5*
, Ruth M Pfeiffer
1,5
, Anna H Wu
3,5
, Xia Xu
2,5
, Larry K Keefer
4,5
, Timothy D Veenstra
2,5
and Regina G Ziegler
1,5
Abstract
Scope: Intake of green tea may reduce the risk of breast cancer; polyphenols in this drink can influence enzymes
that metabolize estrogens, known causal factors in breast cancer etiology.
Methods and results: We examined the associations of green tea intake (<1 time/week, 1-6 times weekly, or 7+
times weekly) with urinary estrogens and estrogen metabolites (jointly EM) in a cross-sectional sample of healthy
Japanese American women, including 119 premenopausal women in luteal phase and 72 postmenopausal women.
We fit robust regression models to each log-transformed EM concentration (picomoles per mg creatinine), adjusting
for age and study center. In premenopausal women, intake of green tea was associated with lower luteal total EM
(P trend = 0.01) and lower urinary 16-pathway EM (P trend = 0.01). In postmenopausal women, urinary estrone and
estradiol were approximately 20% and 40% lower (P trend = 0.01 and 0.05, respectively) in women drink ing green
tea daily compared to those drinking <1 time/week. Adjustm ent for potential confounders (age at menarche,
parity/age at first birth, body mass index, Asian birthplace, soy) did not change these associations.
Conclusions: Findings suggest that intake of green tea may modify estrogen metabolism or conjugation and in
this way may influence breast cancer risk.
Keywords: Estrogens, Metabolism, Green tea, Camellia sinensis, Breast neoplasms, Risk factors, Human, Female,
Middle-aged
Background
Breast cancer is the leading cancer diagnosis among
women worldwide. There is great variability in inter-
national breast cancer incidence rates. The incidence of
breast cancer is three to four times higher in the U.S.
compared to Japan [1]. Migrant studies suggest that
international differences in breast cancer risk are
mediated by environmental rather than genet ic factors
[2].
Green tea is commonly consumed in Japan. Green tea
is an important source of dietary phytochemicals, in-
cluding the polyphenols epigallocatechin gallate (EGCG),
epigallocatechin, epicatechin gallate, and epicatechin.
Together these phytochemicals represent 30% of the dry
weight of fresh tea leaves [3]. Green tea polyphenols in-
hibit tumor development in laboratory models of breast
cancer and other cancers, but epidemiologic evidence
does not consistently support the hypothesis that green
tea drinking lowers breast cancer risk [4]. Mechanisms
of anticancer actions may include interruption of signal
transduction pathways involved in cell proliferation, in-
vasion, angiogenesis, and metastasis [3,5].
Because green tea catechins have been observed to re-
duce catalytic activity of certain cytochrome p450 (CYP)
enzymes [6], we hypothesized that green tea may influ-
ence breast cancer risk, in part, by modifying the pro-
duction or metabolism of estrogens, known carcinogens
of the breast. Caffeine, present in teas and other foods,
is also known to modify expression and/or activity of
some metabolic enzymes, but has not been found to
have a consistent effect on breast cancer risk [7-10].
Therefore we examined the associations of green tea
intake and caffeine intake with urinary estrogens and
* Correspondence: bjfuhrman@uams.edu
1
Division of Cancer Epidemiology and Genetics, National Cancer Institute,
National Institutes of Health, Bethesda, MD, USA
5
Current address: Department of Epidemiology, Fay W. Boozman College of
Public Health, University of Arkansas for Medical Sciences, 4301 W. Markham
St. #820, Little Rock, AR 72205, USA
Full list of author information is available at the end of the article
© 2013 Fuhrman et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Fuhrman et al. Nutrition Journal 2013, 12:25
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estrogen metabolites (jointly referred to a s EM) among
cancer-free pre- and postmenopausal Japanese American
women.
Methods
Study population
Subjects for this analysis were Japanese-American con-
trol subjects who participated in the population-based
Asian American Breast Cancer case-control study that
has already been described in detail [2]. In that study,
cases were women of Chinese, Japanese or Filipino
descent, aged 20-55 years , diagnosed with histologically-
confirmed, first primary breast cancer s in San Francisco-
Oakland, California; Los Angeles, California; or Oahu,
Hawaii, between April 1, 1983 and June 30, 1987. Poten-
tial controls in San Francisco and Los Angeles were
selected by random-digit dialing, while those in Oahu
were selected from an annual population-based health
survey con ducted by the Health Surveillance Program of
the Hawaii Department of Health. Bilingual interviewers
were used when necessary. Controls, up to two per case,
were frequency-matched to cases in their study area by
Asian ethnicity and year of birth in 5-year age groups.
Study participants were interviewed at home by
trained staff with standardized questionnaires, which
included questions about residential history, birthplaces
of parents and grandparents, medical history, and
dietary and lifestyle factors. Only Japanese American
participants were queried about intake of green tea.
Participants were also invited to provide 12-hour over-
night urine and/or fasting blood samples. Women who
reported a recent menstrual period were given urine col-
lection appointments to coincide with the mid-luteal
phase (days 19-26) of the menstrual cycle and were
asked to send a postcard following urine collection to re-
port the first day of the subsequent menstrual period.
Ethical approval
All participants provided informed consent. The re-
search was approved by the responsible Institutional Re-
view Board at the National Cancer Institute.
Menopausal status
We assessed menopau sal status carefully using data from
multiple sources; decision rules were designed to identify
women who were clearly post-menopausal and those
who were premenopausal and in luteal phase.
Postmenopausal women included women who had
experienced natural menopause at least 12 months
earlier. Other women without evidence of ongoing
menses at the time of urine collection and those who
had reported surgical menopause were considered
postmenopausal only if they had circulating FSH ≥ 35 U/
L and either progesterone < 10 ng/dL, progesterone < 30
ng/dL and estradiol < 35 ng/dL, or progesterone < 50 ng/
dL and estradiol < 15 ng/dL. For those women missing
the FSH reading, postmenopausal status was assigned to
those aged >52 y at the time of urine collection and who
had progesterone < 30 ng/dL and estradiol < 35 ng/dL or
progesterone < 50 ng/dL and estradiol < 15 ng/dL. For
premenopausal women, phase of cycle wa s based on 1)
the returned postcards and 2) serum progesterone levels.
A premenopausal woman was considered to be in luteal
phase if her urine collection fell 2–11 days before the
subsequent menstrual period or if her progesterone
levels were >300 ng/dL.
Inclusion / exclusion criteria
Eligible participants in this study were Japanese-
American women without breast cancer (n = 395). Of
these, 284 (72%) provided 12-hour urine samples. We
then excluded participants who reported at the time of
urine collection current or recent use (<6 months)
of exogenous hormones (n = 45), or current / recent
(<6 months) pregnancies or lactation (n = 5), resulting in
a sample of 234 women. Of these, 119 were classified as
premenopausal and in luteal phase at the time of urine
collection , 72 were classified as postmenopa usal, and 43
were either premenopausal but not in luteal phase, or of
uncertain menopausal status. The latter group of 43
women was excluded to avoid variability by menstrual
phase [11]. Therefore the presen t study included
119 premenopausal women in luteal phase and 72
postmenopausal women.
Specimen handling and assay for urinary estrogens and
estrogen metabolites
Participants were instructed to collect 12-hour overn ight
urine samples using half-gallon containers kept at 4°C
on ice or in the refrigerator. Boric acid was added as a
preservative [12]. After delivery to the study center,
urine was mixed, aliquoted into 1 mL cryovials, and
shipped on dry ice to a repository for storage at -80°C.
Unthawed aliquots were sent to SAIC-Frederick
(Frederick, MD) where stable isotope dilution high-
performance liquid chromatography-tandem mass spec-
trometry (LC/MS/MS) was used to measure concurrently
15 urinary estrogens and estrogen metabolites, includ-
ing estrone, estradiol, estriol, 2-hydroxyestrone, 2-
methoxyestrone, 2-hydroxyestradiol, 2-methoxyestradiol,
2-hydroxyestrone-3-methyl ether), 4-hydroxyestrone, 4-
methoxyestrone, 4-methoxyestradiol, 16α-hydroxyestrone,
17-epiestriol 16-ketoestradiol, and 16-epiestriol. The ana-
lytical method for measurement of urinary estrogens and
estrogen metabolites has been described previously [13],
as have the assay conditions as applied to this particular
study [14].
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Urine samples from two premenopausal and two
postmenopausal women were used as blinded quality
control samples. Four quality control samples, including
two from the same subject, were randomly included in
each batch of ~40 samples. Total laboratory coefficients
of variation were <10% for all estrogens and estrogen
metabolites except 4-methoxyestradiol (15%), and were
≤4% for estrone, estradiol, and estriol, and ~1% for total
EM.
Creatinine levels were determined by the National
Institutes of Health clinical chemist ry laboratory and
used to adjust EM levels for differences in urine concen-
tration [ 15].
Tea and other dietary measures
During in-pe rson interviews, Japanese-American partici-
pants were queried about frequency of intake of green
tea, black tea, coffee, decaffeinated coffee and caffeinated
soda; serving size was not queried. Frequencies of intake
were recorded as times per day, week, month, or year,
according to the most convenient time frame for the food
item and respondent. Based on observed distributions for
included participants, green tea consumption frequency
was classified as less than once per week, weekly (1-6
servings per week), or daily (7 or more servings per week).
Caffeine was calculated assuming standard serving sizes
and the following estimates of caffeine content, based on
food composition databases [16] and measures in the lit-
erature [17]: 81 mg caffeine per serving of coffee, 2 mg
caffeine per serving of decaffeinated coffee, 20 mg caffeine
per serving of green tea, 30 mg per serving of black tea,
and 29 mg per serving of caffeinated soda.
Statistics and data analysis
We examined characteristics of study participants in
premenopausal women who provided urine during the lu-
teal phase of the menstrual cycle, and in postmenopausal
women (Table 1) and by category of tea intake (Table 2).
Estrogens and estrogen metabolites were grouped by
metabolic pathway, summed and expressed in picomoles
per mg creatinine. We have previously shown that these
pathway categories appropriately characterize covariation
in urinary EM profiles [14].
Direct standardization was used to calculate represen-
tative geometric means of EM measures for Japanese-
American women by categories of green tea intake. Age
standardization was performed with the log transforms
of each EM measure, and the results were then
exponentiated. For premenopausal women in luteal
phase, standardization was to the age distribution of all
premenopausal women in luteal phase (<40, 40-44, 45+
y), regardless of tea intake For postmenopausal women,
standardization was to the age distribution of all
postmenopausal women (<50, 50-54, 55+ y).
Robust regression models were fit to each log-
transformed EM measure a s the dependent variable.
Regression coefficients associated with each of the tea
categories in linear models were used to estimate per-
cent differences based on the formula: 100*(E
beta
– 1),
where beta is the coefficient associated with each
category of tea intake.
Models were fit separately for pre- and postmenopausal
women and were adjusted for age and study center.
We also considered additional measures as potential
confounders including birthplace, soy intake, age at me-
narche, parity/ age at first birth, and body mass index
(BMI). Models that additionally adjusted for caffeine in-
take were also considered. The statistically significant
findings in Tables 3 and 4 did not differ in their direction,
magnitude, or statistical significance when additional po-
tential confounders were included in models. Here we
present the minimally adjusted models.
Hypotheses of linear trend across categories of intake
were assessed by assigning 0, 1, and 2 to categories and
treating the variable as a continuous covariate. Effect
modification was considered by stratifying on birthpla ce
(Asia/U.S.), median soy intake, and median BMI. Statis-
tical significance of interactions between tea intake,
birthplace, BMI, and soy intake were evaluated by com-
paring models with and without interaction terms using
a likelihood ratio test.
P-values ≤0.05 were considered statistically significant.
All tests were two-sided. Analyses were conducted using
SAS v. 9.1 (SAS Institute, Cary, NC).
Results and discussion
In this sample of Japanese American women, median
frequency of green tea intake was 1 time per week
(interquartile range (IQR): 0.2-7.0). Median frequency of
coffee intake was 1 time per day (IQR: 1 time per week-
2.5 times per day), while the median frequency of black
tea intake was 2-3 times per year (IQR: 0 times per
year – 1 times per week).
Table 1 gives characteristics of study participants by
menopausal status. Premenopausal participants were
younger than their postmenopausal counterparts (with
mean ages of 41 and 53, respectively) but had similar,
normal BMI (mean 21.7 kg/m
2
for both groups).
Premenopausal participants were more likely than their
postmenopausal counterparts to have a history of early
menarche (before or at age 12 y, p = 0.04). Daily intake
of green tea was more prevalent in postmenopausal than
in premenopausal women (33.3% vs. 21.0%, p = 0.049).
In Table 2 we present participant characteristics by
frequencies of green tea drinking. Intake of green tea
was significantly associated with older age (p = 0.02) and
Asian birthplace (p < 0.001). Daily intake of green tea
was less prevalent among controls enrolled in Oahu
Fuhrman et al. Nutrition Journal 2013, 12:25 Page 3 of 14
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compared to those in Los Angeles and San Francisco
(18.1% vs. 37.5% and 43.8%, respectively, p = 0.01). Fre-
quency of green tea intake was also significantly
associated with later menarche (P <0.001) and higher in-
take of soy foods (P <0.001).
As shown in Table 3, among premenopausal wo-
men in luteal phase, intake of green tea was associated
with significantly lower urinary conce ntrations of
total estrogens and e strogen metabolites (P trend =
0.01). Intake of green tea wa s significantly associa-
Table 1 Characteristics of breast cancer controls in the Asian-American Breast Cancer Study by menopausal status
Premenopausal women in luteal phase (n = 119) Postmenopausal women (n = 72)
mean s.d. mean s.d.
Age (y)* 41.2 5.4 53.0 3.4
Body Mass Index (kg / m
2
) 21.7 3.5 21.7 2.5
n column % n column %
Study center, n(%)
Hawaii 79 66.4% 48 66.7%
Los Angeles 19 16.0% 13 18.1%
San Francisco 21 17.6% 11 15.3%
Combined parity and age at first birth, n(%)
Nulliparous 17 14.3% 11 15.3%
1st birth age ≤ 20 y 7 5.9% 4 5.6%
1-2 live births / age ≥ 21 73 61.3% 28 38.9%
3+ live births / age ≥ 21 22 18.5% 29 40.3%
Age at menarche, n(%)
≤ 12 y 72 60.5% 30 41.7%
> 12 y 47 39.5% 42 58.3%
Born in Asia, n (%)
No 93 78.2% 57 79.2%
Yes 26 21.8% 15 20.8%
Soy intake (frequency of weekly intake), n (%)
0-0.5 35 29.4% 12 16.7%
0.5 – 1.0 35 29.4% 22 30.6%
> 1.0 49 41.2% 38 52.8%
Green tea (frequency of weekly intake), n (%)
<once weekly 62 52.1% 25 34.7%
1-6 times weekly 32 26.9% 23 31.9%
7+ times weekly 25 21.0% 24 33.3%
Black tea (frequency of weekly intake), n (%)
<once weekly 85 71.4% 51 70.8%
1-6 times weekly 21 17.6% 16 22.2%
7+ times weekly 13 10.9% 5 6.9%
Coffee (frequency of weekly intake), n (%)
0-2 times weekly 30 25.2% 11 15.3%
3-13 times weekly 39 32.8% 22 30.6%
≥14 times weekly 50 42.0% 39 54.2%
Estimated weekly caffeine intake (mg), n (%)
0-734 41 34.5% 23 31.9%
734-1610 39 32.8% 23 31.9%
>1610 39 32.8% 26 36.1%
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Table 2 Participant characteristics by frequency of green tea intake
Less than weekly intake (< once per week) Weekly intake (1-6 times per week) Daily intake (7+ times per week) P value*
mean s.d. mean s.d. mean s.d.
Age (y)* 45.4 6.8 48.3 8.2 49.7 7.0 0.01
Body Mass Index (kg / m
2
) 21.9 3.3 22.0 3.1 21.0 2.8 0.18
n row % n row % n row %
Menopausal status / menstrual phase 0.049
Premenopausal women in luteal phase 62 52.1% 32 26.9% 25 21.0%
Postmenopausal 25 34.7% 23 31.9% 24 33.3%
Study center, n (%) 0.01
Hawaii 70 55.1% 34 26.8% 23 18.1%
Los Angeles 7 21.9% 13 40.6% 12 37.5%
San Francisco 10 31.3% 8 25.0% 14 43.8%
Combined parity and age at first birth, n (%) 0.07
Nulliparous 12 42.9% 8 28.6% 8 28.6%
1st birth age ≤ 20 y 7 63.6% 4 36.4% 0 .0%
1-2 live births / age ≥ 21 53 52.5% 23 22.8% 25 24.8%
3+ live births / age ≥ 21 15 29.4% 20 39.2% 16 31.4%
Age at menarche, n (%) <0.001
≥ 12 y 56 54.9% 34 33.3% 12 11.8%
> 12 y 31 34.8% 21 23.6% 37 41.6%
Born in Asia, n (%) <0.001
No 74 49.3% 49 32.7% 27 18.0%
Yes 13 31.7% 6 14.6% 22 53.7%
Soy intake (frequency of weekly intake), n (%) <0.001
0-0.5 times weekly 31 66.0% 12 25.5% 4 8.5%
0.5-1 times weekly 27 47.4% 20 35.1% 10 17.5%
> once weekly 29 33.3% 23 26.4% 35 40.2%
Black tea (frequency of weekly intake), n (%) 0.21
< once weekly 69 50.7% 34 25.0% 33 24.3%
1-6 times weekly 12 32.4% 15 40.5% 10 27.0%
7+ times weekly 6 33.3% 6 33.3% 6 33.3%
Coffee (frequency of weekly intake), n (%) 0.75
0-2 times weekly 22 53.7% 11 26.8% 8 19.5%
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Table 2 Participant characteristics by frequency of green tea intake (Continued)
3-13 times weekly 25 41.0% 18 29.5% 18 29.5%
≥14 times weekly 40 44.9% 26 29.2% 23 25.8%
Caffeine (weekly intake in mg), n (%) 0.83
0-734 29 50.0% 15 25.9% 14 24.1%
734-1609 27 47.4% 15 26.3% 15 26.3%
≥1610 31 40.8% 25 32.9% 20 26.3%
* For continuous covariates, p-values were obtained using ANOVA and reflect significance of differences between means by categories of green tea intake. For categorical covariates, p-values were obtained using Chi
Square tests and reflect differences in distribution.
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Table 3 Age standardized geometric means for urinary concentrations of estrogens and estrogen metabolites (EM) and multivariable-adjusted percent
difference
1
across categories of green tea intake in premenopausal women during the luteal phase
Categories of green tea intake
<1 per week
(n = 62)
1-6 times per week
(n = 32)
7+ times per week
(n = 25)
Urinary
concentration
Urinary
concentration
Percent
difference
Urinary
concentration
Percent
difference
P trend
Total Estrogens and Metabolites 218.16 156.13 −25.5% (-40.7%-
-
6.4%) 170.36 −26.3% (-43.0%-
-
4.6%) 0.01
Parent Estrogens 37.58 29.99 −16.0% (-35.2%-8.9%) 34.57 −8.1% (-31.7%-23.6%) 0.42
Estrone 24.45 19.44 −20.2% (-39.2%-4.8%) 23.07 −6.9% (-31.8%-27.2%) 0.43
Estradiol 11.53 10.01 −5.4% (-27.0%-22.5%) 10.28 −8.9% (-32.1%-22.3%) 0.51
2-Hydroxylation pathway 39.11 28.05 −36.9% (-52.3%-
-
16.4%) 38.11 −16.2%(-39.5%-16.0%) 0.10
2-Pathway catechols 30.57 22.42 −38.3% (-54.2%-
-
16.8%) 28.5 −16.9%(-41.2%-17.6%) 0.10
2-Hydroxyestrone 27.65 19.68 −38.8% (-54.6%-
-
17.6%) 27.06 −16.3%(-40.7%-18.2%) 0.10
2-Hydroxyestradiol 3.02 1.90 −43.9% (-61.9%-
-
17.3%) 2.61 −25.5% (-52.4%-16.5%) 0.07
2-Pathway methylated catechols 7.24 5.66 −28.9% (-47.7%-
-
3.5%) 7.77 −9.6%(-36.3%-28.2%) 0.34
2-Methoxyestrone 5.17 4.18 −24.0% (-44.6%-4.2%) 5.74 −1.3%(-31.4%-41.9%) 0.67
2-Methoxyestradiol 0.56 0.41 −28.7% (-50.8%-3.3%) 0.64 0.6% (-34.0%-53.4%) 0.73
2-Hydroxyestrone-3-methyl ether 1.15 0.81 −34.1% (-56.3%-
-
0.5%) 1.06 −22.9%(-51.5%-22.5%) 0.17
4-Hydroxylation pathway EM 4.13 3.32 −21.4% (-43.3%-8.9%) 3.80 −13.5% (-40.3%-25.3%) 0.33
4-Pathway catechol: 4-Hydroxyestrone 3.71 2.95 −21.9% (-44.3%-9.6%) 3.31 −15.5% (-42.4%-24.1%) 0.29
4-Pathway methylated catechols 0.33 0.28 −19.1% (-43.3%-15.3%) 0.36 −7.1% (-38.0%-39.2%) 0.53
4-Methoxyestrone 0.23 0.17 −23.9% (-48.1%-11.6%) 0.24 4.0% (-32.5%-60.4%) 0.93
4-Methoxyestradiol 0.05 0.06 −15.2% (-56.1%-63.6%) 0.08 −8.2% (-56.4%-93.4%) 0.77
16-Hydroxylation pathway 123.03 84.72 −21.3% (-39.7%-2.7%) 87.57 −33.3% (-50.3% -
-
10.4%) 0.001
16α-Hydroxyestrone 12.68 9.31 −24.0% (-40.9%-
-
2.3%) 9.78 −31.1% (-48.2%-
-
8.5%) 0.01
Estriol 68.67 44.67 −23.5% (-43.2%-2.9%) 46.16 −33.1% (-51.9%-
-
7.0%) 0.01
16-Ketoestradiol 25.68 19.98 −17.8% (-39.8%-12.2%) 19.32 −31.5% (-51.3%-
-
3.7%) 0.02
16-Epiestriol 10.09 7.11 −15.1% (-36.6%-13.6%) 7.74 −30.8% (-49.9%-
-
4.2%) 0.02
17-Epiestriol 1.79 0.97 −27.4% (-54.9%-16.8%) 0.95 −40.4% (-65.1%-1.7%) 0.04
Ratios
Parent estrogens / estrogen metabolites 0.21 0.24 10.6% (-11.5%-38.3%) 0.26 23.1% (-3.8%-57.6%) 0.09
2-Hydroxylation pathway / parent estrogens 1.04 0.94 −19.3% (-37.3%-3.8%) 1.10 −9.5% (-31.7%-20.1%) 0.37
4-Hydroxylation pathway / parent estrogens 0.11 0.11 −9.9% (-32.9%-21.2%) 0.11 −15.8% (-39.2%-16.6%) 0.28
16-Hydroxylation pathway / parent estrogens 3.27 2.83 −5.1% (-27.8%-24.8%) 2.53 −20.0% (-41.0%-8.5%) 0.17
2-Hydroxylation pathway / 16-hydroxylation pathway 0.32 0.33 −3.7% (-33.2%-38.8%) 0.44 21.2% (-19.8%-83.0%) 0.41
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Table 3 Age standardized geometric means for urinary concentrations of estrogens and estrogen metabolites (EM) and multivariable-adjusted percent
difference
1
across categories of green tea intake in premenopausal women during the luteal phase (Continued)
4-Hydroxylation pathway / 16-hydroxylation pathway 0.03 0.04 16.8% (-21.3%-73.3%) 0.04 21.8% (-21.8%-89.8%) 0.34
2-Hydroxylation pathway / 4-hydroxylation pathway 9.47 8.46 −13.3% (-28.3%-4.7%) 10.04 −1.2% (-20.2%-22.4%) 0.70
4-Pathway methylated catechols / 4-pathway catechols 0.09 0.09 20.7% (-13.4%-68.1%) 0.11 23.9% (-15.2%-81.0%) 0.20
2-Pathway methylated catechols / 2-pathway catechols 0.23 0.26 9.1% (-11.6%-34.6%) 0.26 7.7% (-15.1%-36.7%) 0.48
Derived measures of estrogen metabolism and statistically significant estimates are presented in bold font.
1
Robust linear regression models were used to estimate percent difference in EM measures with 95% confidence limits across categories of green tea intake while adjusting for age and study center.
2
Robust linear regression was used to test for trends in log-transformed EM measures across tea categories. P
trend
was modeled using categories coded as 0, 1, and 2.
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Table 4 Age-standardized mean urinary concentrations (picomoles per mg creatinine) of estrogens and estrogen metabolites (EM) and multivariable-adjusted
percent difference
1
across categories of green tea intake in postmenopausal women
Categories of green tea intake
<1 per week (n = 62) 1-6 times per week (n = 32) 7+ times per week (n = 25)
Urinary
concentration
Urinary
concentration
Percent difference Urinary
concentration
Percent difference P trend
Total Estrogens and Metabolites 27.7 26.7 −6.2% (-33.7%-32.6%) 26.5 −10.5% (-36.0%-25.1%) 0.52
Parent Estrogens 5.81 3.89 −37.0% (-58.0%-
-
5.4%) 4.01 −38.6% (-58.3%-
-
9.6%) 0.01
Estrone 1.96 0.66 −41.1% (-60.5%-
-
12.0%) 0.59 −47.0% (-63.9%-
-
22.3%) 0.001
Estradiol 2.06 1.36 −41.5% (-65.9%-0.1%) 1.46 −36.0% (-61.8% -7.2%) 0.09
2-Hydroxylation pathway 6.41 4.13 −33.6% (-57.2% -3.0%) 5.92 −15.1% (-44.4%-29.6%) 0.48
2-Pathway catechols 4.90 3.53 −30.8% (-58.4%-15.1%) 4.18 −20.3% (-51.1%-30.0%) 0.37
2-Hydroxyestrone 4.12 2.42 −31.5% (-59.0%-14.6%) 3.29 −24.9% (-54.3%-23.4%) 0.27
2-Hydroxyestradiol 0.65 0.4 −15.3% (-58.4%-72.6%) 0.80 6.7% (-45.1%-107.2%) 0.83
2-Pathway methylated catechols 1.18 0.89 −26.9% (-50.6%-8.1%) 1.39 9.7% (-24.8%-60.0%) 0.54
2-Methoxyestrone 0.72 0.48 −35.8% (-61.3%-6.2%) 0.68 −6.2% (-42.7%-53.4%) 0.85
2-Methoxyestradiol 0.11 0.08 −33.2% (-64.8%-27.0%) 0.12 19.3% (-36.7%-124.8%) 0.60
2-Hydroxyestrone-3-methyl ether 0.2 0.25 −19.4% (-52.8%-37.7%) 0.45 34.9% (-19.1%-124.8%) 0.17
4-Hydroxylation pathway EM 1.01 0.67 −40.1% (-59.2%-
-
11.8%) 1.04 −13.6% (-40.6%-25.7%) 0.60
4-Pathway catechol: 4-Hydroxyestrone 0.81 0.49 −39.1% (-61.7%-
-
3.0%) 0.73 −18.0% (-47.6%-28.2%) 0.43
4-Pathway methylated catechols 0.16 0.13 −14.1% (-49.0%-44.7%) 0.25 48.8% (-10.4%-146.9%) 0.11
4-Methoxyestrone 0.12 0.09 −9.5% (-45.7%-51.0%) 0.15 69.1% (2.0%-180.4%) 0.05
4-Methoxyestradiol 0.02 0.02 −29.9% (-70.7%-67.7%) 0.07 87.2% (-19.3%-334.2%) 0.08
16-Hydroxylation pathway 12.9 15.9 19.5% (-24.8%-90.1%) 13.4 −1.6% (-37.4%-54.8%) 0.95
16α-Hydroxyestrone 1.15 1.22 −6.7% (-42.1%-50.1%) 1.25 −22.1% (-50.6%-22.7%) 0.27
Estriol 5.41 7.24 24.3% (-32.4%-128.6%) 5.85 3.5% (-42.8%-87.6%) 0.91
16-Ketoestradiol 4.28 5.09 20.5% (-22.1%-86.3%) 3.86 −18.5% (-46.8%-25.0%) 0.36
16-Epiestriol 0.88 0.77 −20.6% (-48.9%-23.4%) 0.91 6.4% (-30.5%-63.0%) 0.75
17-Epiestriol 0.15 0.11 −8.8% (-53.5%-79.0%) 0.16 1.6% (-46.2%-91.9%) 0.94
Ratios
Parent estrogens / estrogen metabolites 0.27 0.17 −37.8% (-57.2%-
-
9.5%) 0.18 −32.6% (-53.3%-
-
2.8%) 0.04
2-Hydroxylation pathway / parent estrogens 1.10 1.06 8.7% (-29.4%-67.4%) 1.48 12.0% (-26.4%-70.6%) 0.60
4-Hydroxylation pathway / parent estrogens 0.17 0.17 6.0% (-37.4%-79.5%) 0.26 32.5% (-21.2%-122.6%) 0.28
16-Hydroxylation pathway / parent estrogens 2.22 4.08 95.0% (25.5%-202.9%) 3.34 57.1% (2.6%-140.5%) 0.05
2-Hydroxylation pathway / 16-hydroxylation pathway 0.50 0.26 −50.2% (-70.6%-
-
15.5%) 0.44 −19.9% (-51.7%-33.0%) 0.41
Fuhrman et al. Nutrition Journal 2013, 12:25 Page 9 of 14
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Table 4 Age-standardized mean urinary concentrations (picomoles per mg creatinine) of estrogens and estrogen metabolites (EM) and multivariable-adjusted
percent difference
1
across categories of green tea intake in postmenopausal women (Continued)
4-Hydroxylation pathway / 16-hydroxylation pathway 0.08 0.04 −51.4% (-71.0%-
-
18.6%) 0.08 −10.1% (-45.7%-48.8%) 0.69
2-Hydroxylation pathway / 4-hydroxylation pathway 6.34 6.15 7.6% (-14.9%-36.0%) 5.70 2.6% (-18.9%-29.9%) 0.87
4-Pathway methylated catechols / 4-pathway catechol 0.20 0.26 37.3% (-23.3%-145.7%) 0.35 86.1% (6.6%-225.0%) 0.03
2-Pathway methylated catechols / 2-pathway catechols 0.24 0.29 14.4% (-25.4%-75.4%) 0.32 33.6% (-11.2%-100.8%) 0.16
Derived measures of estrogen metabolism and statistically significant estimates are presented in bold font.
1
Robust linear regression models were used to estimate percent difference in EM measures with 95% confidence limits across categories of green tea intake while adjusting for age and study center.
2
Robust linear regression was used to test for trends in log-transformed EM measures across tea categories. P
trend
was modeled using categories coded as 0, 1, and 2.
Fuhrman et al. Nutrition Journal 2013, 12:25 Page 10 of 14
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ted with lower 16-hydroxylated estrogen metabolites
(P trend = 0.001).
Among postmenopausal women (Table 4), urinary
concentrations of estrone and estradiol declined across
categories of green tea intake (P trend =0.001 and 0.09,
respectively). Each of these was approximately 40%
lower in women drinking at least one cup daily
compared to those drinking less than one cup per week.
Accordingly, the ratio of parent estrogens to all estrogen
metabolites decreased across categories of green tea in-
take (P trend =0.04). Finally, the ratio of methylated
catechols in the 4-hydroxylation pathway to catechols
in the 4-hydroxylation pathway increased significantly
(P trend =0.03), while the same ratio in the 2-hydroxylation
pathway increased non-significantly (P trend =0.16).
These associations were apparent both in minimally
adjusted analyses and in analyses adjusted for additional
potential confounders as described in the methods. Other
measures of acculturation and Asian diet, such as Asian
birthplace and soy intake, acted as negative confounders
of this association, i.e., additional adjustment for these
factors strengthened the observed associations between
green tea intake and urinary concentrations of parent
estrogens. Additional adjustment for caffeine did not
change the magnitude or direction of the associations.
The estrogens and estrogen metabolites observed to be
significantly associated with green tea in premenopausal-
luteal and postmenopausal women did not show similar
associations with categories of black tea intake (data not
shown).
While study findings suggest that green tea intake may
influence urinary concentrations of estrogens, the
observed associations differed by menopausal status. This
may occur because of the marked differences in pre- and
postmenopausal women with respect to the levels and
sources of systemic estrogens. It is recognized, for ex-
ample, that tamoxifen and aromatase inhibitors have dif-
ferent efficacies in premenopausal women with intact
ovaries, and their postmenopausal counterparts.
In premenopausal women, green tea intake was associated
with reduced total estrogens and specifically with markedly
reduced 16-pathway EM. No significant association was
seen between green tea intake and urinary concentrations of
estrone or estradiol. The observed associations did not
change in magnitude or direction with adjustment for po-
tential confounders, including measures of acculturation
and Asian diet.
In contrast, among postmenopausal women, urinary es-
trone and estradiol declined significantly across categories of
green tea intake. Moreover, among postmenopausal women
no trends with green tea intake were seen total EM or for
the metabolites of estrone and estradiol, including 16-
hydroxylated estrogen metabolites. The associations of
green tea with estrone and estradiol observed among
postmenopausal women were robust to additional adjust-
ment for measures of acculturation and Asian diet.
The geometric mean urinary concentrations of total
estrogens and estrogen metabolites observed in the
postmenopausal Japanese-American women from the
present study is substantially lower (~50%) than the
median urinary levels of total estrogens and estrogen
metabolites observed in a recent study of mostly
Caucasian postmenopausal women from Western New
York [18]. In contrast, mean urinary concentrations of
total estrogens and estrogen metabolites measured in
premenopausal Japanese-American women during the
luteal phase appear to be similar to the mean urinary
concentrations observed in Nurses’ Health Study II
participants who were in the luteal phase of the men-
strual cycle and were mostly Caucasian [19]. Relative
representation of different metabolic pathways also
appear to differ across these studies, with both pre-
and postmenopausal Japanese-American women in
the present study showing markedly lower relative
concentrations of 2-hydroxylated estrogen metabolites
when compared to their respective counterparts [18,19].
It is not clear whether these differences are due to ethni-
city, diet or other cultural practices, or te chnical factors.
Several previous studies have investigated the asso-
ciations of green tea intake with circulating or urinary
estrogens. Consis tent with our observation in post-
menopausal women, Wu and colleagues [6] observed
that in postmenopausal Chinese women in Singapore,
green tea intake was associated with lower serum es-
trone and estradiol. However, Wu and colleagues re-
cently reported on a double-blinded, randomized,
placebo-controlled intervention study that was con-
ducted to investigate the effect of a green tea extract
containing epigallocatechin gallate (EGCG) on circulat-
ing hormones [20]. Postmenopausal women (n = 103)
were randomized to receive placebo, 400-mg EG CG, or
800-mg EGCG per day. Serum estrogens and androgens
were measured at baseline and after months 1 and 2 of
the intervent ion. Estrogen metabolites were not mea-
sured. Investigators did not observe consistent changes
in serum estradiol, estrone, or testosterone in any arm of
the trial during the 2-month intervention but they did
observe statistically significant changes in LDL choles-
terol and gluc ose-related parameters in women given
green tea extract. Based upon these findings, the authors
suggest that green tea might modify cancer risk through
other pathways. It should be considered that differences
between the finding s of the present study and the
randomized feeding trial could reflect differences in the
study design or the exposure. While the present study
design is more pro ne than the feeding trial to
confounding by unmeasured covariates, it is also pos-
sible that a true effect of green tea drinking on estrogen
Fuhrman et al. Nutrition Journal 2013, 12:25 Page 11 of 14
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levels is mediated by a component not present in the
EGCG isolate used in the trial.
In a previous cross-sectional study of green tea intake
among 50 premenopausal Japanese women, Nagata and
colleagues found no association of tea with luteal plasma
estradiol levels, but did find an inverse association of
green tea intake with follicular plasma estradiol
concentrations [21,22]. This is con sistent with the null
association observed between tea and luteal-phase
estrogens in the premenopausal women studied here.
The present study is, to our knowledge, the first to
measure a broad panel of urinary estrogen metabolites
in association with intake of green tea. Findings in
premenopausal women could suggest that green tea
drinking reduces 16-hydroxylation of estrogens. The in-
verse association with tea intake was seen for urinary
concentrations of nearly all 16-pathway estrogen
metabolites. Effects of tea catechins on some CYP450
enzymes with site-selective hydroxylation of parent
estrogens (CYP1A and CYP3A) have been observed in
laboratory studies, but the net impact of these changes
on the in vivo estrogen profile is not clear [23,24]. Other
possibilities may also be considered. Green tea may
affect the half-life of circulating 16-hydroxylated
metabolites by modulating their enterohepatic recircula-
tion [25], or, alternatively, their excretion in urine, by
modifying activity of the enzymes important in conjuga-
tion. A specific effect of green tea on 16-hydroxylation
of estrogens should be considered in future studies. In a
recent study of urinary estrogens and estrogen
metabolites in association with premenopausal breast
cancer risk, most 16-hydroxylated estrogen metabolites
were not associated with increased risk; however, urinary
17-epiestriol, which in our study shows a significant, in-
verse trend with green tea intake, was found to be
associated with increased risk [26]. To date, the data on
this metabolite and its association with breast cancer
risk is very limited however, and so the implications of
this fin ding are not clear.
Because aromatization of androgens accounts for most
postmenopausal estrogens, lower estrogens in associ-
ation with green tea intake suggests a possible effect of
green tea on aromatase activity. Laboratory-based evi-
dence suggests that green tea catechins may reduce
aromatase enzyme activity [23,24,27,28] by modulating
expression of CYP19 isoforms [23]. Another study
suggests that chronic exposure to tea catechins may be
associated with increased expression of this enzyme [29].
The overall impact of exposure to green tea catechins on
aromatase-mediated estrogen production is not clear
from these laboratory model-based studies. However,
mediation of a green tea effect by aromatase is
supported by the observation in a previous study,
which found that green tea intake and varia nts in the
aromatase gene had multiplicative effects on the risk of
endometrial cancer [30].
Observations of increased ratio of methylated
catechols to catechols in the 2- and 4-hydroxylation
pathways across categories of green tea intake in
postmenopausal women could suggest that green tea has
an effect on methylation of catechols. In a recent
case-control study of breast cancer, the ratio of
4-hydroxylation pathway methylated catechols to
4-hydroxylation pathway catechols was observed to be
associated with statistically significantly reduced risk of
breast cancer. Catechols in both the 2- and 4- hydroxyl-
ation pathways can be oxidized to form quinones; these
reactive electrophiles can then react with DNA to form
mutagenic adducts [31]. Methylation of the catechols
prevents their conversion to reactive quinones and
therefore could be expected to be protective with respect
to breast cancer risk [32]. Again, it is not clear why this
effect would be more apparent among postmenopausal
women compared to their premenopausal counterparts.
Estrogens are recognized as important causal factors in
the pathogenesis of breast cancer. Prospective studies of
postmenopausal women have consistently found increased
risk of breast cancer in association with higher circulating
[33] and urinary estrogens [34,35]. Recent studies suggest
that elevated endogenous estrogens are associated with
increased risk of both estrogen receptor positive and nega-
tive breast cancers in postmenopausal women [36]. For
premenopausal women the association of circulating
estrogens with breast cancer risk has not been well
supported by the literature, perhaps due to methodologic
challenges posed by variability in estrogen levels across the
menstrual cycle. Of two studies that carefully accounted for
menstrual phase [37,38], one found increased breast cancer
risk with higher plasma estradiol during the follicular but
not the luteal phase of the menstrual cycle [37] while the
other was null [38]. Thus our findings of differences in
premenopausal estrogen metabolite profiles by green tea in-
take have uncertain implications for breast cancer risk . In
contrast, our finding that green tea intake is associated with
reduced urinary estrone and estradiol in our sample of
postmenopausal Japanese-American women, does support
the hypothesis that green tea intake may reduce
postmenopausal breast cancer risk by modifying exposures
to endogenous estrogens.
It should be noted, however, that there are a limited
number of studies of green tea intake and risk of breast
cancer, and that the evidence from these studies does not
consistently support such an association. In particular, of
three prospective studies, all conducted in Asia, two had
null findings [39,40] while the most recent found reduced
premenopausal breast cancer risk in association with
regular intake of green tea before the age of 26, and
increased breast cancer risk in postmenopausal women
Fuhrman et al. Nutrition Journal 2013, 12:25 Page 12 of 14
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with the same exposure [41]. Most studies of green tea
have not considered pre- and postmenopausal women
separately [42]; only one previous study considered meno-
pausal status as a potential modifier of the association
[41]. While adjustment for other measures of accultur-
ation did not lessen the observed associations, it remains
possible that green tea intake observed in our study was
associated with estrogen profiles as a very sensitive marker
of acculturation rather than a causal factor. More pro-
spective studies, with careful assessments of menopausal
status and of green tea intake at susceptible times of life,
are needed to establish whether green tea is associated
with reduced breast cancer risk.
There are a number of strengths of this study worth
noting. This population-based sample of Japanese
American women recruited in three geographic locations
was carefully characterized for varying levels of accultur-
ation. Participants were also queried about breast cancer
risk factors and other dietary factors. We used a highly
sensitive, specific and reliable assay to measure 15
estrogens and estrogen metabolites in urine [43]. The
EM profile is a phenotypic measure and thus provides a
direct way to test hypotheses about the effects of dietary
and lifestyle factors on estrogen metabolism. Study
limitations included the use of questionnaire-based diet-
ary assessment and the lack of information about serving
sizes. As is true in any observational study, there is the
potential for confounding of assoc iations of tea and EM
profiles by unmeasured dietary or lifestyle factors. While
we did adjust for regular intake of soy foods, we were
not able to adjust for some othe r dietary factors such as
alcohol intake.
Conclusions
Among postmenopausal Japanese American women, we
observed that more frequent intake of green tea was
associated with reduced urinary concentrations of es-
trone. As a rich source of phytochemicals that can inter-
act with and regulate xenobiotic metabolizing enzymes,
green tea may modify metabolism [22] or conjugation of
estrogens [44] and may thereby impact breast cancer
risk. Randomized feeding studies will be helpful to estab-
lish the mechanisms by which green tea may modulate
cancer risk.
Competing interests
The authors have declared no conflict of interest.
Authors’ contributions
AW and RZ participated in the design and coordination of the Asian
American Breast Cancer Study from which these participants have been
drawn. BF, AW and RZ conceived of the present study. BF and RP performed
the statistical analyses and drafted the manuscript. XX, TZ, RZ and LK
developed the assay for estrogens and estrogen metabolites and
coordinated its first application in the Asian American Breast Cancer Study.
XX carried out the assays to measure estrogens and estrogen metabolites in
urine samples. All authors read and approved the final manuscript.
Funding
This work was supported by the Intramural Research Program of the Division
of Cancer Epidemiology and Genetics of the National Cancer Institute (NCI),
National Institutes of Health (NIH) and contract # HHSN261200800001E to
SAIC, Inc. from NCI, NIH, DHHS.
Author details
1
Division of Cancer Epidemiology and Genetics, National Cancer Institute,
National Institutes of Health, Bethesda, MD, USA.
2
SAIC-Frederick, Inc,
National Cancer Institute at Frederick, Frederick, MD, USA.
3
University of
Southern California Keck School of Medicine, Los Angeles, CA, USA.
4
National
Cancer Institute at Frederick, Frederick, MD, USA.
5
Current address:
Department of Epidemiology, Fay W. Boozman College of Public Health,
University of Arkansas for Medical Sciences, 4301 W. Markham St. #820, Little
Rock, AR 72205, USA.
Received: 23 July 2012 Accepted: 30 December 2012
Published: 15 February 2013
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doi:10.1186/1475-2891-12-25
Cite this article as: Fuhrman et al.: Green tea intake is associated with
urinary estrogen profiles in Japanese-American women. Nutrition Journal
2013 12:25.
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