47

Cancer Causes and Control 12: 4759, 2001.

2001 Kluwer Academic Publishers. Printed in the Netherlands.

Circulating levels of sex hormones and their relation to risk factors for breast cancer:
a cross-sectional study in 1092 pre- and postmenopausal women (United Kingdom)
Pia K. Verkasalo*, Hollie V. Thomas, Paul N. Appleby, Gwyneth K. Davey & Timothy J. Key
Imperial Cancer Research Fund Cancer Epidemiology Unit, University of Oxford, Gibson Building, Radclie
Inrmary, Oxford OX2 6HE, UK; Ph.: +44-1865-311933; Fax: +44-1865-310545; E-mail: p.verkasalo@
icrf.icnet.uk (*Author for correspondence)
Received 22 February 2000; accepted in revised form 1 August 2000

Key words: body mass index, estrogens, physical activity, reproductive history, sex hormone-binding globulin.

Abstract
Objective: To investigate the relationships between plasma concentrations of sex hormones and risk factors for
breast cancer.
Methods: We investigated the relationship of plasma concentrations of estradiol, progesterone, follicle-stimulating
hormone (FSH), luteinizing hormone (LH) and sex hormone-binding globulin (SHBG) with breast cancer risk
factors in 636 premenopausal and 456 postmenopausal women. Risk factor data were obtained from questionnaires
and hormone concentrations measured by immunoassays; variations in geometric means were compared using
analysis of covariance.
Results: SHBG decreased with increasing body mass index and increasing waisthip ratio both in pre- and
postmenopausal women. In postmenopausal women only, estradiol increased with increasing body mass index. In
premenopausal women, estradiol decreased with increasing physical activity, estradiol was higher in current than in
ex- and non-smokers, and FSH decreased with increasing alcohol intake. No associations were observed between
sex hormones and age at menarche, parity, age at menopause, and previous use of oral contraceptives in either
pre- or postmenopausal women.
Conclusions: Certain factors such as obesity and perhaps waisthip ratio, physical activity and alcohol
consumption, but probably not age at menarche and parity, may mediate their eects on breast cancer risk
by changing circulating concentrations of sex hormones.
Introduction
Breast cancer risk is strongly related to various
hormonal factors, and a high serum concentration of
estradiol, perhaps augmented by progesterone, is an
important determinant of breast cancer risk [1]. Recent
prospective studies have conrmed that high blood
levels of estradiol are associated with an increased
breast cancer risk in postmenopausal women. Seven
out of eight original studies have observed elevated
relative risks in postmenopausal women with high
estradiol levels, and the pooled relative risk estimate is
2.3 for women with high compared to low estradiol
concentrations (95% CI 1.63.2) [2]. Fewer data are
available for premenopausal women, and none of
the four prospective studies has found statistically

signicant associations between estradiol and breast

cancer risk [2].
Lifestyle and reproductive factors that aect the risk
of breast cancer [35] may act by altering exposure to
sex hormones, in particular estrogens. For instance,
early menarche and late menopause increase breast
cancer risk, which indicates that the duration of
exposure to cyclic ovarian function is an important
determinant of breast cancer risk. Obesity in postmenopausal women increases breast cancer risk; this
would be compatible with increased blood estrogen
concentrations in obese postmenopausal women because estrogen synthesis after menopause takes place
primarily in adipose tissue. Thus duration of exposure
to sex hormones and changes in their concentrations
provide potentially important but not yet clearly

48
dened biological mechanisms for breast cancer risk
factors.
The aim of this study was to investigate the relationship between breast cancer risk factors and plasma
concentrations of estradiol, sex hormone-binding
globulin (SHBG), and, in premenopausal women, progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in a cross-sectional sample of
1092 women. The term plasma will be used for convenience to include assays in both plasma (estradiol,
SHBG) and serum (FSH, LH, progesterone). Likewise,
we shall refer to the ``concentrations of hormones'' even
though SHBG is not a sex hormone but a protein that
binds estradiol and other steroids, transports them in
the blood, and regulates their access to target tissues.
Materials and methods
Study subjects and data collection
Between 1993 and 1999, 58,000 subjects (44,500 women)
aged 20 years and above and living in the UK entered
the Oxford component of the European Prospective
Investigation into Cancer and Nutrition (EPIC) [6].
Participants were recruited through collaborating general practitioners, vegetarian and vegan societies, health
food magazines, and from the friends and relatives of
participants. All participants completed a questionnaire
which included details of age, height, weight, hip and
waist circumferences, sexual maturation, reproductive
history, menopausal status, use of oral contraceptives
and other hormonal therapy, occurrence of diseases in
close relatives, current and lifetime consumption of
alcohol and tobacco, physical activity, previous and
current illnesses, current medication, as well as an
extensive food-frequency questionnaire.
A 30 ml blood sample was obtained from a large
proportion of the volunteers, sent through the mail to
the laboratory, aliquoted into plasma, serum, white
blood cells and erythrocytes, and stored either at )70 C
(2 2 ml aliquots of plasma) or in 0.5 ml aliquots in
liquid nitrogen at )196 C (all other samples). At
venepuncture the rst day of the ongoing menstrual
cycle was recorded, and the women subsequently returned a form to report the rst day of the cycle
following venepuncture. All dates of sample and questionnaire processing, time of day of venepuncture,
as well as time since last meal were recorded.
The present study consists of a sample of 1092 women
who had been recruited for EPIC-Oxford during 1994
and 1995 (total = 16,910) and who fullled some
additional criteria to ensure the availability of key

P.K. Verkasalo et al.

information for all participants and to reduce biological
variation due for example to irregular cycles or perimenopausal status at venepuncture. More specically,
the analyses for estradiol and SHBG include 636
premenopausal women who were aged 2044, reported
having 10 or more menstrual periods in the past 12
months and had a most recent menstrual cycle less than
40 days long. The analyses also include 456 postmenopausal women who were aged 55 or more and reported
having no menstrual periods in the past 12 months. In
addition, subsamples of 492 and 341 premenopausal
women were assayed for progesterone and FSH/LH,
respectively, based on day of cycle at venepuncture
(days of cycle 0 to )21 for progesterone and )6 to )21
for FSH and LH); day of cycle was calculated backwards starting from the rst day of menstruation
following venepuncture.
Women were not included in the study if they were
using any exogenous sex hormones or were pregnant at
the times of questionnaire or blood collection, if their
number of menstrual periods in the past 12 months was
unknown, if the day of their menstrual cycle on which
their blood sample was collected was unknown, if they
had undergone a hysterectomy and were aged less than
60, if they had undergone an oophorectomy, or if they
had previously had cancer. This same sample of women
has also been used to investigate the relationships
between diet and hormones [7], except for ve women
who were excluded because they did not fulll the
entrance criteria after further data checking.
Laboratory analyses
Laboratory measurements for hormones were carried
out in three stages: (i) estradiol and SHBG concentrations were measured between January and March 1997
for premenopausal women; (ii) between August 1996
and February 1997 for postmenopausal women; (iii)
FSH, LH and progesterone concentrations were measured between April and June 1999. Each time, samples
were randomly assigned to assay batches and randomly
ordered for assay within each batch. Assays were
performed by batch without any knowledge of the
subjects involved. Postmenopausal but not premenopausal concentrations were measured in duplicate.
The assays for estradiol, progesterone, FSH, and LH
in premenopausal women were carried out on a Bayer
``Immuno 1'' analyzer by heterogeneous competitive
magnetic separation (estradiol, progesterone) or heterogeneous sandwich magnetic separation (FSH, LH)
(Bayer plc, Berkshire, UK). Overall percentage coecients of variation (%CV) were calculated by dividing
the standard deviations for three levels of quality

Sex hormones and breast cancer risk factors

controls by their means (estradiol: 390, 932, 4017 pmol/
L; FSH: 3.68, 8.55 and 51.9 U/L; LH: 3.69, 15.7 and
72.3 U/L; progesterone: 3.57, 35.7 and 98.3 nmol/L).
The respective %CVs were 4.8%, 2.4% and 2.3% for
estradiol; 1.2%, 2.3% and 1.2% for FSH; 2.5%, 1.6%
and 2.1% for LH; and 20.4%, 8.2% and 4.6% for
progesterone.
Postmenopausal estradiol concentrations were measured by radioimmunoassay after ether extraction [8].
This method was especially designed for the purpose of
measuring the very low estradiol concentrations in
postmenopausal women; the lowest detectable concentration was 3.0 pmol/L. For the three successive levels
of quality controls (with means of 22.0, 83.9, and
151 pmol/L), the intra- and inter-assay %CVs were,
respectively, 16.3% and 21.8%, 15.0% and 14.1%, and
11.4% and 11.1%.
SHBG concentrations were measured by immunoassay. For premenopausal women, %CVs were 13.8% and
6.2% for two control levels (means 10.1 and 94.0 nmol/
L); for postmenopausal women, intra- and inter-assay
%CVs were 5.3% and 10.9% for lower-concentration
controls (mean 9.66 nmol/L); and 4.1% and 8.4% for
higher-concentration controls (mean 95.6 nmol/L). It
should be noted that the assays of SHBG in pre- and
postmenopausal women were conducted in dierent
laboratories and direct comparison of concentrations
between these groups should not be made.
Statistical analyses
Concentrations of hormones were logarithmically transformed to reduce the positive skewness of the distributions. Associations between hormone concentrations
and breast cancer risk factors were rst investigated
using Pearson and partial correlation coecients adjusted for age and day of cycle. We then applied analysis
of covariance models (SAS, PROC GLM) to provide
(uncentered) adjusted estimates of means and 95%
condence intervals (CI) of the logarithmically transformed concentrations by breast cancer risk factors. For
comparability these estimates were centered by adding
the quantity c to
P each log-transformed adjusted mean,
where c x i ni si =N and x denotes the unadjusted mean log-transformed concentration calculated using
all observations, ni the number of observations in the ith
category of the factor, si the uncentered adjusted mean
log-transformed hormone concentration in the ith category, and N the total number of observations. Finally,
we exponentiated these values to obtain the geometric
means and 95% CIs. The signicance of a variable
in each model was assessed by a partial sum of squares
F-test; the criterion for statistical signicance was set at

49
the 5% level. We report p-values for heterogeneity and
also, when appropriate, for linear trend. All p-values in
the text denote p-values for heterogeneity, except when
otherwise stated.
The distribution of premenopausal women according
to the day of cycle (counted backwards from the
beginning of the next cycle) was as follows: days
0 to )2 n = 51; days )3 to )5 n = 72; days )6 to
)7 n = 49; days )8 to )10 n = 72; days )11 to
)13 n = 63; days )14 to )17 n = 99; days )18 to )20
n = 74; days )21 to )23 n = 72; and days )24
n = 84. We plotted the age-adjusted geometric mean
concentrations of hormones in premenopausal women
by the day of menstrual cycle (Figure 1). Both FSH
and LH concentrations peaked in midcycle; estradiol
peaked in midcycle, but was also elevated in the luteal
phase; progesterone had the highest values in the luteal
phase; and SHBG did not vary markedly with day of
cycle.
We report results from standard models which included the following variables: age at recruitment
(5-year age groups), day of cycle (estradiol and SHBG:
0 to )2, )3 to )5, )6 and )7, )8 to )10, )11 to )13, )14
to )17, )18 to )20, )21 to )23, and )24 days;
progesterone: 0 to )2, )3 and )4, )5 and )6, )7 and )8,
)9 and )10, )11 and )12, )13 and )14, )15 and )16,
)17 to )19, and )20 days; FSH: )6 to )9, )10 to )12,
)13 to )15, )16 to )18, and )19 to )21 days; LH: )6 to
)8, )9 to )11, )12 and )13, )14 and )15, )16 and )17,
and )18 to )21 days), time of day of venepuncture (in
premenopausal women: before 9.00, 9.0011.59, 12.00
14.59, 15.0017.59, later than 18.00; in postmenopausal
women: before 9.00, 9.0011.59, 12.0014.59, later than
15.00), assay batch (eight assay batches for estradiol and
SHBG in pre- and 15 in postmenopausal women; 10
batches for FSH, LH and progesterone in premenopausal women), hours since last meal, time the sample
was in the mail (days) and in storage (years), body mass
index (BMI; <20, 2022.4, 22.524.9, 25.027.4,
27.5 kg/m2), waisthip ratio (in thirds: <72.54%;
72.5476.80%; 76.80%), physical activity at work
(sedentary occupation, standing occupation, manual
work), vigorous exercise (none, 12, 34, 5 hours per
week), current alcohol use (none, <8, 815, 16 g
daily), smoking status (never, ex-smoker, current
smoker), occurrence of breast cancer in either mother
or sister (no, yes), age at menarche (<12, 12, 13, 14,
15 years), number of births (nulliparous, 12 births,
3 births), and previous uses of oral contraceptives (no,
yes) and hormonal replacement therapy (in postmenopausal women only: no, yes). Standard models were,
when appropriate, also tted to subsets of data stratied
by cycle phase. Missing data for all variables were

50

P.K. Verkasalo et al.

Fig. 1. Age-adjusted geometric mean hormone concentrations by day of cycle in premenopausal women. * Day of cycle counted backwards from
the beginning of the next cycle.

replaced with the mean of non-missing values (or the

modal value for categorical data), calculated separately
for pre- and postmenopausal women; the sensitivity
analyses showed that this had no important eect on the
geometric means. However, for the analyses which also
included age at menopause in postmenopausal women
(<45, 4549, 4054, 55 years), we excluded the 104
observations for which this variable was unknown.
In addition, we tted more parsimonious models to
conrm the results provided by the standard models.
These models were individually tailored and included
the essential variables (age, day of cycle, assay batch,
time of day of venepuncture, hours since last meal, days
in post, and years in storage), the risk factor of interest

and the other covariates with partial sums of squares

p-value and/or linear trend p-value equal to or less than
0.10. We also investigated the inclusion of additional/
alternative variables such as weight, height, and lifetime
smoking. To restrict the estradiol analyses to the
premenopausal women who appeared to be ovulatory
during the cycle of the venepuncture, we excluded 37
premenopausal women whose progesterone, FSH or LH
concentrations at the cycle of the venepuncture were
below the laboratory reference range (progesterone <
16 nmol/L during days )3 to )11; FSH < 5.1 U/L
during days )13 to )15; LH < 17.5 U/L during days
)14 to )15). However, none of these rened analyses
provided additional information.

Sex hormones and breast cancer risk factors

51

Results

LH (increase, p = 0.083). In postmenopausal women,

age was not associated with estradiol but SHBG
increased with age (p = 0.003).

Timing of blood collection and duration of storage

In premenopausal women (Table 1), estradiol concentration increased by 1% per hour since last meal
(p = 0.010 for trend). Estradiol, FSH, progesterone
and LH concentrations were highest before 9 a.m. but
the overall eects of time of day of venepuncture were
not statistically signicant. In postmenopausal women
(Table 2), estradiol increased by 5% per day the blood
sample was in the mail (2 days for 86% of samples;
p = 0.081 for trend). However, estradiol and SHBG did
not show any daily patterns, nor did other features of
sample processing have an eect on the concentrations
in postmenopausal women.

Body mass index and waisthip ratio

In premenopausal women, SHBG decreased with increasing BMI (p < 0.001 for trend). The results of the
standard model for estradiol in premenopausal women
were less clear: while the geometric mean values for the
lowest three categories of BMI were similar, those for
the highest two categories were somewhat lower
(p = 0.055 for trend). To investigate this further, we
supplemented the standard model for estradiol with the
logarithm of SHBG as covariate, and the standard
model for SHBG with the logarithm of estradiol as
covariate. This showed that SHBG concentration accounted for most of the variation in estradiol concentration with BMI, whereas the variation in SHBG
concentration with BMI was largely unaected by
adjustment for estradiol.
In postmenopausal women, we observed a large
increase in estradiol with increasing BMI (p < 0.001
for trend), and a large decrease in SHBG (p < 0.001 for
trend). Inclusion of SHBG in the model for estradiol, or
vice-versa, did not have any substantial eect on the
mean values.
For waisthip ratio (adjusted for BMI), we observed a
decrease in SHBG both in pre- and postmenopausal
women (p = 0.012 and p < 0.001 for trend, respec-

Age
Tables 3 and 4 show the geometric mean concentrations
of sex hormones by breast cancer risk factors in
premenopausal and postmenopausal women, respectively. Age was a highly statistically signicant determinant
of estradiol in premenopausal women (p = 0.007).
Much of this was accounted for by the very low mean
estradiol concentrations among 2024-year-old women
during midcycle (data not shown). In premenopausal
women, age was also associated with concentrations
of SHBG (increase, p = 0.007), FSH (increase,
p < 0.001), progesterone (decrease, p = 0.055) and

Table 1. Relationships between circulating sex hormones and timing of blood collection and duration of storage in 636 premenopausal women.
Geometric mean concentrationsa, percent changes per unit, 95% condence intervals (CI) and p-values are shown for estradiol, SHBG, FSH,
progesterone and LH
Category

Estradiol (pmol/L)

SHBG (nmol/L)

FSH (U/L)

Mean

Mean

Mean

95% CI

Time of the day of venepuncture (missing =

<9
417
344506
911
360
317409
1214
318
271372
1517
348
299405
18
338
280407
p for heterogeneity
0.083
Assay batch
p for heterogeneity

19)
43.6
45.7
49.8
46.5
45.2

0.12

95% CI
37.151.3
41.150.8
43.656.8
41.052.8
38.752.8
0.48

8.1
7.2
6.8
6.8
7.1

0.082

95% CI
6.410.4
6.18.5
5.68.2
5.78.2
5.78.9
0.61

Progesterone (nmol/L)

LH (U/L)

Mean

Mean

16.8
12.3
12.4
10.9
10.4

<0.001

95% CI
11.724.2
9.615.7
9.316.7
8.114.5
7.215.1
0.16
0.005

% change p for trend % change p for trend % change p for trend % change p for trend
Hours since last meal 1.1
(missing = 81)

0.010

0.5

14.9
11.0
10.0
13.1
13.5

0.19

)0.2

0.74

)1.7

0.098

95% CI
10.122.2
8.514.4
7.213.7
9.817.8
9.419.5
0.10
<0.001

% change p for trend

0.7

0.20

Days in mail

3.3

0.11

1.1

0.53

)1.1

0.47

)0.4

0.72

)4.4

0.32

Years in storage

2.6

0.59

2.9

0.46

)1.2

0.91

1.1

0.92

)1.8

0.76

Adjusted for day of cycle and all other variables in Tables 1 and 3.

52

P.K. Verkasalo et al.

Table 2. Relationships between circulating sex hormones and timing of blood collection and duration of storage in 456 postmenopausal women.
Geometric mean concentrationsa, percent changes per unit, 95% condence intervals (CI) and p-values are shown for estradiol and SHBG
Category

Estradiol (pmol/L)
Mean

Time of the day of venepuncture (missing = 21)

<9
19.4
911
18.1
1214
19.8
15
18.1
p for heterogeneity
Assay batch
p for heterogeneity (missing = 18)

0.72

SHBG (nmol/L)
95% CI

Mean

95% CI

14.825.5
15.621.1
16.024.5
15.121.8

45.5
45.2
42.8
44.4

36.357.1
39.951.2
35.851.2
38.251.7

p for trend

% change

<0.001
% change

0.89
0.005

p for trend

Hours since last meal (missing = 36)

0.5

0.44

)0.4

0.95

Days in mail (missing = 18)

4.9

0.081

3.4

0.21

0.69

0.2

0.64

Years in storage
a

)2.2

Adjusted for all other variables in Tables 2 and 4, except age at menopause.

tively); no associations were observed with the other

hormones.
Physical activity
Premenopausal estradiol concentrations decreased with
increasing amount of vigorous exercise (p = 0.043 for
trend). Estradiol also decreased by increasing physical
activity at work but this tendency was not statistically
signicant (p = 0.093 for trend). When we investigated
the eects of physical activity using more parsimonious models, the results remained materially the
same.
Postmenopausal estradiol concentrations in the rst
three groups of vigorous exercise were very similar while
that in the highest group (5 hours per week) was
somewhat elevated (p = 0.036 for trend). No dierence
was observed for postmenopausal estradiol concentrations by physical activity at work, nor were there
associations with any other hormones in pre- or
postmenopausal women. The geometric means and pvalues from more parsimonious models were virtually
identical to those from standard models.
Alcohol
We observed decreasing premenopausal concentrations
of SHBG, FSH and possibly also LH by increasing daily
intake of alcohol (p = 0.014, p = 0.034 and p = 0.059
for trend, respectively). Estradiol was slightly elevated in
women with high alcohol intake but the eect was not
statistically signicant either before or after adjustment

for SHBG (after adjustment the geometric means were

351, 343, 370 and 390 pmol/L; p = 0.091 for trend).
Examination of the association between alcohol and
estradiol by phase of the menstrual cycle suggested that
estradiol was 13% higher in the alcohol consumers than
the non-consumers at midcycle (days )17 to )14); the
age-adjusted geometric mean estradiol was 595 pmol/L
in non-consumers of alcohol (n = 16), 648 pmol/L in
those consuming <8 grams per day (n = 55), and
670 pmol/L in those consuming 8 grams per day
(n = 28; p = 0.50 for trend). In postmenopausal
women, estradiol and SHBG were not associated with
daily alcohol intake.
Smoking
Premenopausal estradiol concentrations in current
smokers were higher than those in ex-smokers and
never smokers (p = 0.003) but no signicant dierences
were observed for the other hormones. No dierences
were observed in estradiol or SHBG concentrations in
postmenopausal women according to smoking.
Family history of breast cancer
SHBG concentrations were lower in premenopausal
women whose mother or sister had been diagnosed
with breast cancer than in other women, but the
dierence was not statistically signicant (p = 0.063).
We observed no other dierences in premenopausal
hormone concentrations, and none in postmenopausal
women.

Sex hormones and breast cancer risk factors

53

Table 3. Relationships between circulating sex hormones and breast cancer risk factors in 636 premenopausal women. Geometric mean
concentrationsa and 95% condence intervals (CI) are shown for estradiol, SHBG, FSH, progesterone and LH
Category

No. of
Estradiol (pmol/L)
subjectsb
Mean
95% CI

Age (years)
2024
42
2529
79
3034
115
3539
197
4044
203
p for heterogeneity

282
321
343
379
369

0.007

232342
272379
296396
331434
323421

SHBG (nmol/L)

FSH (U/L)

Progesterone (nmol/L)

LH (U/L)

Mean

Mean

Mean

95% CI

Mean

10.020.9
9.618.0
10.918.7
9.315.4
8.113.5

10.1
10.4
9.5
12.3
13.1

6.915.0
7.414.6
7.112.7
9.416.0
10.017.2
0.083

43.0
42.7
44.6
44.8
50.6

95% CI

95% CI

95% CI

36.650.5
37.249.1
39.550.4
40.050.2
45.356.6
0.007

6.1
6.1
6.0
7.2
8.5

4.87.8
4.97.5
5.07.1
6.18.5
7.210.0
<0.001

14.4
13.2
14.2
12.0
10.5

54.1
48.060.9
48.0
42.953.6
45.6
40.651.3
38.1
32.944.1
31.7
27.237.1
<0.001/<0.001

7.3
7.2
6.9
7.0
6.9

6.28.7
6.28.5
5.88.1
5.78.7
5.58.7
0.87/0.54

13.3
11.2
12.7
12.8
11.5

10.217.4
8.814.4
9.816.5
9.217.9
8.116.4
0.43/0.66

13.2
11.4
11.2
10.2
10.9

10.017.3
8.814.8
8.514.8
7.114.5
7.515.9
0.49/0.21

47.5
47.6
42.8

42.453.3
42.553.3
38.248.0
0.017/0.012

7.0
7.5
6.7

6.08.3
6.48.9
5.77.9
0.17/0.44

12.2
11.9
12.3

9.415.9
9.215.4
9.516.0
0.94/0.96

10.8
12.2
11.7

8.314.2
9.316.0
8.915.4
0.41/0.46

46.2
46.3
45.1

41.551.4
41.551.7
39.151.9
0.89/0.66

7.0
7.3
7.3

6.08.1
6.28.5
6.08.9
0.64/0.58

11.7
13.0
11.7

9.214.9
10.216.6
8.416.2
0.37/1.00

11.7
11.6
11.1

9.015.1
8.915.0
8.015.4
0.93/0.70

45.8
47.2
44.0
46.4

40.851.4
42.352.7
38.849.8
40.752.8
0.49/0.85

7.2
7.1
7.1
7.0

6.18.6
6.18.3
5.98.6
5.88.4
0.98/0.72

11.4
12.3
13.4
12.0

8.814.8
9.615.7
10.017.9
9.016.1
0.58/0.50

11.0
12.8
11.6
9.62

8.314.6
9.916.5
8.515.8
7.113.1
0.089/0.21

0.055

Body mass index (kg/m ; missing = 12)

<20
124
359
311413
2022.4
255
362
317414
22.524.9
145
365
317420
2527.4
53
309
260369
>27.5
47
322
267387
p for heterogeneity
0.15/0.055
/trend
Waist-hip ratio (missing = 35)
1st
230
356
311408
2nd
188
355
310407
3rd
183
351
306403
p for heterogeneity
0.95/0.77
/trend
Physical activity at work (missing = 14)
Sedentary
322
363
319412
Standing
241
351
308400
Manual
59
323
272382
p for heterogeneity
0.23/0.093
/trend
Vigorous exercise (hours per week)
None
174
361
314415
12
271
367
321418
34
105
338
291394
5
86
324
277378
p for heterogeneity
0.15/0.043
/trend
Current alcohol use (g/day)
None
132
<8 g
315
815 g
128
16 g
61
p for heterogeneity
/trend
Smoking
Never
416
Ex
171
Current
49
p for heterogeneity

362
341
366
383

315417
300388
317423
322454
0.24/0.32

51.1
45.2
44.8
43.7

45.557.5
40.650.4
39.650.5
37.850.4
0.015/0.014

7.8
7.2
6.8
6.3

6.69.1
6.18.4
5.68.1
5.17.9
0.17/0.034

13.5
11.4
12.0
13.9

10.417.5
9.014.6
9.015.9
10.019.3
0.22/0.78

13.5
11.4
11.0
9.8

10.317.6
8.814.8
8.214.8
6.814.1
0.23/0.059

355
331
436

313404
289380
366519
0.003

45.7
46.4
48.9

41.150.9
41.552.0
42.356.6
0.54

7.0
7.4
6.8

6.08.2
6.38.7
5.58.4

12.6
11.1
11.9

9.916.2
8.614.3
8.616.5

11.9
10.4
13.5

9.215.3
8.013.5
9.619.1
0.17

46.5
40.3

42.850.4
34.347.4
0.063

7.2
6.1

6.48.0
4.87.7

12.1
13.5

10.114.4
9.419.5

11.6
10.7

9.714.0
7.315.8
0.65

Breast cancer in a close relative

No
606
355
322391
Yes
30
341
281414
p for heterogeneity
0.66

0.53

0.12

0.31

0.50

54

P.K. Verkasalo et al.

Table 3. (Continued)
Category

No. of
Estradiol (pmol/L)
subjectsb
Mean
95% CI

SHBG (nmol/L)

FSH (U/L)

Progesterone (nmol/L)

LH (U/L)

Mean

Mean

Mean

95% CI

Mean

8.314.4
10.518.2
9.516.1
8.215.0
8.916.0

11.6
12.3
12.1
10.8
10.1

8.715.6
9.116.5
9.216.1
7.914.8
7.513.7
0.58

9.514.9
9.516.1
9.417.7

12.1
11.1
10.8

9.515.3
8.414.6
7.615.2
0.57

8.715.0
9.815.6

11.8
11.5

8.815.9
9.014.7
0.83

95% CI

95% CI

Age at menarche years (missing = 2)

<12
122
360
311416
12
148
354
306409
13
190
357
311410
14
103
342
293400
15
71
357
304419
p for heterogeneity
0.95

43.9
47.3
47.0
44.2
48.4

38.949.6
41.953.4
41.952.8
38.750.3
42.355.3
0.07

7.6
7.3
7.0
6.7
6.8

6.49.1
6.18.8
5.98.3
5.58.1
5.78.2
0.46

10.9
13.8
12.4
11.1
11.9

Number of births
0
351
12
211
3+
74
p for heterogeneity

46.8
45.6
44.5

42.451.7
40.651.2
38.851.1
0.61

7.1
7.1
7.0

6.28.2
6.08.4
5.68.6
0.95

11.9
12.3
12.9

45.4
46.3

40.251.3
41.851.4
0.66

7.1
7.1

5.98.5
6.18.3
0.96

11.4
12.3

359
353
339

319404
307405
287400
0.68

Previous use of oral contraceptives (missing = 1)

Never
124
354
306410
Ever
511
354
313401
p for heterogeneity
0.97
Percent variance
explained by the
model
Percent variance
explained by
factors other
than cycle day

0.21

0.79

0.41

95% CI

52.8%

21.6%

44.7%

71.8%

41.7%

8.4%

20.4%

28.9%

11.2%

20.2%

Adjusted for day of cycle and all other variables in Tables 1 and 3.
The table presents the numbers of subjects who were assayed for estradiol and SHBG, excluding those with missing information for the
variable. The numbers of subjects in each category for progesterone and for FSH/LH were approximately 77% and 54%, respectively, of the
presented numbers. The total numbers of subjects in the statistical analyses were slightly higher (estradiol and SHBG: n = 636; progesterone:
n = 492; and FSH and LH: n = 341), because missing values were replaced either with the mean or typical values of the variable.
b

Reproductive factors and exogenous hormones

SHBG concentrations were non-signicantly elevated in
postmenopausal women who had previously used hormonal replacement therapy. We did not observe any
associations between age at menarche, age at menopause, parity, previous use of oral contraceptives and
sex hormones either in pre- or postmenopausal women.
Relative importance of the factors
In premenopausal women, the percentage variances
explained (R2-values) by the tted standard models were
53% for estradiol, 22% for SHBG, 45% for FSH, 42%
for LH and 72% for progesterone (Table 3). Most of
this was accounted for by day of cycle. Of the other
breast cancer risk factors, BMI explained 8.6% of the
total variance in the model for SHBG and age explained
5.6% of the variance in the model for FSH. None of the
other risk factors explained more than 1.9% of the total
percentage variance.

In postmenopausal women, the percentage variances

explained were 26% for estradiol and 33% for SHBG
(Table 4). In the model for estradiol, 11% of the
variance was accounted for by BMI; in the model for
SHBG, 13% of the variance was explained by BMI,
2.3% by age and 2.2% by waisthip ratio. None of the
other breast cancer risk factors explained more than
1.0% of the total variance in postmenopausal women.
Discussion
The strengths of this study were that the numbers of
pre- and postmenopausal women were larger than in
most earlier studies, that the assay for postmenopausal
estradiol had been optimized to measure very low
concentrations, and that we attempted to adjust the
mean hormone concentrations for all relevant covariates. On the other hand, a limitation of this study is,
in common with all previous studies except one [9],
that only a single blood sample was assayed per

Sex hormones and breast cancer risk factors

55

Table 4. Relationships between circulating sex hormones and breast cancer risk factors in 456 postmenopausal women. Geometric mean
concentrationsa and 95% condence intervals CI of estradiol and SHBG
No. of subjectsb

Category

Estradiol (pmol/L)
Mean

Age (years)
5559
6064
6569
70
p for heterogeneity

108
144
134
70

19.4
17.5
18.3
18.4

Body mass index (kg/m ; missing = 19)

<20
59
2022.4
146
22.524.9
116
2527.4
57
>27.5
59
p for heterogeneity/trend
Waisthip ratio (missing = 10)
1st tertile
2nd tertile
3rd tertile
p for heterogeneity/trend

SHBG (nmol/L)
95% CI

Mean

95% CI

16.323.2
14.720.8
15.322.0
15.022.7

43.4
41.4
46.4
52.6

14.7
16.2
17.9
21.4
28.3

12.018.0
13.619.2
15.021.4
17.526.2
22.935.0
<0.001/<0.001

54.1
53.5
42.3
40.7
30.3

45.764.1
46.261.9
36.549.1
34.448.1
25.436.2
<0.001/<0.001

128
134
184

18.6
18.3
18.1

15.622.3
15.321.9
15.221.5

49.1
46.5
41.0

42.357.0
40.054.0
35.547.4
0.001/< 0.001

Physical activity at work (missing = 19)

Sedentary
214
Standing
184
Manual
39
p for heterogeneity/trend

18.2
18.4
18.5

15.421.5
15.521.9
14.823.0

44.3
45.7
45.0

38.650.8
39.652.7
37.454.0

Vigorous exercise (hours per week)

None
12
34
5
p for heterogeneity/trend

232
135
57
32

17.8
18.3
18.5
22.0

15.220.9
15.321.9
15.222.5
17.327.9
0.20/0.036

44.1
46.5
44.0
46.0

Current alcohol use (g/day)

None
<8 g
815 g
16 g
p for heterogeneity/trend

168
195
67
26

19.7
17.6
16.9
18.9

16.523.4
14.920.9
14.020.5
14.724.2

43.9
45.7
45.5
43.6

Smoking
Never
Ex
Current
p for heterogeneity

299
142
15

18.2
18.4
19.7

15.621.3
15.821.5
14.726.5

45.3
43.8
46.6

Breast cancer in a close relative

No
Yes
p for heterogeneity

416
40

18.2
19.9

15.721.0
16.024.6

44.6
48.0

Age at menarche years (missing = 8)

<12
12
13
14
15
p for heterogeneity

85
71
137
81
74

18.4
17.9
18.5
18.7
18.0

15.222.2
14.821.7
15.522.1
15.322.7
14.821.9

46.3
43.6
44.6
43.7
46.4

0.46

0.003

37.450.3
35.947.8
39.854.0
44.262.6

0.90/0.66

0.97/0.89

0.14/0.63

0.84

0.30

0.98

0.76/0.84

0.68/0.77

0.83/0.92

0.71

0.30

0.81

38.550.4
40.054.0
37.451.8
37.756.1

38.050.8
40.052.7
38.853.3
35.453.6

39.851.7
38.549.8
36.559.5

39.550.4
40.257.4

39.654.2
37.151.1
38.451.8
37.151.6
39.554.6

56

P.K. Verkasalo et al.

Table 4. (Continued)
Category

No. of subjectsb

Estradiol (pmol/L)
Mean

Number of births
0
12
3+
p for heterogeneity

99
213
144

16.8
19.4
17.9

Age at menopause (years; missing = 4)

<45
47
4549
92
5054
179
55
34
p for heterogeneity

17.2
19.4
18.5
19.7

Previous use of oral contraceptives

Never
Ever
p for heterogeneity

18.5
17.9

327
129

Previous use of hormonal replacement therapy

Never
395
Ever
61
p for heterogeneity

18.4
17.6

Percent variance explained by the model

SHBG (nmol/L)
95% CI

0.067/0.38

0.58

0.53

0.53
25.9%

Mean

95% CI

13.920.4
16.422.9
15.021.3

47.1
43.2
46.0

40.155.2
37.649.7
39.753.2
0.20/0.67

13.522.0
15.624.3
15.122.6
15.325.5

44.4
44.6
43.6
45.7

36.254.5
37.153.6
36.951.6
36.956.6

15.621.9
15.021.3

45.3
43.9

15.821.5
14.521.5

44.3
49.1

0.94

0.53

0.088

39.352.1
37.950.9

38.950.4
41.657.9

33.1%

Adjusted for all other variables in Tables 2 and 4, except age at menopause.
The table presents the numbers of subjects, who were assayed for estradiol and SHBG, excluding those with missing information for the
variable. The total numbers of subjects n the statistical analyses were slightly higher (n = 456), because missing values were replaced either with
the mean or typical values of the variable. For analyses of age at menopause, the numbers of subjects were, however, as shown in the table.
b

woman. A single measure provides substantial information for estradiol in postmenopausal women and for
SHBG in pre- and postmenopausal women [10], but in
premenopausal women a single measure of estradiol
may be less informative [11, 12]. Nevertheless, we were
able to detect some signicant associations between
estradiol in premenopausal women and breast cancer
risk factors.
It has long been recognized that obesity in postmenopausal women causes a substantial increase in bioavailable estradiol due to increased production from
androstenedione and estrone and a decrease in SHBG
[13, 14]. Our ndings of a decrease in circulating SHBG
with increasing BMI regardless of menopausal status,
and of an increase in estradiol concentrations in
postmenopausal women, are compatible with most
although not all previous observations [1524]. The fact
that adjustment for estradiol in the models for SHBG
(or for SHBG in the models for estradiol) did not
materially alter the magnitude or statistical signicance
of the eects indicates that increased body mass may
increase breast cancer risk in postmenopausal women by
increasing circulating estradiol concentrations and decreasing circulating SHBG concentrations.

Many studies in premenopausal women have found

that breast cancer risk decreases with increasing BMI
[25]. One study [26] reported that estradiol decreases
with increasing BMI in premenopausal women, and
suggested that this might explain the reduction in breast
cancer risk; but other studies [20, 27, 28] have not clearly
conrmed this association. We observed a 10% decrease
in estradiol between the extreme categories of BMI, but
this dierence was eliminated by adjusting for SHBG.
This implies that the small decrease in estradiol may be
oset by the large decrease in SHBG, and that increasing BMI does not cause a decrease in bioavailable
estradiol.
For waisthip ratio, we observed a negative association with circulating SHBG (adjusted for BMI) regardless of menopausal status. This agrees with the previous
observations that women with a predominance of upper
body or truncal fat have lower SHBG levels independent
of overall adiposity [18, 2932]. Furthermore, there is
indication [33] that the risk for breast cancer may also
increase with increasing waisthip ratio.
Our observations of a decrease in estradiol in premenopausal women with more vigorous exercise and a
possible decrease with greater physical activity at work

Sex hormones and breast cancer risk factors

are consistent and agree with the prior expectation that
increased physical activity may decrease geometric mean
estradiol concentrations [28, 34], perhaps by inducing
anovular cycles [35], although our data did not support
any decrease in progesterone with increasing physical
activity. In contrast, our observation of a small increase
in estrogens in postmenopausal women in association
with vigorous exercise was not expected, is in disagreement with the previous reports on circulating hormone
concentrations [17, 22, 24, 36], and may be due to
chance.
Overall, regular alcohol consumption appears to be
associated with an increase in breast cancer risk,
possibly by increasing estrogen levels [4, 39]. In premenopausal women, we found a positive association
between average daily alcohol consumption and estradiol, which was slightly increased by adjusting for
SHBG but was not statistically signicant. The concentrations of SHBG, FSH, and possibly also LH decreased
with increasing alcohol intake in premenopausal women. Previous data predominantly support acute and
chronic eects of moderate alcohol consumption in
raising circulating estrogen concentrations in premenopausal women [9, 3740]. We have been unable to nd
other epidemiological studies of the possible association
of alcohol with gonadotrophins, but it is possible that
the observed decrease in FSH could be due to the small
increase in estradiol causing a suppression of FSH
secretion. One study [38] found that 30 g alcohol per day
increased plasma estradiol at midcycle but not at other
phases of the menstrual cycle. In our study, estradiol
concentrations at midcycle were 13% higher in women
consuming 8 g of alcohol per day than in nonconsumers; this dierence was not statistically signicant but, on the other hand, only ve women of the
present study consumed 30 g of alcohol per day. In
postmenopausal women, we found no clear changes in
hormone concentrations by alcohol consumption. The
evidence for an eect in postmenopausal women is less
consistent [17, 2124, 41, 42], and even less is known
about the relation of SHBG and alcohol use [23, 24].
Smoking has long been suggested to have an antiestrogenic eect [43, 44] and thus possibly to reduce
breast cancer risk. Signicantly higher concentrations of
adrenal androgens have been reported among female
smokers compared with non-smokers, but changes in
circulating estradiol concentrations have in most cases
not been found [16, 17, 22, 45, 46]. The present study's
nding of no change in estradiol in postmenopausal
women is in line with the earlier studies; our observation
of higher estradiol concentrations in premenopausal
smokers was unexpected and may be a chance nding.
The prevalence of smoking was low in this health-

57
conscious study population. Thus it appears that the
possible anti-estrogenic eect of smoking is not reected
in circulating concentrations of estrogens.
Like the three other studies on circulating hormones
and family history of breast cancer, we found no
statistically signicant dierences in the concentrations
of estradiol [16, 19, 47] or SHBG [19].
Hormonal proles of adult women have been thought
to dier by age at menarche, and pregnancy has been
suggested to result in long-term endocrine changes. We
found no important hormonal changes by age at
menarche regardless of menopausal status. A previous
study in young (mean age 27 years) premenopausal
women observed that follicular phase serum estradiol
concentration was higher, SHBG concentration was
lower and cycle length was shorter among those who
had early menarche [48]. Another study in premenopausal women has reported marginally higher luteal
phase serum estradiol in Japanese but not in British
women with early menarche [49]. Yet another study in
postmenopausal women observed higher estradiol in
women with early menarche [24]. On the other hand,
many other studies [16, 19, 23, 29, 47, 50] have found
little evidence of an association between age at menarche
and serum estrogen levels during adulthood. The association of early menarcheal age and increased breast
cancer risk may result simply from the prolonged
exposure to cyclic ovarian function in women with early
menarche.
For parity, we found no important relationships with
sex hormones. Likewise, most other studies have found
no relationship with estradiol [16, 19, 23, 24, 29, 47, 51
53] or SHBG [16, 23, 24, 29, 53, 54], and it appears that
the inverse relationship between parity and breast cancer
risk cannot be explained by alterations in circulating
estrogen levels in the years after childbirth. Other
hormonal explanations might be found from parity
perhaps decreasing menstrual cycle length [55], changes
in estrogen metabolism [53] that are not reected in
circulating estradiol, and alterations in the metabolism
of other hormones such as prolactin [56]. Alternatively,
the protective eect may be due to dierentiation of
breast epithelial cells during pregnancy [57].
Our nding of no association of estradiol with age at
menopause in postmenopausal women is consistent with
other studies [16, 23, 24, 28]. Finally, we observed no
relationship between prior uses of oral contraceptives or
hormonal replacement therapy and circulating levels of
sex hormones; one previous study reported slightly, but
signicantly, lower mean SHBG concentrations in former users than in never users of oral contraception [58].
We conclude that obesity and other characteristics of
current lifestyle such as physical activity and alcohol

58
consumption may mediate their eect on breast cancer
by changing circulating concentrations of sex hormones.
The present study found no clear evidence that current
hormonal proles of adult women, when measured as
geometric mean concentrations of circulating hormones,
would reect dierences in events such as age at
menarche and parity that have taken place earlier in life.
Acknowledgements
We thank all the participants of this study; the EPIC
study sta at ICRF; Dr Dennis Quantrill, Dr John
Keenan and sta at the Clinical Biochemistry Laboratory at the John Radclie Hospital, Oxford (previously
at the Radclie Inrmary, Oxford); and Professor Mitch
Dowsett and sta at the Biochemical Endocrinology
Laboratory at the Royal Marsden Hospital, London.
The study was supported by the Finnish Cancer
Foundations (P.K.V.), the Finnish Medical Society
Duodecim (P.K.V.), the Academy of Finland grant
(P.K.V.), the European Commission Marie Curie Fellowship BMH4-CT98-5113 under the Biomedicine and
Health Programme (P.K.V.), the European Commission
under the Europe Against Cancer Programme, and the
Imperial Cancer Research Fund.
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