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R E S E A R C H Open Access
Changes in androstenedione,
dehydroepiandrosterone, testosterone,
estradiol, and estrone over the menopausal
transition
Catherine Kim
1*
, Siobàn D. Harlow
2
, Huiyong Zheng
2
, Daniel S. McConnell
2
and John F. Randolph Jr.
3
Abstract
Background: Previous reports have noted that dehydroepiandrosterone-sulfate (DHEAS) increases prior to the final
menstrual period (FMP) and remains stable beyond the FMP. How DHEAS concentrations correspond with other
sex hormones across the menopausal transition (MT) including androstenedione (A4), testosterone (T), estrone (E1),
and estradiol (E2) is not known. Our objective was to examine how DHEAS, A4, T, E1, and E2 changed across the
MT by White vs. African-American (AA) race/ethnicity.
Methods: We conducted a longitudinal observational analysis of a subgroup of women from the Study of
Women’s Health Across the Nation observed over 4 visits prior to and 4 visits after the FMP (n= 110 women over 9
years for 990 observations). The main outcome measures were DHEAS, A4, T, E1, and E2.
Results: Compared to the decline in E2 concentrations, androgen concentrations declined minimally over the MT. T
(β9.180, p < 0.0001) and E1 (β11.365, p < 0.0001) were higher in Whites than in AAs, while elevations in DHEAS (β
28.80, p= 0.061) and A4 (β0.2556, p= 0.052) were borderline. Log-transformed E2 was similar between Whites and
AAs (β0.0764, p= 0.272). Body mass index (BMI) was not significantly associated with concentrations of androgens
or E1 over time.
Conclusion: This report suggests that the declines in E2 during the 4 years before and after the FMP are
accompanied by minimal changes in DHEAS, A4, T, and E1. There are modest differences between Whites and AAs
and minimal differences by BMI.
Keywords: Dehydroepiandrosterone-sulfate, Androstenedione, Testosterone, Estrone, Menopause
Background
The menopausal transition (MT) represents a marked
shift in women’s sex steroid profile, of which changes in
estradiol (E2) are the best studied [1]. On average,
women’s E2 concentrations begin to change more rap-
idly about 2 years prior to the final menstrual period
(FMP) and stabilize several years after the FMP [2]. The
rapidity of decline and average E2 levels may be pre-
dicted by race/ethnicity and body mass index (BMI) at
the beginning of the transition [3, 4]. The most pro-
nounced differences occur between African-American
(AA) and White women, the former group having more
gradual changes than the latter group [4]. Presumably in
part due to adipose tissue production of E2, women with
higher BMI have more gradual changes than women
with lower BMI [3, 4].
The adrenal gland is the primary source of
dehydroepiandrosterone-sulfate (DHEAS) and andro-
stenedione (A4) and also contributes to circulating
testosterone (T) [5]. Aromatase catalyzes A4 and T
into estrogens, i.e. A4 into estrone (E1) and T into
estradiol (E2). Previous reports have suggested that, prior
to the FMP, adrenal DHEAS production increases even as
* Correspondence: cathkim@umich.edu
1
Departments of Medicine and Obstetrics & Gynecology, University of
Michigan, 2800 Plymouth Road, Building 16, Room 430W, Ann Arbor, MI
48109, USA
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Kim et al. Women's Midlife Health (2017) 3:9
DOI 10.1186/s40695-017-0028-4
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
peripheral E2 decreases [6–10]. As adrenal sex hormones
exist in equilibrium with ovarian sex hormones in the per-
ipheral circulation, it is plausible that adrenal hormone
metabolism also changes over the MT [11]. This is con-
sistent with the hypothesis that increasing adrenal sex hor-
mone production and aromatization may be concurrent
with decreasing ovarian estrogen production [12]. It is also
possible that DHEAS production may also eventually de-
cline over time resulting lower peripheral A4 and E1
concentrations.
Few longitudinal studies examine changes in a com-
prehensive array of adrenal sex hormones across the
MT. Since concentrations of circulating DHEAS in-
crease in the 5th decade of life [6–10] and concentra-
tions among women in their 8th decade of life are low
[13], DHEAS must decline in the postmenopause.
However, it is uncertain when in the postmenopause
this might occur. In addition, few reports examine
concentrations of A4 or E1 during the MT and
whether ratios of A4:E1 change over the MT, consist-
ent with changes in aromatase activity or consistent
with increased A4 production and concomitant in-
creases in aromatization. No reports examine whether
E1 concentrations change across the MT. In addition,
studies have not examined whether these patterns dif-
fer by BMI, as has been reported for E2, or between
Whites and AAs.
Therefore, using data from the Study of Women’s
Health Across the Nation (SWAN), we characterized
serum adrenal and ovarian sex steroid changes over the
MT. We assessed concentrations of DHEAS, A4, T, E2,
and E1 annually in the 4 years before and the 4 years
after the FMP. We assessed whether concentrations
changed in relation to the FMP during this time period
and whether patterns differed between White and AA
race/ethnicity, and BMI. We hypothesized that concen-
trations of DHEAS and A4 would increase slightly over
the 4 years prior to and after the FMP, consistent with
augmented adrenal androgen production. We hypothe-
sized that AA women would be less likely to have
adrenal sex hormone changes over the MT, as previous
reports have suggested that AA women have less fluc-
tuation in DHEAS concentrations than White women
[4]. We also hypothesized that women with higher BMI
would be more likely to have more gradual increases in
DHEAS and A4 over the MT, since previous SWAN re-
ports have suggested that women with higher BMI have
more gradual declines in E2 than women with lower
BMI [3].
Methods
The study protocol of SWAN has been described previ-
ously: briefly, eligibility criteria for the SWAN cohort
study enrollment included the following: age 42–52 years,
no surgical removal of uterus and/or both ovaries; not
currently using exogenous hormone medications that
were known to affect ovarian function; at least one men-
strual period as well as one of the following five other
racial/ethnic groups. These groups included women who
were White, AA, Chinese and Japanese, and Hispanic. A
total of 3302 women were recruited. Institutional review
boards approved the study protocol at each site; signed,
written informed consent was obtained from all partici-
pants. The current study included a subsample of White
and AA women who met inclusion criteria. We focused
upon these 2 racial/ethnic groups as they had sufficient
numbers of subjects with a documented final menstrual
period (FMP) and complete hormone data for 4 years
before and after the FMP, they were the largest number
of participants in SWAN, the largest racial/ethnic dif-
ferences in sex steroids have previously been observed
between these 2 populations, and funds restricted
examination of other racial/ethnic groups [3].
Other inclusion criteria included having a BMI of 22–
30 kg/m
2
, a natural FMP i.e. no history of hysterectomy or
oophorectomy, no exogenous hormone therapy use, and
at least 9 sequential annual samples spanning 4 years be-
fore and 4 years after the FMP, for a total of 110 women
with 990 observations. Compared to White participants in
SWAN generally, White women in the current report
were similarly aged at baseline, were more likely to report
excellent or very good self-reported health, and had simi-
lar smoking status. Compared to AA participants who did
not meet inclusion criteria, AA women in the current re-
port had similar age, self-rated health, and smoking status.
Due to the inclusion criteria designed to limit outliers of
BMI, both White and AA women in the current report
had lower BMI than women who did not meet inclusion
criteria.
Annual fasting blood samples were collected. Two
attempts were made to collect a follicular phase sample.
When follicular phase samples were not available or when
a woman stopped menstruating, a random fasting sample
was collected within 90 days of the baseline recruitment
date. All serum hormones were measured at the CLASS/
RSP Central Laboratory at the University of Michigan
(Ann Arbor, MI). A4 was measured using a commercially
available enzyme-linked immunosorbent assay (ELISA)
from Diagnostic Systems Laboratories (DSL). The assay
measures analyte concentrations from 0.1 to 10 ng/mL
with a minimum detectable concentration of 0.1 ng/mL,
and a sensitivity of 0.03 ng/mL. The inter-assay coefficient
of variation (CV) is 3.9% at 0.98 ng/mL and 3.0% at
6.1 ng/mL. The intra-assay CV is 2.1% at 0.98 ng/mL,
1.3% at 6.1 ng/mL. DHEAS was measured using an auto-
mated, ACS:180-based chemiluminescent assay developed
in the CLASS laboratory and based upon the Bayer
Diagnostics ACS:180. The detection level of this assay is
Kim et al. Women's Midlife Health (2017) 3:9 Page 2 of 9
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approximately 1.9 μg/dL. The intra-assay CV is 8.02%
(n= 261) and inter-assay CV is 11.34% (53.32 μg/dL,
n= 37) and 9.74% (250.21 μg/dL, n = 37). The CLASS
laboratory modified the ACS:180 total testosterone chemi-
luminescent assay to measure with greater precision
samples in the low ranges found in women in the peri-
and postmenopause. To accomplish this, sample volume
was increased while evaluating the consequences of this
change on volumes of subsequent reagents. The limit of
detection of this assay is <5.15 ng/dL. The limit of quanti-
fication (lowest reported value) is set at the lowest stand-
ard, 5.15 ng/dL. The intra-assay CV is 11.78% (24.4 ng/dL,
n= 30), 4.6% (191.2 ng/dL, n = 30) and 9.1% (414.2 ng/
dL, n = 30). The inter-assay CVs are 11.34% (53.3 ng/dL,
n= 37) and 9.7% (250.2 ng/dL, n = 37). E1 was measured
using a commercially available ELISA from DSL. This
method features a wide dynamic standard range of 0.05 to
90 ng/mL, and a minimum detectable concentration of
0.01 ng/mL. Inter-assay CVs were 12.7% at 1.2 ng/mL and
10.8% at 9.2 ng/mL, and intra-assay CVs were 6.7% at
1.2 ng/mL and 2.9% at 9.2 ng/mL. E2 concentrations were
measured using the Estradiol-6 III immunoassay performed
on the ADVIA Centaur instrument (Siemens HealthCare
Diagnostics). Inter-assay CVs are 11.0% (102.9 pg/mL) and
7.0% (225.9 pg/mL) and 3.8% (615.9 pg/mL). Intra-assay
CVs are 3.9% (102.9 pg/mL), 5.0% (225.9 pg/mL) and 1.4%
(615.9 pg/mL). Follicle stimulating hormone (FSH) was
measured with a two-site chemiluminescence (sandwich)
immunoassay with a minimum detectable concentration of
0.3 mIU/mL. Inter- and intra-assay CVs are 8.1% and 3.5%,
respectively.
Statistical analyses
For the purposes of this analysis, BMI was analyzed in ter-
tiles (< 25 kg/m
2
,25–26.9 kg/m
2
,>27kg/m
2
)andby
White vs. AA race/ethnicity. Distributions of DHEAS, A4,
T, E2, and E1 were examined at each year in relation to
time before and after the FMP. Population hormone tra-
jectories in relation to FMP and covariates were analyzed
using linear mixed models. Piecewise linear mixed models
were applied to test the rate of changes at each stage, i.e.,
pre-menopause (2 years before FMP), transition stage
(+/−2 years around FMP), and post-menopause (2 years
after FMP). [2, 14, 15] For presentation in Figs. 1 and 2,
data were stratified by race/ethnicity and BMI (normal vs.
overweight and by tertile of BMI). In order to determine
whether race/ethnicity or BMI was associated with serum
hormone concentrations, we created semiparametric sto-
chastic mixed models that accounted for the multiple re-
peated measures in women and adjusted for the time
from the FMP. [16] Hormone distributions were also ex-
amined after log-transformation; log transformation did
not alter the pattern of the results with the exception of
E2, so non-transformed values are presented for other sex
hormones. Racial/ethnic differences in SHBG were also
examined, but differences were minimal (results not
shown). All analyses were performed with SAS Windows
9.2 (SAS Institute, Cary NC).
Results
Thirty-four AA and 76 White women were included.
Participant characteristics are shown in Table 1. Forty-
seven (42%) of women had BMIs of 22–24.9 kg/m
2
vs.
30 (27%) of women who had BMIs 25.0–26.9 kg/m
2
vs.
33 (30%) who had BMIs 27.0–30.0 kg/m
2
. Women had
lower median FSH concentrations at 4 years prior to
their FMP (21.4 IU/L) compared to 4 years after their
FMP (125.7 IU/L), consistent with the transition from
premenopause to postmenopause.
Figure 1 displays the average concentrations of sex
hormones across the FMP for White and AA women for
each year of the MT. Declines in log E2 concentrations
were the most marked out of all of the sex hormone
changes in both Whites and AAs, but E2 declines were
not accompanied by increases in E1 concentrations. The
ratio of E1:A4 remained fairly constant across the MT.
Table 2 shows median values for sex hormones at 4 years
prior the FMP, the year of the FMP, and 4 years after the
FMP for Whites and AAs, and Table 3 shows the associ-
ation between race/ethnicity and hormone concentration
after adjustment for FMP and repeated measures within
women. Hormone concentrations were generally higher
in Whites than AAs, although only T and E1 met criteria
for significance and log E2 concentrations were similar
between Whites and AAs.
Figure 2 shows the average concentration trajectories of
sex hormones across the MT for women by BMI tertile.
Table 2 shows median values for sex hormones at 4 years
prior the FMP, the year of the FMP, and 4 years after the
FMP by BMI tertile. BMI tertile was not associated with
differences in DHEAS, A4, or E1 at different times in rela-
tion to the FMP. Table 4 shows the association between
BMI as a continuous variable and hormone concentration
after adjustment for FMP and repeated measures within
women. Although BMI as a continuous variable was asso-
ciated with slightly higher T concentrations, this associ-
ation was of borderline statistical significance (p=0.051).
Otherwise, higher BMI was not associated with higher
hormone concentrations.
Discussion
In a longitudinal analysis spanning 8 years across the
MT, DHEAS concentrations were stable across the MT
[6, 7]. We also note that A4, T, and E1 concentrations
remain relatively stable as long as 4 years after the FMP.
Moreover, the ratios of E1 and A4 remained fairly constant
across the MT. Although A4 and E1 declined slightly, these
changes did not mirror the dramatic declines in E2
Kim et al. Women's Midlife Health (2017) 3:9 Page 3 of 9
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production. We also found that AAs had slightly lower sex
hormone concentrations than Whites. The racial/ethnic
differences were likely not due to BMI, as the nature and
rate of decline in DHEAS, A4, and E1 were similar by BMI.
Our results are consistent with previous reports that sug-
gest that a rise in DHEAS concentrations prior to meno-
pause is concurrent with the declines in peripheral levels of
other sex steroids, as well as reports that note declines in
Fig. 1 Concentrations of androstenedione (ng/dl) (panel a), estrone (pg/ml) (panel b), log of estradiol (pg/ml) (panel c), dehydroepiandrosterone
(μg/dl) (panel d), testosterone (ng/dl) (panel e), and the ratio of estrone:androstenedione (panel f) by year from the final menstrual period. Red
dashed lines indicate concentrations among White women and blue dashed lines indicate concentrations in African-Americans (AAs)
Kim et al. Women's Midlife Health (2017) 3:9 Page 4 of 9
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DHEAS after the FMP [6–10]. Our report is novel in its
inclusion of AAs, the breadth of sex hormones examined,
the longitudinal analysis of androgens timed to the FMP,
and the length of time spanning the MT.
With the marked decline in ovarian estrogen production
in the postmenopause, the adrenal gland becomes a par-
ticularly important source of sex steroids, chiefly andro-
gens. DHEA produced by the ovary and the adrenal gland
Fig. 2 Concentrations of androstenedione (ng/dl) (panel a), estrone (pg/ml) (panel b), log of estradiol (pg/ml) (panel c), dehydroepiandrosterone
(μg/dl) (panel d), testosterone (ng/dl) (panel e), and the ratio of estrone:androstenedione (panel f) by year from the final menstrual period. Blue
dashed lines indicate concentrations among women with a BMI 22–24.9 kg/m
2
, red dashed lines indicate concentrations among 25–26.9 kg/m
2
,
and black dashed lines indicate concentrations in women with a BMI 27–29.9 kg/m
2
Kim et al. Women's Midlife Health (2017) 3:9 Page 5 of 9
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is aromatized peripherally via A4 to bioactive estrogens
such as E1. The adrenal gland is also an important source
of T which is aromatized to E2. Adrenal-ovarian sex hor-
mone production, conversion to other hormones, and
clearance have been postulated to exist in equilibrium [6].
However, longitudinal studies testing this hypothesis are
few. Previous reports in SWAN have noted that the ma-
jority of women had slight increases in DHEAS prior the
FMP followed by declines after the FMP [6, 7], raising the
possibility that increased production of DHEAS and/or
conversion to other androgens could be a contributor to
women’s increased androgenicity postmenopause.
Our report extends this prior work: we confirm a
modest perimenopausal increase in DHEAS levels, stable
T concentrations, and minimal declines in A4 up to
4 years after the FMP. Additionally, since DHEAS and
A4 changes do not mirror each other over the transition,
it is unlikely that the fluctuations in DHEAS are due to
increased peripheral conversion into A4. Similarly, as
E1:A4 ratios were stable over time, it is also unlikely that
aromatization of A4 to E1 changes significantly over the
MT, assuming that A4 production remains the same,
although it is possible that both A4 production and
aromatization increased concomitantly. Other reports
have not reported changes in DHEAS, A4, and T across
the menopause. In a cohort of 59 Norwegian women,
Overlie and colleagues noted that A4 levels corre-
sponded with both E1 and E2 levels, consistent with the
shift from ovarian to adrenal sex hormone production in
the postmenopause. However, A4 levels declined in the
premenopause, and no significant changes were observed
in DHEAS [17]. In a cohort of Swedish women, Rannevik
and colleagues also observed that A4 correlated with post-
menopausal E1 and E2 concentrations, but concentrations
of DHEAS and A4 declined minimally [18].
Our report and previous SWAN studies may have
found modest perimenopausal elevations in DHEAS due
to larger sample size and our ability to follow women
over a longer period of time prior to and after the FMP.
Thus, changes in the estrogen/androgen ratio are driven
by declines in circulating estrogens, and this relative in-
crease in androgenicity may drive some of the pheno-
typic changes characteristic of later menopause, such as
increased hirsutism [19]. Although speculative, it is pos-
sible that such effects are exerted at the tissue level, due
to the differential binding of A4 and E2 [20]. Changes in
the estrogen/androgen ratio may also be driven by the
adrenal response to changing LH concentrations: studies
in humans have noted the presence of luteinizing
hormone (LH) receptors in the adrenal cortex [21], and
mouse models note increases in LH receptors in re-
sponse to increasing LH levels [22], thus explaining how
the adrenal gland might increase sex hormone produc-
tion even as ovarian response to LH declines.
Previous publications have also reported racial/ethnic
differences in androgens, although the direction of re-
ported associations is inconsistent. In a cross-sectional
study, Spencer and colleagues noted that even after adjust-
ment for age, BMI, and insulin resistance, AA women had
lower DHEAS, A4, and T concentrations than White
women [23]. In contrast, Kim and colleagues noted min-
imal differences in a glucose-intolerant population [24].
Thus, the source of racial/ethnic differences in DHEAS,
A4, E1, and T remain speculative. Previous analyses
using SWAN data have noted that AAs had the lowest
overall DHEAS levels and lowest rates of decline with
chronologic age [6, 7]. In those reports, concentrations
of A4 were not examined, and thus it was unclear
whether racial/ethnic differences in DHEAS concentra-
tions were due to increased adrenal androgen produc-
tion vs. decreased metabolism of DHEAS into A4. Our
report suggests that racial/ethnic differences in A4
metabolism are unlikely to contribute to racial/ethnic
differences in DHEAS concentrations.
Previous reports have also suggested that weight may be
a significant modifier of adrenal sex hormone production,
possibly by affecting E2 concentrations, which in turn
might lead to compensatory increases in E1. However, we
did not find significant effect modification by tertile of
BMI for the sex hormones examined in this report. Our
report agrees with that of population-based studies exam-
ining cross-sectional associations between DHEAS, A4,
and BMI in postmenopausal women [25, 26]. Although E2
and T correlate with waist circumference and BMI in
women, the association between BMI and other sex hor-
mones has been relatively weak. One explanation for our
conflicting results is that we examined non-obese women
within a narrow range of BMI. It is also possible that BMI
and waist circumference do not reflect adipose tissue
Table 1 Characteristics of the study population by race/ethnicity
White women African-American women
(n= 76) (n= 34)
Age at baseline (years) 46.36 (2.47) 45.96 (2.05)
Age at final menstrual
period (years)
52.03 (2.52) 51.96 (1.97)
Self-reported health (n,%)
Excellent 29 (38.67%) 4 (12.50%)
Very good 36 (48.00%) 9 (28.13%)
Good 8 (10.67%) 15 (46.88%)
Fair/Poor 2 (2.67%) 4 (12.50%)
Body mass index (kg/m
2
) 25.61 (2.18) 25.71 (2.01)
Baseline smoking status (n,%)
Never 40 (52.63%) 20 (60.61%)
Past 26 (34.21%) 7 (21.21%)
Current 10 (13.16%) 7 (21.21%)
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Table 2 Median (interquartile range) serum hormone levels of women 4 years prior to their final menstrual period (FMP), at the
time of their FMP, and 4 years after their FMP (n= 110)
4 years prior to FMP Year of the FMP 4 years after the FMP
DHEAS (μg/dl) 127.5 (100.4) 108.2 (89.1) 98.6 (105.9)
African-American 103.2 (82.4) 104.8 (113.5) 98.2 (66.7)
White 130.2 (109.7) 109.6 (79.2) 102.1 (123.3)
p-value 0.116 0.583 0.156
BMI 22.0–24.9 kg/m
2
133.0 (118.2) 108.2 (92.8) 125.1 (128.8)
BMI 25.0–26.9 kg/m
2
110.0 (63.1) 110.3 (58.2) 98.2 (70.6)
BMI 27.0–30.0 kg/m
2
107.2 (69.3) 84.4 (110.8) 95.6 (56.8)
p-value 0.316 0.730 0.772
A4 (ng/ml) 1.03 (0.67) 0.84 (0.58) 0.70 (0.59)
African-American 1.03 (0.72) 0.75 (0.33) 0.61 (0.38)
White 1.01 (0.71) 0.91 (0.65) 0.78 (0.62)
p-value 0.338 0.066 0.075
BMI 22.0–24.9 kg/m
2
1.10 (0.70) 0.86 (0.57) 0.77 (0.59)
BMI 25.0–26.9 kg/m
2
0.99 (0.59) 0.83 (0.52) 0.70 (0.61)
BMI 27.0–30.0 kg/m
2
0.94 (0.53) 0.81 (0.64) 0.68 (0.58)
p-value 0.348 0.800 0.883
T (ng/dl) 35.9 (24.8) 36.3 (21.0) 38.3 (24.4)
African-American 34.6 (18.7) 30.9 (20.0) 33.6 (26.2)
White 36.7 (30.2) 38.7 (20.2) 38.8 (29.6)
p-value 0.095 0.020 0.111
BMI 22.0–24.9 kg/m
2
37.8 (32.8) 36.3 (22.1) 38.8 (24.8)
BMI 25.0–26.9 kg/m
2
31.2 (18.2) 36.2 (20.5) 40.1 (29.9)
BMI 27.0–30.0 kg/m
2
36.4 (19.7) 37.2 (28.3) 37.7 (24.2)
p-value 0.418 0.566 0.831
E2 (pg/ml) 53.0 (74.8) 21.6 (39.8) 16.6 (8.0)
African-American 53.5 (65.5) 18.7 (10.3) 16.6 (14.9)
White 51.6 (79.8) 24.4 (54.8) 16.6 (7.9)
p-value 0.741 0.155 0.692
BMI 22.0–24.9 kg/m
2
59.5 (99.0) 18.8 (27.4) 14.4 (5.3)
BMI 25.0–26.9 kg/m
2
41.7 (123.8) 21.0 (127.6) 18.1 (7.0)
BMI 27.0–30.0 kg/m
2
51.6 (46.6) 24.3 (32.9) 17.5 (9.2)
p-value 0.533 0.166 0.090
E1 (pg/ml) 89.4 (39.4) 87.0 (38.6) 69.9 (31.0)
African-American 77.8 (44.5) 85.4 (34.5) 64.8 (30.6)
White 93.4 (38.4) 88.4 (40.4) 72.7 (29.9)
p-value 0.069 0.232 0.369
BMI 22.0–24.9 kg/m
2
97.0 (42.3) 86.9 (45.9) 67.9 (23.9)
BMI 25.0–26.9 kg/m
2
94.4 (41.8) 100.0 (42.0) 82.8 (42.9)
BMI 27.0–30.0 kg/m
2
80.5 (26.7) 80.3 (34.2) 65.5 (34.5)
p-value 0.111 0.317 0.633
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deposition, as examination of associations between vis-
ceral adiposity and sex steroids using radiographic im-
aging has found stronger associations [27].
Strengths of the current report include the longitudinal
design, inclusion of AAs, examination of a comprehensive
list of adrenal sex hormones, high assay sensitivity for low
androgen concentrations, and observation for 9 years
during the MT for 990 observations. Limitations include a
limited sample size, and thus small fluctuations in hor-
mone concentrations may not have been detected. Our
ability to adjust for confounders, particularly racial-ethnic
differences in adipose tissue deposition, was also limited.
It is possible that self-rated health and smoking status
contributed to racial/ethnic differences along with
unmeausured confounders, but we had limited power to
adjust for these possibilities. We did not use LC/MS for
measurement of E2 concentrations, which are low after
the FMP; however, our objective was to show relative
change over the MT, rather than to establish a definitive
absolute value for E2. Finally, we did not conduct adrenal
and ovarian vein sampling, and thus cannot definitively
distinguish between ovarian and adrenal production of an-
drogens and estrogens.
Conclusions
Our report supports the importance of adrenal androgens
as the primary source of estrogens in the postmenopause
and the increased androgenicity of the postmenopausal
hormonal milieu. It is also possible that ovarian produc-
tion of E1 remains even as E2 declines. Modest increases
in DHEAS concentrations are not accompanied by meas-
urably increased levels of A4, T, or E1. Concentrations of
these hormones appear to be lower in AAs than White
women in the perimenopause, and these racial/ethnic dif-
ferences are unlikely due to BMI. Examination of the
mechanisms for lower DHEAS, A4, and T concentrations
in AA women is needed, particularly prior the FMP when
declines in other sex hormones occur. Examination of
whether these differences contribute to vasomotor symp-
toms or altered risk of chronic disease risk by race/ethni-
city, particularly in other groups besides Whites and AAs,
is needed.
Abbreviations
A4: Androstenedione; AAs: African-Americans; BMI: Body mass index;
DHEAS: Dehydroepiandrosterone sulfate; E1: Estrone; E2: Estradiol;
FMP: Follicle stimulating hormone; FSH: Follicle stimulating hormone; LC/
MS: Liquid chromatography mass spectrometry; LH: Luteinizing hormone;
MT: Menopausal transition; T: Testosterone
Acknowledgments
We thank the study staff at each site and all the women who participated in
the Study of Women’s Health Across the Nation (SWAN). This publication
was supported in part by the National Center for Research Resources and
the National Center for Advancing Translational Sciences, National Institutes
of Health through UCSF-CTSI Grant UL1 RR024131.
Availability of data and materials
The data that support the findings of this study are available from the SWAN
Coordinating Center at the University of Pittsburgh. Restrictions apply to the
availability of these data, which were used under license for the current
study, and so are not publicly available. Data are however available from the
authors upon reasonable request and with permission of the Steering
Committee of SWAN.
Authors’contributions
CK interpreted the data regarding hormone distributions and wrote the
manuscript. HZ performed the analysis, interpreted the data, and revised the
manuscript. DM performed the assays and revised the manuscript. SH
collected the data, guided the analyses, and revised the manuscript. JR
guided the analyses and revised the manuscript. All authors read and
approved the final manuscript.
Funding
The Study of Women’s Health Across the Nation (SWAN) has grant support
from the National Institutes of Health (NIH), Department of Health and
Human Services, through the National Institute on Aging (NIA), the National
Institute of Nursing Research (NINR) and the NIH Office of Research on
Women’s Health (ORWH) (Grants U01NR004061, U01AG012505,
U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553,
U01AG012554, and U01AG012495). The content of this manuscript is solely
the responsibility of the authors and does not necessarily represent the
official views of the NIA, NINR, ORWH, or the NIH.
Ethics approval and consent to participate
An institutional review board at each site (n= 7) approved all study
procedures, and written informed consent was obtained from study
participants prior to assessments.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Table 3 Associations between race/ethnicity and hormone
levels from semiparametric stochastic mixed models, beta-
coefficient (standard error) and p-value
Beta-coefficient (standard error) p-value
DHEAS (μg/dl) 28.80 (15.34) 0.061
A4 (ng/ml) 0.2556 (0.1315) 0.052
T (ng/dl) 9.180 (1.652) <0.00001
ln E2 0.0764 (0.0695) 0.272
E1 (pg/ml) 11.365 (0.7306) <0.00001
E1:A4 −6.527 (7.040) 0.354
Reference group is African-American women; a beta-coefficient greater than 0
indicates higher sex hormone levels in white women
Table 4 Associations between body mass index (BMI) and
hormone levels from semiparametric stochastic mixed models,
beta-coefficient (standard error) is the unit hormone increase
per kg/m
2
Beta-coefficient (standard error) p-value
DHEAS (μg/dl) 0.0000 (0.0000) 1.00
A4 (ng/ml) −0.0026 (0.0289) 0.929
T (ng/dl) 0.7359 (0.3758) 0.051
ln E2 0.0230 (0.0151) 0.128
E1 (pg/ml) −0.3466 (0.912) 0.704
E1:A4 0.0274 (1.5409) 0.354
Kim et al. Women's Midlife Health (2017) 3:9 Page 8 of 9
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Author details
1
Departments of Medicine and Obstetrics & Gynecology, University of
Michigan, 2800 Plymouth Road, Building 16, Room 430W, Ann Arbor, MI
48109, USA.
2
Department of Epidemiology, University of Michigan, Ann
Arbor, MI, USA.
3
Department of Obstetrics & Gynecology, University of
Michigan, Ann Arbor, MI, USA.
Received: 27 January 2017 Accepted: 2 October 2017
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