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PAPER
Effects of hormone replacement therapy on weight,
abdominal fat distribution, and lipid levels in Japanese
postmenopausal women
H Sumino
1
*, S Ichikawa
2
, A Yoshida
3
, M Murakami
3
, T Kanda
4
, H Mizunuma
5
, T Sakamaki
6
and
M Kurabayashi
1
1
Second Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan;
2
Cardiovascular Hospital of
Central Japan, Gunma, Japan;
3
Department of Laboratory Medicine, Gunma University School of Medicine, Maebashi, Japan;
4
Department of General Medicine, Kanazawa Medical University, Kanazawa, Japan;
5
Department of Obstetrics and Gynecology,
Hirosaki University School of Medicine, Hirosaki, Japan; and
6
Medical Informatics and Decision Sciences, Gunma University
School of Medicine, Maebashi, Japan
OBJECTIVE: To investigate the effects of hormone replacement therapy (HRT) on weight, abdominal fat distribution, and fasting
lipid levels in Japanese postmenopausal women (PMW).
DESIGN: Prospective, 12-month-controlled clinical comparison of women with and without HRT.
SUBJECTS: In all, 35 PMW with HRT (conjugated estrogens, 0.625 mg daily; medroxyprogesterone acetate, 2.5 mg daily; HRT
group) and 26 PMW without HRT (control group).
MEASUREMENTS: Weight, abdominal fat distribution by computed tomographic measurements, lipid profiles, and sex
hormones were determined at baseline and after 12 months of treatment or observation.
RESULTS: Weight did not change in any group. Visceral abdominal fat increased in controls, but not in the HRT group. Total and
low-density lipoprotein cholesterol decreased, and triglyceride (TG) and high-density lipoprotein cholesterol increased in the
HRT group; these did not change in the control group. When we divided women into those with android and gynoid types of
abdominal fat distribution. Subjects with an android distribution showed reduced visceral fat with HRT, which also decreased the
proportion of patients maintaining an android distribution. HRT did not alter abdominal fat distribution in subjects with a gynoid
distribution. HRT increased serum TG in the android and the gynoid subgroups.
CONCLUSION: Improved distribution of abdominal fat and fasting lipid levels except for TG may represent beneficial effects of
HRT with respect to cardiovascular disease, but caution is warranted concerning TG elevation from HRT performed in PMW.
International Journal of Obesity (2003) 27, 1044–1051. doi:10.1038/sj.ijo.0802371
Keywords: hormone replacement therapy; estrogen; abdominal fat distribution; menopause; lipid levels
Introduction
Menopause is associated with gains in weight
1–3
and body
fat.
4
Postmenopausal women (PMW) generally gain weight
and develop a fat distribution similar to that in men (android
or central) as opposed to that in premenopausal women
(gynoid or peripheral).
1–4
These changes have been attrib-
uted to diminished estrogen secretion.
5,6
Many menopausal women believe that hormone replace-
ment therapy (HRT) causes weight gain,
7
but whether this
impression is correct remains uncertain. In fact, many
clinical studies indicated that HRT prevented or reduced
weight gain
8–18
and body fat gain,
8–15,18,19
although other
investigators found the opposite both for weight
20,21
and
body fat.
20,21
Thus, the effect of HRT concerning weight and
body fat remains controversial.
In most of the above studies dual-energy X-ray absorptio-
metry (DEXA) or waist-to-hip ratio (WHR) was used as a
measure of central body fat. Unfortunately, these methods
do not differentiate between intra- and extra-abdominal
fat compartments. In recent years, more specific methods
have been applied to measurement of abdominal fat
Received 11 November 2002; revised 29 March 2003;
accepted 3 April 2003
*Correspondence: Dr H Sumino, Second Department of Internal Medi-
cine, Gunma University School of Medicine, 3-39-22 Showa-machi,
Maebashi, Gunma 371-8511, Japan.
E-mail: suminoh@med.gunma-u.ac.jp
International Journal of Obesity (2003) 27, 1044–1051
&
2003 Nature Publishing Group All rights reserved 0307-0565/03
$
25.00
www.nature.com/ijo
compartments, including computed tomography (CT) and
magnetic resonance imaging (MRI).
22–24
Only two CT-based
reports found visceral fat to be lower in HRT patients than in
untreated PMW.
10,11
However, the CT studies merely com-
pared HRT users with nonusers, with none being long-
itudinal.
Lipid profiles undergo changes in menopause. Specifically,
total cholesterol (TC), triglyceride (TG), and low-density
lipoprotein cholesterol (LDL-C) both increase, while high-
density lipoprotein cholesterol (HDL-C) decreases.
25,26
HRT
has been reported to counteract these changes in lipid levels;
HRT increases HDL-C and TG and decreases TC and LDL-C in
PMW.
15,27–29
Excess visceral adipose tissue accumulation
(android fat distribution) is also associated with alterations
in the lipoprotein lipid profile, including elevated TG as well
as decreased HDL-C.
30,31
Thus, HRT might be expected to
alter abdominal fat distribution in addition to lipid levels.
However, no study has described the effect of HRT on
abdominal fat distribution in PMW together with effects on
lipid levels.
We investigated the influence of 12 months of HRT on
weight and on abdominal fat composition according to CT
in Japanese PMW. In addition, since visceral fat deposition is
a risk factor for cardiovascular disease, stroke, and type II
diabetes mellitus,
6,32
we studied the effect of HRT on the
relation between type of abdominal fat distribution and
fasting lipid levels.
Methods
Subjects
In 1997–2000, 75 women, consulting an outpatient for
management of clinic menopause at the Cardiovascular
Hospital of Central Japan, were asked to participate.
Eligibility was determined by a health history questionnaire,
a physical examination including gynecologic examination,
and endocrine blood tests. The questionnaire contained
items concerning medical status and menopausal status.
Inclusion in the study required natural occurrence of
menopause 1–10 y previously, elevated serum gonadotropins
(follicle-stimulating hormone or FSH;440 mIU/ml) and
decreased estradiol or E2;o 20 pg/ml), and no concurrent
illness. No patient had received HRT before enrollment or
had any contraindication to such treatment. All subjects
were nonsmokers. We excluded three perimenopausal wo-
men and 11 women who did not complete the 12-month
trial from the study. Informed consent was obtained from
each participant according to the Second Helsinki Declara-
tion, and the study was approved by the Ethics Committee of
the Cardiovascular Hospital of Central Japan.
The 61 Japanese PMW who were enrolled (46–61 y old,
mean7s.d., 53.374.3) were assigned according to preference
to an HRT group (n ¼ 35) to be given HRT for 12 months, and
a control group (n ¼ 26) consisting of those who did not wish
to receive HRT. All subjects enrolled in the study were
counseled not to change their usual diet or lifestyle habits.
One subject in HRT group and one in control group had
received lipid medications for at least 2 y before the study.
However, these medications were not changed during the
study.
Study design
Except for control subjects, each subject received a daily dose
of oral HRT (0.625 mg of conjugated equine estrogen
combined with 2.5 mg of medroxyprogesterone acetate) for
12 months. All subjects attended to the HRT clinic of the
Cardiovascular Hospital of Central Japan once monthly for
physical check-ups; at baseline and again at 12 months after
HRT initiation, blood sampling and CT were performed.
Blood samples were collected and anthropometric mea-
surements and CT were obtained in the morning after a 12 h
fast. Samples were centrifuged and stored at 801C until
assays.
Physical examination
Anthropometric characteristics then were measured, includ-
ing weight (to the nearest 0.1 kg) and height (to the nearest
0.5 cm). The body mass index (BMI) was calculated (weight
in kilograms divided by height in meters squared).
Assays
Serum TC and TG concentrations were determined using
enzymatic methods (Medca Japan, Konosu, Japan) with an
automatic analyzer (Boehringer Mannheim, Germany).
Serum concentrations of HDL-C were determined electro-
phoretically using the HDL Cholesterol Supply Kit (Helena
Laboratory, Beaumont, TX, USA). The concentration of LDL-
C was calculated according to the Friedewald formula.
33
Serum concentrations of FSH and E2 were analyzed by
radioimmunoassay using commercially available kits (Boeh-
ringer Mannheim, Germany).
Computed tomography
Visceral abdominal fat (VAF) and subcutaneous abdominal
fat (SAF) were measured by CT using a GE High-speed FX
scanner (General Electric Yokogawa Medical Systems, Hino,
Tokyo, Japan). Subjects were examined in the supine
position with both arms extended above their heads. A
position for abdominal scanning was established at the L4 to
L5 level using a scout image of the body. Adipose tissue,
defined as an attenuation range of 150 to 50 Hounsfield
units was highlighted for computation of areas of interest.
VAF area was quantified after outlining the intra-abdominal
cavity at the most internal aspect of the abdominal and
oblique muscle walls surrounding the peritoneal cavity and
the posterior aspect of the vertebral body. SAF area was
quantified by highlighting adipose tissue located between
Estrogen, abdominal fat distribution, and lipids
H Sumino
et al
1045
International Journal of Obesity
the skin and the most external aspect of the abdominal
muscle wall. The coefficient of variation for repeated analysis
of scans of 10 subjects was 1–2%. The ratio between SAF and
VAF (S:V ratio) was calculated for each CT and taken to be an
indicator of predominantly subcutaneous or visceral fat
accumulation.
34
Statistical analyses
Data are reported as means 7s.d. Student’s unpaired t-test
was used to analyze differences in baseline parameters
between the HRT group and the control group. The
following equations were used: percent change ¼ (value at
12 months basal value)/basal value 100 (%) for S:V ratio
of abdominal fat; and difference (delta) between 12-month
value and baseline ¼ value at 12 months for the characteristic
the basal value. Student’s paired t-test was used to analyze
differences between values recorded at baseline and again at
12 months. All probability values are two-tailed. A value of
Po0.05 was accepted as indicating statistical significance.
Results
Patient characteristics and changes in these variables over
the treatment/observation period are shown in Table 1. No
significant differences in age were noted between the HRT
group and the control group, and baseline weight, BMI, TAF,
SAF, VAF, S:V ratio, TC, TG, HDL-C, LDL-C, FSH, and E2 did
not differ significantly between the HRT group and the
control group. After 12 months of HRT, TC, LDL-C, and FSH
had decreased significantly (Po0.01 for all). TG, HDL-C, and
E2 had increased significantly (Po0.01 for all). Weight, BMI,
TAF, SAF, VAF, and S:V ratio did not change from baseline in
the HRT group. In addition, after 12 months of HRT, TAF
and VAF had increased significantly (Po0.05 for both).
Weight, BMI, SAF, S:V ratio, TC, TG, HDL-C, LDL-C, FSH,
and E2 did not change during the year of observation
in the control group. In the control group, TAF had in-
creased significantly (Po0.05). Increased serum con-
centrations of E2 and decreased FSH following treatment in
the HRT group confirmed patient compliance with the
regimen.
Declines at 12 months from baseline for VAF, LDL-C, and
FSH were significantly greater in the HRT group than in the
control group (P o 0.05 for all). Increases in TG, HDL-C, and
E2 between baseline and 12 months were significantly
greater in the HRT group than in the control group (P o
0.05 for all; Table 1). No significant differences were noted
for percent change in the S:V ratio between the HRT group
and the control group (Figure 1).
To determine whether android or gynoid fat distribution at
baseline importantly influenced effects of HRT on abdominal
fat distribution, subjects were divided into two groups
according to the S:V ratio for abdominal fat. Women with
an S:V ratio below 1.99 were assigned to the android
abdominal fat group, while those with an S:V ratio above
1.99 were assigned to the gynoid abdominal fat group. The
cutoff point represented the mean S:V ratio for all subjects in
the study. Finally, subjects were divided into four groups:
android-HRT (n ¼ 19), android-control (n ¼ 16), gynoid-HRT
(n ¼ 16), and gynoid-control (n ¼ 10).
Clinical features and their changes over the course of the
study are presented in Table 2 for HRT and control subjects
with android and gynoid abdominal fat distributions. No
significant differences in age were noted between the HRT
group and the control group with android and gynoid
abdominal fat distribution. At baseline, no significant
Table 1 Characteristics of HRT and control subjects, including changes over 1 y of treatment/observation
HRT group (n ¼ 35) Control group (n ¼ 26)
Baseline 12 months Delta Baseline 12 months Delta
Age (y) 53.773.7 52.775.0
Weight (kg) 56.577.7 56.777.6 0.272.3 55.7710.0 56.17 9.1 0.472.4
BMI (kg/m
2
) 23.973.0 24.073.0 0.170.9 23.973.8 24.17 3.6 0.271.0
TAF (cm
2
)311.5798.9 313.17104.7 1.6741.4 302.97126.2 322.27125.3* 19.3740.5
SAF (cm
2
)202.1771.0 204.8769.9 2.7730.0 197.6782.3 206.0777.5 8.4730.1
VAF (cm
2
)109.4740.4 108.3742.3 1.1721.9# 105.3749.5 116.3755.5* 10.9721.0
S:V ratio 1.9670.63 2.0170.53 0.0570.43 2.0270.67 1.9570.64 0.0770.44
TC (mg/dl) 192.2730.6 180.5727.0** 11.7719.2 197.6733.5 196.0721.7 1.5725.7
TG (mg/dl) 107.4754.3 135.3767.5** 27.9743.3# 116.1766.1 124.0763.0 7.8729.1
HDL-C (mg/dl) 51.1713.9 58.3713.9** 7.279.3# 49.279.5 49.3711.0 0.179.4
LDL-C (mg/dl) 119.7729.2 95.2726.6** 24.5722.8# 125.2730.8 121.9728.0 3.2726.1
FSH (mIU/ml) 72.4729.4 24.6713.0** 47.8725.4# 72.5719.9 71.37 20.8 1.2710.7
E2 (pg/ml) 12.275.0 82.1723.3** 69.9722.5# 12.674.7 12.877.1 0.277.6
HRT ¼ hormone replacement therapy; BMI ¼ body mass index; TAF ¼ total abdominal fat; SAF ¼ subcutaneous abdominal fat; VAF ¼ visceral abdominal
fat; S:V ¼ subcutaneous abdominal fat:visceral abdominal fat; TC ¼ total cholesterol; TG ¼ triglyceride; HDL-C ¼ high-density lipoprotein cholesterol;
LDL-C ¼ low-density lipoprotein cholesterol; FSH ¼ follicle-stimulating hormone; E2 ¼ estradiol. Values are presented as means7s.d. Differences (delta) between
12-month values and baseline ¼ value at 12 months–value at baseline. *Po0.05, **Po0.01 compared with baseline. #Po0.05 compared with delta of control
group.
Estrogen, abdominal fat distribution, and lipids
H Sumino
et al
1046
International Journal of Obesity
differences in weight, BMI, TAF, SAF, VAF, S:V ratio, TC, TG,
HDL-C, LDL-C, FSH, and E2 were noted between the
android-HRT group and the android-control group or
between the gynoid-HRT group and the gynoid-control
group. In the android-HRT group, TC, LDL-C, and FSH
declined significantly (Po0.01 for all) with treatment. SAF,
S:V ratio, TG, HDL-C, and E2 increased significantly
(Po0.05, Po0.01, Po0.05, Po0.05, and Po0.01, respec-
tively). Weight, BMI, TAF, and VAF were not altered. In the
android-control group, VAF had increased significantly
(Po0.05) after 12 months of HRT, but weight, BMI, TAF,
SAF, S:V ratio, TC, TG, HDL-C, LDL-C, FSH, and E2 were not
altered. In addition, in the gynoid-HRT group, LDL-C and
FSH decreased significantly (Po0.01 for both). TG, HDL-C,
and E2 increased significantly (Po0.05, Po0.01, and
Po0.01, respectively). HRT did not change weight, BMI,
TAF, SAF, VAF, S:V ratio, or TC. In the gynoid-control group,
Figure 1 Percent changes in subcutaneous-to-visceral (S:V) ratios for
abdominal fat in PMW who received HRT, and in PMW who did not receive
HRT (control group), during 1 y of treatment/observation. Closed and open
columns indicate percent changes in the S:V ratio for abdominal fat in the HRT
group and the control group, respectively. Data are expressed as means 7s.d.
Table 2 Characteristics in HRT and control subjects with android and gynoid abdominal fat distribution, including changes over 1 y
Android-HRT group (n ¼ 19) Android-control group (n ¼ 16)
Baseline 12 months Delta Baseline 12 months Delta
Age (y) 54.473.2 53.173.6
Weight (kg) 55.876.9 56.376.7 0.571.9 56.3710.5 57.0710.2 0.772.1
BMI (kg/m
2
) 24.073.0 24.272.9 0.270.8 24.474.1 24.774.2 0.370.9
TAF (cm
2
) 305.6793.5 315.5797.1‘ 9.9737.1 317.67138.2 340.47140.4 22.8743.1
SAF (cm
2
) 180.7755.4 195.7758.1* 14.9722.7 196.7791.2 205.2785.5 8.5727.2
VAF (cm
2
) 124.9741.7 119.8743.7 5.1722.6# 120.9750.7 135.3758.1* 14.3721.2
S:V ratio 1.4970.25 1.7370.41** 0.2470.31# 1.6370.30 1.5770.31 0.0670.27
TC (mg/dl) 192.8720.9 178.8718.8** 13.9715.7 205.4735.7 196.2724.7 9.2727.5
TG (mg/dl) 118.2765.0 144.0785.0* 25.8745.1 124.2771.9 124.9764.7 0.7724.9
HDL-C (mg/dl) 50.1715.2 55.5714.4* 5.479.7 48.5710.2 49.2710.5 0.878.5
LDL-C (mg/dl) 119.1722.8 94.6722.5** 24.5719.8 132.1732.3 122.0729.8 10.1728.2
FSH (mIU/ml) 69.1735.0 22.0713.1** 47.2725.4# 68.2712.6 66.4713.4 1.9712.1
E2 (pg/ml) 12.475.7 88.8724.7** 76.3724.2# 12.374.4 11.573.1 0.972.1
Gynoid-HRT group (n ¼ 16) Gynoid-control group (n ¼ 10)
Baseline 12 months Delta Baseline 12 months Delta
Age (y) 53.074.2 52.176.9
Weight (kg) 57.378.8 57.278.7 0.172.7 54.87 9.5 54.677.3 0.272.9
BMI (kg/m
2
) 23.773.0 23.773.2 0.071.1 23.073.1 23.072.4 0.071.2
TAF (cm
2
) 318.47107.7 310.27116.4 8.2745.2 279.47106.7 293.1796.0 13.8737.6
SAF (cm
2
) 227.4780.6 215.6782.4 11.8731.7 199.0770.3 207.2767.2 8.3735.8
VAF (cm
2
) 91.0730.8 94.6737.4 3.6720.7 80.4737.6 85.9735.2 5.5720.7
S:V ratio 2.5270.45 2.3570.46 0.1770.46 2.6570.62 2.5670.55 0.1070.65
TC (mg/dl) 191.6740.0 182.6734.9 9.0722.9# 185.1726.5 195.8717.1 10.7717.5
TG (mg/dl) 94.6736.0 124.9737.8* 30.3742.4 103.2756.8 122.5763.7 19.3733.0
HDL-C (mg/dl) 52.2712.6 61.6713.0** 9.478.6# 50.478.7 49.5712.2 0.9711.1
LDL-C (mg/dl) 120.4736.2 96.0731.6** 24.4726.7# 114.1726.0 121.8726.3 7.7718.7
FSH (mIU/ml) 76.3721.6 27.7712.5** 48.6725.1# 79.3727.5 79.2728.1 0.278.7
E2 (pg/ml) 11.874.1 74.2719.4** 62.4718.2# 12.975.3 14.9710.8 2.0712.1
HRT ¼ hormone replacement therapy; BMI ¼ body mass index; TAF ¼ total abdominal fat; SAF ¼ subcutaneous abdominal fat; VAF ¼ visceral abdominal fat;
S:V ¼ subcutaneous abdominal fat: visceral abdominal fat; TC ¼ total cholesterol; TG ¼ triglyceride; HDL-C ¼ high-density lipoprotein cholesterol; LDL-C ¼ low-
density lipoprotein cholesterol; FSH ¼ follicle-stimulating hormone; E2 ¼ estradiol. Values are presented as means7s.d. Differences (delta) between 12-month values
and baseline ¼ value at 12 months–value at baseline. *Po0.05, **Po0.01 compared with baseline. #Po0.05 compared with delta in control group.
Estrogen, abdominal fat distribution, and lipids
H Sumino
et al
1047
International Journal of Obesity
weight,BMI,TAF,SAF,VAF,S:Vratio,TC,TG,HDL-C,LDL-C,
FSH, and E2 did not change.
A significantly greater decline was seen between 12-month
and baseline values for VAF and FSH in the android-HRT
group than in the android-control group (Po0.05), and
significantly greater increases in S:V ratio and E2 were seen in
the android-HRT group than in the android-control group
(Po0.05; Table 2). The percent increase in S:V ratio of
abdominal fat was significantly greater in the android-HRT
group than in the android-control group (Po0.01; Figure 2).
In addition, a significantly greater decline was seen between
12-month values and baseline for TC, LDL-C, and FSH in the
gynoid-HRT group than in the gynoid-control group
(Po0.05), while HDL-C and E2 rose significantly more in
the gynoid-HRT group than in the gynoid-control group
(Po0.05; Table 2). No significant difference in percent
change in S:V ratio of abdominal fat was noted between
the gynoid-HRT group and the gynoid-control group
(Figure 3).
Discussion
In the Japanese PMW, in this study, HRT did not cause
weight gain; instead, HRT inhibited a postmenopausal
tendency toward an increase in abdominal fat, especially
VAF. HRT also decreased serum TC and LDL-C, while
increasing serum TG and HDL-C. In subjects with an android
abdominal fat distribution, HRT reduced visceral fat and
shifted abdominal fat distribution toward a gynoid pattern.
HRT did not alter abdominal fat distribution in subjects with
a gynoid pattern. Unfortunately, HRT increased serum TG in
the android and the gynoid subgroups.
Data concerning gonadal steroids and changes in weight
and abdominal fat distribution have been conflicting.
Numerous studies have indicated that HRT prevented or
reduced weight gain
8–15,18
and android (central) fat accumu-
lation.
8–15,18,19
Manolio et al
8
reported that estrogen users
had lower weight, BMI, and WHR than subjects never
treated. Espeland et al
9
showed that women randomly
assigned to take conjugated equine estrogen (CEE) with or
without a progestational agent averaged 1.0 kg less weight
gain at the end of 3 y than those assigned to take placebo.
CEE treatment also was associated with an average of 1.2 cm
less increase in waist girth and 0.3 cm less increase in hip
girth. In the long-term prospective, double-blind, placebo-
controlled PEPI trial (postmenopausal estrogen/progestins
interventions),
15
an increase in weight was demonstrated
during menopause. After 36 months, the increase in weight
was significantly higher in untreated PMW (+2.1 kg) than in
women treated with estrogens (+0.7 kg). In a 15-y prospec-
tive and cross-sectional cohort study,
12
no significant
differences were evident between HRT users and nonusers
for BMI at follow-up, change in weight or BMI between
baseline and follow-up, or WHR or fat mass at follow-up.
Kristensen et al
13
demonstrated using DEXA that 5 y of HRT
significantly reduced fat mass accumulation, especially in
the trunk. This effect of HRT was more pronounced in
nonobese than obese subjects. Reubinoff et al
14
reported that
12 months of continuous daily estrogen and progestin
replacement neither prevented nor increased early postme-
nopausal weight gain; the same was true for fat accumula-
tion measured by infrared methods. Yet HRT minimized
increase in WHR, given similar caloric and macronutrient
intake among subjects. Using DEXA, Gambacciani et al
18
demonstrated that 12 months of continuous estrogen and
progestin replacement therapy did not increase weight or
body fat, and prevented the postmenopausal shift to a
central fat distribution. Haarbo et al
19
found that 2 y of
combined estrogen–progestogen therapy prevented an in-
crease after menopause in abdominal fat measured by DEXA.
Figure 2 Percent change in subcutaneous-to-visceral (S:V) ratio of abdom-
inal fat in HRT and control subjects with an android abdominal fat distribution
at baseline. Closed and open columns indicate percent change in S:V ratio of
abdominal fat in the android-HRT group and the android-control group,
respectively. Data are expressed as means 7s.d. *Po0.01 compared with the
control group (Student’s unpaired t-test).
Figure 3 Percent change in subcutaneous-to visceral (S:V) ratio of
abdominal fat in HRT and control subjects with a gynoid abdominal fat
distribution at baseline. Closed and open columns indicate the percent
change in S:V ratio of abdominal fat in the gynoid-HRT group and the gynoid-
control group, respectively. Data are expressed as means 7s.d.
Estrogen, abdominal fat distribution, and lipids
H Sumino
et al
1048
International Journal of Obesity
Sites et al
10,11
found that estrogen users had lower weight
and BMI, and less visceral adipose tissue demonstrable by CT
than patients never treated. Our findings that HRT did not
cause gains in weight and BMI, and prevented an increase in
VAF distribution, are essentially in agreement. These findings
suggest that HRT use may minimize weight gain and
selective accumulation of intra-abdominal fat. On the other
hand, Aloia et al
20
reported that 2.9 y of cyclic combined
estrogen–progestogen therapy in PMW increased weight and
body fat, and decreased the extremity/trunk fat ratio as
determined by dual photon absorption. O’Sullivan et al
21
demonstrated that 6 months of treatment with estradiol
increased weight and body fat measured by DEXA, via
inhibition of lipid oxidation. Differences in findings may
reflect differences in type and dosage of HRT, lengths of
observation periods, numbers of subjects, or methods used to
estimate adipose tissue.
In the present study, HRT increased SAF and the S:V ratio
in PMW who had an android abdominal fat distribution at
the beginning of treatment. The increase in S:V ratio was
greater in HRT users than in nonusers. The ratio between the
subcutaneous and the VAF was taken to be an indicator of
predominantly SAF or VAF accumulation.
34
By these ratios,
HRT shifted abdominal fat distribution from android to
gynoid in PMW with android fat distribution. The preva-
lence of an android abdominal fat deposition is greater in
PMW than in premenopausal women, which has been
attributed to diminished estrogen secretion.
5
Enzi et al
34
demonstrated that among women 40–59-y old, PMW had a
significantly lower S:V ratio than premenopausal women
(1.7370.28 vs 2.8170.25), while above age 60 the S:V ratio
became much lower than in younger subjects, reflecting a
change to an android distribution. In a cross-sectional study
using CT, Zamboni et al
35
found SAF to be greater in
premenopausal women, while VAF was greater in PMW. We
believe that estrogen therapy contributes to a shift from
android to gynoid abdominal fat distribution in PMW.
Although the mechanism by which HRT shifts abdominal
fat distribution from android to gynoid remains obscure, sex
steroid hormones appear to participate in regulation of
adipose tissue distribution. While environmental factors
such as smoking, activity, and stress can increase central
body fat, gender-associated differences in body fat distribu-
tion are largely attributable to circulating sex steroid
hormones.
36
Enzyme activity of lipoprotein lipase (LPL) in
adipocytes has been validated as a reliable indicator of fat
formation and accumulation. The opposite process, lipolysis,
enzymatically degrades lipids within the adipocyte. Women
of reproductive age have a higher femoral than abdominal
LPL activity and a higher abdominal than femoral lipolytic
activity,
36–38
and their lipolytic responsive to noradrenaline
has been shown to be more intense in the abdominal than in
the femoral region. In PMW, however, no differences in LPL
or lipolysis were found between these two regions.
38
Postmenopausal estrogen therapy has been shown to
increase LPL activity in the femorogluteal region.
37
In this
manner, estrogen may contribute to a shift of abdominal fat
from android to gynoid.
HRT has important effects on lipids and lipoproteins.
Favorable changes in lipids and lipoprotein have been
demonstrated in a clinical study evaluating effects of
exogenous estrogen on cardiovascular risk factors in wo-
men.
28
These improvements include an increase in HDL-C
and a decrease in LDL-C. Women in the PEPI trial,
15
randomly selected to receive CEE plus continuous or cyclic
medroxyprogesterone acetate had smaller increases in HDL-
C from baseline than did women who received unopposed
estrogen. Walsh et al
28
and Wakatsuki et al
39
demonstrated
an increase in HDL-C and TG and a decrease in LDL-C and
TC levels in PMW following treatment with equine estrogen.
In our present study, similar effects on lipid and lipoprotein
were observed in PMW.
Estrogen induces changes in lipids and lipoproteins
through a variety of mechanisms. For example, estrogen
causes a decrease in serum TC and LDL-C and an increase in
HDL-C by increasing hepatic LDL receptor activity and
suppressing hepatic TG lipase activity.
28
Menopause is associated with increased risk of cardiovas-
cular morbidity and mortality.
40–43
Several epidemiologic
studies have shown that HRT reduces these events in
PMW.
44–47
In contrast, some recent, well-controlled large
trials such as the Heart and Estrogen/Progenstin Replace-
ment Study (HERS), a follow-up study (HERS II), and the
Women’s Health Initiative Randomized Controlled Trial
failed to show a reduction in coronary heart disease in
PMW receiving HRT.
48–50
In the present study, HRT pre-
vented an increase in VAF and improved fasting lipid levels
excluding TG in PMW. In PMW with android distributions,
HRT also shifted abdominal fat distribution to a gynoid
pattern. This shift in distribution of abdominal fat may be a
reason why HRT reduces risk of cardiovascular disease, since
visceral obesity is a known risk factor for cardiovascular
disease, stroke, and type II diabetes mellitus.
6,32
However,
HRT in the present study remarkably increased serum TG in
PMW with an android as well as a gynoid fat distribution. As
to TG, elevated TG is a risk factor for coronary artery
disease.
51
Furthermore, antioxidant effects of estrogen might
be offset in patients showing such a TG increase because
estrogen-induced plasma TG increases may produce small
low-density lipoprotein particles that are more susceptible to
oxidant.
39
Therefore, HRT might not have a beneficial net
effect on cardiovascular disease in all PMW with an android
abdominal fat distribution.
Previous Western studies have reported that women in
ethnic minorities, including Hispanics, African-Americans,
and Asians, have a higher prevalence of obesity than
Caucasian women.
52,53
In PEPI,
15
however, Hispanic women
exhibited significantly smaller longitudinal changes in waist
girth than women in the other ethnic groups. Few previous
studies have examined associations of HRT with fat distribu-
tion according to ethnicity. PEPI
15
data suggested that the
impact of hormone therapy on weight and adiposity is fairly
Estrogen, abdominal fat distribution, and lipids
H Sumino
et al
1049
International Journal of Obesity
uniform among ethnic groups, but relatively low numbers of
minority women in PEPI limited the statistical power of this
conclusion. The present study is the first to examine the
effect of HRT on body fat distribution in Japanese PMW
according to CT.
Several limitations are inherent to the present study,
including a relatively small number of subjects and a
nonrandomized design. Although this type of study can
provide useful information concerning the effects of HRT,
observed differences might conceivably be attributable to a
selection bias where more health conscious, more healthy
women may have chosen HRT.
In conclusion, Japanese PMW undergoing HRT did not
gain weight, and an increase in VAF that occurs after
menopause was prevented. Fasting lipid levels showed
overall improvement. In PMW with android fat distribu-
tions, HRT reduced visceral fat and favored a shift to a gynoid
abdominal fat distribution, but HRT also increased TG
concentrations in PMW with an android as well as a gynoid
fat distribution. Improvement in the distribution of abdom-
inal fat and fasting lipid levels except for TG may represent
beneficial effects of HRT against cardiovascular disease, but
these effects might be offset by the estrogen-induced
increase in TG concentrations. The elevation of TG seen
with HRT in PMW warrants caution, including careful
biochemical follow-up evaluations.
Acknowledgements
We are grateful to Naoaki Tsunoda, Hiroyuki Takada, and
Hiromitsu Takahashi for technical assistance. We thank
Kazuo Sakaguchi, Miki Shirouzu, Mayumi Ashizaki, Tomoko
Sakurai, Satomi Ono, Mina Aoki, Yuko Masuda, Kanae
Kodaira, Setsuko Saito, Yoko Suetake, Setsuko Kobayashi,
Yoshimi Matsuda, Masumi Tanimoto, and Emiko Ohkura for
assisting with clinical coordination.
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