Clinical Science (2001) 101, 147–157 (Printed in Great Britain)
Effects of hormone replacement therapy and
high-impact physical exercise on skeletal
muscle in post-menopausal women:
a randomized placebo-controlled study
Sarianna SIPILA$ *, Dennis R. TAAFFE*, Sulin CHENG*, Jukka PUOLAKKA†,
Jarmo TOIVANEN‡ and Harri SUOMINEN*
*Department of Health Sciences, University of Jyva$ skyla$ , Box 35 (LL), FIN-40351 Jyva$ skyla$ , Finland, †Department of Obstetrics
and Gynaecology, Central Hospital, FIN-40620 Jyva$ skyla$ , Finland, and ‡Department of Radiology, Central Hospital,
FIN-40620 Jyva$ skyla$ , Finland
A
B
S
T
R
A
C
T
An age-related decline in muscle performance is a known risk factor for falling, fracture and
disability. In women, a clear deterioration is observed from early menopause. The effect of
hormone replacement therapy (HRT) in preserving muscle performance is, however, unclear.
This trial examined the effects of a 12-month HRT and high-impact physical exercise regimen on
skeletal muscle in women in early menopause. A total of 80 women aged 50–57 years were
assigned randomly to one of four groups : exercise (Ex), HRT, exercisejHRT (ExHRT) and
control (Co). The exercise groups participated in a high-impact training programme. The
administration of HRT (oestradiol/noretisterone acetate) or placebo was carried out doubleblind. Knee extension torque and vertical jumping height were evaluated. Lean tissue crosssectional area (LCSA) and the relative proportion of fat within the muscle compartment were
measured for the quadriceps and lower leg muscles. The ExHRT group showed significant
increases in knee extension torque (8.3 %) and vertical jumping height (17.2 %) when compared
with the Co group (k7.2 %). Vertical jumping height also increased after HRT alone (6.8 %). The
LCSA of the quadriceps was increased significantly in the HRT (6.3 %) and ExHRT (7.1 %) groups
when compared with the Ex (2.2 %) and Co (0.7 %) groups. Lower leg LCSA was also increased
in the ExHRT group (9.1 %) when compared with the Ex (3.0 %) and Co (4.1 %) groups. In
addition, the increase in the relative proportion of fat in the quadriceps in the Co group (16.6 %)
was significant compared with those in the HRT (4.9 %) and ExHRT (k0.6 %) groups. Thus, in
post-menopausal women, muscle performance, muscle mass and muscle composition are
improved by HRT. The beneficial effects of HRT combined with high-impact physical training
may exceed those of HRT alone.
INTRODUCTION
An age-related deterioration in muscle performance is
one of the most important factors in the process of frailty.
Functional decline and impaired mobility are serious
threats, especially in elderly women, who have a lower
functional capacity [1–4] and longer life span [5] compared with men. Some studies have suggested that a
Key words: muscle composition, muscle cross-sectional area, muscle force, muscle performance, oestradiol, progestin.
Abbreviations: CSA, cross-sectional area ; CT, computed tomography ; HRT, hormone replacement therapy ; KEt, knee extension
torque ; LCSA, lean tissue cross-sectional area ; VJh, vertical jumping height ; Co group, control group ; Ex group, exercise group ;
ExHRT group, exercisejHRT group.
Correspondence: Dr Sarianna Sipila$ (e-mail sarianna.sipila!berner.fi).
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sudden decline in muscle performance coincides with the
menopause [6,7] because of the loss of ovarian steroids,
especially oestradiol.
It is well known that menopause is accompanied by an
increased incidence of cardiovascular disease and changes
in bone metabolism, and that hormone replacement
therapy (HRT) has potential benefits in reducing cardiovascular risk [8,9] and bone loss [10]. Oestrogen
receptors have also been found to exist in skeletal muscle
[11]. However, the effects of HRT on muscle mass and
performance have been less well investigated. In addition,
previous studies have shown somewhat conflicting
results, which may be due partly to differences in the
treatment combinations of oestrogen and progestin.
Experimental animal and cross-sectional human
studies have suggested that oestrogen status might be
related to muscle strength. In a study by Phillips et al.
[12], ovariectomized mice suffering from oestrogen
deficiency had less muscle force than control mice, with
no difference in the dry weight of the muscle under
investigation. Accordingly, post-menopausal women not
on HRT were weaker than age-matched women on
oestrogen [7,13] or oestrogen\progestin [7] therapy. In
contrast, other studies have failed to show any difference
in muscle performance between oestrogen users and nonusers more than 65 years old [14,15].
Only a few experimental studies have investigated the
effects of HRT administration on muscle force in postmenopausal women. A randomized open trial by Skelton
et al. [16] found that oestrogen therapy for 6–12 months
led to an increase in the isometric strength of the adductor
pollicis muscle of 15 %, without any change in muscle
cross-sectional area (CSA). Similarly, isometric back
extensor muscle strength was increased in a placebocontrolled 2-year intervention of oestrogen\progestin
therapy [17]. However, Armstrong et al. [18] and Greeves
et al. [6] failed to show significant changes in muscle
performance following 9–12 months of HRT in postmenopausal women.
Several experimental studies have shown beneficial
effects of physical training on skeletal muscle strength
[19–24] and bone mineral density [20,25] in postmenopausal and elderly women. High-impact, strainproducing physical exercise seems to be the most
beneficial type of training for bone [26], but effects
on muscle tissue and performance are poorly understood.
There is only one previously reported study investigating the combined effects of the two potentially
beneficial agents, HRT and physical exercise, on skeletal
muscle in post-menopausal women. In the study by
Brown et al. [27], weight-bearing exercise designed to
stimulate aerobic metabolism and bone mass increased
fat-free mass and muscle strength in 60–72-year-old
women. However, HRT with exercise did not produce
additive effects on muscle strength.
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2001 The Biochemical Society and the Medical Research Society
The present randomized placebo-controlled trial
investigates the effects of HRT and high-impact physical
exercise on muscle performance, muscle CSA and muscle
composition in post-menopausal women.
METHODS
Subjects
The study population was taken from post-menopausal
women aged 50–55 years living in the city of Jyva$ skyla$ ,
Finland. To be eligible for the trial, participants had to
have no serious medical conditions, no current or
previous (unless for no longer than 6 months and at least
2 years prior to screening) use of medications including
oestrogen, fluoride, calcitonin, biophosphonates or
steroids, their last menstruation at least 0.5 years but not
more than 5 years ago, follicle-stimulating hormone
levels greater than 30 i.u.\litre, and no contra-indications
for exercise and HRT. The study was carried out in
accordance with the Declaration of Helsinki (1989) of the
World Medical Association, and has been approved by
the Committee on the Ethics of the Middle Finland
Central Hospital. Informed consent was obtained from
all subjects.
Interventions
The combined oestradiol (2 mg) and noretisterone acetate
(1 mg) product (Kliogest2 ; Novo Nordic) was administered continuously, one tablet per day, for 1 year.
The exercise (Ex) and exercisejHRT (ExHRT)
groups participated in a 1-year progressive physical training programme that included a supervised circuit
training session twice a week and a series of exercises at
home on 4 days per week. The supervised programme
comprised five circuit training periods for 8–11 weeks,
interrupted by three high-impact aerobic dance periods
for 2 weeks and a summer pause for 5 weeks. Each session
began with a 10 min warm-up period and concluded with
stretching activities. During the first two circuit training
periods, three rotations were performed of skipping
(30 s), bounding over soft hurdles (13–16 cm), drop
jumping (10–15 cm) and hopping (10 times on one leg ;
added during the second training period). The following
three periods comprised four rotations of bounding
(19–25 cm), drop jumping (20–25 cm), hopping (10 times
per leg) and leaping (10 times). In addition, all circuit
training sessions included three or four of the following
resistance exercises for the upper body : chest fly,
latissimus pull down, military press, seated row and
biceps curl. The home exercise programme was also
designed as a circuit training routine, comprising three
rotations of skipping (30 s), hopping (10 times per leg)
and drop jumping (15 cm). In addition, exercises to
strengthen the abdominal and lower back regions were
included.
Hormone therapy and physical exercise in women
Peak ground reaction forces for the jumping and
bounding activities were determined using a force plate
developed at the University of Jyva$ skyla$ (natural frequency 150 Hz). The average ground reaction force was
4.3ibody weight for drop-landing from a 10 cm height,
and 5.2ibody weight for drop-landing from heights of
20 and 25 cm. Bounding over the hurdles produced
average ground reaction force of 4.9–5.1ibody weight,
while those for skipping, hopping and leaping were 3.8i,
3.4i and 4.8ibody weight respectively.
The women who were not in the exercise groups were
instructed to continue their daily routines and not to
change their physical activity levels. All subjects were
asked to keep a diary concerning the type and duration
of physical activity performed, and also the number of
kilometres travelled when walking, cycling and swimming.
Outcome measures
Anthropometry
Height and body mass were measured. Lean body mass
and percentage body fat were assessed using bioelectrical
impedance (Spectrum II ; RJL Systems, Detroit, MI,
U.S.A.). In our laboratory, the coefficient of variation
between two consecutive measurements is 2 % for lean
body mass and 3 % for body fat.
Germany). Mid-thigh was defined as a midpoint between
the greater trochanter and the lateral joint line of the knee.
Needle muscle biopsies were obtained from the same site,
and the scar was then used as a marker for the 6- and 12month measurements. Lower leg length was defined as
the distance between the tuberositas tibia and the
malleolus medialis. The leg length was then multiplied by
0.25 and 0.30, and the distances obtained were measured
downwards from the tuberositas of the tibia. CT scans
were obtained from both sites, and the mean of the two
measurements was reported. The distance from the floor
to the measuring sites was recorded with the subject in a
sitting position with a knee angle of 90m, and this was used
for the 6- and 12-month measurements.
CT scans were analysed using a software program
developed at our laboratory (BonAlyse 1.0 ; BonAlyse
Oy, Jyva$ skyla$ , Finland). The CSA, lean tissue CSA
(LCSA) and relative proportion of fat within the muscle
compartment were measured in the quadriceps femoris
and lower leg muscles (i.e. ankle flexors and extensors).
In our previous study, the coefficient of variation
between two consecutive measurements varied between
1 and 3 % for CSA, between 1 and 2 % for LCSA, and
between 4 and 9 % for the relative proportion of fat [22].
All results are shown separately for those women who
completed the 6-month measurements and for those
who underwent the 12-month measurements.
Muscle performance
Maximal isometric knee extension force was measured
with the subject in a sitting position on a custom-made
dynamometer chair [28] at a knee angle of 60m from full
extension. The ankle was attached via a belt to a straingauge system. A belt around the pelvis was used to hold
the subject in the chair. After familiarization with the
test, the subject was encouraged to produce maximal
force as rapidly as possible. Between three and five
maximal efforts, separated by 1 min rest periods, were
conducted, and the highest recording was accepted as the
result. To obtain maximal isometric muscle torque (knee
extension torque ; KEt), the highest recording was multiplied by cos30ilever arm length. The coefficient of
variation between two consecutive measurements for
knee extension is 4–6 % [21,28].
As an indication of muscle power production, the
height of the elevation of the body’s centre of gravity was
measured during a vertical jump (vertical jumping height ;
VJh) with counter-movement on a contact mat [29]. The
coefficient of variation for the VJh in our laboratory is
5 % [28].
Computed tomography (CT)
CT scans were obtained of the thigh and lower leg
muscles on the side of the dominant hand using a Siemens
Somatom DR scanner (Siemens AG, Erlangen,
Statistical analysis
Standard procedures were used to calculate means and
S.D.s. Differences among study groups for baseline
measurements were assessed using one-way ANOVA.
The effects of the interventions were assessed using
sphericity-corrected ANOVA for repeated measures. If
the significance of the interaction of group by time was
P 0.10, the effect was localized utilizing simple
contrasts. The level of statistical significance chosen for
the contrasts was P 0.05.
Assignment and blinding
After baseline measurements were performed, the subjects were assigned randomly to one of four groups : Ex,
HRT, ExHRT and control (Co). The randomization was
carried out manually by drawing lots. HRT was carried
out double-blind. This was possible because Kliogest
does not produce withdrawal bleeding in most women.
Women not receiving active hormones took similarlooking placebo tablets. During the trial, the code of the
allocation schedule was kept in a sealed envelope, and
was broken by the physician only if complications or side
effects occurred. The researchers were unaware of the
code until all follow-up measurements were performed
and analysed.
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RESULTS
The progress of the trial is summarized in Figure 1. A
postal questionnaire concerning health, menopausal
status and medication was sent to a random sample of
50–55-year-old women drawn from the population
register of the city of Jyva$ skyla$ . In addition, 56 women,
aged 50–57 years, responded to an announcement in the
local newspaper. Approx. 70 % of the women returned
completed questionnaires. Of the applicants, 87 % were
rejected because they were already taking HRT, were not
at menopause, had undergone menopause more than
5 years ago, were unwilling to participate or had contraindications to exercise or HRT. Those who were accepted
according to the questionnaire results underwent clinical
Figure 1
#
examination and laboratory tests to assess menopausal
status. Finally, 80 women qualified for the study.
The 6-month measurements were completed by 15
women in the Ex group, 17 in the HRT group, 13 in the
ExHRT group and 17 in the Co group. Corresponding
numbers for the 12-month measurements were 12, 15, 10
and 15 respectively. The main reasons for dropping out
or exclusion were lack of time or interest, diseases or selfreported health concerns, side-effects from or poor
compliance (did not take at all or only for a few weeks) in
taking the oestradiol\noretisterone acetate or placebo
pills, or inadequate participation in the exercise sessions
(fewer than 10 supervised sessions during the first
6 months and fewer than 25 sessions during the 12-month
period) (Figure 1).
Flow chart describing the progress of subjects through the trial
2001 The Biochemical Society and the Medical Research Society
Hormone therapy and physical exercise in women
Table 1
Physical characteristics in post-menopausal women before and after HRT and high-impact exercise
Values are mean (S.D.).
Group
1. Ex (n l 12)
Baseline
6 months
12 months
2. HRT (n l 15)
Baseline
6 months
12 months
3. ExHRT (n l 10)
Baseline
6 months
12 months
4. Co (n l 15)
Baseline
6 months
12 months
ANOVA (P )
Group
Time
Interaction
Contrasts
1 vs 2
1 vs 3
1 vs 4
2 vs 3
2 vs 4
3 vs 4
Height (cm)
Body mass (kg)
Lean body mass (kg)
Body fat (%)
164.8 (4.3)
164.5 (4.3)
164.7 (4.3)
67.2 (10.2)
67.4 (10.4)
68.2 (11.0)
45.9 (4.1)
45.9 (3.7)
46.9 (3.8)
31.2 (6.3)
30.7 (6.9)
30.3 (6.4)
159.7 (6.4)
159.2 (6.3)
159.3 (6.5)
69.9 (10.7)
69.8 (9.7)
69.5 (9.4)
45.8 (4.4)
46.3 (4.2)
46.9 (4.1)
33.9 (6.5)
33.1 (5.2)
32.2 (5.3)
160.9 (6.4)
160.8 (6.2)
160.8 (6.4)
64.0 (6.9)
63.5 (6.0)
64.1 (6.9)
45.7 (4.2)
46.1 (3.9)
46.8 (4.3)
28.3 (6.5)
27.4 (5.5)
26.9 (6.3)
163.4 (5.3)
163.1 (5.1)
163.2 (5.2)
68.3 (11.7)
67.9 (10.2)
67.8 (9.3)
47.4 (5.1)
46.7 (4.9)
47.1 (4.2)
29.7 (6.0)
30.7 (5.1)
29.8 (5.6)
0.937
0.001
0.043
0.141
0.023
0.336
0.688
0.001
0.657
0.519
0.753
0.775
At baseline the four study groups, as well as the
women who subsequently dropped out during the 12month trial, did not differ with respect to any physical
characteristic or outcome variable under investigation
(see Tables 1–4). There were also no differences in serum
oestrogen or follicle-stimulating hormone levels between
the study groups at baseline. HRT induced an expected
increase in the mean oestrogen level to 0.23 nmol\l and a
decrease in the mean follicle-stimulating hormone level
of 68.7 to 22.5 i.u.\litre.
After 6 months, the average number of supervised
training sessions that had been attended was 26p9 (range
13–40) for the Ex group and 31p10 (range 10–43) for the
ExHRT group (P l 0.010). After 12 months of training,
the corresponding figures were 53p16 (range 27–77) and
70p13 (range 37–84) respectively (P l 0.047). Instructed
home exercises were performed 32p28 (range 0–82)
times by women in the Ex group and 34p35 (range
0–92) times by women in the ExHRT group during the
first 6-month period. After 12 months of training,
corresponding numbers for home exercises were 73p52
(range 0–191) and 96p72 (range 1–188). There were two
women in each of the Ex and ExHRT groups who
0.589
0.744
0.039
0.981
0.010
0.024
reported less than three instructed home exercise sessions
during the whole year, and an additional three (two in the
Ex group and one in the ExHRT group) who reported no
home exercises during the first 6 months. The minimum
numbers for the other women were 26 over 12 months
and 13 over 6 months.
Apart from the training included in the trial, walking
and home gymnastics (calisthenics) were the principal
activities reported by subjects. In the 2 months preceding
the intervention, women in the HRT group had walked
significantly less than those in the Ex or ExHRT groups.
The amount of walking increased significantly in each
study group during the first 6 months and decreased
significantly during the subsequent 6 months. No group
differences or changes were observed in other types of
physical activity during the trial.
There was no significant interaction of group by time
for body mass or body fat. However, lean body mass
increased in the Ex, HRT and ExHRT groups when
compared with the Co group (Table 1).
Women in the HRT group showed an increase in KEt
after 6 months when compared with the change observed
in the Co group (Table 2). There was also a tendency
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Table 2
Effects of HRT and high-impact training on KEt and VJh in post-menopausal women
Values are mean (S.D.). Results are shown separately for the women who completed the measurements at 6 months only (6-month group) and those who also completed
the measurements at 12 months (12-month group).
KEt/LCSA (Nm:cm−2)
KEt (Nm)
Group
1. Ex (n l 11–15)
Baseline
6 months
12 months
2. HRT (n l 12–17)
Baseline
6 months
12 months
3. ExHRT (n l 10–13)
Baseline
6 months
12 months
4. Co (n l 15–17)
Baseline
6 months
12 months
ANOVA (P )
Group
Time
Interaction
Contrasts :
1 vs 2
1 vs 3
1 vs 4
2 vs 3
2 vs 4
3 vs 4
6-month group
12-month group
6-month group
12-month group
6-month group
12-month group
131.3 (21.2)
135.5 (20.4)
134.4 (22.5)
142.3 (16.1)
135.2 (11.2)
2.91 (0.59)
2.97 (0.47)
2.94 (0.60)
3.08 (0.45)
2.90 (0.34)
15.8 (3.0)
16.5 (3.7)
16.6 (2.5)
17.4 (3.5)
17.6 (3.0)
126.7 (26.8)
136.3 (22.8)
133.0 (22.8)
139.2 (20.6)
131.9 (18.3)
2.83 (0.46)
2.95 (0.36)
2.94 (0.38)
2.94 (0.29)
2.78 (0.24)
15.0 (2.7)
16.1 (2.9)
15.1 (2.8)
16.4 (2.8)
16.1 (3.2)
126.7 (27.4)
132.5 (22.6)
128.9 (29.5)
133.6 (24.6)
137.1 (33.4)
2.86 (0.56)
2.82 (0.40)
2.84 (0.62)
2.82 (0.44)
2.79 (0.46)
16.0 (2.7)
18.7 (3.3)
16.3 (2.8)
18.9 (3.6)
19.1 (4.1)
132.6 (28.7)
127.5 (24.1)
132.3 (30.7)
127.8 (25.5)
121.5 (26.1)
2.85 (0.41)
2.76 (0.35)
2.84 (0.43)
2.77 (0.37)
2.61 (0.47)
16.5 (3.3)
15.5 (2.9)
16.4 (3.5)
15.6 (3.1)
15.6 (3.2)
0.973
0.080
0.052
0.688
0.151
0.096
0.812
0.837
0.360
0.460
0.029
0.636
0.441
0.001
0.001
0.186
0.001
0.001
0.340
0.806
0.099
0.511
0.007
0.067
0.946
0.315
0.106
0.233
0.164
0.020
0.517
0.008
0.015
0.030
0.002
0.001
0.789
0.074
0.054
0.101
0.014
0.001
towards an increased KEt in the ExHRT group compared
with the Co group. After 12 months of follow-up, only
the ExHRT group differed significantly from the Co
group. The individual differences in KEt before the trial
and after 6 and 12 months are shown in Figure 2.
The increase in VJh after 6 months was significant in
the ExHRT group when compared with the other study
groups (Table 2). In addition, the Ex and HRT groups
showed an increased VJh when compared with the
Co group. After 12 months, both the HRT and ExHRT
groups showed an increase in VJh when compared with
the change observed in the Co group. There was also a
trend towards an increased VJh after 12 months in the Ex
group. The mean individual changes in VJh after 6 and
12 months are shown in Figure 2.
Women in the HRT and ExHRT groups who completed the 6-month measurements showed increases in
CSA and LCSA, and a consequent decrease in the relative
proportion of fat, in the quadriceps when compared with
the Co group (Table 3). Subjects in the ExHRT group
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VJh (cm)
2001 The Biochemical Society and the Medical Research Society
also showed increases in the CSA and LCSA of the
muscle when compared with the Ex group. The relative
proportion of fat in the muscle was increased after
6 months in the Co group compared with the Ex group.
Those women who continued in the HRT and ExHRT
groups for 12 months showed increases in their quadriceps CSA and LCSA when compared with the Ex and
Co groups, and a decrease in the relative proportion of fat
in the muscle when compared with the Co group. The
mean difference for the change in the LCSA of the
quadriceps was 5.6 % between the HRT and Co groups
and 6.4 % between the ExHRT and Co groups (Figure 2).
After 12 months, the women in the ExHRT group
showed increases in the CSA and LCSA of the lower leg
when compared with the changes observed in the Ex or
Co groups (Table 4). There was also a trend for a larger
CSA and LCSA after HRT alone when compared with
the Ex group (P l 0.053–0.072). The mean difference
for the change in the LCSA of the lower leg muscles was
5 % between the ExHRT and Co groups (Figure 2).
Hormone therapy and physical exercise in women
Figure 2 Individual changes in the outcome variables in post-menopausal women after 6 months (=) and 12 months (#) of
HRT and/or high-impact physical exercise
Horizontal bars indicates group mean values. For the statistical significance of differences between the study groups, see Tables 2–4.
DISCUSSION
Our study is the first double-blind placebo-controlled
trial in which the effects of HRT on muscle performance
and muscle mass have been investigated. We report that
continuous administration of oestrogen\progestin treatment for 6–12 months increased muscle strength,
explosive-type muscle performance and muscle CSA in
post-menopausal women. Similarly, high-impact exercise
training increased explosive-type muscle performance,
whereas isometric muscle force and muscle mass were
less affected. The combined effects of HRT and highimpact exercise exceeded the effects of either of the agents
alone.
Following the initial 6 months of HRT, changes
observed in KEt and in VJh were 12–13 % greater than
those in the controls. At the conclusion of the 12-month
trial, VJh was 11 % greater in the HRT group compared
with the Co group, although no significant increase in
KEt was noted. In contrast, women in the Co group
experienced a decrease (albeit not statistically significant)
in KEt of 7 %.
A significant increase of 15 % in the muscle force of the
adductor pollicis muscle following HRT (oestradiol\
norgestrel) has also been reported by Skelton and coworkers [16] in 53–67-year-old women who were 5–15
years post-menopausal. As in the present study, all of the
subjects showed increased oestradiol levels due to treatment. However, Amstrong et al. [18] found no effects of
HRT combined with calcium on leg extensor power and
grip strength in 45–70-year-old volunteers. In that study,
previous oestrogen usage was not reported, and medication was administered to subjects who had suffered a
wrist fracture within the previous 7 weeks. In addition,
the results were presented by the intention to treat, and
it appears that the serum oestradiol level was either
unchanged or decreased in approximately one-third of
the subjects. The authors, however, stated that the results
were the same when presented for the compliant subjects
only [18]. Similarly, Greeves et al. [6] reported no changes
in muscle strength following 9 months of HRT in 52year-old post-menopausal women. However, the women
in the control group showed a decrease in muscle force of
9–10 % during the follow-up period. This is in accordance
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Table 3
Effects of HRT and high-impact training on quadriceps muscle mass and composition in post-menopausal women
Values are mean (S.D.). Results are shown separately for the women who completed the measurements at 6 months only (6-month group) and those who also completed
the measurements at 12 months (12-month group).
CSA (cm2)
Group
1. Ex (n l 12–15)
Baseline
6 months
12 months
2. HRT (n l 14–16)
Baseline
6 months
12 months
3. ExHRT (n l 10–13)
Baseline
6 months
12 months
4. Co (n l 15–17)
Baseline
6 months
12 months
ANOVA (P )
Group
Time
Interaction
Contrasts :
1 vs 2
1 vs 3
1 vs 4
2 vs 3
2 vs 4
3 vs 4
LCSA (cm2)
6-month group
12-month group
6-month group
12-month group
6-month group
12-month group
48.4 (7.4)
48.9 (6.9)
48.8 (7.5)
49.3 (6.7)
49.9 (7.2)
46.2 (6.9)
46.6 (6.5)
46.9 (6.9)
47.2 (6.3)
47.8 (6.6)
4.2 (2.0)
4.4 (1.8)
3.8 (2.0)
4.0 (1.7)
3.9 (2.1)
46.4 (7.6)
48.0 (7.2)
46.8 (8.0)
48.5 (7.5)
49.5 (7.1)
44.7 (7.4)
46.2 (7.1)
44.9 (7.8)
46.5 (7.4)
47.5 (7.0)
3.6 (1.7)
3.7 (1.6)
3.9 (1.7)
3.9 (1.6)
3.9 (1.5)
46.6 (7.1)
49.5 (7.3)
47.2 (7.1)
49.3 (7.7)
50.5 (7.6)
45.1 (6.6)
47.8 (6.9)
45.7 (6.7)
47.8 (7.5)
48.9 (7.3)
3.1 (1.6)
3.2 (1.5)
3.0 (1.7)
3.1 (1.7)
3.0 (1.9)
47.8 (7.4)
47.9 (7.3)
47.7 (7.8)
48.0 (7.8)
48.1 (7.2)
46.4 (7.0)
46.2 (7.0)
46.4 (7.5)
46.2 (7.5)
46.6 (6.9)
2.7 (1.2)
3.4 (1.3)
2.6 (1.2)
3.5 (1.4)
3.1 (1.5)
0.960
0.000
0.001
0.959
0.001
0.001
0.975
0.001
0.001
0.966
0.001
0.001
0.105
0.006
0.051
0.376
0.034
0.060
0.122
0.001
0.580
0.060
0.033
0.001
0.025
0.004
0.654
0.672
0.001
0.001
0.123
0.001
0.286
0.055
0.009
0.001
0.030
0.004
0.476
0.631
0.001
0.001
0.674
0.898
0.041
0.783
0.013
0.036
0.734
0.833
0.073
0.881
0.009
0.034
with our muscle strength results obtained after 12 months
of HRT.
In our study, the mean increase in LCSA of the
quadriceps was 3 % after 6 months and 7 % after
12 months of HRT when compared with the control
subjects. There was also a significant change of 4 % in the
LCSA of the quadriceps and the CSA of the lower leg
muscles after 12 months of HRT when compared with
the Ex group. Only one research group, to our knowledge, has reported previously on the effects of HRT
(Prempak-C) on muscle CSA in women, and they failed
to show any significant change in the CSA of the adductor
pollicis muscle in post-menopausal women [16]. The
participants in the study of Skelton et al. [16] were on
average 61 years old and 5–15 years post-menopausal.
The women in our study, however, were younger and
within 5 years of the onset of menopause. In addition,
there was a difference between the two studies with
regard to the HRT regimens applied. Kliogest noretisterone acetate is administered continuously, whereas
#
Relative proportion of fat (%)
2001 The Biochemical Society and the Medical Research Society
Prempak-C includes norgestrel for 12 consecutive days
during a 28-day cycle. The different muscle site may also
play a role. Nevertheless, Aloia et al. [30] also failed to
show any effects of cyclical oestrogen\progestin on lean
body mass, as measured using dual-energy X-ray
absorptiometry, in women with an average age of
51 years and within 6 years of the onset of menopause.
The independent effect of HRT on skeletal muscle
mass and performance is probably the most interesting
finding in the present study. Although previous studies
have shown that both oestrogen and progestogens have
anabolic effects, the mechanism behind this finding is not
totally clear. The anabolic effects of oestrogen have been
demonstrated in cell culture studies. Skeletal muscle
growth has been induced after oestradiol treatment due
to alterations in glucose metabolism and interaction with
androgen receptors [31]. Conversely, Kahlert et al. [11]
showed myoblast growth only after oestrone treatment,
whereas oestradiol had no effect. Further, progestogens
have been shown to induce androgenic and anabolic
Hormone therapy and physical exercise in women
Table 4
Effects of HRT and high-impact training on lower leg muscle mass and composition in postmenopausal women
Values are mean (S.D.). Results are shown separately for the women who completed the measurements at 6 months only (6-month group) and those who also completed
the measurements at 12 months (12-month group).
CSA (cm2)
Group
1. Ex (n l 12–15)
Baseline
6 months
12 months
2. HRT (n l 14–16)
Baseline
6 months
12 months
3. ExHRT (n l 10–13)
Baseline
6 months
12 months
4. Co (n l 15–17)
Baseline
6 months
12 months
ANOVA (P )
Group
Time
Interaction
Contrasts :
1 vs 2
1 vs 3
1 vs 4
2 vs 3
2 vs 4
3 vs 4
LCSA (cm2)
Relative proportion of fat (%)
6-month group
12-month group
6-month group
12-month group
6-month group
12-month group
58.5 (6.3)
59.9 (7.2)
57.8 (6.7)
58.4 (7.4)
59.2 (7.3)
55.7 (5.5)
57.1 (6.3)
55.0 (5.8)
55.9 (6.5)
56.7 (6.4)
4.7 (1.3)
4.4 (1.2)
4.6 (1.4)
4.3 (1.3)
4.1 (1.3)
56.4 (6.6)
58.7 (7.0)
57.0 (6.8)
59.5 (7.2)
60.6 (6.5)
53.8 (6.3)
56.3 (6.7)
54.5 (6.5)
57.0 (6.9)
58.1 (6.3)
4.5 (1.1)
4.1 (1.1)
4.4 (1.1)
4.1 (1.1)
4.2 (1.5)
58.3 (8.9)
61.4 (9.7)
56.6 (6.9)
60.0 (8.8)
61.5 (9.5)
55.8 (8.5)
59.1 (9.4)
54.2 (6.6)
57.9 (8.6)
59.2 (9.2)
4.4 (1.0)
3.7 (0.9)
4.4 (0.9)
3.6 (0.7)
3.7 (0.6)
59.7 (8.9)
61.3 (9.7)
59.3 (9.5)
60.9 (10.3)
61.3 (8.5)
56.7 (8.5)
58.4 (9.4)
56.4 (9.0)
58.0 (10.0)
58.5 (8.3)
4.9 (1.3)
4.7 (1.4)
5.0 (1.4)
4.8 (1.5)
4.5 (1.4)
0.280
0.001
0.183
0.350
0.001
0.220
0.757
0.001
0.325
0.921
0.001
0.016
0.777
0.001
0.216
0.053
0.003
0.611
0.405
0.177
0.012
effects [32], especially the synthetic progestogen derived
from testosterone [9], as used in the present study.
Oestrogen combined with the continuous administration
of progestin also seems to have greater bone-sparing
effect than oestrogen alone [33]. In additon, the relative
risk for fractures has been reported to be lower (0.51)
among users of combined oestrogen\progestin treatment
than in women taking oestrogen without progestin [34].
We could speculate that the increased amount of
leisure-time walking observed in every study group
during the first half of our study provided some support
for the effects of HRT on lower limb muscles. However,
the changes in free-time activity in the HRT group were
not significantly different from those in the other groups.
Weight-bearing physical exercise is known to positively influence bone mineral density [10,26], whereas
resistance training appears to be the appropriate mode of
exercise to increase muscle strength and mass most
efficiently, even in old age [21,22,33,35]. It would, of
0.939
0.001
0.013
0.072
0.002
0.684
0.270
0.228
0.007
course, be beneficial to find a training regimen that has
positive effects on the whole musculoskeletal system in
peri- and post-menopausal women. In the present study,
exercise performed had no significant effects on maximal isometric KEt in our early menopausal women ;
however, muscle function was improved, as assessed by
the vertical jump test. Similarly, in the study by Heinonen
and co-workers [26], isometric muscle force remained
unchanged in concert with significant improvements in
leg explosive performance after 18 months of progressive
high-impact exercise in 35–45-year-old women. On the
other hand, Brown et al. [27] found a significant increase
in muscle strength in 60–72-year-old women after a
weight-bearing exercise programme that included walking, jogging and stair climbing.
It appears that, of the interventions undertaken in the
present study, high-impact training combined with HRT
was the most beneficial for enhanced muscle performance
and muscle CSA. The average increase in KEt was 9 %
#
2001 The Biochemical Society and the Medical Research Society
155
156
S. Sipila$ and others
after 6 months and 16 % after 12 months compared with
the controls. The explosive muscle performance of the
lower extremities also increased by 21–22 % in the
ExHRT group compared with the Co group, and by
10–12 % compared with the HRT and Ex groups. In
contrast, Brown et al. [27] reported that oestrogen and
cyclical progesterone tablets for 11 months did not
augment the increase in muscle strength that occurred in
response to weight-bearing exercise. Subjects in the study
by Brown et al. [27] were older than women in the
present study, and one-third of them had used oestrogen
products previously, for an average duration of 6.3 years.
Exercise combined with HRT resulted in hypertrophy
of both the quadriceps and lower leg muscle groups. The
LCSA of the quadriceps increased by 5–6 % compared
with the controls, and that of the lower leg by 4–6 %
compared with the Ex group. In addition to finding no
additive effects of HRT and exercise on muscle performance, Brown et al. [27] also failed to observe an
enhanced increase in whole-body fat-free mass or lean
mass of the lower extremities compared with that
achieved due to exercise alone. The discrepancy between
the results of the two studies may be due to differences
in the history of HRT usage and the different application
of HRT regimens. The Kliogest product used in the
present study is a combined oestradiol\noretisterone
acetate product which was administered continuously
(one tablet per day) for the duration of the trial. It is
possible that the androgenic effect of noretisterone
treatment used in our study is greater when compared
with earlier studies in which progestin tablets were taken
in a cyclical manner (12 days in a 28-day cycle).
During the present trial, the women in the ExHRT
group participated in supervised training sessions more
often than women in the Ex group. The average attendance was roughly 1.2–1.3 times per week for the
ExHRT group and once per week for the Ex group. No
significant difference was observed in the average number
of home exercises performed. It is possible that the
difference in the number of supervised exercise sessions
may have contributed to the superior results of the
ExHRT group with regard to skeletal muscle ; however,
given the magnitude of the change observed after highimpact exercise alone, this seems unlikely.
An age-related decline in muscle performance, partly
due to muscle atrophy, is a known risk factor for falling,
fracture and disability. The results of the present placebocontrolled trial suggest that continuous administration of
oestradiol\noretisterone acetate has beneficial effects on
muscle performance, muscle mass and muscle composition in early post-menopausal women. Further, highimpact exercise training appears to increase explosivetype muscle performance, whereas isometric muscle force
and muscle mass are less affected. The results also suggest
that the effects of HRT combined with high-impact
physical training may exceed those of the two treatments
#
2001 The Biochemical Society and the Medical Research Society
separately. Additional research is, however, needed to
establish the efficiency and practicability of home-based
exercise as compared with more controlled and supervised training programmes.
ACKNOWLEDGMENTS
We thank Marju Leppa$ nen, Pa$ ivi Norvapalo, Anniina
Oinonen, and Sanna E. Sihvonen for their valuable work
and technical assistance.
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Received 4 October 2000/26 January 2001; accepted 29 March 2001
#
2001 The Biochemical Society and the Medical Research Society
157