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Exercise training reduces the frequency of menopausal hot flushes by
improving thermoregulatory control
Tom G. Bailey, PhD,
1,2
N. Timothy Cable, PhD,
1,3
Nabil Aziz, MD,
4
Rebecca Dobson, MD,
5
Victoria S. Sprung, PhD,
5
David A. Low, PhD,
1
and Helen Jones, PhD
1
Abstract
Objective: Postmenopausal hot flushes occur due to a reduction in estrogen production causing thermoregulatory
and vascular dysfunction. Exercise training enhances thermoregulatory control of sweating, skin and brain blood
flow. We aimed to determine if improving thermoregulatory control and vascular function with exercise training
alleviated hot flushes.
Methods: Twenty-one symptomatic women completed a 7-day hot flush questionnaire and underwent brachial
artery flow-mediated dilation and a cardiorespiratory fitness test. Sweat rate and skin blood flow temperature
thresholds and sensitivities, and middle cerebral artery velocity (MCAv) were measured during passive heating.
Women performed 16 weeks of supervised exercise training or control, and measurements were repeated.
Results: There was a greater improvement in cardiorespiratory fitness (4.45 mL/kg/min [95% CI: 1.87, 8.16];
P¼0.04) and reduced hot flush frequency (48 hot flushes/wk [39, 56]; P<0.001) after exercise compared
with control. Exercise reduced basal core temperature (0.148C [0.01, 0.27]; P¼0.03) and increased basal MCAv
(2.8 cm/s [1.0, 5.2]; P¼0.04) compared with control. Sweat rate and skin blood flow thresholds occurred
approximately 0.198C and 0.178C earlier, alongside improved sweating sensitivity with exercise. MCAvdecreased
during heating (P<0.005), but was maintained 4.5 cm/s (3.6, 5.5; P<0.005) higher during heating after exercise
compared with control (0.6 cm/s [0.4, 1.4]).
Conclusions: Exercise training that improves cardiorespiratory fitness reduces self-reported hot flushes.
Improvements are likely mediated through greater thermoregulatory control in response to increases in core
temperature and enhanced vascular function in the cutaneous and cerebral circulations.
Key Words: Brain blood flow – Exercise training – Hot flushes – Thermoregulation – Vascular function.
Hot flushes are experienced by the vast majority of
postmenopausal women and are associated with
increased cardiovascular disease risk.
1
Menopausal
hot flushes can seriously disrupt the lives of symptomatic
women
2
with approximately 70% of women experiencing hot
flushes 1 to 5 years after the onset of menopause.
3
A hot flush
is typically defined as the subjective sudden intense sensation
of heat causing cutaneous vasodilation and profuse sweating.
4
Hormone therapy (HT) is an effective treatment for hot
flushes and can reduce hot flush frequency by 50% to
72%,
5,6
but has poor uptake.
7
Furthermore, not all women
can be prescribed HT due to time since menopause and a
history of cardiovascular disease or breast cancer.
8
The
current alternatives are limited, but one nonpharmacological
option is exercise training.
The mechanisms causing hot flushes are not completely
understood, yet it is thought that the reduction in estrogen
due to ovarian failure causes thermoregulatory and vascular
dysfunction, leading to the occurrence of hot flushes.
9
An
elevation in basal core body temperature and a narrowed
thermoneutral zone are thought to be primary explanations,
2
with a reduced skin vascular reactivity to increases in core body
temperature also proposed as a mediator.
9,10
No research study
to date has simultaneously investigated the impact of exercise
training on thermoregulatory and vascular dysfunction obser-
ved in symptomatic postmenopausal women and the effect of
improvements in these systems on hot flush symptomology.
A number of research studies, but not all, have shown that
exercise training can reduce the frequency of self-reported hot
flushes
11-17
and improve other nonvasomotor symptoms
including depression, anxiety, and insomnia.
14,18,19
Never-
theless, these studies have solely relied on subjective ques-
tionnaires as the primary outcome. It is also important to
highlight that the most recent randomized control trial
Received September 3, 2015; revised and accepted January 6, 2016.
From the
1
Research Institute for Sport and Exercise Sciences, Liverpool
John Moores University, Liverpool, UK;
2
School of Health and
Sport Sciences, University of the Sunshine Coast, Australia;
3
Depart-
ment of Sports Science, Aspire Academy, Qatar;
4
Department of
Gynaecology and Reproductive Medicine, Liverpool Women’s Hospital,
UK; and
5
Department of Obesity and Endocrinology, University of
Liverpool, UK.
Funding/support: Liverpool Primary Care Trust and National Health
Service (NHS) Liverpool Clinical Commissioning Group.
Financial disclosure/conflicts of interest: None reported.
Address correspondence to: Helen Jones, PhD, Research Institute for
Sport and Exercise Sciences, Liverpool John Moores University, Tom
Reilly Building, Byrom Street, Liverpool L3 3AF, UK.
E-mail: h.jones1@ljmu.ac.uk
Menopause, Vol. 23, No. 7, 2016 1
Copyright ß2016 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
Menopause: The Journal of The North American Menopause Society
Vol. 23, No. 7, pp. 000-000
DOI: 10.1097/GME.0000000000000625
ß2016 by The North American Menopause Society
CE: CE: SS; MENO-D-15-00271; Total nos of Pages: 11;
MENO-D-15-00271
investigating the impact of exercise training (home based and
general advice) using subjective frequency of hot flushes
reported a lack of impact of exercise training despite finding
a 22% decrease in weekly hot flushes compared with control.
17
It is well established that exercise training can improve the
thermoregulatory control system by decreasing core body
temperature, and by changing both the temperature threshold
for the onset, and sensitivity of sweating and cutaneous
vasodilation in premenopausal women.
20
Although HT
reduces hot flushes, it also affects thermoregulatory control
mechanisms via lowering core body temperature and altering
the threshold at which cutaneous vasodilation and sweating
responses are initiated.
21,22
If the thermoregulatory control
system can be altered with exercise training in symptomatic
postmenopausal women, this may also reduce the frequency
of hot flushes. Moreover, exercise training improves endo-
thelial function in the cutaneous and conduit vessels in
postmenopausal women,
23-25
and cerebral blood flow
(CBF) in older individuals.
26,27
Endothelial dysfunction is
associated with hot flush severity,
28
suggesting that if endo-
thelial function is improved with exercise training this may
contribute to a reduction in the occurrence and severity of hot
flushes. Therefore, the aim of this study was to determine
whether improving thermoregulatory control and systemic
vascular function with exercise training alleviates the fre-
quency and severity of menopausal hot flushes. We hypoth-
esized that exercise training reduces the frequency and
severity of hot flushes via improving sweat rate and skin
blood flow responses to increases in core body temperature.
METHODS
Participants
Twenty-one symptomatic postmenopausal women were
recruited from the gynecology and reproductive medicine
clinic at Liverpool Women’s Hospital, local GP practices,
and via local advertisement. Participants were 1 to 4 years
since their last menstrual period and suffered more than 4 hot
flushes over a 24-hour period. All participants had no history of
diabetes, cardiovascular or respiratory disease, were non-
smokers, drank less than 14 units of alcohol per week, and
had no contraindications to exercise. Participants who had used
HT, metformin, vasoactive, or BP lowering medications within
the last 6 months were excluded from the study. Similarly,
women who were currently taking part in regular exercise
(>2 h/wk based on a self-reported questionnaire) were also
excluded. Participants were informed of the methods verbally
and in writing before providing written informed consent. The
study conformed to the Declaration of Helsinki and was
approved by the local research ethics committee.
Research design
Participants reported to the laboratory on two separate
occasions, and were asked to fast overnight, refrain from
alcohol and exercise for 24 hours and caffeine for 12 hours
before each visit. Visit 1 included anthropometric measure-
ments, assessment of brachial artery endothelial function
using flow-mediated dilation (FMD), and a cardiorespiratory
test (VO
2peak
). Visit 2 consisted of a fasting blood sample and
a passive heat stress challenge to assess thermoregulatory,
hemodynamic, and cerebrovascular responses to increases
in core body temperature. Both visits were completed
within 7 days of each other with assessments conducted in a
temperature-controlled laboratory (248C18C). Participants
then underwent a supervised exercise training intervention or a
no-exercise control that was based on participant choice.
Fourteen (n ¼14, 52 4 y, body mass index [BMI] 21.1-
41.8 kg/m
2
) symptomatic women received a 16-week program
of supervised moderate-intensity aerobic exercise training,
whereas seven (n ¼7, 52 6 y, BMI 21.1-41.3 kg/m
2
) symp-
tomatic women comprised the no-exercise control group. After
each intervention, all measurements were repeated.
Measurements
Hot flush frequency and severity questionnaire
Participants completed a 7-day hot flush frequency and
severity diary
29
before and after the 16-week intervention
period. Participants recorded on a daily basis how many hot
flushes they experienced as well as information regarding the
severity of each hot flush on a scale of 1 to 4 (1 being mild, 2
moderate, 3 severe, and 4 very severe). From this, a 7-day sum
of hot flushes provided a weekly hot flush score. A daily
severity score was calculated by the sum of hot flushes
recorded into each severity rating, that is [(3 1 (mild))þ(4
2 (moderate))þ(13 (severe))þ(04 (very severe)) -
¼daily severity score of 14]. A hot flush severity index
was then calculated by the total sum of daily severity scores
over the 7-day period. The use of subjective diaries is
established as a valid approach to obtaining data on subjective
hot flushes when reporting participant symptoms and percep-
tions
29
and in a number of hot flush research studies.
11,12,16,30
Cardiorespiratory assessment for peak oxygen consumption
A fitness test (peak oxygen uptake; VO
2peak
) was performed
on a treadmill after a modified Bruce protocol. After a 2-
minute warm-up at 2.2 km/h on a flat gradient, the initial
workload was set at 2.7 km/h at a 58gradient. Thereafter,
stepwise increments in speed and gradient were performed
each minute until volitional exhaustion. Heart rate (12-lead
electrocardiogram) and rate of perceived exertion were moni-
tored throughout. Peak oxygen uptake was calculated from
expired gas fraction (Oxycon Pro, Jaegar, Hochberg,
Germany) as the highest consecutive 15-second period of
data in the final minute before volitional exhaustion.
Brachial artery endothelial-dependent vasodilation
Brachial artery endothelium-dependent function was
measured using the FMD technique.
31
Measurements were
performed in the supine position after 20 minutes of rest and
are described in detail elsewhere.
31
After a 1-min recording
period of resting diameter and flow, a rapid inflation pneu-
matic cuff (D.E. Hokanson, Bellevue, UK), positioned on the
forearm immediately distal to the olecranon process, was
BAILEY ET AL
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CE: CE: SS; MENO-D-15-00271; Total nos of Pages: 11;
MENO-D-15-00271
inflated (>200 mm Hg) for 5 minutes to provide a stimulus for
forearm ischemia. Diameter and flow recordings resumed 30
seconds before cuff deflation and continued for 3 minutes
thereafter, in accordance with recent technical specifica-
tions.
32,33
Analysis of brachial artery diameter was performed using
custom-designed edge-detection and wall-tracking software,
which is largely independent of investigator bias. Recent
articles contain detailed descriptions of the analysis
approach.
31,32
From synchronized diameter and velocity data,
blood flow (the product of lumen cross-sectional area and
Doppler velocity) were calculated at 30 Hz. Shear rate (an
estimate of shear stress without viscosity) was calculated as 4
times mean blood velocity/vessel diameter. Reproducibility
of diameter measurements using this semiautomated software
is significantly better than manual methods, reduces observer
error significantly, and possesses an intraobserver coefficient
of variation of 6.7%.
34
We also controlled for the baseline
diameter measured before the introduction of hyperemia in
each test of FMD. This allometric approach is more accurate
for scaling changes in diameter than simple percentage
change, which makes implicit assumptions about the relation-
ship between baseline diameter and peak diameter.
35
Passive heat stress challenge
Participants were placed in a tube-lined jacket and trousers
(Med-Eng, Ottawa, Canada), which covered the entire body
except for the head, feet, and the right forearm. Participants
rested quietly in a semirecumbent position, although water
(348C) was perfused through the suit for a 15-minute baseline
period. Participants were then exposed to a moderate heat
stress by perfusing water at 488C through the suit for 60
minutes or until a rise of approximately 18C in core body
temperature. The following measurements were taken during
the baseline and heating periods.
Heart rate was obtained from a 3-lead electrocardiogram
(PowerLab; ADInstruments, Oxford, UK), alongside continu-
ous beat-by-beat finger arterial blood pressure (BP) (Fina-
press, Amsterdam, the Netherlands). Stroke volume and
cardiac output were calculated using the BP waveform using
the Modelflow method, incorporating age, height, sex, and
weight (Beatscope 1.0 software; TNO, Biomedical Instru-
ments, Amsterdam, the Netherlands). To verify continuous
BP measured at the finger, an automated BP (Dinamap,
Germany) reading was collected at regular intervals. Mean
skin temperature was obtained from the weighted average of 4
regional temperatures measured from thermocouples (iBut-
tons data logger; Maxim Integrated, San Jose, CA) secured to
the lateral calf, lateral thigh, upper arm, and chest.
36
Core
body temperature was measured from an ingestible pill
telemetry system taken approximately 5 hours before data
collection began (CoreTemp, HQ Inc, Palmetto, FL),
with the ingestion time recorded and repeated for each
participant’s pre- and post-trials. Mean body temperature
was calculated using the weighted product of core and mean
skin temperatures.
37
Local sweat rate was recorded continuously from the dorsal
forearm and the mid-sternum (not covered by the water-
perfused suit) using capacitance hygrometry. Dry 100% nitro-
gen gas was supplied through acrylic capsules (surface
area ¼2.32 cm
2
) attached to the skin’s surface at a flow rate
of 300 mL/min, with the humidity of the gas flowing out of the
capsules measured by the capacitance hygrometer (Viasala
HMP155, Helsinki, Finland). Local skin blood flow was also
measured at the chest and the forearm, using laser-Doppler
flowmetry (Periflux System 5001; Perimed AB, Stockholm,
Sweden). Laser-Doppler flow probes were affixed with an
adhesive heating ring in close proximity to the ventilated
sweat rate capsule. Cutaneous vascular conductance (CVC)
was calculated as the ratio of laser-Doppler flux units to mean
arterial pressure (MAP) and expressed as both CVC and a
percentage of maximum CVC (%CVC
max
).
Middle cerebral artery blood velocity (MCAv; 1 cm distal
to the MCA-anterior cerebral artery bifurcation) was
measured continuously through the temporal window using
transcranial Doppler ultrasonography. A 2-MHz Doppler
probe (Spencer Technologies, Seattle WA) was adjusted
until an optimal signal was identified, as described in detail
previously,
38-40
and held in place using a headband strap to
prevent subtle movement of the Doppler probe and maintain
insonation angle accuracy. Once the optimal MCA signal was
attained in the temporal window, the probe location and
machine settings (depth, gain, and power) were recorded to
identify the same imaging site during postintervention assess-
ments. Using these guidelines this technique is a valid and
reliable index of CBF.
38
Participants were instrumented with
a two-way valve-breathing mouthpiece from which peak end
tidal CO
2
(P
ET
CO
2
) was measured every 5 minutes and at
each 0.18C increase in core body temperature. An index of
cerebrovascular conductance (CBVC) was calculated from
the ratio of MCAvto MAP. All data were calculated as 60-
second averages at every 0.18C increase in core temperature
during heating. All data during the heat stress challenge were
sampled at 50 Hz with a data acquisition system (PowerLab;
ADInstruments).
After the passive heat stress, local skin heating was per-
formed simultaneously at the chest and forearm laser-Doppler
flowmetry sites to assess maximal cutaneous blood flow.
Temperature of the local heating units was increased at a
rate of 18C every 5 seconds to a temperature of 428C. This
resulted in an increase in skin temperature to approximately
428C at the heating probe-skin surface interface. The protocol
was complete once flux at both sites had reached a stable
plateau (30 min).
Data reduction
The temperature thresholds for the onset of sweating (mean
body temperature) and cutaneous vasodilation (core body
temperature) were calculated in a blinded fashion by the same
analyst.
41
The sensitivity of the sweating responses was
estimated from the slope of the relationships between sweat
rate per unit change in mean body temperature beyond the
EXERCISE REDUCES HOT FLUSHES
Menopause, Vol. 23, No. 7, 2016 3
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CE: CE: SS; MENO-D-15-00271; Total nos of Pages: 11;
MENO-D-15-00271
mean body temperature threshold, and any sweat rate plateau,
or increase during a hot flush episode, were excluded from the
slope calculation. Skin blood flow sensitivity was estimated in
the same way, instead using the rate of CVC per unit change in
core temperature.
Supervised exercise training intervention
Before commencing the exercise intervention, all partici-
pants attended a thorough familiarization session. Participants
were required to attend the university gym on a weekly basis
during which time they wore a heart rate monitor (Polar
Fitness, Polar Electro Oy, Finland) and were provided with
full exercise supervision and guidance from a trained exercise
physiologist. During these sessions, participants were issued
with a weekly progressive exercise program that was specific
to their own rate of progression.
42,43
On the basis of individual
fitness level, participants underwent 30 minutes of moderate-
intensity aerobic exercise 3 times per week (30% heart rate
reserve), which progressed weekly based on HR responses
and included treadmill walking/running, cycling, cross-train-
ing, and rowing. At week 12, participants were exercising 4 to
5 times per week for 45 minutes at 60% heart rate reserve. To
facilitate compliance throughout the 16-week intervention,
participants were monitored via the Wellness Key system, a
software program that enables remote and accurate tracking of
exercise activity. A moderate-intensity program was used in
line with National Health Service (NHS) guidelines and our
previous studies that have shown improvements in cardior-
espiratory fitness.
23,42-44
Control intervention
After consent and physiological flush assessment, women
who opted for the control group had little contact with the
research team throughout the 16 weeks. The research team did
not influence life-style during the 16-week period. This type
of control intervention reflects current convention care for
nonpharmacological hot flush treatment in the UK.
Statistical analyses
For comparison of exercise versus control, delta changes
(D) from preintervention were calculated for each group and
entered as the dependent variable in a linear mixed model
(ANCOVA), with preintervention data entered as a covariate,
this allows all differences between changes to be covariate-
adjusted for the preintervention values.
45
This analysis
approach is more statistically precise and adjusts properly
for any study group imbalances at preintervention. Ulti-
mately, this analysis provides 1 Pvalue for the effect of
intervention, which is adjusted for the preintervention values.
Data are presented in the text for intervention-adjusted
effects as mean and 95% CIs. Data in the tables are absolute
values (point estimates) for pre- and postintervention and are
presented as mean (SD). Correlations between the Dinter-
vention changes in hot flush frequency and SR and CVC
thresholds were quantified using Pearson’s correlation coef-
ficient (r).
For comparison of exercise versus control during the
passive heat stress, a three-factor [(group 0.18C increase)
time(pre/postintervention)] linear mixed model was used
for the analysis of the CBF and P
ET
CO
2
responses to each
0.18C increase in core body temperature. If any hot flushes
occurred during heat stress, the CBF and P
ET
CO
2
data during
such episodes were excluded from the CBF and P
ET
CO
2
data
analyses. Owing to variable individual increments in core
body temperature during the passive heat stress, data up to an
increase of 0.68C were used for the CBF and P
ET
CO
2
analyses. Statistically significant interactions were followed
up with the least significant difference approach to multiple
comparisons.
46
RESULTS
Participants undertaking the exercise intervention demon-
strated 93% compliance to the exercise sessions. After adjust-
ment for baseline values, the body mass normalized change in
VO
2peak
was 4.5 (1.9, 8.2) mL/kg/min greater in the exercise
group versus control (P¼0.04). The absolute change was
21.0 (0.4, 41.5) mL/min greater in the exercise group versus
control (P¼0.05). The mean frequency of hot flushes per
week was 48 (39, 56) events lower after the exercise inter-
vention versus control (P<0.001). The hot flush severity
index was 109 (80, 121) arbitrary units lower after exercise
training versus control (P<0.001).
Conduit brachial artery endothelial function
FMD was 2.3% (0.3, 4.9) greater after exercise training
versus control, but this did not reach statistical significance
(P¼0.08; Table 1). Baseline and peak diameter did not
change with either intervention.
Resting measurements
Hemodynamics
Heart rat e was 4 (2, 5) beats/min lower after exercise
training versus control (P¼0.003; Table 2). There were
negligible differences in MAP, cardiac output, or stroke
volume with the interventions.
Thermoregulatory
Basal core body temperature was 0.14 (0.01, 0.27)8Clower
after exercise training versus control in (P¼0.03; Table 2).
There were negligible differences between interventions for
basal skin blood flow (Table 2). Maximal skin blood flow
(CVC
max
) at the arm was 1.2 (0.1, 2.4)arbitrary units/mm Hg
greater after exercise trainingversus control (P¼0.05; Table2).
This difference was not evident at the chest CVC
max
.
CBF
Basal MCAvwas 2.8 (1.0, 5.2) cm/s greater after exercise
training versus control (P¼0.04; Table 2). This improvement
was reduced when accounting for BP, with CBVC 0.05
(0.02, 0.13) cm/s higher after exercise training versus con-
trol, but this did not reach statistical significance (P¼0.09;
Table 2).
BAILEY ET AL
4Menopause, Vol. 23, No. 7, 2016 ß2016 The North American Menopause Society
Copyright ß2016 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
CE: CE: SS; MENO-D-15-00271; Total nos of Pages: 11;
MENO-D-15-00271
Measurements during the heat stress challenge
Hemodynamics
Heart rate during heat stress was 5 (1, 10) beats/min lower
after exercise training versus control, but this did not reach
statistical significance (P¼0.08; Table 2).
Thermoregulatory
There were no differences in the changes in core body
temperature (0.07 [0.09, 0.24]8C; P¼0.40) or weighted
mean skin temperature at the end of heating after the inter-
ventions (0.06 [0.57, 0.66]8C; P¼0.88; Table 2).
Sweat rate
Mean body temperature for chest sweating was 0.19 (0.04,
0.34)8C lower after exercise training versus control (P¼0.01;
Fig. 1A). Similarly, mean body temperature for the onset of arm
sweating was 0.19 (0.05, 0.36)8C lower after exercise training
versus control (P¼0.01; Fig. 1B). Mean body temperature
onset of sweating at the chest (r¼0.688; P¼0.006) and the
forearm (r¼0.688; P¼0.006) after the exercise intervention
were correlated with the frequency of self-reported hot flushes.
The rate of chest sweating was 0.13 (0.05, 0.20)
mgmincm
1
/8C greater after exercise training versus control
(P¼0.002; Fig. 1C). The rate of forearm sweating was 0.19
(0.05, 0.34) mgmincm
1
/8C greater after exercise training
versus control (P¼0.01; Fig. 1D).
Cutaneous blood flow
Mean body temperature onset of chest cutaneous vasodila-
tion was a 0.17 (0.04, 0.29)8C lower after exercise training
versus control (P¼0.01; Fig. 2A). Similarly, the mean body
temperature onset of forearm cutaneous vasodilation was 0.15
(0.02, 0.28)8C lower after exercise training versus control
(P¼0.02; Fig. 2B).
TABLE 2. Resting and heating cardiovascular and thermoregulatory data before and after exercise training or control
Variable Pre-exercise Postexercise Precontrol Postcontrol P
Resting
Heart rate, beats/min 64 (7) 60 (7) 66 (11) 65 (12) 0.003
a
MAP, mm Hg 75 (7) 75 (5) 76 (4) 75 (6) 0.58
Stroke volume, mL 109 (16) 114 (27) 105 (18) 103 (16) 0.47
Cardiac output, L/min 7.2 (1.6) 7.6 (1.8) 7.1 (1.4) 7.3 (1.1) 0.69
Core temperature, 8C 36.93 (0.19) 36.79 (0.21) 36.86 (0.31) 36.84 (0.27) 0.03
a
Skin temperature, 8C 32.2 (0.7) 32.9 (0.6) 32.8 (0.5) 32.9 (0.7) 0.10
MCAv, cm/s 51 (6) 54 (7) 51 (5) 51 (5) 0.05
a
CBVC, cm/s/mm Hg 0.69 (0.11) 0.74 (0.13) 0.68 (0.06) 0.69 (0.04) 0.08
P
ET
CO
2
, Torr 42 (2) 42 (2) 41 (3) 42 (2) 0.36
CVC
chest
, %CVC
max
10.9 (5.0) 11.2 (6.9) 9.5 (4.5) 8.6 (3.2) 0.93
CVC
arm
, %CVC
max
9.7 (5.2) 10.2 (5.6) 8.8 (4.5) 9.5 (3.3) 0.13
Chest CVC
max
, LDF/mm Hg 5.1 (1.6) 5.9 (1.4) 5.4 (1.1) 5.2 (1.4) 0.58
Arm CVC
max
, LDF/mm Hg 2.9 (0.7) 3.9 (0.9) 3.3 (0.9) 3.4 (0.8) 0.05
a
Heating
Heart rate, beats/min 93 (10) 88 (12) 89 (9) 93 (9) 0.08
Core temperature, 8C 37.75 (0.17) 37.71 (0.21) 37.63 (0.22) 37.58 (0.24) 0.40
Skin temperature, 8C 37.3 (0.7) 37.2 (0.8) 36.9 (0.4) 36.9 (0.5) 0.88
Data are presented as mean (SD).
CBVC, cerebrovascular conductance; CVC, cutaneous vascular conductance; LDF, laser-Doppler flux; MAP, mean arterial pressure; MCAv, middle
cerebral artery velocity; P
ET
CO
2
, peak end tidal CO
2
.
a
Significant difference between change Din exercise and Din control.
TABLE 1. Anthropometric, hot flush, and vascular function data after exercise training or control
Variable Pre-exercise Postexercise Precontrol Postcontrol P
Weight, kg 77.9 (18.3) 73.5 (16.5) 75.5 (19.9) 75.2 (20.4) 0.02
a
BMI, kg/m
2
29 (5.8) 27 (4.5) 28 (7.2) 28 (7.0) 0.03
a
Systolic, mm Hg 128 (5) 126 (7) 127 (10) 128 (8) 0.25
Diastolic, mm Hg 78 (8) 75 (7) 77 (11) 77 (9) 0.58
VO
2peak
, mL/kg/min 22.5 (3.3) 27.3 (4.1) 23.2 (2.4) 22.6 (3.1) 0.04
a
VO
2peak
, L/min 1.7 (0.4) 2.0 (0.3) 1.7 (0.3) 1.6 (0.4) 0.05
a
Hot flushes
Frequency, hot flushes/wk 64 (20) 23 (13) 45 (21) 49 (36) <0.001
a
Severity index, AU 137 (49) 37 (22) 91 (49) 102 (70) <0.001
a
Vascular measurements
FMD, % 5.0 (1.2) 7.4 (1.5) 5.6 (1.9) 5.5 (1.8) 0.08
Baseline diameter, mm 0.37 (0.03) 0.37 (0.05) 0.36 (0.04) 0.35 (0.04) 0.97
Peak diameter, mm 0.39 (0.04) 0.40 (0.04) 0.38 (0.04) 0.37 (0.04) 0.86
Shear rate
AUC
,s
1
10
3
16.3 (8.6) 17.8 (10.4) 21.5 (13.9) 20.4 (12.8) 0.95
Time to peak, s 69.7 (32.5) 54.2 (34.6) 70.5 (33.2) 76.7 (35.6) 0.19
Data are presented as mean (SD).
AU, arbitrary units; BMI, body mass index; FMD, flow-mediated dilation.
a
Significant difference between change Din exercise and Din control values (P<0.05).
EXERCISE REDUCES HOT FLUSHES
Menopause, Vol. 23, No. 7, 2016 5
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MENO-D-15-00271
The rate of cutaneous vasodilation was similar between
interventions at the chest (P¼0.62; Fig. 2C) and forearm
(P¼0.31; Fig. 2D).
CBF
CBF decreased during the heat stress (P<0.001). There
was an intervention pre/postinteraction (P<0.001), where
the reduction in MCAvduring heat stress was attenuated in the
exercise group versus control (Table 3). MCAvwas 4.5 cm/s
(3.6, 5.5, P<0.001) higher during heating after exercise
training versus 0.7 (0.3, 1.7) cm/s in control (P¼0.27).
Similarly, CBVC decreased during the heat stress
(P<0.001). There was a significant intervention pre/post-
interaction (P¼0.01). CBVC was 0.07 (0.04, 0.09) cm/s/mm
Hg higher during heat stress in the following exercise
(P<0.001) compared with 0.01 (0.01, 0.03) cm/s/mm Hg
in control (P¼0.91). P
ET
CO
2
decreased during heat stress
(P<0.001), but there was no interaction (Table 3; P<0.05).
DISCUSSION
The novel findings of the present study were that reductions
in self-reported hot flush frequency and severity with exercise
training coincided with improved thermoregulatory and vas-
cular function in symptomatic postmenopausal women. These
findings provide evidence that improving thermoregulatory
and vascular function with moderate-intensity aerobic exer-
cise training can be effective in the treatment of hot flushes in
postmenopausal women.
Exercise training has been shown in a number of studies to
improve the subjective ratings of self-reported hot flushes in
postmenopausal women,
11-15
but the underlying physiologi-
cal mechanisms responsible have not yet been investigated.
The results of the current study suggest that the improvements
in the occurrence of postmenopausal hot flushes after 16
weeks of moderate-intensity aerobic exercise training are
linked to improvements in thermoregulatory control. We
found that exercise training reduces thermoregulatory dys-
function via stabilization of central thermoregulatory control,
that is, lowering core body temperature and improving heat
dissipation thresholds, alongside improvements in peripheral
mechanisms that allow for greater heat dissipation (sweating
sensitivity). These adaptations likely include increases in the
number of sweat expulsions per minute, sweat gland hyper-
trophy, increased nitric oxide (NO) availability, and/or
enhanced sweat gland recruitment at a given internal tempera-
ture, or a combination of all of the above.
47
Importantly, these
findings of improved thermoregulatory efficiency with
exercise training support previous studies that suggest an
FIG. 1. Delta (D) change from pretraining in mean body temperature threshold for the onset of chest (A) and forearm (B) sweating. Delta (D) change
from pretraining in sweat rate sensitivity (slope) at the chest (C) and forearm (D). Error bars are SD.
Significant difference between exercise black bars
and control grey bars (P<0.05).
BAILEY ET AL
6Menopause, Vol. 23, No. 7, 2016 ß2016 The North American Menopause Society
Copyright ß2016 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
CE: CE: SS; MENO-D-15-00271; Total nos of Pages: 11;
MENO-D-15-00271
improvement in VO
2peak
in the range of approximately 15% to
20% mediates positive adaptations to thermoregulatory func-
tion in premenopausal women.
20,48
This is the first study to
demonstrate that postmenopausal women can improve ther-
moregulatory function with exercise training, and, impor-
tantly, that this contributes to alleviating the frequency and
severity of hot flushes with exercise training.
The precise mechanisms underlying the pathophysiology of
hot flushes is unclear; however, it is acknowledged that
thermoregulatory dysfunction is a key contributing fac-
tor.
4,9,49
Elevated basal core body temperature and a narrow-
ing of the thermoneutral zone (where shivering and sweating
do not occur) are thought to be responsible for the large, rapid,
and transient increases in skin blood flow, sweating, and
flushing that characterize hot flushes.
2
This study suggests
that improving the control, and stability, of the thermoreg-
ulatory system through lowering core body temperature and
improving heat dissipation mechanisms per se reduces the
occurrence of hot flushes.
The ability of the blood vessels (including the cutaneous,
conduit, and cerebral vasculature) to vasodilate and thus deliver
blood flow systemically is implicated in the pathophysiology of
hot flushes and also contributes to thermoregulatory control.
The reduction in estrogen associated with menopause causes
endothelial dysfunction via decreased NO bioavailability
50
and/or increased reactive oxygen species scavenging NO.
51
Exercise increases endothelial NO synthase expression via
similar mechanisms of transcriptional regulation to that of
estrogen
52
and augments NO-mediated vasodilation.
53
We
provide evidence (approaching statistical significance) for an
improvement in NO-mediated conduit artery endothelial func-
tion, measured using FMD, after exercise training. Previous
studies in postmenopausal women have not always observed
exercise training-mediated increases in endothelial function
using FMD,
24,25
but exercise training has been shown to
enhance cutaneous endothelial function and microvascular
reactivity in postmenopausal women.
23,54
One reason for the
lack of statistical significance in FMD with exercise training
maybe due to the vascular remodeling that occurs over the
intervention period. Previous studies in young healthy males
and type 2 diabetic individuals have been shown to improve
function (increase in FMD) and then normalize due to changes
in artery structure/remodelling.
55,56
Although the time course
of changes in vascular function have not been investigated in
postmenopausal women, this is the first investigation of exer-
cise-mediated changes in endothelial function in symptomatic
postmenopausal women. Recent research studies have
suggested that menopausal hot flushes are associated with
greater vascular impairments, including endothelial dysfunc-
tion,
1
with FMD a determinant of hot flush severity in early
postmenopausal women.
28
Therefore, it is likely that sympto-
matic women have greater impairments in endothelial function
and increased cardiovascular disease risk, a condition that
exercise training in this study seems to ameliorate.
FIG. 2. Delta (D) change from pretraining in mean core body temperature threshold values for onset of chest (A) and forearm (B) cutaneous
vasodilation. Delta (D) change from pretraining in cutaneous vascular conductance (CVC) sensitivity at the chest (C) and forearm (D). Error bars are
SD.
Significant difference between exercise black bars and control grey bars (P<0.05).
EXERCISE REDUCES HOT FLUSHES
Menopause, Vol. 23, No. 7, 2016 7
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MENO-D-15-00271
Reductions in CBF are evident during a hot flush
57
and
during a passive heat stress challenge,
58,59
and thus are
implicated in thermoregulatory control via a reduction of
blood flow to the thermoregulatory center (hypothalamus) in
the brain. Improved basal bloodflowtothecerebralcircu-
lation was observed with exercise training along with attenu-
ation in the reduction of CBF typically observed with passive
heat stress in the current study. Short-term exercise training
improves cerebrovascular health across the lifespan
27
and our
resting CBF data support this notion in postmenopausal
women. No study to date has examined the exercise-mediated
changes in CBF during passive heat stress; yet given that CBF
reductions occur during a hot flush (which could be described
as a heat stress response per se), it is plausible that an
exercise-mediated attenuation in CBF decreases during heat
stress may positively impact on cerebrovascular function
during a hot flush and possibly other perturbations
that challenge the maintenance of CBF. The mechanisms
responsible for these adaptations could include an exercise-
mediated increases in stroke volume,
60
plasma volume
expansion,
61
and/or improved endothelial function as
described above.
62
An alternative, although not mutually exclusive expla-
nation for the improvement in hot flush frequency and
severity, could be related to the central sympathetic nervous
system that influences the cutaneous, conduit, and cerebral
vasculature by activating changes in blood flow via the
noradrenergic and cholinergic systems.
63,64
Sympathetic
noradrenergic nerve outflow increases after menopause
65
and elevates peripheral vascular resistance,
66
whereas sym-
pathetic cholinergic nerve activity is also increased during
hot flushes.
67
Moreover, muscle sympathetic nerve activity,
an index of sympathetic nerve activity measured using micro-
neuography, is reduced in postmenopausal women after 6
months of moderate-intensity cycling exercise alongside
improvements in basal forearm blood flow.
68
Such a
reduction in basal sympathetic nerve activity could have
directly reduced the occurrence and/or severity of hot flushes
in this study, or, indirectly, by reducing vascular resistance.
The impact of a reduction in body mass with exercise
training on hot flushes also deserves consideration.
Reductions in BMI were evident with exercise training in
the current study in accordance with one previous study that
reported lower BMI and hot flush symptoms after increases in
self-reported physical activity.
69
Although the role of obesity
on hot flush prevalence is unclear, observational studies have
reported that women with low
70
and high
71
body fat are at
increased risk of hot flushes. Although speculative, increased
adiposity may increase hot flushes due to elevated insulation
and/or affect vascular function via the release of adipokines
and inflammatory markers from visceral adipose tissue, which
could decrease with exercise training. It is also important to
highlight that an intervention causing body mass reduction
that did not involve exercise would not mediate the thermo-
regulatory and vascular function improvements observed in
the current study.
72
TABLE 3. Cerebrovascular responses to 0.18C increments in core temperature during passive heat stress before and after 16 weeks of exercise training or no-exercise control
Variable
Exercise training
Pre Post
Core temperature, 8C Rest 0.1 0.2 0.3 0.4 0.5 0.6 Rest 0.1 0.2 0.3 0.4 0.5 0.6
MCAv, cm/s 51 (6) 50 (7) 47 (7) 45 (7) 43 (9) 43 (8) 42 (8) 54 (7) 54 (7) 51 (8) 50 (8) 49 (9) 48 (9) 48 (10)
CBVC, cm/s/mm Hg 0.69 (0.08) 0.67 (0.08) 0.65 (0.08) 0.63 (0.08) 0.60 (0.09) 0.60 (0.12) 0.59 (0.09) 0.74 (0.06) 0.74 (0.07) 0.70 (0.06) 0.69 (0.04) 0.68 (0.05) 0.67 (0.08) 0.68 (0.05)
P
ET
CO
2
, Torr 42 (4) 42 (5) 41 (5) 40 (6) 40 (6) 39 (5) 39 (5) 42 (3) 42 (4) 40 (6) 40 (5) 40 (4) 39 (3) 39 (5)
Control
Pre Post
Core temperature, 8C Rest 0.1 0.2 0.3 0.4 0.5 0.6 Rest 0.1 0.2 0.3 0.4 0.5 0.6
MCAv, cm/s 51 (5) 50 (5) 49 (5) 48 (6) 47 (6) 44 (5) 41 (6) 51 (5) 50 (4) 48 (4) 46 (4) 44 (4) 44 (6) 43 (6)
CBVC, cm/s/mm Hg 0.68 (0.06) 0.68 (0.07) 0.67 (0.08) 0.66 (0.05) 0.64 (0.07) 0.61 (0.10) 0.60 (0.09) 0.69 (0.05) 0.68 (0.03) 0.66 (0.04) 0.65 (0.05) 0.64 (0.06) 0.62 (0.07) 0.61 (0.08)
P
ET
CO
2
, Torr 41 (5) 41 (6) 41 (6) 40 (8) 39 (6) 39 (5) 38 (6) 42 (5) 42 (5) 41 (5) 40 (7) 40 (5) 39 (5) 39 (5)
Data are presented as mean (SD). Pvalues for MCAv(intervention P¼0.83, pre/post P<0.0001, intervention pre/postinteraction P<0.001, intervention pre/post temp interaction P¼0.52),
CBVC (intervention P¼0.84, pre/post P<0.0001, intervention pre/postinteraction P<0.05, intervention pre/post temp interaction P¼0.65) and P
ET
CO
2
(intervention P¼0.79, pre/post P<0.001,
intervention pre/postinteraction P¼0.47, intervention pre/post temp interaction P¼0.59).
CBVC, cerebrovascular conductance; MCAv, middle cerebral artery velocity; P
ET
CO
2
, peak end tidal CO
2
.
BAILEY ET AL
8Menopause, Vol. 23, No. 7, 2016 ß2016 The North American Menopause Society
Copyright ß2016 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
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Despite the benefits of the exercise training intervention on
reducing hot flushes, they were not completely abolished after
exercise training (62% reduction in weekly frequency).
Using various indices, previous studies have reported
reductions in hot flush frequency in the range of 8% to
33%
12,16
and severity in the range of 10% to 30%.
12-14,16
The reasons for the higher reductions in frequency and severity
in the present study are likely due to differences in exercise
training program design (eg, supervised vs unsupervised and/or
program duration).
12
In a similar study to ours with supervision
and high exercise adherence, Lindh et al reported similar
reductions in hot flush frequency and severity with exercise
training.
15
The frequency and severity responses of the present
study mimic those observed (50%-72% reduction in hot
flushes) after HT administration (ie, usual clinical care) in
symptomatic women over 12 weeks.
5
HT administration over
12 months further reduces hot flushes,
6,73
and thus the effects of
exercise training may also further alleviate hot flushes in a
similar dose-response manner. Despite a reduction in hot
flushes with both HT and exercise training, it is currently
unknown if the effects of exercise and HT act by the same
mechanisms, via an increase in estrogen. Whether the com-
bined effects of exercise training and HT further improve hot
flushes and offset the increases in cardiovascular risk observed
with HT is worth considering. Furthermore, whether the
positive effects of exercise on reducing hot flushes remain
after cessation of exercise training is currently unknown;
however, it can be speculated that the positive effects may
be transient in the absence of exercise training, that is approxi-
mately 4 weeks, in line with the reductions observed in thermo-
regulatory function after the cessation of exercise training in
young women.
20
Nevertheless, the findings of the present study
suggest that improving thermoregulatory function in sympto-
matic postmenopausal women is beneficial for hot flushes.
Although exercise training clearly confers improvements in
thermoregulatory function these findings also suggest that
improving thermoregulatory function per se (eg, passive heat
acclimation) may also be of benefit for symptomatic
postmenopausal women.
One limitation of this study is that it was not a randomized
controlled trial, with participants free to choose which treat-
ment group they entered. Although this convenience sampling
and small sample size limit generalizability, these findings are
labeled preliminary and need to be confirmed in a larger
randomized controlled trial, the reduction in hot flush fre-
quency in the exercise group is similar to that observed in
previous studies, and the hot flush frequency remained
unchanged in the control group. Furthermore, thermoreg-
ulatory measurements are objective and cannot be influenced
by the participant,
41
and were analyzed in a blinded fashion.
Nonetheless, it is acknowledged that the current findings are
specific to early postmenopausal women (1-4 y since last
menstrual period) that were free of cardiovascular disease
and not engaged in regular physical activity. The impact of
exercise training in alleviating hot flushes in individuals with
cardiovascular risk factors, or disease, or other populations
who experience hot flushes (eg, cancer participants) warrants
further research.
CONCLUSIONS
In summary, improvements in the occurrence of hot flushes
with short-term exercise training are mediated via thermo-
regulatory and cardiovascular adaptation(s). This study pro-
vides mechanistic evidence that exercise training is indeed a
useful nonpharmacological alternative intervention in the
treatment of hot flushes. These findings suggest that targeting
the thermoregulatory and cardiovascular systems with inter-
ventions may be useful in treating symptomatic postmeno-
pausal women that suffer from hot flushes.
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EXERCISE REDUCES HOT FLUSHES
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