J Appl Physiol 119: 37–46, 2015.
First published April 30, 2015; doi:10.1152/japplphysiol.00092.2015.
Females have a blunted cardiovascular response to one year
of intensive supervised endurance training
Erin J. Howden,1,2 Merja Perhonen,1 Ronald M. Peshock,2 Rong Zhang,1,2 Armin Arbab-Zadeh,1
Beverley Adams-Huet,2 and Benjamin D. Levine1,2
1
Institute for Exercise and Environmental Medicine, Dallas, Texas; and 2University of Texas Southwestern Medical Center,
Dallas, Texas
Submitted 4 February 2015; accepted in final form 23 April 2015
Howden EJ, Perhonen M, Peshock RM, Zhang R, Arbab-
Zadeh A, Adams-Huet B, Levine BD. Females have a blunted
cardiovascular response to one year of intensive supervised endurance
training. J Appl Physiol 119: 37– 46, 2015. First published April 30,
2015; doi:10.1152/japplphysiol.00092.2015.—Cross-sectional studies
in athletes suggest that endurance training augments cardiovascular
structure and function with apparently different phenotypes in athletic
males and females. It is unclear whether the longitudinal response to
endurance training leads to similar cardiovascular adaptations be-
tween sexes. We sought to determine whether males and females
demonstrate similar cardiovascular adaptations to 1 yr of endurance
training, matched for training volume and intensity. Twelve previ-
ously sedentary males (26 ⫾ 7, n ⫽ 7) and females (31 ⫾ 6, n ⫽ 5)
completed 1 yr of progressive endurance training. All participants
underwent a battery of tests every 3 mo to determine maximal oxygen
uptake (V̇O2max) and left ventricle (LV) function and morphology
(cardiac magnetic resonance imaging). Pulmonary artery catheteriza-
tion was performed before and after 1 yr of training, and pressure-
volume and Starling curves were constructed during decreases (lower-
body negative pressure) and increases (saline infusion) in cardiac
volume. Males progressively increased V̇O2max, LV mass, and mean
wall thickness, before reaching a plateau from month 9 to 12 of
training. In contrast, despite exactly the same training, the response in
females was markedly blunted, with V̇O2max, LV mass, and mean wall
thickness plateauing after only 3 mo of training. The response of LV
end-diastolic volume was not influenced by sex (males ⫹20% and
females ⫹18%). After training Starling curves were shifted upward
and left, but the effect was greatest in males (interaction P ⫽ 0.06).
We demonstrate for the first time clear sex differences in response to
1 yr of matched endurance training, such that the development of
ventricular hypertrophy and increase in V̇O2max in females is markedly
blunted compared with males.
cardiac magnetic resonance imaging; exercise training; gender
REGULAR EXERCISE TRAINING leads to changes in the structure and
function of cardiac and skeletal muscle, which is fundamen-
tally influenced by the type of exercise performed (endurance
vs. strength training) (36). Physiological skeletal muscle hy-
pertrophy is associated with strength training, whereas endur-
ance training is a more potent stimulus to induce physiological
cardiac hypertrophy. Clear sex differences are observed be-
tween strength-trained athletes, such that males demonstrate a
greater magnitude of skeletal muscle mass compared with
females (1), primarily due to the profound anabolic effect of
testosterone on protein synthesis within the skeletal muscle (9).
It is less clear whether the cardiovascular response to en-
durance training is also influenced by sex. Cross-sectional
Address for reprint requests and other correspondence: B. D. Levine,
Institute for Exercise and Environmental Medicine, 7232 Greenville Ave., Ste.
435, Dallas, TX 75321 (e-mail: BenjaminLevine@Texashealth.org).
http://www.jappl.org 8750-7587/15 Copyright © 2015 the American Physiological Society
studies of endurance athletes suggest that females have a lower
maximal oxygen uptake (V̇O2max) and cardiac output (Qc) and
smaller left ventricular (LV) dimensions and wall thickness
compared with similar male athletes (12, 34, 40). Confounding
the interpretation of sex differences is the effect that body size
has on cardiovascular anatomic and physiological variables
(11). Typically studies have scaled cardiovascular variables to
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body size or lean body mass, which eliminates some, but not
all, of the differences between sexes.
Cross-sectional studies are also limited by the different
sports played by male and female athletes and different training
performed, which may alter the magnitude of the effect on the
cardiovascular adaptations observed. Longitudinal studies
comparing the cardiovascular response in males and females
with a comparable endurance training program is lacking.
We have recently demonstrated in previously sedentary
young subjects that 1 yr of intensive endurance training in-
creases cardiac mass to levels similar to elite endurance ath-
letes, results in favorable cardiac remodeling, and improves LV
compliance (3). In this secondary analysis of the same study,
we sought to determine whether males and females demon-
strate similar cardiovascular adaptations to 1 yr of endurance
training, matched for training volume and intensity. We hy-
pothesized that the response to training would be similar in
males and females, evidenced by a similar change in V̇O2max,
cardiac morphology, and function in response to training. To
test this hypothesis, we prescribed a progressive training plan,
identical between males and females, based on a strategy
derived from optimal training by competitive athletes; this
study design allowed us to collect time-dependent measures of
metabolic and LV structure parameters in response to 1 yr of
training.
METHODS
Subjects
This study is a secondary analysis of 12 healthy previously seden-
tary males (n ⫽ 7) and females (n ⫽ 5), who completed 1 yr of
intensive endurance training. The primary findings from this study
have been published recently (3). One subject completed all of the
initial testing but became pregnant in the second quarter of training
and was excluded from the study. Participants were not eligible for the
study if they had engaged in any regular endurance training defined as
⬎30 min/day more than three times per week. All participants were
carefully screened and underwent a physical examination, electrocar-
diogram (ECG), and echocardiogram. None of the subjects smoked,
used recreational drugs, or had significant chronic medical problems.
All female subjects were eumenorrheic when they commenced train-
ing and remained so for the duration of the study.
37
38 Sex Differences in Response to Endurance Training
Ethical Approval
All subjects signed an informed consent, which was approved by
the Institutional Review Boards of the University of Texas South-
western Medical Center at Dallas and Texas Health Resources Pres-
byterian Hospital of Dallas.
Exercise Training
Endurance training was designed to enable subjects to complete a
marathon at the end of the 1-yr period. All subjects performed an
incremental treadmill test for determination of V̇O2max at baseline and
every 3 mo to document exercise performance and for optimal
training prescription. A detailed description of the exercise interven-
tion has been previously described (3, 18). Training zones for optimal
training prescription were individualized by heart rate (HR) and
lactate response to incremental treadmill exercise. “Maximal steady
state” was first estimated from the ventilatory and lactate threshold
according to standard criteria (18). The HR at maximal steady state
and maximum HR were then used to calculate training zones for each
subject; five training zones were determined for individualized train-
ing prescription as follows: zone 1, recovery, zone 2, base pace, zone
3, maximal steady state or “threshold,” zone 4, race pace/critical
power, and zone 5, intervals. During the early phase of the training
program, the subjects trained three to four times per week for 30-45
min/session at base pace by brisk walking, slow jogging, swimming,
or cycling. As subjects became fitter, the duration of the base training
sessions was prolonged, including the addition of one long run per
week, which was performed at the lower end of base pace HR range.
In addition, during the second and third quarters of the training
program, sessions of increased intensity (maximal steady-state and
interval sessions) were added first one time and then two times and
occasionally three times per week. Interval sessions were followed the
next day by a recovery session to maximize performance gains. By the
end of the year-long training program, subjects were exercising for
7–9 h/wk, including long runs of up to 3 h, plus regular interval
sessions on the track and races. The purpose of this template was to
maximize training efficiency and to provide a periodization of the
training program. This strategy of varying intensity and duration of
training session within any given week (microcycles) applying peri-
ods of increasing stress followed by recovery from month to month
(mesocycle) with an ultimate goal of a specific competition (macro-
cycle) is a classic training routine used by competitive athletes and is
widely considered the optimal approach to training (37). Although the
majority of subjects chose to complete a marathon at completion of
the intervention, one female subject completed a 100-mile endurance
cycling race, and one male subject completed an Olympic distance
triathlon. We followed the principles of training specificity; thus, the
subjects completing the marathon performed predominantly running
and the cyclist cycled while the triathlete performed a combination of
swimming, cycling, and running.
HR was recorded during each training session using a HR monitor
provided to each participant. This approach was an important aspect
of the study and gave us the ability to match and quantify training load
throughout the intervention. To quantify the training stimulus, we
calculated the training impulse (“TRIMP”) (5). This method multi-
plies the duration of a training session by the average HR achieved
during that session, weighted for exercise intensity as a function of
HR reserve. With the use of this method, exercise sessions of longer
duration and/or greater intensity such as interval workouts are as-
signed relatively higher TRIMP values (higher HR and higher weight-
ing factor) than sessions of shorter duration and/or lower intensity.
The average TRIMP for the male and female subjects is presented in
Fig. 1. Note the oscillations in TRIMP score throughout the training
period, i.e., micro- and macrocycles of training in Fig. 1 and the
remarkably similar training load between sexes.
J Appl Physiol • doi:10.1152/japplphysiol.00092.2015 • www.jappl.org
• Howden EJ et al.
3200 Males
Females
Monthly TRIMP, arbitary units
2800
2400
2000
1600
1200
800
400
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Month of Training
Fig. 1. Average training impulse (TRIMP) scores per month in males and
females. Individual sex values are presented as means ⫾ SD.
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Study Protocol
All measurements were performed before training (baseline) and
repeated after 3, 6, 9, and 12 mo of training. Pressure/volume studies
were completed pre- and posttraining.
Exercise Testing
A modified Astrand-Saltin incremental treadmill protocol (individ-
ualized treadmill speed, with changes in grade of 2% every 2 min) was
used to determine maximal exercise capacity. Measures of ventilatory
gas exchange were made by use of the Douglas bag technique. Gas
fractions were analyzed by mass spectrometry (Marquette MGA
1100), and ventilatory volume was measured by a dry-gas meter
(Collins). V̇O2max was defined as the highest oxygen uptake measured
from ⱖ40 s Douglas bag. In nearly all cases, a plateau in V̇O2 was
observed with increasing work rate, confirming the achievement of
V̇O2max. Qc was measured with the acetylene rebreathing method,
which has been previously validated in this laboratory (19). HR was
monitored continuously via ECG (Polar). Systemic arteriovenous
oxygen difference (a-vO2 diff) was calculated from the Fick equation
(a-vO2 diff ⫽ V̇O2/Qc) while stroke volume (SV) was calculated as
Qc/HR. SV and Qc were scaled relative to baseline body surface area
[stroke index (SI) and cardiac index (QI)] by clinical convention to
reduce the confounding effect of body size and composition (11).
Body Composition
Body density and composition were determined by underwater
weighing with correction for residual lung volume (41). Each partic-
ipant performed at least three adequate measurements defined as a
definite plateau in underwater weight, and the mean value was
calculated.
Plasma, Blood Volume, and Hematocrit
At baseline and at each quarter testing session, all subjects under-
went measurement of plasma volume using Evans Blue dye indicator
dilution technique. The methods from this technique have been
published (14). Briefly, individuals rested in the supine position for at
least 30 min after which a known quantity of Evans Blue dye was
injected through a peripheral intravenous catheter, and venous blood
was drawn at 10, 20, and 30 min after injection for the measurement
of absorbance at 620 and 740 nm via spectrophotometry (DU 600;
Beckman). Hematocrit was measured via microcapillary centrifuge,
and blood volume was estimated by dividing plasma volume by 1 ⫺
hematocrit using appropriate corrections for trapped plasma and
 Sex Differences in Response to Endurance Training
peripheral sampling. To reduce the confounding effect of body size
and composition on blood volume (11), absolute values were scaled
relative to total body mass (ml/kg) and fat-free mass (FFM; ml/kg
FFM).
Cardiac Magnetic Resonance Imaging
Cardiac morphometric parameters were assessed by a cardiac
magnetic resonance imaging (cMRI) 1.5-tesla Phillips NT MRI Scan-
ner (Phillips Medical Systems, Best, The Netherlands). Short-axis,
gradient echo, and cine magnetic resonance imaging (MRI) sequences
with a temporal resolution of 39 ms were obtained to calculate
ventricular volumes as previously described (17). Ventricular mass
was computed as the difference between epicardial and endocardial
areas multiplied by the density of heart muscle, 1.05 g/ml (21). The
Simpson’s rule technique was used to measure LV mass, which has
been demonstrated to be accurate and reproducible in our laboratory
(21) and by others (15).
For LV volumes, the endocardial border of each slice was identified
manually at end diastole and end systole, and volumes were counted
by summation (31). Mean wall thickness (MWT) for the entire LV,
• Howden EJ et al. 39
Data were used to construct Frank-Starling (SV/PCWP) and pres-
sure-volume (PCWP/LVEDV) curves. For the purpose of the present
study, we characterized two explicitly different but related mechanical
properties of the heart during diastole: 1) static stiffness or overall
chamber stiffness referred to as the stiffness constant, S, of the
logarithmic equation describing the pressure-volume curve (see be-
low); and 2) distensibility, which is used to mean the absolute
LVEDV at a given distending pressure, independent of dP/dV, or S.
To characterize the LV pressure-volume relation, we modeled the
data in the present experiment according to the equation described by
Nikolic et al. (28):
P ⫽ ⫺S ln关共Vm ⫺ V兲 ⁄ (Vm ⫺ Vo)兴
where P is PCWP, V is LVEDV, V0 is equilibrium volume or the
volume at which P ⫽ 0, Vm is the maximal volume obtained by this
chamber, and S is a stiffness constant that describes the shape of the
curve. In addition, pressure-volume curves were also calculated using the
difference between PCWP and right atrial (RA) pressure (PCWP ⫺ RA)
as an index of transmural filling pressure (8) to assess the contribution of
pericardial constraint.

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including the papillary muscle, was calculated as previously described Statistics
(30). For each short-axis slice, the epicardial area (LV chamber plus
myocardial wall) and endocardial area (chamber area) were deter- Continuous data are expressed as means ⫾ SD except for in Figs.
mined using software on the imaging device. The “average” radius for 2–7 in which SE is used. Baseline sex differences were compared with
each area was calculated by approximating the cross section as a circle Student’s t-test. Continuous variables measured over the 12-mo study
and using the equation for the area of a circle (area ⫽ ␲r2). To reduce duration were analyzed longitudinally using linear mixed-effects
the confounding effects of body size and lean mass on LV and right model repeated-measures analysis. The repeated-measures model had
ventricle (RV) mass, measures were scaled to FFM (7). five repeated measurements (time points at baseline and 3, 6, 9, and 12
mo), and the study participant was modeled as a random effect. The
Cardiac Catheterization and Experimental Protocol covariance structure was selected based on Akaike’s Information
Cardiac catheterization was performed at baseline and after the
completion of the training period. Participants were studied in the Table 1. Baseline characteristics, body size and
resting supine position. A 6-Fr balloon-tipped fluid-filled catheter composition, and total blood volume after endurance
(Swan-Ganz; Baxter) was placed using fluoroscopic guidance through training
an antecubital vein in the pulmonary artery. All intracardiac pressures
were referenced to atmospheric pressure with the pressure transducer P Value (sex difference
(Transpac IV; Abbott) zero reading set at 5 cm below the sternal Males Females at baseline)
angle. The wedge position of the catheter tip was confirmed using Age, yr
fluoroscopy, as well as the presence of an appropriate pulmonary Baseline 26 ⫾ 7 31 ⫾ 6 0.21
capillary wedge pressure (PCWP) waveform. The mean PCWP was Height, cm
determined visually at end expiration and was used as an estimation of Baseline 177 ⫾ 2 169 ⫾ 6 0.031
LV end-diastolic pressure. Weight, kg
Qc was measured, and SV was calculated from Qc/HR measured Baseline 78 ⫾ 6 60 ⫾ 3 ⬍0.0001
during rebreathing. Left ventricular end-diastolic volume (LVEDV) 12 Months 77 ⫾ 6 60 ⫾ 4
was measured with two-dimensional echocardiography using standard BSA, m2
Baseline 1.96 ⫾ 0.07 1.67 ⫾ 0.07 0.0006
views and formulas as described by the American Society of Echo-
12 Months 1.93 ⫾ 0.07 1.69 ⫾ 0.08
cardiography (27). Images were obtained with an annular phased- FFM, kg
array transducer using a frequency of 2.5–3.5 MHZ (Interspec Apogee Baseline 62 ⫾ 5 47 ⫾ 5 0.0007
CX) and stored on VCR tapes for off-line analysis by a skilled 12 Months 65 ⫾ 4 50 ⫾ 3**
technician. For calculation of LVEDV for each subject, either the Body fat, %
modified Simpson’s rule method, the area length method, or the bullet Baseline 19 ⫾ 6 23 ⫾ 4 0.270
model (cylinder hemiellipsoid) was chosen on the basis of which 12 Months 15 ⫾ 3* 16 ⫾ 4*
views provided the most optimal endocardial definition (39). The Hematocrit, %
same formula was used for each individual subject throughout the Baseline 44 ⫾ 3 39 ⫾ 3 0.0089
12 Months 42 ⫾ 2** 41 ⫾ 4
study.
TBV, ml/kg
Testing protocol. Resting supine measures (baseline 1) were col- Baseline 66 ⫾ 9 63 ⫾ 4 0.493
lected after ensuring hemodynamic stability (⬃20 min of quiet rest), 12 Months 67 ⫾ 12 67 ⫾ 4*
and then cardiac filling was decreased using lower-body negative TBV, ml/kg FFM
pressure (LBNP) as previously described (26). Measurements of Baseline 82 ⫾ 7 82 ⫾ 8 0.947
PCWP, Qc (and therefore SV), LVEDV, HR, and blood pressure were 12 Months 79 ⫾ 15 80 ⫾ 5
made after 5 min each of ⫺15 and ⫺30 mmHg LBNP. The LBNP was PV, ml/kg
then released. After repeat baseline measurements to confirm a return Baseline 40 ⫾ 5 42 ⫾ 2 0.513
to hemodynamic steady state (usually 20 –30 min), cardiac filling was 12 Months 42 ⫾ 8 43 ⫾ 3
increased by rapid (200 ml/min) infusion of warm (37°C), isotonic Values are means ⫾ SD. BSA, body surface area; FFM, fat-free mass; TBV,
saline. Measurements were repeated after 15 and 30 ml/kg had been total blood volume; PV, plasma volume. *P ⬍ 0.05 and **P ⬍ 0.01 vs.
infused. baseline.

J Appl Physiol • doi:10.1152/japplphysiol.00092.2015 • www.jappl.org

40 Sex Differences in Response to Endurance Training • Howden EJ et al.

A B
Fig. 2. A and B: effect of 1 yr of endurance 60 4.0
training on maximal oxygen uptake (V̇O2max) Male *†‡ * †‡ *† †
*†
indexed to baseline body mass in males and 55 Female
*

VO2 max, ml·kg·min-1

* * *

LV mass, g/kg FFM

females (left), significant sex ⫻ time interac-
*
3.5 * *
tion P ⫽ 0.084 and changes in left ventricle 50
(LV) mass measured by magnetic resonance
imaging (MRI) scaled to baseline fat-free
mass, significant sex ⫻ time interaction P ⫽
45
* * * * 3.0

0.031 (right). Both measured every 3 mo dur-

ing the training program. FFM, fat-free mass. 40
Post hoc comparison with baseline (*), with 2.5
month 3 (†), and with month 6 (‡) for P ⬍ 0.05 35

•
from linear mixed model.
30 2.0
Baseline 3 mo 6 mo 9 mo 12 mo Baseline 3 mo 6 mo 9 mo 12 mo

Criteria and model parsimony. Our analysis was unadjusted, and the or 100-mile endurance cycling race (n ⫽ 1 female). One male
analysis was by available data (last observation was not varied subject had a metal implant and was unable to undergo MRI,
forward). To test our primary hypothesis whether previously seden-

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tary healthy young males and females differ in response to 1 yr of
endurance training, the sex ⫻ time interaction was used, with a P
value of ⬍0.10 declared significant. Similar regression models were
used to assess pressure-volume curves with the addition of a fixed
effect to test for the difference and response interactions between the
baseline and training curves and sex. To express the dose-response
relationship between the exercise training stimulus and changes in LV
mass, the relationship between the quarterly training impulse
(monthly TRIMP) and cardiac adaptations at baseline and 3, 6, 9, and
12 mo was estimated with quadratic polynomial regression models.
Statistical analysis was performed using commercially available soft-
ware (IBM SPSS, SAS version 9.3; SAS Institute, Cary, NC). Statis-
tical significance was declared at a P value of ⬍0.05.
RESULTS
At 1 yr, all subjects completed either a marathon (n ⫽ 10, 4
females and 6 males), Olympic distance triathlon (n ⫽ 1 male),
but completed all other testing. The baseline characteristics and
effect of training on body size, composition, and blood volume
are summarized in Table 1. Comparison between the sexes
showed that females had smaller body size, less FFM and
higher percent body fat (P ⱕ 0.031), and lower hematocrit
levels (P ⫽ 0.009) before training than males. After training
there was no difference between sexes for hematocrit, body fat,
and indexed blood volume. There was a significant sex ⫻ time
interaction (P ⫽ 0.081) for percent body fat. Females demon-
strated a reduction in body fat after 6 mo of training (22.8 ⫾
4.5 vs. 18.1 ⫾ 2.1%, P ⫽ 0.048); a further 6 mo of training
sustained the reduction in body fat (P ⫽ 0.006, month 12
compared with baseline, 16.2 ⫾ 4.2%). In males, percent body
fat did not decrease significantly until month 12 of training
(19.3 ⫾ 6.1 vs. 15.0 ⫾ 3.4%, P ⫽ 0.026). The effect of the
intervention on lean body mass was similar between sexes

Table 2. Effect of 1 yr of endurance training on maximal exercise response

Month
P Value (main P Value
Baseline 3 6 9 12 effect of time) (sex ⫻ time)

V̇O2, l/min
Males 3.36 ⫾ 0.44 3.75 ⫾ 0.43* 3.85 ⫾ 0.35* 4.07 ⫾ 0.43*†‡ 4.09 ⫾ 0.47*†‡ ⬍0.001 0.013
Females 2.19 ⫾ 0.14 2.48 ⫾ 0.16* 2.57 ⫾ 0.18* 2.48 ⫾ 0.21*† 2.51 ⫾ 0.12*†
V̇O2, ml/kg FFM
Males 53.6 ⫾ 5.0 59.9 ⫾ 4.9* 61.4 ⫾ 3.6* 64.9 ⫾ 4.9*†‡ 65.3 ⫾ 5.6*† ⬍0.001 0.094
Females 47.0 ⫾ 3.5 53.3 ⫾ 5.8* 55.2 ⫾ 5.4* 53.1 ⫾ 4.5* 54.2 ⫾ 7.1*
Heart rate, beats/min
Males 200 ⫾ 12 189 ⫾ 7 189 ⫾ 10 190 ⫾ 12 188 ⫾ 12 ⬍0.001 0.56
Females 192 ⫾ 7 185 ⫾ 9 185 ⫾ 6 183 ⫾ 6 186 ⫾ 8
Cardiac index, l·m⫺2·min⫺1
Males 12.2 ⫾ 1.3 13.6 ⫾ 1.3 12.5 ⫾ 1.3 12.0 ⫾ 1.9 12.9 ⫾ 1.6 0.029 0.32
Females 8.9 ⫾ 1.1 9.9 ⫾ 1.5 8.9 ⫾ 0.8 10.3 ⫾ 2.1 10.4 ⫾ 1.4
Stroke index, ml/m2
Males 60.8 ⫾ 5.2 72.5 ⫾ 6.8 66.6 ⫾ 9.3 63.7 ⫾ 12.6 69.1 ⫾ 12.0 0.002 0.37
Females 46.2 ⫾ 5.8 53.9 ⫾ 9.8 48.1 ⫾ 3.9 56.3 ⫾ 10.9 55.7 ⫾ 5.9
a-vO2 diff, ml/100 ml
Males 14.2 ⫾ 1.6 14.2 ⫾ 1.4 15.9 ⫾ 2.0 17.6 ⫾ 2.0*† 16.4 ⫾ 1.8 0.021 0.009
Females 14.8 ⫾ 1.5 15.1 ⫾ 2.7 17.2 ⫾ 1.3* 14.6 ⫾ 2.4‡ 14.6 ⫾ 1.8‡
Lactate, mmol/l
Males 10.4 ⫾ 1.6 10.6 ⫾ 3.2 10.6 ⫾ 1.4 9.3 ⫾ 1.0 9.2 ⫾ 1.7 0.55 0.59
Females 9.9 ⫾ 3.4 9.0 ⫾ 1.9 10.6 ⫾ 2.9 10.1 ⫾ 1.7 9.2 ⫾ 2.7
Values are means ⫾ SD. a-vO2 diff, systemic arteriovenous oxygen difference. The P value within the table represents the main effect of time. Post hoc
comparisons are indicated from the linear mixed-effects model where there was a statistically significant, P ⬍ 0.10 sex ⫻ time interaction; P ⬍ 0.05 vs. baseline
(*), 3 mo (†), and 6 mo (‡).

J Appl Physiol • doi:10.1152/japplphysiol.00092.2015 • www.jappl.org

 Sex Differences in Response to Endurance Training
(sex ⫻ time P ⫽ 0.38), with training resulting in a similar
significant increase (main effect of time P ⫽ 0.019).
Training Impulse
The amount of training performed was virtually identical
between sexes (males total TRIMP ⫽ 19,919 ⫾ 8,687 vs.
females total TRIMP ⫽ 19,989 ⫾ 2,695, P ⫽ 0.98; Fig. 1).
Maximal Exercise Response
• Howden EJ et al. 41
increase in V̇O2max occurring during the initial 3 mo of training
(13% increase from baseline) plateauing thereafter despite the
further increases in training load. In both sexes, training de-
creased maximal HR and increased QI, which resulted in a
significant increase in SI after completion of 1 yr of training
(Table 2). There was a significant sex ⫻ time interaction for
a-vO2 diff (P ⫽ 0.026; Table 2), where males increased a-vO2
after 9 mo of training while females increased after 6 mo of
training before decreasing back to baseline levels.

The effect of the 1 yr of training on V̇O2max indexed to body
mass is shown in Fig. 2A. Endurance training increased V̇O2max
by 22% in males and 15% in females. There was a significant
sex ⫻ time interaction for absolute (P ⫽ 0.018; our primary
outcome variable) and V̇O2max scaled to body mass (P ⫽ 0.084)
and FFM (P ⫽ 0.094), which resulted in the males demon-
strating a progressive increase in V̇O2max over the first 9 mo of
endurance training and then plateauing from months 9 to 12
(Fig. 2A and Table 2). The response of V̇O2max in the females
Effect of Sex on Left Ventricular Adaptations to Training
The adaptations in LV structure to the intervention are
presented in Figs. 2–5 and Table 3. Similar to the response of
V̇O2max, we detected a significant sex ⫻ time interaction for LV
mass indexed to FFM (P ⫽ 0.031). The pattern in LV mass
relative to FFM remodeling is shown in Fig. 2B. In males, LV
mass increased by 11 ⫾ 2% (P ⬍ 0.05) during the first 3 mo
of training and 9 ⫾ 2 (P ⬍ 0.01) between 3 and 6 mo, with the

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was blunted compared with the males, with the majority of the total increase during the first 6 mo being 20 ⫾ 2% (P ⬍ 0.01).

Table 3. Effect of 1 yr of endurance training on left and right ventricle morphology and function measured by cardiac MRI
P Value (main P Value
Baseline Month 3 Month 6 Month 9 Month 12 effect of time) (sex ⫻ time)

MWT, cm
Males 1.00 ⫾ 0.13 1.19 ⫾ 0.13* 1.27 ⫾ 0.11*† 1.23 ⫾ 0.12* 1.23 ⫾ 0.06* ⬍0.001 ⬍0.001
Females 1.00 ⫾ 0.05 1.11 ⫾ 0.05* 1.12 ⫾ 0.02* 1.05 ⫾ 0.05†‡ 1.07 ⫾ 0.07*
LV mass, g
Males 192 ⫾ 31 212 ⫾ 27* 230 ⫾ 24*† 234 ⫾ 23*† 238 ⫾ 26*† ⬍0.001 0.001
Females 140 ⫾ 15 158 ⫾ 13* 160 ⫾ 12* 157 ⫾ 13*‡ 164 ⫾ 12*
LV EDV, ml
Males 132 ⫾ 10 136 ⫾ 11 143 ⫾ 11 151 ⫾ 14 158 ⫾ 13 ⬍0.001 0.39
Females 98 ⫾ 10 99 ⫾ 9 104 ⫾ 10 118 ⫾ 14 116 ⫾ 15
LV ESV, ml
Males 43 ⫾ 8 40 ⫾ 6 41 ⫾ 7 44 ⫾ 8 44 ⫾ 8 ⬍0.001 0.79
Females 30 ⫾ 6 28 ⫾ 4 31 ⫾ 3 32 ⫾ 5 34 ⫾ 6
LV SV, ml
Males 89 ⫾ 3 96 ⫾ 5* 102 ⫾ 5*† 107 ⫾ 7*†‡ 113 ⫾ 7*†‡§ ⬍0.001 0.035
Females 68 ⫾ 5 71 ⫾ 6 74 ⫾ 6* 85 ⫾ 10*†‡ 81 ⫾ 9*†‡
LV ejection fraction, %
Males 68 ⫾ 4 71 ⫾ 3 71 ⫾ 3 71 ⫾ 3 72 ⫾ 3 0.001 0.28
Females 69 ⫾ 4 72 ⫾ 2 71 ⫾ 1 72 ⫾ 2 70 ⫾ 2
LV mass/volume
Males 1.45 ⫾ 0.19 1.56 ⫾ 0.16* 1.61 ⫾ 0.13* 1.55 ⫾ 0.11* 1.51 ⫾ 0.08‡ ⬍0.001 0.008
Females 1.42 ⫾ 0.04 1.60 ⫾ 0.03* 1.54 ⫾ 0.14* 1.34 ⫾ 0.11† 1.34 ⫾ 0.11†‡
RV EDV, ml
Males 156 ⫾ 9 180 ⫾ 8 188 ⫾ 11 193 ⫾ 10 198 ⫾ 17 ⬍0.001 0.20
Females 112 ⫾ 13 126 ⫾ 9 128 ⫾ 10 146 ⫾ 16 144 ⫾ 14
RV ESV, ml
Males 70 ⫾ 6 82 ⫾ 5 86 ⫾ 6 86 ⫾ 6 88 ⫾ 12 ⬍0.001 0.26
Females 46 ⫾ 7 53 ⫾ 5 54 ⫾ 5 63 ⫾ 11 61 ⫾ 9
RV SV, ml
Males 87 ⫾ 4 98 ⫾ 5 103 ⫾ 5 107 ⫾ 7 110 ⫾ 7 ⬍0.001 0.31
Females 66 ⫾ 7 73 ⫾ 4 74 ⫾ 7 85 ⫾ 9 82 ⫾ 7
RV mass, g
Males 69 ⫾ 7 78 ⫾ 7* 83 ⫾ 7* 86 ⫾ 8*† 91 ⫾ 9*†‡ ⬍0.001 0.066
Females 56 ⫾ 6 62 ⫾ 5 61 ⫾ 5 63 ⫾ 14 69 ⫾ 11*‡
RV ejection fraction, %
Males 56 ⫾ 2 55 ⫾ 1 55 ⫾ 1 55 ⫾ 2 55 ⫾ 2 0.70 0.82
Females 59 ⫾ 2 58 ⫾ 2 58 ⫾ 2 58 ⫾ 2 58 ⫾ 2
RV mass/vol
Males 0.44 ⫾ 0.05 0.44 ⫾ 0.04 0.45 ⫾ 0.04 0.45 ⫾ 0.02 0.46 ⫾ 0.05 0.037 0.019
Females 0.51 ⫾ 0.03 0.48 ⫾ 0.03 0.46 ⫾ 0.05* 0.42 ⫾ 0.06*†‡ 0.49 ⫾ 0.06§
Values are means ⫾ SD; n ⫽ 6 male and 5 female subjects for all parameters. All variables were measured by cardiac magnetic resonance imaging (MRI).
MWT, mean wall thickness; RV, right ventricle; LV, left ventricle; EDV, end-diastolic volume; ESV, end-systolic volume; SV, stoke volume. The P value within
the table represents the main effect of time. Post hoc comparisons are indicated from the linear mixed-effects model where there was a statistically significant,
P ⬍ 0.10 sex ⫻ time interaction; P ⬍ 0.05 vs. baseline (*), 3 mo (†), 6 mo (‡), and 9 mo (§).

J Appl Physiol • doi:10.1152/japplphysiol.00092.2015 • www.jappl.org

42 Sex Differences in Response to Endurance Training • Howden EJ et al.

A B

250 250

LV mass, g

LV mass, g
Fig. 3. A and B: quadratic regression analysis
between average quarterly TRIMP values as 200 200
measure of training stimulus and LV mass.
Light gray lines, individual curves; solid
black line, curves for males and females.

150 150

0 2000 4000 6000 8000 0 2000 4000 6000 8000

TRIMP TRIMP

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In females, the greatest increase in LV mass indexed to FFM
(13 ⫾ 2%, P ⬍ 0.01) occurred during the first 3 mo of training.
In contrast to the males, there was no further statistically
significant increase in LV mass indexed to FFM in the females
(Fig. 2B). When the mean quarterly values for LV mass were
compared with the average TRIMP values obtained for each
quarter in males and females, we observed a strong positive
relationship in the males such that as training impulse in-
creased LV mass was markedly augmented, whereas in the
females the effect of increased training impulse was markedly
attenuated with a small gradual increase in mass with increas-
ing training stimulus (Fig. 3, A and B).
MWT was increased by training and paralleled the increase
in LV mass in both sexes (Table 3). In males, MWT increased
by 27 ⫾ 3% during the first 6 mo of training. In females the
increase in MWT was 11 ⫾ 2% during the first 3 mo.
The effect of endurance training on LVEDVI was similar
between sexes (sex ⫻ time P ⫽ 0.34; Fig. 4A). The overall
increase in LVEDVI was 20% for males and 18% for females.
The pattern of concentric and eccentric modelling was over-
all similar between males and females; however, the time
course of change was different (sex ⫻ time P ⫽ 0.008, Table
3). Both sexes demonstrated an initial increase in mass and
wall thickness, consistent with concentric remodeling. The LV
mass-to-volume ratio returned to near baseline levels in the
males at completion of the study, whereas in the females the
mass-to-volume ratio decreased to below baseline values, sug-
gesting even greater eccentric remodeling.
Effect of Sex on Right Ventricular Adaptations to Training
The RV volumetric adaptations that occurred during the 1 yr
of training were similar between sexes (Fig. 4B and Table 3).
There was a sex ⫻ time (P ⫽ 0.066) interaction for RV mass
(Table 3), demonstrating again that males have a more pro-
nounced hypertrophic response to training compared with fe-
males. There was a significant sex ⫻ time interaction for RV
mass-to-volume ratio (Table 3). Interestingly, males main-
tained a similar mass-to-volume ratio throughout the interven-
tion. However, the ratio decreased in females as the training
progressed.
Pressure-Volume Curves
The LV pressure-volumes curves constructed from group
mean data in males and females are shown in Fig. 5, A and B,
respectively. Both Vm and V0 increased in the males and
females consistent with significant physiological remodeling.
The response to endurance training for the pressure-volume
curves was similar between sexes (sex ⫻ time P ⫽ 0.18), with
both males (P ⫽ 0.039) and females (P ⬍ 0.001) demonstrat-
ing a significant rightward shift. LV pressure-volume curves
(Fig. 6, A and B) constructed using transmural pressure dem-

A B
Fig. 4. A and B: effect of 1 yr of endurance Male
training on left ventricle end-diastolic vol- 100 100
Female
ume (LVEDV, A) and right ventricle end-
diastolic volume (RVEDV, B) scaled to
RVEDVI, ml/m2
LVEDVI, ml/m2

baseline total body surface area, measured

by MRI every 3 mo during the 1-yr training 80 80
program. For left ventricular end-diastolic
volume index (LVEDVI) and right ventricu-
lar end-diastolic volume index (RVEDVI),
males and females responded in a similar 60 60
manner to the training (LVEDVI sex ⫻ time
P ⫽ 0.48 and RVEDVI sex ⫻ time P ⫽
0.22).
40 40
Baseline 3 mo 6 mo 9 mo 12 mo Baseline 3 mo 6 mo 9 mo 12 mo

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 Sex Differences in Response to Endurance Training • Howden EJ et al. 43

A B 25
25
Pre Pre
S= 8.1 S= 7.7
20
20
Vmax= 81 Vmax= 59
Fig. 5. A and B: group mean pressure-volume
PCWP, mmHg

PCWP, mmHg
V0= 23 V0= 22
curves for male (A) and female (B) subjects
15 15
with data points derived from baseline, low-
er-body negative pressure (LBNP), and rapid
10 Post 10 saline infusion, similar to Fig. 6. Each data
Post
S= 8.8 S= 8.4 point represents the mean ⫾ SE of males or
5 Vmax= 84 5 females, pre vs. post (sex ⫻ time P ⫽ 0.18).
Vmax= 67
V0= 35 V0= 28
0 0
30 40 50 60 70 80 90 30 40 50 60 70 80 90
LVEDVI, mL/m 2
LVEDVI, mL/m2

onstrated a significant interaction (sex ⫻ time P ⫽ 0.07), with anism has been shown to be a hallmark characteristic of
females demonstrating a significant shift in the pressure-vol- endurance athletes (26).
ume curve posttraining (P ⫽ 0.02), but not males (P ⫽ 0.75).

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Frank-Starling Curves
Frank-Starling curves are shown in Fig. 7, A and B, for
males and females, respectively. There was a significant sex ⫻
time interaction (P ⫽ 0.06). The training effect in females was
⬃7.1 ml less than in the males.
DISCUSSION
The main new findings from the present study were clear
differences in the time course and magnitude of cardiovascular
adaptation between previously sedentary males and females in
response to identical endurance training loads. Males had more
pronounced LV hypertrophy throughout the 1 yr of training,
whereas females reached the maximal LV mass after only 3 mo
of training. The LV hypertrophic response closely paralleled
the increase in V̇O2max in both sexes, which was blunted in
females. We found that ventricular remodeling and increased
compliance were similar between sexes, but endurance training
resulted in greater augmentation of the Frank-Starling mecha-
nism in the males compared with females. The greater effect of
endurance training on the Frank-Starling mechanism (relation-
ship between LV filling pressures and SV) in the males
means that males had a greater diastolic reserve after 1 yr of
training. This adaptation to training is extremely beneficial
for performing exercise, allowing individuals to generate a
higher SV and cardiac output in response to an increase in
filling pressure. Indeed, an enhanced Frank-Starling mech-
Effect of One Year of Endurance Training on Exercise
Performance and Cardiac Morphology
This is the first study to demonstrate that healthy previously
sedentary males have a markedly greater increase in LV mass
and V̇O2max compared with the response in females to 1 yr of
identical endurance training. To that end, we recorded each
heart beat during exercise to carefully quantify the amount of
training performed using the TRIMP method (6). As can be
seen from Fig. 1, males and females received a nearly identical
training stimulus. However, there was a divergent response in
the observed adaptations to training. Surprisingly V̇O2max pla-
teaued after only 3 mo of training in females, but continued to
increase progressively in males until month 9, resulting in an
⬃7% greater increase in V̇O2max at month 12. Indeed, as
training intensity increased in the males, we observed a pro-
gressive increase in LV mass that was not evident in the
females (Fig. 2B). To our knowledge no endurance training
studies have compared sex differences in healthy young sub-
jects beyond 3 mo of training. Therefore, until now, important
differences in the cardiovascular response to training may have
been missed. Indeed 90 days of intense endurance training in
female and male rowers resulted in no significant differences
between sexes for change in any cardiovascular variables (4).
Thus it seems likely that cardiovascular sex differences have
been underestimated due to the duration of prior training
studies.

A B
8 8
Pre Pre
S= 1.9 S= 2.5
6 Vmax= 80 6 Vmax= 60 Fig. 6. A and B: group mean transmural pres-
TMP, mmHg

V0= 1.208e-16 V0 = 8 sure (TMP)-volume curves for male (A) and

female (B) subjects with data points derived
TMP

4 4 from baseline, LBNP, and rapid saline infu-

Post Post sion. Each data point represents the mean ⫾
S= 2.4 S= 2.3 SE of males or females, pre vs. post (sex ⫻
2
Vmax= 86
2
Vmax= 69
time P ⫽ 0.07).
V0= 1.208e-16 V0= 2.6
0 0
30 40 50 60 70 80 90 30 40 50 60 70 80 90
LVEDVI, mL/m2 LVEDVI, mL/m2

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44 Sex Differences in Response to Endurance Training
A B
80
Fig. 7. A and B: group mean Frank-Starling
curves representing pulmonary capillary
wedge pressure (PCWP) as an index of LV
end-diastolic pressure vs. stroke volume in-
POST
SI (ml/m2)
dex (SI), over a range of LV filling produced
by lower-body negative pressure (two lowest 60
levels of PCWP), quiet baseline (two middle
values of PCWP), and rapid saline infusion
(two highest values of PCWP) as described in
text. Each data point represents the mean ⫾ SE
of males or females, pre vs. post (sex ⫻ time 40
P ⫽ 0.06).
0 5
Consistent with the sex difference observed in the LV, the
RV also increased in mass in response to training. The re-
sponse in males was again more prominent than the females,
who did not demonstrate a significant increase in RV mass
until completion of the study. Few prospective studies have
assessed the degree of RV hypertrophy with endurance train-
ing, due to the difficulty in reliably assessing morphology
using echocardiography. Recent evidence from cross-sectional
studies with cMRI suggests that the mass of RV is increased to
match the increased work of the LV and maintain a balanced
ratio to enhance function in male and female athletes (32, 33).
Transient increases in pulmonary artery pressure during exer-
cise likely contribute to the enlargement of the RV. Endurance
athletes have greater RV enlargement and wall thickening,
which is thought to be due to the disproportionate increase in
hemodynamic load placed on the RV during endurance exer-
cise (25). Given these prior findings, our results raise the
possibility that the male participants may have been under a
greater hemodynamic stress during training, which is reflected
by the greater increase in RV mass. In the present studies, the
increase in RV and LV mass in females was attenuated com-
pared with the changes observed in the LV and in the males,
but still reached levels comparable with female athletes (29).
Potential Underlying Mechanisms Regulating Sex
Differences in Response to Training
Sex differences in the endogenous androgens play a key role
in the development of both skeletal muscle and cardiac hyper-
trophy. In male rats who have undergone orchiectomy ventric-
ular mass is decreased, while testosterone administration in-
duces myocellular hypertrophy (22). Regular exercise training
is a strong stimulus to increase circulating endogenous testos-
terone levels, which promotes muscle growth, through protein
synthesis and inhibits protein degradation (38). Circulating
estrogen levels influence cardiac hypertrophy by preventing the
development of pathological cardiac hypertrophy in premeno-
pausal females, with the benefit reduced in the postmenopausal
state (16). It remains unclear whether estrogen also influences
exercise-induced cardiac hypertrophy. Indeed, rodent studies
suggest an enhanced cardiac hypertrophic response to training
in females compared with males (24). However, key differ-
ences in animal and human female reproductive physiology,
namely estrous vs. menstrual cycle, limit the interpretation of
the influence of sex hormones on cardiac adaptations in mice
and must be considered when interpreting animal studies.
J Appl Physiol • doi:10.1152/japplphysiol.00092.2015 • www.jappl.org
• Howden EJ et al.
80
POST
SI (ml/m2)
60
PRE
PRE
40
10 15 20 25 0 5 10 15 20 25
PCWP (mmHg) PCWP (mmHg)
Moreover, diet also influences cardiac adaptation in mice and
must be considered when using this model to assess sex
differences (23). The present study suggests that endurance
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training has an early anabolic effect on female hearts while the
increase in male heart size is more progressive possibly due to
small elevations in androgens.
It should be noted that we observed a marked reduction in
body fat in female participants from month 6 of training
onward. This reduction in fat mass coincided with an increase
in training impulse (Fig. 1), since both intensity and duration of
training were dramatically increased. We did not observe
similar changes in body fat in the males in response to the
increase in training load. Our intervention provided only gen-
eral dietary advice. Thus a possible explanation for the lack of
effect of endurance training on V̇O2max and cardiac mass in
females may be partially explained by a suboptimal energy
intake. The American College of Sports Medicine recognizes
that female athletes are plagued by low energy intake (2). A
reduced energy intake will result in the utilization of fat and
lean tissue stores to fuel the body during exercise and may
impair muscle protein synthesis (35).
Alternatively, other aspects of the subject’s lives may have
influenced the lack of adaptation observed in the female sub-
jects, including lack of appropriate recovery or other life-
related stressors (e.g., sleep, work, and emotional upheavals).
Indeed all subjects showed some signs of overtraining toward
the end of the study. We have previously reported that pro-
longed intense training does not necessarily result in greater
enhancement of dynamic regulation of HR or blood pressure
(18). In our prior study, we demonstrated a bell-shaped relation
with late changes in autonomic control of the circulation,
possibly due to the effects of overtraining. Unfortunately, we
did not collect information on the subject’s quality of life
throughout the study or indicators of overtraining. Future
studies should plan to include specific dietary advice as would
be recommended to male and female athletes performing such
a high volume of endurance training, and include assessments
of quality of life.
Another possible explanation for the observed sex differ-
ences in cardiac hypertrophy may relate to differences in
signaling events that mediate hypertrophy. Cardiac hypertro-
phy due to exercise is mediated by peptide growth factors and
signaling through the phosphatidylinositol 3-kinase/Akt path-
way (13). Premenopausal females have a fivefold increase in
Akt when compared with age-matched males (10). We specu-
 Sex Differences in Response to Endurance Training
late that young females may be somewhat protected from
marked increases in ventricular hypertrophy by the increased
levels of Akt. Evidence from animal studies also provides
some support for this hypothesis. Endurance-trained female
mice have been shown to have higher levels of phosphorylated
glycogen synthase kinase-3beta (GSK) in isolated cardiac tis-
sue compared with male mice (24). GSK is a downstream
target of Akt kinase and negative regulator of cardiac hyper-
trophy. Thus the hypertrophic response to endurance training
in young females may be blunted by a combination of in-
creased levels of Akt and GSK.
Ventricular Remodeling
The superior athletic ability of the elite athlete is partially
due to a large compliant LV and enhanced ability to utilize the
Frank-Starling mechanism to increase SV during exercise (26).
Endurance athletes have a greater augmentation in SV for any
given filling pressure and increased diastolic reserve, meaning
their LVs are more compliant and distensible compared with
sedentary subjects (26). We recently demonstrated that 1 yr of
training resulted in a significant improvement in ventricular
distensibility and possible reduction in pericardial constraint in
healthy young individuals (3). In the present study, we extend
these findings to examine whether the response to training
differs in males and females. Despite clear sex differences in
the hypertrophic response to endurance training, both males
and females had a similar augmentation in end-diastolic vol-
ume and LV compliance and distensibility. The Frank-Starling
mechanism was augmented to a greater extent in males com-
pared with females, which is likely due to the greater amount
of hypertrophy in the males and therefore larger SV (26). An
increase in wall thickness of the ventricle results in a reduction
in wall stress and afterload. This in turn allows for a smaller
end-systolic volume and thus larger SV. In addition, ventricu-
lar remodeling occurs in response to endurance training, which
increases muscle mass and results in greater ventricular com-
pliance. Therefore, for a given filling pressure, the males were
able to generate a greater end-diastolic volume. We speculate
that even more prolonged training (e.g., years), or the com-
mencement of training during developmental years, may be
required to improve LV compliance to levels similar to endur-
ance athletes (26). Long-term follow-up is also required to
determine whether maintenance of this training frequency
through middle age and beyond will indeed maintain LV
compliance.
Limitations
The primary limitation with this study is its small sample
size, a direct reflection of the intensive and invasive nature of
the training and assessment tools. Few studies have reported
the effects of sex on cardiac adaptations to exercise training.
Thus, while our sample size is small, these results are highly
novel in the field of exercise physiology. The small sample size
is also offset by our observations of significant sex ⫻ time
interactions, and our within-subject design, which minimized
important sources of error. It is also notable that MRI is
substantially more precise in terms of cardiac morphological
assessment than echocardiography (20). LV pressure-volume
curves were evaluated by use of mean PCWP as a surrogate for
LV end-diastolic pressure. Unfortunately we do not have direct
J Appl Physiol • doi:10.1152/japplphysiol.00092.2015 • www.jappl.org
• Howden EJ et al. 45
measures of sex hormones, although all females experienced
normal menstrual cycles at all times during the study. Future
studies should include these measures. Although we observed
a divergent response between sexes for a-vO2 diff, this finding
seems to be driven by the response of one female, a further
limitation of our small sample size.
Conclusion
In summary, the cardiovascular adaptation to 1 yr of endur-
ance training has a different time course and magnitude of
effect in males and females, even when performing identical
endurance training. Males had a more prominent increase in
LV mass throughout the study, whereas females reached max-
imal LV hypertrophy in 3 mo, although the intensity of training
was similar in both sexes. Aerobic power was clearly related to
LV hypertrophy. Ventricular compliance and distensibility
improved similarly in males and females, but males demon-
strate greater enhancement in the Frank-Starling mechanism
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compared with the females, emphasizing the divergent sex
response to endurance training.
ACKNOWLEDGMENTS
We thank Matthew J. Morrow for work in training the subjects, Fatima
Franco for assistance with MRI analysis, and Julie H. Zuckerman for nursing
care during the invasive studies and performance of the ultrasound measure-
ments.
GRANTS
This study was supported by National Aeronautic and Space Administration
Specialized Center for Research and Training Grant NGW-3582, the S. Finley
Ewing Chair for Wellness at Texas Health Presbyterian Hospital, and the Harry
S. Moss Heart Chair for Cardiovascular Research.
DISCLOSURES
The authors declare no conflict of interest.
AUTHOR CONTRIBUTIONS
Author contributions: E.J.H., M.P., R.M.P., A.A.-Z., B.A.-H., and B.D.L.
analyzed data; E.J.H., M.P., R.M.P., R.Z., A.A.-Z., B.A.-H., and B.D.L.
interpreted results of experiments; E.J.H. prepared figures; E.J.H. and M.P.
drafted manuscript; E.J.H. and B.D.L. edited and revised manuscript; E.J.H.,
M.P., R.M.P., R.Z., A.A.-Z., B.A.-H., and B.D.L. approved final version of
manuscript; M.P., R.M.P., R.Z., A.A.-Z., and B.D.L. performed experiments;
R.Z. and B.D.L. conception and design of research.
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