J. Appl. Physiol.

88: 246–256, 2000.

Women at altitude: carbohydrate utilization

during exercise at 4,300 m
BARRY BRAUN,1 JACINDA T. MAWSON,1 STEPHEN R. MUZA,2 SHANNON B. DOMINICK,1
GEORGE A. BROOKS,3 MICHAEL A. HORNING,3 PAUL B. ROCK,2 LORNA G. MOORE,4
ROBERT S. MAZZEO,5 STEVEN C. EZEJI-OKOYE,1 AND GAIL E. BUTTERFIELD1
1Aging Study Unit, Geriatric Research, Education, and Clinical Center, Veterans Affairs Health

Care System, and Division of Gerontology, Endocrinology, and Metabolism, Stanford University
Medical School, Palo Alto, California 93404; 2Thermal and Mountain Division, US Army Research
Institute of Environmental Medicine, Natick, Massachusetts 01760; 3Department of Integrative
Biology, University of California, Berkeley, California 94720; 4Womens Health Research Center,
University of Colorado, Denver 80262; and 5Department of Kinesiology and Applied Physiology,
University of Colorado, Boulder, Colorado 80309

Braun, Barry, Jacinda T. Mawson, Stephen R. Muza,
Shannon B. Dominick, George A. Brooks, Michael A.
Horning, Paul B. Rock, Lorna G. Moore, Robert S.
Mazzeo, Steven C. Ezeji-Okoye, and Gail E. Butterfield.
Women at altitude: carbohydrate utilization during exercise
at 4,300 m. J. Appl. Physiol. 88: 246–256, 2000.—To evaluate
the hypothesis that exposure to high altitude would reduce
blood glucose and total carbohydrate utilization relative to
sea level (SL), 16 young women were studied over four 12-day
periods: at 50% of peak O2 consumption in different men-
strual cycle phases (SL-50), at 65% of peak O2 consumption at
SL (SL-65), and at 4,300 m (HA). After 10 days in each
condition, blood glucose rate of disappearance (Rd ) and respi-
ratory exchange ratio were measured at rest and during 45
min of exercise. Glucose Rd during exercise at HA (4.71 6 0.30
mg · kg21 · min21 ) was not different from SL exercise at the
same absolute intensity (SL-50 5 5.03 mg · kg21 · min21 ) but
was lower at the same relative intensity (SL-65 5 6.22 mg ·
kg21 · min21, P , 0.01). There were no differences, however,
when glucose Rd was corrected for energy expended (kcal/
min) during exercise. Respiratory exchange ratios followed
the same pattern, except carbohydrate oxidation remained
lower (223.2%, P , 0.01) at HA than at SL when corrected for
energy expended. In women, unlike in men, carbohydrate
utilization decreased at HA. Relative abundance of estrogen
and progesterone in women may partially explain the sex
differences in fuel utilization at HA, but subtle differences
between menstrual cycle phases at SL had no physiologically
relevant effects.
stable isotope; hypobaric hypoxia; substrate utilization; glu-
cose flux; gender differences; ovarian hormones; menstrual
cycle
EXPOSURE TO HYPOBARIC hypoxia at high altitudes alters
substrate utilization at rest and during exercise (6, 7,
21, 29–31, 40). Brooks (5) and Hochachka (20) proposed
that a change in the regulation of metabolic pathways
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246 8750-7587/00 $5.00 Copyright r 2000 the American Physiological Society
to favor greater dependence on glucose, rather than
fatty acids, would aid in maintaining homeostasis by
optimizing the energy yield per unit O2. Experimental
evidence tends to support this theory; results from
studies on rat hindlimbs exposed to hypoxic buffer (11),
hypoxic dogs (42), high-altitude natives (21), and low-
landers exposed to high altitude (7, 30, 31) show a shift
toward increased glucose utilization relative to nor-
moxic conditions. In two separate studies on men in
which the weight loss commonly observed at high
altitude was prevented by rigorous dietary control,
whole body glucose uptake and glucose extraction by
exercising leg muscles were markedly higher after 2 h
and remained elevated after 21 days of exposure to
4,300 m (14,100 ft) compared with sea level (7, 31).
Generalizing results of studies on men to the whole
population is risky, because exposure to high altitude
may alter substrate utilization differently in women
and men (4). Metabolic regulation in the presence of
estrogen and progesterone appears to redirect sub-
strate selection toward reduced carbohydrate and in-
creased fat use (9, 15, 16, 22, 25, 34–39). This effect
may be accentuated during the midluteal phase of the
menstrual cycle, when estrogen and especially proges-
terone are considerably elevated (9, 16, 18, 23). In other
physiological situations that stimulate a sympathoadre-
nal response (hypoglycemia and exercise), increases in
carbohydrate utilization tend to be considerably smaller
in women than in men (1, 12, 14, 22, 34, 38). Recently,
McClelland et al. (29) reported that carbohydrate utili-
zation in female rats acclimated to high altitude did not
increase compared with rats living at sea level. They
found that the contribution of carbohydrate to total
energy expenditure was wholly dependent on the exer-
cise intensity, relative to the altitude-specific maximal
O2 consumption (V̇O2), regardless of the elevation.
We hypothesized that blood glucose utilization and
total glucose oxidation would be lower after 10 days of
exposure to 4,300-m elevation than at sea level. In
addition, we expected that, on the basis of changes in
substrate levels and the hormonal environment, exer-
cise at high altitude was most appropriately compared
http://www.jap.org
 CARBOHYDRATE UTILIZATION IN WOMEN AT HIGH ALTITUDE
with sea-level exercise at the same relative intensity.
Finally, we anticipated that making comparisons be-
tween elevations in the same phase of the menstrual
cycle would be important, because carbohydrate utiliza-
tion would be greater in the follicular than in the luteal
phase of the cycle.
METHODS
Study Design
As part of a larger study of how women acclimatize to high
altitude, we measured blood glucose utilization and total
carbohydrate oxidation during rest and submaximal exercise
three times at sea level and again after 10 days of exposure to
4,300-m elevation. The potential confounding effects of weight
loss were limited by feeding subjects a controlled diet (see
Dietary Control) to maintain energy balance and body weight.
The first two sea-level study periods were identical (subjects
exercised at exactly the same workload), except they were
conducted in opposite phases of the menstrual cycle (order
was randomized), so that the single high-altitude study
period could be directly compared with the matching cycle
phase at sea level. The third sea-level study period included
exercise at a higher intensity and was designed to allow
comparison between sea level and high altitude at the same
absolute and relative exercise intensities.
Subjects
Eighteen women, 21–34 yr old, completed the sea-level
portion of the study. Because of illness not related to participa-
tion in the study, two women did not perform the test at high
altitude, and one test was canceled because of a prolonged
power outage (final n 5 15). All the women were sea-level
residents (,1,500-m elevation), although one woman spent
several days at .1,500 m shortly before the high-altitude
phase; the subjects were nonsmokers and had regular men-
strual cycles (see Menstrual Cycle Phase Determinations). All
subjects were in good overall health on the basis of a routine
physical examination and were in the clinically normal range
for standard blood and urine chemistry panels, including Hb
and serum ferritin. They had normal fasting and 2-h postpran-
dial blood glucose concentrations. All subjects reported being
moderately to very physically active and underwent a stan-
dard graded exercise test to peak V̇O2 (V̇O2 peak) on a cycle
ergometer. Subject characteristics are summarized in Table
1. The protocol was approved by institutional review boards
Table 1. Subject characteristics
Sea Level 4,300 m
Age, yr 21.7 6 0.7 21.7 6 0.7
Height, cm 167.4 6 1.3 167.4 6 1.3
Weight, kg 62.2 6 1.2 62.6 6 1.2
V̇O2 peak , ml · kg21 · min21 42.0 6 1.7 31.9 6 1.3*
Estrogen, pg/ml
E 51 6 19 80 6 17*
E1P 96 6 11† 83 6 12
Progesterone, ng/ml
E 0.43 6 0.10 0.81 6 0.15*
E1P 7.66 6 1.35† 5.72 6 1.96†
Values are means 6 SE. Serum estrogen and progesterone concen-
trations were measured the day of metabolic tests, usually day 10 of
cycle phase. E, estrogen-only phase (‘‘follicular’’); E 1 P, estrogen 1
progesterone phase (‘‘luteal’’); V̇O2 peak , peak O2 consumption. * Signi-
ficantly different between elevations. † Significantly different across
cycle phases.
247
at Stanford University, the US Army Research Institute of
Environmental Medicine, and the University of Colorado.
Before admission, subjects were briefed on all aspects of the
studies and gave written consent to participate.
Sea-Level and High-Altitude Conditions
At sea level (Palo Alto, CA, 15-m elevation, atmospheric
pressure 748–762 Torr), subjects participated in the study for
12 days on each of three occasions, usually ,6 wk apart. The
women were admitted as patients to the metabolic ward at
the Palo Alto Veterans Affairs Health Care System and were
housed there on nights 6–11 of each study period. One to 3 mo
after the sea-level studies, subjects were flown to Colorado
Springs, CO (1,850 m), and immediately driven by car to
Pikes Peak, CO, arriving at the summit (4,300 m, atmo-
spheric pressure 458–464 Torr) 2 h later. On Pikes Peak,
women were housed in the laboratory facility, managed by the
US Army Research Institute of Environmental Medicine, for
the entire 12-day study.
Protocol
To assess maximal aerobic capacity at both elevations,
V̇O2 peak was determined on day 5 by graded cycle ergometry at
a cadence of 60 rpm, starting at 50 W (3 min) and increasing
the work by 25 W/min until voluntary exhaustion with
standard criteria [attainment of $2 of the following 3 param-
eters: plateau in V̇O2, respiratory exchange ratio (RER) . 1.1,
and predicted maximal heart rate] employed to validate the
test. Because V̇O2 peak does not change during at least several
weeks of acclimatization to high altitude (5–7, 27), the value
recorded on day 5 was assumed to be applicable on day 10.
Subjects fasted after 9 PM on day 9. On the next morning,
subjects consumed a standardized breakfast meal (energy
content 5 2,063 kJ 5 493 kcal) composed of 70% carbohy-
drate, 10% protein, and 20% fat. After completion of the meal,
a catheter was inserted into the radial artery for blood
sampling and a second catheter was placed in the antecubital
vein of the contralateral arm for infusion of isotope. Subjects
rested semisupine for the duration of the resting measure-
ments. Two to 3 h after the meal was completed, an arterial
blood sample was collected for determination of background
isotopic enrichment, and the O2 and CO2 concentrations in
expired air were analyzed by indirect calorimetry with a
metabolic cart (model 2900, SensorMedics, Anaheim, CA). A
priming bolus of 200 mg of [6,6-2H]glucose (Cambridge Iso-
tope Lab, Andover, MA) in 0.9% sterile saline (125 times the
resting minute infusion rate) was rapidly injected into the
venous catheter. A continuous infusion of [6,6-2H]glucose in
0.9% sterile saline was started at a rate of 1.67 mg/min.
Arterial blood samples were collected (for analysis of glucose
isotopic enrichment and concentrations of glucose, lactate,
and glucoregulatory hormones), and gas exchange was mea-
sured 75 and 90 min after the start of the infusion. Immedi-
ately after the last resting measurement, subjects moved to
an electrically braked cycle ergometer (SensorMedics) and
began pedaling at 60 rpm. The infusion rate of [6,6-2H]glucose
was increased to 5.00 mg/min to maintain a steady isotopic
enrichment of blood glucose. Subjects were allowed to drink
water ad libitum and were cooled with a fan. During sea-level
trial 1, the workload was adjusted during the first 15 min un-
til V̇O2 was steady at ,50% of sea-level V̇O2peak (SL-50). After the
appropriate V̇O2 was obtained, the workload was kept con-
stant from minutes 15 to 45. Blood and breath samples were
collected at 15, 30, and 45 min of exercise, as described above.
In trial 2 (alternate menstrual phase, see below), the work-
load was manipulated to exactly simulate the pattern from
248 CARBOHYDRATE UTILIZATION IN WOMEN AT HIGH ALTITUDE
trial 1. In sea-level trial 3, the workload was adjusted in the
first 15 min to achieve a V̇O2 of 65% sea-level V̇O2 peak (SL-65).
At 4,300 m, the workload was adjusted to exactly mimic
sea-level trials 1 and 2, so that comparisons between eleva-
tions could be made at the same V̇O2 (same absolute exercise
intensity). Because V̇O2 peak at 4,300 m is reduced by ,25%
compared with sea level, the exercise workload at 4,300 m
was expected to elicit 65% high-altitude V̇O2 peak, allowing
comparison with sea-level trial 3 at the same percent V̇O2 peak
(same relative intensity).
Relative and Absolute Exercise Intensities
The actual exercise intensities, exercise workloads, and
V̇O2 values are shown in Table 4. At sea level, work output
(140 vs. 102 W), V̇O2, percent sea-level V̇O2 peak (64.8 vs.
52.0%), and energy expenditure were significantly higher
during SL-65 than during SL-50. Work output, V̇O2, percent
sea-level V̇O2 peak (52.0 vs. 51.1%), and energy expenditure
were similar between SL-50 and 4,300 m. At 4,300 m, V̇O2 peak
declined by 23.4%, so that exercise at 102 W required 66.0% of
altitude-specific V̇O2 peak, which was very similar in relative
intensity to SL-65 (64.8%).
Dietary Control
To minimize the effects of changes in energy balance, body
weight, and carbohydrate intake on substrate utilization,
subjects consumed the same standardized diet every day of
each 12-day study period. The diet was composed of whole,
readily available foods along with a liquid supplement (En-
sure, Ross Laboratories, Columbus, OH). Approximately 64%
of energy came from carbohydrate, 12% from protein, and
24% from fat at sea level and 4,300 m. Energy intake was
adjusted daily to compensate for any changes in body weight.
There was no significant change in body weight during days
1–12 at sea level (62.33 6 2.09 to 62.20 6 1.98 kg) or 4,300 m
(63.07 6 2.28 to 62.61 6 2.28 kg). Individual diet components
and the effects of high altitude on energy and nitrogen
balance in these subjects are described in detail elsewhere
(26).
Menstrual Cycle Phase Determinations
To ensure that testing occurred in the appropriate phase at
the appropriate time, each subject kept a menstrual cycle
diary in which she noted the date of her menses, the date of a
surge in luteinizing hormone (monitored with an ovulation
predictor kit from OvuQuick, Becton-Dickson, Rutherford,
NJ), and duration of the cycle. Day 1 of each study period at
sea level and high altitude was the day after menses began
(beginning of the follicular phase) or the day after a luteiniz-
ing hormone surge was detected (beginning of the luteal
phase). After the study was completed, menstrual diaries,
body temperature profiles, and, most importantly, serum
concentrations of the ovarian hormones estrogen and proges-
terone were reviewed. Ovarian hormone concentrations are
shown in Table 1. In 10 cases, women had abnormal phases,
as defined by low concentrations of estrogen (below the
normal clinical range of 10 pg/ml in the ‘‘follicular’’ phase) or
progesterone (never exceeding 2.4 ng/ml in the ‘‘luteal’’ phase).
Statistical comparison of the absolute hormone concentra-
tions in these cases did not differ from those of women with
documented normal follicular phases. We included the data
collected in the 10 abnormal cases with those measured
during the follicular phase, since most of the available
evidence indicates that absolute and relative blood concentra-
tions of the ovarian hormones are mainly responsible for
mediating cycle-related effects on intermediary metabolism
(16). Because this decision oversimplifies the complex interac-
tions that characterize the follicular and luteal cycle phases,
we refer to the two conditions according to the ovarian
hormone environment: estrogen alone (E) or estrogen plus
progesterone (E 1 P). We believe this terminology is more
consistent with one of the main study objectives: to under-
stand how the ovarian hormones influence the regulation of
substrate metabolism at rest and during exercise. Although
equal numbers of subjects were scheduled to arrive at high
altitude in the E and E 1 P condition, only five subjects had
progesterone concentrations indicative of a normal luteal
phase. An overview of the cycle phases at sea level and high
altitude during which testing occurred is shown in Table 2.
Biochemical Assays
Samples of arterial blood were collected in tubes containing
4 ml of 7% HClO4 to which 2 ml of blood (for analysis of
glucose, lactate, and glucose isotopic enrichment) or 100 µg of
aprotinin (Trasylol, Sigma Chemical) as a protease inhibitor
(for analyses of insulin and cortisol) were added. All samples
were immediately stirred with a vortex mixer and kept ice
cold until they were centrifuged at 4°C at 3,000 rpm for 10
min, and the plasma was transferred to cryogenic vials and
frozen at 220°C (glucose, glucose isotopic enrichment, and
lactate) or 280°C (insulin and cortisol) until analysis. Plasma
glucose and lactate concentrations were determined using a
CHEM1 analyzer corrected for HClO4 dilution. Concentra-
tions of insulin and cortisol in plasma were measured by
competitive binding with Coat-A-Count RIA kits and double-
antibody RIA kits (Diagnostic Products, Los Angeles, CA),
respectively. To measure glucose isotopic enrichment, plasma
was neutralized by backtitration with 2 N KOH, passed
through anion- and cation-exchange resins (Bio-Rad Life
Sciences, Hercules, CA), lyophilized, reconstituted with acetic
anhydride-pyridine (2:1), dried under a stream of nitrogen,
and reconstituted in 100 µl of ethyl acetate. The sample was
injected, and pentaacetate derivatives were separated on a
model 5890 gas chromatograph, with spectra recorded on a
model 5989A mass spectrometer (both Hewlett-Packard Ana-
lytical, Wilmington, DE). Selected ion monitoring was used to
compare the abundance of the unlabeled fragment (mass-to-
charge ratio 5 331) with that of the dideuterated isotopomer
(mass-to-charge ratio 5 333). After correction for background
enrichment (,0.06%) the abundance of [6,6-2H]glucose was
expressed as a percentage of total glucose species.
Calculations
Glucose rates of appearance (Ra ) and disappearance (Rd )
were calculated using equations originally designed by Steele
Table 2. Overview of hormonal conditions in which
subjects were tested at sea level and 4,300 m
Trial 1 Trial 2 Trial 3 Trial 4 n
SL-50 SL-50 SL-65 4,300 m
E E1P E E 5
E1P E E E 4
E E1P E1P E1P 3
E1P E E1P E1P 2
E1P E E1P E 1
Tests used for comparisons between sea level and 4,300 m are
shown in boldface.
 CARBOHYDRATE UTILIZATION IN WOMEN AT HIGH ALTITUDE 249

and later modified for use with stable isotopes (40)
glucose Ra (mg/min)
F 2 V[(C1 1 C2 )/2][( IE2 2 IE1 )/(t2 2 t1 )]
5 similar between cycle phases at rest. RER was signifi-
(IE2 1 IE1 )/2
where F represents the isotopic infusion rate, IE1 and IE2 are
the isotopic enrichments of plasma glucose with [6,6-
2H]glucose at times t and t , respectively, C and C are the
1 2 1 2
concentrations of plasma glucose at t1 and t2, respectively, and
V is the estimated volume of distribution for glucose of 180
ml/kg. At rest, glucose Rd was calculated using the isotopic
enrichment at 75 and 90 min after the infusion was started.
During exercise, glucose Rd was calculated from the isotopic
enrichment at 30 and 45 min after exercise was started. To
account for the higher rate of energy expenditure during
SL-65, glucose Rd per unit energy expenditure (mg
glucose · kcal21 · min21 ) was calculated. Carbohydrate oxida-
tion (mg carbohydrate/l O2 ) was calculated from RER by
using standard values (23) and multiplied by V̇O2 (l/min) to
obtain carbohydrate oxidation rates in milligrams of carbohy-
drate per minute. Again, to account for differences in energy
expenditure, carbohydrate oxidation rates per unit energy
(mg · kcal21 · min21 ) were calculated.
Statistical Analysis
Values are means 6 SE. Statistical comparisons between
menstrual cycle phases at sea level and high altitude and
between elevations within the same menstrual cycle phase
were made with a two-way ANOVA with repeated measures
(by group, over time, and group 3 time interaction). Tukey’s
Studentized range test was used to compare individual time
points when significant (P , 0.05) F ratios were obtained.
Correlations between ovarian hormone concentrations and
carbohydrate utilization were evaluated by Pearson product-
moment analysis.
RESULTS
Comparison Across Menstrual Cycle Phase
As shown in Table 2, 15 subjects were studied at sea
level in the follicular (E) and luteal (E 1 P) phases of
the cycle. Exercise workload and V̇O2 were the same
between E and E 1 P (Table 3). Because V̇O2 peak was not
different, relative exercise intensity (%V̇O2 peak) was also
the same. Glucose Ra and Rd were not different between
E and E 1 P at rest or during exercise. RER was also
cantly greater at 30 min of exercise for E (P , 0.05), but
the magnitude of the difference (20.014 unit) was very
small (87.5 vs. 82.8% of energy attributable to carbohy-
drate oxidation). Concentrations of blood glucose, lac-
tate, insulin, and cortisol were generally similar be-
tween menstrual cycle phases at sea level with a couple
of exceptions (Table 3): insulin concentration was higher
in E at 15 min of exercise (P , 0.01), and plasma lactate
values tended to be lower in E 1 P at 30 min of exercise
(0.05 , P , 0.10).
Comparison Across Elevations
Glucose kinetics. As shown in Fig. 1, isotopic enrich-
ment of plasma glucose with the [6,6-2H]glucose isotope
reached a stable plateau during the last sampling
points at rest and during exercise in all three condi-
tions. Glucose Ra and Rd at rest (Fig. 2) were signifi-
cantly lower (mean decline 218%) after 10 days at high
altitude (4,300 m) than in sea-level conditions. During
exercise, glucose Rd was significantly higher at SL-65
(6.22 6 0.26 mg · kg21 · min21 ) than at SL-50 (5.03 6
0.22 mg · kg21 · min21 ) or 4,300 m (4.71 6 0.24 mg · kg21 ·
min21 ). When compared at the same absolute exercise
intensity (102 6 3 W at SL-50 and 4,300 m), glucose Rd
was not different between elevations: 4,300 m was
lower by 9.4%. At the same relative intensity, however
(140 6 5 W at SL-65 vs. 102 6 3 W at 4,300 m), glucose
Rd was 24.3% lower at 4,300 m. When glucose utiliza-
tion rates were scaled to rates of exercise energy
expenditure (Table 4), the glucose Rd per unit energy
expenditure was almost identical (differences ,2.5%)
among all three conditions (Fig. 3).
Gas exchange. As shown in Fig. 4, resting RER was
significantly lower at both sampling times at high

Table 3. Comparison of metabolic parameters across menstrual cycle ‘‘phases’’ at rest and during
sea-level exercise at 52% V̇O2 peak
Rest 15 min 30 min 45 min

E E1P E E1P E E1P E E1P

Workload, W 101 6 3 101 6 3 101 6 3 101 6 3 101 6 3 101 6 3

RER 0.865 6 0.010 0.870 6 0.014 0.972 6 0.006 0.962 6 0.010 0.961 6 0.005* 0.947 6 0.008 0.941 6 0.007 0.942 6 0.012
Glucose Ra ,
mg · kg21 · min21 2.89 6 0.31 3.31 6 0.33 4.63 6 0.27 4.34 6 0.29
Glucose Rd ,
21
mg · kg · min 21 2.95 6 0.31 3.37 6 0.33 4.66 6 0.27 4.38 6 0.29
[Glucose], mM 5.60 6 0.24 5.22 6 0.18 4.88 6 0.14 4.89 6 0.15 4.70 6 0.10 4.72 6 0.14 4.66 6 0.09 4.69 6 0.13
[Lactate], mM 0.44 6 0.04 0.40 6 0.04 2.21 6 0.31 2.04 6 0.34 2.13 6 0.38 1.56 6 0.31 1.70 6 0.33 1.34 6 0.30
[Epinephrine], ng/ml 3.08 6 0.26 2.80 6 0.23 4.49 6 0.41 4.51 6 0.17 4.25 6 0.34 4.21 6 0.27 4.04 6 0.30 4.28 6 0.31
[Norepinephrine],
ng/ml 5.62 6 0.40 5.98 6 0.41 10.14 6 0.62 10.65 6 0.54 10.03 6 0.79 9.63 6 0.38 10.00 6 0.75 10.34 6 0.52
[Cortisol], nM 227 6 25 218 6 25 239 6 27 264 6 33 301 6 35 294 6 34 308 6 32 334 6 35
[Insulin], pM 116 6 28 94 6 16 52 6 7* 30 6 7 35 6 8 31 6 5 30 6 3 25 6 3
Values are means 6 SE. RER, respiratory exchange ratio; Ra , rate of appearance; Rd , rate of disappearance; [glucose], [lactate],
[epinephrine], [norepinephrine], [cortisol], and [insulin], glucose, lactate, epinephrine, norepinephrine, cortisol, and insulin concentrations.
* Significantly different from E 1 P condition at same time point.
250 CARBOHYDRATE UTILIZATION IN WOMEN AT HIGH ALTITUDE

Glucoregulatory hormones. Mean plasma concentra-

tions of epinephrine and norepinephrine between 30
and 45 min of exercise are shown in Fig. 7. Epinephrine
was the same at SL-65 and 4,300 m and was signifi-
cantly higher than at SL-50. Norepinephrine was signifi-
cantly elevated during moderate-intensity (SL-65) com-
pared with low-intensity (SL-50) exercise at sea level
and was even higher at 4,300 m. The plasma concentra-
tion of cortisol (Fig. 8A) was not different at rest in all
three conditions. Cortisol concentrations rose through-
out the exercise period and were significantly higher
than at rest at 30 and 45 min of exercise. Cortisol
concentrations were significantly higher at SL-65 than
at SL-50 and were elevated even further at 4,300 m
relative to SL-65. As shown in Fig. 8B, plasma insulin
concentrations were variable at rest and did not differ

Fig. 1. Isotopic enrichment of plasma glucose with [6,6-2H]glucose in

all 3 conditions. Pre, before isotope infusion; Rest, during 90 min of
infusion with subjects resting semisupine; Exercise, during 45 min of
steady-state cycle ergometry. Mean values are shown without error
bars to indicate how isotopic enrichment changed over time and
reached a steady state at relevant sampling times. SL, sea level;
V̇O2 peak, peak O2 consumption.

altitude (4,300 m) than in either sea-level condition.

During exercise, RER was significantly elevated during
moderate-intensity (SL-65) compared with low-inten-
sity (SL-50) exercise. RER during exercise was lower at
4,300 m than at SL-65 and tended to be lower than that
at SL-50 (0.05 , P , 0.10). When RER values were
used to calculate the rate of carbohydrate oxidation and
scaled to energy expenditure, carbohydrate oxidization
per kilocalorie per minute was not different between
SL-50 and 4,300 m but was significantly higher at
SL-65 (Fig. 5). Therefore, whether expressed as RER or
the rate of carbohydrate oxidized per unit energy,
values were not different between elevations when
compared at the same absolute exercise intensity (4,300
m 5 SL-50) and were lower at 4,300 m than at the same
relative exercise intensity (4,300 m , SL-65).
Glucose and lactate concentrations. Figure 6A shows
the plasma glucose concentration at each time point. At
rest, plasma glucose concentration was significantly
lower after 10 days at 4,300 m than in either sea-level
condition. At sea level, plasma glucose concentrations
declined significantly in the transition from rest to
exercise and remained lower throughout the exercise
bout, with values lower at SL-65 than at SL-50. A
different pattern was observed during exercise at 4,300
m: glucose concentrations did not fall in the rest-to-
exercise transition and were greater than at SL-50 or
SL-65. Plasma lactate concentrations were virtually
the same at rest in all three conditions (Fig. 6B). Fig. 2. Glucose rates of appearance (Ra, A) and disappearance (Rd, B)
During exercise, plasma lactate concentration rose at at rest and during submaximal exercise. Values are means 6 SE.
sea level and 4,300 m. Plasma lactate concentrations SL-50 and SL-65, sea-level exercise trials performed at 50 and 65%
V̇O2 peak, respectively. Resting values represent mean values from 2
were considerably higher during exercise at SL-50 than preexercise time points; exercise values represent mean values
at 4,300 m. Relative to SL-65, however, plasma lactate between 30 and 45 min. Conditions that do not share a superscripted
levels at 4,300 m were not different. letter (a, b) are significantly different from each other.
 CARBOHYDRATE UTILIZATION IN WOMEN AT HIGH ALTITUDE 251

Table 4. Comparison of selected physiological

parameters and catecholamine concentrations
during exercise trials at the same absolute
and relative exercise intensity
SL-50 4,300 m SL-65

Workload, W 102 6 3 102 6 3 140 6 5*

O2 consumption, l/min 1.40 6 0.05 1.37 6 0.06 1.75 6 0.06*
Energy expenditure,
kcal/min 6.99 6 0.22 6.80 6 0.21 8.76 6 0.28*
V̇O2 peak , l/min 2.70 6 0.10 2.08 6 0.11* 2.70 6 0.10
%Sea-level V̇O2 peak 52.0 6 0.3 51.1 6 0.4 64.8 6 1.1*
%High-altitude V̇O2 peak 66.0 6 0.9
Values are means 6 SE. * Significantly different from other condi-
tions.

among conditions. During exercise, plasma insulin

concentrations fell to lower values than at rest. Insulin
levels at SL-50 remained elevated above those observed
in the other two conditions, but this difference was
significant only at 45 min of exercise. Insulin response
at 4,300 m was virtually identical to that at SL-65.
Gas exchange during daily measurements of basal
metabolic rate. The RER values measured during daily
assessments of basal metabolic rate at sea level and
over the 12 days at 4,300 m are shown in Fig. 9. RER
values were significantly lower on days 2–7 and 10 at
4,300 m than at sea level.
Correlations between ovarian hormones and glucose
utilization. Glucose Rd or RER values were not signifi-
cantly correlated with estrogen or progesterone concen-
trations alone, estrogen plus progesterone, or the estro-
gen-to-progesterone ratio (data not shown).
DISCUSSION
The main findings in this study were that blood
glucose utilization rates in young women after 10 days
of exposure to 4,300-m elevation were lower at rest and
not different during submaximal exercise from those
Fig. 4. Respiratory exchange ratio at rest and during submaximal
exercise. Values are means 6 SE for 3 conditions. * Significantly
different from other 2 conditions at that time point.
observed at sea level. Whole body carbohydrate utiliza-
tion, as determined by RER, was lower at rest and
during exercise at the same relative intensity at 4,300
m than at sea level. Blood glucose utilization was not
different, and carbohydrate oxidation was only margin-
ally altered (lower at 30 min of exercise in E 1 P than in
E) across phases of the menstrual cycle. Neither mea-
sure was correlated with circulating levels of estrogen
and/or progesterone.
Effects of Energy Balance
Our main findings could be confounded by negative
energy balance, resulting in weight loss, which reduces
carbohydrate utilization (13). At high altitude, a reduc-
tion in energy intake coupled with increased basal

Fig. 3. Glucose Rd per unit energy expenditure (EE), calculated by Fig. 5. Rate of carbohydrate (CHO) oxidation per unit energy expen-
scaling glucose Rd to rate of energy expended (kcal/min) during diture (kcal/min) during 3 exercise trials. Values are means 6 SE.
exercise trials. Values are means 6 SE. * Significantly different from other 2 conditions.
252 CARBOHYDRATE UTILIZATION IN WOMEN AT HIGH ALTITUDE

Time Course of Changes

Because we made a single measurement after 10
days at 4,300 m, we cannot address how substrate
utilization might change over time during high-
altitude acclimatization in women. Roberts et al. (31)
found that blood glucose Rd and glucose uptake by the
working leg muscles declined in men after 21 days at
4,300 m relative to acute exposure (although both
parameters remained modestly elevated over sea-level
values). In contrast, Larsen et al. (24) reported no
change in resting glucose Rd and a rise in insulin-
stimulated glucose uptake in men after 7 days, com-
pared with 2 days, at 4,550 m. The only data available
on women were provided by Hannon et al. (19). All (n 5
8) women showed a decrease in fasting plasma glucose
concentrations and an increase in plasma free fatty
acid concentrations during 14 days of exposure to 4,300
m. Those changes were transient: free fatty acid levels
returned to sea-level values after 7 days, and glucose
concentrations approached baseline after 14 days. Al-
though the authors interpreted those data to suggest
that fat utilization was not enhanced at high altitude,
without directly measuring substrate utilization, that
conclusion remains speculative. In the present study,
basal V̇O2 and CO2 production were measured on three
mornings at sea level and every morning at 4,300 m.
The RER (Fig. 8) was consistently lower at 4,300 m
throughout the altitude exposure than at sea level.
These data independently confirm the reduction in rest
and exercise RER we observed on day 10 and imply that
this effect was likely to have been present throughout
the stay at altitude. One pitfall related to use of gas
exchange measurements at altitude is the increase in
ventilation that occurs. During acclimatization, a non-
steady-state relationship between alveolar and arterial
gases could limit the accuracy of the RER. In the
present study, however, ventilatory acclimatization, as

Fig. 6. Plasma glucose (A) and lactate (B) concentrations at rest and
during submaximal exercise. Values are means 6 SE. * Significantly
different from other 2 conditions at that time point.

energy demands commonly results in weight loss (10).

For example, men who spent 18 days at 4,300 m and
lost several kilograms of body weight used less muscle
glycogen and had lower RER values during exercise
than at sea level or with acute altitude exposure (41). In
contrast, when men were kept at 4,300 m for 21 days in
a weight-stable condition, blood glucose utilization
during rest and exercise was higher (7, 30) and muscle
glycogen use was unchanged (17) relative to that at sea
level. In the present study, energy balance was main-
tained and body weights were unchanged after a slight
loss during the initial 4 days of altitude exposure.
Therefore, it is likely that the reduction in whole body
Fig. 7. Plasma concentrations of epinephrine and norepinephrine.
carbohydrate oxidation we observed is attributable to Values are means 6 SE at 30 and 45 min of exercise. Conditions that
altitude exposure and not a consequence of negative do not share a superscripted letter (a–c) are significantly different
energy balance. from each other.
 CARBOHYDRATE UTILIZATION IN WOMEN AT HIGH ALTITUDE 253

51.1% of sea-level V̇O2 peak but represented 66.0% of

high-altitude V̇O2 peak. For this reason, our sea-level
studies were done at 102 W (producing the same
absolute exercise intensity as at 4,300 m to match
energy flux) and 140 W (producing the same relative
exercise intensity as at 4,300 m to match percentage of
maximal capacity). The choice of comparison has a
profound impact on the interpretation of the metabolic
data. At the same absolute exercise intensity, blood
glucose utilization was approximately the same and
whole body carbohydrate oxidation tended to be lower
(P 5 0.07) at 4,300 m than at sea level. At the same
relative exercise intensity, blood glucose utilization and
total carbohydrate oxidation were markedly reduced at
4,300 m.
Several lines of evidence suggest that comparison
across elevations at the same relative exercise intensity
is more appropriate. Substrate utilization during exer-
cise at sea level is directly related to the relative
exercise intensity (8, 32). Plasma epinephrine and
norepinephrine concentrations during exercise at 4,300
m (Fig. 7) are much more closely matched with sea-
level exercise at the same relative intensity. Further-
more, plasma concentrations of the glucoregulatory
hormones cortisol (Fig. 8A) and insulin (Fig. 8B) during
exercise at 4,300 m more closely resemble the pattern
observed during sea-level exercise at the same relative
intensity. Lactate concentrations (Fig. 6B) follow a
similar pattern, but there appears to be a slightly
greater response early in exercise (15 min) during
SL-65. Although there is no significant difference be-
tween the pattern of change at SL-65 and 4,300 m,
higher lactate levels and lower blood pH may result in
greater production of nonmetabolic CO2, potentially
inflating gas exchange values and leading to an overes-
timate of carbohydrate utilization. The absolute differ-
ence between SL-65 and 4,300 m (maximum difference

Fig. 8. Plasma cortisol (A) and insulin (B) concentrations at rest and
during submaximal exercise. Values are means 6 SE. Values at a
given time point that do not share a superscripted letter (a–c) denote
significant differences between conditions at that time point. * Signifi-
cantly different from other 2 conditions at that time point.

measured by resting ventilation and end-tidal CO2

values, was complete with reestablishment of steady-
state conditions by day 5 at 4,300 m (S. R. Muza,
personal communication). Therefore, it is unlikely that
hyperventilation was a confounding variable during
the metabolic studies on day 10.
Relative vs. Absolute Exercise Intensity
Although comparing data between sea level and high
altitude is straightforward at rest, making similar
comparisons during submaximal exercise is compli-
cated by altitude-induced changes in the relative exer-
cise intensity. In the present study, V̇O2 peak was reduced Fig. 9. Respiratory exchange ratio during measurements of basal
by 23.4% at 4,300 m compared with sea level. As a metabolic rate at sea level and on each day at 4,300 m. Values are
consequence, an exercise workload of 102 W elicited means 6 SE. * Significantly different from sea-level value.
254 CARBOHYDRATE UTILIZATION IN WOMEN AT HIGH ALTITUDE
is 1.08 mM at 15 min) is fairly minor, however, and the
potential contribution to CO2 production is unlikely to
be quantitatively important.
A major pitfall with making the comparison between
sea level and high altitude at the same relative exercise
intensity, however, is the higher rate of energy expendi-
ture (223.4%) at sea level (Table 2). To correct for this,
a reasonable approach is to scale blood glucose utiliza-
tion and carbohydrate oxidation to the rate of energy
expenditure. Blood glucose Rd per unit energy expendi-
ture (Fig. 3) is almost identical across all three condi-
tions. Expressed in this way, there is clearly no change
in the contribution of blood glucose to energy produc-
tion at 4,300 m compared with sea level. If it is assumed
that 70–100% of blood glucose Rd is oxidized (14, 29),
the contribution of blood glucose to total energy expen-
diture ranges from 12.4 to 17.7% (SL-50), from 12.0 to
17.1% (4,300 m), and from 12.2 to 17.5% (SL-65). These
data are in excellent agreement with results reported
recently by McClelland et al. (29) in female rats accli-
mated to high altitude. Female rats exercising at high
altitude utilized less blood glucose, in absolute terms,
than rats exercising at the same relative intensity at
sea level. When the difference in energy expenditure
was accounted for, the blood glucose Rd was the same
between elevations. In the present study, however, the
rate of total carbohydrate oxidation scaled to the rate of
energy expenditure (Fig. 5) was still significantly lower
at 4,300 m than at sea level. Taken together, these data
suggest that, relative to sea level, the contribution of
intramuscular carbohydrate sources (glycogen) to total
energy expenditure may be diminished after high-
altitude exposure in these young women. This result is
consistent with observations made in men losing body
weight (41) but not with observations made in weight-
stable men (7, 17, 31).
Comparison With Men
Compared with studies done under similar experi-
mental conditions in men, the present results show
some striking differences. Using isotopic tracer tech-
niques (whole body substrate use) and arteriovenous
differences across the leg (muscle substrate use) in
young men, Brooks and colleagues (7, 31) consistently
demonstrated that glucose uptake and oxidation were
markedly increased after 2 h and still significantly
higher after 21 days at 4,300 m than at sea level.
Although there were two notable differences (women in
this study were more physically trained, and the period
of acclimatization was 10, rather than 21, days), sev-
eral key parameters were nearly identical in those
studies and the present one: the same elevation (4,300
m), strict maintenance of energy balance, the same
exercise protocol (45 min at ,50% of sea level V̇O2 peak),
and almost identical absolute workload (100 W for men
and 102 W for women). Blood glucose, lactate, and
insulin concentrations in these women do not differ
from values reported in men. These similarities serve
to highlight the disparate results: unlike men, blood
glucose uptake at high altitude in women does not
increase, and total carbohydrate oxidation is lower
than at sea level.
The difference in acclimatization time between stud-
ies on men and women is not likely to have a big impact
on the comparison; glucose utilization in men de-
creased between the acute and acclimatized studies at
4,300 m, and a shorter exposure might have exagger-
ated, rather than diminished, the differences from our
study in women. The effects of training state on the
results are potentially important, however. Longitudi-
nal studies of exercise training in women showed that
glucose flux and carbohydrate oxidation were de-
creased in both sexes at the same absolute exercise
intensity (but unchanged at the same relative inten-
sity), and women showed a decrease in RER at the
same relative exercise intensity (14). It is possible that
a predisposition to conserve carbohydrate, especially
intramuscular glycogen (as evidenced by a lower RER
with no change in blood glucose Rd ), in trained subjects
explains at least part of the ‘‘sex difference’’ in carbohy-
drate utilization at altitude. Further studies using
untrained women and/or trained men are necessary to
separate the effects of training status from the effects of
biological sex.
There is a wealth of evidence, from several indepen-
dent lines of research, that women utilize less muscle
glycogen and/or total carbohydrate under conditions in
which catecholamine concentrations are elevated (1, 9,
12, 14, 15, 22, 33, 34, 36–39). At the same relative
intensity, women tend to use more fatty acids and less
glycogen to fuel exercise than men (14, 22, 34, 36–38).
In response to induced hypoglycemia, women switch to
fatty acid utilization more readily than men (1, 12).
Men and women increase sympathoadrenal activity in
response to altitude, resulting in higher concentrations
of the catecholamines epinephrine (increase on acute
exposure, then return to sea level after ,7 days) and
norepinephrine (steadily increasing over the course of
2–3 wk) (27, 28). Catecholamines upregulate the rate of
lipolysis as well as muscle glycogenolysis (27, 30, 31)
and also stimulate hepatic glucose production. Al-
though epinephrine concentrations were similar at the
same relative exercise intensity (4,300 m vs. SL-65),
norepinephrine was higher at 4,300 m that at SL-65.
The same increase at 4,300 m was observed in plasma
cortisol concentrations (Fig. 8A), which could further
stimulate lipolysis and reduce the uptake of blood
glucose. Larsen et al. (24) observed a sharp rise in
plasma cortisol levels at 4,550 m in association with
lower blood glucose uptake. In the present study,
plasma glucose Rd exceeded Ra and glucose concentra-
tion declined in the early stages of exercise at sea level,
indicating that glucose uptake by cells exceeded he-
patic glucose production (Fig. 6A). At 4,300 m, however,
blood glucose did not decrease in the rest-to-exercise
transition and remained higher than sea-level values
throughout exercise. Taken together, the data suggest
that, in women, physiological stresses that stimulate
the production of catecholamines and cortisol, such as
exposure to high altitude, provoke a shift away from
 CARBOHYDRATE UTILIZATION IN WOMEN AT HIGH ALTITUDE
carbohydrate utilization and toward greater reliance
on fatty acids.
Effects of Ovarian Hormones
Substrate use at high altitude may be altered by the
presence of the ovarian hormones estrogen and proges-
terone, both of which have direct and indirect effects on
carbohydrate and lipid metabolism (9, 16, 25, 33, 34,
36–39). Administration of estrogen to women with
amenorrhea causes blood glucose utilization to diverge
from that seen in men (35). Differences from men may
be especially pronounced if women are studied during
the midluteal phase of the menstrual cycle, when the
concentrations of estrogen and progesterone are high-
est (2, 9, 16, 18, 33, 34). Rates of carbohydrate oxidation
during exercise in the follicular phase of the cycle are
often, but not always, lower than in the luteal phase of
the cycle (2, 9, 34, 36–39). We showed that glucose
tolerance was significantly reduced in the E 1 P
compared with the E only phase of the cycle in this
same group of women (3).
Glucose utilization was not different in the E and E 1
P phases of the menstrual cycle (Table 3). When the
absolute or relative concentrations of estrogen and/or
progesterone were regressed against blood glucose up-
take or RER, there were no significant correlations. The
finding that there were no (glucose Ra and Rd ) or minor
(RER and possibly lactate) changes in response to
fluctuations in ovarian hormone levels may be due to
the subject population chosen. Differences in the rela-
tive concentrations of estrogen and progesterone across
cycle phases (Table 1) in this group of physically fit,
lean women tended to be small. Similar studies in
less-trained women with larger variations in estrogen
and progesterone across the menstrual cycle might
result in more obvious cycle phase differences and a
stronger relationship between the ovarian hormones
and carbohydrate use. Our results do not exclude the
ovarian hormones as mediators of sex differences in
substrate utilization at high altitude. The changes in
ovarian hormone levels between cycle phases are al-
ways subtle in comparison with differences between the
sexes. In addition, the presence or relative absence of
testosterone is likely to be important. Also, interactions
with other hormones, receptor and postreceptor metabo-
lism, and the physiological characteristics of the organ-
ism modulate the magnitude and direction of any
metabolic perturbation.
‘‘Oxygen-Efficiency’’ Theory
Brooks (5) and Hochachka (20) independently pro-
posed hypotheses to explain a shift toward greater
utilization of carbohydrate at high altitude. Because
the caloric equivalent of 1 liter of consumed O2 is higher
when pure carbohydrate is oxidized (5.05 kcal/l) vs.
pure fat (4.68 kcal/l), it follows that any increase in the
percentage of energy derived from carbohydrate sources
will result in a more economical use of O2 resources.
Data obtained in the present study in women do not
support the theory, however, and suggest that in-
255
creased carbohydrate utilization at high altitude may
occur only in men.
Recently, a new perspective was introduced by McClel-
land et al. (29) challenging the ‘‘oxygen-efficiency’’
theory. These investigators identified the relative exer-
cise intensity as the primary determinant of substrate
utilization in female rats acclimated to high altitude.
Furthermore, they speculated that the energetic advan-
tages of increased dependence on glucose may be
balanced by the need to conserve limited glycogen
stores. Our data are consistent with this perspective
and suggest that, in women, conservation of carbohy-
drate stores may not only balance but may override a
shift toward increased glucose utilization in response to
hypoxia. Whatever the mechanism, the net effect of
femaleness appears to be a constraint on carbohydrate
utilization at high altitude.
We acknowledge the tremendous cooperation of the subjects; the
nursing and dietetics staff of the Aging Study Unit and the Clinical
Laboratory at the Palo Alto Veterans Affairs Health Care System;
Sgt. James Kenney and other personnel at the US Army Research
Institute of Environmental Medicine; Bobbye Chang at the San
Francisco General Hospital Clinical Research Center (National Insti-
tutes of Health Grant M01 RR-00083-33); Gene McCullough, Rosann
McCullough, Dr. Margaret Weirman, and the Clinical Laboratories at
the University of Colorado Health Sciences Center (National Insti-
tutes of Health Grant 5 01 RR-00051); Ross Laboratories; Hershey
Corporation; Shaklee Corporation; and United Airlines.
This study was supported by Department of Defense Contract
DAMD-17-95-C-5110.
Present address for B. Braun: Dept. of Exercise Science, 110
Totman Building, University of Massachusetts, Amherst, MA 01003
(E-mail: bbrown@excsci.umass.edu).
Received 11 March 1999; accepted in final form 14 September 1999.
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