Am J Physiol Endocrinol Metab 290: E1078 –E1088, 2006.
First published December 27, 2005; doi:10.1152/ajpendo.00449.2005.
Endocrine responses to acute and chronic high-altitude exposure
(4,300 meters): modulating effects of caloric restriction
Kimberly E. Barnholt,1 Andrew R. Hoffman,1,2 Paul B. Rock,3 Stephen R. Muza,4 Charles S. Fulco,4
Barry Braun,5 Leah Holloway,1 Robert S. Mazzeo,6 Allen Cymerman,4 and Anne L. Friedlander1,2
1
Clinical Studies Unit and Medical Service, Veterans Affairs Palo Alto Health Care System; 2Department of Medicine and
Program in Human Biology, Stanford University, Palo Alto, California; 3Center for Aerospace and Hyperbaric Medicine,
Oklahoma State University Health Science Center, Tulsa, Oklahoma; 4Thermal and Mountain Medicine Division, United
States Army Research Institute for Environmental Medicine, Natick; 5Department of Exercise Science, University of
Massachusetts, Amherst, Massachusetts; and 6Department of Kinesiology, University of Colorado, Boulder, Colorado
Submitted 15 September 2005; accepted in final form 12 December 2005
is a widely documented consequence of
high-altitude (HA) sojourns, the influence of energy balance on
the acclimatization response is unclear. Hypoxia per se is a
sufficient trigger for appetite suppression and reduced caloric
consumption (40, 51). In addition, mountain expeditions with
severe environmental conditions, inadequate diet, and intense
physical exertion (1, 4, 34, 42) lead to increases in individual
energy requirements while energy intake declines. Consequently, HA sojourners are often forced to adapt to the hypoxemic effects of altitude and the metabolic effects of energy
imbalance concurrently. Although hypobaric hypoxic chambers have eliminated stresses such as cold, limited food availability, and rugged terrain, many subjects at simulated altitude
still show progressive weight loss during prolonged investigations when caloric consumption is not carefully controlled (40,
51, 56).
Altitude-induced weight loss can be minimized by matching
dietary intake with energy requirements (5, 6, 30). The stabilization in body weight achieved from such studies allows
assessment of the unique physiological effects of altitude
independent of any confounding effects from negative energy
balance. However, to our knowledge, no investigation has
directly compared altitude-induced neuroendocrine changes
with or without energy imbalance or examined how energy
sufficiency at altitude alters the endocrine acclimatization response. Furthermore, although adipocytokines, such as leptin
and adiponectin, have been highlighted as major factors in the
regulation of appetite and metabolism at sea level (SL) in
recent years, their roles in preserving energy homeostasis at
altitude are not well understood.
Altitude exposure is known to stimulate neuroendocrine
systems as part of the acute hypoxic and chronic adaptive
acclimatization process (2). In contrast, prolonged caloric restriction (CR) tends to blunt some of the same neuroendocrine
pathways that are stimulated at altitude as the body attempts to
reduce basal energy expenditure (44). In this report, we describe the hormone and metabolic responses to HA as measured in three groups of subjects over the course of a 21-day
dietary intervention. The goals of the investigation were to 1)
determine the physiological response to altitude independent of
CR using a weight-stable group at Pikes Peak, CO (4,300
meters), 2) compare the altitude-induced hormonal response of
an adequately fed group with that of a CR group, and 3)
compare endocrine and metabolic patterns in a CR group at
altitude with those of a CR group at SL. We hypothesized that
effects of altitude and CR would oppose each other to create a
more moderate response pattern in the CR subjects compared
with the fully fed subjects at Pikes Peak. This study was part of
a larger investigation designed to determine the interactive
Address for reprint requests and other correspondence: A. L. Friedlander,
GRECC, 182B, Bldg. MB2, VA Palo Alto Health Care System, 3801 Miranda
Ave., Palo Alto, CA 94304 (e-mail: [email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
altitude; hypoxia; hormones; energy balance; acclimatization; caloric
restriction
ALTHOUGH WEIGHT LOSS
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Barnholt, Kimberly E., Andrew R. Hoffman, Paul B. Rock,
Stephen R. Muza, Charles S. Fulco, Barry Braun, Leah Holloway,
Robert S. Mazzeo, Allen Cymerman, and Anne L. Friedlander.
Endocrine responses to acute and chronic high-altitude exposure
(4,300 meters): modulating effects of caloric restriction. Am J Physiol
Endocrinol Metab 290: E1078 –E1088, 2006. First published December 27, 2005; doi:10.1152/ajpendo.00449.2005.—High-altitude anorexia leads to a hormonal response pattern modulated by both
hypoxia and caloric restriction (CR). The purpose of this study was to
compare altitude-induced neuroendocrine changes with or without
energy imbalance and to explore how energy sufficiency alters the
endocrine acclimatization process. Twenty-six normal-weight, young
men were studied for 3 wk. One group [hypocaloric group (HYPO),
n ⫽ 9] stayed at sea level and consumed 40% fewer calories than
required to maintain body weight. Two other groups were deployed to
4,300 meters (Pikes Peak, CO), where one group (ADQ, n ⫽ 7) was
adequately fed to maintain body weight and the other [deficient group
(DEF), n ⫽ 10] had calories restricted as above. HYPO experienced
a typical CR-induced reduction in many hormones such as insulin,
testosterone, and leptin. At altitude, fasting glucose, insulin, and
epinephrine exhibited a muted rise in DEF compared with ADQ. Free
thyroxine, thyroid-stimulating hormone, and norepinephrine showed
similar patterns between the two altitude groups. Morning cortisol
initially rose higher in DEF than ADQ at 4,300 meters, but the
difference disappeared by day 5. Testosterone increased in both
altitude groups acutely but declined over time in DEF only. Adiponectin and leptin did not change significantly from sea level baseline
values in either altitude group regardless of energy intake. These data
suggest that hypoxia tends to increase blood hormone concentrations,
but anorexia suppresses elements of the endocrine response. Such
suppression results in the preservation of energy stores but may
sacrifice the facilitation of oxygen delivery and the use of oxygenefficient fuels.
ENDOCRINE RESPONSE TO CALORIC RESTRICTION AT ALTITUDE
effects of altitude and CR on work performance and metabolism.
METHODS
Subjects
Screening
Upon admission to the Clinical Studies Unit (CSU), participants
completed a medical history questionnaire and underwent a physical
examination, a resting 12-lead electrocardiogram, routine blood and
urine analyses, and a nutrition assessment. Each participant then
completed a continuous, progressive exercise test to volitional exhaustion on a cycle ergometer (model 800; Sensormedics, Yorba Linda,
CA) for the determination of peak oxygen consumption (V̇O2 peak)
using an on-line Truemax system (Parvomedics Consentius Technologies, Sandy, UT). For participation in the study, subjects were
required to have a V̇O2 peak ⬎40 ml 䡠 kg⫺1 䡠 min⫺1.
General Study Design
Three different groups of subjects were studied during a 21-day
intervention period. All subjects completed a body weight stabilization period and baseline measurements at SL during the spring months
in the CSU at the Veterans Affairs Palo Alto Health Care System. One
group completed the entire intervention at the CSU in Palo Alto. This
group was fed a hypocaloric diet (HYPO) that was 40% deficient in
calories needed to maintain body weight. Two other groups traveled
to the USARIEM facility on the summit of Pikes Peak (4,300 meters)
in Colorado during the summer months for 21 days of HA exposure.
Subjects traveled by air directly from SL in California to Colorado
Springs, CO (1,840 m). Subjects remained overnight on oxygen,
maintaining an arterial O2 saturation ⬎96% and continued on oxygen
during the morning ascent to the summit of Pikes Peak. This additional control ensured that the subjects experienced an acute altitude
exposure from SL to 4,300 meters on the first day of testing. One
group remained adequately fed (ADQ) throughout the stay at HA to
maintain the weight stability achieved at SL. The other group was fed
a diet deficient in calories (DEF) during the 3-wk HA exposure.
Throughout SL and altitude intervention periods, subjects were required to perform set exercise bouts at various intensities to comply
with other aspects of the broader scope investigation.
Stabilization Diet
To calculate initial caloric intake, basal energy expenditure was
estimated using the Harris-Benedict equation. Energy need was calculated by multiplying the basal energy expenditure by an activity
factor determined from the subjects’ physical activity records (24).
Participants were weighed every other day during the stabilization
period, and caloric intake was altered as needed to maintain body
weight. Energy intake was adjusted by adding or subtracting fat- and
carbohydrate-containing foods. Protein content was held constant (1.2
g 䡠 kg body wt⫺1 䡠 day⫺1) for all groups. The body weight maintenance
diet therefore consisted of ⬃11% protein, 21% fat, and 68% carboAJP-Endocrinol Metab • VOL
hydrate. Subjects were given food for each day in an individual bag
and were expected to finish all the food provided and eat nothing else.
The food items consisted of whole foods (e.g., pasta with red sauce,
bread, cheese, apples, etc.) that were adjusted in quantity according to
subject needs. The diets for all subjects provided 100% of the
recommended daily allowances for nutrients. A multivitamin and
mineral supplement were also provided daily.
Intervention Diet
Energy deficit was created by decreasing the intake of fat and
carbohydrate foods. However, the carbohydrate intake was kept above
at least 3 g 䡠 kg⫺1 䡠 day⫺1 to minimize the effect of low carbohydrate
intake on glycogen stores. To meet all the dietary criteria listed above,
only subjects who normally consumed ⬎2,700 kcal/day at SL were
selected for participation. Adjustments were made as needed in
accordance with daily weight measurements. All foods were preweighed, packaged, and given to the subjects throughout the study
period. As in the stabilization period, diets for all subjects provided
100% of the recommended daily allowances for nutrients. A multivitamin and mineral supplement were also provided daily.
SL Group
Subjects in the HYPO group (n ⫽ 9) were fed the stabilization diet
for 7 days (Baseline ⫺7 to ⫺1) before the intervention phase to attain
energy, nitrogen, and body weight balance. Immediately after this
stabilization period, subjects were fed a hypocaloric diet for 21 days
based on a 40% reduction from their baseline calorie requirements.
Participants in the HYPO group lived in the CSU throughout the 3-wk
intervention. Subjects were allowed to leave the CSU to attend
classes, work, etc., during the day but were expected to return when
not actively engaged in outside activities. All daily food was provided,
and subjects were required to eat both breakfast and dinner in the unit
everyday. Participants were asked to continue with their normal
activity patterns during the intervention period, and a daily schedule
of activities was given to them based on their preintervention exercise
logs.
Altitude Groups
Subjects in the two altitude groups (ADQ and DEF) also underwent
a 7-day dietary stabilization period at SL. Subjects then underwent 5
days of SL baseline testing. Deployment to Pikes Peak for the 21-day
intervention phase took place 1–2 mo after SL baseline testing. To
minimize acute effects of diet on initial altitude measurements, subjects in the ADQ and DEF groups completed an additional 3-day
dietary stabilization period immediately before the HA intervention.
During the 21-day intervention, the ADQ group (n ⫽ 7) consumed the
SL body weight stabilization diet plus an additional 200 kcal/day to
account for the increases in basal metabolic rate (BMR) associated
with acute altitude exposure (6). In contrast, the DEF group (n ⫽ 10)
ate a diet deficient by ⬃40% of the calories (mean deficit ⫽ 1,300
kcal/day) from their SL body weight maintenance intake plus an
additional 200 kcal/day to account for the anticipated altitude-induced
BMR increase.
Participants in the ADQ and DEF groups resided at the USARIEM
Laboratory for the entire 21-day intervention period. All food was
provided for them daily and adjusted as needed. Activity level at SL
was monitored through 24-h exercise logs. At altitude, these diaries
were used to devise an exercise program mimicking SL activities as
much as possible to prevent detraining and to balance energy expenditure under the two environmental conditions. The program included
cycle ergometry, hiking, and weight lifting.
Body Composition
Fasting body weight was measured every other morning throughout
the study. Skinfold measurements were made using calipers (Lange
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Twenty-nine nonsmoking, normal-weight, active men between the
ages of 18 and 35 yr volunteered to participate in the study. For
inclusion, subjects were required to have maintained a stable body
weight for the previous 6 mo, to be in good health without chronic
illnesses, and to have been born and to have resided at an altitude
2,000 meters for the previous three years. Subjects were recruited
from advertisements and fliers placed in local newspapers in and
around the Palo Alto/San Jose, CA, area. The protocol was approved
by the Administrative Panels for the Protection of Human Subjects at
Stanford University and the U.S. Army Research Institute for Environmental Medicine (USARIEM). Each participant gave written consent before screening.
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ENDOCRINE RESPONSE TO CALORIC RESTRICTION AT ALTITUDE
Table 1. Baseline subject characteristics
Variable
ADQ (n ⫽ 7)
DEF (n ⫽ 10)
HYPO (n ⫽ 9)
Age, yr
Height, cm
Weight, kg
Body fat, %
LBM, kg
V̇O2 peak, (ml䡠kg⫺1䡠min⫺1)
21.3⫾2.8
178.6⫾5.1
74.1⫾6.9
9.2⫾2.9*
67.2⫾5.7
52.6⫾5.5
22.1⫾2.8
178.9⫾6.6
79.6⫾11.7
13.6⫾3.1
68.5⫾7.7
51.9⫾6.6
23.1⫾5.5
176.9⫾7.8
78.8⫾6.1
16.8⫾4.8
65.4⫾6.1
45.2⫾7.3†
Values are means ⫾ SD; n, no. of subjects. ADQ, adequately fed; DEF, diet
deficient in calories; HYPO, hypocaloric diet; LBM, lean body mass; V̇O2 peak,
peak oxygen consumption. P ⬍ 0.05, *significant from DEF and HYPO and
†significant from DEF and ADQ.
Blood Sample Collection and Analysis
Fasting blood samples were collected upon rising between 6:00
A.M. and 8:00 A.M. on days ⫺3, 3, 5, 10, 19, and 21. Samples were
immediately placed on ice, centrifuged for 10 min at 3,000 rpm,
decanted, and frozen. Blood samples for the analysis of glucose
concentration were collected in 8% perchloric acid. Plasma glucose
concentration was determined by the Veterans Affairs Clinical Laboratories using a Beckman LX20 multichannel analyzer. Serum for
the analysis of insulin, cortisol, testosterone, sex hormone-binding
globulin (SHBG), lipid panel, erythropoietin (EPO), and adiponectin
was collected in chilled tubes, and plasma for the analysis of leptin
and thyroid hormones was collected in chilled tubes containing
EDTA. All samples were stored at ⫺80°C for future analysis using
RIA kits (Diagnostic Systems Laboratories, Webster, TX). Adiponectin samples were analyzed using ELISA kits (Linco Research, St.
Charles, MO). Twenty-four-hour urine samples were collected for the
analysis of catecholamine levels at SL and during the 21 days at HA.
Once the 24-h sample volume was determined, a 10-ml aliquot was
mixed with glutathione and then frozen at ⫺80°C for future analysis
using HPLC (model 1330 pump, model 1340 electrochemical detector; Bio-Rad, Hercules, CA; see Ref. 29).
Calculations
Homeostasis model assessment insulin resistance (HOMA-IR) was
assessed from the HOMA calculation: [FI (␮l/ml) ⫻ FG (mmol/l)]/
22.5, where FI is fasting insulin and FG is fasting glucose (26). Free
testosterone was calculated by dividing the total testosterone concentration by fasting SHBG concentration.
Statistics
One-way ANOVA was used for the analysis of subject baseline
characteristics. Two-way ANOVAs (group ⫻ time) with repeated
measures were used for analyzing hormone levels at all time points
throughout the intervention. Post hoc analyses were performed where
appropriate using the Fisher’s least-significant difference procedure.
Statistical significance was accepted at P ⬍ 0.05. When significant
baseline differences occurred, data were graphed and analyzed as a
change from baseline. All values are presented as means ⫾ SE unless
otherwise noted.
RESULTS
Subject Characteristics, Diet, and Body Composition
Subject characteristics recorded during the baseline body
weight stabilization period at SL (day ⫺3) are presented in
AJP-Endocrinol Metab • VOL
Glucose, Insulin, and HOMA-IR
There was no difference in fasting glucose concentration
among the three groups at baseline. However, both ADQ and
DEF groups experienced a significant increase in blood glucose
concentration (9.3 and 5.1%, respectively, P ⬍ 0.05) upon
acute exposure to altitude, whereas blood glucose fell (⫺5.5%,
P ⬍ 0.05) in the HYPO group with the onset of CR (Fig. 1A).
The disparate responses resulted in significantly different fasting glucose values between groups for days 3 and 5, but most
differences between groups disappeared by the end of the
intervention.
Baseline insulin values for DEF (12.4 ⫾ 1.0 ␮l/ml) and
ADQ (9.6 ⫾ 1.3 ␮l/ml) were lower than the HYPO group
(19.3 ⫾ 3.2 ␮l/ml, P ⬍ 0.05). ADQ and DEF exhibited a
transient increase in insulin concentration upon arrival at Pikes
Peak (⫹68 and ⫹23%, respectively), but only the rise in ADQ
was significant from SL baseline (P ⬍ 0.05; Fig. 1B). The
insulin level change in ADQ peaked on day 5 at 113% above
baseline before returning to prealtitude values. Insulin in
HYPO dropped significantly (⫺36% at day 3; P ⬍ 0.05) from
baseline values and remained suppressed throughout the intervention (Fig. 1B).
Table 2. Energy and macronutrient intake at
SL and 4,300 meters HA
ADQ
SL baseline (day ⫺7 to ⫺1)
HA (day 1–4)
HA (day 18–21)
DEF
SL Baseline (day ⫺7 to ⫺1)
HA (day 1–4)
HA (day 18–21)
HYPO
Baseline (day ⫺7 to ⫺1)
Hypocaloric (day 1–21)
kcal
CHO,
g
Protein,
g
Fat,
g
Change
in kcal, %
3,340
3,557
3,679
574
633
650
90
83
92
76
77
79
⫹1*
⫹4*
3,530
2,190
2,186
589
348
348
100
87
86
86
50
50
⫺41*
⫺41*
3,245
1,950
555
299
92
85
73
46
⫺40
SL, sea level; HA, high altitude; CHO, carbohydrate. Protein set between 1.1
and 1.2 g/kg. *Change relative to SL diet ⫹200 kcal to account for expected
altitude-induced basal metabolic rate increase.
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Skinfold Caliper; Cambridge Scientific Industries, Cambridge, MD)
and standard equations (19) during the stabilization period at SL (day
⫺3) and during the intervention period on days 3, 10, and 21. Body
weight and skinfold measurements were used to calculate lean body
mass, fat mass, and body fat percentage.
Table 1. Twenty-nine subjects were recruited to participate in
this study, but three subjects withdrew from ADQ after baseline testing because of schedule conflicts, leaving n ⫽ 10, 7,
and 9 for DEF, ADQ, and HYPO, respectively. There were no
differences in age, height, weight, or lean body mass among
groups. The mean percentage body fat was greater in HYPO
and DEF compared with ADQ (P ⬍ 0.05). HYPO had lower
V̇O2 peak values than ADQ or DEF (P ⬍ 0.05).
Post hoc analyses of the diets from daily food checklists
indicated that target caloric intakes were achieved for each
group (Table 2). Both calorie-restricted groups showed a significant decrease from baseline values across all body composition measurements (Table 3). Changes in body composition
were assessed from day 3 of the intervention as well as baseline
to minimize the potential impact of altitude-induced fluid loss
on weight measurements in the HA groups (22). Changes in
weight, lean mass, and fat mass were negligible in the ADQ
group when the standard fluid reduction phase (days 1 and 2)
at altitude was omitted from the calculations (Table 3).
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ENDOCRINE RESPONSE TO CALORIC RESTRICTION AT ALTITUDE
Table 3. Changes in body composition from SL baseline and day 3 (to account for body fluid losses
at altitude) to day 21 of the intervention period
Body Wt, kg
ADQ
DEF
HYPO
Lean Body Mass, kg
Fat Body Mass, kg
Baseline to
day 21
day 3 to day 21
Baseline to
day 21
day 3 to day 21
Baseline to
day 21
day 3 to day 21
⫺0.8⫾0.7
⫺5.8⫾0.9*‡
⫺3.9⫾0.4*‡
⫺0.9⫾0.5
⫺4.0⫾0.3*†‡
⫺2.9⫾0.3*‡
⫺1.4⫾0.5*
⫺2.9⫾0.7*
⫺2.0⫾0.4*
⫺0.1⫾0.4
⫺1.2⫾0.3*‡
⫺1.7⫾0.3*‡
⫹0.5⫾0.8
⫺2.9⫾0.5*‡
⫺1.7⫾0.4*‡
⫺0.8⫾0.2
⫺2.8⫾0.4*†‡
⫺1.3⫾0.3*
Values are means ⫾ SE. P ⬍ 0.05, *significant change from baseline or day 3, †significant from HYPO, and ‡significant from ADQ.
Other Hormones
Thyroid. No significant changes occurred in serum levels of
thyroid-stimulating hormone (TSH) for either group that resided at the summit of Pikes Peak apart from a slight fluctuation in the DEF group at day 21 (Fig. 2A). However, at SL, CR
Fig. 1. A: glucose levels. B: change in insulin levels. C: change in HOMAinsulin resistance levels for each group at sea level (SL) and over the 21-day
intervention period. DEF, diet deficient in calories. Values are means ⫾ SE.
P ⬍ 0.05, significant from SL baseline (*), significant from adequately fed
subjects (ADQ; ‡), and significant from subjects fed a hypocaloric diet
(HYPO; §).
AJP-Endocrinol Metab • VOL
Fig. 2. Thyroid-stimulating hormone (A) and free thyroxine (B) for each group
at SL and over the 21-day intervention period. Values are means ⫾ SE. P ⬍
0.05, significant from SL baseline (*), significant from ADQ (‡), and significant from HYPO (§).
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Figure 1C displays the change from baseline in insulin
resistance (HOMA-IR) over time. IR increased temporarily in
ADQ early in the acclimatization process but returned to SL
values by day 10. HYPO exhibited a significant fall in
HOMA-IR by day 3 that was maintained for the duration of the
study. Subjects in DEF experienced no alteration in HOMA-IR
values.
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ENDOCRINE RESPONSE TO CALORIC RESTRICTION AT ALTITUDE
EPO. EPO increased with HA exposure in both the DEF and
ADQ groups (Table 4). However, EPO concentrations rose
higher and remained elevated above baseline for longer in
ADQ compared with DEF. In contrast, EPO levels in the
HYPO group did not change throughout the intervention period
at SL.
Adipocytokines
led to a small but significant increase in TSH levels between
days 5 and 10 of the intervention (HYPO, Fig. 2A).
Free thyroxine (fT4) levels changed in all three intervention
groups (Fig. 2B). Subjects in DEF and ADQ exhibited a
significant rise in serum fT4 values upon acute HA exposure
(⫹24.0 and ⫹17.1%, respectively, P ⬍ 0.05), and concentrations in both groups remained elevated for the 3 wk at 4,300
meters. In contrast, HYPO demonstrated an immediate suppression of fT4 after initiating the reduced calorie diet, and
values remained low throughout the entire 21 days of CR
(Fig. 2B).
Cortisol. In the DEF group, cortisol levels increased ⬃32%
(P ⬍ 0.05) from baseline by day 3 at 4,300 meters, and
concentrations remained elevated throughout the entire stay at
altitude (Fig. 3). Cortisol levels in ADQ rose more gradually to
reach a peak on day 10. From day 10 to day 21, there was no
difference in cortisol levels between ADQ and DEF, and both
altitude groups had values significantly higher than baseline at
the majority of the intervention measurement points. The
serum cortisol concentrations in HYPO did not demonstrate
any significant alterations throughout the 21-day period, but
they were significantly lower than the HA groups from day 5
to 21.
Testosterone. Testosterone rose 30% in DEF and nearly 24%
in the ADQ group within the first 48 h at 4,300 meters (P ⬍
0.05; Fig. 4A). Testosterone in ADQ remained elevated, but
concentrations in DEF started to decline after the initial peak
on day 3. In contrast, HYPO exhibited a gradual decrease in
testosterone concentration throughout the intervention that
reached significance by day 19. No significant difference
existed between calorie-restricted groups by the end of the
intervention.
Both HA groups show an initial rise in free testosterone
(calculated as total testosterone/SHBG) upon ascent to Pikes
Peak, although only the increase in DEF was a significant
change from SL baseline (Fig. 4B). Free testosterone remained
elevated in ADQ, but concentrations gradually declined in
DEF after the spike on day 3. Free testosterone also started
decreasing in HYPO after day 3, and values in both calorierestricted groups fell significantly lower than baseline by
day 19.
AJP-Endocrinol Metab • VOL
Fig. 4. Total testosterone levels (A) and free testosterone levels (total testosterone/fasting sex hormone-binding globulin; B) for each group at SL and over
the 21-day intervention period. Values are mean ⫾ SE. P ⬍ 0.05, significant
from SL baseline (*), significant from ADQ (‡), and significant from HYPO
(§).
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Fig. 3. Cortisol levels for each group at SL and over the 21-day intervention
period. Values are means ⫾ SE. P ⬍ 0.05, significant from SL baseline (*),
significant from ADQ (‡), and significant from HYPO (§).
Adiponectin. There was no difference in baseline adiponectin levels between ADQ (9.43 ⫾ 1.38 ␮g/ml) and HYPO
(9.99 ⫾ 1.94 ␮g/ml), but initial concentrations in DEF (7.06 ⫾
1.27 ␮g/ml) were lower (P ⬍ 0.05). Levels of adiponectin
remained constant in both groups that embarked to 4,300
meters (Fig. 5A). In contrast, subjects who remained at SL
experienced a marked decline in adiponectin levels throughout
the CR phase (Fig. 5A). HYPO subjects experienced a more
dramatic change in adiponectin from baseline values than
either HA group.
Leptin. Baseline leptin levels in the HYPO group were
significantly higher (8.58 ⫾ 2.98 ng/ml) compared with both
the ADQ group (1.33 ⫾ 0.24 ng/ml) and DEF group (2.26 ⫾
0.78 ng/ml; P ⬍ 0.05). This discrepancy is likely because of
the elevated percentage of body fat in the HYPO group at the
start of the study in relation to the other groups. Leptin
concentrations maintained a strong positive correlation with
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ENDOCRINE RESPONSE TO CALORIC RESTRICTION AT ALTITUDE
Table 4. Erythropoietin levels at baseline and throughout the 21-day intervention period
Group
SL Baseline
Day 1
Day 3
Day 5
Day 10
Day 19
Day 21
ADQ
DEF
HYPO
9.1⫾0.6
11.0⫾1.8
11.0⫾1.9
7.9⫾0.5
9.7⫾1.9
9.5⫾1.9
34.2⫾14.8*
28.5⫾6.2*
11.7⫾2.0†
19.5⫾4.8*
15.9⫾2.7
11.5⫾1.9
9.6⫾0.6
11.1⫾2.0
10.9⫾1.8
8.9⫾0.7
9.2⫾1.8
11.3⫾1.8
10.1⫾0.8
9.8⫾2.0
11.0⫾2.3
Values are means ⫾ SE. Units are ␮l/ml. P ⬍ 0.05, *significant from SL baseline and †significant from DEF and ADQ.
line SL values, returning to normal within 7 days after ascent
to 4,300 meters. Urinary norepinephrine levels were slower to
rise in both groups, reaching peak values between days 4 and
7 of HA exposure (Fig. 6B) and remaining high throughout the
remainder of the stay at Pikes Peak.
Other analytes. Changes in total cholesterol and triglyceride
concentration are listed in Table 5. Initial blood lipid levels
were significantly higher in HYPO compared with DEF and
ADQ (P ⬍ 0.05), but there was no difference in baseline values
between the HA groups. Total cholesterol in DEF increased
significantly upon acute exposure to altitude, whereas ADQ
experienced a more gradual rise. HYPO experienced a steady
decline in total cholesterol, attaining lower levels than baseline
by the end of the study. There was no discernible pattern in
high- or low-density lipoprotein among the three groups over
the course of the intervention (data not shown). Triglyceride
levels in both altitude groups increased slightly, but insignificantly, upon acute exposure at Pikes Peak. Triglycerides in the
ADQ group continued rising, reaching levels ⬎100% greater
than baseline by day 21. Triglycerides did not show any
significant changes in the DEF group throughout the investigation. HYPO exhibited a significant reduction of triglycerides
by day 5 of the diet intervention.
DISCUSSION
Group comparisons in this study isolated the influence of
hypoxia from that of CR on the neuroendocrine system. As
predicted, some of the endocrine responses at altitude in the
energy-deficient group (DEF) tended to be muted by CR
relative to adequately fed subjects (ADQ), although a few
interesting exceptions emerged. Those altitude-induced hormonal responses that were altered by CR, such as epinephrine
and insulin, could cause an inhibition of the normal altitude
acclimatization process. The unanticipated deviation in DEF of
many hormones, especially the adipocytokines, from their SL
response to CR suggests that the priority of function among
hormones may be altered during times of hypoxic stress. This
theory warrants further discussion and investigation.
Hormone Responses with Distinct Interactive Effects:
Support for Dietary Modulation
Fig. 5. Change in adiponectin (A) and leptin levels (B) for each group at SL
and over the 21-day intervention period. Values are means ⫾ SE. P ⬍ 0.05,
significant from SL baseline (*), significant from ADQ (‡), and significant
from HYPO (§).
AJP-Endocrinol Metab • VOL
CR has been shown to reduce blood glucose concentration
and circulating insulin levels at SL (14), and both effects were
evident in the HYPO group. In contrast, glucose and insulin
both transiently increased at HA in ADQ and DEF, although
the rise was less robust in DEF subjects. Our findings suggest
that CR at altitude dampens the rise in blood glucose availability normally experienced at increased elevations (23, 35).
Lower blood glucose concentrations contribute to a shift in
substrate selection from carbohydrate to alternate fuel sources
such as fat or ketones to support energy needs. Indeed, previ-
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body fat mass for all groups throughout the entire intervention
phase (r ⫽ 0.71, P ⬍ 0.001).
Neither DEF nor ADQ registered any significant change in
leptin concentration throughout the 21 days at 4,300 meters,
but the small changes from baseline in leptin levels upward in
ADQ and downward in DEF led to a separation between HA
groups by day 5 on Pikes Peak (Fig. 5B). CR at SL caused a
28% reduction of circulating leptin concentration in the HYPO
group almost immediately (Fig. 5B). Leptin levels remained
suppressed in HYPO group subjects throughout the 21-day CR
period.
Urinary catecholamines. Urinary catecholamines were only
determined in the HA groups. As shown in Fig. 6A, epinephrine increased significantly in both DEF and ADQ upon acute
altitude exposure, although the rise in DEF was more modest
than that of the ADQ group (⫹3.14 ⫾ 1.20 vs. ⫹6.23 ⫾ 2.13
␮g/24 h by day 1, respectively, P ⬍ 0.05). After the initial
peak, urinary epinephrine levels steadily declined toward base-
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ENDOCRINE RESPONSE TO CALORIC RESTRICTION AT ALTITUDE
ous investigators have demonstrated that sojourners exposed to
both hypoxia and energy deficit rely more heavily on lipid
metabolism (55), sparing the more limited carbohydrate supply. However, a reduction in lipid dependence at altitude has
been noted when weight stability is maintained through a
controlled diet in altitude-exposed subjects (5, 39). Teleologic
argument suggests that a shift toward glucose metabolism may
be advantageous under hypoxic conditions since carbohydrate
is a more oxygen-efficient fuel source than fat (39).
The muted glucoregulatory response in DEF subjects was
also associated with reduced hyperinsulinemia, suggesting that
Table 5. Blood lipid data measured at baseline and over the 21-day intervention
Total cholesterol, mg/dl
ADQ
DEF
HYPO
Triglycerides, mg/dl
ADQ
DEF
HYPO
Baseline (SL)
Day 3
(HA or SL)
Day 5
(HA or SL)
Day 10
(HA or SL)
Day 21
(HA or SL)
135.4⫾8.4†
135.5⫾9.0†
171.2⫾7.6
136.4⫾10.3†
148.8⫾11.4*†‡
163.4⫾6.2
86.1⫾11.0
81.6⫾4.2†
109.3⫾10.2
109.6⫾16.7
98.3⫾14.6
87.7⫾8.0
Change from
Baseline,a %
131.9⫾9.4†
149.6⫾10.6*†‡
160.8⫾7.8*
148.0⫾5.3*
144.7⫾9.6*†
155.6⫾6.2*
153.9⫾7.6*†
147.4⫾10.4*
143.0⫾6.7*
⫹13.7
⫹8.8
⫺16.5
114.4⫾13.2*†
84.2⫾5.7‡
78.8⫾7.8*
151.1⫾19.0*†
77.5⫾5.1‡
79.1⫾8.4*
174.0⫾25.4*†
89.7⫾4.2‡
78.7⫾10.9*
⫹102.1
⫹9.9
⫺28.0
Values are means ⫾ SE. P ⬍ 0.05, †significant from HYPO, ‡significant from ADQ, and *significant from SL baseline. a Represents %change between
baseline and day 21 even though day 21 may not yield the peak change value.
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Fig. 6. Urinary epinephrine (A) and norepinephrine (B) concentrations for the
two altitude groups at SL and over the 21-day intervention period. Values are
means ⫾ SE. P ⬍ 0.05, significant from SL baseline (*) and significant from
ADQ (‡).
calorie-restricted subjects may bypass the transient rise in IR
that hypoxia has been shown to elicit (23). Negative energy
balance per se influences insulin sensitivity as evidenced by
previous studies in obese subjects (11, 33) and confirmed by
our HYPO group results. The transient impairment of insulin
action at altitude has been attributed to acute increases in stress
hormones (23) with an additive effect from hypoxia itself (35).
The acute rise in insulin concentration upon altitude exposure
may facilitate oxygen availability over time via increased
hematocrit/Hb (12) and erythropoiesis (31). Insulin has been
shown to stimulate hypoxia-inducible factor-1␣, a factor responsive to both hypoxia and iron deficiency that promotes
transcription of proteins such as EPO and vascular endothelial
growth factor (31). Insulin may also be a growth factor for
erythroid precursors as demonstrated in cell culture models
(32). The greater increase in both insulin levels and EPO
concentration experienced by ADQ compared with DEF subjects supports the hypothesis that the acclimatization process
may be impaired in calorie-restricted individuals.
Elevated blood lipid concentration experienced by ADQ
subjects may also be a result of the rise in insulin levels. Young
et al. (56) documented a similar increase in plasma triglyceride
concentration at altitude and attributed the dyslipidemia to the
influence of elevated insulin levels on hepatic triglyceride
production. However, the time course in this study suggests
that hyperinsulinemia may not be the sole cause of the increased blood lipids in ADQ, since the rise in HOMA-IR was
acute and transient while triglycerides were not significantly
elevated until day 5. Studies in animal models have demonstrated that hypoxia can induce dyslipidemia (25), and this
effect in humans may be exacerbated by a shift in diet macronutrient content. A diet high in simple carbohydrates as consumed by our ADQ subjects has been shown to raise triglycerides
even with no change in the percentage of dietary fat (36).
The chronic testosterone response to HA may also be modulated by caloric consumption. Acutely, testosterone levels
increased in all HA subjects regardless of energy intake. The
ADQ subjects who remained weight stable and adequately fed
at altitude continued to experience a gradual rise in serum
testosterone concentration, suggesting that hypoxia may exert a
positive stimulus on the hypothalamic-gonadotroph-testicular
axis throughout the exposure. However, in accord with our
hypothesis, the chronic altitude influence on testosterone levels
seemed to be mitigated by CR in DEF. Measurements from
previous studies taken after periods of intense trekking or
diminished caloric intake (4, 34) often show a decrease in
ENDOCRINE RESPONSE TO CALORIC RESTRICTION AT ALTITUDE
pituitary-testicular hormone release that may be the result of
the confounding influences of a negative energy state rather
than altitude. The steady decline of testosterone levels over
time in both HYPO and DEF may represent an adaptive
response of the reproductive system to a low-energy, catabolic
state (13).
Catecholamines: a Varied Response
Hormones with Overriding Altitude Effects
There appears to be no strong interactive effect of CR and
altitude on thyroid, cortisol, and adipocytokine concentrations,
since there were little or no differences between the ADQ and
DEF groups in these hormone levels. Both the TSH and fT4
results confirm previous HA studies that document a TSHindependent rise in thyroxine upon acute hypoxic exposure
(21, 37, 43). Thyroid hormones are known to increase levels of
2,3-diphosphoglycerate in erythrocytes, facilitating the unloading of oxygen to tissues through a rightward shift in the
oxyhemoglobin dissociation curve (45). However, the concomitant rise in thyroid concentration and basal energy expenditure
that Surks et al. (46) have shown at HA may be detrimental
when combined with periods of prolonged CR in lean subjects.
During CR at SL, investigators have shown fT4 to remain
unchanged (38) or to decrease (10) depending on the severity
of energy deficit, findings consistent with data from our HYPO
group. However, our results suggest that the hypoxic stimulus
at altitude is capable of overriding the fall in fT4 induced
by CR.
AJP-Endocrinol Metab • VOL
Altitude also exerts a strong influence over the hypothalamic-pituitary-adrenal axis. In this study, fasting serum cortisol was elevated in both HA groups at Pikes Peak, although CR
tended to augment the acute rise. The pattern suggests that an
increase in cortisol is accentuated when altitude exposure is
associated with another stress, such as CR. Results from
previous altitude studies show either a significant rise in
cortisol (1, 18) or no change from SL values (4, 42). This
discrepancy in the literature and the difference in acute cortisol
response between our HA groups may reflect a varying response based on substrate availability. Cortisol is catabolic to
fat and protein and is known to increase levels of serum free
fatty acids (FFA), glycerol, and amino acids in circulation (8,
9). Although these substrates were not directly measured in this
study, energy deficiency at altitude has been shown to increase
dependence on lipid metabolism (55). Elevated cortisol concentration may have helped compensate for the early muted
glucose response in DEF subjects by providing FFA as an
alternate fuel and/or stimulating gluconeogenesis via elevated
precursor availability (glycerol and amino acids). By day 5 at
Pikes Peak, the between-group differences in both fasting
glucose and cortisol concentrations disappeared. Although a
causal relationship cannot be determined with these data, the
parallel pattern is suggestive of an interaction between cortisol
and glucose availability. The sustained increase in cortisol in
both HA groups contrasts with the observed response in subjects at SL where prolonged CR either does not alter (20) or
suppresses plasma cortisol concentrations (15), possibly preserving lean mass. Although these prior studies were conducted in obese rather than lean subjects, our HYPO group
demonstrated similar results.
The adipocytokine response to CR also appears to be overridden by hypoxic exposure. We had anticipated that CR and
loss of adipose tissue at altitude would translate into alterations
in adiponectin and leptin concentrations. Adiponectin, abundant in the circulation of healthy, normal-weight volunteers,
has an established role in improving insulin sensitivity and
lipid profiles (52, 53). In our study, subjects on a restricted diet
at SL experienced a gradual decline (⫺26%) in adiponectin
levels over the course of the intervention period. This observed
fall of adiponectin in HYPO conflicts with many previous
studies investigating CR in obese subjects (33, 54). However,
the one previous study in nonobese subjects by Wolfe et al.
(52) measuring the adiponectin response to prolonged CR
showed a similar decrease of adiponectin with reduced energy
intake. In contrast to SL results, a fall in adiponectin with CR
was not evident at altitude. Studies in animal models have
demonstrated a direct and significant correlation between adiponectin levels and microvascular flow (47), suggesting a
potential role for adiponectin in improving oxygen delivery
during times of hypoxic stress. Therefore, it is possible that the
energy homeostasis role of adiponectin becomes secondary to
its regulation of the microvasculature at HA. However, further
studies will be necessary to understand adiponectin’s function
and mechanism of action during adaptation to a HA environment.
Leptin is another adipose-derived hormone that plays a key
role in the neuroendocrine regulation of energy homeostasis
and appetite. Low levels of circulating leptin signal food
deprivation and trigger the hypothalamic receptors to increase
energy intake (48, 50). Our results showing a significant
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In our study, altitude exposure led to a rapid rise in urinary
epinephrine concentration between days 1 and 3 in ADQ
subjects. Epinephrine also increased acutely in DEF, but peak
levels in DEF were significantly less than those experienced by
the ADQ group. In contrast, norepinephrine levels rose gradually over the first 4 –7 days of exposure, indicating that
sympathetic nervous activity increased similarly in both HA
groups over time (7, 30, 41). These results are consistent with
the theory that there is a dissociation between the adrenal
medullary and sympathetic response to HA exposure (3, 28).
Hypoxia per se can act directly on the adrenal system to secrete
epinephrine based on the severity of hypoxemia, even before
sympathetic activity is elevated (2). The muted epinephrine
rise in DEF subjects supports a negative interactive effect
between hypoxia and CR on the adrenal medulla. Conversely,
the similarity in norepinephrine levels between DEF and ADQ
subjects throughout the intervention implies that the sympathetic nervous system may be activated during hypoxia independent of energy intake status. We did not obtain HYPO
group catecholamine data, but previous investigations conducted at SL have reported both significant (16) and insignificant (44) decreases in epinephrine concentrations after a
period of clinically controlled hypocaloric dieting. A dampened epinephrine response upon acute altitude exposure may
diminish the body’s compensatory response to reduced arterial
oxygen, placing calorie-restricted sojourners at a greater risk
for altitude sickness and decrements in physical performance.
Furthermore, the negative influence of CR on epinephrine
availability could also reduce muscle glycogenolysis directly
and hepatic glucose production indirectly, thus decreasing
carbohydrate availability and use upon acute altitude exposure.
E1085
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ENDOCRINE RESPONSE TO CALORIC RESTRICTION AT ALTITUDE
Limitations of This Study
Despite our best efforts to match baseline characteristics,
each subject’s availability to spend 3 wk in Colorado did factor
into the initial group assignments. Unfortunately, this resulted
in a SL HYPO group that consisted of less-fit, heavier individuals with elevated baseline energy balance-related hormone
levels. The uneven group numbers resulting from the withdrawal of three ADQ subjects before altitude exposure also
exacerbated discrepancies in group characteristics. To clarify
comparisons among the three groups, we presented the data of
certain hormones as a change from baseline levels. Although
this method highlighted differences in the overall group responses to hypoxia and CR, it was difficult to determine if the
observed trends were confounded by the higher (HYPO) or
lower (DEF) starting values.
In addition, this study was part of a broader performancebased investigation with set exercise days that may have
impacted the endocrine data. For example, prolonged cycling
trials on day 1 and a V̇O2 peak test on day 2 may have impacted
the hormone response on day 3. Similarly, prolonged exercise
on day 18 may have caused a lingering influence on metabolic
measurements taken at day 19. This effect may explain some of
the acute fluctuations in hormone levels we observed between
days 19 and 21. However, all three groups followed identical
protocols, so scheduled exercise testing should not have impacted the group comparisons.
Finally, despite similar dietary restrictions and compensation for increased energy expenditure at altitude, DEF and
HYPO subjects did not lose equivalent amounts of weight.
Although this may indicate a synergistic effect of HA and CR
on weight loss, either through increased fluid shift (6) or
AJP-Endocrinol Metab • VOL
unexplained “energy requirement excess” (27), it could also be
an issue of control. The DEF group resided on the summit of
Pikes Peak throughout the intervention and had no access to
additional food sources other than what was provided to them.
In contrast, the HYPO subjects were permitted to leave the
CSU for portions of most days, and their compliance to the
dietary regimen may have been compromised during their
absence. However, DEF lost significantly more weight than
HYPO yet showed a muted effect from CR on the endocrine
system. Therefore, the discrepancy in weight loss between
HYPO and DEF does not impact our conclusions of a hypoxic
overriding stimulus on the normal SL calorie restricted response of the endocrine system.
In conclusion, the altitude-induced rise of many hormones
measured in the adequately fed subjects of this investigation
provides evidence that acute exposure to hypoxia tends to
stimulate the neuroendocrine system. A strong endocrine response can improve oxygen delivery via cardiorespiratory and
hemopoietic adaptations. However, for some hormones, prolonged CR causes the body to modify or suppress the altitudeinduced adaptive response in favor of enhanced energy preservation. Thus maintenance of an adequate energy intake may
be necessary to facilitate the acclimatization process. Deviations in the CR endocrine response at altitude from the CR
response observed at SL supports emerging data that the
relative importance of certain hormones may shift in times of
hypoxic stress. Further investigation is needed to elucidate
whether the function of hormones such as adiponectin and
leptin at altitude extends beyond their currently accepted roles
in energy homeostasis.
ACKNOWLEDGMENTS
We are grateful to the subjects for their participation and compliance to this
strenuous and taxing protocol. In addition, we thank the nurses and dietitians
in the Clinical Studies Unit at the Veterans Affairs Palo Alto Health Care
System for assistance with the testing procedures and dietary controls. We
extend a special thanks to Ron Van Gronigan for assistance with hormone
analyses.
GRANTS
This work was supported by a grant from the Department of Defense and
the Department of Veterans Affairs.
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