0021-972X/99/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 1999 by The Endocrine Society
Vol. 84, No. 6
Printed in U.S.A.
Differential Hypothalamic-Pituitary-Adrenal Axis
Reactivity to Psychological and Physical Stress*
ANITA SINGH, JOHN S. PETRIDES, PHILIP W. GOLD, GEORGE P. CHROUSOS,
AND PATRICIA A. DEUSTER
Department of Military and Emergency Medicine, Uniformed Services University of the Health
Sciences (A.S., P.A.D.), Bethesda, Maryland 20814; the Department of Physical and Occupational
Medicine, Duke University Medical Center (J.S.P.), Durham, North Carolina 00000; and the Clinical
Neuroendocrinology Branch, National Institute of Mental Health (P.W.G.), and the Developmental
Endocrinology Branch, National Institute of Child Health and Human Development (G.P.C.), National
Institutes of Health, Bethesda, Maryland 20892
ABSTRACT
Healthy men exhibit a differential hypothalamic-pituitary-adrenal
axis (HPA) response to exercise stress and fall into two groups: high
responders (HR) and low responders (LR). The present study examined whether HR to physical stress also exhibit higher HPA reactivity
to psychological stress than LR. We examined 14 HR and 13 LR
classified based on their ACTH responses to high intensity exercise
after pretreatment with dexamethasone. Both groups were of similar
age, height, weight, and fitness level. Trait anxiety scores on the
Spielberger Trait Anxiety Scale were not different. Subjects underwent a psychological stress test consisting of an interview and mental
T
HE HYPOTHALAMIC-PITUITARY-ADRENAL axis
(HPA) and the autonomic nervous system are activated
in response to stressful stimuli. Interestingly, it appears that
healthy individuals react differentially to stressful stimuli,
such as psychological stress and high intensity exercise (1–5).
Berger et al. (1) administered a battery of psychological stress
tests to men and noted a continuum of cortisol responses,
ranging from those who did not react to any test to those who
reacted to all tests. Sgoutas-Emch et al. (6) classified subjects
as high and low heart rate reactors based on their reactivity
to a speech stressor. Subsequently, these high and low heart
rate reactors exhibited differential endocrine and immune
responses to a speech and math stress paradigm. Kirschbaum
et al. (2) noted that a subgroup of individuals, about one third
of the sampled population, mounted an exaggerated cortisol
response to a psychological stress test; these subjects were
termed high responders. Similarly, we noted that about one
third of normal healthy men exhibited an exaggerated neuroendocrine response to high intensity exercise (4). Our high
responders showed significantly greater ACTH, cortisol, and
Received July 22, 1998. Revision received December 16, 1998.
Rerevision received February 17, 1999. Accepted February 24, 1999.
Address all correspondence and requests for reprints to: Anita Singh,
Ph.D., Department of Military and Emergency Medicine, Uniformed
Services University of the Health Sciences, 4301 Jones Bridge Road,
Bethesda, Maryland 20814-4799. E-mail: [email protected].
* The opinions and assertions expressed herein are those of the authors and should not be construed as reflecting those of the Uniformed
Services University of the Health Sciences or the Department of Defense.
This project was supported by Uniformed Services University of the
Health Sciences Grant RO9142.
arithmetic. This test raised heart rate, blood pressure, and plasma
ACTH and cortisol levels in both HR and LR. HR tended to have
higher heart rates and blood pressures in anticipation of the psychological stress test than LR. ACTH responses of HR were higher,
although not significantly, throughout the psychological stress test
than LR. HR had a significantly (P , 0.05) greater net integrated
cortisol response to the psychological stress than LR. This suggests
that the adrenal cortexes of the HR are hypertropic and/or hypersensitive to ACTH. We conclude that men who are highly responsive
to exercise stress are also highly responsive to psychological stress.
(J Clin Endocrinol Metab 84: 1944 –1948, 1999)
arginine vasopressin (AVP) responses to exercise, with and
without pretreatment with dexamethasone, compared to low
responders (4, 5).
Although, it appears that stressful stimuli differentially
activate the HPA, it is not known whether a high responder
to exercise stress will also be a high responder to psychological stress. This is an important issue because stress reactivity may have implications for health status. It appears
that HPA reactivity at the two ends of the continuum, hypoand hyperreactivity, may influence an individual’s susceptibility to developing various psychological, metabolic, inflammatory, and autoimmune disorders (2, 7). The present
study was undertaken to determine whether high and low
responders to exercise stress would exhibit corresponding
HPA reactivity to psychological stress.
Subjects and Methods
The study was approved by the institutional review board of the
Uniformed Services University of the Health Sciences (Bethesda, MD),
and informed, written consent was obtained from all participants. All
men were healthy, physically active, nonsmokers, and no one was taking
any medications, including steroids. A medical history, physical examination, and resting 12-lead electrocardiogram were obtained from each
volunteer before participation in the study. Subjects underwent a classification test for determining stress responsivity, a high intensity treadmill exercise test, and the psychological stress test. Subjects were instructed to abstain from caffeine and alcohol consumption as well as
running or other strenuous activities for 24 h before testing, and they
fasted for at least 6 h before the tests.
Classification for stress responsivity
Subjects were characterized as either high (HR) or low (LR) responders to stress based on their hormonal responses to high intensity exercise
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HPA REACTIVITY TO MENTAL AND PHYSICAL STRESS
(;90% of maximal oxygen consumption) 4 h after ingesting 4 mg dexamethasone (4, 5). Blood for measuring plasma ACTH concentrations was
collected before and immediately after high intensity exercise and at the
end of the 10-min cool-down period. Subjects who showed a significant
net increase (peak ACTH minus preexercise ACTH) greater than 1.1
pmol/L were termed HR (n 5 14) (5). Those who did not have a
significant net increase in plasma ACTH concentrations were termed LR
(n 5 13). Details of the classification criterion have been previously
published.
High intensity treadmill exercise test
Subjects reported to the human performance laboratory (HPL) 1 h
before the exercise test (between 0630 – 0730 h or between 1530 –1630 h),
weighed themselves, and drank a volume of water that was equivalent
to 0.5% of their body weight (5 mL/kg) to insure uniform hydration.
Forty minutes before testing an iv catheter was placed in a forearm vein
for blood sampling; the catheter was kept patent with a heparin lock. To
minimize postural effects, all blood samples were collected while the
subject was in an upright position.
The exercise test began with a 5-min warm-up during which the
subject jogged at an intensity equivalent to 50% of his maximal aerobic
capacity (V̇O2 max). Oxygen uptake and CO2 production were determined with a Metabolic Measurement Cart 2900c (SensorMedics, Yorba
Linda, CA). The treadmill grade was 5%, and the speed was adjusted to
produce the desired relative workload. The speed for each subject was
determined from his maximal aerobic capacity (VO2 max), which had
been determined during a progressive maximal treadmill test to volitional exhaustion. The grade of the treadmill was increased to 10% after
the warm-up, and the speed was adjusted accordingly. The type of
exercise used to elicit 90% intensity in the morning and that used in the
afternoon were different. In the morning subjects exercised continuously
for 5 min at 90% of their V̇O2 max, but in the afternoon a 10-min intermittent exercise protocol (30 s of exercise alternated with 30 s of rest) was
used (4, 5). Regardless of the type of exercise, continuous or intermittent,
subjects achieved 90% of their V̇O2 max with both protocols. A 10-min
active recovery of slow jogging/walking followed the run. Blood samples were collected before exercise (Pre), immediately after exercise, and
10, 20, 30, and 55 min after the cessation of exercise. Electrocardiograms
and heart rates were monitored continuously throughout the test. Blood
collection and processing techniques are described below.
An equal number of HR and LR were exercised in the morning and
the afternoon. Moreover, we have shown that exercising at 90% of
V̇O2 max overrides any time of day effects on HPA activation (8). Therefore, exercise data from the morning and afternoon exercise tests were
combined.
1945
lected, and heart rate and blood pressure were recorded. The test period
began when the four-member (men and women) panel filed into the
room and sat across the table from the subject. The subject was told to
listen carefully to the taped instructions for the first task, the job interview. He was told that he was interviewing for the position of a hospital
administrator and that in a 5-min speech he should convince the panel
that he was the best candidate for the job. Furthermore, he was told that
he must maintain eye contact with the panel throughout the interview
and that the interview would be videotaped and tape recorded so that
nonverbal behavior could be assessed. He was given 10 min to mentally
prepare for the interview: the panel left the room while he prepared.
After the subject completed his speech he was given instructions for the
mental arithmetic test.
For the mental arithmetic test, the subject was told to repeat a fourdigit number after the male tester, subtract 13 from it, and call out the
answer. He had to continue subtracting and calling out answers for 1
min. A new number was introduced every minute for a total of 5 min.
Throughout this challenge, the tester distracted the subject by commenting on the speed and accuracy of his responses and urged the
subject to look at the tester at all times. The same individual (J.S.P.)
served as the tester for all tests. At the end of the mental arithmetic, the
subject was asked to sit quietly for the remainder of the protocol.
Baseline blood pressure and heart rate were measured and recorded
before the start of the test (220, 210, and 22 min), at 2 -min intervals
during the test, and at 10-min intervals for 40 min after the test. Mean
arterial blood pressure was calculated from the systolic and diastolic
blood pressure recordings (11). Blood pressure and heart rate were
always measured before the blood draw. Blood was drawn at 220, 210,
and 22 min relative to the start of the test protocol, immediately after
the TSST, and at 10-min intervals for 40 min of recovery. Blood collection
and processing techniques are described below.
Blood collection and assays
Blood samples to measure ACTH and cortisol were collected in
chilled ethylenediamine tetraacetate tubes, which were centrifuged, and
the plasma was frozen until analysis; all samples for one subject were
analyzed in one assay. Plasma ACTH concentrations were assayed by
a two-site immunoradiometric assay (Nichols Institute Diagnostics, San
Juan Capistrano, CA), and plasma cortisol concentrations were measured by RIA (Diagnostic Products, Los Angeles, CA).
Chilled sodium fluoride tubes were used for collecting samples (1
mL) for glucose and lactate determinations. These samples were centrifuged, and plasma was removed and stored refrigerated until analyzed within 24 h of collection. Lactate and glucose concentrations were
determined in duplicate (SELECT 2700 Analyzer, YSI, Inc., Yellow
Springs, OH).
Psychological stress test
Subjects reported to the HPL between 1500 –1600 h, 75 min before the
start of the test protocol. Upon arrival in the HPL, subjects were given
details of the Trier Social Stress Test (TSST) (9) protocol and the consent
form. The TSST was chosen because this test activates the HPA and the
sympathetic nervous system. Subjects were requested not to reveal the
details of the test protocol to potential participants. After giving written
informed consent, subjects participated in the study as described below.
To insure uniform hydration, subjects weighed themselves 60 min
before the start of the protocol, then drank a volume of water that was
equivalent to 0.5% of their body weight (5 mL/kg). The Spielberger State
and Trait Anxiety Scale and the Spielberger State Anxiety Scale were
completed before and after the TSST, respectively (10). Forty minutes
before testing, an iv catheter was placed in a forearm vein for blood
sampling; the catheter was kept patent with a heparin lock. Next, the
subject was taken to the testing room, where he sat in a chair until the
test session was completed. The subject’s chair faced a table that held the
automated blood pressure-monitoring equipment. A video camera and
a portable tape recorder were also placed on the table. Four chairs to seat
the test panel were placed behind the table.
After the subject was seated, the blood pressure cuff was wrapped
around the subject’s upper arm; measurements were automatically
taken and recorded at preset intervals. The subject was asked to sit
quietly, relax, and await instructions for the test protocol. During this
waiting period, which lasted 20 min, baseline blood samples were col-
Statistical analyses
The Statistical Analysis System computer software package was used
for data analyses (SAS Institute, Inc., Cary, NC). Data are presented as
the mean 6 sem. The data were analyzed by two-way (group and time)
repeated measures ANOVA. Differences in peak ACTH and cortisol
responses to TSST and exercise were analyzed using t tests. Changes
from baseline were calculated for ACTH and cortisol responses to exercise. The net integrated response or area under the curve for ACTH
and cortisol responses to TSST and exercise, respectively, was calculated
by the trapezoidal method after subtraction of the baseline. Correlations
among variables measured during TSST and the exercise test were
computed. The level of significance was set at 0.05.
Results
Physical characteristics of the subjects are presented in
Table 1. As described in Subjects and Methods, subjects were
classified as HR and LR based on ACTH responses to exercise
after pretreatment with 4 mg dexamethasone. HR and LR
were of similar ages, heights, and weights, and subjects in
both groups were physically fit. Trait anxiety scores of the
HR and LR on the Spielberger Trait Anxiety Scale were not
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SINGH ET AL.
significantly different (10) (Table 1). The average length of
time between the exercise and psychological stress tests was
13.6 6 2.4 months.
High intensity exercise test
As shown in Fig. 1, baseline ACTH and cortisol concentrations of HR and LR were similar. However, HR mounted
significantly greater ACTH and cortisol responses to exercise
compared to LR (P , 0.05). Changes in ACTH and cortisol
responses from baseline values were also calculated. HR had
significantly greater (P , 0.05) ACTH increases over baseline
immediately after exercise (27.3 6 3.3 vs. 9.6 6 2.1 pmol/L)
than LR. These changes over baseline continued to be significantly greater (P , 0.05) in HR compared to LR up to 30
TABLE 1. General characteristics of the high (HR) and low (LR)
responders
Age (yr)
Ht (cm)
Wt (kg)
V̇O2 max (mL/kgzmin)
Trait anxiety scoresa
HR (n 5 14)
LR (n 5 13)
29 6 1
179 6 2
77 6 3
47.1 6 1.5
32 6 2
30 6 2
179 6 2
79 6 2
53.0 6 1.7
29 6 2
Values are the mean 6 SEM.
a
Spielberger State/Trait Anxiety Scale (10).
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Vol 84 • No 6
min postexercise. Cortisol concentrations of HR had begun
to rise immediately after exercise, but those of LR did not
(changes over baseline were 147 6 35 and 24 6 25 nmol/L
for HR and LR, respectively). Peak cortisol concentrations
occurred 20 min postexercise for both HR and LR. Again, the
change over baseline at 20 min postexercise was significantly
(P , 0.05) greater in HR compared to LR (436 6 52 vs. 241 6
70 nmol/L).
Psychological stress test
Baseline heart rates and mean blood pressures of HR and
LR were similar (Fig. 2). However, HR tended to exhibit
greater anticipatory stress, as evidenced by higher heart rates
and mean arterial blood pressure while preparing for the
interview. Higher heart rate and blood pressure were also
noted during the oral interview. A larger sample size is
needed to determine whether these trends could be significant. Once the mental arithmetic began, responses of both
HR and LR were similar. Additionally, state anxiety responses of HR and LR before and after the psychological
stress test were not significantly different (HR: before, 28 6
3; after, 37 6 3; LR: before, 27 6 2; after, 40 6 3).
Plasma lactate and plasma glucose (data not shown) were
measured in a subset of subjects (HR, n 5 8; LR, n 5 11).
FIG. 1. Plasma ACTH (upper panels) and cortisol (lower panels) concentrations in response to the psychological and exercise stress tests. AUC,
Area under the curve. P , 0.05, significant time effect for ACTH and cortisol responses. *, HR significantly greater than LR.
HPA REACTIVITY TO MENTAL AND PHYSICAL STRESS
1947
FIG. 2. Heart rate and mean arterial blood pressure (BP) measured in HR and LR during the psychological stress test. Pre or baseline, Mean
of 220, 210, and 22; Prep, while preparing for the interview; Oral, during the interview; Math, during mental arithmetic; Post, end of the test;
Rec, recovery.
Whereas psychological stress did not significantly alter circulating lactate and glucose concentrations in HR or LR, the
HPA was activated, as shown by significant (P , 0.05) increases in plasma ACTH and cortisol concentrations (Fig. 1).
The baseline ACTH concentrations of HR and LR were
similar, and ACTH concentrations in both groups peaked
immediately after TSST. Changes in the plasma ACTH concentration from baseline to peak (D) for HR (3.69 6 0.61
pmol/L) and LR (3.16 6 1.20 pmol/L) were not different.
Although ACTH concentrations in HR were higher after
TSST than those in LR, this difference was not significant.
Whereas plasma ACTH concentrations in LR had returned to
baseline 40 min after TSST, ACTH concentrations in HR
continued to be elevated over baseline values. The mean net
integrated ACTH responses of HR and LR were similar
(Fig. 1).
Plasma cortisol concentrations in both groups were similar
at baseline (Fig. 1). Cortisol concentrations in both groups
rose significantly (P , 0.05) during the TSST, and peak concentrations were noted 10 min after TSST. The D (peak minus
baseline) response of HR (267 6 41 nmol/L) was significantly
greater (P , 0.05) than that of LR (136 6 38 nmol/L). The
mean net integrated cortisol response of HR was also significantly greater than that of LR (P , 0.05; Fig. 1).
Discussion
Psychological stress activated the HPA and the autonomic
nervous system in both HR and LR. Individuals classified as
HR based on their HPA reactivity to high intensity exercise
after pretreatment with dexamethasone maintained high adrenocortical reactivity to psychological stress. Additionally,
HR tended to demonstrate greater anticipatory stress than
LR, as evidenced by higher heart rate and mean arterial blood
pressure values during the preparatory period for the psychological stress test. Thus, inherent HPA reactivity may be
an important determinant of endocrine and autonomic responses to a variety of stressors.
Previously we have shown that a subgroup of men escaped suppression of ACTH and cortisol by dexamethasone
when they underwent high intensity exercise (4, 5); we classified these men as HR. In contrast, men who maintained
dexamethasone suppression of ACTH and cortisol during
exercise were termed LR. In the present study, we demonstrated that this classification also holds for psychological
stress; after exercise, HR exhibited greater HPA activity in
response to psychological stress test than LR. Heuser et al.
(12) suggested that the combined dexamethasone/CRH challenge serves as an indicator of adaptive states. Thus, the
dexamethasone/exercise test used in the present study for
classifying subjects as HR and LR may also reflect genetically
and/or constitutionally determined adaptive states. Further
work is required to address this possibility.
In the present study, HR had a significantly (P , 0.05)
greater net integrated cortisol response to the psychological
stress than LR. Our findings of differential cortisol responses
to psychological stress are in accord with those of Kirschbaum et al. (2). The mechanisms responsible for this differential pattern of neuroendocrine activation remain to be determined, but we hypothesize that the HPA axis is inherently
more active in HR than in LR, which leads to slightly larger
adrenal cortexes in the HR. This difference in adrenocortical
size could be maintained not only by slightly higher ACTH
levels, but also by increased adrenomedullary activity, which
produces substances that synergize with ACTH to stimulate
cortical growth and function (13).
We should also note that although the ACTH responses of
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SINGH ET AL.
HR were higher than those of LR during the psychological
stress test, they were not significantly higher. In contrast,
ACTH responses to exercise in HR were significantly higher
than those in LR. This exercise/psychological stress difference may be accounted for by AVP. AVP is an important
mediator of ACTH release (14, 15), and HR have markedly
greater exercise-induced AVP responses than LR during high
intensity exercise (4, 5). Moreover, AVP infusion resulted in
significantly higher plasma ACTH concentrations in HR
compared to LR, an indication that HR may a greater pituitary sensitivity to AVP than LR (5). It is likely that the AVP
stimulus during psychological stress is less than that during
exercise stress.
The sympathomedullary system is activated at a lower
stress level than the HPA (16, 17). However, unlike HPA
responses, individuals cannot be differentiated into HR and
LR based on their catecholamine responses to psychological
(3, 6, 17) or exercise (our unpublished data) stress. A possible
explanation for the dichotomy in stress responsiveness of the
HPA axis and the sympathomedullary system may be that
although cortisol responses are influenced by the amount of
threat or distress produced by an event, catecholamine responses are also driven by effort (18).
Alterations in cardiovascular reactivity and vagal tone by
factors such as chronic stress may contribute to cardiovascular disease. Both strenuous exercise and psychological
stress increase heart rates and blood pressure. A combination
of the two stressors was reported to further increase cardiovascular responses in men (19). We noted that despite similar
baseline heart rate and mean arterial blood pressure values,
HR tended to have a higher anticipatory cardiovascular response to the speech task and than LR. Interestingly, Kirchbaum et al. (20) reported an increase in salivary cortisol when
men were anticipating a psychological stress test. As their ses
showed considerable variability, it is likely that some subjects may not have exhibited a cortisol response or that they
had some HR in their sample. Cacioppo et al. (3) also noted
that high cardiac reactors had higher ACTH and cortisol
responses to psychological stress than low cardiac reactors.
Thus, psychological stress appears to have a concordant effect on cardiac and neuroendocrine reactivities.
There was no association between trait anxiety and HPA
reactivity to psychological or exercise stress for HR and LR.
Similarly, Kirschbaum et al. (9) found no correlation between
personality traits and cortisol responses to the TSST. Expression
of trait anxiety may be related to an individual’s ability to cope
with stress. Coping styles, which include copers, nonspecific
defenders, and avoiders, may influence stress reactivity (21).
Coping styles were not examined in the present study, and
future work should be undertaken to determine what effect
coping style has on HPA axis reactivity and if a particular
coping style is found predominantly in HR or LR.
In conclusion, the present study demonstrated that men
who are HR to exercise stress are also HR to psychological
stress. Such a generalized response would indicate a nonspecific tendency for greater stress reactivity. Based on our
findings of differential HPA responsivity to stress in healthy
individuals and similar findings by others (3, 6) for autonomic nervous system and immune responses, it is important to examine all three systems concurrently. Future lon-
gitudinal studies should determine whether high or low
stress responsiveness in healthy individuals is a transitional
state due to some underlying perceived stress or is an inherent genetic (22) and or constitutional characteristic. Finally, clinicians and researchers should consider differential
HPA axis responses when interpreting patient records and
study results, respectively.
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