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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
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: asingh{at}usuhs.mil
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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, hypo- and 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.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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 (
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 = 14)
(5). Those who did not have a significant net increase in plasma ACTH
concentrations were termed LR (n = 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 (
O2 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 O2 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
O2 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
O2 max overrides any time of day effects
on HPA activation (8). Therefore, exercise data from the morning and
afternoon exercise tests were combined.
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 collected, 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 four-digit 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 (-20, -10, and -2 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 -20, -10, and -2 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).
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 ± 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.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. 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 significantly different
(10) (Table 1). The average length of time between the exercise and
psychological stress tests was 13.6 ± 2.4 months.
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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 ± 3.3 vs.
9.6 ± 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 min postexercise. Cortisol concentrations of HR had
begun to rise immediately after exercise, but those of LR did not
(changes over baseline were 147 ± 35 and -4 ± 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 ± 52 vs. 241 ±
70 nmol/L).
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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 ± 3; after,
37 ± 3; LR: before, 27 ± 2; after, 40 ± 3).
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).
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 (
) for HR
(3.69 ± 0.61 pmol/L) and LR (3.16 ± 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 (peak minus baseline) response of
HR (267 ± 41 nmol/L) was significantly greater (P
< 0.05) than that of LR (136 ± 38 nmol/L). The mean net
integrated cortisol response of HR was also significantly greater than
that of LR (P < 0.05; Fig. 1).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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 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 longitudinal 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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Footnotes |
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Received July 22, 1998.
Revised December 16, 1998.
Revised February 17, 1999.
Accepted February 24, 1999.
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