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ORIGINAL ARTICLES |
From the Center for Psychobiology and Psychosomatic Research (N.C.S., D.H.H., C.K.), University of Trier, Trier, Germany; and Institute of Experimental Psychology (C.K.), University of Duesseldorf, Duesseldorf, Germany.
Address reprint requests to: Prof. Dr. Clemens Kirschbaum, Institute of Experimental Psychology II, University of Düsseldorf, D-40225 Düsseldorf, Germany. Email: ck{at}uni-duesseldorf.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: Sixty-five healthy subjects (19–45 years), 38 men and 27 women, were exposed to the Trier Social Stress Test (TSST) three times with a 4-week interval between stress sessions. Adrenocorticotropic hormone (ACTH), plasma cortisol, salivary cortisol, epinephrine, norepinephrine, and heart rates were measures repeatedly before and after each stress exposure.
RESULTS: All endocrine measures as well as heart rates increased significantly after each of the three stress sessions (F values >16.00, all p values < .01). Although salivary free cortisol, total plasma cortisol, ACTH, and heart rate stress responses showed a significant decrease across the three stress sessions (all F values > 5.8, p < .01), no such decrease could be observed for the levels of norepinephrine and epinephrine. A cluster analysis performed on the salivary free cortisol responses to all three stress sessions revealed two response groups consisting of 30 so-called "high responders" and 35 "low responders." The high responders also showed larger ACTH and total plasma cortisol responses compared with the low responders (all F values > 10.00, p < .01). No such differences between high and low responders could be observed with regard to catecholamine and heart rate responses.
CONCLUSIONS: From these data we conclude that habituation to psychosocial stress seems to be specific for a given response system. Although HPA responses quickly habituate, the sympathetic nervous system shows rather uniform activation patterns with repeated exposure to psychosocial challenge.
Key Words: habituation, • hypothalamus-pituitary-adrenal axis, • sympathetic-adrenal-medullary system, • psychosocial stress.
Abbreviations: ACTH = adrenocorticotropic hormone;; ADS = Allgemeine Depressionsskala (depression scale);; ANOVA = analysis of variance;; AUC = area under the curve;; BMI = body mass index;; HPA = hypothalamus-pituitary-adrenal;; SAM = sympathetic-adrenal-medullary;; TSST = Trier Social Stress Test.
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INTRODUCTION |
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However, there are also reports of unchanged or increasing HPA responses after repeated stimulation. Good evidence suggests that intensity, number, and frequency of stress administration as well as previous stress experience are important mediators determining the development of habituation of HPA responses to repeated stress (5, 7–10). Application of seven 2-minute restrained stress periods during 1 day failed to induce attenuation of adrenocorticotropic hormone (ACTH) or corticosterone reactions with interstressor intervals of 90 minutes. In contrast, interstressor intervals of 30 or 60 minutes resulted in decreased magnitudes of plasma corticosterone responses after the second stress application, whereas corticosterone peak levels after further stress exposure remain unchanged (7). Repeated application of high-intensity foot shocks resulted in a sensitization of corticosterone responses, whereas responsivity to repeated exposure to a lower intensity of foot shocks followed a U-shaped curve with, first, habituating corticosterone reactions to no-shock levels and, later, a return to initial response magnitudes (9). Again attenuated ACTH responses and absence of norepinephrine responses after repeated restraint stress compared with single stress exposure were reported, but exposure to a novel stressor results in higher norepinephrine and similar ACTH responses in prestressed rats compared with inexperienced single-stressed rats (5). Gerra et al. (11) observed in 20 healthy young men, in a study similar to ours, attenuated cortisol and ACTH responses after the second exposure to a psychosocial stress test, but norepinephrine and epinephrine increases were not significantly blunted.
On the basis of data suggesting that glucocorticoid low responders might be more susceptible to autoimmune disorders (12) while cortisol hyperactivity might render individuals more susceptible to infectious diseases (13), it is reasonable to search for subgroups of high and low HPA responders. Interesting results concerning different adrenocortical response patterns have been found in Fisher rats (F344) as compared with Sprague-Dawley and Lewis rats. Dhabhar et al. (14) reported significantly higher ACTH and corticosterone levels in Fisher rats during a 4-hour persistent stress exposure compared with the control animals. The high-responding Fischer rats showed no indication of habituation of corticosterone responses after repeated stress exposure.
Similar results were obtained in two recent studies with healthy young men (11, 15). Habituating cortisol responses were observed by the second or third exposure to moderate psychosocial stress in approximately two of three males, but a second group of subjects clearly failed to show such habituation. The fact that only men and no other biological stress response system were studied in one of the previous experiments (15), and that no results about SAM reactivity in HPA subgroups were reported (11), posed significant limitations to the interpretation of these results. Furthermore, it remained to be shown that with larger intervals between stress sessions, a consistent dissociation between high and low responders (or rapid vs. slow habituating subjects) would occur. Another important issue refers to the potential dissociation between response systems. Although the HPA axis and the SAM system have important protective effects in the short run, they may cause damage if they are repeatedly activated over prolonged periods. Based on the concept of allostasis with a lack of adaptation, prolonged or inadequate stress responses as conditions that may lead to allostatic load (16), it was of particular interest to investigate whether 1) the HPA axis and the SAM system would show parallel or divergent stress response patterns and 2) whether HPA high responders/slow habituators would show a stronger activation of the sympathetic nervous system than HPA low responders. To address these questions, the present study investigated HPA axis, SAM, and heart rate response patterns after repeated psychosocial stress in a group of 65 healthy men and women who were exposed three times to a psychosocial stressor with a 4-week interval between each session.
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METHODS |
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Experimental Protocol
Subjects were invited to the laboratory one or three times to examine the reactivity of the HPA axis, peripheral catecholamines, and the cardiovascular system after psychosocial stress. The Trier Social Stress Test (TSST) mainly consists of a free speech and a mental arithmetic task in front of an audience; the duration of the test is 15 minutes, including introduction to the speech and a preparation phase. The TSST has been repeatedly found to induce endocrine and cardiovascular responses in 70% to 80% of all tested subjects; approximately 20% to 30% do not show a substantial physiological stress response (18). To avoid the possibility that participants would present a prelearned speech or remember the sequence of correct responses for the mental arithmetic task on the second and third visits to the laboratory, the tasks of the stress test were changed (minimally) over the course of three sessions. For the speech we changed the job description that subjects were applying for. For the arithmetic task we altered the initial number of the serial subtraction task. All other details of the experimental setup were kept identical across the three TSST sessions. Because the HPA axis is not activated by a task per se but rather reflects the individual’s responses to the psychosocial setting in which the experiment is performed (35), both the job description of the free speech task and the concrete numbers for the arithmetic task are negligible details for this stress protocol.
For assessment of endocrine parameters, a venous catheter was inserted 90 minutes before the TSST. Blood samples were collected immediately before the stress sessions as well as 1, 10, 20, 30, 45,60, and 90 minutes after cessation of stress. Total plasma cortisol was determined from all blood samples; ACTH levels were determined at baseline and 1, 10, 20, and 90 minutes after cessation of the TSST. Basal blood samples as well as the samples obtained 1, 10, 20, and 30 minutes after stress were used to measure epinephrine and norepinephrine levels. To measure salivary free cortisol responses, saliva samples were collected in parallel to blood samples. In addition to endocrine parameters, heart rates were measured continuously at 1-minute intervals with ECG precision using wireless transmission (Sport Tester Profi, Polar Instruments, Gross-Gerau, Germany) during a period lasting from 10 minutes before onset of the TSST to 10 minutes after stress cessation.
To be able to study habituation patterns, subjects had to show a salivary cortisol response of at least 2.5 nmol/liter over individual baseline levels, which corresponds to an elevation of approximately 1 µg/dl total cortisol in serum or plasma. Such an elevation is thought to reflect a cortisol secretory episode (19). Thus, only subjects with an initial salivary free cortisol response greater than 2.5 nmol/liter were invited to participate in the second and third TSST sessions. Salivary cortisol responses to the first TSST were assayed a few days after the stress test to determine whether subjects qualified for the other two stress sessions. All samples were rerun after completion of the three TSST sessions (see below).
Psychological Assessment
Mood.
To detect possible relationships between mood status and psychophysiological stress responses, momentary mood was measured before and after the TSST with the Mehrdimensionaler Befindlichkeitsfragebogen (20), a German multidimensional mood questionnaire. The instrument has 32 items that assess elevated vs. depressed mood, wakefulness vs. sleepiness, and calmness vs. restlessness. Subjects rate their mood using a five-point scale ranging from 1 (not at all) to 5 (very much).
Subjective ratings of task stressfulness.
Twelve visual analog scales were applied immediately after the stress sessions to detect possible relationships between perceived stressfulness of the TSST and the biological response systems. Subjects were asked to rate novelty, difficulty, and satisfaction with the performance separate for the two stress tasks (free speech and mental arithmetic) as well as stressfulness, controllability, unpredictability, stress due to poor performance, extent of ego involvement, and challenge by the stress test.
Depression.
The "Allgemeine Depressionsskala" (ADS; Ref. 21), a revised German version of the Center for Epidemiologic Studies–Depression Scale (22) assessing depressive symptoms, was used to control for a possible impact of depression on the stress responses. The ADS consists of 20 items; subjects respond using a four-point rating scale ranging from 0 (rare) to 3 (mostly). Scores higher than 23 are assumed to indicate the presence of clinically relevant depressive symptoms.
Blood and Saliva Sampling
Immediately after collection, blood samples were centrifuged at 3000 rpm for 10 minutes, and blood plasma was stored at -20°C until biochemical analysis. Saliva was collected by subjects using Salivette collection devices (Sarstedt, Rommelsdorf, Germany). The devices were also stored at -20°C until biochemical analysis. Before the saliva samples were assayed for cortisol, they were thawed and spun at 3000 rpm for 10 minutes, which results in low-viscosity saliva.
Biochemical Analysis
The cortisol in saliva was determined by a time-resolved immunoassay with fluorometric detection as described in detail elsewhere (23). Saliva cortisol levels were determined twice for all subjects: A first analysis was run to determine whether a subject had significantly responded to the first TSST session. A second assay was performed with all samples of a subject included after the last TSST exposure. ACTH as well as total plasma cortisol were measured using commercial chemiluminescence assays (Nichols Institute, Bad Nauheim, Germany). Inter- and intraassay coefficients of variance were below 10% to 12% for all analytes. Epinephrine and norepinephrine were assayed by high-performance liquid chromatography with electrochemical detection, as described by Smedes et al. (24). Intraassay coefficients of variance were 7.9% for epinephrine and 5.4% for norepinephrine.
Statistical Analysis
Analyses of variance (ANOVAs) for repeated measures were performed to reveal time and group-by-time effects for salivary and total plasma cortisol, ACTH, epinephrine, norepinephrine, and heart rate responses after the stressful stimulation. Absolute mean endocrine and heart rate increases were entered as the dependent variables in ANOVAs with the repeated measure factor "session" (three levels). Contrast analyses were performed to test specific a priori hypotheses concerning the kinetic of mean stress responses over the three stress tests. All reported results were corrected by the Greenhouse/Geisser procedure where appropriate. To compare age, body mass index (BMI), and mood and stress ratings between HPA stress responders and nonresponders, Mann-Whitney U tests were applied because of the large discrepancy between number of nonresponders and responders. To test relationships between stability of endocrine and heart rate reactivity over the three TSSTs and the stability of subjective stress ratings, Pearson correlations were computed for the degree of habituation from the first to the second or third stress exposure as well as from the second to the third stress test between psychophysiological and subjective stress reactivity.
To identify subgroups of subjects who differ with respect to HPA responsiveness corresponding to previous experiments (11, 15) , we performed a cluster analysis (method: 
means). According to both, the "free hormone hypothesis" (25) and the allostatic load concept (16), the unbound (free) cortisol levels will most likely be a better index for measuring the individuals’ susceptibility to stress-related diseases. In an attempt to base the classification of subjects on the same variables as in a our previous study (15), but also because neither ACTH nor total cortisol levels will necessarily reflect the potential tissue effects of high or low HPA functioning, we decided to use the salivary free cortisol responses across all three TSST sessions (area under the curve, trapezoid formula) as the categorization variable. A chi-square analysis was used to test distribution differences between females and males in subgroups of HPA high and low responders. Student’s t tests were applied for comparing age and BMI between high and low responders and for comparing mood and stress ratings before and after the three stress sessions. Significant effects were assumed at 
< 0.05. For multiple comparisons the nominal level was adjusted by Bonferroni correction. All results are the mean ± SEM.
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RESULTS |
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2 = 0.03, p = NS; Table 1). Additionally there were no differences between responders and nonresponders with respect to age (25.8 ± 0.8 vs. 23.9 ± 0.9; Z = -1.13, p = NS) or BMI (22.3 ± 0.3 vs. 21.6 ± 0.3; Z = -0.98, p = NS).
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Endocrine and Heart Rate Data for Responders and Nonresponders
Group-by-time ANOVAs for repeated measures revealed significant interaction effects, showing much higher salivary free cortisol (F(2.7,227.5) = 21.5, p < .0001), total plasma cortisol (F(3.5,298.7) = 20.5, p < .0001), and ACTH responses (F(1.4,113.7) = 17.5, p < .0001) and higher epinephrine (F(2.2,178) = 4.5, p < .01) responses in responders than in nonresponders after the first TSST. No such differences were observed for norepinephrine (F(4,328) = 1, p = NS) or heart rate reactivity (F(4,324) = 1.7, p = NS). As for mood ratings, Mann-Whitney U tests revealed group differences only with respect to wakefulness. Nonresponders described themselves after the TSST (Z = -2.8, p < .005) as significantly less wakeful than responders described themselves. No differences were observed for subjective stress ratings after stress exposure (all Z scores < ±2.5, p = NS; = 0.004 for 12 comparisons).
Endocrine and Heart Rate Data for All Responders
HPA responders had significant increases in salivary free cortisol (TSST 1: F(2.5,161.1) = 69.9, p < .001; TSST 2: F(2.4,150.8) = 58.8, p < .001; TSST 3: F(2.8,171.1) = 52.3, p < .001), total plasma cortisol (TSST 1: F(3.5,223.5) = 111.5, p < .001; TSST 2: F(2.8,177.9) = 102.4, p < .001; TSST 3: F(3.3,198.3) = 85.6, p < .001), and ACTH (TSST 1: F(1.3,84.1) = 79.5, p < .001; TSST 2: F(1.4,83.9) = 50.0, p < .001; TSST 3: F(1.4,80.7) = 37.4, p < .001). Peak hormone levels were observed 1 minute (ACTH) and 10 minutes (salivary free and total plasma cortisol) after stress cessation on all 3 days. ANOVAs with the repeated-measures factor "day" revealed significant decreases in mean salivary free cortisol responses (F(1.9,117.3) = 20.9, p < .001), total plasma cortisol responses (F(2,121.2) = 22.5, p < .001), and ACTH responses (F(1.8,103.7) = 19.6, p < .001) (see Fig. 1). Contrast analyses revealed that salivary free cortisol increases were significantly higher after TSST 1 than after TSST 2 (F(1,64) = 34.4, p < .001) or TSST 3 (F(1,61) = 35.1, p < .001). No decrease could be observed between the second and the third stress sessions (F(1,61) = 0.001, p = NS). For total plasma cortisol responses the same habituation pattern could be observed, with significantly higher stress responses after TSST 1 compared with TSST 2 (F(1,62) = 24.6, p < .001) and TSST 3 (F(1,62) = 38.2, p < .001) and similar increases after the second and third stress stimulations (F(1,62) = 1.1, p = NS). Mean absolute ACTH increases were also highest after TSST 1 compared with TSST 2 (F(1,57) = 19.6, p < .001) and TSST 3 (F(1,57) = 43.2, p < .001). But in contrast to cortisol response contrast analyses, ACTH responses were lower after the third compared with the second test (F(1,57) = 10.3, p < .01).
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Pearson correlations were computed to determine whether the changes in HPA or SAM responses over the three TSST sessions were related to changes in the subjective stress ratings. Of a total of 216 correlations (12 visual analog scales, 3 TSST sessions, 5 hormone responses plus heart rate responses) between the biological and the subjective responses, only three significant correlations were observed. Heart rate responses habituated more strongly with increased perception of controllability (r = 0.53, p < .0001). A stronger ACTH response decrease between TSST 2 and 3 was observed when subjects reported higher satisfaction with their performance in the mental arithmetic subtest (r = 0.62, p < .0001). In contrast to expectations, the decrease in ACTH responses from TSST 1 to TSST 3 became stronger as subjects rated the TSST as more stressful from session 1 to session 3 (r = 0.51, p < .0001).
Endocrine and Heart Rate Reactivity in HPA High Responders and Low Responders
A cluster analyses performed on salivary free cortisol responses to all three stress exposures revealed two response groups, one of 30 high responders and one of 35 low responders. With regard to sociodemographic variables like age and BMI, Student’s t tests revealed no group differences (age: t(63) = 0.9, p = NS; BMI: t(63) = -0.4, p = NS). Furthermore, the two groups did not differ in distribution of males and females (2 = 0.05, p = NS; Table 2).
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= 0.008 for six comparisons on each test day). Furthermore, none of the perceived stress ratings from 12 visual analog scales differed after any stress session between the high and low responders (all t(63) values < 2.5, p = NS, = 0.004 for 12 comparisons after each stress test; Table 4).
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DISCUSSION |
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With 73.9% of subjects showing salivary free cortisol responses of at least 2.5 nmol/liter after the first stress test, a responder rate similar to previous studies from this laboratory was observed (18). Because the study was intended to investigate habituation of HPA parameters in the first place, subjects who failed to show a significant stress response to the first TSST were excluded from the following two stress sessions. Therefore, the following discussion of HPA and SAM habituation patterns hold for only the 65 cortisol responders to the first TSST.
We again observed a significant habituation of HPA responses with a mean decrease of about 37% to 46% from TSST 1 to TSST 3; heart rate responses decreased by approximately 18%. In contrast, norepinephrine responses remained unchanged over the three stress sessions. Although epinephrine net increases after the third stress session were reduced compared with the preceding stress tests, poststress peak levels as well as AUCs were similar for the three TSST sessions. The reduced net increases were caused by increased basal epinephrine levels before the third stress session, which may reflect anticipatory stress and/or physical activity. This interpretation is supported by the observation of an increased extent of subjective restlessness before TSST 3 compared with TSST 1. However, these anticipatory stress effects were observed for plasma cortisol, ACTH, norepinephrine, and heart rate. Also, there were no significant correlations between baseline hormone levels or heart rates and subjective mood ratings before the third stress session.
The decreasing HPA reactivity after repeated stimulation with the same stressor is in line with a lot of results reported in animal (1–5) as well as human studies (11, 15, 26) using a variety of repeated stressors, such as a prolonged shock avoidance situation (1), noise stress (2), electroconvulsive shocks (3), handling (4), immobilization (5), three consecutive parachute jumps (26), and psychosocial stress (11, 15). In contrast to the present results, Hashiguchi et al. (27) reported decreasing baselines of corticosterone after repeated shaker stress, but decreasing corticosterone response magnitudes were not observed. The authors interpreted the decreased baselines as habituation to daily handling but the lack of habituation to subsequent stress, which might be always "perceived," as a novel experience.
Similar to the declining heart rate reactivity in the present data, decreasing heart rate responses were reported over a period of three blocks of mental arithmetic tasks and three blocks of public speaking (28), after the second exposure to three different mental arithmetic tasks (29) as well as after the second exposure to a psychosocial stress test (11).
With respect to habituation of plasma catechola-mines to repeated stressful stimulation, results in the literature are rather inconsistent. Although some studies report decreasing reactivity of both epinephrine as well as norepinephrine after repeated stress (2, 6), others observed declining poststress epinephrine levels only with sustained high norepinephrine levels after repeated handling (4) or after repeated shaker stress (27). Even sensitization of both adrenomedullary hormones was reported after a series of 10 electroconvulsive shocks (3). Possible moderating factors explaining these conflicting results could be the total number of stressor administrations or the length of interstressor intervals (2, 6).
In summary, habituation of HPA hormones after recurrent exposure to the same stressful stimulation seemed to be a key characteristic of the HPA axis, whereas habituation of catecholamine responses seems to have a different temporal profile. Although no significant habituation of catecholamine responses was observed in the present study, other experimental protocols may lead to decreasing norepinephrine and epinephrine levels with repeated stress exposure.
A second focus of our study was to detect possible subgroups with respect to individual HPA responses. Similar to results of previous studies (11, 15), there was clear evidence for the existence of at least two subgroups of individuals, termed high and low responders. Extending our previous observations, we show here that young women seem to have the same response patterns after repeated stress as young men. In the present study nearly half of the subjects were high responders, compared only one third in previous studies. One reason for the higher proportion of high responders in the present study is that subjects who had no response to the first TSST (nonresponders) were excluded from further investigations and statistical analyses. A cluster analysis of the cortisol responses to the first TSST including only nonresponders yielded a distribution of high/low responders resembling the distribution observed in our previous study, that is, approximately 1/3 high and 2/3 low (15).
Most interesting, the high and low responders did not differ with respect to their catecholamine and heart rate reactivity patterns. Neither the initial response nor the development of habituation to the TSST differed between high and low HPA responders. At least with respect to the methods used here, the discrepancy in HPA reactivity between high and low responders could not be attributed to perceived stressfulness or momentary mood before or after the psychosocial stress situations. Likewise, the habituation patterns were not correlated with changes in subjective stress ratings across the three TSST sessions. This dissociation between subjective and biological indices of stress is most interesting from a psychosomatic point of view. Unfortunately, few experimental data are available to help explain why outflow from these different response levels hardly ever converges consistently.
The present results suggest that the response and habituation patterns to repeated stressful stimulation are rather specific for a given response system with a clearcut dissociation between the HPA axis and the SAM system. Several animal studies (3, 30) and human studies (11, 31, 32) support the idea of a dissociating stress reactivity of the HPA system and the SAM. Similar to the present results, Thiagarajan et al. (3) reported decreasing HPA reactivity after the 10th electroconvulsive shock; even epinephrine and norepinephrine reactions showed sensitization. In contrast, Britton et al. (30) observed during a 1-hour noise presentation that cortisol levels remained high, whereas hippocampal norepinephrine levels were elevated only during the first 20 minutes of stress. Although Gerra et al. (11) detected two subgroups of cortisol and ACTH high and low responders, cluster analyses of the mean catecholamine and heart rate delta peaks failed to show subgroups of subjects with different responsiveness or different habituation patterns. In a human study, an experimental achievement situation characterized by high controllability, only urinary epinephrine and norepinephrine levels increased compared with a control day, whereas urinary cortisol concentrations were even lower than the control levels (31). McCann et al. (32) observed increasing epinephrine and norepinephrine levels after an extended laboratory stress stimulation (1-hour Stroop test, 1-hour mental arithmetic). However, with regard to plasma cortisol, only a diminished circadian rhythm compared with a control day, but no stress-induced increase, was observed. Henry (33) discussed the role of specific perceptions of control for neuroendocrine activation: "The effort required on the one hand, and the degree of frustration conflict and uncertainty on the other, determine the ratio of catecholamines to corticoids." With respect to the HPA axis, Mason (34) concluded in his classic review that situational characteristics like novelty, predictability, controllability, and anticipation of negative consequences are important modulators. The decreasing HPA and heart rate reactivity in the present study was accompanied by increasing subjective perception of controllability and decreasing subjective perception of novelty and unpredictability (see Table 4), whereas the extent of ego involvement, a characteristic that might reflect the subjects effort to perform well, remained stable over the three TSST sessions.
The observation of a dissociated stress habituation pattern of the HPA axis compared with SAM parameters corroborates recent findings from this laboratory. A stress protocol such as the Stroop color-word interference test elicits SAM responses (eg, heart rate increase); however, it is insufficient for significant HPA activation if performed in a one-on-one (one subject, one experimenter) setting. If the same task is performed in front of an evaluative audience, then a significant increase in cortisol levels can also be observed (35). These data are in line with findings from the Frankenhäuser laboratory. Frankenhäuser suggested that effort, distress, and control are the forces driving an endocrine stress response. Although effort without distress (like in the Stroop test) will result in an epinephrine response, only distress will lead to cortisol secretion in her model (36).
From a psychosomatic point of view, it is very interesting to consider the potential health implications for a subject to be a high or low HPA responder. In a recent review concerning protective and damaging effects of stress mediators, McEwen (16) described the concept of allostasis and allostatic load. Although allostatic systems enable individuals to cope with a variety of (stressful) stimulations, allostatic load occurs when inactivation of stress response systems are inefficient. McEwen described four situations of allostatic load: frequent stress stimulation, inability to shut off allostatic responses, inadequate responses, and lack of adaptation to repeated stressors of the same type. Although the high responders in the present study showed adaptation to the repeated psychosocial stress, it is tempting to speculate that these subjects suffer from a much greater allostatic load provided that the response measured here reflects a trait rather than a state-dependent response pattern. An increased allostatic load due to large HPA and SAM responses to repeated stress might render a subject vulnerable to various diseases, from the common cold to cardiovascular diseases in the long run. Studies proving this hypothesis are anxiously awaited.
Received for publication July 13, 2001.
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