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Original Studies |
Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, Developmental Endocrinology Branch (P.A.D., J.S.P., A.S., E.B.L.); National Institutes of Child Health and Human Development (G.P.C.); and Clinical Neuroendocrinology Branch, National Institutes of Mental Health (P.W.G.), Bethesda, Maryland 20814
Address all correspondence and requests for reprints to: Patricia A. Deuster, Ph.D., M.P.H., Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4799. E-mail: pdeuster{at}usuhs.mil
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Abstract |
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Introduction |
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Physical exercise is a physiological challenge that induces threshold- and intensity-dependent HPA activation (9, 10). Furthermore, individuals with marked differences in physical training exhibit similar neuroendocrine and metabolic responses to the same relative exercise intensities (9, 10). Thus, exercise, as a physiological stressor, could be used in combination with DEX to assess alterations in HPA function. We recently showed that healthy men exhibit differential pituitary-adrenal responses to high intensity exercise after pretreatment with 4 mg DEX (11, 12). Specifically, about 30% of the subjects showed persistence of pituitary-adrenal responsiveness to exercise, as evidenced by significant increases in plasma concentrations of ACTH and cortisol. Those who were able to mount a stress response to exercise after DEX were designated high responders, whereas those who showed no exercise-induced pituitary-adrenal responses were designated low responders. Of particular interest was the finding that without DEX, high responders exhibited differential metabolic and neuroendocrine responses to exercise compared to low responders. In particular, high responders had significantly higher concentrations of plasma arginine vasopressin (AVP), ACTH, cortisol, lactate, and glucose.
The results with the DEX/exercise test for healthy individuals raised several fundamental questions regarding this potential physiological challenge test. One related to the strength of the stimulus, another to diurnal variability, and a third to potential sexual dimorphism. Specifically, in the present investigation, we sought to determine whether the strength of the exercise stimulus would dictate the magnitude of the neuroendocrine and metabolic responses in healthy men and women during DEX suppression. In addition, we wanted to assess whether HPA reactivity or glucocorticoid sensitivity during DEX suppression was affected by the time of day.
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Subjects and Methods |
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The study was approved by the institutional human use review committee, and informed, written consent was obtained from all participants. Ten healthy, moderately trained, medication-free male (n = 5) and female (n = 5) subjects whose weekly exercise consisted of running 24–40 km (15–25 miles)/week were recruited.
Subjects reported to the laboratory on 5 occasions: first for a screening visit in the morning (AM) and then for 4 exercise test visits. During the screening visit, a medical history, a physical examination, and a resting 12-lead electrocardiogram were obtained, and each subject underwent a progressive maximal treadmill test to volitional exhaustion to determine maximal oxygen uptake (VO2 max). The maximal exercise test, as described by Kyle et al. (13), was conducted on a motorized treadmill and began with a 10-min warm-up walk at 3.5 mph on a 10% grade. Treadmill speed was then increased to 5, 6, or 7 mph (depending on the usual running pace) at a 0% grade for 2 min; every 2 min thereafter the treadmill grade increased by 2.5% increments. Blood samples were obtained before and at the end of exercise through an iv catheter inserted 30 min before exercise. Oxygen uptake and CO2 production during all exercise tests were determined with a Metabolic Measurement Cart 2900c (SensorMedics, Yorba Linda, CA). Electrocardiograms and heart rates were monitored continuously throughout all exercise protocols. The results of the maximal treadmill test were used to determine the work rate (treadmill speed at 10% grade) that would elicit exercise intensities of 90% and 100% of each individual’s maximal oxygen uptake. Verification that each subject actually attained VO2 max at the end of the maximal oxygen uptake test consisted of meeting 3 of the following criteria: 1) achieving predicted maximal heart rate, 2) Borg’s perceived exertion scale rating of 17 or higher (14), 3) respiratory exchange ratio of 1.10 or higher, 4) an increase in oxygen uptake of 150 mL or less for an increase in workload, and 5) lactate concentration of 8.0 mmol/L or more.
There were four test visits, which consisted of high intensity exercise runs; two runs were at 90% and two were at 100% of VO2 max. One 90% and one 100% test were conducted in the early AM at approximately 0800 h, and the others were conducted in the evening (PM) at 1700 h. All subjects completed each test in a randomized fashion, and tests were separated by at least 1 week to allow for drug metabolism and washout. Subjects abstained from caffeine and alcohol consumption and running or other strenuous activities 24 h before testing; they fasted for 6 h before each test.
Eight hours before each of the 4 high intensity exercise tests, subjects ingested 4 mg DEX (Pathway Pharmacy, Bethesda, MD). After arriving at the laboratory, subjects were uniformly hydrated by having them drink 0.5% of their weight as water (5 mL/kg BW); next, an iv catheter for blood sampling was inserted in one forearm vein 30 min before exercise. Blood was drawn for baseline measurements at -10 and 0 min relative to the start of exercise, at the end of the high intensity exercise (15 min), 5 min after the cool down period (25 min), and every 10 min after exercise for 40 min. Heart rate was also monitored before each blood sampling. The Spielberger State-Trait Anxiety scale, a 40-item self-report questionnaire for measuring state and trait anxiety, was completed before and at the end of each test to assess each subject’s mood and anxiety level at that moment (15). The scale evaluates feelings of overall apprehension, tension, nervousness, and worry.
The exercise test consisted of 15 min of jogging/running and a 10-min cool down. The initial 5 min served as a warm-up, during which each subject jogged at an intensity equivalent to 50% of their VO2 max. Immediately after the warm-up, the treadmill grade was increased to 10%, and the subject exercised at 70% VO2 max for 5 min. The next 5 min of exercise involved performing a high intensity run at either 90% or 100% VO2 max at a 10% treadmill grade; a 10-min cool-down of walking (3.3 mph) followed the run. The speeds and grades of the treadmill for a given subject were identical under each experimental condition.
Blood samples were collected in heparinized tubes (15 IU heparin/mL blood) containing fluoride (1 mg fluoride/mL blood) for lactate and glucose determinations and in chilled ethylenediamine tetraacetate tubes (1.6 mg ethylenediamine tetraacetate/mL blood) for hemoglobin, hematocrit, ACTH, cortisol, AVP, and DEX determinations. Plasma was separated and stored at -40 C for later analyses.
Biochemical assays
Lactate and glucose concentrations were determined in duplicate (YSI Analyzer model 27, Yellow Springs Instrument Co., Yellow Springs, OH). Hemoglobin and hematocrit were determined in triplicate by the cyanomethemoglobin and microcapillary methods, respectively. Plasma cortisol was measured by RIA (Diagnostic Products Corp., Webster, TX). Plasma ACTH concentrations were assayed by a two-site immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA). The detection limits of the assays were 8.3 nmol/L for cortisol and 0.22 pmol/L for ACTH. The intraassay coefficients of variation (CVs) for cortisol and ACTH were less than 6% and 8%, respectively. The interassay CVs were less than 10% and 15% for cortisol and ACTH, respectively. Samples from all tests for one individual were assayed together. Plasma AVP was extracted and assayed by RIA as previously described by Rittmaster et al. (16). The recovery using this procedure was greater than 90%; the intraassay CV for AVP was 7%. All samples from a single subject were analyzed in one assay to eliminate interassay variations. Plasma DEX concentrations were measured by RIA (Endocrine Sciences, Calabasas Hills, CA).
Statistical analyses
The statistical software program, SAS (SAS Institute, Cary, NC), was used for all data analyses. Data were analyzed as a factorial design with repeated measures; a multivariate ANOVA, general linear model was used. When significant effects were detected by multivariate ANOVA, Duncan’s multiple range test was used to identify differences across time and treatments. Significance was set at the 0.05 level. Areas under the curve (AUCs) were calculated by the trapezoidal method after subtracting the baseline. Data are presented as the mean ± SE.
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Results |
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Table 1
presents general
characteristics for the subject population. The mean speed and grade of
the treadmill during the maximal oxygen uptake test averaged 6.4
± 0.3 mph and 11.0 ± 0.26%, respectively. Maximal treadmill
exercise significantly increased baseline plasma ACTH from 7 ±
0.8 to 34 ± 6.4 pmol/L at the end of exercise. Similarly, the
mean plasma AVP concentration was 0.57 ± 0.03 nmol/L before
exercise and 30.8 ± 17.14 nmol/L at the end of maximal exercise.
The mean heart rate was 188 ± 3 beats/min at the end of maximal
exercise.
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The oral administration of 4 mg DEX was well tolerated, and none
of the subjects experienced any adverse effects from the treatment.
Interestingly, plasma DEX levels were significantly lower in women than
in men (women, 725 ± 172; men, 928 ± 44 ng/100 mL), but all
were in the predicted range for a 4-mg dose. Treadmill grade was
maintained at 10% for the 90% and 100% exercise tests, whereas
treadmill speed was higher during the 100% tests (6.2 ± 0.1 mph)
compared to the 90% tests (5.3 ± 0.1 mph). As presented in Table 2 for each exercise intensity, peak
plasma lactate, heart rate, and relative VO2 values
averaged over the last 2 min of the high intensity work rate and the
Borg scale rating were unaffected by time of day. As expected, mean
peak lactate, heart rate, relative VO2, and Borg scale
ratings were higher during the 100% compared to the 90% exercise
tests.
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Marked intensity-dependent increases in plasma lactate levels were
noted for all subjects by the end of the high intensity runs (15 min;
Fig. 1a); pretreatment with DEX did not
affect the response. Analysis of AUCs for the two exercise intensities
demonstrated that increases in plasma lactate were significantly
(P = 0.0003) greater in response to the 100% runs
compared to the 90% runs in both the AM and PM (Fig. 1b). However, no
differences between AM or PM runs were found for the exercise-induced
lactate response. Increases in lactate concentrations were similar
between men and women (data not shown).
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, c and d), and time of day did not affect the
magnitude of the response. A trend toward higher plasma glucose
concentrations was noted for the 100% exercise intensity (90%,
83.7 ± 18.7; 100%, 105.2 ± 18.4 mmol x 65 min/L), but
this did not achieve statistical significance. Interestingly, women had
a significantly (P = 0.03) greater net integrated
glucose response to exercise than men (AUC:women, 125.4
± 19.7; men, 68.1 ± 15.7 mmol x 65 min/L; P <
0.01).
Pretreatment with DEX significantly (P < 0.05) reduced
basal levels of ACTH in all subjects (0.6 ± 0.05 pmol/L) compared
to basal levels before the maximal oxygen uptake test (7 ± 0.8
pmol/L). Figure 2, a and b, presents the
time courses and AUCs for plasma ACTH across all four exercise tests.
Plasma concentrations of ACTH in all subjects were similar between AM
and PM exercise test runs. In contrast, the plasma ACTH response was
greater during the 100% compared to the 90% exercise test. Moreover,
AUCs for plasma ACTH were significantly (P = 0.04)
higher for the 100% compared to the 90% exercise test (Fig. 2b), but
did not differ with respect to time of day (Fig. 2b). In addition, no
significant differences were found for plasma ACTH responses between
men and women.
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, c and d. As was noted with ACTH,
increasing the exercise intensity from 90% to 100% of VO2
max elicited a further rise in plasma cortisol concentrations.
Interestingly, AUCs for cortisol were significantly (P
= 0.04) greater for women (women, 90%, 152 ± 384.1; men, 90%,
-345 ± 147.5 nmol x 75 min/L; women, 100%, 3850 ±
1803.8; men, 100%, 332 ± 255.2 nmol x75 min/L). Finally, no
significant differences in the net integrated exercise-induced cortisol
response were noted, but there was a trend toward greater responsivity
in the AM compared to the PM (P = 0.13).
In contrast to the ACTH and cortisol responses, pretreatment with DEX
before the onset of the high intensity exercise tests did not alter
basal plasma AVP levels (0.57 ± 0.02 nmol/L) compared to basal
values before the maximal exercise test (0.57 ± 0.03 nmol/L).
However, plasma concentrations of AVP (P < 0.05) were
significantly (P = 0.03) elevated after 15 min of
exercise, with a definitive intensity-dependent pattern (Fig. 3, a and
b); the peak plasma AVP response to the 100% test was 4-fold that
observed for the 90% test (100%, 43.1 ± 12.0 nmol/L; 90%,
8.9 ± 3.4 nmol/L; P < 0.01). Of interest was the
finding that AUCs for plasma AVP were significantly (P
< 0.01) higher in women than in men at both exercise intensities (Fig. 3b). The AUCs for AVP release were not
significantly different in the AM compared to the PM (P
= 0.12), but a trend toward higher responses in the AM compared to the
PM was noted (data not shown). If a larger sample size had been
studied, a diurnal difference may have been noted. Finally, a
significant correlation between peak plasma AVP and cortisol was noted
(r = 0.72; P = 0.0001).
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presents the individual peak
plasma responses of each man and woman for AVP, ACTH, cortisol,
glucose, and lactate. Exercise-induced ACTH and lactate responses were
comparable for men and women, whereas the AVP, cortisol, and glucose
responses were higher for women than for men.
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State anxiety scores before and after exercise were not significantly affected by time of day, degree of exercise intensity, or gender. Interestingly, men (34 ± 1.3) had a significantly higher score (P < 0.01) for trait anxiety than women (27 ± 1.3). Compared with normal data for adults, 18–39 yr of age, both the men and women scored within the normal range (36 ± 10.4) (15).
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Discussion |
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Exercise-induced HPA activation is intensity and duration dependent (9, 10); thus, intensity-dependent increases in ACTH, AVP, and cortisol were not unexpected. However, several studies have shown that HPA axis responses, stimulated by mental stress and infusion of CRH, can be completely suppressed in the face of increased glucocorticoid negative feedback (17). The results of the present study indicate that the stress of exercise may be different from that of other stimuli. We have previously shown that although HPA axis responses after exercise at 90% of maximal capacity are suppressed by 4 mg DEX in most men, a subgroup of normal, healthy, men maintain exercise-induced HPA responses (11, 12). It appears that a stronger stimulus, in this case exercise at approximately 100% of maximal capacity, further augmented HPA activation during high glucocorticoid negative feedback. Plasma concentrations of ACTH and cortisol increased more than 2-fold over baseline values in 5 of 10 and 3 of 10 subjects during the 90% tests and in 10 of 10 and 6 of 10 subjects during the 100% exercise test despite pretreatment with 4 mg DEX. This finding indicates that the strength of the stimulus, in this case exercise intensity, can override glucocorticoid negative feedback and profoundly increase HPA axis responsiveness. Whereas the mechanism for activation cannot be determined from the present data, it seems likely that glucocorticoid receptor sensitivity, density, synthesis, and function may be important. Furthermore, glucocorticoid feedback regulation may change depending on the hormonal milieu or tissue specificity.
One hormone that may serve an important role is AVP. The magnitude of the AVP response to high intensity exercise in this study was marked, particularly for the 100% intensity in some women; values in excess of 100 pmol/L were noted. This finding in combination with previous findings that individuals with exaggerated pituitary-adrenal activation in response to exercise demonstrate marked increases in plasma AVP (11, 12) lend support to a role for AVP. Within the supraoptic and paraventricular (PVN) nucleus of the hypothalamus, there are two known sources of AVP: magnocellular and parvocellular neurons (8, 18). AVP is released from magnocellular neurons of the supraoptic nucleus and PVN in response to changes in blood pressure, volume, and/or osmolality, and these neurons are believed to be the primary source of plasma AVP (8, 18). In contrast, AVP released from parvocellular neurons exerts a strong synergistic effect in cooperation with CRH to modulate pituitary-adrenal function (18, 19, 20, 21, 22). However, AVP secreted by collateral fibers of the magnocellular axons may also reach the anterior pituitary and stimulate ACTH release via the short portal vessels (23) or by entering the long portal vessels through axonal varicosities observed in the median eminence (16, 18, 24, 25, 26, 27). Thus, magnocellular AVP may also influence the release of ACTH from the anterior pituitary, particularly in response to osmotic stress (16, 24).
Within the parvocellular component of the PVN there are neurons that secrete CRH, AVP, and both CRH and AVP (28, 29, 30). Salata et al. (22) observed that AVP-induced ACTH responses were significantly greater in the AM than in the PM, an indication that CRH secretion peaks in the AM. Our trend toward greater exercise-induced release of ACTH, AVP, and cortisol in the AM lends support to the findings of Salata et al. (22).
In addition, some reports have suggested that the CRH component may be more sensitive to suppression by glucocorticoids than the CRH/AVP and AVP components (8, 28). Thus, the AVP and CRH/AVP components may serve to overcome glucocorticoid negative feedback invoked by previous stressors (28). Certainly, our previous data (11, 12), which show that exercise-induced plasma AVP is not suppressed by DEX, provide evidence that magnocellular AVP release is insensitive to glucocorticoid suppression during exercise. Moreover, our data suggest that exercise may modulate the sensitivity of the parvocellular CRH, CRH/AVP, or AVP neurons to glucocorticoids. Other selected signals, such as hypovolemia, hypotension, hyperosmolality, and/or nausea may also be capable of overriding DEX suppression of the HPA axis (16, 18). During exercise, hypotension is clearly not a stimulus, whereas plasma volume and osmolality changes are potential candidates. In the present study, plasma volume at the end of exercise had decreased 15% and 17.5% during the 90% and 100% protocols, respectively. Our previous work indicated that osmolality may increase to 296 mmol/kg during this exercise paradigm (unpublished data), but changes in plasma AVP do not correlate with changes in either plasma volume (r = 0.02; P = 0.89) or osmolality (r = 0.29; P = 0.22) at this exercise intensity. Thus, although volume and osmolality may be contributing factors, it is unlikely that they are the only factors. Although we did not quantify symptoms of gastrointestinal distress, none of the subjects complained of nausea. Finally, Whitnall (28) has suggested that the CRH neurons serve to maintain baseline levels of ACTH, whereas the CRH/AVP and AVP neurons are selectively activated to induce ACTH release during stress. Differential activation of these neurons in response to various stressors may modulate the parvocellular AVP/CRH ratio in portal plasma and thereby provide a robust mechanism for regulating the activity of the HPA axis.
Lastly, although the number of men and women who participated in the present study was small, women clearly had significantly greater exercise-induced increases in plasma glucose, AVP, and cortisol concentrations, but not ACTH or lactate, in the face of high dose DEX suppression compared to men. Although plasma levels of DEX were lower and the variability greater in women compared to men, the magnitude of the difference cannot explain the cortisol data. Plasma concentrations of DEX were not related to body weight, height, body mass index, maximal aerobic capacity, or any of the endocrine measures. Interestingly, Maes et al. (31) noted that buspirone evoked a significantly greater post-DST cortisol, but not ACTH, in women compared to men. The cause of the greater plasma cortisol, but not ACTH, response in our women is not known, but could reflect long standing hyperactivity of the HPA axis, so that the adrenal becomes hypersensitive to ACTH. In this context, plasma ACTH could get caught between relative hyperstimulation and greater glucocorticoid negative feedback from above, so that a quantitatively normal plasma ACTH level would result in an increased cortisol secretion from hyperresponsive adrenals. Similar findings have been noted in depression (32).
Alternatively, the greater plasma AVP response could directly increase plasma cortisol responses during exercise in women. Several studies suggest that the adrenal cortex secretes cortisol directly in response to AVP (33, 34). In this regard, we found stronger positive correlations between AVP and cortisol (r = 0.72; P < 0.0001) responses than between ACTH and cortisol responses (r = 0.39; P < 0.01). If the first mechanism is predominant, women may have greater overall CRH secretion in the HPA axis. If the latter is operative, then AVP-mediated glucocorticoid secretion may down-regulate hypothalamic CRH secretion. It is of potential interest that women show a higher incidence of disorders associated with CRH-mediated hypercortisolism (e.g. melancholic depression) as well as other illnesses postulated to be associated with altered CRH secretion (e.g. fibromyalgia) (35, 36). Whatever the mechanism, these data, like those reported by Altemus et al. (37), which show reduced sensitivity to glucocorticoid feedback during the luteal compared to the follicular phase, indicate significant effects of the reproductive axis on HPA function.
In summary, despite high dose glucocorticoid treatment, high intensity exercise can override the negative feedback of HPA axis activation in normal men and women, as evidenced by increases in ACTH and cortisol. This occurs to a greater extent in women. Although a definitive role for AVP in exercise-induced pituitary-adrenal activation has not been directly demonstrated, the ability of intense exercise to override negative feedback inhibition by cortisol may relate to the magnitude of the AVP response and the potency or specificity of the stressor to elicit an AVP response. In addition, the magnitude of the ACTH and cortisol responses may reflect the degree of hypothalamic drive for AVP and CRH secretion and the sensitivity of the glucocorticoid negative feedback system at the time of the stress. Ultimately, this DEX/exercise challenge test may help further elucidate mechanisms of HPA axis activation and allow for further characterization of disorders in which regulation of the HPA axis has been disturbed.
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Footnotes |
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Received February 12, 1998.
Revised May 28, 1998.
Accepted June 3, 1998.
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References |
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