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Vol. 83, Issue 6, 1822-1831, December 1997
1 Department of Military and
Emergency Medicine and
2 Anesthesiology, ABSTRACT Galliven, E. A., A. Singh, D. Michelson, S. Bina, P. W. Gold, and P. A. Deuster. Hormonal and metabolic responses to exercise across time of day and menstrual cycle phase.
J. Appl. Physiol. 83(6):
1822-1831, 1997.
adrenocorticotropic hormone; circadian variation; cortisol; estrogen; eumenorrheic; glucose; running
INTRODUCTION EXERCISE INITIATES a coordinated series of
physiological responses, including hypothalamic-pituitary-adrenal (HPA)
axis and sympathetic nervous system activation, that, in combination,
lead to the appropriate selection and utilization of metabolic
substrates. Although hormonal, sympathetic, and metabolic responses as
a function of exercise intensity and duration have been extensively
studied (14, 24), the role other physiological variables serve in modulating these responses has received less attention. Specifically, whether diurnal variations in neuroendocrine hormones or cyclic fluctuations in gonadal steroid hormones affect responses to exercise remains unclear. The HPA axis, in particular, has marked diurnal variations in activity and is highly sensitive to negative feedback restraint by basal cortisol concentrations.
Corticotropin-releasing hormone (CRH) is the principal effector of
circadian- and stress-induced HPA axis activation. Although hypophyseal
CRH levels have not been measured directly, a diurnal rhythm in
secretion has been hypothesized; the highest levels in the early
morning lead to the well-documented rise in adrenocorticotropic hormone
(ACTH) levels at this time. The morning rise in ACTH culminates in
relatively high cortisol levels in the morning; these may enhance negative feedback on the HPA axis (4).
Some (12, 30) but not all HPA-axis challenge studies (29) have
demonstrated reduced responsivity of the axis in the morning. Whereas
alterations in some aspects of HPA-axis function have been demonstrated
diurnally, the regulatory effects of the female gonadal steroid
hormones remain less well understood. Strong preclinical data in rats
suggest that estrogen enhances HPA-axis reactivity to stress (6, 16),
possibly through reduced glucocorticoid receptor binding and gene
transcription (7, 8, 27). However, the majority of studies in humans
have reported no baseline differences in cortisol across menstrual
cycle phase (2, 13, 20, 23), and little evidence exists to support
stress-induced differences (2, 9, 13, 20).
We report here two studies assessing circadian variations in the
magnitude of metabolic and hormonal responses of women to 20 min of
high- and moderate-intensity treadmill exercise. In addition,
study 2 also examined menstrual
cycle-related variations in responses to moderate-intensity exercise.
We chose to use graded treadmill exercise because it is a reproducible
and quantifiable stimulus to the HPA axis, the intensity of which
[% maximal O2 uptake
( METHODS All women were eumenorrheic according to self-reports of regular
menstrual cycles and normal menses. No subject with a history of
menstrual irregularity or other gynecological problems was admitted to
the study. All women were nonsmokers, medication free, and had not been
on oral contraceptives for at least 6 mo. Before participation, each
subject had a physical examination and an electrocardiogram. All
subjects had normal results from laboratory screening tests including
routine chemistries, thyroid function tests, urinalysis, and complete
blood counts. Subjects were asked to refrain from caffeine
and alcohol for 16 h before studies, from strenuous activity for 24 h,
and from food for at least 6 h before testing. Resting hemoglobin (Hb)
and hematocrit (Hct) determinations before all exercise tests were
within the normal range for each subject. Electrocardiograms and heart
rate were monitored continuously throughout exercise testing. Both
studies were approved by the Institutional Review Board of the
Uniformed Services University of the Health Sciences. Participants were informed of the risks of the study and gave written informed consent before participation.
Study 1: High-Intensity Exercise
Two studies, each utilizing short-term treadmill
exercise of a different intensity, assessed the metabolic and hormonal
responses of women to exercise in the morning (AM) and late afternoon
(PM). In study 1, plasma
concentrations of growth hormone, arginine vasopressin, catecholamines,
adrenocorticotropic hormone, cortisol, lactate, and glucose were
measured before, during, and after high-intensity exercise (90%
maximal O2 uptake) in the AM and
PM. In study 2, plasma concentrations
of adrenocorticotropic hormone, cortisol, lactate, and
glucose were measured before, during, and after
moderate-intensity exercise (70% maximal
O2 uptake) in the AM and PM in the
follicular (days 3-9), midcycle (days 10-16), and luteal
(days 18-26) phases of the
menstrual cycle. The results of studies
1 and 2 revealed no
significant diurnal differences in the magnitude of responses for any
measured variable. In addition, study
2 revealed a significant time-by-phase interaction for
glucose (P = 0.014). However, net
integrated responses were similar across cycle phases. These data
suggest that metabolic and hormonal responses to short-term,
high-intensity exercise can be assessed with equal reliability in the
AM and PM and that there are subtle differences in blood glucose
responses to moderate-intensity exercise across menstrual cycle phase.
O2 max)
achieved] can be standardized across individuals with different
fitness levels (24). Moreover, 20 min of graded treadmill exercise has
been used previously as a nonpharmacological challenge test of the HPA
axis (1). To date, only one study has examined diurnal variations in
cortisol responses to treadmill exercise (32), and no treadmill study
has examined diurnal variations in HPA-axis responsivity across
menstrual cycle phase. We hypothesized that
1) glucocorticoid negative feedback
would attenuate the magnitude of pituitary-adrenal responses in the AM
compared with the PM to exercise at 90 or 70%
O2 max and
2) pituitary-adrenal responses to
exercise would not differ across the menstrual cycle phase.
Table 1.
Descriptive characteristics of women in study 1 and study 2
Age, yr
Weight, kg
Height, cm
Absolute
O2 max,
ml/min
1
Study 1 (n = 7)
Mean ± SE
29 ± 1
64.6 ± 3.3
165 ± 3
2,645 ± 211
Range
23-36
52.5-82.0
157-185
2,001-3,880
Study 2 (n = 8)
Mean ± SE
31 ± 1
58.0 ± 1.2
162 ± 2
2,681 ± 116
Range
24-37
51.9-66.0
155-173
2,040-3,420
O2 max,
maximum O2 uptake; n = no. of women.
O2 max by using a
modification of the procedure described by Kyle et al. (22). Two
follow-up exercise tests were scheduled on separate occasions: one
between 0700 and 0800, after an overnight fast, and one between 1500 and 1600, after a 6-h fast. The order of testing was randomized, and each test was separated by at least 1 wk. Exercise testing was conducted on a motorized treadmill (Q65 Quinton Instruments, Bothell, WA). O2 uptake
(O2) and
CO2 production were determined
with a metabolic measurement cart (2900c Sensor Medics, Yorba Linda, CA).
40 min relative to the
start of exercise, time 0). Samples
were collected before exercise (20 and 10 min), midway
through exercise (10 min), and immediately after exercise (20 min);
subjects were kept in a standing position. Four
postexercise blood samples were taken (30, 40, 60, and 80 min after the
start of exercise) with the subject in a semirecumbent position. The
total treadmill exercise lasted 20 min followed by a 5-min cool-down
period. During the initial 5 min, each subject exercised at an
intensity equivalent to 50% of her
O2 max as determined
from her O2 max test.
During this time, the treadmill grade was maintained constant at 5%
while the speed was adjusted to produce 50%
O2 max. For
the next 5 min, the treadmill was set at a 10% grade, and the speed
was adjusted to elicit 70%
O2 max. Then there
was a 2-min break for blood sampling, after which each subject resumed
exercise at an intensity of 70%
O2 max for another 5 min. For the last 5 min of exercise the speed was adjusted to produce a
relative intensity of 90% of each subject's
O2 max; the grade was
set at 10%. A 5-min cool-down perdiod (3 miles/h, 2% grade) followed
each test. The speeds and grades of the treadmill were identical during
the AM and PM tests for each subject to ensure identical workloads
across test sessions.
Blood samples were collected into a syringe and dispensed into chilled
EDTA tubes (1.6 mg EDTA/ml blood) for hormonal analyses and into room
temperature EDTA tubes for determination of Hb and Hct. Additional
blood was aliquoted into chilled heparinized tubes (15 IU heparin/ml
blood) containing sodium fluoride (1 mg fluoride) for lactate and
glucose measurements and into chilled tubes containing ethylene
glycol-bis(
-aminoethyl
ether)-N,N,N
,N-tetraacetic acid and glutathione [90 mg ethylene glycol-bis(-aminoethyl
ether)-N,N,N,N-tetraacetic acid/ml deionized water with 90 mg glutathione, pH 8.2-8.4] for catecholamine determination. Plasma for hormones and catecholamines was
separated by centrifugation within 30 min and stored at 50°C until assayed. Plasma samples for lactate and glucose were refrigerated and assayed within 24 h.
Biochemical analyses.
Lactate and glucose concentrations were determined in duplicate (model
27 YSI analyzer; Yellow Springs Instruments, Yellow Springs, OH). Hb
and Hct were determined in duplicate by the cyanomethemoglobin and
microcapillary methods, respectively. Plasma cortisol was measured by
using a commercial radioimmunoassay (RIA) kit (Diagnostic Systems
Laboratory, Webster, TX). Plasma ACTH and growth hormone (GH) were
determined by using a commercial immunoradiometric kit (Nichols
Institutes Diagnostics, San Juan Capistrano, CA). Detection limits of
the assays were 8.3 nM for cortisol, 0.22 pM for ACTH, and 0.02 µg/l
for GH. The intra-assay coefficients of variation (CV) for ACTH,
cortisol, and GH were <8, 6, and 5%, respectively. The interassay CV
for ACTH was <15 and <10% for both cortisol and GH. Samples from
all tests for one individual were assayed together. Plasma arginine
vasopressin (AVP) was extracted and assayed by RIA as previously
described by Rittmaster et al. (28). The recovery with use of this
procedure was >90%. All samples were included in one assay; the
intra-assay CV for AVP was 7%. Catecholamines were extracted and
measured by high-performance liquid chromatography using a modification
of the procedure described by Hunter et al. (17). All catecholamine
samples were measured in one assay; the percent recovery for the
extraction was 60 ± 5%. The intra-assay CV was 17.0% for
norepinephrine (NE) and 20.4% for epinephrine (Epi).
Study 2: Moderate-Intensity Exercise
Eight healthy female subjects (6 Caucasian, 2 African- American; age: 31 ± 1 yr) participated in this study. Subjects were of low to moderate fitness and of normal body fat [(BF): 21 ± 0.6%; range = 16-25%]. BF was determined from skinfold thickness at four sites (triceps, suprailiac, abdomen, and thigh) on the right side of the body by using calipers, and percent BF was calculated by using an equation from Jackson et al. (19). Subject characteristics are shown in Table 1. Experimental procedure. All subjects reported to the laboratory on seven occasions. During the first visit, each subject underwent a progressive maximal aerobic treadmill test and used the same procedure described for study 1. Each subject then underwent six identical submaximal treadmill tests at a relative intensity of 70% of her previously determinedO2 max. Subjects were
tested over the course of two menstrual cycles during the
1) follicular phase between
days 3-9 after the start of
menses; 2) midphase between
days 10-16; and 3) luteal phase between
days 18-26. Menstrual cycle phase
was verified from estrogen and progesterone samples taken 20 min before each submaximal-exercise test. Testing across one menstrual cycle occurred in the AM (subjects reported to the lab between 0700 and
0800). Testing through the other phase occurred in the PM (subjects
reported to the lab between 1500 and 1600). The order of AM and PM
testing cycles was randomized. The exercise test session has already
been described for study 1. In
contrast with study 1, subjects
remained standing for all recovery blood draws in
study 2. The treadmill exercise test
employed here was the same as described in study
1, except for the last 5 of the 20 min, at which time
subjects in study 2 continued
exercising at 70%
O2 max
instead of achieving 90%
O2 max. A 5-min
cool-down period (3 miles/h, 2% grade) again followed each test.
Respiratory exchange ratios (RER) were continuously calculated from the
O2 and
CO2 production data collected
during the exercise test.
RER at 70% O2 max
for the data analysis was taken as the average of the last 2 min of
exercise. The blood collection procedures for lactate, glucose, ACTH,
cortisol, Hb, and Hct determinations have been described above. For
estrogen and progesterone determinations, blood was collected in tubes
without an anticoagulant, allowed to clot, and centrifuged for the
removal of serum. The serum was stored as described above.
Biochemical analyses.
Lactate, glucose, ACTH, cortisol, Hb, and Hct determinations were made
by using the same procedure described in study
1. Detection limits of the assays were 8.3 nM for
cortisol and 0.22 pM for ACTH. The intra-assay CV values for ACTH and
cortisol were <8 and 6%, respectively. The interassay CV for ACTH
and cortisol were <15% and <10%, respectively. All samples from
one individual were included in the same assay. Estrogen and
progesterone were determined by using a commercial RIA kit (Diagnostic
Products, Los Angeles, CA). Detection limits of the assays
were 29 pM for estrogen and 0.1 nM for progesterone. Each sex hormone
was measured in one assay. The intra-assay CV for either estrogen or
progesterone was <7%.
Statistical Analyses
A Statistical Analysis System software program (SAS Institute, Cary, NC) was used for all data analyses. Data in text, Tables 1 and 2, and Figs. 1, 2, 3, 4, 5, 6, 7 are presented as the mean ± SE. Differences across time of day and menstrual cycle phase were evaluated by using repeated-measures analysis of variance. If significant effects were noted, Duncan's multiple-range test was used to find differences across phase. Paired t-tests were performed to detect baseline differences across time of day. Significance was set at the 0.05 level. Net integrated area under the curve (AUC) was calculated by the trapezoidal method after subtraction of the baseline. AUC across time of day was analyzed by using paired t-tests. Pearson's correlation coefficient was used to test relationships among variables.
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O2 max) in morning
(AM; dashed line) and afternoon (PM; solid line).
Insets: corresponding net integrated
area under the curve (AUC) in AM and PM. Values are means ± SE.
O2 max in AM (dashed
line) and PM (solid line). Insets:
corresponding net integrated AUC in AM and PM. Values are means ± SE. * P < 0.001 compared with
PM.
O2 max in AM (dashed
line) and PM (solid line). Insets:
corresponding net integrated AUC in AM and PM. Values are means ± SE.
O2 max
in AM (dashed line) and PM (solid line). Values are means ± SE.
O2 max in AM (dashed
lines) and PM (solid lines). Insets: corresponding net integrated AUC in AM and PM. Values are
means ± SE. * P < 0.001 compared with level in PM.
O2 max in follicular
(FOL; 
, solid line), midcycle (MID; 
, dotted line), and luteal
(LUT; 
, dashed line) phases.
Insets: corresponding net integrated
AUC for menstrual cycle phase. Values are means ± SE.
* P < 0.05 compared with
midcycle phase. ** P < 0.05 compared with other 2 phases of menstrual cycle.
O2 max FOL (, solid
line), MID (, dotted line), and LUT (, dashed line) phases.
Insets: corresponding net integrated AUC for menstrual cycle phase. Values are means ± SE.
RESULTS
Study 1: High-Intensity Exercise
Physiological and metabolic responses. Percentage ofO2 max
achieved, heart rates, and ratings of perceived exertion (RPE) across
exercise intensities did not differ significantly between AM and PM
tests (Table 2). Lactate and glucose
responses to exercise across test sessions are presented in Fig.
1. As expected, plasma concentrations of
lactate increased in an intensity-dependent manner and achieved an
increase of ~10-fold over basal levels at the 90%
O2 max intensity. No
differences were noted in the pattern of change over time or AUC
between test sessions. Similarly, the patterns of change and AUC for
glucose were not significantly different between the AM and PM; peak
glucose concentrations were noted at 10 min postexercise.
Hormonal responses.
Plasma ACTH and cortisol responses to exercise in the AM and PM are
shown in Fig. 2. Basal concentrations of
ACTH were not significantly different in the AM (3.5 ± 0.6 pM) and
PM (2.6 ± 0.4 pM). The patterns of ACTH responses to exercise in
the AM and PM were similar, with peak concentrations achieved at the end of high-intensity exercise (time
20). The net integrated ACTH responses in the AM and
PM were also similar. Although mean basal plasma cortisol levels (357.5 ± 24.3 vs. 206.4 ± 19.3 nM, AM vs. PM, respectively;
P < 0.001) were significantly higher
in the AM compared with the PM, analysis of AUC revealed no significant differences in the net integrated response in the AM and PM.
Similar patterns of response were noted for both AVP and GH (Fig.
3). Peak levels were attained at the end of
high-intensity exercise and returned to resting levels 20 min after
exercise. The changes in AVP and GH over time in the AM and PM were not significantly different. Additionally, analysis of AUC for AVP and GH
revealed no significant differences in the magnitude of response across
test sessions.
Catecholamine responses to exercise in the AM and PM are shown in Fig.
4. Relative to basal levels, the
concentration of NE and Epi increased significantly during exercise but
returned to resting levels 20 min after terminating exercise. The
pattern of change over time in the AM and PM was also similar for both catecholamines.
Study 2: Moderate-Intensity Exercise
Test sessions took place during the early follicular (day 6.1 ± 0.3; range, day 4-8), midcycle (day 13.6 ± 0.4; range, day 10-16), and luteal (day 21.1 ± 0.4; range, day 19-24) phases. Basal estradiol concentrations for each subject were in the expected range with respect to menstrual cycle phase (follicular: 200 ± 29 pM; midcycle: 489 ± 73 pM; luteal: 398 ± 55 pM). As expected, estradiol concentrations were significantly lower during the follicular phase compared with either the midcycle or luteal phases (P < 0.002). Basal progesterone levels were significantly higher in the luteal phase (30.2 ± 2.9 nM) compared with either follicular (1.1 ± 0.1 nM) or midcycle phases (6.8 ± 2.0 nM; P < 0.0001). Despite the expected higher group mean blood progesterone value in the luteal phase, one subject presented with low progesterone levels for both AM and PM tests (0.02 and 0.09 nM, respectively). Luteal-phase data from this subject were omitted from all analyses. Diurnal comparisons. The patterns of change over time for ACTH and cortisol and their respective net integrated responses in the AM and PM are shown in Fig. 5. Basal concentrations of ACTH were not significantly different in the AM (3.7 ± 0.3 pM) and PM (3.3 ± 0.3 pM). The net integrated ACTH responses in the AM and PM were not significantly different (3.6 ± 0.9 vs. 6.5 ± 1.8 pM/80 min, AM vs. PM, respectively; P = 0.30). Although mean basal plasma cortisol levels (287.3 ± 30.4 vs. 186.4 ± 17.5 nM, AM vs. PM, respectively) were significantly higher in the AM compared with the PM (P <0.001), analysis of AUC revealed no significant diurnal differences in the magnitude of responses (22.4 ± 38.8 vs. 141.0 ± 46.1 nM/80 min, AM vs. PM, respectively; P = 0.13). Similarly, the patterns of change in ACTH and cortisol were similar in the AM and PM (Fig. 5). Lactate and glucose determinations were not significantly different in the AM and PM (data not shown). Menstrual phase comparisons: physiological and metabolic responses. Percentage ofO2 max
achieved, heart rates, and RPE across exercise intensities did not
differ significantly between menstrual cycle phase tests (Table 2). In
all cycle phases, exercise induced a significant increase in plasma
lactate concentrations, achieving an increase of approximately fivefold
over basal levels immediately after exercise (time
20, Fig. 6). The magnitudes
of the lactate responses were similar across menstrual cycle phase. For
all cycle phases, exercise induced a significant increase in glucose
concentrations. In addition, there was a significant difference in the
glucose responses across phases (P = 0.014). Glucose
responses midway through exercise (time
10, Fig. 6) were higher in the luteal phase compared
with the midcycle phase (P < 0.05).
Moreover, luteal-phase glucose responses were higher compared with both
the midcycle and follicular phase immediately after exercise
(time 20) and for the next 20 min
thereafter (times 30 and
40; P < 0.05). There was a marginal main effect of phase for the net
integrated glucose responses (P = 0.083).
RER values were not significantly different across menstrual cycle
phase (follicular: 0.89 ± 0.02; midcycle: 0.88 ± 0.02; luteal:
0.88 ± 0.02).
Menstrual phase comparisons: hormonal responses.
The patterns of change over time for plasma ACTH and cortisol and their
respective net integrated responses across menstrual cycle phase are
shown in Fig. 7. In all phases of the
menstrual cycle, exercise induced a significant increase in plasma
levels of ACTH and cortisol. Basal, exercise, and recovery
concentrations of ACTH were similar across menstrual cycle phase, with
peak concentrations achieved at the end of high-intensity exercise
(time 20). The net integrated ACTH
responses during each phase were also similar. Similarly, mean basal
plasma cortisol levels were similar across menstrual cycle phase, as
was the pattern of change over time. The
P value for the net integrated
cortisol responses across phases was 0.056.
No significant correlations between basal estrogen levels and peak
responses or AUC were noted for any of the measured variables. In
addition, there were no significant correlations between basal progesterone levels and peak responses or AUC for any of the measured variables. The ratio of estrogen to progesterone was not correlated with any of these variables. There was a significant positive correlation between RER at 70%
O2 max and cortisol
levels immediately after exercise at time
20 (follicular: r = 0.68, P < 0.004; midcycle: r = 0.63 P < 0.02; luteal:
r = 0.64, P < 0.02) for each cycle phase. In
addition, there was a significant positive correlation between RER and
cortisol levels at times 30 and
40 for each cycle phase (data not
shown). No significant correlations were detected between RER and
postexercise glucose concentrations.
DISCUSSION
The present data provide evidence that the magnitudes of metabolic and pituitary-adrenal responses to either high- or moderate-intensity exercise are not significantly different in the AM and PM, despite high cortisol levels in the AM compared with the PM. In addition, the magnitudes of GH, AVP, and catecholamine responses to high-intensity exercise were similar in the AM and PM (not assessed in study 2). The present data also provide evidence for subtle differences in blood glucose responses across phases of the menstrual cycle.
Diurnal Comparisons
Data on circadian rhythms in the present study are not consistent with several previous studies. Decreased adrenal responses in the AM compared with the PM have been reported in studies with other provocative tests of pituitary-adrenal function, including ovine CRH (oCRH) stimulation and insulin administration (10, 12, 18, 25, 31). Some investigators have reported no significant diurnal differences in the cortisol response to oCRH (33, 34); however, these studies involved fewer subjects and thus may have been more subject to a type 2 error. However, one prior study (5) suggested that diurnal differences in adrenocortical activation to exercise are not caused by the progressive decline in cortisol throughout the day but rather are caused by the timing of exercise relative to several major cortisol peaks associated with food intake.The results of the present studies suggest that diurnal variations in
cortisol do not significantly modulate acute hormonal responses to
exercise at 90 and 70%
O2 max. Our
findings are consistent with those of Thuma et al. (32), who reported
similar magnitudes of change in cortisol in response to 40 min of
treadmill exercise at 70%
O2 max in the AM and
PM, after correcting for circadian baselines. The discrepancy between
the exercise studies (Thuma et al. and the present study) and those
using oCRH (10, 12, 18, 25, 31) may be caused by the fact that exercise is a central stimulus, whereas oCRH is a pituitary stimulus. It is
possible that glucocorticoid negative feedback may operate differently
for a central stimulus than for a pituitary stimulus, thereby making it
possible to mount a stress response despite elevated cortisol levels.
Salata et al. (29) provide compelling evidence that the apparent failure of high cortisol levels in the AM to significantly blunt pituitary responses to stress may actually reflect increased glucocorticoid restraint in combination with increased hypothalamic CRH drive in the AM. Using AVP stimulation, Salata et al. reported higher net integrated ACTH responses in the AM compared with the PM. This diurnal response in ACTH is opposite of that for oCRH administration, for which higher responses are reported in the PM when levels of cortisol are low. Salata et al. (29) speculated that perhaps an AVP stimulus might show greater potentiation of ACTH release in the AM when CRH levels are at a maximum compared with PM when CRH levels are presumably low. This possibility is supported by the finding that AVP by itself is a weak secretagogue for ACTH but markedly potentiates the effects of CRH (15). Consistent with this model, oCRH stimulation in the AM, when endogenous levels are high, should have little appreciable effect on ACTH release, thus accounting for the previously reported finding of reduced responses to oCRH in the AM.
Because the diurnal ACTH responses reported in the present study are more similar to those obtained by Salata et al. (29) for AVP and inconsistent with those obtained with oCRH, we speculate that AVP plays an important role in the acute pituitary-adrenal responses to exercise stress. Indeed, we have shown that short-term, high-intensity exercise is a potent stimulus for AVP release. Consistent with the model proposed by Salata et al., exercise performed in the AM, when endogenous CRH levels are high, may produce a relatively greater stimulation of ACTH release, which is partially blunted by higher ambient cortisol levels. Conversely, the same exercise stimulus in the PM, when CRH levels are low, may produce less ACTH secretion, which is partially offset by reduced glucocorticoid negative feedback. Our finding of nearly identical ACTH and cortisol responses to intense exercise in the context of differing cortisol levels suggests that these responses are determined, in part, by the degree of hypothalamic CRH drive in combination with the degree of glucocorticoid negative feedback at the time of the stress.
Also of particular interest is the finding that high-intensity exercise
resulted in nearly identical net integrated ACTH and cortisol responses
in the AM and PM (Fig. 2), whereas moderate-intensity exercise resulted
in a trend towards decreased responses in the AM compared with the PM
(Fig. 5). This trend raises the possibility of detecting diurnal
differences with a less intense bout of exercise and/or with a
greater number of subjects. It should be noted that the present studies
were not designed to directly examine the effect of exercise intensity
on the diurnal responsivity of the HPA axis to exercise. However, the
two study populations were nearly identical (e.g., fitness level, age,
weight, and race; see Table 1), and the experimental protocols were
identical except for exercise intensity. General inspection of these
data suggests that future research carefully examine diurnal variations
in activation of the HPA axis as a function of exercise intensity. The
ability of intense exercise (90%
O2 max) to override
negative feedback inhibition by cortisol may relate to the potency of
the stressor to elicit an AVP response. The magnitude of the AVP
responses to high-intensity exercise is typically greater than that
observed for other challenge tests of the HPA axis, such as oCRH
stimulation.
To our knowledge no studies have assessed whether there is a diurnal variation in stimulated AVP secretion. We measured basal and exercise-induced levels of plasma AVP in the AM and PM. Consistent with Altemus et al. (1), we found intense exercise to be a potent stimulus for AVP release in women, which resulted in a >35-fold increase over preexercise values. However, the patterns and magnitudes of change in AVP were essentially the same at both times of the day.
Our finding that exercise-induced GH release does not show a diurnal variation is in agreement with two studies of circadian rhythm that utilized insulin-induced hypoglycemia (18, 25). Another study reported significantly greater GH responses to insulin in the PM compared with the AM (31). However, these investigators measured PM GH levels at midnight, ~6 h later than determinations made in other studies. This raises the possibility that a small effect might be demonstrable at times of maximal quiescence.
In summary, our findings do not support a diurnal variation in the
magnitude of metabolic, pituitary-adrenal, or sympathetic responses to
exercise at 90%
O2 max. From
a methodological perspective, the present data suggest that time of day
does not have a significant effect on pituitary-adrenal responses to
high-intensity exercise. Thus, these responses can be assessed with
equal reliability in the AM and PM. No definitive conclusions can be
drawn for ACTH and cortisol responses to exercise <90%
O2 max until diurnal differences in HPA axis responsivity, as a function of exercise intensity, are better characterized. However, it seems prudent to
control the time of day for exercise at 70%
O2 max to reduce variability of pituitary-adrenal responses.
Menstrual Phase Comparisons
The present study provides little evidence for significant differences in the hormonal and metabolic responses to short-term, moderate-intensity exercise across menstrual cycle phase. The patterns of responses for ACTH and cortisol were similar across menstrual cycle phase. Furthermore, analysis of AUC revealed only a marginal main effect for cortisol. Although the pattern of glucose responses over time revealed a main effect of phase, net integrated glucose responses were not significantly different across cycle phase. Although the effect of phase for glucose suggests a subtle metabolic difference across menstrual cycle phase, this is not supported by analysis of RER. Additionally, there were no significant correlations between basal levels of progesterone or estrogen and either glucose or cortisol responses to exercise.The majority of prior research examining the effect of menstrual cycle phase on the metabolic and/or hormonal responses to exercise have excluded assessment of the midcycle phase. With the exception of a few reports (e.g., Ref. 23), most studies examining the follicular and luteal phases report no effect of menstrual cycle phase on the metabolic responses to exercise (2, 26). Metabolic data from the present study are consistent with those of Kanaley et al. (21), who examined all three phases of the menstrual cycle and reported no phase-related differences in either glucose responses or RER during exercise.
With regard to pituitary-adrenal responses to exercise, the present
results are consistent with those of De Souza et al. (13). Using a
similar exercise protocol and the same preexercise 6-h fast as the
present study, De Souza et al. reported no difference in ACTH and
cortisol responses to exercise when comparing the follicular and luteal
phases of the menstrual cycle. Our finding that exercise-induced
cortisol release does not vary according to menstrual cycle phase is
also in agreement with Bonen et al. (2), who reported similar findings
for subjects who fasted for 24 h. Kanaley et al. (20) also assessed
cortisol responses to exercise across three phases of the menstrual
cycle and reported no effect of cycle phase. However, their exercise
protocol did not appear to activate the HPA axis. In fact, the
endocrine responses they reported were similar to those noted for
exercise at 50% O2 max
(24). One study that has reported differential pituitary-adrenal
responses to exercise as a function of menstrual phase was that of
Lavoie et al. (23). They reported higher cortisol concentrations during
the luteal compared with the follicular phase after 90 min of exercise.
However, this finding may reflect the fact that subjects consumed a
carbohydrate-poor diet 24 h before exercise (23). Thus controlling for
exercise intensity and nutritional status is necessary when assessing
pituitary-adrenal responses to exercise across the menstrual cycle.
In summary, most prior investigations report no effect of menstrual cycle phase on the metabolic (2, 21, 26) or hormonal (2, 13, 20) responses to exercise. The results of the present study demonstrate that, with the possible exception of glucose, the metabolic and responses to exercise are not significantly different in the follicular, midcycle, and luteal phases of the menstrual cycle. Future research should replicate the phase effect for glucose and extend the present research by examining glucose and cortisol, as well as AVP and NE, responses to exercise across all three phases of the menstrual cycle. Because glucose mobilization is stimulated by a number of hormonal responses to exercise, including AVP and NE, such a study could examine the possibility that glucose provides a more integrated and sensitive reflection of cyclic-related changes in metabolic responses to exercise.
ACKNOWLEDGEMENTS
The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense, Uniformed Services University of the Health Sciences, or the National Institutes of Health.
FOOTNOTES
Address for reprint requests: P. A. Deuster, Dept. of MIM, USUHS, 4301 Jones Bridge Rd., Bethesda, MD 20814-4799 (E-mail: PDEUSTER{at}USUHS.MIL).
Received 7 October 1996; accepted in final form 14 August 1997.
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