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The cortisol awakening response - normal values
and confounds
Stefan Wüst
1
, Jutta Wolf
1
, Dirk H. Hellhammer
1
, Ilona Federenko
1
,
Nicole Schommer
1
, and Clemens Kirschbaum
2
1
Center for Psychobiological and Psychosomatic Research, University of Trier, Germany
2
Institute of Physiological Psychology II, University of Duesseldorf, Germany
In several recent investigations it could be demonstrated that the free cortisol response to
awakening can serve as an useful index of the adrenocortical activity. When measured with
strict reference to the time of awakening the assessment of this endocrine response is able to
uncover subtle changes in hypothalamus-pituitary-adrenal (HPA) axis activity, which are, for
instance, related to persisting pain, burnout and chronic stress. Furthermore, it has been
suggested that the HPA axis might serve as an indicator of allostatic load in subjects exposed
to prolonged environmental noise. In the present paper four separate studies with a total of 509
adult subjects were combined in order to provide reliable information on normal values for the
free cortisol response to awakening. Corresponding with earlier findings, a mean cortisol
increase of about 50% within the first 30 minutes after awakening was observed. The
intraindividual stability over time was shown to be remarkably high with correlations up to
r=.63 (for the area under the response curve). Furthermore, the cortisol rise after awakening
is rather consistent, with responder rates of about 75%. Gender significantly influenced early
morning free cortisol levels. Although women showed a virtually identical cortisol increase
after awakening compared to men, a significantly delayed decrease was observed. Confirming
and extending previous findings, the present study strongly suggests that neither age, nor the
use of oral contraceptives, habitual smoking, time of awakening, sleep duration or using / not
using an alarm clock have a considerable impact on free cortisol levels after awakening. The
cortisol awakening response can be assessed under a wide variety of clinical and field settings,
since it is non-invasive, inexpensive and easy-to-employ. The present data provide normal
values and information on potential confounds which should facilitate investigations into the
endocrine consequences of prolonged exposure to environmental noise.
Keywords: Hypothalamus-pituitary-adrenal axis, cortisol awakening response, saliva
Introduction
Anticipation and exposure to psychological or
physical stress frequently causes an activation of
the hypothalamus-pituitary-adrenal (HPA) axis.
Elevated CRH, ACTH and cortisol levels during
stress are interpreted as allostatic (McEwen,
1998) or homeostatic (Munck et al., 1984)
responses of the body. Chronic dysregulation of
HPA activity seems to be associated with the
onset and course of psychosomatic and
psychiatric disorders. For instance, HPA
hyperactivity was observed in major depression
(Carroll et al., 1976, Holsboer et al., 1994, Staner
et al., 1994, Pitts et al., 1995) and furthermore
seems to be associated with susceptibility to
infectious (Mason, 1991) and cardiovascular
diseases (McEwen, 1998). On the other hand,
HPA hyporeactivity was reported to be related to
Noise & Health 2000; 7, 77-85
autoimmune processes, such as lupus
erythematosus (Weiner, 1991), multiple sclerosis
(Adams and Victor, 1989), or neurodermitis
(Schnyder, 1960, Buske-Kirschbaum et al.,
1997). Moreover, with respect to the allostasis
concept it was recently suggested that the HPA
axis might serve as a read-out system for the
sequelae of a prolonged exposure to
environmental noise (Kirschbaum and
Hellhammer, 1999).
Clinical or basic research on this neuroendocrine
system depends on the availability of appropriate
markers since HPA activity is characterised by
large interindividual differences (Mason, 1968).
Frequently, single blood or saliva samples for
analysis of total or free cortisol are collected
time-locked in the early morning hours and the
resulting hormone value is interpreted as an
index of unstimulated HPA activity (Gray et al.,
1991, Vasankari et al., 1993, Walker et al., 1997).
Although easy to assess, this index has a number
of weaknesses. Single basal cortisol values
measured during this time period are reported to
have a rather low intraindividual stability
(Schulz and Knabe, 1994, Coste et al., 1994).
Moreover, they show large interindividual
variation with a significant overlap between
healthy individuals and patients with adrenal
insufficiency or Cushing's disease (Laudat et al.,
1988). Along with other factors these limitations
may explain why significant and consistent
correlations between single basal cortisol values
and psychological variables, e.g. personality
measures, cannot be expected. A more reliable
index of unstimulated HPA activity is, for
instance, a day-time cortisol profile. However,
the assessment of this measure requires the
collection of numerous saliva or blood samples
over a long period of time. This relatively
expensive and time-consuming method is of only
limited use in studies with large cohorts, e.g. in
epidemiological investigations.
Recently, it has been reported that cortisol levels
rapidly increase after awakening (Späth-
Schwalbe et al., 1992, Linkowski et al., 1993,
Van Cauter et al., 1994). Studies from this and
other laboratories suggest that repeated
assessment of the awakening cortisol response
can serve as a more useful index of
adrenocortical activity. It can provide important
information on the (re)activity of the HPA axis in
addition to challenge tests like stimulation with
hCRH or ACTH
1-24
. Within the first 30 minutes
after awakening, free cortisol levels rise by 50-
60 % and remain elevated for at least 60 minutes
(Pruessner et al., 1997, Schulz et al., 1998,
Schmidt-Reinwald et al., 1999). This response
was found to be independent of the time of
awakening, total time slept, sleep quality,
physical activity, or morning routines.
Furthermore, the free cortisol response to
awakening appears to be able to uncover subtle
changes in HPA activity. The response
magnitude and time course was shown to be
significantly influenced by gender, persisting
pain, burnout and chronic stress (Geiß et al.,
1997, Pruessner et al., 1997, Pruessner et al.,
1999, Schulz et al., 1998). In a recent study a
further significant impact of genetic factors as
well as birth weight and duration of pregnancy
on the cortisol awakening response could be
observed (unpublished data). Moreover, this
HPA index is significantly correlated with the
adrenocortical response to ACTH
1-24
(Schmidt-
Reinwald et al., 1999) and with a decrease of
secretory immunoglobulin A after awakening
(Hucklebridge et al., 1998). Early morning free
cortisol levels, measured with strict reference to
the time of awakening, are easy and inexpensive
to assess, consistent and show relatively good
intraindividual stability across days and weeks.
Based on these encouraging findings the present
paper aims to provide normal values and other
basic methodological information on the free
78
cortisol response to awakening for researchers
who are interested in employing this novel index
of adrenocortical activity.
Methods
Subjects and geral experimental outline
In four independent studies a total of 509 adult
subjects with a mean age of 37.3 yrs. (18-71 yrs.,
SD=13.63) was investigated for early morning
free cortisol levels after awakening. The group
consisted of 319 females and 190 males and all
subjects reported to be in good health. Twenty-
three percent of the participants were smokers
and 28.8% of the female subjects used oral
contraceptives (OC). In one of the four studies
(n=81) smokers as well as OC users were
excluded. Moreover, on days of saliva sampling,
a state questionnaire provided information on
time of going to bed, total time slept, time of
awakening, physical activity and self reports of
health status and acute stress. Subjects
completed the questionnaires at home and
returned them to the laboratory along with the
saliva samples.
Saliva collection
Early morning salivary cortisol levels were
assessed at home on two consecutive days.
Using the Salivette sampling device (Sarstedt,
Rommelsdorf, Germany), subjects obtained
saliva samples 0, 30, 45 and 60 minutes after
awakening, on each day. Subjects were
instructed not to brush their teeth before
completing saliva sampling to avoid
contamination of saliva with blood caused by
micro-injuries in the oral cavity. Food intake 10
minutes before saliva sampling as well as
smoking during the sampling period was not
allowed. Besides these restrictions, subjects
were free to follow their normal daily routines on
the sampling days. Subjects stored the saliva
samples in their freezers until completing the
experimental protocol and then returned the
samples to the laboratory.
Cortisol analysis
Salivary cortisol was analysed with a time-
resolved immunoassay with fluorescence
detection (DELFIA) as described in detail
elsewhere (Dressendörfer et al., 1992). Intra- and
79
Minutes after Awakening
0304560
Cortisol (nmol/l)
0
14
16
18
20
22
24
26
Day 1
Day 2
Figure 1. Mean salivary cortisol levels (SE) after morning awakening on two consecutive sampling days
(n=509)
interassay variability of the assay was less than
10 and 12 percent, respectively.
Statistical analysis
Three-way analyses of variance (ANOVAs) with
repeated measures (group by day by time) were
computed to test for possible effects of several
variables (e.g. sex, OC use, smoking) on the free
cortisol response to awakening. Adjustments of
degrees of freedom were employed according to
Greenhouse-Geisser where appropriate and
effect sizes were computed when ANOVA
procedures revealed significant results. In order
to receive indices for the cortisol response to
awakening, areas under the curve (AUC) as well
as ‘mean increases’ (MnInc: (Awakening
cortisol
30min
+AC
45
+AC
60
)/3-AC
0
) were
calculated. Pearson correlations were computed
between cortisol levels across the two sampling
days in order to assess the stability of the cortisol
awakening response over time. Furthermore,
Pearson correlations were calculated between
AUC as well as MnInc values and the subjects'
age, total hours slept and awakening time.
Results
Corresponding with earlier findings, a
significant increase of salivary cortisol levels
after awakening could be observed (F=223.08,
p<.0001). The effect size for the cortisol
response was f²=.33, explaining 25% of the
variation of cortisol levels during the first hour
after awakening. (Figure 1).
The mean cortisol levels as well as mean AUC
and MnInc values across the two sampling days
are shown in Table 1. Within the first 30 minutes,
cortisol levels rose by approximately. 50% (7.84
80
Mean
(nmol/l)
SD Minimum
(nmol/l)
Maximum
(nmol/l)
r
day1 x day2
*
AC
0 min
15.12 6.25 1.35 44.78 0.37
AC
30 min
22.95 9.13 1.00 60.30 0.51
AC
45 min
22.31 9.33 0.80 74.25 0.62
AC
60 min
20.23 8.89 1.14 67.49 0.66
MnInc
6.77 8.25 -24.33 43.42 0.47
AUC
(arbitrary units)
1233.41 435.82 62.78 3295.50 0.63
(
AC
”x”min
= cortisol level “x” minutes after awakening,
MnInc
= mean increase
{AC
30
+AC
45
+AC
60
}/3-AC
0
},
AUC
= area under the curve {AC
0
x30+{{AC
30
-
AC
0
}x30}/2}+{AC
30
x15+ {{AC
45
-AC
30
}x15}/2}+{AC
45
x15+{{AC
60
-AC
45
}x15}/2};
*
all correlations p<0.001)
Table 1. Normal values and retest reliability coefficients of salivary cortisol levels (SE) after morning
awakening (n=509)
nmol/l) and started to decrease thereafter,
without reaching baseline levels at the end of the
sampling interval. A mean cortisol increase of
34% was still observed 60 minutes after
awakening. Cortisol levels showed the expected
marked interindividual variation, as indicated by
the large standard deviations as well as the large
differences between minimum and maximum
values.
In order to estimate the consistency of the
cortisol rise after awakening, responder rates
were assessed. A cortisol response was defined
as an increase of salivary cortisol levels of at
least 2.5 nmol/l above individual baseline. This
criterion was chosen according to Weitzman et
al. (Weitzman et al., 1971) who viewed an
increase of at least 55.2 nmol/l in total plasma
cortisol measures as a secretory episode. Since in
saliva only about two to five percent of total
plasma cortisol levels are found this criterion
appears to be rather strict. According to this
criterion a cortisol response to awakening was
observed in 76.8% of the subjects (mean across
day 1 and 2).
The correlation between AUC values, which
included the basal cortisol levels (AC
0
) and
MnInc values, which indicates the average
change from AC
0
was r=0.52 (p<0.001). In order
to assess the relationship between baseline levels
and the magnitude of the cortisol awakening
rise, a Pearson correlation between AC
0
and
MnInc levels was calculated. The resulting
coefficient of r=-.34 (p<0.001) indicates that
high baseline levels are followed by smaller
cortisol awakening responses. Next, the stability
of the cortisol awakening response was
estimated and the corresponding
intercorrelations (day 1 x day 2) are also shown
in Table 1. The resulting coefficients for MnInc
and AUC were r=0.47 and r=0.63, respectively
(both p<0.001). Thus, the explained variance for
these correlations varied between 22 and 40
percent, indicating a moderate to high stability of
the cortisol awakening response across days.
81
Minutes after Awakening
0304560
Cortisol (nmol/l)
0
14
16
18
20
22
24
26
Men
Women
Figure 2. Mean salivary cortisol levels (SE) after awakening in women (n=390) compared to men
(n=119)
In the present investigation, which included only
adult subjects, no significant impact of age on
free cortisol levels after awakening could be
observed. Correlations between age and AUC
(r=-0.07) as well as MnInc levels (r=0.01) did
virtually not exceed zero (both p>.10).
Corresponding results were obtained with a
median-split (<36 yrs. vs. ≥36 yrs.) and a
subsequent ANOVA. The main effect as well as
the time by age interaction did not reach
statistical significance (both p>0.10).
As previously described (Pruessner et al., 1997)
woman showed significantly larger increases of
early morning free cortisol levels after
awakening compared to men (interaction effect:
F=18.35, p< 0.001; Figure 2). However, the size
of this time by gender effect was rather small
(f²=0.03), thus explaining three percent of
variability in cortisol levels after awakening.
Next, the influence of oral contraceptive (OC)
usage on the cortisol awakening response was
tested and ANOVA did neither reveal a
significant main effect (F=0.78, p>0.10) nor a
significant time by OC interaction (F=2.14,
p>0.05).
In smokers a slightly attenuated cortisol rise after
awakening compared to non-smokers was
observed. However, even though the time by
smoking interaction reached statistical
significance (F=3.22, p<0.05), the corresponding
effect size of f²=0.003 indicates that this effect
explains less than one percent of variability in
early morning cortisol levels and therefore it
appears to be virtually negligible.
An effect of similar magnitude was observed
when the impact of sleep duration on the cortisol
awakening response was tested. On one hand
this variable significantly influenced free
cortisol levels after awakening. The correlation
between sleep duration (mean=7.3 hrs.,
SD=0.99) and MnInc levels was r=-0.16
(p<0.05),suggesting a slightly larger cortisol
awakening response in subjects who reported a
shorter sleep length. And correspondingly,
ANOVA revealed a significant time by sleep
duration interaction after a median-split had
assigned subjects to a 'short sleep' group and a
'long sleep' group, respectively (F=6.89;
p<0.001). But on the other hand, this effect also
can be almost ignored, since it explains less than
one percent of variability in free cortisol levels
after awakening (f²=0.008). Moreover, no
significant correlation between the cortisol
awakening response and the individual
awakening time (mean=7:45 AM, SD=1.06)
could be observed, with correlation coefficients
of r=0.04 (awakening time x MnInc) and r=-0.05
(awakening time x AUC; both
p>0.10),respectively.
In the present study the subjects were free to
wake up either spontaneously or to use an alarm
clock. Therefore, the possible impact of this
difference on the cortisol awakening response
was tested. Combining both sampling days
47.5% of the participants reported that they
woke up spontaneously and 52.5% used an alarm
clock. As tested by ANOVA, neither the
corresponding main effect (F=.06) nor the time
by group interaction (F=1.00) turned out to be
statistically significant (both p>0.10).
Discussion
Appropriate markers of HPA activity, which is
characterised by both large inter- as well as
marked intraindividual variability, are a
substantial prerequisite for research on this
neuroendocrine system. Several recent studies
could demonstrate that the free cortisol response
to awakening can serve as an useful index in
psychobiological studies. The assessment of the
cortisol awakening response is able to uncover
subtle changes in HPA activity, which are, for
instance, related to persisting pain, burnout and
chronic stress (Geiß et al., 1997, Schulz et al.,
1998, Pruessner et al., 1999).
82
In the present paper data from 509 adult subjects
were combined in order to replicate recent
findings and to provide further information on
the free cortisol response to awakening for
researchers who consider to include this index of
adrenocortical activity in future studies.
Summarising the present data, waking up in the
morning is a potent stimulus for the HPA axis.
Corresponding with earlier findings, the
magnitude of the cortisol increase within the first
30 minutes after awakening was about 50 % over
individual baselines (i.e., at the time of
awakening). An important characteristic of this
endocrine response is the observed
intraindividual stability over time, which was
shown to be remarkably high for a basal cortisol
measure. It varied between r=0.47 for the mean
increase and r=0.63 for the area under the curve,
respectively. In addition to the stability across
days reported here, Pruessner et al., (1997) found
correlation coefficients of comparable size even
with a one week interval between sampling days.
This intraindividual stability enhances the
chance of finding consistent relations between
basal HPA activity and psychological variables,
e.g. personality measures or individual stress
load.
Furthermore, the cortisol rise after awakening is
rather consistent, with responder rates of about
77%. The finding that about 23% of the subjects
do not show an increase of cortisol levels after
awakening again documents the above
mentioned marked interindividual variability of
HPA activity. On the other hand, however, one
could speculate that at least in some of the
subjects the missing of a cortisol response is an
artifact. For instance, the observed endocrine
pattern would probably be significantly altered,
if participants awake early in the morning, doze
for a short period of time and fall asleep again
for 30 minutes before they start to collect the
first saliva sample. Nevertheless, preliminary
findings from a study in shift-workers
(unpublished data) suggest that 'real' non-
responders do exist. Although all subjects in this
study used an alarm clock and awoke between
4:00 AM and 5:00 AM, some participants did
not show an cortisol increase after awakening.
In this study only data from adult subjects are
presented, but recent findings from this
laboratory suggest, that the cortisol awakening
response is also useful in children. Pruessner et
al. (1997) reported virtually identical retest
reliability coefficients in a group of 42 children
compared with adults and similar mean AUC
levels in both age groups.
The previous finding that the cortisol awakening
response is a rather robust phenomenon could be
replicated in the present study. The data strongly
suggest that neither age, nor the use of oral
contraceptives, habitual smoking, time of
awakening, total time slept or using / not using
an alarm clock have a considerable impact on
free cortisol levels after awakening. Not being
forced to carefully control these variables can be
regarded as a further advantage of this index..
Concerning the awakening time this conclusion
has to be qualified by mentioning that in all
reported studies the mean awakening time was in
a normal range. Preliminary findings from the
above mentioned study in shift-workers
(unpublished) suggest an enhanced cortisol
awakening response in subjects who awoke
between 4:00 AM and 5:00 AM while a
diminished response was found in participants
who awoke between 11.30 AM and 2.30 PM.
A sex difference was observed in early morning
salivary cortisol levels with woman showing
larger responses compared to men. For the first
30 minutes after awakening, cortisol increases in
woman were similar to those in men. However,
while cortisol concentrations clearly decreased
in men thereafter, women showed a delayed
decrease resulting in larger AUC values
compared to men. This result supports similar
83
findings in a previous study (Pruessner et al.,
1997) suggestive of a rather consistent sex
difference. It should be kept in mind, however,
that only 3% of the total variability in cortisol
levels are explained by the subject´s gender. The
difference in cortisol levels 60 minutes after
awakening between women and men was about
3 nmol/l. Future studies have to clarify whether
or not such differences are of functional
relevance for target tissues. Since large intra- as
well as interindividual variability is a well
known characteristic of HPA (re)activity, it can
generally be assumed that most effects on the
cortisol awakening response are relatively small.
This assumption is consistent with previously
uncovered effects with comparable sizes, for
instance the impact of several aspects of chronic
stress on the cortisol rise after awakening
(Schulz et al., 1998, Wüst et al., unpublished).
In sum, the awakening cortisol response fulfils a
number of important criteria required for the
study of the HPA axis in larger cohorts. With
respect to the impact of environmental noise on
health, a repeated assessment of cortisol
responses to awakening might prove to be a
valuable tool for uncovering even subtle changes
in HPA function resulting from noise exposure.
In our view the morning cortisol rise qualifies as
an easy yet potent method to evaluate the health
consequences of environmental noise in
epidemiological studies.
Correspondence Address
Stefan. Wüst
Center for Psychobiological and Psychosomatic
Research, University of Trier, Dietrichstrasse
10-11, 54290 Trier, Germany.
Phone: +49-651-9758634
Fax: +49-651-9758640
e-mail: wuests@fpp.uni-trier.de
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