Abstract
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.
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 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 ACTH1-24. 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 ACTH1-24 (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 cortisol response to awakening for researchers who are interested in employing this novel index of adrenocortical activity.
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).
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 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.