Genetic factors, perceived chronic stress, and the free cortisol response to awakening
Introduction
The availability of appropriate markers of hypothalamus–pituitary–adrenal axis (HPA) activity can be regarded as a substantial prerequisite for clinical or basic science studies of this neuroendocrine system. Frequently, single blood or saliva samples for analysis of total or free cortisol are collected at a predefined time 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 (Coste et al., 1994, Schulz and Knabe, 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.
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 which provides 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 this response was found to be independent of the time of awakening, sleep duration, sleep quality, physical activity, or morning routines (Pruessner et al., 1997, Schulz et al., 1998, Schmidt-Reinwald et al., 1999, Wüst et al., 2000). Furthermore, although the cortisol awakening response was shown to be altered in subjects who were woken earlier than they expected (Born et al., 1999), in a large cohort the free cortisol response did not differ between subjects who either woke up spontaneously or used an alarm clock (Wüst et al., 2000).
However, a number of factors influence the response magnitude and time course including gender, use of oral contraceptives, persisting pain, burnout or chronic stress (Geiß et al., 1997, Pruessner et al., 1997, Schulz et al., 1998, Pruessner et al., 1999). Moreover, this HPA index is significantly correlated with the adrenocortical response to ACTH1–24 (Schmidt-Reinwald et al., 1999) and with the decrease of secretory immunoglobulin A after awakening (Hucklebridge et al., 1998). The relatively high intraindividual stability of the free cortisol awakening response (mean correlation of r=0.55 across studies) justifies the hypothesis that it can, in part, be regarded as a person trait, which, in turn may be influenced by genetic factors.
Although twin studies constitute a powerful method for identifying genetic influences on human physiological variables, only few attempts were previously made to estimate the impact of genetic factors on the regulation of cortisol levels. While Maxwell et al. (1969) observed a higher resemblance of unstimulated plasma cortisol levels in monozygotic (MZ) twin pairs compared to dizygotic (DZ) twin pairs only in female subjects, Meikle et al. (1988) found evidence for a moderate genetic impact on basal cortisol levels also in male twin pairs. Moreover, some aspects of the 24-h plasma cortisol profile were reported to be affected by genetic factors (Linkowski et al., 1993) while a decided genetic influence on the cortisol response to hCRH and, to a lower degree, to psychosocial stress has been observed by this laboratory (Kirschbaum et al., 1992).
Taking advantage of the unique genetic relationship among twins, the present study investigated genetic factors as potential sources of the large interindividual variation of the free cortisol response to awakening. In addition, the relationship between several psychological variables and early morning cortisol levels was studied.
Section snippets
Subjects
All twin pairs in the age range 8–65 yrs listed in the residents registration office of the city of Trier were contacted by mail and invited to participate in the study. A total of 104 pairs with a mean age of 19.6 yrs (8–64 yrs) signed up. As confirmed by later DNA fingerprint analysis (see below), this group comprised 52 monozygotic (MZ) and 52 dizygotic (DZ) pairs. The MZ group consisted of 62 females and 42 males, while in the DZ group 52 females and 52 males were investigated. The latter
Results
Corresponding with earlier findings, a significant increase of salivary cortisol levels after awakening could be observed with a F-value of 58.97 for the main effect of awakening (P<0.0001). Within the first 30 minutes, cortisol levels showed a 38.5% (i.e. 4.47 nmol/l) mean elevation and then started to decrease. The effect size for the cortisol response was f2=0.22, explaining 18% of the variation of cortisol levels during the first hour after awakening. The short day-time cortisol profile
Discussion
Several studies could demonstrate that the free cortisol response to awakening can serve as a useful index, which is rather consistent, shows good intraindividual stability across time and appears to be able to uncover subtle changes in HPA activity (Geiß et al., 1997, Pruessner et al., 1997, Hucklebridge et al., 1998, Schulz et al., 1998, Pruessner et al., 1999, Schmidt-Reinwald et al., 1999).
To these findings, the present study adds strong evidence for a significant genetic influence on the
Acknowledgements
We are indebted to Prof. Rittner and Dr. Schneider, University of Mainz, for their invaluable support in zygosity testing in this study.
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