Genetic factors, perceived chronic stress, and the free cortisol response to awakening.

Recent studies have demonstrated that the free cortisol response to awakening can serve as a useful index of hypothalamus-pituitary-adrenal axis (HPA) activity. This endocrine marker is rather consistent, shows good intraindividual stability across time and appears to be able to uncover subtle changes in HPA regulation. The present twin study investigated genetic factors as sources of the interindividual variation of the cortisol awakening response. Furthermore, the relationship between psychological variables and morning cortisol levels was studied. On two consecutive days saliva samples were collected 0, 30, 45 and 60 minutes after awakening in 52 monozygotic and 52 dizygotic twin pairs. Moreover, samples were obtained at 0800, 1100, 1500 and 2000 h. ('short day-time profile'). Additionally, the participants filled out questionnaires assessing chronic stress load, self-esteem and self-efficacy.Heritability estimates of h(2)=0.40 for the mean increase and of h(2)=0.48 for the area under the response curve indicate a significant impact of genetic factors on cortisol levels after awakening. However, no genetic influence on the short day-time profile could be observed. Furthermore, several aspects of perceived chronic stress, namely 'worries', 'social stress' and 'lack of social recognition' were significantly associated with the awakening cortisol response. The evidence for a medium-sized, yet distinct genetic influence on cortisol levels after awakening is discussed with regard to a potential clinical relevance of genetic determinants of HPA (re)activity. In line with several recent studies, the present findings further support the view that the cortisol awakening responses is consistently enhanced under chronic stress conditions.

The cortisol response to awakening in relation to different challenge tests and a 12-hour cortisol rhythm.

Recent studies have shown that cortisol levels rapidly increase within the first 30 minutes after awakening. This response is rather robust over weeks or months and is altered by chronic stress and burnout. The present study investigated to what extent the cortisol response to awakening relates to responses following hCRH, ACTH(1-24), or psychosocial stress challenges in 22 healthy subjects. Furthermore, a 12-hour circadian cortisol profile was obtained to compare the morning response with cortisol levels obtained throughout the day. Results show that the morning cortisol response was of similar magnitude to that following injection of 1 microg/kg h-CRH or exposure to a brief psychosocial stressor (TSST). All of these were significantly smaller compared to maximal stimulation of the adrenal cortex by ACTH(1-24). Correlation analyses revealed that the morning cortisol response was closely related only to the cortisol response following 0.25 mg ACTH(1-24) (r=0.63, p=0.002). We conclude that the morning cortisol response to awakening can provide important information on the (re)activity of the HPA axis in addition to more 'traditional' methods like hCRH or Synacthen challenge tests. The sensitivity/capacity of the adrenal cortex appears to play a crucial role for the magnitude of cortisol responses observed after awakening.

Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men.

Evidence from animal studies and clinical observations suggest that the activity of the pituitary-adrenal axis is under significant influence of sex steroids. The present study investigated how a short term elevation of estradiol levels affects ACTH, cortisol, norepinephrine, and heart rate responses to mental stress in healthy men. In a double blind study, 16 men received a patch delivering 0.1 mg estradiol/day transdermally, and age- and body mass index-matched control subjects received a placebo patch. Twenty-four to 48 h later, they were exposed to a brief psychosocial stressor (free speech and mental arithmetic in front of an audience). In response to the psychosocial stressor, ACTH, cortisol, norepinephrine, and heart rate were increased in both experimental groups (all P < 0.0001). However, the estradiol-treated subjects showed exaggerated peak ACTH (P < 0.001) and cortisol (P < 0.002) responses compared to the placebo group. Also, the norepinephrine area under the response curve was greater in the estradiol group (P < 0.05). Although heart rate responses differences failed to reach statistical significance, they, too, tended to be larger in the estradiol group. Neither mood ratings before or after the stressor, nor ratings of the perception of the stressor could explain the observed endocrine response differences. In conclusion, short term estradiol administration resulted in hyperresponses of the pituitary-adrenal axis and norepinephrine to psychosocial stress in healthy young men independent of psychological effects, as assessed in this study.

Persistent high cortisol responses to repeated psychological stress in a subpopulation of healthy men.

The present study tested the hypothesis that some subjects may not readily show habituation of adrenocortical stress responses to repeated psychological stress. Twenty healthy male subjects were each exposed five times to the same, brief psychosocial stressor (public speaking and mental arithmetic in front of an audience) with one stress session per day. Salivary cortisol levels were assessed as an index of adrenocortical stress responses. For the total group, cortisol levels were significantly elevated on each of the 5 days. The mean response decreased from day 1 to day 2; however, no further attenuation could be observed on the remaining days. Cluster analysis revealed two groups of subjects who showed completely different response kinetics. In the first group (N = 13), termed "low responders," cortisol levels were elevated on day 1 only. Day 2 to 5 cortisol levels were unaltered. In contrast, subjects in the second group ("high responders") displayed large increases to each of the five experimental treatments. This group had no significant response decrement from day 1 to day 2 to 4 and only a marginal response difference between day 1 and day 5. Discriminant analysis revealed that a combination of five personality scales plus the scores on a symptoms checklist significantly discriminated between high and low responders. With this discriminant function, all 20 subjects were correctly classified to the two groups. These results are discussed with a focus on the possible impact of adrenocortical response types on health and disease.