Sex differences in glucocorticoid sensitivity of proinflammatory cytokine production after psychosocial stress.

OBJECTIVE: Men and women show marked differences in susceptibility to disorders related to the immune system. These gender differences have been proposed to be mediated by functional interactions of the hypothalamus-pituitary-adrenal (HPA) and hypothalamus-pituitary-gonadal (HPG) axes. A potential mechanism involved in this interaction is the glucocorticoid (GC) sensitivity of relevant target tissues for GC. Therefore, the aim of the study reported here was to investigate the impact of psychosocial stress and HPA axis activation on the GC sensitivity of proinflammatory cytokine production in men and women. METHODS: A total of 45 healthy subjects were investigated. Eighteen women in the luteal phase of their menstrual cycle and 27 men were exposed to a psychosocial stress test (Trier Social Stress Test). Salivary free cortisol levels were measured repeatedly after exposure to the stressor. GC sensitivity was assessed in vitro by dexamethasone inhibition of lipopolysaccharide-stimulated production of interleukin-6 and tumor necrosis factor-alpha. RESULTS: The stress test induced significant increases in salivary free cortisol with no significant differences between men and women. In contrast, GC sensitivity and lipopolysaccharide-stimulated cytokine production showed large gender differences. In men GC sensitivity was markedly increased 1 hour after stress, whereas GC sensitivity decreased significantly in women. Similarly, lipopolysaccharide-induced cytokine production decreased in response to stress in men but increased in women. CONCLUSIONS: These results demonstrate that despite similar free cortisol responses of men and women (studied in the luteal phase) to psychosocial stress, gender may exert differential effects on the immune system by modulating GC sensitivity of proinflammatory cytokine production.

The relationship between stress induced cortisol levels and memory differs between men and women.

Epidemiological as well as experimental studies in elderly subjects have suggested that postmenopausal women are more susceptible to the memory impairing effects of elevated cortisol levels than elderly men. Little is known however about gender differences in the susceptibility to acute stress in young subjects. In the present study a total of 58 healthy young subjects learned a word list, with recall being tested after a brief distraction task. Twenty-two subjects had to learn the list after exposure to a psychosocial stressor (Trier Social Stress Test: TSST), while the remaining subjects served as controls. Free cortisol was determined via saliva samples taken before and 10 minutes after stress. Subjects exposed to the stressor, did not show impaired memory performance per se when compared to the control group. However the cortisol increase in response to the stressor was negatively correlated (r=-0.43, P<0.05) with the memory performance within the stressed group (i.e., subjects showing a larger cortisol response recalling less words than subjects showing only a small cortisol increase). Additional analysis revealed, that this correlation was solely caused by the strong association observed in men (r=-0.82, P<0.05), while no association was observed in women (r=-0.05, P=ns). Our data suggests, that gender modulates the association between cortisol and memory after stress. Whether these differences reflect activational effects of sex steroids or developmentally-programmed sex differences awaits to be determined.

No evidence for a close relationship between personality traits and circadian cortisol rhythm or a single cortisol stress response.

Personality traits measured with the Eysenck Personality Questionnaire-Revised did not show associations with basal or stimulated concentrations of cortisol in a sample of 81 subjects. Cortisol responses to a single exposure to psychosocial stress as well as circadian salivary-free cortisol patterns did not distinguish between subjects with high or low scores on Extraversion, Neuroticism, or Psychoticism, respectively.

Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis.

OBJECTIVE: Results from animal and human studies suggest that disregulations of the hypothalamus-pituitary-adrenal (HPA) axis are involved in several behavioral, circulatory, endocrine, and immune disorders with clear-cut gender differences in disease prevalence. The aim of the present study was to investigate sex-specific HPA response patterns with a focus on the contribution of gonadal steroids as possible mediators. METHODS: A total of 81 healthy adults were investigated in the present study. Twenty men, 19 women in the follicular phase of the menstrual cycle, 21 women in the luteal phase, and 21 women using oral contraceptives (OC) were exposed to a brief psychosocial stress test (Trier Social Stress Test; TSST) and injected with 0.25 mg ACTH1-24 on consecutive days. Basal HPA activity was investigated by repeatedly measuring cortisol levels immediately after awakening, as well as in 30-minute intervals from 9:00 AM to 9:00 PM. Additionally, questionnaires were used to assess psychological state and trait parameters. RESULTS: Results show that the TSST induced significant increases in ACTH, salivary-free cortisol, total plasma cortisol, and heart rates, as well as increased wakefulness and reduced calmness in the total group. Significant group differences emerged for ACTH and salivary-free cortisol stress responses: Although men showed higher ACTH responses to the TSST compared with each of the three groups of women, salivary cortisol responses showed the following response pattern: Luteal = Men > Follicular = OC. The salivary cortisol responses to ACTH1-24 showed a similar response pattern: Luteal > Men > Follicular > OC. In contrast, total blood cortisol levels did not reveal any group difference between sexes or follicular versus luteal phase in either test. Although a similar salivary-free cortisol increase after awakening was found in the four groups, the circadian cortisol profile was significantly different throughout the first 4 hours of sampling. Questionnaire-derived psychological variables, as measured in the present study, could not explain the observed results. CONCLUSIONS: We conclude that gender, menstrual cycle phase, and OC use exert important effects on HPA responsiveness to psychosocial stress in healthy subjects. Although men seem to have a stronger hypothalamic drive in response to stressful stimulation than women, differences in salivary-free cortisol levels, at least in part, may be explained by estradiol-induced changes in corticosteroid-binding protein levels. ACTH and cortisol secretion is not affected by OC use per se but the amount of bioavailable unbound cortisol ("free") is greatly reduced in this group of women after stimulation. Inasmuch as none of these differences between the study groups emerged in total blood cortisol levels, we strongly advocate for the simultaneous measurement of free and total cortisol levels in future studies on HPA functioning.

Increasing correlations between personality traits and cortisol stress responses obtained by data aggregation.

Attempts to link personality traits and cortisol stress responses have often been inconclusive. The aim of this paper was to investigate this association by aggregating cortisol stress responses. Therefore, 20 healthy men were exposed to a task consisting of public speaking and mental arithmetics in front of an audience on five days. Six cortisol levels were measured in relation to the stressful task obtained at 10-min intervals on each day. Psychological assessment included the Questionnaire for Competence and Control (FKK) and the Giessen-Test (G-T). These questionnaires focus on assessing personality traits, i.e. locus of control and self-concept. Areas under the response curve (AUC) of the six cortisol samples were computed to obtain an index of the individual's cortisol stress response on each day. Since novelty is a random situational factor likely to mask individual differences in the stress response, the AUC cortisol stress responses of days two to five were consecutively aggregated, excluding the first day. Scales of the two questionnaires employed did not correlate with the AUC cortisol stress response of the first stress trial. The correlation pattern of the AUC cortisol measures of days two to five with the questionnaire scales was inconclusive. However, significant correlations emerged with an increasing number of cortisol stress responses aggregated. Correlations between the measure of social dominance and aggregated AUC cortisol stress responses rose from r = -.47 on day two of the experimental session to r = -.70 after aggregating days two to five. Similarly, measures of locus of control and cortisol stress responses became increasingly correlated with aggregation of several stress exposures. These data provide preliminary evidence for a relationship between questionnaire scales aiming at assessing personality traits and cortisol stress responses uncovered by repeated stress exposure and data aggregation. While novelty may mask the impact of personality on the cortisol stress response on the first exposure, differences in the ability to cope with the stressful situation may lead to different cortisol stress response patterns on subsequent stress exposures. With data aggregation, an association between the trait component of cortisol stress responses and questionnaire scales might be uncovered. For reliable investigation of correlations between personality variables and cortisol stress responses, repeated stress exposure and data aggregation is suggested.

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.