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From the Center for Psychobiological and Psychosomatic Research, University of Trier, Germany.
Address reprint requests to: Clemens Kirschbaum, PhD, Center for Psychobiological and Psychosomatic Research, University of Trier, Dietrichstr. 10–11, 54290 Trier, Germany. E-mail: Kirschba{at}uni-trier.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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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.
Key Words: psychosocial stress, • HPA axis, • sex differences, • menstrual cycle, • oral contraceptives, • salivary cortisol, • TSST, • CBG.
Abbreviations: ACTH = adrenocorticotropic hormone;; ANOVA = analysis of variance;; AUC = area under curve;; BDI = Beck Depression Inventory,; BMI = body mass index;; CBG = corticosteroid-binding globulin;; CRF = corticotropin-releasing hormone;; CNS = central nervous system;; DHEA = dehydroepiandrosterone;; FBL = Freiburger Beschwerde Liste;; HPA = hypothalamus-pituitary-adrenal axis;; MANOVA = multivariate analysis of variance; MDBF = Mehrdimensionaler Befindlichkeitsfragebogen;; OC = oral contraceptive;; RIA = radioimmunoassay;; TSST = Trier social stress test;; VAS = visual analog scale.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Among the multitude of factors contributing to individual differences in HPA activity, a complex sexual dimorphism seems to exist. Evidence from animal as well as human studies suggests that there are marked differences in HPA response patterns between males and females. Whereas in rodents, basal ACTH and corticosterone levels, as well as responses to various stimuli, are uniformly greater in females (12, 13), the picture is more complex in humans. Men seem to secrete more ACTH than women with comparable total cortisol levels under basal conditions, which suggests an increased sensitivity of the female adrenal cortex (14). At the pituitary level, no gender differences are observed after injection of synthetic human corticotropin-releasing factor (h-CRF) with or without pretreatment with dexamethasone (15–17). However, women may be more responsive to ovine CRF (18) or to a combination of h-CRF and vasopressin with respect to ACTH secretion (17). At a suprapituitary level, consistent gender differences in the HPA response to psychosocial stress have been observed in our laboratory. Concerning similar subjective or emotional responses, men always showed enhanced salivary (ie, unbound or "free") cortisol responses to a public speaking and mental arithmetic task in many studies (eg, 15, 19, 20). However, neither ACTH nor total blood cortisol levels have been measured in these studies, which would have allowed a more detailed localization of the observed sexual dimorphism.
Gonadal steroids, especially estradiol, seem to exert a substantial influence on the reactivity of the HPA axis responsiveness in rodents as well as in humans. Animal studies show that ovariectomy leads to attenuated HPA responses, whereas estradiol substitution induces HPA stimulation (21–23). Similarly, a short-term estradiol treatment leads to an enhanced ACTH and cortisol stress response in healthy young men (24) and a 2-week treatment with DHEA, a sex steroid precursor, increases the ACTH stress response in elderly postmenopausal women (25).
Pronounced changes in estradiol levels occur over the course of the menstrual cycle with low levels in the early follicular phase, which peak shortly before or during ovulation and slowly decrease throughout the luteal phase. Studies investigating HPA functions with respect to the menstrual cycle found that basal as well as stimulated ACTH and corticosterone levels are highest around the time of ovulation in the rat (26, 27). In contrast, human studies have produced inconsistent results with respect to possible changes of HPA (re)activity over the menstrual cycle (28–31).
Another consistent finding is rather puzzling and calls for explanation: women using ethinyl-estradiol-containing oral contraceptives (OC user) were found repeatedly to show blunted free cortisol responses to psychosocial or physical stress (32–33). It is unknown whether the lower free cortisol responses reflect a hyporeactive HPA axis in these women. Alternatively, OC users may secrete similar amounts of cortisol, but due to the increased production of CBG induced by OC medication, the biologically active free cortisol fraction is largely reduced.
The aim of the present study, therefore, was to investigate pituitary and adrenal responses to a potent psychosocial laboratory stress protocol (the TSST) (34) in different phases of the menstrual cycle. These endocrine, heart rate, and subjective responses were compared with OC users and men, respectively. In addition, a Synacthen (ACTH1–24) test was performed to measure the capacity of the adrenal cortex in the experimental groups. Moreover, basal HPA activity was investigated with salivary-free cortisol levels after wakening in the morning and a 12-hour salivary-free cortisol profile.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Before entering the study, all subjects provided written consent and underwent a comprehensive medical examination for past and current health problems. Smokers, subjects suffering from allergies, women with irregular menstrual cycles, or using multiphasic contraceptives were excluded. The study protocol was approved by the ethics committee of the University of Trier. Table 1 shows the number of subjects, mean age, BMI, sex steroid, and CBG levels for the four experimental groups.
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For assessment of basal free cortisol levels, participants collected saliva samples on the morning of day 2. Immediately after waking up and 15, 30, 45, and 60 minutes thereafter, saliva samples were obtained to measure the individual cortisol response to awakening. Recently, this laboratory has reported that salivary-free cortisol levels increase 50% to 150% within the first 30 minutes after waking up in the morning, independent of sleep duration, time of day, or other variables (35). Moreover, all subjects collected saliva from 9:00 AM to 9:00 PM at 30-minute intervals in their natural environment for assessment of the daytime circadian rhythm. The subjects were free to choose a day for collection of the circadian profile after completion of all laboratory tests. Accuracy of ambulatory saliva collection was not validated, but relied on the compliance of the subjects.
Psychological Assessment
Four psychological questionnaires were used to measure depression, physical complaints, mood changes, and perceived stressfulness of the TSST:
The Depression Inventory and the FBL were administered at baseline, mood was assessed before and after the stress task, and the VAS was applied only after the stress test.
Biochemical Analyses
Basal blood samples were used to measure estradiol (RIA; Biermann, Bad Nauheim, Germany), progesterone (RIA; IBL, Hamburg, Germany), and CBG (IBL, Hamburg, Germany). Salivary-free cortisol concentration in saliva was measured using a time-resolved immunoassay with fluorometric detection, as described in detail elsewhere (40). Total plasma cortisol was measured with a radioimmunoassay (RIA; IBL, Hamburg, Germany). ACTH was determined with a two-site chemiluminescence assay (Nichols Institute, Bad Nauheim, Germany). Interassay and intraassay coefficients of variance were below 12% and 10%, respectively, for all analyses.
Heart Rate
Heart rates were measured continuously at 1-minute intervals with ECG precision using wireless transmission (Sport Tester Profi, Polar Instruments, Gross-Gerau, Germany). Heart rate responses were computed from 7 minutes before stress exposure to 9 minutes after cessation of stress.
Statistical Analyses
ANOVAs for repeated measures were computed to analyze endocrine and heart rate responses to the stressor. To control for different baseline levels, hormone samples obtained directly before the stress exposure were treated as covariates. All reported results were corrected by the Greenhouse-Geisser procedure where appropriate. Newman-Keuls post hoc tests were applied for significant effects. Correlations were computed by Pearson product-moment correlations. Psychological parameters were analyzed by ANOVAs. Furthermore, factor analyses (principal component, varimax oblique) and reliability analyses were used to create the scale "stressfulness" based on items of the VAS. For all analyses, the significance level was 
= 5%. For multiple comparisons the nominal level was adjusted by Bonferroni correction. All results shown are means ± SEM.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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The psychosocial stress protocol caused significant endocrine, cardiovascular, and psychological responses. In the total group, ACTH, salivary-free cortisol, and total plasma cortisol increased significantly with 60% to 100% changes from baseline values. ACTH concentrations peaked 1 minute after cessation of the TSST with continuously decreasing hormone concentrations thereafter (ACTH: F = 48.28; p < .0001). Cortisol levels were highest 10 minutes after cessation of stress (salivary-free cortisol: F = 32.90; p < .0001; total plasma cortisol: F = 47.78; p < .0001). Maximum heart rate responses were observed between 6 and 13 minutes of stress exposure (F = 29.0; p < .0001). Correlations between ACTH and cortisol stress responses (expressed as areas under the response curves) were significant with r = .57 for total plasma cortisol (p < .001) and r = .53 for salivary-free cortisol (p < .001). Total plasma cortisol and salivary-free cortisol showed a correlation of r = .62 (p < .001).
MANOVAs revealed significant response differences between groups for ACTH stress responses (F = 2.52: p = .05; Figure 1) and salivary-free cortisol (F = 2.96; p = .007). Newman-Keuls post hoc tests confirmed that men showed significantly larger ACTH responses than women in the follicular phase at 1 and 10 minutes after stress exposure (both p values < .004) and at 1, 10, and 20 minutes after stress than both OC users and women in the luteal phase (all p values < .01). Concerning cortisol responsiveness, men had significantly higher salivary-free cortisol reactions than women in the follicular phase (all p values < .03) 10, 20, and 30 minutes after cessation of stress, and higher than OC users 1, 10, 20 and 30 after stress (all p values < .025). No differences in saliva cortisol emerged between men and women in the luteal phase (all not significant). Furthermore, women in the luteal phase showed higher salivary-free cortisol responses compared with women in the follicular phase 10 minutes after cessation of stress (p = .016) and higher saliva free cortisol concentrations than OC users 10 and 20 minutes after stress (both p values < .002). Women in the follicular phase and OC users did not differ in their salivary-free cortisol responses. Concerning total plasma cortisol, we only found significantly increased hormone concentrations 1 minute before stress in OC users compared with the other groups (F = 5.38; p < .002). No differences between groups emerged in total cortisol response patterns (F < 1). Likewise, heart rate responses did not differ among groups (F < 1).
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Analyses of the multidimensional mood scale, MDBF, revealed that stress exposure did not generally worsen mood (F = 1.99; p < .16), but significantly increased wakefulness (F = 8.35; p < .005) and reduced calmness (F = 8.83; p < .004) in the total group. No group differences in any of the three scales were observed.
The participants’ ratings of the stressfulness of the TSST were measured by six VASs. A factor analysis clustered the items to the factor "perceived stressfulness." Reliability of the resulting factor was = .65 (Cronbach’s ). No differences emerged among groups, neither by comparing the clustered factor nor by comparing the single items. Also no group differences were found in any of the five scales of the questionnaire on physical complaints (FBL). Comparing sexes, women in general reported more strain than men (scale 3: F = 6.73; p < .011). However, after adjustment of nominal level by Bonferroni correction for multiple comparisons, this result could be considered as a trend only.
Referring to basal HPA activity in their natural environment, the four groups did not show a clear-cut difference in salivary-free cortisol profiles after awakening (F = 1.33; p > .22). There was only a trend toward higher morning cortisol levels in women in the luteal phase (F = 2.70; p < .07) when the area under the response curve was compared. In 12-hour salivary-free cortisol profiles, ANOVA results indicated a small but statistically significant difference (F = 1.61; p > .044). However, the cortisol levels showed a rather inconclusive picture (Figure 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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The results demonstrate that, whereas gender differences or changes in HPA functioning over the course of the menstrual cycle are barely reflected in basal parameters, they are rather prominent when the system is activated by a potent psychosocial stressor. Although two studies reported cyclic variations of basal ACTH levels throughout the menstrual cycle (41, 42), no differences in prestress ACTH concentrations were observed in the present study. This difference can be explained by the timing of blood sampling: Whereas in the previous studies samples were obtained early in the morning or values collapsed over a 12-hour period (41, 42), we measured baseline ACTH levels in the late afternoon hours only. Like ACTH, basal cortisol levels before stimulation or immediately after awakening in the morning did not seem to show cyclic variation as measured in the follicular versus luteal phase, this observation agrees with several previous reports (42–44). There are only small, if any, differences in the circadian rhythm (9:00 AM-11:00 AM) between these subgroups.
In contrast to the findings of basal HPA activity, exposure to psychosocial stress resulted in different endocrine response profiles: Men showed larger ACTH increases compared with all three groups of women, lending support to the idea of an enhanced hypothalamic drive in men (45). It seems rather unlikely that differences in pituitary sensitivity to CRF are responsible for this result, inasmuch as challenge tests with human CRF result in similar ACTH responses in men and women in the same age group (16, 17).
Interestingly, the stress-induced cortisol patterns deviated to some degree from the ACTH picture: Men and women in the luteal phase had the largest salivary-free cortisol responses, which were clearly enhanced compared with women in the follicular phase. This was actually the first time that we have observed similar salivary-free cortisol responses to psychosocial stress in men and (one group of) women. In contrast to the biologically active free hormone fraction, total blood cortisol levels masked these differences with similar levels in the three groups (for discussion of the OC results, see below). This supports findings that suggest that the female adrenal cortex may be more sensitive to ACTH (45, 46) with no apparent change of net cortisol secretion in follicular versus luteal phases. The capacity of the female adrenal cortex to synthesize and secrete cortisol in response to maximal stimulation, however, is similar to men, as shown in the Synacthen test. However, women in the luteal phase clearly have higher circulating salivary-free cortisol levels after ACTH1–24 stimulation. These findings agree with a previous report (47).
The consistent differences between salivary-free and total plasma cortisol levels in response to psychosocial stress and synthetic ACTH1–24 in the present study may explain discrepant results on gender response differences described in the literature. The measurement of total cortisol levels only suggest that there is a similar cortisol response in the sense of cortisol secretion in men and women. However, this research strategy might miss a biologically important message: There seems to be a significant gender and menstrual cycle phase difference in the availability of free cortisol (ie, biologically active steroid). In our view, these results call for simultaneous measurement of free and total cortisol levels whenever feasible. Only this enables the investigator to relate hyporesponsive versus hyperresponsive patterns to differences in cortisol production or tissue availability of the endocrine signal. Whether the target tissue counterregulates intracellular signal cascades in response to a changing free glucocorticoid signal in vivo is completely unknown.
We have previously reported that women using oral contraceptives show blunted salivary-free cortisol responses to physical and psychosocial stress (32, 33) and suggested that this was due to the well-documented CBG-enhancing effect of ethinyl-estradiol (43, 48, 49). The present results strengthen this hypothesis: OC users can produce and secrete similar amounts of ACTH and total plasma cortisol in response to psychosocial stress and ACTH1–24; however, the salivary-free cortisol levels were clearly lower under both conditions. The notion that higher CBG levels may lead to lower salivary-free cortisol responses is supported by the negative correlations between cortisol and CBG. Although this might help to explain the group difference in saliva free cortisol levels, the observed gender difference in ACTH stress responsiveness without apparent influence of the menstrual cycle or OC use requires additional regulatory factors. Likely candidates are obviously gonadal steroids. Among them, estradiol is known to exert a strong stimulatory influence on the axis in several animal species (22, 23, 27, 50–52) with important modulatory effects on mineralocorticoid and glucocorticoid receptors (26, 53–56). Moreover, estradiol may directly enhance CRF gene transcription in the hypothalamus through binding to estrogen responsive elements on the CRF gene (57). But why should men have a stronger estrogen-driven CRF signal (as indicated by larger ACTH baselines and response levels), given that women usually produce significantly more estradiol over the course of the menstrual cycle than men? What seems to be a paradox may be explained by the metabolism of sex steroids in the brain. Most, but not all, CNS effects of testosterone are, in fact, estradiol-induced. In several tissues, it has been shown that testosterone must be aromatized to estradiol to modulate brain processes (58–63). Thus, the relative abundance of free testosterone in men favors a stronger stimulation of hypothalamic or hippocampal structures after conversion into estradiol compared with women.
Although estradiol seems to be the best candidate for explaining the different HPA responses observed in this study, changes in progesterone levels also might have contributed to these findings. Data on the impact of progestins on the HPA axis in humans are sparse; however, the available results do not suggest a significant mediation of ACTH and cortisol stress responses (64, 65).
The present results raise a number of questions concerning the consequences of high/low HPA activity. Are subjects who vigorously respond to psychosocial stress in the laboratory more susceptible or more resilient with respect to health outcome measures? Are lower free cortisol levels in the follicular phase or in OC users prospectively associated with an increased number of physical complaints? Or does their organism adapt to this endocrine situation by increasing intracellular responses to a given cortisol signal by, eg, upregulation of receptors or transcription factors? Future psychobiological studies most probably will include the intracellular components of the HPA axis signal cascade in order to understand in more detail how this multilevel regulated endocrine system helps the individual to fight off diseases and remain healthy, despite ever-changing environmental strains and demands.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Received for publication May 5, 1998.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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-OH-progesterone, and androgen response to a standardized ACTH-stimulation in different stages of the normal menstrual cycle. Acta Endocrinol 1982; 100: 427–33.
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