Cortisol and ACTH responses to psychosocial stress are modulated by corticosteroid binding globulin levels

The hypothalamus-pituitary-adrenal (HPA) axis is vital for an organisms' response to physiological and psychological stress. Cortisol, secreted upon activation of the HPA axis, impacts on physiological systems throughout the organism. Responses to cortisol are influenced and modified by a number of factors, including corticosteroid binding globulin (CBG) levels. A major part of circulating cortisol is bound to CBG and only the unbound fraction is thought to be biologically active. The aim of the present study was to examine the modulating effect of CBG levels on hormonal responses following psychosocial stress in women using oral contraceptives (n=115) and in medication-free men (n=93). In women, CBG levels were negatively associated with ACTH and salivary cortisol and positively with total cortisol levels following the TSST. In men, positive associations were observed between CBG and ACTH and total cortisol levels following the TSST. CBG is an important regulatory element of HPA axis response patterns; therefore, CBG levels have to be taken into account as a potential modifier of ACTH and cortisol responses to psychosocial and pharmacological stimulation. Investigations of the consequences of long-lasting OC intake on the neuroendocrine stress regulation in women might be warranted.     

HPA axis response to a psychological stressor in generalised social phobia

Social phobia may be associated with a dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. In this study we determined HPA axis responsivity to a psychological stressor in patients with social phobia and compared them to healthy controls. Fifteen patients with DSM IV social phobia with a mean score of 77.7 on the Liebowitz Social Anxiety Scale and 15 age and sex matched controls underwent the stressor consisting of mental arithmetic and a short term memory test performed in front of an audience. Plasma levels of cortisol and corticotropin were measured at various intervals throughout the test. Although baseline measures of cortisol did not differ between patients (319.8+/-34.6 nmol/l) and controls (279.5+/-42.7 nmol/l)(t=0.7, df=28, P<0.5) nor did baseline corticotropin values (8.6+/-2.1 pg/ml vs 13.7+/-2.0 pg/ml respectively) (t=-1.8, df=28, P<0.08) this stressor resulted in a significantly greater delta max cortisol response (the difference between baseline values and the maximum increase during the stressor) in patients (167.1+/-23.7 nmol/l) than in controls (106.7+/-16 nmol/l) (t=2.1, df=28, P<0.04). There was no significant difference in delta max corticotropin between groups (patients 8.8+/-2.1 pg/ml vs controls 9.1+/-1.9 pg/ml) (t=-0.08, df=28, P<0.9). This preliminary study indicates that patients with social phobia appear to have a hyper-responsive adrenocortical response to psychological stress.     

Assessment of the hypothalamic-pituitary-adrenal axis over a 24-hour diurnal period and in response to neuroendocrine challenges in women with and without childhood sexual abuse and posttraumatic stress disorder.

BACKGROUND: Preclinical studies showed that early stress results in long-term alterations in the hypothalamic-pituitary-adrenal (HPA) axis. We performed a comprehensive assessment of the HPA axis in women with and without a history of early childhood sexual abuse and posttraumatic stress disorder (PTSD). METHODS: Fifty-two women with and without a history of early childhood sexual abuse and PTSD underwent a comprehensive assessment of the HPA axis, including measurement of cortisol in plasma every 15 min over a 24-hour period and cortisol and corticotropin (ACTH) following corticotropin-releasing factor (CRF) and ACTH challenge. RESULTS: Abused women with PTSD had lower levels of cortisol during the afternoon hours (12:00-8:00 PM) of a 24-hour period compared with non-PTSD women. Their ACTH response to a CRF challenge was blunted compared with nonabused non-PTSD (but not abused non-PTSD) women. There were no differences in cortisol response to CRF and ACTH challenges between the groups. Increased PTSD symptom levels were associated with low afternoon cortisol levels. CONCLUSIONS: These findings suggest that early abuse is associated with increased CRF drive as evidenced by decreased pituitary sensitivity to CRF, whereas in abuse with PTSD there is a specific hypocortisolemia that is most pronounced in the afternoon hours.     

Whites have a more robust hypothalamic-pituitary-adrenal axis response to a psychological stressor than blacks

OBJECTIVE: Differences in the hypothalamic-pituitary-adrenal (HPA) axis response to stress may confer differences in susceptibility to a variety of diseases. We hypothesized that whites would differ from blacks in HPA axis response to a psychological stressor. DESIGN: Healthy subjects aged 18-30 were recruited from Baltimore, Maryland. At initial assessment, they completed psychometric tests measuring anxiety, mood, and personality. Subjects then participated in the Trier Social Stress Test (TSST), which consisted of 10 min of public speaking and mental arithmetic exercises. Subjective anxiety was measured immediately pre- and post-TSST. Race effects on cortisol, adrenocorticotrophin (ACTH), and prolactin responses to the TSST were analyzed by GEE longitudinal analysis methods. The analysis controlled for gender, baseline hormone levels, socioeconomic factors, anxiety, mood, and dimensions of personality. RESULTS: Ninety-eight subjects participated in the TSST. Whites had 36% greater relative mean cortisol response than blacks (95% CI: 10-67%, P=0.004). Whites had significantly higher mean ACTH compared to blacks at 25 min after the start of the TSST (35%, 95% CI: 16-58% greater, P<0.001). There was no difference in prolactin response. Of note, whites and blacks did not differ in subjective anxiety response to the TSST. CONCLUSIONS: In sum, we found that whites have a more robust HPA axis response to the TSST compared with blacks, even after controlling for several socioeconomic and psychological factors. In contrast, we observed no difference in prolactin response. There were no differences in subjective response to the TSST to explain the difference in HPA axis response. Further study is indicated to explain this finding and to test whether it can be extrapolated to other forms of stress.     

Acute HPA axis responses, heart rate, and mood changes to psychosocial stress (TSST) in humans at different times of day

There is evidence showing that HPA axis responses to pharmacological provocation depend on time of day with larger cortisol responses in the afternoon and evening compared to the morning hours. However, it is still unknown whether HPA axis responses to psychological stress are affected by time of day and whether they can be assessed with equal reliability in the morning and afternoon, respectively. The present reanalysis is based on five independent studies conducted in the same laboratory by and. All subjects were confronted with the Trier Social Stress Test (TSST) either in the morning or in the afternoon. The total sample consisted of 180 adults with 115 younger (49 females, 66 males) and 65 older adults (32 females, 33 males). All ANCOVA results controlled for possible age and gender effects. Stress-related free salivary cortisol, total plasma cortisol and ACTH net increases did not differ according to time of day (all p = n.s.). However, as expected pre-stress free salivary and total plasma cortisol levels differed significantly between the morning and afternoon group (both p < 0.005), leading to a significantly higher free cortisol area under the curve (AUC) in the morning (p = 0.02). Taken together, these observations suggest that the adrenal glands may be more sensitive to ACTH in the morning. Additionally, higher basal salivary cortisol levels were related to a lower stress-related net increase in salivary cortisol (p = 0.02), total plasma cortisol (p < 0.0001), and marginally ACTH (p = 0.09). Stress-related heart rate increases did not differ between groups (p = n.s.). The finding that the TSST-induced mood change was differentially affected by time of day requires further exploration. We conclude that comparable HPA axis and heart rate stress responses to psychosocial stress can be measured in the morning and afternoon.     

Effort-reward-imbalance and overcommitment are associated with hypothalamus-pituitary-adrenal (HPA) axis responses to acute psychosocial stress in healthy working schoolteachers

In this study, we examined HPA axis responses to acute psychosocial stress in relation to effort-reward-imbalance (ERI) and overcommitment (OC) to test whether chronic stress at work is accompanied by altered HPA axis stress responses in teachers. According to Siegrist's work stress model, ERI reflects stress due to a lack of reciprocity between personal costs and gains at work, whereas OC is conceptualized as a personality trait mainly characterized by the inability to withdraw from work obligations. Fifty-three medication-free, non-smoking, healthy teachers (33 women, 20 men, 29–63 years, mean age 49.9 ± 8.58 years) were confronted with the Trier Social Stress Test (TSST), a widely used standardized stress protocol to induce acute psychosocial stress in the laboratory. ACTH (five samples), total plasma (six samples) and free salivary cortisol (eight samples) were repeatedly measured before and after challenge. In the total group, ERI and OC were only marginally associated with HPA axis responses to acute stress. However, in the subgroup of responders (N = 30) high levels of OC were significantly associated with lower ACTH (p = 0.03) as well as plasma (p = 0.02) and salivary cortisol (p < 0.001) responses and results remained significant controlling for depressive symptoms. When additionally controlling for acute perceived stressfulness of the TSST, significant associations between OC and HPA axis responses emerged in responders as well as the total study sample. In respect to ERI, higher stress levels were solely related to significantly stronger plasma cortisol increases after TSST exposure, but this effect became non-significant controlling for depressive symptomatology. In sum, our findings support the notion of HPA axis hyporeactivity in highly overcommitted schoolteachers.     

Gender differences in hypothalamic-pituitary-adrenal (HPA) axis reactivity

The present study was designed to determine whether there are gender differences in hormonal response patterns to HPA axis activation. To this end, two methods of activating the HPA axis were employed: a standardized psychological stress test and a pharmacological challenge. Healthy subjects (mean age 23.4 years, SD 7.0 years) completed a naloxone challenge and/or the modified Trier Social Stress Test (TSST). For the naloxone challenge, two baseline blood samples were obtained. Placebo was then administered (0 min), followed by increasing doses of intravenous naloxone (50, 100, 200 and 400 microg/kg) at 30-min intervals. Post-placebo blood samples were collected at 15-min intervals for 180 min. The TSST consisted of 5 min of public speaking followed by 5 min of mental arithmetic exercises. Three baseline and five post-TSST blood samples were drawn. Eighty subjects (53 male, 27 female) underwent the TSST. Following the psychological stressor, adrenocorticotropin (ACTH) and cortisol responses were significantly greater in male subjects compared to female subjects (z=-2.34, p=0.019 and z=-2.12, p=0.034, respectively). Seventy-two subjects (52 male, 20 female) underwent HPA axis activation induced by naloxone. In contrast to the TSST, cortisol responses to the naloxone challenge were significantly greater in female subjects compared to male subjects (z=4.11, p<0.001). Forty-one subjects (25 male, 16 female) completed both the TSST and naloxone challenge. In this subset, ACTH and cortisol responses to the TSST did not differ significantly by gender, although the effect size was moderate to large. Adrenocorticotropin and cortisol responses to the naloxone challenge were significantly greater in female subjects compared to male subjects (z=2.29, p=0.022 and z=4.34, p<0.001, respectively). In summary, male subjects had greater HPA axis responses to a psychological stressor than female subjects, and females had greater hormonal reactivity than males to pharmacological stimulation with naloxone. Such differences are of interest as potential contributors to gender differences in health risks.     

HPA axis responses to laboratory psychosocial stress in healthy elderly adults, younger adults, and children: impact of age and gender

Data from five independent studies were reanalyzed in order to investigate the impact of age and gender on HPA axis responses to an acute psychosocial laboratory stress task. The total sample consisted of 102 healthy subjects with 30 older adults (mean age: 67.3 y), 41 young adults (mean age: 23.5 y), and 31 children (mean age: 12.1 y). All participants were exposed to the Trier Social Stress Test (TSST).The stress protocol caused highly significant ACTH and total plasma cortisol responses in older and younger male and female adults (all p<0.0001) as well as salivary free cortisol responses in all six age and gender groups (all p<0.0001). Three-way ANOVAs for repeated measurement were applied to investigate the impact of age and gender on ACTH and cortisol responses. Results showed that the ACTH response to stress was higher in younger adults compared to older adults (main effect: p=0.009, interaction: p=0.06). Post hoc analyses revealed that there was no age effect in the subgroup of women (p=n.s.), while younger men had higher ACTH responses compared to older men (p=0.01). For total plasma cortisol, ANOVA results showed that the pattern of reactivity did not differ between age and gender groups (all interactional effects p=n.s.), although older females had hightened overall cortisol levels compared to the other groups, as proofed in post hoc analyses (all p<0.05). For free salivary cortisol, a significant main effect of gender (p=0.05) and an almost significant three-way-interaction (p=0.09) emerged. Post hoc analyses showed an elevated overall free salivary cortisol response in elderly men compared to elderly women (p=0.006), while no gender differences emerged in neither young adults nor children (both p=n.s.).In sum, the stressor induced significant HPA axis responses in all age and gender groups. The observed ACTH response patterns in young and elderly adults may suggest that a heightened hypothalamic drive in young men decreases with age, resulting in similar ACTH responses in elderly men and women. Alternative interpretations are also discussed. The data also supports the idea of a greater adrenal cortex sensitivity to ACTH signals in young females. Free salivary cortisol responses were elevated in elderly men compared to elderly women, an effect which cannot be explained by gender differences in perceived stress responses to the TSST. It can be speculated if corticosteroid binding globulin (CBG) and/or sex steroids are important modulators of these effects.     

Comparison of HPA axis hormonal responses to naloxone vs psychologically-induced stress

Although the naloxone challenge has been used to draw inferences about the dynamics of the stress response, this procedure has never actually been compared "head to head" with a psychological stressor. In the present study, we asked 14 healthy volunteers to complete the naloxone challenge and the Trier Social Stress Test in an outpatient GCRC laboratory setting so that the degree of correspondence between the two procedures could be examined. Findings indicated that subjects who had greater ACTH responses to naloxone also had greater ACTH responses to the psychologically-induced stressor. This was true for both ACTH peak (r=0.57; p<0.04) and ACTH AUC response (r=0.64; p<0.02) measures; none of the cortisol summary score measures correlated significantly across the two challenges. Associations were also found between subjects' baseline personality characteristics and their ACTH responses to each of the challenges. Furthermore, the kinds of characteristics that predicted greater ACTH response to the pharmacological challenge were similar to the kinds of characteristics that predicted ACTH response to the psychological challenge. In general, higher scores on the NEO dimensions of Extraversion and Openness predicted greater ACTH responses. These findings give preliminary evidence that novelty-seeking behavior may be associated with HPA axis lability. The commonalities in personality predictors between the two challenges further support the notion that a common biological substrate may be, at least partially, responsible for the similarities in responses. However, caution should be used in assuming that responses to naloxone directly parallel responses to physiological stress.     

Increased nocturnal secretion of ACTH and cortisol in obsessive compulsive disorder

Information on the function of the hypothalamic-pituitary-adrenal (HPA) axis, the main mammalian system of stress response, in obsessive compulsive disorder (OCD) is inconsistent. In this study, nine inpatients with a DSM-IV diagnosis of OCD without comorbid major depression (Yale-Brown Obsessive Compulsive Scale [Y-BOCS] score >15; HAMD-21 total score 16) and nine healthy matched controls were included. Blood of patients (seven males; 31.8 +/- 9.3 years, Y-BOCS: 27.3 +/- 4.3, HAMD-21: 13.3 +/-1.9) and controls (seven males, 31.6 +/- 9.1 years) was drawn every 20 min between 23:00 and 7:00 h during sleep using a long catheter for later ACTH and cortisol analysis. Secretion patterns of cortisol and ACTH were similar in both groups, in OCD, however, at a higher level. Area under the curve plasma concentrations of both ACTH (p<0.05) and cortisol (p<0.005) were significantly greater in patients with OCD (ACTH: 674.3 +/- 57.4; cortisol: 2148.4 +/-271.7) than in controls (ACTH: 460.2 +/- 61.0; cortisol: 1191.2 +/- 124.1). In conclusion, our findings suggest that the activity of the HPA axis in patients with OCD is increased compared to healthy controls.     

Sex specific associations between common glucocorticoid receptor gene variants and hypothalamus-pituitary-adrenal axis responses to psychosocial stress.

BACKGROUND: Alterations in glucocorticoid (GC) signaling have been associated with a number of psychiatric disorders. Genetic variation of the glucocorticoid receptor (GR) might be one of the factors underlying susceptibility to stress related disease. METHODS: We investigated 206 healthy subjects and assessed associations between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9beta) and hypothalamic-pituitary-adrenal (HPA) axis responses to psychosocial stress (Trier Social Stress Test, TSST) and glucocorticoid sensitivity measured by a dexamethasone suppression test (DST). RESULTS: Male 9beta AG carriers displayed the highest adrenocorticotropic hormone (ACTH) and total cortisol TSST responses (for ACTH: main effect genotype p = .02) whereas male BclI GG carriers showed diminished responses. Remarkably, the BclI GG genotype in women (all using oral contraceptives) was associated with the highest total cortisol TSST responses, resulting in a significant sex by genotype interaction (p = .03). Following the DST, male 9beta AG carriers had elevated ACTH levels (sex by genotype interaction p = .03). CONCLUSIONS: We observed significant sex specific associations between GR gene polymorphisms and HPA axis responses to psychosocial stress as well as GC sensitivity. These findings support the relevance of GR gene polymorphisms in HPA axis regulation. Genetic variations of the GR might constitute a risk factor in development of HPA axis related disorders.     

Hypothalamic pituitary adrenocortical and sympathetic nervous system responses to the cold pressor test in Alzheimer's disease.

BACKGROUND: Increased basal activity of the hypothalamic-pituitary-adrenocortical (HPA) axis has been repeatedly demonstrated in Alzheimer's disease (AD), and some studies suggest increased basal activity of the sympathetic nervous system (SNS) in this disorder; however, the effects of AD on HPA axis or SNS responses to a standardized aversive stressor have not been examined. The neuroendocrine response to aversive stress may be relevant to the pathophysiology of AD. METHODS: Plasma adrenocorticotropic hormone (ACTH), cortisol, norepinephrine (NE), and epinephrine responses to a 1-min cold pressor test (CPT) were measured in nine medically healthy AD outpatients (age 76 +/- 2 years) and nine age- and gender-matched medically healthy cognitively normal older subjects (age 76 +/- 1 year). RESULTS: The cortisol response to CPT was increased in the AD group but the ACTH response did not differ between groups. Basal NE concentrations were higher in the AD group. Although NE responses to CPT did not differ between groups, the blood pressure response to CPT was higher in the AD subjects. CONCLUSIONS: These results suggest increased HPA axis responsiveness to CPT at the level of the adrenal cortex in AD. The results also suggest increased basal sympathoneural activity and increased cardiovascular responsiveness to sympathoneural stimulation in AD under the conditions of this experimental protocol. Increased SNS stimulatory modulation of the adrenal cortex is a possible mechanism contributing to the observed enhanced cortisol response to CPT in these AD subjects.     

Impaired Neuroendocrine and Immune Response to Acute Stress in Medication-Naive Patients With a First Episode of Psychosis

Little is known about how the biological stress response systems—the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal (HPA) axis, and the immune system—function during psychosis. Results of studies on the effect of stress on the immune and autonomic system in patients with schizophrenia are inconsistent. The present study investigates whether the stress response is impaired in medication-naive patients with a first episode of psychosis. Ten male patients with a first episode of psychosis and 15 controls were exposed to the stress of public speaking. Parameters of the ANS (heart rate and catecholamines), the HPA axis (plasma adrenocorticotropic hormone [ACTH] and cortisol), and the immune system (number and activity of natural killer [NK] cells) were measured. Peak responses were calculated to examine the relationship between stress-induced activation of the different systems. Subjective stress and anxiety before and during the task were assessed. Patients and controls displayed similar autonomic responses to acute stress. However, there was an impaired HPA axis response, slow onset and return of ACTH, and flattened cortisol response and a reduced increase in number NK cells and NK cell activity in patients with a first episode of psychosis. Furthermore, in patients, the relationship between the different stress response systems was weaker or absent compared with controls. These findings indicate that impairments in stress processing are associated with the endophenotype of psychosis and are not a result of illness progression or antipsychotic medication.     

Intranasal insulin attenuates the hypothalamic-pituitary-adrenal axis response to psychosocial stress

Previous studies have shown that intranasally administered insulin exerts an inhibitory influence on the basal hypothalamic-pituitary-adrenal (HPA) axis activity. To date, however, it remains unclear as to whether intranasal insulin does furthermore affect HPA axis responsiveness in situations of stress. Here, we tested whether intranasally administered insulin attenuates the HPA axis response to psychosocial stress. Fifty minutes before being exposed to the Trier Social Stress Test (TSST), 26 healthy young male participants received a single intranasal dose of human insulin (40 I.U.) or placebo in a placebo controlled, double-blind between-subject design. Plasma cortisol, saliva cortisol, heart rate, and blood pressure were measured at resting baseline and in response to the TSST. Plasma cortisol (P<.001) and saliva cortisol (P<.001) increased in response to stress, as did heart rate (P<.001) and blood pressure (P<.001). Intranasal insulin did not influence plasma or saliva cortisol, heart rate, blood pressure, blood glucose, and plasma insulin levels at baseline. However, intranasal insulin diminished the saliva cortisol (two-way ANOVA; treatment by time interaction: P=.05) and plasma cortisol (two-way ANOVA; treatment by time interaction: P=.05) response to the TSST without affecting heart rate, and blood pressure stress reactivity. Our data show that a single intranasal insulin administration effectively lowers stress-induced HPA axis responsiveness. Intranasal insulin may offer a therapeutic potential to prevent hyperactivity of the HPA system.     

The low-dose dexamethasone suppression test in fibromyalgia

OBJECTIVE: Fibromyalgia syndrome (FMS) has been associated with decreased cortisol secretion. Patients with posttraumatic stress disorder (PTSD) exhibit similar hypocortisolism in the context of increased negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis. Because trauma and PTSD have been associated with fibromyalgia, we evaluated whether patients with fibromyalgia demonstrate increased HPA feedback sensitivity. METHOD: Baseline blood samples were obtained at 0800 h, and 0.5 mg of dexamethasone was administered to 15 female patients with FMS and 20 normal controls at 2300 h. Adrenocorticotropin (ACTH), cortisol, and dexamethasone levels were measured at 0800 h after dexamethasone intake. RESULTS: There were no group differences in mean ACTH or cortisol levels or in ACTH/cortisol ratio at baseline. After dexamethasone intake, patients with FMS exhibited more pronounced suppression of cortisol but not of ACTH, as well as increased ACTH/cortisol ratios compared with controls. Percent cortisol suppression was associated with pain and fatigue, while ACTH/cortisol ratio and dexamethasone availability were associated with stress and anxiety measures. CONCLUSION: Our results suggest increased sensitivity to glucocorticoid feedback, manifested at the adrenal level, in FMS.     

Poor sleep is associated with exaggerated cortisol response to the combined dexamethasone/CRH test in a non-clinical population

Although sleep disturbance has been shown to be associated with psychological distress and the hypothalamic-pituitary-adrenal (HPA) axis function, the simultaneous relationship between sleep, distress and HPA axis function is less clear. Here we examined the relationship between sleep quality as assessed with the Pittsburgh Sleep Quality Index, psychological distress as assessed with the Hopkins Symptom Checklist, and cortisol responses to the dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test in 139 non-clinical volunteers. Poor sleep was significantly correlated with greater cortisol response to the combined DEX/CRH challenge, but not with the cortisol level just before CRH challenge. When subjects were divided into three groups based on the suppression pattern of cortisol (i.e., incomplete-, moderate-, and enhanced-suppressors), poor sleep was significantly associated with the incomplete suppression in women while no significant association was found between sleep and the enhanced suppression. The association between poor sleep and exaggerated cortisol response to the CRH challenge became more clear in the regression analysis where the confounding effect of psychological distress was taken into consideration. These results indicate that poor sleep would be associated with exaggerated cortisol reactivity. The observed association of poor sleep with reactive cortisol indices to the CRH challenge, but not with the cortisol level after DEX administration alone, might add to the well-established evidence demonstrating the role of CRH in the regulation of sleep. Our findings further suggest that the mediation model would work better than the bivariate approach in investigating the relationship between sleep, distress and HPA axis reactivity.     

Hypothalamic-pituitary adrenal response to cholecystokinin-B receptor agonism is resistant to cortisol feedback inhibition

Intravenous injection of the cholecystokinin (CCK)-B receptor agonist, pentagastrin, produces robust, dose-dependent release of adrenocorticotropin (ACTH) and cortisol, supporting the hypothesis that CCK-B agonists pharmacologically activate the hypothalamic-pituitary-adrenal (HPA) axis. The mechanism of activation and its physiological relevance remain uncertain. Preliminary data suggest that the ACTH response to pentagastrin may be differentiated from the response to exogenous corticotropin releasing hormone (CRH) by its relative resistance to cortisol feedback inhibition. To more directly test the relationship between cortisol levels and ACTH response to pentagastrin, this study examined responses to pentagastrin (a) during a peak (8 a.m.) and a nadir (4 p.m.) period of endogenous cortisol secretion and (b) when cortisol levels were artificially reduced to low levels by administration of metyrapone. ACTH responses to pentagastrin were identical in the morning and afternoon, despite substantial differences in basal cortisol levels. Suppression of cortisol with metyrapone had little impact on ACTH response to pentagastrin. These data support the hypothesis that CCK-B receptor mediated activation of the HPA axis is relatively resistant to cortisol feedback inhibition. This differentiates it from CRH-mediated activation and raises the possibility that CCK could contribute to acute activation of the HPA axis even in the face of elevated basal cortisol levels, such as those seen in chronic stress or some psychiatric disorders.     

Cognitive modulation of the endocrine stress response to a pharmacological challenge in normal and panic disorder subjects

CONTEXT: The hypothalamic-pituitary-adrenal (HPA) axis may mediate the deleterious effects of stress on health. It is sensitive to cognitive and emotional aspects of organism-environment interactions, such as familiarity, control, and social support. Scientific study of how such factors moderate human HPA axis activity has been limited. Their relevance to HPA axis disturbances in psychiatric patients is largely unexplored. OBJECTIVE: To determine whether cognitive manipulation can alter HPA axis activity in laboratory studies and whether patients with panic disorder are differentially sensitive to the manipulated factors. DESIGN: Pharmacological activation paradigm (cholecystokinin-B agonist pentagastrin) by which we examined symptom and endocrine effects on subjects randomly assigned to a standard introduction or a cognitive intervention. SETTING: Clinical research center. PARTICIPANTS: Recruited from university clinic and newspaper advertisements. Fourteen patients with panic disorder and 14 controls, individually matched for age and sex.Intervention Half of each group received a 9-minute cognitive intervention designed to reduce novelty, increase cognitive coping, and provide a sense of control. MAIN OUTCOME MEASURES: Corticotropin (ACTH) and cortisol levels. RESULTS: The cognitive intervention significantly reduced cortisol (P = .02) and ACTH (P = .01) levels, despite pentagastrin's robust stimulation of both hormones (P<.001). The intervention effect was evident in patients and controls, who did not differ in basal HPA axis activity or response to pentagastrin. They did differ in panic symptom responses, which were unaffected by the intervention, and in ACTH effects of the intervention. Patients' exaggerated anxiety responses to pentagastrin were normalized by the intervention. CONCLUSIONS: Cognitive/emotional manipulation can substantially modulate HPA axis responses to pharmacological activation in humans, and HPA disturbances in panic disorder may be secondary to manipulable cognitive/emotional sensitivities. Further study of such factors as novelty, control, and coping may help clarify the origins of HPA axis disturbance in psychiatric disorders and the mediators linking psychosocial stress to disease.     

Attenuation of the hypothalamic-pituitary-adrenal axis responsivity to the Trier Social Stress Test by the benzodiazepine alprazolam

Little is known about effects of commonly used anxiolytic drugs on psychologically evoked responses of two major stress systems, the hypothalamic–pituitary–adrenal (HPA) and the sympathetic–adrenal–medullary (SAM) axis. The purpose of the present study was to assess effects of the anxiolytic alprazolam on responses of the HPA and the SAM axes to a standardized psychosocial stress protocol, the Trier Social Stress Test (TSST). Forty-six healthy, non-smoking, non-medicated males, aged between 18 and 45 years, were invited once to the laboratory and received a single oral dose of 1 mg alprazolam or placebo, respectively, 1 h prior to the TSST. The secretion of ACTH, cortisol, epinephrine, norepinephrine as well as changes in heart rate, blood pressure, and psychological states (anxiety, wakefulness, good mood, calmness) in response to the TSST were measured. Subjects pre-treated with alprazolam showed a strongly blunted response of ACTH as well as total and free cortisol to the TSST. Whereas alprazolam-treated subjects displayed significantly lower systolic blood pressure immediately before the TSST, neither the secretion of epinephrine, norepinephrine nor changes of heart rate in response to the stress test differed from placebo-treated subjects. Regarding psychological parameters, alprazolam clearly decreased subjective ratings on the questionnaire scale “wakefulness” and increased ratings on the scale “good mood”, whereas ratings on scales assessing “state anxiety” or “agitation” were not affected.

In healthy subjects, we observed a dissociation of the effects of alprazolam on the endocrine and the autonomic response to psychosocial stress. The psychological responses seemed to be masked by sedative properties of alprazolam.     

Psychophysiological biomarkers of workplace stressors

Workplace stressors are associated with greater coronary heart disease risk, although there is debate over the psychophysiological consequences of work stress. This study builds on recent reviews and examines the literature linking work stress with sympatho-adrenal biomarkers (plasma catecholamines and heart rate variability) and HPA axis biomarkers – the post-morning profile of cortisol.MethodsRelevant studies using appropriate search terms were searched using the bibliographic databases PubMed, Embase, Biosys and Toxline. Four studies on plasma catecholamines, 10 studies on heart rate variability, and 16 studies on post-morning cortisol were reviewed.ResultsIn the majority of studies that examined the association of HRV and work stress, greater reports of work stress is associated with lower heart rate variability. The findings for plasma catecholamines and cortisol secretion are less clear cut and suffer from poorer quality of studies in general.ConclusionThere is evidence that work stress is related to elevated stress responses in terms of sympatho-adrenal and HPA axis biomarkers.