Frequency of Perceived Poststress Symptoms in Inpatients, Outpatients and Healthy Controls: The Role of Perceived Exhaustion and Stress.

BACKGROUND: Poststress symptoms occur as a consequence of stress, most commonly during leisure periods such as weekends and vacations. However, the prevalence and the pathological mechanisms of poststress symptoms are poorly understood. METHODS: Here, we compared the frequency of poststress symptoms in healthy controls (n = 984), outpatients (n = 420), and inpatients (n = 101). In outpatients, demographic factors, psychosocial stress, and perceived exhaustion were tested as predictors of poststress symptoms with multivariate regression analysis. Poststress symptoms and perceived exhaustion were assessed using 2 Neuropattern Questionnaires (the NPQ - Patient Questionnaire and the NPQ - Symptom List), and psychosocial stress was evaluated using the Patient Health Questionnaire (PHQ). RESULTS: Poststress symptoms appeared in 2.9% of healthy controls, 20.0% of outpatients, and 34.7% of inpatients. Predictors were educational level, psychosocial stress, and perceived exhaustion. Poststress symptoms differed primarily between exhausted (75.0%) and nonexhausted patients (25.0%). CONCLUSION: Poststress symptoms are rather common in clinical populations, and they are primarily associated with the degree of perceived exhaustion. Preliminary evidence suggests that poststress symptoms are possibly related to depletion of norepinephrine stores, which may facilitate a stratified preventive and therapeutic treatment of these subjects.

Stress exposure in intrauterine life is associated with shorter telomere length in young adulthood.

Leukocyte telomere length (LTL) is a predictor of age-related disease onset and mortality. The association in adults of psychosocial stress or stress biomarkers with LTL suggests telomere biology may represent a possible underlying mechanism linking stress and health outcomes. It is, however, unknown whether stress exposure in intrauterine life can produce variations in LTL, thereby potentially setting up a long-term trajectory for disease susceptibility. We, therefore, as a first step, tested the hypothesis that stress exposure during intrauterine life is associated with shorter telomeres in adult life after accounting for the effects of other factors on LTL. LTL was assessed in 94 healthy young adults. Forty-five subjects were offspring of mothers who had experienced a severe stressor in the index pregnancy (prenatal stress group; PSG), and 49 subjects were offspring of mothers who had a healthy, uneventful index pregnancy (comparison group; CG). Prenatal stress exposure was a significant predictor of subsequent adult telomere length in the offspring (178-bp difference between prenatal stress and CG; d = 0.41 SD units; P < 0.05). The effect was substantially unchanged after adjusting for potential confounders (subject characteristics, birth weight percentile, and early-life and concurrent stress level), and was more pronounced in women (295-bp difference; d = 0.68 SD units; P < 0.01). To the best of our knowledge, this study provides the first evidence in humans of an association between prenatal stress exposure and subsequent shorter telomere length. This observation may help shed light on an important biological pathway underlying the developmental origins of adult health and disease risk.

How to measure prenatal stress? A systematic review of psychometric instruments to assess psychosocial stress during pregnancy.

BACKGROUND: A growing body of literature documents associations of maternal psychosocial stress during pregnancy with fetal, infant and child behaviour and development. However, findings across studies are often inconsistent, which may in part be due to differences in stress definitions and assessments. METHODS: We systematically reviewed methods applied to assess maternal psychosocial stress during pregnancy in studies looking at associations with biobehavioural outcomes in the offspring. A systematic literature search was performed on Web of Science and PubMed for the time period between January 1999 and October 2009. Psychometric instruments assessing maternal psychosocial stress during pregnancy were identified and described if data on psychometric properties were available. RESULTS: We identified 115 publications that assessed psychosocial stress during pregnancy with validated methods. These publications applied overall 43 different instruments assessing constructs falling under seven categories, ordered according to their frequency of use: anxiety, depression, daily hassles, aspects of psychological symptomatology (not reduced to anxiety or depression), life events, specific socio-environmental stressors and stress related to pregnancy and parenting. If available, we provide information on validity and reliability of the instruments for samples of pregnant women. CONCLUSIONS: Within the 'prenatal stress' research, a broad range of instruments is applied to assess psychosocial stress during pregnancy. Prenatal stress research should take into consideration that the variety of methods in use might hamper the comparability of stress research results. In each category of stress constructs, one instrument with good psychometric properties in pregnant women is highlighted as the best currently available measure.

Salivary cortisol in ambulatory assessment--some dos, some don'ts, and some open questions.

The impact of stress on health and disease is an important research topic in psychosomatic medicine. Because research on hypothalamic-pituitary-adrenal (HPA) axis regulation under controlled laboratory studies lacks ecological validity, it needs to be complemented by a research program that includes momentary ambulatory assessment. The measurement of salivary cortisol offers the possibility to trace the free steroid hormone concentrations in ambulant settings. Therefore, in this article, we first discuss the role of salivary cortisol in ambulatory monitoring. We start with a brief description of HPA axis regulation, and we then consider cortisol assessments in other organic materials, followed by a presentation of common salivary markers of HPA axis regulation suitable for ambulatory assessment. We further provide an overview on assessment designs and sources of variability within and between subjects (intervening variables), acknowledge the issue of (non)compliance, and address statistical aspects. We further give an overview of associations with psychosocial and health-related variables relevant for ambulatory assessment. Finally, we deal with preanalytical aspects of laboratory salivary cortisol analysis. The relative simplicity of salivary cortisol assessment protocols may lead to an overoptimistic view of the robustness of this method. We thus discuss several important issues related to the collection and storage of saliva samples and present empirical data on the stability of salivary cortisol measurements over time.

Increased peripheral NF-κB pathway activity in women with childhood abuse-related posttraumatic stress disorder.

In addition to neuroendocrine changes PTSD pathophysiology may also involve dysfunction of the innate immune inflammatory system. PTSD patients have been found to exhibit increased concentrations of circulating inflammatory markers such as C-reactive protein and interleukin-6, suggesting dysfunction of the innate immune inflammatory system. However, few studies have investigated molecular signaling pathways known to critically regulate inflammation. Additionally, the relationship between inflammatory function and immune cell glucocorticoid sensitivity has not been extensively explored in PTSD. Nuclear factor-κB (NF-κB) pathway activity was examined in peripheral blood mononuclear cells obtained from 12 women with childhood abuse-related PTSD and 24 healthy controls (ages 19-48) using DNA-binding ELISA. Glucocorticoid sensitivity of monocytes in whole blood was measured as the concentration of dexamethasone needed to suppress in vitro lipopolysaccharide-induced tumor necrosis factor-alpha production by 50% (DEX IC(50)). Women with PTSD displayed increased NF-κB pathway activity compared to controls (t [34]=2.45, p=0.02) that was positively correlated with PTSD severity (determined by PTSD symptom severity scale) (r(s)=0.39, p=0.02). Increased NF-κB pathway activity was associated with increased whole blood monocyte DEX IC(50) (i.e. decreased sensitivity of monocytes to glucocorticoids) across all participants (r=0.66, p<0.001). These findings suggest that enhanced inflammatory system activity in participants with childhood abuse-related PTSD is observable at the level of NF-κB, and that in general decreased immune cell glucocorticoid sensitivity may contribute to increased NF-κB pathway activity. Enhanced inflammation may contribute to co-morbid somatic disease risk in persons with childhood abuse-related PTSD.

Neuropattern: a new translational tool to detect and treat stress pathology. II. The Teltow study.

The present study was designed to test the clinical utility of Neuropattern (NP), a newly developed translational diagnostic tool. NP consists of biological and psychological measures that facilitate the identification of functional changes (called "neuropatterns") in patients with stress-related health problems. In this prospective, randomized control trial, we expected NP to improve therapeutic efficacy, as compared with the usual treatment. NP was applied to 101 in-patients suffering from various mental disorders (mainly depression, anxiety disorders, and adjustment disorders), and scoring high on the Symptom Checklist-90-R (SCL-90-R) somatization scale. The patients (73% females, mean ± standard deviation age 46 ± 9.03 years) were randomly assigned to two groups: in the experimental group (n = 51), physicians received results from NP diagnostics, while in the control group (n = 50), this information was not available until discharge from the hospital. Improvements of symptoms in consequence of treatment were monitored by two self-rating scales, the SCL-90-R and Short Form-12 health survey, and a physician's clinical global rating (Beeinträchtigungs-Schwere Score). There was a significantly greater improvement in the experimental group in the self-rating assessments on symptom severity (p = 0.03) and quality of life (p = 0.05), but not in the observer rating of emotional, physical, and social-communicative functioning (p = 0.13). Treatment efficacy in patients can be improved by providing the attendant physician and the patient with diagnostic information and treatment recommendations by NP. The role of concrete mediators of treatment efficacy awaits further research.

Negative emotionality, depressive symptoms and cortisol diurnal rhythms: analysis of a community sample of middle-aged males.

Prior research suggests that individuals with particular personality traits, like negative emotionality, are at greater risk for adverse health outcomes. Despite bivariate associations between negative emotionality, depressive symptoms and the hypothalamic pituitary adrenal axis (HPA axis), few studies have sought to understand the biological pathways through which negative emotionality, depressive symptomatology and cortisol-one of the primary hormonal products of the HPA axis--are associated. The present study explored whether negative emotionality influenced cortisol dysregulation through current depressive symptomatology and whether negative emotionality served as a moderator of the relationship between depressive symptoms and cortisol. In the community-based Vietnam Era Twin Study of Aging, 783 male twins completed two days of cortisol saliva sampling in their natural environments. Three measures of cortisol were analyzed: waking levels, the cortisol awakening response, and the peak to bed slope. Depressive symptoms significantly mediated the associations between negative emotionality and the peak to bed slope. A 2-way interaction between depressive symptoms and negative emotionality was significant for the peak to bed slope and for waking levels of cortisol. Exploration of the interactions illustrated that depressive symptoms only affected cortisol slopes at average or high levels of negative emotionality and only affected waking levels at low levels of negative emotionality. Negative emotionality and depressive symptoms were not related to the cortisol awakening response. This is the first study to find indirect associations between negative emotionality and peak to bed cortisol slopes through depressive symptoms. These findings illustrate the complex interplay between personality characteristics, depressive symptoms and different indices of the cortisol diurnal rhythm.

Cortisol levels in pregnancy as a psychobiological predictor for birth weight.

Antenatal maternal stress is thought to negatively affect fetal development, birth outcomes, and infant's development. Glucocorticoids are suggested to be a common link between prenatal stressors and infant's health. However, data on these mechanisms are rare and sometimes conflicting. The objective of this study was to examine the effects of maternal distress during pregnancy on fetal development and birth weight in humans prospectively. This study focuses on cortisol as one mediating the mechanism of the association between maternal distress and birth outcomes. Pregnancy-related and general distress was measured in 81 women with uncomplicated, singleton pregnancies. The rise of salivary cortisol on awakening (CAR) was assessed in weeks 13-18 and 35-37 postmenstrual age of pregnancy. Mothers completed a structured interview, the perceived stress scale, a widely used psychological instrument that provided a global measure of perceived stress, as well as the Prenatal Distress Questionnaire, a self-report questionnaire designed to assess worries and anxiety in pregnancy. Pre-, peri-, and postnatal medical risk factors as well as birth characteristics were extracted from medical records routinely kept by the attending obstetricians. Hierarchical multiple regressions indicate that maternal cortisol levels explained 19.8% of the variance in birth weight and 9% of the variance in body length at birth, even after controlling for gestational age, parity, pre-pregnancy BMI, smoking, and infant's sex. Newborns of mothers with higher cortisol levels in pregnancy had lower birth weights and were shorter at birth. An ANCOVA for repeated measures indicated that, after controlling for covariates, pregnancy-related as well as general distress in pregnancy did not influence cortisol levels after awakening (area under the curve). No significant associations between perceived stress and anthrometric measures at birth were found. In conclusion, maternal cortisol levels in pregnancy influence intrauterine growth and may be a better predictor for birth outcome than perceived stress.

Salivary cortisol and prefrontal cortical thickness in middle-aged men: A twin study.

Although glucocorticoid receptors are highly expressed in the prefrontal cortex, the hippocampus remains the predominant focus in the literature examining relationships between cortisol and brain. We examined phenotypic and genetic associations of cortisol levels with the thickness of prefrontal and anterior cingulate cortex regions, and with hippocampal volume in a sample of 388 middle-aged male twins who were 51-59 years old. Small but significant negative phenotypic associations were found between cortisol levels and the thickness of left dorsolateral (superior frontal gyrus, left rostral middle frontal gyrus) and ventrolateral (pars opercularis, pars triangularis, pars orbitalis) prefrontal regions, and right dorsolateral (superior frontal gyrus) and medial orbital frontal cortex. Most of the associations remained significant after adjusting for general cognitive ability, cardiovascular risk factors, and depression. Bivariate genetic analyses suggested that some of the associations were primarily accounted for by shared genetic influences; that is, some of the genes that tend to result in increased cortisol levels also tend to result in reduced prefrontal cortical thickness. Aging has been associated with reduced efficiency of hypothalamic-pituitary-adrenal function, frontal lobe shrinkage, and increases in health problems, but our present data do not allow us to determine the direction of effects. Moreover, the degree or the direction of the observed associations and the extent of their shared genetic underpinnings may well change as these individuals age. Longitudinal assessments are underway to elucidate the direction of the associations and the genetic underpinnings of longitudinal phenotypes for changes in cortisol and brain morphology.

Genetic and environmental influences on cortisol regulation across days and contexts in middle-aged men.

Cortisol is an indicator of hypothalamic-pituitary-adrenal axis responsivity to stress, but few twin studies have examined the heritability of cortisol concentrations in adults across the diurnal cycle and in different contexts. Saliva samples were provided by 783 middle-aged male twins on one laboratory and two home days as part of the Vietnam Era Twin Study of Aging. Significant cortisol heritability estimates were found for laboratory measures only: awakening (.56); 30 min after awakening (.48); 1000 h (.42); mean output across the day (.43); and mean cortisol awakening response (.64). Twin correlations at home were low. In the laboratory, they were unchanged for fraternal twins, but increased for identical twins. Greater measurement error at home did not appear to account for home-laboratory differences. The results suggest that genetic factors influence cortisol responses to specific environmental stressors. Thus, cortisol levels are correlated in identical twins only when they undergo similar experiences.

Salivary cortisol as a biomarker in stress research.

Salivary cortisol is frequently used as a biomarker of psychological stress. However, psychobiological mechanisms, which trigger the hypothalamus-pituitary-adrenal axis (HPAA) can only indirectly be assessed by salivary cortisol measures. The different instances that control HPAA reactivity (hippocampus, hypothalamus, pituitary, adrenals) and their respective modulators, receptors, or binding proteins, may all affect salivary cortisol measures. Thus, a linear relationship with measures of plasma ACTH and cortisol in blood or urine does not necessarily exist. This is particularly true under response conditions. The present paper addresses several psychological and biological variables, which may account for such dissociations, and aims to help researchers to rate the validity and psychobiological significance of salivary cortisol as an HPAA biomarker of stress in their experiments.

Prenatal exposure to maternal psychosocial stress and HPA axis regulation in young adults.

Epidemiological studies have reported associations between measures of size and weight at birth and disease risk in later life. Alteration in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis in response to prenatal stress has been proposed as one underlying mechanism. The present study investigated in humans the association of prenatal psychosocial stress exposure with subsequent HPA axis regulation in adult life, with a focus on measures of response to challenge and feedback sensitivity. Healthy young adults whose mothers experienced severe stress during their pregnancy in form of major negative life events (e.g. death of someone close; prenatal stress (PS) group, n=31) and an age-matched comparison group (CG, n=30) underwent the Trier Social Stress Test (TSST) and a 1 microg ACTH(1-24) stimulation test. In addition, a diurnal cortisol profile was assessed. ACTH concentrations following a standardized behavioural challenge paradigm (TSST) were marginally significantly higher in PS subjects than in CG subjects (p=.06). Pre-TSST adrenocortical (cortisol) levels were lower (p=.007), whereas the increase in cortisol in response to the TSST was higher (p=.03) in PS subjects compared to CG subjects. Cortisol concentrations following a pharmacological stimulation test simulating pituitary activity (ACTH(1-24) test) were significantly lower in PS than in CG subjects (p=.006). No differences emerged between the two groups in basal diurnal cortisol levels. This study provides first evidence in humans of an association between prenatal psychosocial stress exposure and subsequent alterations in the regulation of the HPA axis.

Behavioral response to methylphenidate challenge: influence of early life parental care.

Rat studies have shown that pups subjected to suboptimal rearing conditions exhibited permanently dysregulated dopamine activity and altered behavioral responses to dopamine stimulation. In humans, heightened stress-induced mesoaccumbens dopamine release in adults reporting low maternal care experience has been shown. We explored the relationship between quality of parental care and behavioral responsivity to reward and 20 mg of the dopamine agonist methylphenidate (MPH). Forty-three male university students accomplished a monetarily rewarded card-sorting task in a placebo controlled between-subjects study design. In participants scoring above the cut-off score for high parental care as assessed by the Parental Bonding Inventory, MPH decreased performance accuracy in the reward condition of the task. Contrarily, reward-induced performance accuracy of low care participants was enhanced with MPH. Activity measures in response to reward and MPH were uninfluenced by parental care. This is the first human study to reveal that the behavioral MPH response interacts with early life parental care experience.

Maternal care modulates the relationship between prenatal risk and hippocampal volume in women but not in men.

Smaller hippocampal volume is associated with psychiatric disorders. Variations in hippocampal volume are discussed as both a consequence of the neurotoxic effects of stress and as a pre-existing condition leading to increased vulnerability for cognitive and emotional impairments. To investigate whether early experience can account for variability in hippocampal volume in adulthood (vulnerability hypothesis), we assessed the relationship between birth weight and hippocampal volume in 44 subjects. The reported quality of maternal care in early childhood, as evaluated by the Parental Bonding Inventory, was used as index of the quality of the postnatal environment. Hippocampal volume was assessed from magnetic resonance images using a manual segmentation protocol. We show that birth weight significantly predicts hippocampal volume in adulthood only in female subjects reporting low maternal care. The results suggest that the postnatal environment modulates the neurodevelopmental consequences of prenatal risk and that this effect is sex-specific.

HPA axis reactivity and lymphocyte glucocorticoid sensitivity in fibromyalgia syndrome and chronic pelvic pain.

OBJECTIVE: Chronic pelvic pain (CPP) and fibromyalgia syndrome (FMS) have been associated with hypothalamic-pituitary-adrenal (HPA) axis alterations, i.e., mild hypocortisolism and enhanced feedback sensitivity. We tested the hypothesis of reduced cortisol release in response to a psychosocial stressor and pharmacological stimulation. Furthermore, glucocorticoid (GC) sensitivity was evaluated. METHODS: Plasma total and salivary-free cortisol concentrations were measured in response to a standardized social laboratory stressor, the Trier Social Stress Test, and to adrenocorticotropin (ACTH)(1-24) stimulation. In the Trier Social Stress Test, we additionally measured ACTH. GC sensitivity was measured by dexamethasone inhibition of lipopolysaccharide-induced interleukin-6 and tumor necrosis factor-alpha production in whole blood. RESULTS: There were no HPA axis alterations in women with CPP (N = 18) in these tests. Patients with FMS (N = 17) showed lower total cortisol release in response to the social stressor and exogenous ACTH, but normal free cortisol and ACTH levels compared with controls (N = 24). GC sensitivity was similar in all groups. CONCLUSIONS: Our results suggest normal HPA responses to stress and ACTH stimulation in patients with CPP but reduced adrenal reactivity in patients with FMS, namely in total cortisol release. Free cortisol on the other hand was unaltered, possibly reflecting an adaptation to reduced circulating total cortisol.

Glucocorticoid sensitivity in fibromyalgia patients: decreased expression of corticosteroid receptors and glucocorticoid-induced leucine zipper.

In fibromyalgia (FM) patients, differences in glucocorticoid receptor (GR) affinity and disturbances associated with loss of hypothalamic-pituitary-adrenal (HPA) axis resiliency have been observed. Based on these studies, we investigated whether FM would be associated with abnormalities in glucocorticoid (GC) sensitivity. Salivary and blood samples were collected from 27 FM patients and 29 healthy controls. Total plasma cortisol and salivary free cortisol were quantified by ELISA and time-resolved fluorescence immunoassay, respectively. GR sensitivity to dexamethasone was evaluated through IL-6 inhibition in stimulated whole blood. The corticosteroid receptors, GR alpha and mineralocorticoid receptor, as well as the glucocorticoid-induced leucine zipper (GILZ) and the FK506 binding protein 5 mRNA expression were assessed in peripheral blood mononuclear cells (PBMCs) by real-time RT-PCR. Furthermore, the corticosteroid receptors were analysed for polymorphism. We observed lower basal plasma cortisol levels (borderline statistical significance) and a lower expression of corticosteroid receptors and GILZ in FM patients when compared to healthy controls. The MR rs5522 (I180V) minor allele was found more often in FM patients than in controls and this variant was recently associated with a mild loss of receptor function. The lower GR and MR expression and possibly the reduced MR function may be associated with an impaired function of the HPA axis in these patients which, compounded by lower anti-inflammatory mediators, may sustain some of symptoms that contribute to the clinical picture of the syndrome.

Prenatal psychosocial stress exposure is associated with insulin resistance in young adults.

OBJECTIVE: The objective of the study was to examine the association in humans between maternal psychosocial stress exposure during pregnancy and measures of glucose-insulin metabolism in the adult offspring. STUDY DESIGN: Healthy young adults whose mothers experienced major stressful life events during their pregnancy (n = 36, prenatal stress, PS group, mean age 25 +/- 5.14 [SD] years) and a comparison group (n = 22, CG, mean age 24 +/- 3.7 [SD] years) underwent an oral glucose tolerance test. RESULTS: Glucose levels were not significantly different across the groups; however, prenatally stressed subjects showed significantly elevated 2-hour insulin (P = .01) and C-peptide levels (P = .03). These differences were independent of other major risk factors for insulin resistance, including birth phenotype (birthweight, length of gestation), a family history of diabetes, gestational diabetes, body mass index, proinflammatory state, and smoking. CONCLUSION: Higher insulin responses reflect relative insulin resistance in these prenatally stressed young adults. This study is the first to provide evidence for a link in humans between prenatal psychosocial stress exposure and alterations in glucose-insulin metabolic function.

Influence of prenatal psychosocial stress on cytokine production in adult women.

The aim of the present study was to determine the association between prenatal stress and immune function in human adults. Peripheral blood mononuclear cells (PBMCs) from 34 healthy young women whose mothers experienced major negative life events during their pregnancy (Prenatal Stress, PS group, mean age 25, SD +/- 4.34 years), and from a female comparison group (n = 28, CG, mean age 24 +/- 3.40 years), were stimulated with phytohemagglutinin (PHA), and subsequent cytokine production was measured. A bias for T-helper 2 (Th2) cytokine production due to an overproduction of IL-4 relative to IFN-gamma after PHA stimulation was observed in PS subjects. In addition, IL-6 and IL-10 were also significantly elevated. To the best of our knowledge, this study is the first to suggest a direct association between prenatal stress exposure and alterations in immune parameters in adult women.

Conceptual endophenotypes: A strategy to advance the impact of psychoneuroendocrinology in precision medicine.

Psychobiological research has generated a tremendous amount of findings on the psychological, neuroendocrine, molecular and environmental processes that are directly relevant for mental and physical health, but have overwhelmed our capacity to meaningfully absorb, integrate, and utilize this knowledge base. Here, we reflect about suitable strategies to improve the translational success of psychoneuroendocrinological research in the era of precision medicine. Following a strategy advocated by the National Research Council and the tradition of endophenotype-based research, we advance here a new approach, termed "conceptual endophenotypes". We define the contextual and formal criteria of conceptual endophenotypes, outline criteria for filtering and selecting information, and describe how conceptual endophenotypes can be validated and implemented at the bedside. As proof-of-concept, we describe some of our findings from research that has adopted this approach in the context of stress-related disorders. We argue that conceptual endophenotypes engineer a bridge between the bench and the bedside. This approach readily lends itself to being continuously developed and implemented. Recent methodological advances, including digital phenotyping, machine learning, grassroots collaboration, and a learning healthcare system, may accelerate the development and implementation of this conceptual endophenotype approach.

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.