Smokers Display Reduced Glucocorticoid Sensitivity Prior to Symptomatic Chronic Disease Development.

Background: Chronic stress plays a critical role in many of today's diseases and causes of death. Tobacco use reliably increases the likelihood of chronic disease development and premature death. In addition, habitual tobacco use elevates risk of chronic inflammatory diseases, and glucocorticoid therapy is often less effective in smokers compared with nonsmokers. Taken together, smokers may develop glucocorticoid insensitivity, thereby removing the body's greatest anti-inflammatory mechanism. Purpose: The purpose of this study was to examine glucocorticoid sensitivity among 24 smokers and 24 age-, sex-, and body mass index-matched never smokers who were clinically healthy individuals (i.e., no diagnosis or medication use for chronic diseases and normotensive). Method: Participants visited the lab after a 12 hr fast, provided a blood sample, and completed a series of psychosocial questionnaires. Smokers continued smoking ad libitum before the lab visit. Group differences in glucocorticoid sensitivity were examined using ANCOVA and repeated with linear mixed model to account for possible dependence among immune outcomes that matching participants on age, sex, and body mass index may have introduced. Results: Prior to clinical disease onset, smokers' peripheral blood mononuclear cells (PBMCs) exhibited reduced glucocorticoid sensitivity as well as a diminished inflammatory response to lipopolysaccharide compared with never smokers' PBMCs; results were identical regardless of statistical modeling used. Conclusions: Cigarette smoking, a self-initiated pharmacological chronic stressor, may provide a unique opportunity to examine early wear and tear on physiological functioning that may lead to chronic disease development. Additional research into PBMCs' intracellular changes must be examined as well as repeating this study in a larger, more heterogeneous population.

Perioperative serum levels of procalcitonin, C-reactive protein, and leukocytes in head and neck free flaps.

Microvascular free flaps are considered to be the gold standard in reconstructive head and neck surgery. However, reduced postoperative transplant perfusion is one of the serious postoperative complications and calls for close and reliable monitoring. Procalcitonin, C-reactive protein, and leukocytes are closely associated with local and systemic inflammatory reactions and might have prognostic capacity concerning tissue necrosis. This study aimed to evaluate perioperative serum levels of these three biomarkers to assess their potential in postoperative flap monitoring. A total of 100 patients with microvascular head and neck reconstructions were included in the study. Perioperative serum levels of parameters were measured and the clinical data were analyzed and correlated. A total of 13% of all flaps developed reduced postoperative perfusion. Analysis of the parameters revealed statistically significant differences in the overall patient collective over time, irrespective of clinically reduced flap perfusion. Co-factors such as sex and history of tobacco and alcohol abuse showed significant differences. The efficacy of the parameters in free flap monitoring has not been verified, although the role of procalcitonin in postoperative monitoring, with special regard to the early detection of infections, is underlined by the present study results.

Radiotherapy for oral cancer decreases the cutaneous expression of host defence peptides.

INTRODUCTION: Bacterial resistance against antibiotics has become an increasing challenge in the treatment of cutaneous infections. Consequences can be severe, especially in infected wounds following previous local radiotherapy. Certain endogenous peptide antibiotics, the host defence peptides (HDPs), exhibit broad-spectrum antimicrobial activity and promote wound healing. Their use as supplements to conventional antibiotics is a current topic of discussion; however, knowledge of their quantities in healthy and compromised tissue is a prerequisite for such discussion. To date, no data concerning HDP quantities in irradiated skin are available. METHODS: Expression profiles of the genes encoding HDPs, namely human beta-defensin-1 (DEFB1, hBD-1), beta-defensin-2 (DEFB4A, hBD-2), beta-defensin-3 (DEFB103, hBD-3) and S100A7, were assessed in samples of non-irradiated and irradiated neck. RESULTS: A reduction in the expression of all of the examined genes was observed in irradiated skin when compared with non-irradiated skin (statistically significant in the case of S100A7, P = 0.013). Immunohistochemistry revealed differences in HDP distribution with respect to the epithelial layers. CONCLUSION: The study demonstrates a significant reduction in HDP gene expression in neck skin as a result of radiotherapy. These findings might represent a starting point for novel treatments of cutaneous infections in irradiated patients, such as topical supplementation of synthetic HDP.

Accuracy of mandibular reconstruction by three-dimensional guided vascularised fibular free flap after segmental mandibulectomy.

Mandibular reconstruction with a fibular free flap has become standard in specialised centres for head and neck reconstruction, particularly for defects with more than one osteotomy that are challenging even for experienced surgeons. Virtual surgical planning is a potential tool to facilitate harvesting of the fibula and the osteostomy. The purpose of this study was to compare the two methods of mandibular reconstruction - conventionally planned (conventional group) and "virtually" planned (virtual group) - with regard to accuracy, bony consolidation, complications, and operating time. Fifty patients who required mandibular reconstruction after segmental mandibulectomy were evaluated retrospectively, 24 virtually planned and 26 conventionally planned. The overall survival of flaps was 92% (46/50). The bony consolidation rate in the virtual group was significantly better than that in the conventional group (p=0.002). The difference between the angle of the mandible before and after was highly significant with a median of 11.5° (range 2°-75°) in the conventional group and 4.5° (range 0-18°) in the virtual group (p=0.0001). Operations were mean (SD) of 34 (21.2) minutes shorter in virtually-planned cases (p=0.12). The overall morbidity did not differ significantly between the groups. The use of virtual surgical planning in mandibular reconstruction by fibular free flap is beneficial for optimising accuracy, consolidation of bony segments, and operating time, while increasing the predictability of results for the surgeon. However, additional costs have to be carefully weighed against the benefits.

Which kind of frontal mandibulotomy is the smartest? A biomechanical study.

PURPOSE: Retrospective clinical evaluation and biomechanical tests were performed to compare the primary stability and the rate of pseudarthrosis formation after irradiation for two types of mandibular split osteotomies: the stairstep osteotomy (SSO) and the straight-line osteotomy (SLO). METHODS: The postoperative occurrence of pseudarthrosis was retrospectively analysed in 46 non-consecutive clinical cases of SSO and SLO between 2003 and 2013. Biomechanical tests were performed on 12 standardised synthetic mandibles (Synbone) to compare the SSO and SLO approaches. Two 2.0 mm monocortical miniplates (Medartis) were used for osteosynthesis. The artificial mandible specimens were loaded to 300 N on the Mandibulator test bench while interfragmentary motion was measured using the PONTOS optical measurement device. RESULTS: The retrospective clinical analysis showed a rate of pseudarthrosis of 19% in the SLO group versus only 5% in the SSO group (p = 0.17). In the biomechanical investigation, the average interfragmentary movement was 14.3 ± 7.70 for the SLO group and 4.57 ± 2.33 for the SSO group under a maximum load of 300 N, resulting in a statistically significant difference between the two approaches (p = 0.014). CONCLUSION: To minimise the rate of postoperative pseudarthrosis formation, SSO is superior to SLO for mandibular split procedures, because SSO provides greater resistance to vertical loads and allows less interfragmentary movement. LEVEL OF EVIDENCE: 2C (Outcomes research).

Expression of antimicrobial peptides in cutaneous infections after skin surgery.

BACKGROUND: Increasing numbers of antibiotics have lost efficiency because of bacterial resistance. The consequences can be severe when surgical wounds become infected during postoperative care. Natural peptide antibiotics, the so-called host defence peptides (HDPs), have been investigated since the 1990s in a search for alternative treatment strategies. HDPs build up a protection shield against pathological microorganisms, especially in human epithelium. The use of HDPs is currently being discussed as a new antimicrobial therapeutic strategy. Accordingly, a profound knowledge of the quantitative relationships of the effectors is essential. OBJECTIVES: To evaluate differences in HDP expression between postoperatively inflamed and healthy epithelium. METHODS: Expression profiles of the genes encoding HDP human beta-defensin (hBD)-1 (DEFB1, previously known as HBD-1), hBD-2 (DEFB4A, previously known as HBD-2), hBD-3 (DEFB103A, previously known as HBD-3) and psoriasin (S100A7) were assessed in samples of surgical wound healing disorders (n = 27) and healthy epithelium (n = 16) by using real-time polymerase chain reaction. Immunohistochemical staining was performed in the same samples. RESULTS: A significant overexpression of DEFB4A (P < 0.001), DEFB103A (P = 0.001) and S100A7 (P < 0.001) was found in cutaneous surgical site infections. Immunohistochemistry revealed intensely elevated protein levels of psoriasin in infected wounds, and differences in distribution with respect to the epithelial layers. CONCLUSIONS: The study demonstrates upregulated mRNA expression and protein levels of HDPs in postoperatively inflamed epithelium. The results may be a starting point for novel pharmacological treatments.

Neuroendocrine and psychometric evaluation of a placebo version of the 'Trier Social Stress Test'.

The "Trier Social Stress Test" (TSST) is one of the most prominent laboratory stress paradigms. It is often used to investigate the effects of stress on cognitive or affective parameters. Such studies need a non-stress control condition. However, control conditions currently employed are often rather ill defined and do not parallel important modulating variables, e.g., physical or cognitive load of the TSST. We here introduce a placebo version of the TSST, which contains a free speech and a simple mental arithmetic task without uncontrollability and social-evaluative threat. In two studies, this control condition was evaluated using salivary markers of stress reactivity (cortisol and alpha-amylase) and a questionnaire for anticipatory cognitive stress appraisal (PASA). In experiment 1 participants who were treated with the placebo condition showed no cortisol response and a small, but significant salivary alpha-amylase (sAA) response. Both responses were significantly smaller than those of TSST-treated participants. The placebo-treated participants also rated the treatment situation as less stressful. In experiment 2 a crossover study with the use of an intercom to instruct the participants and ensure their compliance was conducted. Again there was a strong cortisol response to the TSST, which differed significantly from the cortisol levels observed during the placebo condition. Importantly the cortisol response was not influenced by treatment order (TSST or placebo first). However, in this study we found similar reactions between TSST- and placebo-treated participants with regard to sAA-response. We suggest that the introduced placebo protocol for the TSST is a promising tool for future psychobiological research. The exact procedure for a given experiment should be tailored to the specific needs of the empirical question studied.

Salivary alpha-amylase as a non-invasive biomarker for the sympathetic nervous system: current state of research.

Development of new biomarkers is a constantly evolving field of research endeavor in psychoneuroendocrinology. Salivary biomarkers have received special attention since they are readily accessible and easily obtained. Salivary alpha-amylase (sAA) has been proposed as a sensitive biomarker for stress-related changes in the body that reflect the activity of the sympathetic nervous system (SNS), and a growing body of research is accumulating to support the validity and reliability of this parameter. However, questions remain to be answered before sAA can be accepted as an index of SNS activity. This review describes sAA as an emerging biomarker for stress and provides an overview of the current literature on stress-related alterations in sAA. It critically discusses how sAA might reflect changes in the autonomic nervous system. Finally, current and future fields for the application of sAA measurement are outlined.

Cyclic AMP-inducible genes respond uniformly to seasonal lighting conditions in the rat pineal gland.

The encoding of photoperiodic information ensues in terms of the daily profile in the expression of cyclic AMP (cAMP)-inducible genes such as the arylalkylamine N-acetyltransferase (AA-NAT) gene that encodes the rate-limiting enzyme in melatonin formation. In the present study, we compared the influence of the photoperiodic history on the cAMP-inducible genes AA-NAT, inducible cyclic AMP early repressor (ICER), fos-related antigen-2 (FRA-2), mitogen-activated protein kinase phosphatase-1 (MKP-1), nerve growth factor inducible gene-A (NGFI-A) and nerve growth factor inducible gene-B (NGFI-B) in the pineal gland of rats. For this purpose, we monitored the daily profiles of each gene in the same pineal gland under a long (light/dark 16:8) and a short (light/dark 8:16) photoperiod by measuring the respective mRNA amounts by real-time polymerase chain reaction analysis. We found that, for all genes under investigation, the duration of increased nocturnal expression is lengthened and, in relation to light onset, the nocturnal rise is earlier under the long photoperiod (light/dark 16:8). Furthermore, with the exception of ICER, all other cAMP-inducible genes tend to display higher maximum expression under light/dark 8:16 than under light/dark 16:8. Photoperiod-dependent changes persist for all of the cAMP-inducible genes when the rats are kept for two cycles under constant darkness. Therefore, all cAMP-inducible genes are also influenced by the photoperiod of prior entrained cycles. Our study indicates that, despite differences regarding the expressional control and the temporal phasing of the daily profile, cAMP-inducible genes are uniformly influenced by photoperiodic history in the rat pineal gland.

Role of endocrine and inflammatory alterations in comorbid somatic diseases of post-traumatic stress disorder.

Since its first description in the Diagnostic and Statistical Manual for Mental Disorders, post-traumatic stress disorder (PTSD) has been characterized as a disorder of altered affective functioning which causes tremendous distress. In addition, it has been recognized that PTSD is not only accompanied by ''poor health'' but also by a number of specific and non-specific ''somatic'' pathologies, such as cardiovascular, autoimmune and physical complaints/chronic pain. It has been hypothesized that alterations of the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic-adrenal-medullary (SAM) and the immune system may mediate or facilitate these somatic conditions. The aims of this review are to summarize studies that report altered somatic functioning in PTSD and to review how endocrine and immune function differentially affect PTSD-related somatic malfunction. It is hypothesized that alterations of HPA axis and SAM system permit disinhibition of inflammatory mechanisms, which in turn foster the development of somatic diseases as well as self-reported physical complaints.

Psychological determinants of the cortisol stress response: the role of anticipatory cognitive appraisal.

Psychosocial stress is a potent activator of the hypothalamus-pituitary-adrenal (HPA) axis. While the physiological mechanisms of HPA axis responses to stress as well as its short and long-term consequences have been extensively examined, less is known why someone elicits an acute neuroendocrine stress response, i.e. what are the psychological processes involved and how are they related to the acute neuroendocrine stress response. To examine this question, a questionnaire to assess anticipatory cognitive appraisal processes was developed and administered to 81 male healthy subjects in a standardized psychosocial stress situation (Trier social stress test). Cortisol stress responses were assessed with repeated measurement of salivary free cortisol. Hierarchical regression analyses show that anticipatory cognitive appraisal, in contrast to general personality factors and retrospective stress appraisal is an important determinant of the cortisol stress response, explaining up to 35% of the variance of the salivary cortisol response. The reported results emphasize the importance of psychological stress processing for the understanding of psychobiological stress responses. Since stress and its biological consequences have been shown to be associated with the onset and the maintenance of somatic illnesses and psychiatric disorders, psychological processes are prime targets for prevention and intervention.

Monocyte proinflammatory cytokine release is higher and glucocorticoid sensitivity is lower in middle aged men than in women independent of cardiovascular risk factors.

OBJECTIVE: To investigate whether stimulated monocyte cytokine release and its inhibition by glucocorticoids differs between men and women. DESIGN: In vitro monocyte interleukin 6 (IL-6) and tumour necrosis factor alpha (TNFalpha) release after lipopolysaccharide stimulation were assessed with and without co-incubation with increasing doses of dexamethasone and hydrocortisone separately. Glucocorticoid sensitivity was defined as the amount of a particular glucocorticoid required to inhibit lipopolysaccharide stimulated monocyte cytokine release by 50%. The established cardiovascular risk factors of age, body mass index, number of cigarettes smoked daily, low density cholesterol to high density cholesterol ratio, systolic and diastolic blood pressure, and haemoglobin A1c were used as covariates. SETTING: Aircraft manufacturing plant in southern Germany. PATIENTS: 269 middle aged male and 36 middle aged female employees. RESULTS: Release of monocyte IL-6 and TNFalpha (each p = 0.001) was higher in samples from men than in those from women. Inhibition of lipopolysaccharide stimulated IL-6 and TNFalpha release by either glucocorticoid was less pronounced in samples from men than in those from women (IL-6: dexamethasone p = 0.033, hydrocortisone p = 0.029; TNFalpha: dexamethasone p < 0.001, hydrocortisone p = 0.089). CONCLUSIONS: The finding suggests that proinflammatory activity of circulating monocytes is higher in men than in women independent of cardiovascular risk factors, thereby providing one explanation for the relatively greater coronary risk in men.

Impact of oral contraceptive use on glucocorticoid sensitivity of pro-inflammatory cytokine production after psychosocial stress.

We previously reported that women using oral contraceptives (OC) show blunted free cortisol responses to psychosocial stress compared to medication-free women. Low cortisol responses to stress have been shown to be associated with increased susceptibilities to chronic inflammatory and autoimmune processes in animal models and certain human diseases.To address the question if the blunted free cortisol response of OC users may be compensated at the level of the target tissue, we measured hypothalamus-pituitary-adrenal (HPA) axis activation and glucocorticoid (GC) sensitivity of pro-inflammatory cytokine production after psychosocial stress in 14 women using OC and 11 women in the luteal phase of the menstrual cycle. All subjects were exposed to the psychosocial stress paradigm 'Trier Social Stress Test' (TSST). Free cortisol was measured repeatedly before and after stress. GC sensitivity was assessed by dexamethasone (DEX) inhibition of lipopolysaccharide (LPS) stimulated production of interleukin-6 (IL-6) in whole blood, immediately before, as well as 10 and 60 min after the stress test. As expected, the stress test induced significant increases in free cortisol in luteal phase women, while OC users showed blunted responses (F=3.31;p<0.05). GC sensitivity showed different response patterns; In luteal phase women a slight but not significant decrease was observed throughout the experiment. In contrast, women using OC showed a significant increase in GC sensitivity after stress (F=3.559;p<0.05). These results show, that an increase in GC sensitivity of pro-inflammatory cytokine production may at least in part compensate the low cortisol levels seen in OC users after stress. This could be one mechanism to protect women using OC medication from chronic inflammatory and autoimmune diseases.

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.

Tissue specificity of glucocorticoid sensitivity in healthy adults.

Contradicting data exist as to whether interindividual patterns in glucocorticoid (GC) sensitivity vary between different target tissues in humans. This study therefore measured GC sensitivity in 36 healthy subjects in three target tissues: the immune system; the cardiovascular system, and the hypothalamus-pituitary-adrenal axis. For this purpose, dexamethasone inhibition of lipopolysaccharide-induced interleukin-6 and tumor necrosis factor-alpha production in peripheral leukocytes, beclomethasone dipropionate-induced skin blanching, and suppression of cortisol levels after low-dose (0.5 mg) dexamethasone suppression test were determined in each subject. The results showed the expected glucocorticoid-induced suppression of interleukin-6 and tumor necrosis factor-alpha production (both P < 0.001), dose-dependent skin blanching (P < 0.001), and suppression of salivary cortisol response to awakening (P < 0.001). However, neither simple correlations nor cluster analysis revealed a significant association among the three bioassays for GC sensitivity. In contrast to the idea that interindividual variation in GC sensitivity is an intrinsic trait affecting all tissues, these results suggest that this variability is target tissue specific in healthy subjects.

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

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

Effects of fasting and glucose load on free cortisol responses to stress and nicotine.

The availability of energy appears to exert important regulatory functions in pituitary-adrenal stress responses. In two studies, the effects of short-term fasting and subsequent glucose administration on the free cortisol response to psychological stress and nicotine consumption were investigated. Study 1: After fasting for 8-11 h, healthy young men ingested either 100 g glucose (n = 13) or water (n = 12). One hour later they were exposed to a psychosocial stress task (Trier Social Stress Test). A third group also ingested 100 g glucose, but they were not exposed to any additional treatment (n = 10). Capillary blood glucose levels were in the lower euglycemic range before and significantly elevated after the glucose load (64.9 +/- 9.8 vs. 162.5 +/- 43.5 mg/dL; F = 149.04, P < 0.001). Although glucose load per se did not affect free cortisol levels, psychosocial stress induced a large cortisol response in glucose-treated subjects. In contrast, fasted subjects who received tap water did not respond to the Trier Social Stress Test with significant changes in cortisol levels (F = 6.27, P < 0.001). Both groups responded with a similar increase in heart rates (F = 33.53, P < 0.001) with no statistically significant difference between glucose and water-treated subjects. Study 2: Twelve habitual smokers received 100 g glucose or tap water after fasting for at least 8 h on two separate sessions (cross-over, random sequence). Forty-five min after glucose/water ingestion, they smoked two cigarettes with a nicotine content of 1.0 mg/cigarette. Subjects were euglycemic before smoking, with a significant rise of glucose levels after consumption of 100 g glucose (64.4 +/- 8.3 vs. 143.5 +/- 40.0 mg/dL; F = 40.25, P < 0.001). As in Exp 1, subjects showed a substantially larger free cortisol response to nicotine under glucose load compared with water load (F = 4.91, P < 0.001). From these data we conclude that the free cortisol response to stimulation is under significant control of center responsible for monitoring energy availability. Low glucose levels appear to inhibit adrenocortical responsiveness in healthy subjects. In agreement with results from animal studies, the present results suggest that ready access to energy is a prerequisite for hypothalamus-pituitary-adrenal stress responses.

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.