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1.  Effects of perceived control and cognitive coping on endocrine stress responses to pharmacological activation 
Biological psychiatry  2008;64(8):701-707.
Background
The hypothalamic-pituitary adrenal (HPA) axis may mediate negative health effects of stress. It is sensitive to cognitive/emotional factors like novelty, perceived control and coping. Psychological intervention that reduces novelty, and enhances cognitive coping and sense of control can reduce cortisol responses to pentagastrin, a pharmacological HPA activator. This study attempted to identify the core factors that modulate HPA axis activity in this model.
Methods
Varying instructions were administered prior to drug exposure in a two-visit (placebo first) pentagastrin infusion paradigm. Healthy subjects (n=40) were randomly assigned to 1 of 4 instruction groups: (1) Standard instruction (SI); (2) Full cognitive intervention (CI); (3) The CI control component alone; or (4) The CI novelty reduction/coping components alone. Blood samples were obtained via intravenous catheter before and after pentagastrin.
Results
Subjects receiving an intervention had smaller cortisol responses than subjects receiving standard instructions. “Coping” alone had as strong an impact as the more complex intervention that combined “coping” and “control.” “Control alone” also reduced cortisol but its HPA impact appeared less robust.
Conclusions
Brief psychological manipulation can significantly reduce HPA activation in challenge paradigms. Cognitive preparation that focused on side effects, reduced potential surprise and enhanced cognitive coping modulated HPA axis activity as effectively as a previously tested intervention that combined coping and control manipulations. A sense of control alone also reduced cortisol release. The results support development of “control” or “coping” techniques to combat negative health effects of stress that are mediated by HPA axis activation.
doi:10.1016/j.biopsych.2008.05.007
PMCID: PMC2579765  PMID: 18571624
stress; cortisol; pentagastrin; control; coping; anxiety
2.  CRH-stimulated cortisol release and food intake in healthy, non-obese adults 
Psychoneuroendocrinology  2009;35(4):607-612.
Summary
Background
There is considerable anecdotal and some scientific evidence that stress triggers eating behavior, but underlying physiological mechanisms remain uncertain. The hypothalamic-pituitary-adrenal (HPA) axis is a key mediator of physiological stress responses and may play a role in the link between stress and food intake. Cortisol responses to laboratory stressors predict consumption but it is unclear whether such responses mark a vulnerability to stress-related eating or whether cortisol directly stimulates eating in humans.
Methods
We infused healthy adults with corticotropin-releasing hormone (CRH) at a dose that is subjectively undetectable but elicits a robust endogenous cortisol response, and measured subsequent intake of snack foods, allowing analysis of HPA reactivity effects on food intake without the complex psychological effects of a stress paradigm.
Results
CRH elevated cortisol levels relative to placebo but did not impact subjective anxious distress. Subjects ate more following CRH than following placebo and peak cortisol response to CRH was strongly related to both caloric intake and total consumption.
Conclusions
These data show that HPA axis reactivity to pharmacological stimulation predicts subsequent food intake and suggest that cortisol itself may directly stimulate food consumption in humans. Understanding the physiological mechanisms that underlie stress-related eating may prove useful in efforts to attack the public health crises created by obesity.
doi:10.1016/j.psyneuen.2009.09.017
PMCID: PMC2843773  PMID: 19828258
stress; cortisol; CRH; appetite; HPA
3.  Bouncing back - trauma and the HPA-axis in healthy adults 
European Journal of Psychotraumatology  2010;1:10.3402/ejpt.v1i0.5844.
Background
Dysregulation of the hypothalamic–pituitary–adrenal (HPA)-axis is thought to underlie stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD). Some studies have reported HPA-axis dysregulation in trauma-exposed (TE) adults in the absence of psychiatric morbidity. In this dissertation we set out to unravel part of the mechanism that underlies the complex relations between trauma exposure, stress regulation, and psychopathology.
Method
Mentally healthy TE subjects were compared with non-trauma-exposed (NE) healthy controls. To distinguish between the potential effects of childhood trauma and adulthood trauma, we included women exposed to childhood trauma as well as men who were exposed to trauma during adulthood. Basal HPA-axis functioning was assessed with salivary cortisol samples. HPA-axis reactivity was assessed with the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test.
Results
The results show that childhood trauma exposure is associated with an attenuated cortisol response after the Dex/CRH challenge test in women. In contrast, trauma exposure during adulthood was not associated with alterations in HPA-axis regulation after the Dex/CRH test. Neither childhood trauma nor adulthood trauma were associated with basal HPA-axis functioning.
Conclusion
Childhood trauma rather than adulthood trauma may chronically affect HPA-axis functioning. Since the association between adulthood trauma and resilience to psychopathology cannot be explained by HPA-axis functioning alone, other factors must play a role.
doi:10.3402/ejpt.v1i0.5844
PMCID: PMC3402002  PMID: 22893796
HPA-axis; cortisol; trauma; childhood trauma; adults; resilience
4.  GENDER DIFFERENCES IN THE EFFECT OF EARLY LIFE TRAUMA ON HYPOTHALAMIC–PITUITARY–ADRENAL AXIS FUNCTIONING 
Depression and anxiety  2011;28(5):383-392.
Background
The objective of this study was to examine the modifying effect of gender on the association between early life trauma and the hypothalamic–pituitary–adrenal (HPA) axis response to a pharmacologic challenge and a social stress task in men and women. Participants (16 men, 23 women) were the control sample of a larger study examining HPA axis function. Individuals with major depressive disorder, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded.
Methods
In two test sessions, subjects received 1 μg/kg of corticotropin-releasing hormone (CRH) intravenously and participated in the Trier Social Stress Test (TSST). Primary outcomes included plasma cortisol and corticotropin levels measured at baseline and more than five time points following the challenges. Predictors included gender and early life trauma, as measured by the Early Trauma Index. Using factor analysis, the domains general trauma, severe trauma, and the effects of trauma were established. Using regression, these constructs were used to predict differential HPA reactivity in men and women following the challenges.
Results
The three factors accounted for the majority of the variance in the ETI. Following the CRH challenge, women had higher overall corticotropin response as dictated by the area under the curve analysis. There were no significant associations between trauma and neuroendocrine response to the TSST.
Conclusions
CRH challenge results indicate that gender differences in the impact of early trauma may help explain the differential gender susceptibility to psychopathology following adverse childhood events. This may help explain gender differences in some stress-sensitive psychiatric disorders.
doi:10.1002/da.20795
PMCID: PMC3243643  PMID: 21328636
trauma; gender; HPA axis; hypothalamic–pituitary–adrenal axis; cortisol; corticotropin
5.  On the role of the corticotropin-releasing hormone signalling system in the aetiology of inflammatory skin disorders 
The British journal of dermatology  2009;160(2):229-232.
Corticotropin-releasing hormone (CRH; previously known as corticotropin-releasing factor) is the central regulator of the hypothalamic-pituitary-adrenal (HPA) axis, which is the main organizer of the body’s response to stress.1–5 Stress induces the hypothalamic production and release of CRH, which then causes the activation of the CRH receptor (CRHR) type 1 (CRHR-1) in the anterior pituitary to stimulate ACTH release, as well as proopiomelanocortin (POMC) expression and processing. 1,2,6 ACTH stimulates the production and secretion of cortisol (humans) or corticosterone (rodents) by the adrenal cortex. These steroids regulate the body’s response to counteract effects of the stressor and suppress the HPA through the negative feedback mechanism. CRH/POMC expression can also be activated by the cytokines interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-α, thus involving the immune system in the central regulation of the HPA axis.7 In addition, CRH together with related urocortin (URC) peptides regulate behavioural, autonomic, endocrine, reproductive, cardiovascular, gastrointestinal and metabolic functions both on the central and on the peripheral levels, and CRH has immunosuppressive effects via the HPA.6,8–12 It is also accepted that peripheral CRH and related peptides have predominantly proinflammatory functions,13,14 and in this way differ from their central immunosuppressive activity.2 However, recent data also suggest that the peripheral CRH may have dual effects: a direct, short-term proinflammatory function and an indirect, remote anti-inflammatory function.15–18
doi:10.1111/j.1365-2133.2008.08958.x
PMCID: PMC2649670  PMID: 19187344
6.  Sex differences in cortisol response to Corticotropin Releasing Hormone challenge over puberty: Pittsburgh Pediatric Neurobehavioral Studies 
Psychoneuroendocrinology  2011;36(8):1226-1238.
Summary
Objective
Consistent sex differences in regulation of the hypothalamic pituitary adrenocortical (HPA) axis have been shown in animal models and emerge over puberty. However, parallel work in humans is lacking despite implications for elucidating the emergence of sex differences in depression over puberty. We investigated sex differences in HPA response to corticotropin releasing hormone (CRH) challenge over puberty in a carefully screened normative sample.
Methods
Participants were 68 healthy children (41% girls), ages 6–16, with no personal or family history of psychiatric disorder. Pubertal maturation was determined by Tanner staging. Following 24 hours of adaptation, 9–10 plasma cortisol samples were collected over 30–40 minutes pre-infusion baseline, 1 μg/kg CRH infusion, and 90–180 minutes post-infusion recovery. Thirty-seven participants completed 2+ CRH challenges allowing inclusion of cross-sectional and longitudinal data in all analyses. The influence of gender and pubertal maturation on parameters of cortisol response to CRH challenge was investigated using nonlinear mixed model metholodogy.
Results
Girls showed increasing total cortisol output following CRH challenge over puberty, while boys showed little change in total cortisol output over puberty. Increased cortisol output in girls was explained by slower reactivity and recovery rates leading to prolonged time to reach peak cortisol and delayed return to baseline over puberty. Girls also showed increasing baseline cortisol over puberty, while boys showed declining baseline over puberty.
Conclusion
Results reveal subtle normative sex differences in the influence of pubertal maturation on HPA regulation at the pituitary level. This normative shift may tip the balance towards stress response dysregulation in girls at high risk for depression, and may represent one potential mechanism underlying elevated rates of depression among pubescent girls.
doi:10.1016/j.psyneuen.2011.02.017
PMCID: PMC3270708  PMID: 21489699
CRH challenge; cortisol; sex differences; puberty; depression; adolescent; children; HPA; gender differences
7.  Hypothalamic-Pituitary-Adrenal Axis Dysregulation in Depressed Children and Adolescents: A Meta-Analysis 
Psychoneuroendocrinology  2009;34(9):1272-1283.
Summary
Research findings on the hypothalamic-pituitary-adrenal (HPA) axis and pediatric depression reflect a variety of methodological approaches that tap different facets of HPA-axis functions. Partly owing to the methodological heterogeneity of studies, descriptive reviews of this area have produced inconsistent conclusions. Therefore, we conducted formal meta-analyses of pertinent studies in order to advance our understanding of HPA-axis dysregulation in pediatric depression. We examined: a) 17 published studies of HPA-axis response to the dexamethasone suppression test in depressed youth (DST; N=926) and b) 17 studies of basal HPA-axis functioning (N=1,332). We also examined descriptively studies that used corticotropin releasing hormone (CRH) infusion, and those that used psychological probes of the HPA-axis. The global standardized mean effect size difference in HPA-axis response to the DST between depressed and non-depressed youth was .57, z = 4.18 p< .01. The global standardized mean difference effect size in basal HPA-axis functioning was .20, z = 4.53, p < .01. Age, sex, timing of sampling, dexamethasone dosage, or type of control group was not a significant source of variability for the DST or basal studies. In addition, when compared to non-depressed peers, depressed youth have a normative response to CRH infusion but an overactive response to psychological stressors. In conclusion, the HPA-axis system tends to be dysregulated in depressed youth, as evidenced by atypical responses to the DST, higher baseline cortisol values, and an overactive response to psychological stressors. This pattern of dysregulation suggests anomalies within the axis's negative feedback system and CRH production, but intact pituitary and adrenal sensitivity.
doi:10.1016/j.psyneuen.2009.03.016
PMCID: PMC2796553  PMID: 19406581
HPA-Axis; Depression; Children; Adolescents; Dexamethasone Suppression Test
8.  Escitalopram and Neuroendocrine Response in Healthy First-Degree Relatives to Depressed Patients – A Randomized Placebo-Controlled Trial 
PLoS ONE  2011;6(6):e21224.
Introduction
The mechanisms by which selective serotonin re-uptake inhibitors (SSRI) act in depressed patients remain unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. The aim of the AGENDA trial was to investigate whether long-term intervention with SSRI versus placebo affects the cortisol response in the dexamethasone corticotropin-releasing hormone (DEX-CRH) test in healthy first-degree relatives to patients with major depressive disorder (MDD).
Methods
Eighty healthy first-degree relatives to patients with MDD were randomized to escitalopram 10 mg versus matching placebo daily for four weeks. The primary outcome measure was the intervention difference in the change of the total area under the curve (CorAUCtotal) for plasma cortisol in the DEX-CRH test at entry to after four weeks of intervention.
Results
Change in CorAUCtotal showed no statistically significant difference between the escitalopram and the placebo group, p = 0.47. There were large intra- and inter-individual differences in the results of the DEX-CRH test. There was statistically significant negative correlation between the plasma escitalopram concentration and change in CorAUCtotal, rho = −0.41, p = 0.01. Post-hoc analyses showed a statistically significant interaction between age and intervention group and change in log CorAUCtotal.
Conclusion
The present trial does not support an effect of escitalopram 10 mg daily compared with placebo on the HPA-axis in healthy first-degree relatives to patients with MDD. Increasing levels of escitalopram tended to decrease the HPA-response in the DEX-CRH test and this effect increased with age.
Trial Registration
ClinicalTrials.gov [NCT00386841
doi:10.1371/journal.pone.0021224
PMCID: PMC3124484  PMID: 21738622
9.  CORTICOTROPIN-RELEASING-HORMONE RECEPTORS IN THE MEDIAL PREFRONTAL CORTEX REGULATE HYPOTHALAMIC-PITUITARY-ADRENAL ACTIVITY AND ANXIETY-RELATED BEHAVIOR REGARDLESS OF PRIOR STRESS EXPERIENCE 
Brain research  2007;1186:212-223.
The hypothalamic-pituitary-adrenal (HPA) axis habituates, or gradually decreases its activity, with repeated exposure to the same stressor. During habituation, the HPA axis likely requires input from cortical and limbic regions involved in processing of cognitive information that is important in coping to stress. Brain regions such as the medial prefrontal cortex (mPFC) are recognized as important in mediating these processes. The mPFC modulates stress-related behavior and some evidence suggests that the mPFC regulates acute and repeated stress-induced HPA responses. Interestingly, corticotropin releasing hormone(CRH)-1 receptors, which integrate neuroendocrine, behavioral and autonomic responses to stress, are localized in the mPFC but have not been specifically examined with respect to HPA regulation. We hypothesized that CRH receptor activity in the mPFC contributes to stress-induced regulation of HPA activity and anxiety-related behavior, and that CRH release in the mPFC may differentially regulate HPA responses in acutely- compared to repeatedly-stressed animals. In the present experiments, we found that blockade of CRH receptors in the mPFC with the non-selective receptor antagonist, D-Phe-CRH (50ng or 100ng) significantly inhibited HPA responses compared to vehicle regardless of whether animals were exposed to a single, acute 30min restraint or to the eighth 30min restraint. We also found that intra-mPFC injections of CRH (20ng) significantly increased anxiety-related behavior in the elevated plus maze in both acutely- and repeatedly-restrained groups compared to vehicle. Together, these results suggest an excitatory influence of CRH in the mPFC on stress-induced HPA activity and anxiety-related behavior regardless of prior stress experience.
doi:10.1016/j.brainres.2007.07.100
PMCID: PMC2175080  PMID: 18001698
prefrontal cortex; corticotropin releasing hormone; restraint; anxiety; ACTH; corticosterone
10.  Response to CRH Infusion in Cocaine-Dependent Individuals 
Archives of general psychiatry  2009;66(4):422-430.
Context
Corticotropin-releasing hormone (CRH), through the hypothalamic pituitary adrenal (HPA) axis and other brain stress systems, is involved in the emotional dysregulation associated with cocaine dependence. Little is known about the response of cocaine-dependent individuals to CRH administration.
Objective
The primary objective was to examine the HPA axis, subjective and physiologic response to CRH in cocaine-dependent individuals and controls.
Design
Case-control study
Setting
Subjects were admitted to a General Clinical Research Center (GCRC) for testing and abstinence verified with urine drug screening.
Participants
Participants were control males (n=23), control females (n=24), cocaine-dependent males (n=28), and cocaine-dependent females (n=25). Individuals with dependence on other substances (except caffeine, nicotine) or with major depression, PTSD, bipolar, psychotic and eating disorders were excluded.
Intervention
Subjects received i.v. CRH (1ug/kg).
Main Outcome Measures
Primary outcomes included plasma ACTH and cortisol, heart rate, and subjective measurements.
Results
Cocaine-dependent individuals exhibited higher stress (P < 0.001) and craving to CRH compared to controls. A positive correlation (rs=.51, P=0.0002) between stress and craving was found in cocaine dependent subjects. CRH elevated heart rates in all groups, however cocaine dependent females, demonstrated a significantly higher heart rate at all time points (P=0.05). Women had higher cortisol response to CRH (P=0.028). No effect of cocaine status was observed. ACTH response to CRH was independent of gender and cocaine. Cortisol and ACTH were positively correlated in the controls and cocaine-dependent males, but not in cocaine-dependent females (rs = 0.199; P = 0.4).
Conclusion
There is an increased subjective and heart rate response to CRH and a relationship between stress and craving in cocaine-dependent individuals. The lack of difference in HPA axis response between the cocaine and control groups suggests that the heart rate and subjective responses in the cocaine group may be mediated by sensitization of non-hypothalamic stress-responsive CRH systems.
doi:10.1001/archgenpsychiatry.2009.9
PMCID: PMC2696287  PMID: 19349312
11.  Behavioral Studies and Genetic Alterations in Corticotropin-Releasing Hormone (CRH) Neurocircuitry: Insights into Human Psychiatric Disorders 
Behavioral sciences  2012;2(2):135-171.
To maintain well-being, all organisms require the ability to re-establish homeostasis in the presence of adverse physiological or psychological experiences. The regulation of the hypothalamic-pituitary adrenal (HPA) axis during stress is important in preventing maladaptive responses that may increase susceptibility to affective disorders. Corticotropin-releasing hormone (CRH) is a central stress hormone in the HPA axis pathway and has been implicated in stress-induced psychiatric disorders, reproductive and cardiac function, as well as energy metabolism. In the context of psychiatric disorders, CRH dysfunction is associated with the occurrence of post-traumatic stress disorder, major depression, anorexia nervosa, and anxiety disorders. Here, we review the synthesis, molecular signaling and regulation, as well as synaptic activity of CRH. We go on to summarize studies of altered CRH signaling in mutant animal models. This assembled data demonstrate an important role for CRH in neuroendocrine, autonomic, and behavioral correlates of adaptation and maladaptation. Next, we present findings regarding human genetic polymorphisms in CRH pathway genes that are associated with stress and psychiatric disorders. Finally, we discuss a role for regulators of CRH activity as potential sites for therapeutic intervention aimed at treating maladaptive behaviors associated with stress.
doi:10.3390/bs2020135
PMCID: PMC3471213  PMID: 23077729
corticotropin-releasing hormone; anxiety; depression; psychiatric disorders; human polymorphisms; CRH receptors; CRH binding-protein
12.  Behavioral Studies and Genetic Alterations in Corticotropin-Releasing Hormone (CRH) Neurocircuitry: Insights into Human Psychiatric Disorders 
Behavioral Sciences  2012;2(2):135-171.
To maintain well-being, all organisms require the ability to re-establish homeostasis in the presence of adverse physiological or psychological experiences. The regulation of the hypothalamic-pituitary adrenal (HPA) axis during stress is important in preventing maladaptive responses that may increase susceptibility to affective disorders. Corticotropin-releasing hormone (CRH) is a central stress hormone in the HPA axis pathway and has been implicated in stress-induced psychiatric disorders, reproductive and cardiac function, as well as energy metabolism. In the context of psychiatric disorders, CRH dysfunction is associated with the occurrence of post-traumatic stress disorder, major depression, anorexia nervosa, and anxiety disorders. Here, we review the synthesis, molecular signaling and regulation, as well as synaptic activity of CRH. We go on to summarize studies of altered CRH signaling in mutant animal models. This assembled data demonstrate an important role for CRH in neuroendocrine, autonomic, and behavioral correlates of adaptation and maladaptation. Next, we present findings regarding human genetic polymorphisms in CRH pathway genes that are associated with stress and psychiatric disorders. Finally, we discuss a role for regulators of CRH activity as potential sites for therapeutic intervention aimed at treating maladaptive behaviors associated with stress.
doi:10.3390/bs2020135
PMCID: PMC3471213  PMID: 23077729
corticotropin-releasing hormone; anxiety; depression; psychiatric disorders; human polymorphisms; CRH receptors; CRH binding-protein
13.  Modulation of cortisol responses to the DEX/CRH test by polymorphisms of the interleukin-1beta gene in healthy adults 
Background
Recently, hypothalamus-pituitary-adrenal (HPA) axis function assessed with the combined dexamethasone (DEX)/corticotropin releasing hormone (CRH) test has been shown to be associated with response to antidepressant treatment. A polymorphism (rs16944) in the interleukin-1beta (IL-1β) gene has also been reported to be associated with the medication response in depression. These findings prompted us to examine the possible association between IL-1β gene polymorphisms and HPA axis function assessed with the DEX/CRH test.
Methods
DEX/CRH test was performed in 179 healthy volunteers (45 males: mean age 40.5 ± 15.8 years; 134 females: mean age 47.1 ± 13.2 years). Five tagging single nucleotide polymorphisms (SNPs) of IL-1β gene (rs2853550, rs1143634, rs1143633, rs1143630, rs16944) were selected at an r2 threshold of 0.80 with a minor allele frequency > 0.1. Genotyping was performed by the TaqMan allelic discrimination assay. A two-way factorial analysis of variance (ANOVA) was performed with the DEX/CRH test results as the dependent variable and genotype and gender as independent variables. To account for multiple testing, P values < 0.01 were considered statistically significant for associations between the genotypes and the cortisol levels.
Results
The cortisol levels after DEX administration (DST-Cortisol) showed significant associations with the genotypes of rs16944 (P = 0.00049) and rs1143633 (P = 0.0060), with no significant gender effect or genotype × gender interaction. On the other hand, cortisol levels after CRH administration (DEX/CRH-Cortisol) were affected by gender but were not significantly influenced by the genotype of the examined SNPs, with no significant genotype × gender interaction.
Conclusions
Our results suggest that genetic variations in the IL-1β gene contribute to the HPA axis alteration assessed by DST-Cortisol in healthy subjects. On the other hand, no significant associations of the IL-1β gene polymorphisms with the DEX/CRH-Cortisol were observed. Confirmation of our findings in futures studies may add new insight into the communication between the immune system and the HPA axis.
doi:10.1186/1744-9081-7-23
PMCID: PMC3141407  PMID: 21726461
14.  In Search of HPA Axis Dysregulation in Child and Adolescent Depression 
Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis in adults with major depressive disorder is among the most consistent and robust biological findings in psychiatry. Given the importance of the adolescent transition to the development and recurrence of depressive phenomena over the lifespan, it is important to have an integrative perspective on research investigating the various components of HPA axis functioning among depressed young people. The present narrative review synthesizes evidence from the following five categories of studies conducted with children and adolescents: (1) those examining the HPA system’s response to the dexamethasone suppression test (DST); (2) those assessing basal HPA axis functioning; (3) those administering corticotropin-releasing hormone (CRH) challenge; (4) those incorporating psychological probes of the HPA axis; and (5) those examining HPA axis functioning in children of depressed mothers. Evidence is generally consistent with models of developmental psychopathology that hypothesize that atypical HPA axis functioning precedes the emergence of clinical levels of depression and that the HPA axis becomes increasingly dysregulated from child to adult manifestations of depression. Multidisciplinary approaches and longitudinal research designs that extend across development are needed to more clearly and usefully elucidate the role of the HPA axis in depression.
doi:10.1007/s10567-011-0084-5
PMCID: PMC3095794  PMID: 21290178
Depression; Childhood and adolescence; Hypothalamic–pituitary–adrenal (HPA) axis; Developmental psychopathology
15.  Cortisol and ACTH Responses to the Dex/CRH Test: Influence of Temperament 
Hormones and behavior  2008;53(4):518-525.
Temperament and personality traits such as neuroticism and behavioral inhibition are prospective predictors of the onset of depression and anxiety disorders. Exposure to stress is also linked to the development of these disorders, and neuroticism and inhibition may confer or reflect sensitivity to stressors. Several lines of research have documented hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in some patients with major depression, as well as in children and non-human primates with inhibited temperaments. The present investigation tested the hypothesis that stress-reactive temperaments would be predictive of plasma adrenocorticotropin (ACTH) and cortisol concentrations in the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Sixty adults completed diagnostic interviews and questionnaires assessing the temperament domains of novelty seeking and harm avoidance and symptoms of anxiety and depression. All subjects were free of any current or past Axis I psychiatric disorder. The Dex/CRH test was performed on a separate visit. A repeated measures general linear model (GLM) showed a main effect of harm avoidance in predicting cortisol concentrations in the test (F(1, 58) = 4.86, p < .05). The GLM for novelty seeking and cortisol response also showed a main effect (F(1, 58) = 5.28, p <.05). Higher cortisol concentrations were associated with higher levels of harm avoidance and lower levels of novelty seeking. A significant interaction of time with harm avoidance and novelty seeking (F(4, 53) = 3.37, p < .05) revealed that participants with both high levels of harm avoidance and low levels of novelty seeking had the highest cortisol responses to the Dex/CRH test. Plasma ACTH concentrations did not differ as a function of temperament. The results indicate that temperament traits linked to sensitivity to negative stimuli are associated with greater cortisol reactivity during the Dex/CRH test. Increased adrenocortical reactivity, which previously has been linked to major depression and anxiety disorders, may contribute to the association between temperament/personality traits and these disorders.
doi:10.1016/j.yhbeh.2007.12.004
PMCID: PMC2637444  PMID: 18294637
Cortisol; Dex/CRH test; HPA axis; temperament; personality; inhibition
16.  Altered Response to Neuroendocrine Challenge Linked to Indices of the Metabolic Syndrome in Healthy Adults 
Metabolic syndrome (MetS) is characterized by central obesity, hypertension, insulin resistance, and hypercholesterolemia. Hypothalamic-pituitary-adrenal (HPA) axis activity is frequently abnormal in MetS, and excessive cortisol exposure may be implicated in metabolic derangements. We investigated the hypothesis that cortisol and adrenocorticotropic hormone (ACTH) responses to a standardized neuroendocrine challenge test would be associated with indices of MetS in a community sample of healthy adults. Healthy adults, 125 men and 170 women, without significant medical problems or chronic medications were recruited from the community. Participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, and anthropometric measurements, blood pressure, glycosylated hemoglobin (HbA1c), and cholesterol were measured. Participants reported on their history of early life stress and recent stress, as well as mood and anxiety symptoms. Cortisol and ACTH responses to the Dex/CRH test were negatively associated with measures of central adiposity (p < 0.001) and blood pressure (p < 0.01), and positively associated with HDL cholesterol (p < 0.01). These findings remained significant after controlling for body mass index (BMI). Measures of stress and anxiety and depressive symptoms were negatively correlated with cortisol and ACTH responses in the Dex/CRH test but were not related to MetS indices. That altered HPA axis function is linked to MetS components even in a healthy community sample suggests that these processes may be involved in the pathogenesis of MetS. Identification of premorbid risk processes might allow for detection and intervention prior to the development of disease.
doi:10.1055/s-0032-1306342
PMCID: PMC3580172  PMID: 22549400
metabolic syndrome; HPA axis; cortisol; ACTH; corticotrophin-releasing hormone
17.  Seizure-induced disinhibition of the HPA axis increases seizure susceptibility 
Epilepsy research  2013;108(1):10.1016/j.eplepsyres.2013.10.013.
Stress is the most commonly reported precipitating factor for seizures. The proconvulsant actions of stress hormones are thought to mediate the effects of stress on seizure susceptibility. Interestingly, epileptic patients have increased basal levels of stress hormones, including corticotropin-releasing hormone (CRH) and corticosterone, which are further increased following seizures. Given the proconvulsant actions of stress hormones, we proposed that seizure-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to future seizure susceptibility. Consistent with this hypothesis, our data demonstrate that pharmacological induction of seizures in mice with kainic acid or pilocarpine increases circulating levels of the stress hormone, corticosterone, and exogenous corticosterone administration is sufficient to increase seizure susceptibility. However, the mechanism(s) whereby seizures activate the HPA axis remain unknown. Here we demonstrate that seizure-induced activation of the HPA axis involves compromised GABAergic control of CRH neurons, which govern HPA axis function. Following seizure activity, there is a collapse of the chloride gradient due to changes in NKCC1 and KCC2 expression, resulting in reduced amplitude of sIPSPs and even depolarizing effects of GABA on CRH neurons. Seizure-induced activation of the HPA axis results in future seizure susceptibility which can be blocked by treatment with an NKCC1 inhibitor, bumetanide, or blocking the CRH signaling with Antalarmin. These data suggest that compromised GABAergic control of CRH neurons following an initial seizure event may cause hyperexcitability of the HPA axis and increase future seizure susceptibility.
doi:10.1016/j.eplepsyres.2013.10.013
PMCID: PMC3872265  PMID: 24225328
stress; epilepsy; GABA; KCC2; HPA axis; seizures
18.  Excess corticotropin releasing hormone-binding protein in the hypothalamic-pituitary-adrenal axis in transgenic mice. 
Journal of Clinical Investigation  1998;101(7):1439-1447.
Corticotropin-releasing hormone (CRH) is the primary hypothalamic releasing factor that mediates the mammalian stress response. The CRH-binding protein (CRH-BP) is secreted from corticotropes, the pituitary CRH target cells, suggesting that the CRH-BP may modulate hypothalamic-pituitary-adrenal (HPA) axis activity by preventing CRH receptor stimulation. Transgenic mice were generated that constitutively express elevated levels of CRH-BP in the anterior pituitary gland. RNA and protein analyses confirmed the elevation of pituitary CRH-BP. Basal plasma concentrations of corticosterone and adrenocorticotropin hormone (ACTH) are unchanged, and a normal pattern of increased corticosterone and ACTH was observed after restraint stress. However, CRH and vasopressin (AVP) mRNA levels in the transgenic mice are increased by 82 and 35%, respectively, to compensate for the excess CRH-BP, consistent with the idea that CRH-BP levels are important for homeostasis. The transgenic mice exhibit increased activity in standard behavioral tests, and an altered circadian pattern of food intake which may be due to transgene expression in the brain. Alterations in CRH and AVP in response to elevated pituitary CRH-BP clearly demonstrate that regulation of CRH-BP is important in the function of the HPA axis.
PMCID: PMC508722  PMID: 9525987
19.  Dissection of Hypothalamic-Pituitary-Adrenal Axis Pathology in 1-Month-Abstinent Alcohol-Dependent Men, Part 2: Response to Ovine Corticotropin-Releasing Factor and Naloxone 
Background
Pituitary and adrenal responsiveness is suppressed in abstinent alcohol-dependent individuals. To clarify the specific organizational disruption in hypothalamic-pituitary-adrenal functioning during early abstinence, the authors separately assessed each level of the stress-response axis. In this second of a two-part study, ovine corticotropin-releasing factor (oCRH) was used to stimulate the pituitary corticotrophs, and naloxone was used to activate the axis at the hypothalamic level. In addition, pulsatile characteristics of corticotropin and cortisol were assessed over a 12-hr period (0800 to 2000 hr).
Methods
Eleven abstinent alcohol-dependent men and 10 healthy comparison participants were assessed. All participants were between the ages of 30 and 50 years, and alcohol-dependent patients were abstinent from 4 to 6 weeks. Basal concentrations of corticotropin and cortisol were obtained every 10 min from 0800 to 2000 hr and subjected to pulsatile analysis. Plasma corticotropin and cortisol concentrations were then obtained every 5 to 10 min after low-dose, intravenously administered doses of oCRH (0.4 μg/kg) or naloxone (0.125 mg/kg). Medications were administered at 2000 hr and the two challenge studies were separated by 48 hr.
Results
Pulsatile analysis revealed that the mean corticotropin amplitude was increased in alcohol-dependent patients relative to controls (p < 0.05). Other pulsatile characteristics of corticotropin and all cortisol pulsatile measures were not significantly different between the two groups. The integrated cortisol response to oCRH was significantly lower in alcohol-dependent patients compared with controls (p < 0.01), but the integrated corticotropin response was not significantly different. In contrast, neither the corticotropin nor the cortisol response to naloxone was significantly different between groups.
Conclusions
Adrenocorticoid hyposensitivity persists after oCRH infusion for at least 1 month after cessation of drinking, whereas hyporesponsiveness of the pituitary corticotrophs to CRH seems to resolve with continued abstinence. The authors suggest that adrenocortical hyporesponsiveness during prolonged abstinence may impact relapse risk.
doi:10.1097/01.ALC.0000158939.25531.EE
PMCID: PMC1906932  PMID: 15834217
Adrenal Cortex; Alcoholism; Corticotropin-Releasing Hormone; Naloxone; Pituitary-Adrenal System
20.  DIFFERENTIAL EXPRESSION OF HPA AXIS HOMOLOG IN THE SKIN 
Molecular and cellular endocrinology  2006;265-266:143-149.
Summary
Human skin expresses elements of the hypothalamo-pituitary-adrenal (HPA) axis including pro-opiomelanocortin (POMC), corticotropin releasing hormone (CRH), the CRH receptor-1 (CRH-R1), key enzymes of corticosteroid synthesis and synthesizes glucocorticoids. Expression of these elements is organized in functional, cell type-specific regulatory loops, which imitate the signaling structural hierarchy of the HPA axis. In melanocytes and fibroblasts CRH-induced CRH-R1 stimulation upregulates POMC expression and production of ACTH through activation of cAMP dependent pathway(s). Melanocytes respond with enhanced production of cortisol and corticosterone, which is dependent on POMC activity. Fibroblasts respond to CRH and ACTH with enhanced production of corticosterone, but not cortisol, which is produced constitutively. Organ-cultured human scalp hair follicles also show a fully functional HPA axis equivalent, including cortisol synthesis and secretion and negative feedback regulation by cortisol on CRH expression. Thus differential, CRH-driven responses of skin reproduce key features of the central HPA axis at the tissue/single cell levels.
doi:10.1016/j.mce.2006.12.012
PMCID: PMC1839836  PMID: 17197073
CRH; CRH-R1; POMC; cutaneous steroidogenesis; cutaneous P450scc; stress response
21.  Differential hypothalamic-pituitary-adrenal activation of the neuroactive steroids pregnenolone sulfate and deoxycorticosterone in healthy controls and alcohol-dependent subjects 
Psychoneuroendocrinology  2007;33(2):214-226.
Summary
Ethanol and the neuroactive steroids have interactive neuropharmacological effects and chronic ethanol administration blunts the ethanol-induced increase in neuroactive steroid levels in rodent plasma and brain. Few studies have explored neuroactive steroid regulation in alcohol-dependent human subjects. In fact, the regulation of adrenal neuroactive steroids has not been well defined in healthy controls. We thus explored the regulation of two neuroactive steroids, pregnenolone sulfate (PREG-S) and deoxycorticosterone, by pharmacological challenges to the hypothalamic-pituitary-adrenal (HPA) axis in healthy controls and one-month abstinent alcohol-dependent patients with co-occurring nicotine dependence. Plasma levels of PREG-S and deoxycorticosterone were measured by radioimmunoassay in controls and alcohol-dependent patients after challenges of naloxone, ovine corticotrophin releasing hormone (oCRH), dexamethasone, cosyntropin, and cosyntropin following high-dose dexamethasone. In addition, basal diurnal measures of both hormones were obtained. PREG-S plasma levels in healthy controls were increased by cosyntropin challenge (with and without dexamethasone pretreatment) and decreased by dexamethasone challenge. However, PREG-S concentrations were not altered by naloxone or oCRH challenges, suggesting that PREG-S is not solely regulated by hypothalamic or pituitary stimulation. Deoxycorticosterone, in contrast, is regulated by HPA challenge stimulation in a manner similar to cortisol. Alcohol-dependent patients had a blunted PREG-S response to cosyntropin (with and without dexamethasone pretreatment). Furthermore, the time to peak deoxycorticosterone response following oCRH was delayed in alcohol-dependent patients compared to controls. These results indicate that plasma PREG-S and deoxycorticosterone levels are differentially regulated by HPA axis modulation in human plasma. Further, alcohol-dependent patients show a blunted PREG-S response to adrenal stimulation and a delayed deoxycorticosterone response to oCRH challenge.
doi:10.1016/j.psyneuen.2007.11.003
PMCID: PMC2262103  PMID: 18096321
Pregnenolone Sulfate; Deoxycorticosterone; Hypothalamic-Pituitary-Adrenal Axis; Alcohol Dependence; Neuroactive Steroids
22.  Childhood Adversity and Epigenetic Modulation of the Leukocyte Glucocorticoid Receptor: Preliminary Findings in Healthy Adults 
PLoS ONE  2012;7(1):e30148.
Background
A history of early adverse experiences is an important risk factor for adult psychopathology. Changes in stress sensitivity and functioning of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the association between stress and risk for psychiatric disorders. Preclinical work in rodents has linked low levels of maternal care to increased methylation of the promoter region of the glucocorticoid receptor (GR) gene, as well as to exaggerated hormonal and behavioral responses to stress. Recent studies have begun to examine whether early-life stress leads to epigenetic modifications of the GR gene in humans.
Methods
We examined the degree of methylation of a region of the promoter of the human GR gene (NR3C1) in leukocyte DNA from 99 healthy adults. Participants reported on their childhood experiences of parental behavior, parental death or desertion, and childhood maltreatment. On a separate day, participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, a standardized neuroendocrine challenge test.
Results
Disruption or lack of adequate nurturing, as measured by parental loss, childhood maltreatment, and parental care, was associated with increased NR3C1 promoter methylation (p<.05). In addition, NR3C1 promoter methylation was linked to attenuated cortisol responses to the Dex/CRH test (p<.05).
Conclusions
These findings suggest that childhood maltreatment or adversity may lead to epigenetic modifications of the human GR gene. Alterations in methylation of this gene could underlie the associations between childhood adversity, alterations in stress reactivity, and risk for psychopathology.
doi:10.1371/journal.pone.0030148
PMCID: PMC3266256  PMID: 22295073
23.  Increased hypothalamic-pituitary-adrenal drive is associated with decreased appetite and hypoactivation of food motivation neurocircuitry in anorexia nervosa 
Objective
Corticotropin releasing hormone (CRH)-mediated hypercortisolemia has been demonstrated in anorexia nervosa (anorexia), a psychiatric disorder characterized by food restriction despite low body weight. While CRH is anorexigenic, downstream cortisol stimulates hunger. Using a food-related fMRI paradigm, we have demonstrated hypoactivation of brain regions involved in food motivation in women with anorexia, even after weight-recovery. The relationship between hypothalamic-pituitary-adrenal (HPA) axis dysregulation and appetite, and the association with food motivation neurocircuitry hypoactivation is unknown in anorexia. We investigated the relationship between HPA activity, appetite and food motivation neurocircuitry hypoactivation in anorexia.
Design
Cross-sectional study of 36 women [13 anorexia (AN), 10 weight-recovered AN (ANWR), 13 healthy controls (HC)].
Methods
Peripheral cortisol and ACTH levels were measured fasting and 30, 60, and 120min after a standardized mixed meal. The Visual Analogue Scale was used to assess homeostatic and hedonic appetite. fMRI was performed during visual processing of food and non-food stimuli to measure brain activation pre- and post-meal.
Results
In each group, serum cortisol levels decreased following the meal. Mean fasting, 120min post-meal, and nadir cortisol levels were high in AN vs. HC. Mean postprandial ACTH levels were high in ANWR compared to HC and AN. Cortisol levels were associated with lower fasting homeostatic and hedonic appetite, independent of BMI and depressive symptoms. Cortisol levels were also associated with between-group variance in activation in food-motivation brain regions (e.g., hypothalamus, amygdala, hippocampus, OFC and insula).
Conclusions
HPA activation may contribute to the maintenance of anorexia by suppression of appetitive drive.
doi:10.1530/EJE-13-0433
PMCID: PMC3807591  PMID: 23946275
Anorexia nervosa; cortisol; fMRI; appetite; neuroimaging
24.  Suppressed neuroendocrine stress response in depressed women on job-stress related long-term sick-leave: A stable marker potentially suggestive of pre-existing vulnerability 
Biological psychiatry  2008;65(9):742-747.
Background
We recently reported marked hyporeactivity of the hypothalamo-pituitary-adrenal (HPA) axis in depressed females on job-stress related long-term sick-leave (LTSL). This unexpected finding prompted the question whether HPA-axis hypofunction in this group results from stress exposure, or reflects pre-existing vulnerability. Here, as a first step toward addressing this question, we assessed temporal stability of HPA-axis reactivity in these subjects.
Methods
We used the combined dexamethasone/corticotropin-releasing hormone (DEX-CRH) test to retest HPA-axis reactivity in 29 patients and 27 controls after 12 months follow-up. Clinical status and cognitive performance was also retested.
Results
Despite marked clinical improvement, and normalization of initially observed impairments in attention and working memory, marked HPA-axis hyporeactivity persisted in patients. A high test – retest correlation was found both at the level of ACTH (R=0.85, p<0.001) and cortisol (R=0.76, p<0.001) responses.
Conclusions
Hyporeactivity of the HPA was stable over 12 months in LTSL subjects, independently of clinical improvement and normalized cognitive function. The stability of this response over time suggests that decreased DEX-CRH responses in this group may be a trait rather than a state marker. This finding is compatible with a hypothesis that HPA-axis hyporeactivity may reflect a pre-existing vulnerability in these subjects.
doi:10.1016/j.biopsych.2008.10.035
PMCID: PMC2745651  PMID: 19058782
stress; depression; burnout; Dex-CRH-test; ACTH; cortisol; vulnerability
25.  Effects of sex and early maternal abuse on adrenocorticotropin hormone and cortisol responses to the corticotropin-releasing hormone challenge during the first 3 years of life in group-living rhesus monkeys 
In this study we investigated the development of the hypothalamic–pituitary–adrenal (HPA) axis in 21 group-living rhesus monkeys infants that were physically abused by their mothers in the first few months of life and in 21 nonabused controls. Cortisol and adrenocorticotropin hormone (ACTH) responses to a corticotropin-releasing hormone (CRH) challenge were assessed at 6-month intervals during the subjects’ first 3 years of life. Abused infants exhibited greater cortisol responses to CRH than controls across the 3 years. Abused infants also exhibited blunted ACTH secretion in response to CRH, especially at 6 months of age. Although there were no significant sex differences in abuse experienced early in life, females showed a greater cortisol response to CRH than males at all ages. There were no significant sex differences in the ACTH response to CRH, or significant interactions between sex and abuse in the ACTH or cortisol response. Our findings suggest that early parental maltreatment results in greater adrenocortical, and possibly also pituitary, responsiveness to challenges later in life. These long-term alterations in neuroendocrine function may be one the mechanisms through which infant abuse results in later psychopathologies. Our study also suggests that there are developmental sex differences in adrenal function that occur irrespective of early stressful experience. The results of this study can enhance our understanding of the long-term effects of child maltreatment as well as our knowledge of the development of the HPA axis in human and nonhuman primates.
doi:10.1017/S0954579409990253
PMCID: PMC3954978  PMID: 20102646

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