HPA axis and cortisol

HPA axis and aging in depression: systematic review and meta-analysis.: One of the most consistent findings in the biology of depression is an altered activity of the hypothalamic-pituitary-adrenal (HPA) axis. However, data concerning this issue have never been examined with a focus on the older population. Here we present a systematic review and meta-analysis, based on studies investigating levels of cortisol, adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) in depressed participants older than 60 and compared with healthy controls. We f

The HPA axis in bipolar disorder: Systematic review and meta-analysis.: Objectives: To provide a quantitative and qualitative synthesis of the available evidence on the role of Hypothalamic-Pituitary-Adrenal (HPA) axis in the pathophysiology of Bipolar Disorder (BD). Methods: Meta-analysis and meta-regression of case-control studies examining the levels of cortisol, ACTH, CRH levels. Systematic review of stress reactivity, genetic, molecular and neuroimaging studies related to HPA axis activity in BD. Results: Forty-one studies were included in the meta-analyses. BD

Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research.: Objectives: To summarize quantitatively the literature comparing hypothalamic-pituitary-adrenal (HPA) axis function between depressed and nondepressed individuals and to describe the important sources of variability in this literature. These sources include methodological differences between studies, as well as demographic or clinical differences between depressed samples. Methods: The current study used meta-analytic techniques to compare 671 effect sizes (cortisol, adrenocorticotropic hormone,

The stress-buffering effect of acute exercise: Evidence for HPA axis negative feedback.: According to the cross-stressor adaptation hypothesis, physically trained individuals show lower physiological and psychological responses to stressors other than exercise, e.g. psychosocial stress. Reduced stress reactivity may constitute a mechanism of action for the beneficial effects of exercise in maintaining mental health. With regard to neural and psychoneuroendocrine stress responses, the acute stress-buffering effects of exercise have not been investigated yet. A sample of highly traine

Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: A systematic review.: Background: Although there is substantial evidence of differential hypothalamic-pituitary-adrenal (HPA) axis activity in both generalized and abdominal obesity, consistent trends in obesity-related HPA axis perturbations have yet to be identified. Objectives: To systematically review the existing literature on HPA activity in obesity, identify possible explanations for inconsistencies in the literature, and suggest methodological improvements for future study. Data sources: Included papers used

Cortisol stress reactivity across psychiatric disorders: A systematic review and meta-analysis.: The hypothalamus-pituitary-adrenal (HPA) axis and its end product cortisol are essential for an adequate response to stress. Considering the role of stress as a risk factor for psychiatric disorders, it is not surprising that cortisol stress reactivity has frequently been investigated in patients versus healthy individuals. However, the large heterogeneity in measures of the cortisol stress response has hampered a systematic evaluation of the evidence. We here report of a systematic literature r

Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia.

Diathesis-stress models of schizophrenia and other psychotic disorders have dominated theorizing about etiology for over three decades. More recently, with advances in our understanding of the biological processes mediating the effects of stress, these models have incorporated mechanisms to account for the adverse impact of stress on brain function. This review examines recent scientific findings on the role of the hypothalamic-pituitary-adrenal (HPA) axis, one of the primary neural systems triggered by stress exposure, in the expression of vulnerability for schizophrenia. The results indicate that psychotic disorders are associated with elevated baseline and challenge-induced HPA activity, that antipsychotic medications reduce HPA activation, and that agents that augment stress hormone (cortisol) release exacerbate psychotic symptoms. The cumulative findings are discussed in light of a …

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Oxytocin buffers cortisol responses to stress in individuals with impaired emotion regulation abilities.

Oxytocin facilitates stress regulation but little is known about individual differences in this effect. The present study investigates whether the effect of intranasal oxytocin on stress-contingent cortisol release differs between individuals with high vs. low emotional regulation abilities (ERA). In a double-blind study thirty-six healthy male students with either high or low ERA were randomly assigned to receive intranasally 24 IU oxytocin or placebo. Cortisol was measured at several times before and after a social stressor (public speaking). Individuals with impaired ERA showed a reduced cortisol response to stress after oxytocin but an increased cortisol response after placebo application. The results suggest that healthy individuals with low ERA benefit from intranasal oxytocin application. Neurobiological mechanisms potentially underlying the link between oxytocin, cortsiol and ERA…

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Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins.

Background: Childhood adverse experiences are known to induce persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress. However, the mechanisms by which these experiences shape the neuroendocrine response to stress remain unclear. Method We tested whether bullying victimization influenced serotonin transporter gene (SERT) DNA methylation using a discordant monozygotic (MZ) twin design. A subsample of 28 MZ twin pairs discordant for bullying victimization, with data on cortisol and DNA methylation, were identified in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative 1994-1995 cohort of families with twins. Results: Bullied twins had higher SERT DNA methylation at the age of 10 years compared with their non-bullied MZ co-twins. This group difference cannot be attributed to the children's genetic makeup or their shared famil…

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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.

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Cortisol dysregulation: the bidirectional link between stress, depression, and type 2 diabetes mellitus.

Controversy exists over the role of stress and depression in the pathophysiology of type 2 diabetes mellitus. Depression has been shown to increase the risk for progressive insulin resistance and incident type 2 diabetes mellitus in multiple studies, whereas the association of stress with diabetes is less clear, owing to differences in study designs and in forms and ascertainment of stress. The biological systems involved in adaptation that mediate the link between stress and physiological functions include the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous and immune systems. The HPA axis is a tightly regulated system that represents one of the body's mechanisms for responding to acute and chronic stress. Depression is associated with cross-sectional and longitudinal alterations in the diurnal cortisol curve, including a blunted cortisol awakening response and flatt…

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The cortisol awakening response--applications and implications for sleep medicine.

The stress hormone cortisol is the end product of the hypothalamic-pituitary-adrenal (HPA) axis, and the cortisol awakening response (CAR) refers to the rapid rise in cortisol levels observed immediately following awakening. During the CAR period, cortisol levels typically increase by 38%-75%, peaking approximately 30 min after awakening. Evidence suggests the function of the CAR may be related to arousal, energy boost and/or anticipation, although its precise function is still unknown. The CAR has been investigated in a range of clinical populations including the assessment of daytime dysfunction in insomnia; however little research, if any, has specifically examined its relation to sleep architecture, or night-time difficulties associated with insomnia. The aim of this review is to provide an overview of the CAR, a description of the factors which can affect it, and to outline the CAR …

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Assessing the relationship between rumination and cortisol: a review.

Objective and methods: For individuals who ruminate, or mentally rehearse past stressful events, the physiological effects of a stressor may be longer lasting. This is well-supported within the cardiovascular domain. In the context of the hypothalamic-pituitary-adrenal (HPA) axis and cortisol, the results are inconsistent. This review summarizes key theoretical and methodological issues that contribute to these mixed findings among the 15 studies to date that have examined the association between rumination and cortisol. Results: State measures of rumination were consistently linked to increased cortisol concentrations. Stress-related rumination questionnaires were often positively associated with cortisol, whereas depression-related rumination scales predicted lower cortisol concentrations or were unrelated to cortisol. Rumination manipulations in the laboratory (e.g., ruminative self-f…

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Human models in acute and chronic stress: assessing determinants of individual hypothalamus-pituitary-adrenal axis activity and reactivity.

Stress is one of the most significant health problems in modern societies and the 21st century. This explains a pressing need for investigations into the biological pathways linking stress and health. Besides the locus coeruleus-noradrenaline/autonomic (sympathetic) nervous system ( Chrousos and Gold 1992 ), the hypothalamus-pituitary-adrenal (HPA) axis is the major physiological stress response system in the body. Since alterations in HPA axis regulation under basal conditions and in response to acute stress appear to be a close correlate or even a determining factor of the onset of different diseases or disease progression ( Holsboer 1989 ; Chrousos and Gold 1992 ; Tsigos and Chrousos 1994, 2002 ; Stratakis and Chrousos 1995 ; McEwen 1998 ; Heim et al. 2000a ; Raison and Miller 2003 ), the characterization of an individual's HPA axis activity as well as reactivity pattern to psychosoci…

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The cortisol awakening response (CAR): facts and future directions.

In humans, the secretion of cortisol from the adrenal glands follows a diurnal cycle with a profound increase after awakening. This increase after awakening, a phenomenon termed the cortisol awakening response (CAR), appears to be a distinct feature of the hypothalamus-pituitary-adrenal (HPA) axis, superimposing the circadian rhythmicity of cortisol secretion. Several studies point towards an important role of the hippocampus and, additionally, other brain structures (e. g. amygdala, prefrontal cortex, suprachiasmatic nucleus) in the regulation of the CAR. There is increasing knowledge that the CAR is influenced by a variety of factors such as gender, health status, and health behavior or stress perception. However, the exact function of the profound cortisol increase after awakening is still not clarified. We hypothesize that the anticipation of the upcoming day is of major relevance fo…

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Self-compassion training modulates alpha-amylase, heart rate variability, and subjective responses to social evaluative threat in women.

A growing body of research has revealed that social evaluative stressors trigger biological and psychological responses that in chronic forms have been linked to aging and disease. Recent research suggests that self-compassion may protect the self from typical defensive responses to evaluation. We investigated whether brief training in self-compassion moderated biopsychological responses to the Trier Social Stress Test (TSST) in women. Compared to attention (placebo) and no-training control conditions, brief self-compassion training diminished sympathetic (salivary alpha-amylase), cardiac parasympathetic, and subjective anxiety responses, though not HPA-axis (salivary cortisol) responses to the TSST. Self-compassion training also led to greater self-compassion under threat relative to the control groups. In that social stress pervades modern life, self-compassion represents a promising a…

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A clinical allostatic load index is associated with burnout symptoms and hypocortisolemic profiles in healthy workers.

Chronic stress causes stress hormones to strain many biological systems in a process referred to as allostatic load (AL) that is measurable using an index of biomarkers. While the AL framework has been successfully applied in studies of workplace stress, few studies have investigated burnout, a debilitating condition sometimes characterized by blunted stress hormone levels. Using an AL index based on clinical norms, we hypothesized that higher AL indices would be associated with increased chronic stress, burnout symptoms, as well as hypoactive diurnal and reactive stress hormone levels. Fifteen neuroendocrine, immune, metabolic, and cardiovascular biomarkers were collected for 30 healthy participants from various professions and values were transformed into an AL index using clinical norms. Stress reactivity was assessed for salivary cortisol and α-amylase levels in response to the Trier…

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Momentary work worries, marital disclosure, and salivary cortisol among parents of young children.

Objective: To investigate whether worries about work are linked to people's own cortisol levels and their spouses' cortisol levels in everyday life and whether marital factors may moderate these links. Although research has shown that satisfying marriages can buffer the physiological effects of everyday stress, the specific mechanisms through which marriage influences the processing and transmission of stress have not yet been identified. Methods: Thirty-seven healthy married couples completed baseline measures and then provided saliva samples and indicated their worries about work for six times a day from a Saturday morning through a Monday evening. Results: Wives' cortisol levels were associated positively with their own work worries (p = .008) and with their husbands' work worries (p = .006). Husbands' cortisol levels were associated positively only with their own work worries (p = .0…

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Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes.

Background: Cocaine dependence is associated with high rates of relapse. Stress and drug cue exposure are known to increase cocaine craving and stress arousal, but the association between these responses and cocaine relapse has not been previously studied. Objective: To examine whether stress-induced and drug cue-induced cocaine craving and hypothalamic-pituitary-adrenal axis responses evoked in the laboratory are associated with subsequent cocaine relapse. Design: Prospective study design assessing cocaine relapse and drug use during a 90-day follow-up period after discharge from inpatient treatment and research. Data were analyzed by Cox proportional hazards regression and multiple regression. Setting: Inpatient treatment and research unit in a community mental health center. Patients: Forty-nine treatment-seeking cocaine-dependent individuals. Main outcome measures: Time to cocaine re…

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The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma.

Background: The dexamethasone/corticotropin-releasing factor (CRF) test is considered to be the most sensitive measure of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and has been demonstrated to be altered in patients with major depression (MDD). Although childhood trauma is a demonstrated risk factor for MDD and patients with a history of childhood abuse and MDD demonstrate HPA axis hyperactivity, the dexamethasone/CRF test remains unstudied in this population. We determined the impact of childhood trauma on dexamethasone/CRF test results in patients with MDD. Methods: Forty-nine healthy men, ages 18-60 years, without mania or psychosis, active substance abuse, or eating disorder and medication-free were recruited into four study groups, including: 1) normal subjects with no childhood abuse history or psychiatric disorder (n = 14); 2) men with childhood abuse histories witho…

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Aging and the HPA axis: Stress and resilience in older adults.

Hypothalamic-pituitary-adrenal (HPA) axis function may change over the course of aging, and altered diurnal or stress-induced secretion of the hormone cortisol could predispose older adults to negative health outcomes. We propose that psychological resilience may interact with diurnal cortisol to affect health outcomes later in life. Emotion regulation and social support are two constructs that contribute to resilience and exhibit age-specific patterns in older adults. Determining how the use of resilience resources interacts with age-related diurnal cortisol will improve our understanding of the pathways between stress, resilience, and well-being. In this review, we assess published studies evaluating diurnal cortisol in older adults to better understand differences in their HPA axis functioning. Evidence thus far suggests that diurnal cortisol may increase with age, although cross-sect…

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Measurement and meaning of salivary cortisol: a focus on health and disease in children.

Measurement of salivary cortisol can provide important information about hypothalamic-pituitary-adrenal (HPA) axis activity under normal conditions and in response to stress. However, there are many variables relating to the measurement of cortisol in saliva which may introduce error and therefore may render difficult the comparison and interpretation of data between, and within, laboratories. This review addresses the effects of gender, age, time and location of sampling, units of measurement, assay conditions and compliance with the protocol, all of which have the potential to impact upon the precision, accuracy and reliability of salivary cortisol measurements in the literature. Some of these factors are applicable to both adults and children, but the measurement of salivary cortisol in children introduces aspects of unique variability which demand special attention. The specific focu…

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Therapy Insight: is there an imbalanced response of mineralocorticoid and glucocorticoid receptors in depression?

In severely depressed patients, emotional arousal, cognitive abnormality and vulnerability to psychotic episodes are linked to a hyperactive hypothalamic-pituitary-adrenal (HPA) axis and high levels of circulating cortisol. The susceptibility pathways underlying these disturbed brain functions are influenced by genetic factors, early-life priming experiences and later-life events. Cortisol is an important determinant in this so-called three hit model. The action of cortisol is protective, but can become harmful if exposure of susceptibility pathways to the stress hormone is excessive and sustained or inadequate. In this article we argue that this change in role of cortisol from protective into harmful depends on the functioning of the mineralocorticoid and glucocorticoid receptors and the context in which the organism experiences the stressor. Actions mediated by the mineralocorticoid an…

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Sex differences in early-life programming of the hypothalamic-pituitary-adrenal axis in humans suggest increased vulnerability in females: a systematic review.

Fetal glucocorticoid overexposure is a key mechanism linking early development with later-life disease. In humans, low birth weight associates with increased fasting cortisol, hypothalamic-pituitary-adrenal (HPA) axis reactivity, and with cardiovascular risk and cognitive decline. As there are sex differences in these adult diseases, we hypothesized that there may be sex differences in programming of the HPA axis in response to prenatal stressors. We conducted a systematic review following Meta-Analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analysis. We searched Embase, MEDLINE and Web of Science from inception to 31 October 2016. We included studies related to sex differences, prenatal exposures and HPA axis. We excluded studies investigating specific disease states. The 23 included studies investigated the consequences of…

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How does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans.

There is evidence that excessive stress exposure of the brain, mediated through the neurotoxic effects of cortisol and possibly neuroinflammation, causes damage to brain structure and function: the glucocorticoid cascade hypothesis. Functional changes of hypothalamic-pituitary-adrenal (HPA) axis as well as alterations in brain structures like the hippocampus have been consistently reported in major depression. However, there has not been a lot of emphasis on bringing findings from studies on early childhood stress, HPA axis functioning and hippocampal imaging together. This is the subject for this systematic review of the literature on how developmental stress, specifically childhood maltreatment, may impact on HPA axis function and hippocampal structure. We will also review the literature on the relationship between HPA axis function and hippocampal volume in healthy, depressed and othe…

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Signalling cognition: the gut microbiota and hypothalamic-pituitary-adrenal axis.

Cognitive function in humans depends on the complex and interplay between multiple body systems, including the hypothalamic-pituitary-adrenal (HPA) axis. The gut microbiota, which vastly outnumbers human cells and has a genetic potential that exceeds that of the human genome, plays a crucial role in this interplay. The microbiota-gut-brain (MGB) axis is a bidirectional signalling pathway that operates through neural, endocrine, immune, and metabolic pathways. One of the major neuroendocrine systems responding to stress is the HPA axis which produces glucocorticoids such as cortisol in humans and corticosterone in rodents. Appropriate concentrations of cortisol are essential for normal neurodevelopment and function, as well as cognitive processes such as learning and memory, and studies have shown that microbes modulate the HPA axis throughout life. Stress can significantly impact the MGB…

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Understanding the relationships between physiological and psychosocial stress, cortisol and cognition.

Stress is viewed as a state of real or perceived threat to homeostasis, the management of which involves the endocrine, nervous, and immune systems. These systems work independently and interactively as part of the stress response. The scientific stress literature, which spans both animal and human studies, contains heterogeneous findings about the effects of stress on the brain and the body. This review seeks to summarise and integrate literature on the relationships between these systems, examining particularly the roles of physiological and psychosocial stress, the stress hormone cortisol, as controlled by the hypothalamic-pituitary-adrenal (HPA) axis, and the effects of stress on cognitive functioning. Health conditions related to impaired HPA axis functioning and their associated neuropsychiatric symptoms will also be considered. Lastly, this review will provide suggestions of clini…

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The hypothalamic-pituitary-adrenal axis and serotonin abnormalities: a selective overview for the implications of suicide prevention.

Suicidal behavior and mood disorders are one of the world's largest public health problems. The biological vulnerability for these problems includes genetic factors involved in the regulation of the serotonergic system and stress system. The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that regulates the body's response to stress and has complex interactions with brain serotonergic, noradrenergic and dopaminergic systems. Corticotropin-releasing hormone and vasopressin act synergistically to stimulate the secretion of ACTH that stimulates the biosynthesis of corticosteroids such as cortisol from cholesterol. Cortisol is a major stress hormone and has effects on many tissues, including on mineralocorticoid receptors and glucocorticoid receptors in the brain. Glucocorticoids produce behavioral changes, and one important target of glucocorticoids is the hypothalamus,…

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Comfort food is comforting to those most stressed: evidence of the chronic stress response network in high stress women.

Chronically stressed rodents who are allowed to eat calorie-dense "comfort" food develop greater mesenteric fat, which in turn dampens hypothalamic-pituitary-adrenocortical (HPA) axis activity. We tested whether similar relations exist in humans, at least cross-sectionally. Fifty-nine healthy premenopausal women were exposed to a standard laboratory stressor to examine HPA response to acute stress and underwent diurnal saliva sampling for basal cortisol and response to dexamethasone administration. Based on perceived stress scores, women were divided into extreme quartiles of low versus high stress categories. We found as hypothesized that the high stress group had significantly greater BMI and sagittal diameter, and reported greater emotional eating. In response to acute lab stressor, the high stress group showed a blunted cortisol response, lower diurnal cortisol levels, and greater su…

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Prolactin in response to acute psychosocial stress in healthy men and women.

Background: Serum levels of the anterior pituitary hormone prolactin have been reported to increase in response to different types of psychological stressors in humans. However, experimental laboratory stress studies investigating the acute response of prolactin to psychological stress show inconsistent results as increased, as well as decreased or unchanged levels of prolactin have been reported. Objective: The aim of this study was to investigate the effect of acute psychosocial stress on serum concentrations of prolactin in healthy men and women and possible sex differences. Method: Thirty men and 15 women (age 30-50 years) underwent Trier Social Stress Test (TSST), a tool for investigating psychobiological stress responses in a laboratory setting. Blood samples were collected before and directly after the stress test and after 30 min of recovery. Results: We observed significantly el…

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Sex differences in emotional and physiological responses to the Trier Social Stress Test.

Women are more likely than men to be diagnosed with depression and anxiety-related disorders, and it has been hypothesized that this difference is related to sex differences in stress reactivity. Women typically report higher levels of negative affect than men in response to psychosocial stressors, but the evidence for sex differences in physiological reactivity to stressful situations is not consistent. The present study sought to expand this work by evaluating sex differences in reactivity to a social stress challenge across neuroendocrine, autonomic and affective response domains. Participants (32 women, 30 men) completed a standardized psychosocial stress challenge (i.e., the Trier Social Stress Test (TSST)), during which several physiological (e.g., cortisol reactivity, heart rate) and psychological (e.g., depression, irritability, anger, fear) measures were assessed. The findings d…

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