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

Nutritional omega-3 modulates neuronal morphology in the prefrontal cortex along with depression-related behaviour through corticosterone secretion.

Understanding how malnutrition contributes to depression is building momentum. In the present study we unravel molecular and cellular mechanisms by which nutritional disturbances lead to impaired emotional behaviour in mice. Here we report that nutritional n-3 polyunsaturated fatty acids (PUFA) deficiency induces a chronic stress state reflected by disrupted glucocorticoid receptor (GR)-mediated signalling pathway along with hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. This hyperactivity in turn resulted in neuronal atrophy in the dorsolateral (dl)- and dorsomedial (dm)- prefrontal cortex (PFC) and subsequent mood-related behaviour alterations, similarly to chronic social defeat stress. Supplementation of n-3 PUFA prevented detrimental chronic social defeat stress-induced emotional and neuronal impairments by impeding HPA axis hyperactivity. These results indicate a role for …

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Neurosteroidogenesis is required for the physiological response to stress: role of neurosteroid-sensitive GABAA receptors.

The hypothalamic-pituitary-adrenal (HPA) axis, which mediates the body's response to stress, is largely under GABAergic control. Here we demonstrate that corticotropin-releasing hormone (CRH) neurons are modulated by the stress-derived neurosteroid, tetrahydrodeoxycorticosterone (THDOC), acting on δ subunit-containing GABA(A) receptors (GABA(A)Rs). Under normal conditions, THDOC potentiates the inhibitory effects of GABA on CRH neurons, decreasing the activity of the HPA axis. Counterintuitively, following stress, THDOC activates the HPA axis due to dephosphorylation of KCC2 residue Ser940, resulting in a collapse of the chloride gradient and excitatory GABAergic transmission. The effects of THDOC on CRH neurons are mediated by actions on GABA(A)R δ subunit-containing receptors since these effects are abolished in Gabrd(-/-) mice under both control and stress conditions. Interestingly, b…

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Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation.

The dynamic interplay between serotonin [5-hydroxytryptamine (5-HT)] neurotransmission and the hypothalamic-pituitary-adrenal (HPA) axis has been extensively studied over the past 30 years, but the underlying mechanism of this interaction has not been defined. A possibility receiving little attention is that 5-HT regulates upstream corticotropin-releasing hormone (CRH) signaling systems via activation of serotonin 2C receptors (5-HT(2C)Rs) in the paraventricular nucleus of the hypothalamus (PVH). Through complementary approaches in wild-type rodents and 5-HT(2C)R-deficient mice, we determined that 5-HT(2C)Rs are necessary for 5-HT-induced HPA axis activation. We used laser-capture PVH microdissection followed by microarray analysis to compare the expression of 13 5-HTRs. Only 5-HT(2C)R and 5-HT(1D)R transcripts were consistently identified as present in the PVH, and of these, the 5-HT(2C…

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Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health.

Environmental effects on the materno-foetal interaction determine birth outcomes that predict health over the lifespan. Thus, maternal undernutrition or stress associate with low birth weight, leading to an increased risk of metabolic and cardiovascular illness in the offspring. We argue that these effects are, in part, mediated by direct and indirect effects on the hypothalamic-pituitary-adrenal (HPA) axis such that (i) the effect of maternal adversity on foetal growth is mediated by adrenal glucocorticoids and (ii) environmental adversity alters maternal physiology and behaviour, which then programs HPA activity in the offspring.

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Regional differentiation of the medial prefrontal cortex in regulating adaptive responses to acute emotional stress.

The medial prefrontal cortex (mPFC) is an important neural substrate for integrating cognitive-affective information and regulating the hypothalamo-pituitary-adrenal (HPA) axis response to emotional stress. mPFC modulation of stress responses is effected in part via the paraventricular hypothalamic nucleus (PVH), which houses both autonomic (sympathoadrenal) and neuroendocrine (HPA) effector mechanisms. Although the weight of evidence suggests that mPFC influences on stress-related PVH outputs are inhibitory, discordant findings have been reported, and such work has tended to treat this cortical region as a unitary structure. Here we compared the effects of lesions of the dorsal versus ventral aspects of mPFC, centered in the prelimbic and infralimbic fields, respectively, on acute restraint stress-induced activation of PVH cell groups mediating autonomic and neuroendocrine responses. Le…

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Utilization of machine learning for prediction of post-traumatic stress: a re-examination of cortisol in the prediction and pathways to non-remitting PTSD.

To date, studies of biological risk factors have revealed inconsistent relationships with subsequent post-traumatic stress disorder (PTSD). The inconsistent signal may reflect the use of data analytic tools that are ill equipped for modeling the complex interactions between biological and environmental factors that underlay post-traumatic psychopathology. Further, using symptom-based diagnostic status as the group outcome overlooks the inherent heterogeneity of PTSD, potentially contributing to failures to replicate. To examine the potential yield of novel analytic tools, we reanalyzed data from a large longitudinal study of individuals identified following trauma in the general emergency room (ER) that failed to find a linear association between cortisol response to traumatic events and subsequent PTSD. First, latent growth mixture modeling empirically identified trajectories of post-tr…

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The empathic, physiological resonance of stress.

Physiological resonance between individuals is considered fundamental to the biological capacity for empathy. Observers of pain and distress commonly exhibit increases in reported distress, autonomic arousal, facial mimicry, and overlapping neural activity. An important, unstudied question is whether physiological stress can also resonate. Physiological stress is operationalized as activation of the hypothalamic pituitary adrenocortical (HPA) and sympatho-adrenomedullary (SAM) axes. People often report an aversive state resulting from the stress of another, but this could be conveyed through resonating arousal or distress, without activating the physiological stress response. Physiological stress is particularly important to examine since it commonly occurs chronically, with known negative effects on health. Salivary cortisol and salivary alpha-amylase (sAA) were measured in both speaker…

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The role of child adrenocortical functioning in pathways between interparental conflict and child maladjustment.

This study examined the interplay between interparental conflict and child cortisol reactivity to interparental conflict in predicting child maladjustment in a sample of 178 families and their kindergarten children. Consistent with the allostatic load hypothesis (McEwen & Stellar, 1993), results indicated that interparental conflict was indirectly related to child maladjustment through its association with individual differences in child cortisol reactivity. Analyses indicated that the multimethod assessment of interparental conflict was associated with lower levels of child cortisol reactivity to a simulated phone conflict between parents. Diminished cortisol reactivity, in turn, predicted increases in parental reports of child externalizing symptoms over a 2-year period. Associations between interparental conflict, child cortisol reactivity, and child externalizing symptoms remained ro…

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Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-controlled trial in patients with advanced cancer.

Purpose: Cancer-related fatigue (CRF) is the most common symptom in patients with advanced cancer. The primary objective of this prospective, randomized, double-blind, placebo-controlled study was to compare the effect of dexamethasone and placebo on CRF. Patients and methods: Patients with advanced cancer with ≥ three CRF-related symptoms (ie, fatigue, pain, nausea, loss of appetite, depression, anxiety, or sleep disturbance) ≥ 4 of 10 on the Edmonton Symptom Assessment Scale (ESAS) were eligible. Patients were randomly assigned to either dexamethasone 4 mg or placebo orally twice per day for 14 days. The primary end point was change in the Functional Assessment of Chronic Illness-Fatigue (FACIT-F) subscale from baseline to day 15. Secondary outcomes included anorexia, anxiety, depression, and symptom distress scores. Results: A total of 84 patients were evaluable (dexamethasone, 43; pl…

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Social Isolation and Breast Cancer.

Although the role of life stressors in breast cancer remains unclear, social isolation is consistently associated with increased breast cancer risk and mortality. Social isolation can be defined as loneliness or an absence of perceived social connections. In female mice and rats, social isolation is mimicked by housing animals 1 per cage. Social isolation causes many biological changes, of which an increase in inflammatory markers and disruptions in mitochondrial and cellular metabolism are commonly reported. It is not clear how the 2 traditional stress-induced pathways, namely, the hypothalamic-pituitary-adrenocortical axis (HPA), resulting in a release of glucocorticoids from the adrenal cortex, and autonomic nervous system (ANS), resulting in a release of catecholamines from the adrenal medulla and postganglionic neurons, could explain the increased breast cancer risk in socially isol…

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Role of prefrontal cortex glucocorticoid receptors in stress and emotion.

Background: Stress-related disorders (e.g., depression) are associated with hypothalamic-pituitary-adrenocortical axis dysregulation and prefrontal cortex (PFC) dysfunction, suggesting a functional link between aberrant prefrontal corticosteroid signaling and mood regulation. Methods: We used a virally mediated knockdown strategy (short hairpin RNA targeting the glucocorticoid receptor [GR]) to attenuate PFC GR signaling in the rat PFC. Adult male rats received bilateral microinjections of vector control or short hairpin RNA targeting the GR into the prelimbic (n = 44) or infralimbic (n = 52) cortices. Half of the animals from each injection group underwent chronic variable stress, and all were subjected to novel restraint. The first 2 days of chronic variable stress were used to assess depression- and anxiety-like behavior in the forced swim test and open field. Results: The GR knockdow…

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Long-term anxiolytic and antidepressant-like behavioural effects of tiagabine, a selective GABA transporter-1 (GAT-1) inhibitor, coincide with a decrease in HPA system activity in C57BL/6 mice.

Gamma-aminobutyric acid (GABA) system plays a pivotal role in the pathophysiology of anxiety and mood disorders. This study was aimed to assess the anxiolytic and antidepressant-like properties of tiagabine, an inhibitor of the GABA transporter-1 (GAT-1), after acute and chronic administration in C57BL/6JOlaHsD mice with paroxetine as a positive control. In first experiments, the acute administration of tiagabine (7.5 mg/kg, orally [PO]) and paroxetine (10 mg/kg PO) induced anxiolytic effects in the elevated plus maze test and the modified hole board test and an antidepressant-like effect in the forced swim test. Chronic application of tiagabine (7.5 mg/kg PO) and paroxetine (10 mg/kg PO) for 22 days revealed an anxiolytic and antidepressant-like efficacy of tiagabine only. In a further experiment, we analysed the impact of chronic tiagabine versus paroxetine treatment on the hypothalami…

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Stress history and pubertal development interact to shape hypothalamic-pituitary-adrenal axis plasticity.

Both the magnitude and the duration of the hormonal stress response change dramatically during neonatal development and aging as well as with prior experience with a stressor. However, surprisingly little is known with regard to how pubertal maturation and experience with stress interact to affect hypothalamic-pituitary-adrenal axis responsiveness. Because adolescence is a period of neurodevelopmental vulnerabilities and opportunities that may be especially sensitive to stress, it is imperative to more fully understand these interactions. Thus, we examined hormonal and neural responses in prepubertal (28 d of age) and adult (77 d of age) male rats after exposure to acute (30 min) or more chronic (30 min/d for 7 d) restraint stress. We report here that after acute stress, prepubertal males exhibited a significantly prolonged hormonal stress response (e.g. ACTH and total and free corticost…

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Distress conditions during pregnancy may lead to pre-eclampsia by increasing cortisol levels and altering lymphocyte sensitivity to glucocorticoids.

Psychological stress may affect up to 18% of all pregnant women, altering the function of both neuroendocrine and immune systems. Distress conditions may directly change the hypothalamic-pituitary-adrenal (HPA) axis, leading to increased cortisol levels and associated changes in cellular immunity. Psychological events such as high stress levels, anxiety or depression may directly or indirectly affect pregnancy and may thus lead to pre-eclampsia (PE). Here, we suggest that distress conditions during pregnancy may lead the development of PE by enhancing in vivo cortisol levels. High cortisol levels are associated with hypertension and endothelial dysfunction, features often observed in patients with PE. Lymphocytes from patients with high cortisol levels may have a reduced sensitivity to the synthetic glucocorticoid dexamethasone (DEX). Stress-related steroid resistance may disrupt the HPA…

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Decreased cortisol response to awakening is associated with cognitive vulnerability to depression in a nonclinical sample of young adults.

Due to its high intraindividual stability, the cortisol awakening response (CAR) may be regarded as a trait measure of the dynamics of the HPA-axis activity. The present study aimed at investigating associations of the CAR with rumination as a cognitive vulnerability marker for depression assessed by both a trait measure and by experimental manipulation. After induction of sad mood by viewing a sad sequence of a movie, 42 healthy university students were randomly induced to either ruminatively self-focus on their feelings or to distract themselves from their mood by concentrating on respective text cards for 8min. Trait rumination and distraction were measured by the Response Styles Questionnaire (RSQ) at baseline (T0), while current mood was recorded before (T1) and after (T2) the mood induction as well as after the rumination/distraction induction (T3) using the Positive and Negative A…

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The Role of the Microbiome-Brain-Gut Axis in the Pathogenesis of Depressive Disorder.

The role of gut microbiota and its association with the central nervous system via the microbiome-brain-gut axis has been widely discussed in the literature. The aim of this review is to investigate the impact of gut microbiota on the development of depression and underlying molecular mechanisms. There are two possible pathways in which this interaction might occur. The first one suggests that depressive disorder could lead to dysbiosis and one of the causes may be the influence on the hypothalamic-pituitary-adrenal (HPA) axis. The second one considers if changes in the composition of gut microbiota might cause depressive disorder. The mechanisms that could be responsible for this interaction include the secretion of neurotransmitters, gut peptides and the activation of the immune system. However, current knowledge on this topic does not allow for us to state an unambiguous conclusion, a…

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Altered immunoemotional regulatory system in COVID-19: From the origins to opportunities.

The emergence of the novel coronavirus (SARS-CoV-2) and the worldwide spread of the coronavirus disease (COVID-19) have led to social regulations that caused substantial changes in manners of daily life. The subsequent loneliness and concerns of the pandemic during social distancing, quarantine, and lockdown are psychosocial stressors that negatively affect the immune system. These effects occur through mechanisms controlled by the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenocortical (HPA) axis that alter immune regulation, namely the conserved transcriptional response to adversity (CTRA), which promotes inflammation and diminishes antiviral responses, leading to inadequate protection against viral disease. Unhealthy eating habits, physical inactivity, sleep disturbances, and mental health consequences of COVID-19 add on to the pathological effects of loneliness…

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The importance of n-6/n-3 fatty acids ratio in the major depressive disorder.

This review aims to clarify the relation between the ratio of omega-6 to omega-3 fatty acids and the development of depression. It is explained how these fatty acids are involved in the production of eicosanoids and how these fatty acids can affect the membrane fluidity, by their incorporation into membrane phospholipids. In addition, it is described how omega-3 derivatives are shown to regulate gene transcription. In view of the pathophysiology of depression, the mechanisms of how an altered ratio of omega-6 to omega-3 could be involved in depression are discussed. Possible mechanisms could include an increased production of pro-inflammatory cytokines, which can activate the HPA axis and a changed membrane fluidity, which potentially affects membrane bound enzymes, ion channels, receptor activity and neurotransmitter binding. In view of clinical trials, it is also discussed whether omeg…

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HPA function in adolescence: role of sex hormones in its regulation and the enduring consequences of exposure to stressors.

The hypothalamic-pituitary-adrenal (HPA) axis is one of the physiological systems involved in coping with stressors. There are functional shifts in the HPA axis and its regulation by sex hormones over the lifespan that allow the animal to meet the challenges of the internal and external environment that are specific to each stage of development. Sex differences in HPA function emerge over adolescence, a phenomenon reflecting the concomitant initiation of regulatory effects of sex hormones. The focus of this review is recent research on differences between adolescents and adults in HPA function and the enduring effects of exposure to stressors in adolescence. During adolescence, HPA function is characterized by a prolonged activation in response to stressors compared to adulthood, which may render ongoing development of the brain vulnerable. Although research has been scarce, there is a g…

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Gender differences in the effects of prenatal stress on brain development and behaviour.

An increased incidence of anxiety, depression and attention deficits in children has been linked to psychological stress during pregnancy. Subjection of a pregnant rat to stress at a time when the foetal limbic and hypothalamic pituitary adrenal (HPA) axes develop results in anxiogenic and depressive behaviour and learning and attention deficits in the offspring, which depend on its gender, intensity and timing of the maternal stress and behaviour being tested. Maternal stress increases corticosterone levels in the foetal brain, decreases foetal testosterone and brain aromatase activity in males, and alters brain catecholamine activity to that in females. Learning deficits, reductions in hippocampal neurogenesis, LTP and dendritic spine density in the prefrontal cortex are more readily seen in prenatally-stressed males, while anxiety, depression and increased response of the HPA axis to …

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Influence of mindfulness practice on cortisol and sleep in long-term and short-term meditators.

Background: There is growing scientific interest in assessing the biological correlates of non-pharmacological interventions such as mindfulness. Examinations of the beneficial effects of mindfulness on hypothalamus-pituitary-adrenocortical system activity (HPA SA) and sleep are sparse. The aim of the present study was to explore the impact of long- and short-term meditation experience on HPA SA and sleep. Method: There were 20 participants, 9 of whom had long-term experience in meditation (mean = 264 months) and 11 novices. Novices underwent an 8-week course in Mindfulness-Based Stress Reduction (MBSR), and cortisol samples were taken in the lab at the beginning and end of the course. To assess the cortisol awakening response, 4 morning cortisol samples were collected. Sleep and mindfulness were assessed by self-rating questionnaires. Results: Among participants with long-term meditatio…

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Decreased hair cortisol concentrations in generalised anxiety disorder.

Previous research examining hypothalamic-pituitary-adrenal (HPA) axis activity in generalised anxiety disorder (GAD) has suggested a general hypercortisolism. These studies have mostly relied on salivary, plasma or urinary assessments, reflecting cortisol secretion over short time periods. The current study utilised the novel method of cortisol assessment in hair to obtain a retrospective index of cortisol secretion over a prolonged period of time. Hair cortisol levels were determined in 15 GAD patients and in 15 age- and gender-matched controls. In addition, participants collected six saliva samples (on awakening, +30 min, 12:00, 16:00, 20:00 h and at bedtime) on two consecutive weekdays for the assessment of the diurnal cortisol profile. Results revealed significantly lower (50-60%) cortisol levels in the first and second 3-cm hair segments of GAD patients compared to those of controls…

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Area under the curve and other summary indicators of repeated waking cortisol measurements.

Objective: To derive the area under the curve and related summary measures of stress from saliva samples collected over time and to provide insight into the interpretation of the derived parameters. In research designed to assess the health consequences of stress these samples are often used as a physiologic indicator of the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis. To make these repeated measurements of salivary cortisol more useful in defining the relationships between stress and health there is a need to derive two forms of area under the curve that summarize the measurements: area under the curve with respect to ground (AUC(G)) and area under the curve with respect to increase (AUC(I)). The latter parameters, AUC(I), however, is seldom used by research scientists. Methods: In this study, interpretation and generic definition of the area under the curve was prov…

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Chrononutrition in the context of Ramadan: Potential implications.

Every year, healthy adult Muslims practice dawn to sunset fasting for a whole lunar month. No food or fluid is allowed for the fasting time window. After sunset, eating is allowed. The dramatic change in the timing of meals is accompanied by changes in sleeping hours and thus alterations in circadian rhythms. Hormonal mechanisms mainly determined by the latter also change. These include shifts in cortisol and melatonin. Food-dependent hormones such as Ghrelin and leptin also show changes. A well-established principle of chrononutrition is that the timing of eating may be as or more important than the content of food. Ramadan fasting (RF) is distinct from other forms of intermittent fasting, although there are also some similarities with time restricted eating (TRE). Both have been shown to have health benefits. Here, we examine existing literature to understand and learn from this very c…

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Evolutionary and neuroendocrine foundations of human aggression.

Humans present a behavioural paradox: they are peaceful in many circumstances, but they are also violent and kill conspecifics at high rates. We describe a social evolutionary theory to resolve this paradox. The theory interprets human aggression as a combination of low propensities for reactive aggression and coercive behaviour and high propensities for some forms of proactive aggression (especially coalitionary proactive aggression). These tendencies are associated with the evolution of groupishness, self-domestication, and social norms. This human aggression profile is expected to demand substantial plasticity in the evolved biological mechanisms responsible for aggression. We discuss the contributions of various social signalling molecules (testosterone, cortisol, oxytocin, vasopressin, serotonin, and dopamine) as the neuroendocrine foundation conferring such plasticity.

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