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

Diurnal salivary cortisol is associated with body mass index and waist circumference: the Multiethnic Study of Atherosclerosis.

Objective: Neuroendocrine abnormalities, such as activation of the hypothalamic-pituitary-adrenal (HPA) axis, are associated with obesity; however, few large-scale population-based studies have examined HPA axis and markers of obesity. We examined the cross-sectional association of the cortisol awakening response (CAR) and diurnal salivary cortisol curve with obesity. Design and methods: The Multiethnic Study of Atherosclerosis Stress Study includes 1,002 White, Hispanic, and Black men and women (mean age 65 ± 9.8 years) who collected up to 18 salivary cortisol samples over 3 days. Cortisol profiles were modeled using regression spline models that incorporated random parameters for subject-specific effects. Cortisol curve measures included awakening cortisol, CAR (awakening to 30-min postawakening), early decline (30 min to 2-h postawakening), late decline (2-h postawakening to bedtime),…

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Perceived discrimination and diurnal cortisol: examining relations among Mexican American adolescents.

Perceived discrimination remains a salient and significant environmental stressor for ethnic and racial minority youth. Although many studies have examined the impact of racial/ethnic discrimination on mental health symptomatology and physical health, little is known of the potential physiological processes underlying such experiences, especially during adolescence. In an attempt to understand how varying perceptions of discrimination relate to functioning of the hypothalamic-pituitary-adrenal axis (HPA axis), the current study examined the relation between Mexican American adolescents' (N = 100, M(age) = 15.3 years old) perceptions of discrimination and aspects of their diurnal cortisol profiles. Three salivary samples (wakeup, +30 waking, bedtime) were collected across 3 days (total of 9 samples). Utilizing multi-level modeling, results revealed that adolescents' perceived discriminati…

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The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders.

Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays a pivotal role in various physiological processes. Its release is finely orchestrated by the suprachiasmatic nucleus, governing the circadian rhythm and activating the intricate hypothalamic-pituitary-adrenal (HPA) axis, a vital neuroendocrine system responsible for stress response and maintaining homeostasis. Disruptions in cortisol regulation due to chronic stress, disease, and aging have profound implications for multiple bodily systems. Animal models have been instrumental in elucidating these complex cortisol dynamics during stress, shedding light on the interplay between physiological, neuroendocrine, and immune factors in the stress response. These models have also revealed the impact of various stressors, including social hierarchies, highlighting the role of social factors in cortisol regulation. M…

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Linking the hemodynamic consequences of adverse childhood experiences to an altered HPA axis and acute stress response.

Adverse childhood experiences (ACEs), such as maltreatment and severe household dysfunction, represent a significant threat to public health as ACEs are associated with increased prevalence of several chronic diseases. Biological embedding, believed to be rooted in dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, is the prevailing theory by which chronic diseases become imprinted in individuals following childhood adversity. A shift towards HPA axis hypoactivity occurs in response to ACEs exposure and is proposed to contribute towards altered cortisol secretion, chronic low-grade inflammation, and dysregulated hemodynamic and autonomic function. This shift in HPA axis activity may be a long-term effect of glucocorticoid receptor methylation with downstream effects on hemodynamic and autonomic function. Emerging evidence suggests syncopal tendencies are increased among those …

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The Relationship Between Perinatal Mental Health and Stress: a Review of the Microbiome.

Purpose of review: Our current understanding of the underlying mechanisms and etiologies of perinatal mood and anxiety disorders (PMADs) is not clearly identified. The relationship of stress-induced adaptations (i.e., the hypothalamic-pituitary-adrenal (HPA) axis, the autonomic nervous system (ANS), the immune system) and the microbiota are potential contributors to psychopathology exhibited in women during pregnancy and postpartum and should be investigated. Recent findings: The stress response activates the HPA axis and dysregulates the ANS, leading to the inhibition of the parasympathetic system. Sustained high levels of cortisol, reduced heart variability, and modulated immune responses increase the vulnerability to PMAD. Bidirectional communication between the nervous system and the microbiota is an important factor to alter host homeostasis and development of PMAD. Future research …

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Measuring Stress in Young Children Using Hair Cortisol: The State of the Science.

Extensive literature suggests that adverse experiences in early childhood may deleteriously impact later health. These effects are thought to be related to the impact of persistent or chronic stress on various biological processes, mediated by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and ultimately irregularities in cortisol levels. Ameliorating persistent stress in young children requires accurately measuring the chronicity of physiologic stress, which is difficult in young children because of unreliable self-report and the burden and inaccuracy associated with using invasive acute-stress biomeasures. A better way to approximate persistent stress in young children is measuring hair cortisol concentration (HCC), as it only requires one noninvasive collection to measure months of HPA-axis activity or experienced stress. However, few studies measure HCC in young chil…

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Clinical applications of cortisol measurements in hair.

Cortisol measurements in blood, saliva and urine are frequently used to examine the hypothalamus-pituitary-adrenal (HPA) axis in clinical practice and in research. However, cortisol levels are subject to variations due to acute stress, the diurnal rhythm and pulsatile secretion. Cortisol measurements in body fluids are not always a reflection of long-term cortisol exposure. The analysis of cortisol in scalp hair is a relatively novel method to measure cumulative cortisol exposure over months up to years. Over the past years, hair cortisol concentrations (HCC) have been examined in association with a large number of somatic and mental health conditions. HCC can be used to evaluate disturbances of the HPA axis, including Cushing's syndrome, and to evaluate hydrocortisone treatment. Using HCC, retrospective timelines of cortisol exposure can be created which can be of value in diagnosing cy…

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"More than skin deep": stress neurobiology and mental health consequences of racial discrimination.

Ethnic minority groups across the world face a complex set of adverse social and psychological challenges linked to their minority status, often involving racial discrimination. Racial discrimination is increasingly recognized as an important contributing factor to health disparities among non-dominant ethnic minorities. A growing body of literature has recognized these health disparities and has investigated the relationship between racial discrimination and poor health outcomes. Chronically elevated cortisol levels and a dysregulated hypothalamic-pituitary-adrenal (HPA) axis appear to mediate effects of racial discrimination on allostatic load and disease. Racial discrimination seems to converge on the anterior cingulate cortex (ACC) and may impair the function of the prefrontal cortex (PFC), hence showing substantial similarities to chronic social stress. This review provides a summar…

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Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome.

The weight of current evidence supports the presence of the following factors related to hypothalamic-pituitary-adrenal (HPA) axis dysfunction in patients with chronic fatigue syndrome (CFS): mild hypocortisolism; attenuated diurnal variation of cortisol; enhanced negative feedback to the HPA axis; and blunted HPA axis responsiveness. Furthermore, HPA axis changes seem clinically relevant, as they are associated with worse symptoms and/or disability and with poorer outcomes to standard treatments for CFS. Regarding etiology, women with CFS are more likely to have reduced cortisol levels. Studies published in the past 8 years provide further support for a multifactorial model in which several factors interact to moderate HPA axis changes. In particular, low activity levels, depression and early-life stress appear to reduce cortisol levels, whereas the use of psychotropic medication can in…

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Psychophysiological biomarkers of workplace stressors.

Unlabelled: Workplace stressors are associated with greater coronary heart disease risk, although there is debate over the psychophysiological consequences of work stress. This study builds on recent reviews and examines the literature linking work stress with sympatho-adrenal biomarkers (plasma catecholamines and heart rate variability) and HPA axis biomarkers - the post-morning profile of cortisol. Methods: Relevant studies using appropriate search terms were searched using the bibliographic databases PubMed, Embase, Biosys and Toxline. Four studies on plasma catecholamines, 10 studies on heart rate variability, and 16 studies on post-morning cortisol were reviewed. Results: In the majority of studies that examined the association of HRV and work stress, greater reports of work stress is associated with lower heart rate variability. The findings for plasma catecholamines and cortisol s…

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Stress and memory in humans: twelve years of progress?

Stress leads to an enhanced activity of the hypothalamus-pituitary adrenal (HPA) axis resulting in an increased release of glucocorticoids from the adrenal cortex. These hormones influence target systems in the periphery as well as in the brain. The present review paper describes the impact of the human stress hormone cortisol on episodic long-term memory. Starting out with our early observation that stress as well as cortisol treatment impaired declarative memory, experiments by the author are described, which result in an enhanced understanding of how cortisol influences memory. The main conclusions are that stress or cortisol treatment temporarily blocks memory retrieval. The effect is stronger for emotional arousing material independent of its valence. In addition cortisol only influences memory when a certain amount of testing induced arousal occurs. A functional magnetic resonance …

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Regulation of the hypothalamic-pituitary-adrenal axis.

Glucocorticoids (GCs) are essential for the maintenance of homeostasis and enable the organism to prepare for, respond to and manage stress, either physical or emotional. Cortisol, the principal GC in humans, is synthesized in the adrenal cortex. It is released in the circulation in a pulsatile and circadian pattern. GC secretion is governed by hypothalamus and pituitary. The hypothalamus senses changes in the external and internal environment that may disrupt the homeostatic balance of the organism (i.e. stressors), and responds by releasing corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) from parvocellular neurons projecting from the paraventricular nucleus to the median eminence. These neurohormones are released into the anterior pituitary where they act synergistically via specific receptors (CRH-R1 and V1B receptor, respectively) to trigger the release of the ad…

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The brain and the stress axis: the neural correlates of cortisol regulation in response to stress.

The hypothalamic-pituitary-adrenal (HPA) axis is the major endocrine stress axis of the human organism. Cortisol, the final hormone of this axis, affects metabolic, cardiovascular and central nervous systems both acutely and chronically. Recent advances in neuroimaging techniques have led to the investigation of regulatory networks and mechanisms of cortisol regulation in the central nervous system in human populations. In the following review, results from human and animal studies are being presented that investigate the specific role of hippocampus (HC), amygdala (AG), prefrontal cortex (PFC), and brainstem nuclei in cortisol regulation in response to stress. In general, the types of stressors need to be distinguished when discussing the contributions of these structures in regulating the HPA axis. We propose a basic framework on how these structures communicate as a network to regulat…

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Cortisol secretion patterns in addiction and addiction risk.

Addiction to alcohol or nicotine involves altered functioning of the brain's motivational systems. Altered functioning of the hypothalamic-pituitary-adrenocortical (HPA) axis may hold clues to the nature of the motivational changes accompanying addiction and vulnerability to addiction. Alcohol and nicotine show at least three forms of interaction with HPA functioning. Acute intake of both substances causes stress-like cortisol responses. Their persistent use may dysregulate the HPA. Finally, the risk for dependence and for relapse after quitting may be associated with deficient cortisol reactivity to a variety of stressors. The HPA is regulated at the hypothalamus by diurnal and metabolic signals, but during acute emotional states, its regulation is superseded by signals from the limbic system and prefrontal cortex. This top-down organization makes the HPA responsive to inputs that refle…

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A meta-analysis of cortisol response to challenge in human aging: importance of gender.

An increased cortisol response to challenge is associated with a variety of age-related disorders such as Alzheimer's disease, depression, diabetes, metabolic syndrome, and hypertension. Among the healthy elderly, an increased cortisol response to challenge may be a risk factor for developing these age-related disorders. We searched Pubmed, Embase, PsychInfo, Biosis, and Digital Dissertations (January 1966-June 2003) and included 45 parallel-group (young vs. old subjects) studies that used either a pharmacological or psychological challenge in healthy volunteers and measured cortisol response to challenge. We calculated effect sizes (Cohen's d) for the standardized mean differences between groups. Compared to younger controls (n=670, mean age 28 years +/-5), older subjects (n=625, 69+/-6) showed a larger cortisol response to challenge defined as stronger response to stimulation or less i…

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Do different types of stress differentially alter behavioural and neurobiological outcomes associated with depression in rodent models? A systematic review.

Cataloguing the effects of different types of stress on behaviour and physiology in rodent models has not been comprehensively attempted. Here, we systematically review whether chronic exposure to physical stress, psychosocial stress, or both types of stress can induce different behavioural and neurobiological outcomes in male and female rodents. We found that physical stress consistently increased depressive-like behaviour, impaired social interaction and decreased body weight, while psychosocial stress consistently increased both anxiety- and depressive-like behaviour, impaired social interaction and learning and memory, increased HPA axis activity, peripheral inflammation and microglial activation, and decreased hippocampal neurogenesis in male rodents. Moreover, we found that the combined effect of both stress types resulted in a more severe pathological state defined by increased an…

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Inflammation as a neurobiological substrate of cognitive impairment in bipolar disorder: Evidence, pathophysiology and treatment implications.

Background: Bipolar disorder (BD) has been associated with cognitive impairment during depressed, manic and euthymic periods. Inflammation has been shown to be involved in the pathophysiology of BD and cognitive impairment. Methods: For this systematic review, the MEDLINE/PubMed, Embase, Google Scholar and ClinicalTrials.gov databases were searched for relevant articles assessing the association between cognitive function and inflammatory markers in BD subjects. A discussion of potential mechanisms and therapeutic implications is also included to provide further context to the subject matter. Results: Eight studies, including a total of 555 BD subjects, assessing the association between cognitive function and inflammatory markers were identified. Cognitive dysfunction was associated with elevated levels of pro-inflammatory markers YKL40, IL-6, sCD40L, IL-1Ra, hsCRP and TNF-α. Mechanistic…

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Telomere length and hypothalamic-pituitary-adrenal axis response to stress in elderly adults.

Objective: Telomere shortening, a biomarker of cellular aging, has been associated with aging-related diseases. While psychological stress has been implicated in the process of telomere shortening, associations with activity of physiological stress systems have remained elusive. We studied whether leukocyte telomere length (LTL) is associated with hypothalamic-pituitary-adrenal (HPA) axis responses to psychosocial stress in elderly adults. Methods: LTL, measured by qPCR method was available in 1964 women and men from the Helsinki Birth Cohort Study at a mean age of 61.5 (SD=2.9) years. At a mean age of 63.5 (SD=2.7) years a subsample of them took part in the Trier Social Stress Test (TSST) during which salivary cortisol (n=283) and plasma cortisol and ACTH concentrations (n=215) were measured. Results: Mixed model regression analyses showed no linear or non-linear associations between LT…

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Covariance between psychological and endocrine responses to pharmacological challenge and psychosocial stress: a question of timing.

Objective: To test if the covariance of hypothalamus-pituitary-adrenal (HPA) axis and subjective-psychological responses to stress is dependent on different dynamics of these systems. Although stress theories typically assume substantial correlations of psychological and endocrine stress responses, studies have produced inconsistent results. One reason for this might be imperfect coupling of the different stress response systems. However, inconsistent correlations might also be a result of different on-/offsets of these stress responses, i.e., specific dynamics of the systems. Methods: HPA axis indicators and subjective-psychological states were repeatedly and synchronously measured in a pharmacological challenge test (injection of corticotropin-releasing hormone and infusion of arginine vasopressin; Study 1; n = 42) and a psychosocial stress situation (Trier Social Stress Test; Study 2;…

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Stress risk factors and stress-related pathology: neuroplasticity, epigenetics and endophenotypes.

This paper highlights a symposium on stress risk factors and stress susceptibility, presented at the Neurobiology of Stress workshop in Boulder, CO, in June 2010. This symposium addressed factors linking stress plasticity and reactivity to stress pathology in animal models and in humans. Dr. J. Radley discussed studies demonstrating prefrontal cortical neuroplasticity and prefrontal control of hypothalamo-pituitary-adrenocortical axis function in rats, highlighting the emerging evidence of the critical role that this region plays in normal and pathological stress integration. Dr. M. Kabbaj summarized his studies of possible epigenetic mechanisms underlying behavioral differences in rat populations bred for differential stress reactivity. Dr. L. Jacobson described studies using a mouse model to explore the diverse actions of antidepressants in brain, suggesting mechanisms whereby antidepr…

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Dissociation of ACTH and glucocorticoids.

It is increasingly clear that significant differential regulation of pituitary and adrenal gland activation exists, leading to a dissociation of plasma adrenocorticotropic hormone and corticosteroid secretion during fetal, postnatal and adult life. An increasing number of preclinical and clinical studies report dissociation of adrenocorticotropic hormone and cortisol levels in critical illness, inflammation and mental disorders. Mechanisms involve an altered adrenal sensitivity, aberrant receptor expression or modulation of adrenal function by cytokines, vasoactive factors or neuropeptides. The degree of dissociation has been associated with the level of complications of sepsis, surgery, malignant disease and depression. The separation of adrenocorticotropic hormone and corticosteroid secretion is of clinical relevance and should be incorporated into our view on endocrine stress regulati…

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Differential effects of acute and chronic social defeat stress on hypothalamic-pituitary-adrenal axis function and hippocampal serotonin release in mice.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) stress axis and disturbances in serotonin (5-HT) neurotransmission have been implicated in the pathogenesis of depressive disorder. Repeated social defeat of male NMRI mice has been shown to induce increases in core body temperature and corticosterone, indicative of a state of chronic stress in subordinate animals. The present study further characterised the HPA axis response to social defeat stress, and also examined hippocampal extracellular 5-HT release during the stress. Exposure to an acute social defeat elicits increases in plasma adrenocorticotrophic hormone and corticosterone levels, peaking at 15 and 30 min, respectively, and enhances corticotrophin-releasing factor (CRF) mRNA, but not arginine vasopressin (AVP) mRNA within the medial parvocellular division of the hypothalamic paraventricular nucleus. A concomitant increa…

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Neurobiology of early life adversity: A systematic review of meta-analyses towards an integrative account of its neurobiological trajectories to mental disorders.

Adverse childhood experiences (ACEs) may leave long-lasting neurobiological scars, increasing the risk of developing mental disorders in later life. However, no review has comprehensively integrated existing evidence across the fields: hypothalamic-pituitary-adrenal axis, immune/inflammatory system, neuroimaging, and genetics/epigenetics. We thus systematically reviewed previous meta-analyses towards an integrative account of ACE-related neurobiological alterations. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline, a total of 27 meta-analyses until October 2021 were identified. This review found that individuals with ACEs possess blunted cortisol response to psychosocial stressors, low-grade inflammation evinced by increased C-reactive protein levels, exaggerated amygdalar response to emotionally negative information, and diminished hippocam…

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Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation.

Neuropsychiatric disease frequently presents with an underlying hyporeactivity or hyperreactivity of the HPA stress axis, suggesting an exceptional vulnerability of this circuitry to external perturbations. Parental lifetime exposures to environmental challenges are associated with increased offspring neuropsychiatric disease risk, and likely contribute to stress dysregulation. While maternal influences have been extensively examined, much less is known regarding the specific role of paternal factors. To investigate the potential mechanisms by which paternal stress may contribute to offspring hypothalamic-pituitary-adrenal (HPA) axis dysregulation, we exposed mice to 6 weeks of chronic stress before breeding. As epidemiological studies support variation in paternal germ cell susceptibility to reprogramming across the lifespan, male stress exposure occurred either throughout puberty or in…

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Early-life adversity and cortisol response to social stress: a meta-analysis.

Early-life adversity has been associated with a life-long increased risk for psychopathology and chronic health problems. These long-term negative effects have been explained through stress sensitization, which may involve dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis through either increased or decreased reactivity. The present meta-analysis assessed for the first time the effect of early-life adversity on cortisol response to social stress. Thirty data sets were included in the meta-analysis, in which early-life adversity and salivary cortisol response to social stress were assessed in 4292 individuals of different ages. Results indicated a moderate effect size (g = -0.39) in overall cortisol levels across studies. Separate analyses of cortisol at different stages of response showed large effect sizes at peak and recovery, and a moderate effect at baseline. Heterogenei…

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