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Regulation of the Hypothalamic‐Pituitary‐Adrenocortical Stress Response
Open accessAbstract
The hypothalamo‐pituitary‐adrenocortical (HPA) axis is required for stress adaptation. Activation of the HPA axis causes secretion of glucocorticoids, which act on multiple organ systems to redirect energy resources to meet real or anticipated demand. The HPA stress response is driven primarily by neural mechanisms, invoking corticotrophin releasing hormone (CRH) release from hypothalamic paraventricular nucleus (PVN) neurons. Pathways activating CRH release are stressor dependent: reactive responses to homeostatic disruption frequently involve direct noradrenergic or peptidergic drive of PVN neurons by sensory relays, whereas anticipatory responses use oligosynaptic pathways originating in upstream limbic structures. Anticipatory responses are driven largely by disinhibition, mediated by trans‐synaptic silencing of tonic PVN inhibition via GABAergic neurons in the amygdala. Stress responses are inhibited by negative feedback mechanisms, whereby glucocorticoids act to diminish drive (brainstem) and promote transsynaptic inhibition by limbic structures (e.g., hippocampus). Glucocorticoids also act at the PVN to rapidly inhibit CRH neuronal activity via membrane glucocorticoid receptors. Chronic stress‐induced activation of the HPA axis takes many forms (chronic basal hypersecretion, sensitized stress responses, and even adrenal exhaustion), with manifestation dependent upon factors such as stressor chronicity, intensity, frequency, and modality. Neural mechanisms driving chronic stress responses can be distinct from those controlling acute reactions, including recruitment of novel limbic, hypothalamic, and brainstem circuits. Importantly, an individual's response to acute or chronic stress is determined by numerous factors, including genetics, early life experience, environmental conditions, sex, and age. The context in which stressors occur will determine whether an individual's acute or chronic stress responses are adaptive or maladaptive (pathological). © 2016 American Physiological Society. Compr Physiol 6:603‐621, 2016.
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“The hypothalamic–pituitary–adrenal (HPA) axis constitutes the principal neuroendocrine pathway through which stress alters immune responses, mainly via glucocorticoid secretion [4,5].”
From Chronic Stress and Autoimmunity: The Role of HPA Axis and Cortisol Dysregulation (2025) · cites this paper as [4]
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“Dysbiosis leads to heightened stress responses with elevated cortisol and adrenocorticotropic hormone (ACTH) levels [141,142].”
From Unraveling the Connections: Eating Issues, Microbiome, and Gastrointestinal Symptoms in Autism Spectrum Disorder (2025) · cites this paper as [142]
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“Moreover, integrating psychological and neurobiological perspectives highlights how trauma, attachment insecurity, and stress dysregulation both contribute to and result from abusive dynamics (Herman et al., 2016; González-Acosta et al., 2021).”
From From use to abuse: psychological, neurobiological, and spiritual pathways in relational harm and recovery (2026) · cites this paper as Herman et al., 2016
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“Prolonged exposure to emotional abuse constitutes a chronic stressor that persistently activates the hypothalamic–pituitary–adrenal (HPA) axis, resulting in dysregulated cortisol secretion–the primary glucocorticoid involved in stress regulation (Herman et al., 2016).”
From From use to abuse: psychological, neurobiological, and spiritual pathways in relational harm and recovery (2026) · cites this paper as Herman et al., 2016
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“This neurobiological embedding of trauma helps explain why individuals subjected to prolonged emotional abuse often experience enduring psychological distress and face challenges in achieving recovery even after the cessation of overt abuse (Herman et al., 2016; Teicher et al., 2016).”
From From use to abuse: psychological, neurobiological, and spiritual pathways in relational harm and recovery (2026) · cites this paper as Herman et al., 2016
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Neural regulation of endocrine and autonomic stress responses
Ulrich-Lai, Y. M., & Herman, J. P. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2647 · Cited by 3,318
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Research works printed but not linked: 7
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- 10.1210/en.134.4.1611 · DOI
- 10.1210/en.134.3.1528 · DOI
- Herman JP, 2007, Handbook of Neurochemistry and Molecular Neurobiology Behavioral Neurochemistry, Neuroendocrinology, and Molecular Neurobiology
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Early and Long-term Consequences of Nutritional Stunting: From Childhood to Adulthood.
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Yoga, mindfulness-based stress reduction and stress-related physiological measures: A meta-analysis.
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Metadata
- Authors
- Herman, J. P., McKlveen, J. M., Ghosal, S., Kopp, B., Wulsin, A., Makinson, R., Scheimann, J., & Myers, B.
- Affiliations
- University of Cincinnati (US)
- Corresponding author
- Herman, James P.
- ORCID
- Venue
- Comprehensive Physiology
- Publisher
- Wiley
- Published
- 2016-03-15
- Volume
- 6
- Issue
- 2
- Pages
- 603-621
- ISSN
- 2040-4603 (ISSN-L)
- PMC
- PMC4867107
- OpenAlex
- W2413515606
- Cited by
- 1,819
- References
- 180
- Citations by year
- 2026: 115 · 2025: 220 · 2024: 309 · 2023: 277 · 2022: 238 · 2021: 199 · 2020: 174 · 2019: 124 · 2018: 92 · 2017: 60 · 2016: 11
- Type
- other
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Comprehensive physiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH101729, R01MH049698, R01MH069860)
- National Institute of Neurological Disorders and Stroke (F30NS095578, T32NS007453)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- hypothalamic-pituitary-adrenal axis, stress response, corticotropin-releasing factor, paraventricular nucleus, glucocorticoid negative feedback, amygdala, hippocampus, chronic stress, anticipatory stress, noradrenergic activation, GABAergic inhibition, limbic system, stress adaptation
- MeSH terms
- Animals, Glucocorticoids, Homeostasis, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Stress, Physiological
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- Herman, J. P., McKlveen, J. M., Ghosal, S., Kopp, B., Wulsin, A., Makinson, R., Scheimann, J., & Myers, B. (2016). Regulation of the Hypothalamic‐Pituitary‐Adrenocortical Stress Response. Comprehensive Physiology. https://doi.org/10.1002/cphy.c150015
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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