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Regulation of the Hypothalamic‐Pituitary‐Adrenocortical Stress Response
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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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The Role of the Forebrain Glucocorticoid Receptor in Acute and Chronic Stress
Furay, A. R., Packard, A. E. B., & Herman, J. P. (2008) · Endocrinology · doi:10.1210/en.2008-0642 · Cited by 192
Self-citationEffect of stressor intensity on habituation of the adrenocortical stress response
Natelson, B. H., Ottenweller, J. E., Cook, J. A., Pitman, D. L., McCarty, R. C., & Tapp, W. N. (1988) · Physiology & Behavior · doi:10.1016/0031-9384(88)90096-0 · Cited by 186
Stress-induced changes in human decision-making are reversible
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The Proopiomelanocortin System
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Neural Regulation of the Stress Response: The Many Faces of Feedback
Myers, B., McKlveen, J. M., & Herman, J. P. (2012) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-012-9801-y · Cited by 175 · cited 2×
“Control of glucocorticoid release is mediated by glucocorticoid feedback at varying levels of the HPA axis, serving to limit prolonged exposure to catabolic actions of glucocorticoids (117).”
Self-citationSon, S. J., Filosa, J. A., Potapenko, E. S., Biancardi, V. C., Zheng, H., Patel, K. P., Tobin, V. A., Ludwig, M., & Stern, J. E. (2013) · Neuron · doi:10.1016/j.neuron.2013.04.025 · Cited by 174
Estrogen potentiates adrenocortical responses to stress in female rats
Figueiredo, H. F., Ulrich‐Lai, Y. M., Choi, D. C., & Herman, J. P. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00102.2006 · Cited by 174
Self-citationBoyle, M. P., Kolber, B. J., Vogt, S. K., Wozniak, D. F., & Muglia, L. J. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2173-05.2006 · Cited by 172
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Role of the paraventricular nucleus microenvironment in stress integration
Herman, J. P., Cullinan, W. E., Ziegler, D. R., & Tasker, J. G. (2002) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2002.02133.x · Cited by 168
Self-citationAnterior pituitary response to stress : time‐related changes and adaptation
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Costorage and coexistence of neuropeptides in the mammalian CNS
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Chronic stress plasticity in the hypothalamic paraventricular nucleus
Herman, J. P., Flak, J. N., & Jankord, R. (2008) · Progress in brain research · doi:10.1016/s0079-6123(08)00429-9 · Cited by 154
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Stress risk factors and stress-related pathology: Neuroplasticity, epigenetics and endophenotypes
Radley, J. J., Kabbaj, M., Jacobson, L., Heydendael, W., Yehuda, R., & Herman, J. P. (2011) · Stress · doi:10.3109/10253890.2011.604751 · Cited by 149
Self-citationLimbic and HPA axis function in an animal model of chronic neuropathic pain
Ulrich-Lai, Y. M., Xie, W., Meij, J. T. A., Dolgas, C. M., Yu, L., & Herman, J. P. (2006) · Physiology & Behavior · doi:10.1016/j.physbeh.2006.03.012 · Cited by 146
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Salivary cortisol and memory function in human aging
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Glucocorticoids and hippocampal damage
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Time-Dependent Effects of Cortisol on the Contextualization of Emotional Memories
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“, in vitro study suggest that AVP acts as a stronger stimulus for pituitary ACTH secretion in sheep corticotropes (43).”
Role of central glucagon-like peptide-1 in stress regulation
Ghosal, S., Myers, B., & Herman, J. P. (2013) · Physiology & Behavior · doi:10.1016/j.physbeh.2013.04.003 · Cited by 108
Self-citationRaff, H., Raff, J. L., Duthie, E. H., Wilson, C. R., Sasse, E. A., Rudman, I. W., & Mattson, D. L. (1999) · The Journals of Gerontology Series A · doi:10.1093/gerona/54.9.m479 · Cited by 108
Choi, D. C., Evanson, N. K., Furay, A. R., Ulrich‐Lai, Y. M., Ostrander, M. M., & Herman, J. P. (2007) · Endocrinology · doi:10.1210/en.2007-0883 · Cited by 106
Self-citation11β‐hydroxysteroid dehydrogenase isoforms and their implications for blood pressure regulation
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Human Glucocorticoid Feedback Inhibition Is Reduced in Older Individuals: Evening Study
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Flak, J. N., Myers, B., Solomon, M. B., McKlveen, J. M., Krause, E. G., & Herman, J. P. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12587 · Cited by 101
Self-citationTavares, R. F., Corrêa, F. M. D. A., & Resstel, L. B. M. (2009) · Journal of Neuroscience Research · doi:10.1002/jnr.22070 · Cited by 98
Age-related alterations of hypothalamic-pituitary-adrenal axis function in male Fischer 344 rats
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Solomon, M. B., Furay, A. R., Jones, K., Packard, A. E. B., Packard, B. A., Wulsin, A. C., & Herman, J. P. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2011.12.014 · Cited by 96
Self-citationAdrenal Splanchnic Innervation Modulates Adrenal Cortical Responses to Dehydration Stress in Rats
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Novel Aspects of Glutamatergic Signalling in the Neuroendocrine System
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Stress activation of IL-6 neurons in the hypothalamus
Jankord, R., Zhang, R., Flak, J. N., Solomon, M. B., Albertz, J., & Herman, J. P. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00131.2010 · Cited by 88
Self-citationDynamic Pituitary-Adrenal Interactions in Response to Cardiac Surgery*
Gibbison, B., Spiga, F., Walker, J. J., Russell, G. M., Stevenson, K., Kershaw, Y., Zhao, Z., Henley, D., Angelini, G. D., & Lightman, S. L. (2015) · Critical Care Medicine · doi:10.1097/ccm.0000000000000773 · Cited by 87
Ferguson, A. V. (2009) · Neuroendocrinology · doi:10.1159/000211202 · Cited by 87
Flak, J. N., Solomon, M. B., Jankord, R., Krause, E. G., & Herman, J. P. (2012) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2012.08161.x · Cited by 87
Self-citationSolomon, M. B., Loftspring, M., de Kloet, A. D., Ghosal, S., Jankord, R., Flak, J. N., Wulsin, A. C., Krause, E. G., Zhang, R., Rice, T., et al. (2015) · Endocrinology · doi:10.1210/en.2015-1276 · Cited by 85
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Jones, K. R., Myers, B., & Herman, J. P. (2011) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.03.021 · Cited by 81
Self-citationGlucocorticoid and estrogen regulation of corticosteroid-binding globulin production by rat liver.
Feldman, D., Mondon, C. E., Horner, J., & Weiser, J. N. (1979) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1979.237.6.e493 · Cited by 80
Ulrich‐Lai, Y. M., Jones, K. R., Ziegler, D. R., Cullinan, W. E., & Herman, J. P. (2010) · The Journal of Comparative Neurology · doi:10.1002/cne.22571 · Cited by 79
Self-citationFlak, J. N., Jankord, R., Solomon, M. B., Krause, E. G., & Herman, J. P. (2011) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.03.002 · Cited by 79
Self-citationNahar, J., Haam, J., Chen, C., Jiang, Z., Glatzer, N. R., Muglia, L. J., Dohanich, G. P., Herman, J. P., & Tasker, J. G. (2015) · Endocrinology · doi:10.1210/en.2015-1273 · Cited by 77
Self-citationTinnikov, A. A. (1999) · Endocrine · doi:10.1385/endo:11:2:145 · Cited by 77
CRH Deficiency Impairs but Does Not Block Pituitary-Adrenal Responses to Diverse Stressors
Jacobson, L., Muglia, L. J., Weninger, S. C., Pacák, K., & Majzoub, J. A. (2000) · Neuroendocrinology · doi:10.1159/000054524 · Cited by 76
Human Glucocorticoid Feedback Inhibition Is Reduced in Older Individuals: Evening Study
Wilkinson, C. W. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.2.545 · Cited by 76
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Defense of Adrenocorticosteroid Receptor Expression in Rat Hippocampus: Effects of Stress and Strain
Herman, J. P., Watson, S. J., & Spencer, R. L. (1999) · Endocrinology · doi:10.1210/endo.140.9.6962 · Cited by 73
Self-citationAge-Related Changes in Glucocorticoid Fast Feedback Inhibition of Adrenocorticotropin in Man
Boscaro, M., Paoletta, A., Scarpa, E., Barzon, L., Fusaro, P., Fallo, F., & Sonino, N. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.4.4745 · Cited by 73
Russell, G. M., Kalafatakis, K., & Lightman, S. L. (2014) · Journal of Neuroendocrinology · doi:10.1111/jne.12247 · Cited by 71
Regulation of Proopiomelanocortin Gene Expression
Jenks, B. G. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2008.03620.x · Cited by 70
The Medial Amygdala Modulates Body Weight but not Neuroendocrine Responses to Chronic Stress
Solomon, M. B., Jones, K., Packard, B. A., & Herman, J. P. (2009) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2009.01933.x · Cited by 68
Self-citationSplanchnicotomy increases adrenal sensitivity to ACTH in nonstressed rats
Jasper, M. S., & Engeland, W. C. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.273.2.e363 · Cited by 67
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Food and the circadian activity of the hypothalamic-pituitary-adrenal axis
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Role of corticosteroid binding globulin in the fast actions of glucocorticoids on the brain
Moisan, M., Minni, A., Dominguez, G., Helbling, J., Foury, A., Henkous, N., Dorey, R., & Béracochéa, D. (2013) · Steroids · doi:10.1016/j.steroids.2013.10.013 · Cited by 58
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Hypothalamo-pituitary-adrenocortical dysregulation in aging F344/Brown-Norway F1 hybrid rats
Herman, J. P., Larson, B. R., Speert, D. B., & Seasholtz, A. F. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00242-6 · Cited by 55
Self-citationBrainstem origins of glutamatergic innervation of the rat hypothalamic paraventricular nucleus
Ziegler, D. R., Edwards, M., Ulrich‐Lai, Y. M., Herman, J. P., & Cullinan, W. E. (2012) · The Journal of Comparative Neurology · doi:10.1002/cne.23043 · Cited by 53
Self-citationAge-Related Changes in Glucocorticoid Fast Feedback Inhibition of Adrenocorticotropin in Man
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The physiology of corticotropin-releasing hormone deficiency in mice
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Synaptic transmission of baro- and chemoreceptors afferents in the NTS second order neurons
Accorsi‐Mendonça, D., & Machado, B. H. (2013) · Autonomic Neuroscience · doi:10.1016/j.autneu.2012.12.002 · Cited by 51
The ontogeny of the neuroendocrine response to endotoxin
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Schroeder, R., & Henning, S. (1989) · Endocrinology · doi:10.1210/endo-124-5-2612 · Cited by 51
Ghosal, S., Osacká, J., Dolgas, C. M., Myers, B., & Herman, J. P. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.03.018 · Cited by 46
Self-citationDi, S., Popescu, I., & Tasker, J. G. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2971-12.2013 · Cited by 45
Heterogeneity of neuroendocrine stress responses in aging rat strains
Segar, T. M., Kasckow, J., Welge, J. A., & Herman, J. P. (2008) · Physiology & Behavior · doi:10.1016/j.physbeh.2008.07.024 · Cited by 42
Self-citationSchotanus, K., Tilders, F. J. H., & BERKENBOSCH, F. (1993) · Endocrinology · doi:10.1210/endo.133.6.8243265 · Cited by 42
Responses of Cortisol Secretion to Repeated Hemorrhage in the Anesthetized Dog*
Lilly, M. P., Engeland, W. C., & Gann, D. S. (1983) · Endocrinology · doi:10.1210/endo-112-2-681 · Cited by 39
Surgery Potentiates Adrenocortical Responses to Hypoxia in Dogs
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Interleukin‐1, but Not Stress, Stimulates Glucocorticoid Output during Early Postnatal Life in Micea
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Effect of acute and chronic stress on testosterone secretion in male rats
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Physiological inhibition and facilitation of adrenocortical response to hemorrhage
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Defense of Adrenocorticosteroid Receptor Expression in Rat Hippocampus: Effects of Stress and Strain
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Potentiated hormonal responses in a model of traumatic injury
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Research works printed but not linked: 7
- 10.1210/en.131.1.57 · DOI
- 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
- 10.1523/JNEUROSCI.4297-06.2006 · DOI · Paper page
- 10.1210/edrv-7-3-284 · DOI · Paper page
- 10.1210/en.133.6.2461 · DOI
Cited by
Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286
Oyola, M. G., & Handa, R. J. (2017) · Stress · doi:10.1080/10253890.2017.1369523 · Cited by 710
Early and Long-term Consequences of Nutritional Stunting: From Childhood to Adulthood.
Sanctis, V. D., Soliman, A. T., Alaaraj, N., Ahmed, S., Alyafei, F., & Hamed, N. (2021) · Acta bio-medica dell'Ateneo parmense/Acta biomedica · doi:10.23750/abm.v92i1.11346 · Cited by 394
Yoga, mindfulness-based stress reduction and stress-related physiological measures: A meta-analysis.
Pascoe, M. C., Thompson, D. R., & Ski, C. F. (2017) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2017.08.008 · Cited by 570
Heck, A., & Handa, R. J. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0167-9 · Cited by 573
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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Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
