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Although rodent studies and mathematical models have clarified the mechanisms of ultradian pulsatility, a quantitative, human\u2010specific description of HPA axis dynamics is lacking. Here, we analyse 24\u2010h high\u2010frequency hormonal profiles from a cohort of healthy humans to quantify inter\u2010individual variability in adrenocorticotropic hormone and cortisol rhythms and to calibrate a foundational mathematical model of the human HPA axis. The model reproduces key human\u2010specific features, including an asymmetric circadian rhythm peaking at waking and ultradian oscillations with a longer period than those observed in rodents. We show that a simplified representation of the negative feedback between the pituitary and adrenal glands suffices to generate ultradian pulsatility, arising in the model via a Hopf bifurcation. Computational simulations further show how idealised stressors of different intensity, duration and timing perturb HPA axis dynamics, providing a theoretical basis for understanding the heterogeneous stress responses observed in clinical settings. This study provides a quantitative, proof\u2010of\u2010concept framework for human HPA axis regulation, offering insights into the potential mechanisms underlying the individual variability and robustness of hormonal rhythms.<\/jats:p>","DOI":"10.1111\/jne.70264","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:43:18Z","timestamp":1788910998000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Regulation of ultradian pulsatility and stress responses in the human hypothalamic\u2013pituitary\u2013adrenal axis"],"prefix":"10.1111","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6116-0479","authenticated-orcid":false,"given":"Belinda","family":"Lombard","sequence":"first","affiliation":[{"name":"School of Mathematics, College of Engineering and Physical Sciences University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0138-3982","authenticated-orcid":false,"given":"Thomas J.","family":"Upton","sequence":"additional","affiliation":[{"name":"Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Translational Health Sciences, Faculty of Health Sciences University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3635-6212","authenticated-orcid":false,"given":"Ben","family":"Gibbison","sequence":"additional","affiliation":[{"name":"Bristol Medical School University of Bristol  Bristol UK"},{"name":"NIHR Bristol Biomedical Research Unit University Hospitals Bristol and Weston NHS Foundation Trust  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0194-7194","authenticated-orcid":false,"given":"David","family":"Henley","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes Sir Charles Gairdner Hospital  Perth Australia"},{"name":"Medical School The University of Western Australia  Perth Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1299-4116","authenticated-orcid":false,"given":"Georgina","family":"Russell","sequence":"additional","affiliation":[{"name":"Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Translational Health Sciences, Faculty of Health Sciences University of Bristol  Bristol UK"},{"name":"Department of Diabetes and Endocrinology North Bristol NHS Trust  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6829-5736","authenticated-orcid":false,"given":"John R.","family":"Terry","sequence":"additional","affiliation":[{"name":"Centre for Intellectual Disability Equitable Research (CIDER), Peninsula Medical School University of Plymouth  Truro UK"},{"name":"Neuronostics Ltd.  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