Regulation of ultradian pulsatility and stress responses in the human hypothalamic-pituitary-adrenal axis

The hypothalamic-pituitary-adrenal (HPA) axis is a vital neuroendocrine system that maintains homeostasis by regulating stress hormone secretion through tightly controlled circadian and ultradian rhythms. Although rodent studies and mathematical models have clarified the mechanisms of ultradian pulsatility, a quantitative, human-specific description of HPA axis dynamics is lacking. Here, we analyse 24-h high-frequency hormonal profiles from a cohort of healthy humans to quantify inter-individual variability in adrenocorticotropic hormone and cortisol rhythms and to calibrate a foundational mathematical model of the human HPA axis. The model reproduces key human-specific 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-of-concept framework for human HPA axis regulation, offering insights into the potential mechanisms underlying the individual variability and robustness of hormonal rhythms.