The Hypothalamic-Pituitary-Adrenal (HPA) axis is a major neuroendocrine system, and its dysregulation is implicated in various diseases. This system also presents interesting mathematical challenges for modeling. We consider a nonlinear delay differential equation model and calculate pseudospectra of three different linearizations: a time-dependent Jacobian, linearization around the limit cycle, and dynamic mode decomposition (DMD) analysis of Koopman operators (global linearization). The time-dependent Jacobian provided insight into experimental phenomena, explaining why rats respond differently to perturbations during corticosterone secretion's upward versus downward slopes. We developed new mathematical techniques for the other two linearizations to calculate pseudospectra on Banach spaces and apply DMD to delay differential equations, respectively. These methods helped establish local and global limit cycle stability and study transients. Additionally, we discuss using pseudospectra to substantiate the model in experimental contexts and establish bio-variability via data-driven methods. This work is the first to utilize pseudospectra to explore the HPA axis.
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