A mechanistic modeling framework to interpret ACTH stimulation tests across HPA axis adaptation states and glucocorticoid feedback dynamics.

The hypothalamic pituitary adrenal (HPA) axis is a key regulatory system coordinating endocrine responses to physiological and psychological stress. While the ACTH stimulation test remains a cornerstone of adrenal function assessment, its interpretation is complicated by the dynamic and adaptive nature of the HPA axis under chronic stress exposure. In particular, prolonged stress induces glandular remodeling, glucocorticoid receptor (GR) resistance and delayed feedback recovery, all of which may alter test outcomes without indicating primary adrenal failure. In this study, we present a mechanistic modeling framework that integrates hormonal kinetics, feedback inhibition and functional mass adaptation of the corticotroph and adrenal compartments. We simulate the HPA axis over 180 days encompassing three phases - baseline, chronic stress and recovery, while introducing a time varying GR resistance function to mimic feedback desensitization and its resolution. Using this framework, we evaluate both low dose (1μg) and high dose (250μg) ACTH stimulation tests across physiological phases. Our simulations show that cortisol responses are highly sensitive to both the magnitude and timing of stress exposure and that ACTH responsiveness is phase dependent and often blunted during recovery due to persistent feedback resistance. Low dose ACTH testing more reliably reflects partial adrenal adaptation, while high dose tests risks masking dysfunction due to supraphysiological drive. These results highlight the limitations of static testing paradigms and suggest that accounting for glandular plasticity and GR feedback dynamics is essential for effective endocrine diagnosis particularly in stress related or treatment induced adrenal disorders.