A Mechanistic Model for the HPA Axis Cortisol Paradox in PTSD

Post-traumatic Stress Disorder (PTSD) is a debilitating psychiatric condition characterized by intrusive memories, hyperarousal, avoidance, and cognitive and mood disturbances. A longstanding biological paradox in PTSD is the observation of low basal cortisol levels, despite the expectation of elevated cortisol under chronic stress. This “low cortisol paradox” challenges traditional hypothalamic-pituitary-adrenal (HPA) axis regulation models. Individuals with PTSD also exhibit normal or near-normal adrenocorticotropic hormone (ACTH) levels despite reduced cortisol and blunted hormonal responses to acute stress. In this paper, we provide further evidence of reduced cortisol levels using a large medical database from thousands of individuals diagnosed with PTSD. To understand this dysregulation, we apply a systems-level mathematical model of HPA axis regulation that incorporates dynamic changes in gland functional mass, the pituitary corticotrophs and adrenal cortex, over weeks to months. Using this model, we demonstrate that enhanced glucocorticoid receptor (GR) sensitivity, a known risk factor for PTSD, can lead to a steady state with low cortisol and normal ACTH, reconciling key clinical observations. The model also recapitulates the blunted cortisol and ACTH responses to acute stress and the dexamethasone/ corticotropin-releasing hormone (DEX/CRH) test, reported in PTSD cohorts. Importantly, despite low cortisol levels, basal glucocorticoid receptor (GR) activity is higher than normal due to the reduced receptor affinity. Thus, individuals with PTSD effectively experience elevated cortisol signaling relative to their GR sensitivity. These findings provide a unified mechanistic explanation for HPA axis dysregulation in PTSD, grounded in the slow time scale of changes in gland functional mass and supported by literature and clinical data.