Hormonal Characteristics of Chronic Stress

HPA Axis Dysregulation in Chronic Stress

Chronic stress leads to persistent activation of the HPA axis, which differs significantly from the adaptive, beneficial response seen in acute stress 1, 2

Increased long-term catecholamine release occurs during chronic stress, leading to increased carnitine acyl transferase activity, causing mitochondrial overflooding with free fatty acids, excessive beta-oxidation and inhibition of pyruvic acid dehydrogenase, and cytosolic lactic acid accumulation 2

Insulin resistance and compensatory hyperinsulinemia develop as a direct result of chronic stress, predisposing individuals to hyperglycemia and diabetes 2, 3

Pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α become elevated, contributing to depression and anxiety disorders commonly comorbid with chronic stress 1, 4, 5

Chronic stress and elevated glucocorticoids are associated with reduced volume and functionality of the hippocampus and medial prefrontal cortex, decreased hippocampal neurogenesis, and dendritic retraction in both hippocampus and prefrontal cortex 4, 5

Chronic stress induces a state of "chronic stress-mediated dysmetabolism" or metabolic remodeling, with key features including disturbed tricyclic acid cycle function, deficient macroerg phosphate generation, tendency toward ketosis development, accumulation of toxic fatty acid products, increased intracellular triglyceride synthesis leading to lipotoxicity, and shift from efficient mitochondrial energy production to less efficient cytosolic anaerobic glycolysis 2, 3

The hormonal dysregulation of chronic stress significantly increases risk for metabolic disorders, mental health disorders, and immune dysfunction 2, 4, 5

Microglial activation occurs in the brain, perpetuating neuroinflammation through IL-1β-related pathways, contributing to depression and anxiety disorders commonly comorbid with chronic stress, as reported by BioScience Trends 6
The inflammatory cascade activates indoleamine 2,3-dioxygenase (IDO), shifting tryptophan metabolism away from serotonin production toward the kynurenine pathway, mechanistically linking chronic stress to depression, according to BioScience Trends 6