The HPA axis's role in chronic stress and neuropsychiatric disorders. Pathways to malignant formations and autoimmune disorders through chronic stress

Chronic stress is not merely a psychological state — it is a physiological cascade with measurable, compounding consequences across the endocrine, immune, and nervous systems. This ongoing literature synthesis maps the hypothalamic-pituitary-adrenal (HPA) axis and its dysregulation under chronic stress, integrating neuroendocrinology, immunology, and psychiatric research into a single mechanistic account. Coverage includes the CRH–ACTH–glucocorticoid pipeline, AVP and POMC contributions, glucocorticoid receptor signaling, endocannabinoid-mediated fast feedback at PVN CRH neurons, hippocampal and prefrontal regulation of stress termination, amygdalar excitatory drive, and the locus coeruleus–noradrenergic system. Modulators of the stress response (gonadal steroids, developmental stage, stressor type) are also examined. Three downstream pathologies are traced in detail: thymic atrophy via glucocorticoid-induced DP thymocyte apoptosis — linking chronic stress to autoimmune disorders and impaired antitumor surveillance — hippocampal damage from sustained hypercortisolism, and HPA hyperactivity in depression and PTSD. Work in progress; the closing section on glucocorticoid-induced hippocampal damage in neuropsychiatric disorders is forthcoming.