Cortisol (hydrocortisone, C₂₁H₃₀O₅) is a glucocorticoid steroid synthesized from cholesterol in the adrenal cortex. Its four fused rings share the same cyclopentanoperhydrophenanthrene nucleus as cholesterol — same scaffold, completely different function.
The HPA axis
Cortisol release follows a three-level cascade: hypothalamus (detects stress → releases CRH) → anterior pituitary (CRH → ACTH) → adrenal cortex (ACTH → cortisol). A negative feedback loop — cortisol inhibits both hypothalamus and pituitary — normally maintains basal levels with a marked circadian rhythm (peak ~30 min after waking, minimum around midnight).
Acute effects: adaptive and necessary
Cortisol acts via an intracellular glucocorticoid receptor (GR) that translocates to the nucleus and activates/represses hundreds of genes. Key acute effects: hyperglycemia (stimulates hepatic gluconeogenesis, inhibits peripheral glucose uptake — more glucose available for brain and muscles); anti-inflammation (suppresses COX-2, IL-1, IL-6, TNF-α — prevents immune overreaction from damaging host tissues); immune redistribution (mobilizes neutrophils from bone marrow while suppressing adaptive lymphocyte responses).
Chronic effects: the silent destruction
Sustained cortisol elevation produces: hippocampal atrophy (highest GR density in the brain; chronic cortisol reduces neurogenesis, dendrite branching, increases excitotoxicity vulnerability — documented in chronic major depression and PTSD); insulin resistance (sustained hyperglycemia → chronic pancreatic overload); visceral fat accumulation (cortisol promotes abdominal fat deposition with simultaneous muscle catabolism); immune suppression (chronic adaptive immune suppression increases infection susceptibility and reduces vaccine efficacy).