Cortisol and the HPA axis

The HPA axis is a neuroendocrine feedback loop central to stress adaptation, metabolic regulation, and immune modulation. Operating through the release of CRH (Corticotropin-Releasing Hormone), ACTH (Adrenocorticotropic Hormone), and cortisol, the system is governed by circadian / ultradian rhythms and regulated by negative feedback. While essential for survival, HPA dysregulation is pathogenic: chronic hyperactivity drives metabolic and cardiovascular disease, whereas blunted reactivity is implicated in PTSD and fatigue syndromes.

Anatomical and hormonal components

• Hypothalamus: Paraventricular nucleus (PVN) secretes CRH and AVP into the portal system 
• Pituitary: Anterior corticotrophs release ACTH in response to CRH/AVP 
• Adrenal cortex: Zona fasciculata produces cortisol, the main glucocorticoid in humans 

Physiological functions

• Stress response: Rapidly mobilizes energy, increases cardiovascular tone, and modulates immunity 
• Circadian regulation: Cortisol peaks at waking, supporting alertness and metabolism 
• Metabolic control: Regulates glucose, lipid, and protein metabolism 
• Immune modulation: Balances pro- and anti-inflammatory responses 

Regulatory mechanisms

• Negative feedback: Cortisol inhibits CRH/ACTH at hypothalamus and pituitary 
• Circadian rhythm: Suprachiasmatic nucleus (SCN) drives daily cortisol variation 
• Ultradian rhythm: Hourly pulses optimize tissue sensitivity and gene expression 

Modulation by internal and external factors

• Sex steroids: Estrogens and androgens modulate HPA tone 
• Age: HPA activity changes across the lifespan 
• Early-life stress: Programs long-term HPA responsivity 
• Sleep: Poor sleep increases HPA reactivity 

Pathological consequences of dysregulation

• Chronic stress: Hypercortisolism drives metabolic syndrome, obesity, and cardiovascular disease
• Psychiatric disorders: Hyperactivity is linked to depression and anxiety; blunted responses to PTSD and chronic fatigue
• Critical illness: Peripheral adaptations sustain cortisol; prolonged ICU stay can cause central suppression.