Hypothalamic–Pituitary–Adrenal (HPA) Axis

The HPA axis regulates endogenous cortisol production and maintains physiologic stress response.

It operates through a three-tier hormonal cascade:

Hypothalamus → Pituitary → Adrenal Cortex

The hypothalamus secretes:

• Corticotropin-Releasing Hormone (CRH)

CRH is released in response to:

• Stress
• Hypoglycemia
• Illness
• Circadian rhythm (early morning peak)

CRH stimulates the anterior pituitary.

The anterior pituitary secretes:

• Adrenocorticotropic Hormone (ACTH)

ACTH:

• Travels via bloodstream
• Stimulates adrenal cortex (zona fasciculata)
• Promotes cortisol synthesis and release

The adrenal cortex produces:

• Cortisol (glucocorticoid)
• Aldosterone (mineralocorticoid)
• Androgens

Cortisol effects:

• ↑ Gluconeogenesis
• ↑ Blood glucose
• Suppresses immune response
• Maintains vascular tone
• Supports stress response

Cortisol exerts negative feedback at:

• Hypothalamus → ↓ CRH
• Pituitary → ↓ ACTH

This maintains hormonal balance.

If cortisol rises:

ACTH decreases.

If cortisol falls:

ACTH increases.

Cortisol secretion follows a diurnal pattern:

• Highest in early morning (~6–8 AM)
• Lowest at midnight

This is why:

• Morning steroid dosing mimics physiology.
• Late-night cortisol testing screens for Cushing syndrome.

During physiologic stress:

• CRH increases
• ACTH increases
• Cortisol increases

This supports:

• Blood pressure maintenance
• Glucose availability
• Anti-inflammatory control

Patients with adrenal insufficiency cannot mount this response.

Systemic steroids (e.g., Prednisone, Dexamethasone):

• Mimic cortisol
• Suppress ACTH production
• Lead to adrenal atrophy over time

Abrupt withdrawal after chronic use may cause:

• Adrenal insufficiency
• Hypotension
• Fatigue
• Crisis in severe cases

See:

• Corticosteroids

• Primary (Addison disease)
• Secondary (low ACTH)
• Tertiary (chronic steroid suppression)

Symptoms:

• Fatigue
• Hypotension
• Hyponatremia
• Hyperkalemia (primary)

• Excess cortisol
• Can be ACTH-dependent or independent
• May be exogenous (chronic steroid therapy)

Symptoms:

• Central obesity
• Moon facies
• Purple striae
• Hyperglycemia

Dexamethasone:

• Suppresses ACTH in normal physiology
• Fails to suppress cortisol in Cushing syndrome

See:

• Dexamethasone

• CRH → ACTH → Cortisol.
• Cortisol provides negative feedback at two levels.
• Chronic steroid therapy suppresses ACTH.
• Morning dosing reduces HPA disruption.
• Stress dosing required in adrenal insufficiency.
• Dexamethasone suppression testing evaluates feedback integrity.