====== 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

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===== Step 1 – Hypothalamus =====

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.

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===== Step 2 – Anterior Pituitary =====

The anterior pituitary secretes:

  * Adrenocorticotropic Hormone (ACTH)

ACTH:

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

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===== Step 3 – Adrenal Cortex =====

The adrenal cortex produces:

  * Cortisol (glucocorticoid)
  * Aldosterone (mineralocorticoid)
  * Androgens

Cortisol effects:

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

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===== Negative Feedback Loop =====

Cortisol exerts negative feedback at:

  * Hypothalamus → ↓ CRH
  * Pituitary → ↓ ACTH

This maintains hormonal balance.

If cortisol rises:
  ACTH decreases.

If cortisol falls:
  ACTH increases.

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===== Circadian Rhythm =====

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.

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===== Response to Stress =====

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.

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===== Exogenous Glucocorticoids =====

Systemic steroids (e.g., [[endocrine:drugs:prednisone|Prednisone]], [[endocrine:drugs:dexamethasone|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:
  * [[endocrine:drug_classes:corticosteroids|Corticosteroids]]

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===== Disorders of the HPA Axis =====

==== Adrenal Insufficiency ====

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

Symptoms:
  * Fatigue
  * Hypotension
  * Hyponatremia
  * Hyperkalemia (primary)

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==== Cushing Syndrome ====

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

Symptoms:
  * Central obesity
  * Moon facies
  * Purple striae
  * Hyperglycemia

----

===== Dexamethasone Suppression Test =====

Dexamethasone:

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

See:
  * [[endocrine:drugs:dexamethasone|Dexamethasone]]

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===== High-Yield Pearls =====

  * 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.