hypothalamic-pituitary-adrenal axis

**Pathway:** Stress, hypoglycemia, cytokines (IL-1, IL-6, TNF-α), and circadian input (suprachiasmatic nucleus) -> paraventricular nucleus of hypothalamus releases CRH -> anterior pituitary corticotrophs cleave POMC into ACTH (plus β-endorphin, MSH) -> ACTH binds MC2R (Gs/cAMP/PKA) on adrenal cortex -> cortisol synthesis, mainly in the zona fasciculata (also adrenal androgens from zona reticularis). ACTH has only a minor, permissive role for aldosterone (zona glomerulosa), which is mainly controlled by the renin-angiotensin system and K+.

**Feedback:** Cortisol inhibits CRH and ACTH (negative feedback at both hypothalamus and pituitary). ACTH also short-loop inhibits CRH. Cortisol is highest in the early morning (peak around 6-8 AM) and lowest around midnight.

**Cortisol actions:** Increases gluconeogenesis, glycogenolysis, proteolysis, and lipolysis. Causes insulin resistance. Is anti-inflammatory and immunosuppressive (inhibits phospholipase A2, decreases leukocyte function, lymphocytopenia, eosinopenia, neutrophilia). Is permissive for catecholamine action (maintains vascular tone and BP). Upregulates α1 receptors on arterioles. Increases bone resorption. Contributes to fetal lung maturation (surfactant). Cortisol is bound by corticosteroid-binding globulin (CBG); estrogen/pregnancy and OCPs raise CBG and total cortisol, but free cortisol is unchanged.

**Clinical disorders (high-yield patterns):** - **Cushing syndrome:** Most common cause is exogenous (iatrogenic) glucocorticoids, which gives low ACTH and adrenal atrophy bilaterally. Endogenous causes: ACTH-secreting pituitary adenoma (Cushing disease), which has high ACTH and suppresses with high-dose dexamethasone. Ectopic ACTH (small cell lung cancer, carcinoids) has high ACTH and does NOT suppress with high-dose dexamethasone. Adrenal adenoma/carcinoma has low ACTH. Features: central obesity, moon facies, buffalo hump, purple striae, HTN, hyperglycemia, osteoporosis, proximal myopathy, hirsutism, and psychiatric symptoms. Screening: late-night salivary cortisol, 24-h urinary free cortisol, or 1 mg overnight dexamethasone suppression test. Then measure ACTH to localize. - **Primary adrenal insufficiency (Addison disease):** Autoimmune destruction is the most common cause in developed countries (TB worldwide). Low cortisol and aldosterone with high ACTH. Features: hyperpigmentation (POMC/MSH), hypotension, hyponatremia, hyperkalemia, non-anion-gap metabolic acidosis, hypoglycemia, and fatigue. Adrenal crisis: Waterhouse-Friderichsen syndrome (meningococcemia with adrenal hemorrhage). - **Secondary/tertiary adrenal insufficiency:** Low ACTH (pituitary disease or chronic exogenous steroid withdrawal). No hyperpigmentation, no hyperkalemia (aldosterone is preserved), and the RAAS is intact. Diagnosis: ACTH (cosyntropin) stimulation test. Treatment is glucocorticoid replacement, and stress dosing is needed during illness or surgery. - **Congenital adrenal hyperplasia:** For example, 21-hydroxylase deficiency (the most common cause) leads to low cortisol, then high ACTH, adrenal hyperplasia, and excess androgens. 17-OHP is elevated. Patients may have a salt-wasting crisis and virilization. - **Chronic exogenous steroids:** These suppress the axis and cause adrenal atrophy, so taper them to avoid adrenal crisis.

**Other associations:** Chronic stress and depression (melancholic type) can involve HPA hyperactivity. Sheehan syndrome (postpartum pituitary necrosis) causes secondary adrenal insufficiency. Pituitary apoplexy can acutely cause ACTH deficiency. Nelson syndrome (pituitary adenoma growth after bilateral adrenalectomy) causes hyperpigmentation. Metyrapone (blocks 11β-hydroxylase) can be used to test axis integrity; ketoconazole inhibits steroidogenesis.