HPA axis

**Pathway** - Stress, hypoglycemia, and the circadian rhythm (suprachiasmatic nucleus; cortisol peaks in early morning) drive the paraventricular nucleus of the hypothalamus to release corticotropin-releasing hormone (CRH). - CRH acts on corticotrophs of the anterior pituitary. These cells cleave POMC into ACTH, β-endorphin, and MSH. ACTH release follows. - ACTH binds MC2R on the adrenal cortex. The signal runs through Gs, cAMP, and PKA. ACTH mainly stimulates the zona fasciculata (cortisol) and zona reticularis (androgens). It has little effect on aldosterone, which is controlled mainly by the RAAS and K+. - Cortisol gives negative feedback on both the hypothalamus (CRH) and the pituitary (ACTH).

**Cortisol effects** - Raises blood glucose through gluconeogenesis, insulin resistance, and lipolysis. - Causes protein catabolism, leading to muscle wasting, skin thinning, and osteoporosis. - Is anti-inflammatory and immunosuppressive. It inhibits phospholipase A2, decreases lymphocytes and eosinophils, and increases neutrophils (demargination). - Is permissive for catecholamine action, which helps maintain vascular tone and blood pressure. - Excess can cause mineralocorticoid-like effects because cortisol binds the mineralocorticoid receptor when 11β-HSD2 is overwhelmed. - In plasma, cortisol is bound to corticosteroid-binding globulin (CBG). Estrogen (pregnancy, OCPs) raises CBG, which increases total cortisol but not free cortisol.

**Clinical correlates** - **Cushing syndrome** (the most common cause is exogenous glucocorticoids): - *ACTH-dependent*: Cushing disease (pituitary adenoma) and ectopic ACTH (small cell lung cancer, carcinoid). - *ACTH-independent*: adrenal adenoma or carcinoma, and primary bilateral adrenal hyperplasia. - Workup: 24-hour urinary free cortisol, late-night salivary cortisol, or low-dose dexamethasone suppression test. Then measure ACTH. - High-dose dexamethasone suppresses a pituitary source (Cushing disease) but not an ectopic source. - Features: central obesity, moon facies, buffalo hump, purple striae, hypertension, hyperglycemia, and osteoporosis. - **Primary adrenal insufficiency (Addison disease)**: cortisol is low and ACTH is high. Hyperpigmentation results from excess POMC-derived MSH. Aldosterone is also lost, causing hyperkalemia, hyponatremia, and hypotension. The most common cause in the US is autoimmune adrenalitis. Worldwide, it is TB. - **Secondary adrenal insufficiency** (pituitary failure): low ACTH and low cortisol. There is no hyperpigmentation, and no hyperkalemia because the RAAS is intact. - **Tertiary adrenal insufficiency**: chronic exogenous steroids suppress CRH and ACTH, causing adrenal atrophy. Taper steroids and give stress dosing during illness or surgery. - **Waterhouse-Friderichsen syndrome**: acute adrenal hemorrhage, classically from meningococcemia, causes acute adrenal crisis. - **Adrenal crisis**: hypotension, shock, hypoglycemia, and hyponatremia. Treat with IV hydrocortisone and fluids. - **Congenital adrenal hyperplasia** (21-hydroxylase deficiency is the most common): low cortisol removes negative feedback. ACTH rises, causing adrenal hyperplasia and androgen excess. Presentations include ambiguous genitalia in females, salt-wasting, and hypotension. 11β-hydroxylase deficiency causes hypertension through excess deoxycorticosterone. - **Nelson syndrome**: after bilateral adrenalectomy for Cushing disease, the pituitary adenoma enlarges and ACTH rises, causing hyperpigmentation. - **Chronic stress and psychiatric disease**: HPA hyperactivity is seen in major depression (melancholic type) and can cause nonsuppression on the dexamethasone test. Hypoactivity is described in PTSD.

**High-yield pearls** - ACTH and cortisol are high in the morning and lowest at night. Loss of this diurnal rhythm is an early sign of Cushing syndrome. - ACTH and cortisol levels together help localize the lesion. High cortisol with low ACTH means an adrenal source or exogenous steroid. High cortisol with high ACTH means a pituitary or ectopic source. - The cosyntropin (ACTH) stimulation test distinguishes primary from secondary adrenal insufficiency. - Exogenous glucocorticoids suppress the HPA axis, so abrupt discontinuation can cause adrenal crisis. - Drugs: ketoconazole and metyrapone inhibit steroidogenesis. Mifepristone blocks the glucocorticoid receptor.