Adrenal Cortex & Medulla

Adrenal zones and their hormones

GFR: the deeper, the sweeter. The cortex (mesoderm) has three zones. The zona glomerulosa makes aldosterone under angiotensin II and potassium control, independent of ACTH; the zona fasciculata makes cortisol and the zona reticularis makes androgens (DHEA), both driven by ACTH. The medulla, derived from neural crest, contains chromaffin cells that make catecholamines. Salt, sugar, sex, then catecholamines.

Catecholamine synthesis. Tyrosine → DOPA → dopamine → norepinephrine → epinephrine. The last step (PNMT) is induced by cortisol flowing from the cortex through the medulla, which is why the adrenal is the main source of epinephrine. Catecholamines are broken down to metanephrines and vanillylmandelic acid (VMA); dopamine yields homovanillic acid (HVA).

Cortisol does a bit of everything. It raises blood pressure by upregulating α1 receptors and permitting catecholamine action; causes insulin resistance and drives gluconeogenesis (hyperglycemia), lipolysis and proteolysis; and is anti-inflammatory, inhibiting phospholipase A2 and NF-κB, blocking histamine release and IL-2 production, and causing lymphopenia and eosinopenia. It decreases bone formation and fibroblast activity, so wounds heal poorly and skin thins.

Cortisol is BIG: increased Blood pressure, Insulin resistance and Gluconeogenesis, while inflammation, immunity, fibroblasts and bone formation are all decreased.

Cushing syndrome

Clinical picture. Chronic cortisol excess causes moon facies, a buffalo hump, central obesity, wide purple striae, proximal muscle weakness, hyperglycemia, hypertension, osteoporosis, thin skin with easy bruising and immunosuppression. The most common cause overall is exogenous glucocorticoids. Among endogenous causes, Cushing disease (a pituitary ACTH adenoma, ~70%) leads, followed by ectopic ACTH (classically small cell lung carcinoma, also bronchial carcinoids) and then adrenal tumors.

Screening. Use the low-dose dexamethasone suppression test, late-night salivary cortisol or 24-hour urine free cortisol. Dexamethasone normally suppresses cortisol; it fails to do so in every form of Cushing syndrome.

Localizing. Next measure ACTH: high in Cushing disease and ectopic ACTH, low in an adrenal tumor, which also causes atrophy of the other adrenal. A pituitary adenoma retains partial feedback, so a high dose of dexamethasone suppresses it, whereas ectopic ACTH and adrenal tumors do not suppress.

Aldosterone excess and adrenal insufficiency

Primary hyperaldosteronism (Conn). An aldosterone-producing adenoma or bilateral adrenal hyperplasia causes hypertension, hypokalemia and metabolic alkalosis, typically with little edema because of aldosterone escape (pressure natriuresis and ANP). The key finding is high aldosterone with low renin, a high aldosterone-to-renin ratio. Secondary hyperaldosteronism (renal artery stenosis, heart failure, cirrhosis) has high renin driving aldosterone. An adenoma is resected; bilateral hyperplasia is treated with spironolactone or eplerenone.

Primary adrenal insufficiency (Addison). Destruction of the cortex, most often autoimmune in developed countries and tuberculosis worldwide, removes both cortisol and aldosterone. Patients have fatigue, weight loss, hypotension, salt craving, hyponatremia and hyperkalemia, with hypoglycemia possible. Hyperpigmentation of skin creases and mucosa comes from high ACTH, because its precursor POMC also yields MSH. Diagnosis is a low cortisol response to cosyntropin (synthetic ACTH) with a high ACTH; treatment is hydrocortisone plus fludrocortisone.

Secondary and tertiary insufficiency. In secondary disease, low pituitary ACTH lowers cortisol but aldosterone is intact because renin-angiotensin controls the glomerulosa, so there is no hyperpigmentation and no hyperkalemia, although sodium may still fall. Tertiary insufficiency follows abrupt withdrawal of long-term steroids, which have suppressed CRH.

Adrenal crisis. Acute insufficiency causes shock, hypoglycemia and hyperkalemia and is treated immediately with IV hydrocortisone and saline. Waterhouse-Friderichsen syndrome is bilateral adrenal hemorrhage, classically from Neisseria meningitidis septicemia with DIC.

Congenital adrenal hyperplasia

Principle. A block in cortisol synthesis removes negative feedback, ACTH rises and the adrenals become hyperplastic, and precursors are shunted toward whichever pathways remain open. Blood pressure and androgen status identify the enzyme.

21-Hydroxylase deficiency. Everything falls (cortisol, aldosterone, blood pressure) except androgens. Affected girls have ambiguous genitalia at birth; boys look normal and may first present with a salt-wasting crisis in the first weeks of life. Newborn screening measures 17-hydroxyprogesterone, and treatment replaces glucocorticoid (which also suppresses ACTH-driven androgen excess) plus mineralocorticoid. Milder nonclassic forms present later with hirsutism and irregular menses.

The hypertensive forms. In 11β-hydroxylase deficiency aldosterone is low, but 11-deoxycorticosterone, itself a mineralocorticoid, accumulates and causes hypertension alongside androgen excess. In 17α-hydroxylase deficiency, androgens and cortisol are low and mineralocorticoids high, so there is hypertension and hypokalemia; genetic males are undervirilized with female-appearing external genitalia, and genetic females lack puberty.

Adrenal medulla tumors

Pheochromocytoma. A chromaffin-cell tumor that secretes catecholamines in bursts: episodic hypertension, headache, palpitations and diaphoresis. The rule of 10s: 10% bilateral, 10% malignant, 10% extra-adrenal (organ of Zuckerkandl near the aortic bifurcation, bladder wall), 10% calcify, 10% pediatric and 10% familial (MEN 2A/2B, von Hippel-Lindau, NF1). Genetic testing has since shown the hereditary share to be much higher, roughly a third of cases.

Classic pheo pentad: Pressure (episodic hypertension), Pain (headache), Perspiration, Palpitations, Pallor.

Diagnosis and treatment. Plasma free or 24-hour urinary metanephrines are the most sensitive tests, followed by imaging.

Never β-block first: removing β2-mediated vasodilation leaves unopposed α vasoconstriction and can trigger a hypertensive crisis.

Neuroblastoma. The most common adrenal medulla tumor in children, usually under 4, and the most common extracranial solid tumor of childhood. It arises from neural crest cells anywhere along the sympathetic chain, presenting as a firm abdominal mass that crosses the midline (unlike Wilms tumor) and does not usually cause hypertension. Urine HVA and VMA are elevated. Histology shows small round blue cells with Homer-Wright rosettes. N-myc (MYCN) amplification signals a poor prognosis, and opsoclonus-myoclonus ("dancing eyes, dancing feet") is a paraneoplastic clue.