Adrenal cortex

What it normally does

• Three layers, three products, made from cholesterol down a largely shared assembly line. Outer layer (zona glomerulosa) makes aldosterone; middle layer (zona fasciculata) makes cortisol; inner layer (zona reticularis) makes weak androgens, mostly DHEA, DHEA-sulfate and androstenedione. Salt, sugar, sex — outside in. The early steps are common to all three (cholesterol side-chain cleavage, 3-beta-HSD), and 21-hydroxylase (CYP21A2) is needed for BOTH cortisol and aldosterone but not for androgens. The final 11-beta-hydroxylation step is done by two different isoenzymes: 11-beta-hydroxylase (CYP11B1) finishes cortisol in the fasciculata, while aldosterone synthase (CYP11B2) finishes aldosterone in the glomerulosa — so a block in one does not automatically block the other. Block a shared enzyme and everything upstream backs up and spills into whichever branch is still open. The medulla in the middle is a different organ entirely (neural crest tissue making adrenaline) and fails independently.

  Explains why destroying the whole cortex (Addison) takes out salt AND sugar together, why losing pituitary drive takes out only sugar, why a 21-hydroxylase block in congenital adrenal hyperplasia produces a salt-losing, androgen-flooded newborn, and why an 11-beta-hydroxylase block does not cause salt wasting at all.

• Cortisol is on a chain of command with a feedback loop: hypothalamus releases CRH, the anterior pituitary corticotrophs release ACTH, the zona fasciculata releases cortisol, and cortisol switches off both the hypothalamus and the pituitary [hypothalamic-pituitary-adrenal, HPA, axis]. Two features matter clinically. First, ACTH is cut out of a bigger precursor molecule (pro-opiomelanocortin, POMC) that also yields melanocyte-stimulating hormone, and ACTH itself stimulates melanocortin-1 receptors in skin (weakly per molecule, but enough when ACTH is grossly elevated). Second, cortisol runs on a daily rhythm — peaking around waking, lowest around midnight — with stress, illness and surgery overriding the rhythm and driving output up several-fold. Aldosterone is essentially NOT on this axis: the zona glomerulosa answers to angiotensin II and to plasma potassium, and ACTH has only a small, short-lived effect on it.

  Explains the dark palmar creases of Addison disease, why cortisol is measured early morning (or late at night when hunting excess) rather than at any convenient hour, why prescribed steroid shuts the whole axis down, and why the outer layer keeps working when the pituitary fails.

• What cortisol actually does, in a sentence each. It raises blood glucose (drives gluconeogenesis in the liver, breaks down muscle protein for the raw material, opposes insulin in fat and muscle). It lets catecholamines work — without cortisol, alpha-1 receptors on vessels are under-expressed and noradrenaline barely holds blood pressure up [permissive effect]. It suppresses inflammation and immunity (fewer cytokines, fewer circulating eosinophils and lymphocytes, more neutrophils released from the marrow). It inhibits bone formation and collagen synthesis and reduces intestinal calcium absorption. And at high enough concentration it will bind the mineralocorticoid receptor and act like aldosterone.

  Explains every feature of Cushing syndrome read forwards, every feature of Addison disease read backwards, and every adverse effect of prescribed steroid — one list, three diseases.

• Aldosterone binds the mineralocorticoid receptor in the principal cells of the collecting duct: more sodium channels (ENaC) in the apical membrane and more Na/K-ATPase in the basolateral, so sodium (and water behind it) is reabsorbed. Sodium entering through ENaC leaves the lumen electrically negative, which drives potassium out of the principal cell and favours hydrogen ion secretion by the neighbouring alpha-intercalated cells (whose H-ATPase aldosterone also stimulates) — so potassium and acid are lost in the urine. There is a trick here. Cortisol circulates at roughly a hundred to a thousand times the concentration of aldosterone and binds the mineralocorticoid receptor just as well, so the kidney defends the receptor with an enzyme, 11-beta-hydroxysteroid dehydrogenase type 2, that converts cortisol to inactive cortisone at the doorstep.

  Explains low sodium, high potassium and postural hypotension in Addison; high blood pressure with low potassium and alkalosis in cortisol excess and in liquorice excess (which poisons that protective enzyme); and why a synthetic mineralocorticoid has to be built to survive it.

What goes wrong

• Addison disease (primary adrenal insufficiency)← from “Three layers, three products, made from choles…”

  The cortex itself is destroyed, so all three layers go together. In Australia the cause is autoimmune in around 80-90% — antibodies against 21-hydroxylase, often alongside autoimmune thyroid disease, type 1 diabetes, coeliac disease or vitiligo. Tuberculous adrenalitis is now uncommon here but not historical: Australian TB notifications are concentrated in overseas-born residents and, among the Australian-born, rates are several times higher in Aboriginal and Torres Strait Islander people, so it stays on the list. Other causes: bilateral haemorrhage (meningococcal sepsis, anticoagulation, antiphospholipid syndrome), metastases, adrenoleukodystrophy in boys. Without cortisol, gluconeogenesis falters and vascular tone loses its permissive support. Without aldosterone, sodium is lost in the urine while potassium and hydrogen ions are retained. No cortisol also means no negative feedback, so ACTH and its POMC relatives climb and stimulate melanocytes.

  Whole cortex gone, so both salt and sugar hormones gone: low sodium, HIGH potassium, and pigmentation from the ACTH that is screaming at a gland that cannot answer.

  You would find: Months of fatigue, weight loss, nausea, dizziness on standing, craving for salt, and a tan in places the sun never reaches — palmar creases, buccal mucosa, old scars, nipples. Bloods: sodium low, potassium high, mild metabolic acidosis, hypoglycaemia, sometimes eosinophilia and mild hypercalcaemia. Confirm with an early-morning cortisol and a short synacthen (tetracosactrin) test — in adrenal failure the stimulated cortisol fails to reach the laboratory's cut-off, traditionally around 500 nmol/L and roughly 400-450 nmol/L with newer specific assays, so read it against the local reference. ACTH is high, renin high, aldosterone low. The dangerous presentation is adrenal crisis: vomiting, abdominal pain, fever and shock that will not respond to fluid alone, usually triggered by infection or surgery in someone whose diagnosis nobody had made.

• Secondary adrenal insufficiency and steroid withdrawal← from “Cortisol is on a chain of command with a feedb…”

  Prescribed glucocorticoid does exactly what cortisol does at the top of the axis: it switches off CRH and ACTH. The corticotrophs go quiet and the zona fasciculata, with nothing telling it to work, atrophies over weeks. The zona glomerulosa is essentially untouched, because it never depended on ACTH — it runs on angiotensin II and potassium. So when the steroid is stopped suddenly, or the patient gets pneumonia or goes to theatre, cortisol cannot rise while aldosterone is perfectly normal. Pituitary disease (tumour, surgery, radiotherapy, Sheehan syndrome, hypophysitis from immune checkpoint inhibitors) produces the same picture from the other end.

  Pigmented and hyperkalaemic means the adrenal is the problem. Pale and normokalaemic on prednisolone means the pituitary has been switched off. Assume anyone on a treatment dose of glucocorticoid beyond about three weeks has a suppressed axis, and it can take months to recover after stopping.

  You would find: This is far and away the commonest cause of adrenal insufficiency in Australia — the patient on long-term prednisolone for polymyalgia rheumatica, asthma, inflammatory bowel disease or a transplant, not a rare autoimmune gland. Two absences do the work of a diagnosis: NO hyperpigmentation (ACTH is low, not high) and NO hyperkalaemia (aldosterone is intact). Sodium can still be low, because cortisol deficiency releases ADH from its brake and water is retained. Look for the rest of the pituitary failing too — amenorrhoea, loss of libido, secondary hypothyroidism.

• Cushing syndrome← from “What cortisol actually does, in a sentence eac…”

  Too much glucocorticoid for too long, and every action in the physiology list is turned up. Gluconeogenesis and insulin resistance raise glucose; protein catabolism strips muscle from the proximal limbs, thins the skin and weakens capillary walls; fat is redistributed centrally, to the face and the interscapular pad; bone formation is inhibited while calcium absorption falls; immunity is suppressed. Hypertension is usual and multifactorial, and when the excess steroid is cortisol itself in large amounts it overwhelms 11-beta-HSD2 in the kidney and acts on the mineralocorticoid receptor, adding hypokalaemia and metabolic alkalosis — most strikingly in ectopic ACTH. Synthetic steroids such as dexamethasone have almost no mineralocorticoid activity, so iatrogenic Cushing syndrome usually does NOT come with hypokalaemic alkalosis. The cause matters for the pattern: prescribed steroid is the commonest cause overall; of the endogenous causes, about 70% are a pituitary ACTH-secreting adenoma (Cushing DISEASE), the rest an adrenal adenoma making cortisol autonomously, or ectopic ACTH from a tumour — classically small cell lung cancer.

  Take the physiology of cortisol and turn the dial up: high glucose, wasted proximal muscle, thin bruised skin, brittle bone, blunted immunity, and — when the excess hormone is cortisol itself — mineralocorticoid spillover giving hypertension with low potassium.

  You would find: Weight gain with THIN arms and legs, a round plethoric face, proximal weakness (cannot rise from a low chair without pushing), purple striae wider than a finger, easy bruising, new hypertension and new diabetes, osteoporotic fractures, poor wound healing. Screen with a late-night salivary cortisol, 24-hour urinary free cortisol, or an overnight (1 mg) dexamethasone suppression test — in Cushing, cortisol fails to suppress. Then measure ACTH: suppressed means the adrenal is driving it, normal or high means ACTH is. Ectopic ACTH looks different — pigmentation, profound hypokalaemic alkalosis, weight loss and myopathy, and often not enough time for the classic body shape to develop. Alcohol excess, depression and obesity produce a mild biochemical mimic (pseudo-Cushing).

• Congenital adrenal hyperplasia (21-hydroxylase deficiency)← from “Three layers, three products, made from choles…”

  About 1 in 15,000 births, autosomal recessive, and 21-hydroxylase accounts for over 90% of cases. The enzyme is needed to make both cortisol and aldosterone but not androgens. So cortisol cannot be made, feedback fails, ACTH pours out and the cortex grows (hence hyperplasia), but all that drive only piles up precursors — chiefly 17-hydroxyprogesterone — which have nowhere to go except down the androgen branch that never needed 21-hydroxylase. The baby is therefore short of cortisol, short of aldosterone, and flooded with adrenal androgens. Contrast 11-beta-hydroxylase deficiency: the block is past the 21-hydroxylase step, so the precursor that accumulates is 11-deoxycorticosterone, which is itself a mineralocorticoid; those children are androgenised and become hypertensive (usually later in childhood) rather than salt-wasting, with renin and aldosterone suppressed.

  One missing enzyme, three consequences: no cortisol, no aldosterone, too much androgen. Salt-wasting crisis at 1-3 weeks in a boy who looked completely normal at birth is the exam presentation, and 17-hydroxyprogesterone is the test.

  You would find: A newborn girl with ambiguous or virilised genitalia (normal ovaries and uterus inside — the androgens act on the external structures only). A boy looks entirely normal at birth, which is why he is the one who comes back at about one to three weeks vomiting, not feeding, losing weight and shocked: sodium low, potassium high, glucose low, 17-hydroxyprogesterone markedly raised. Congenital adrenal hyperplasia is on the Australian newborn bloodspot screening panel (17-hydroxyprogesterone, with a second-tier steroid profile), which is designed to catch that baby before the crisis — but screening does not replace clinical suspicion in a collapsing neonate. The milder non-classic form declares itself later as hirsutism, acne, irregular periods and subfertility in a young woman, and is easily mistaken for polycystic ovary syndrome.

• Primary hyperaldosteronism (Conn syndrome)← from “Aldosterone binds the mineralocorticoid recept…”

  The outer layer works too hard on its own — a unilateral aldosterone-producing adenoma or, more often, bilateral adrenal hyperplasia — independent of angiotensin II. Constant mineralocorticoid receptor stimulation in the collecting duct means sodium retention and volume expansion (so blood pressure rises and renin is suppressed) with potassium and hydrogen ions poured into the urine. Sodium itself usually stays normal because water follows it and the kidney escapes the sodium-retaining effect after a few days; the potassium loss does not escape. Note that most patients are normokalaemic — hypokalaemia is a clue when present, not a requirement.

  High blood pressure plus suppressed renin, with or without low potassium. Aldosterone driving ENaC in the collecting duct: sodium in, potassium and acid out.

  You would find: Not rare — around 5-10% of hypertension, and higher among people with resistant hypertension. Suspect it in hypertension that resists three drugs, hypertension with unexplained low potassium (cramps, weakness, polyuria) or a metabolic alkalosis, hypertension under 40, or an adrenal mass found incidentally. Screen with the aldosterone-to-renin ratio: aldosterone high, renin flat. Worth finding, because the excess aldosterone damages heart, vessels and kidney beyond what its blood pressure alone would predict.

What we give, and how it works

Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.