Adrenal hormones

Zones of the adrenal (outside in)

Outer to inner: salt, sugar, sex. The fetal adrenal is large; its fetal zone makes DHEA sulphate, which the placenta converts to oestriol.

Steroid synthesis

• All steroids come from cholesterol. The rate-limiting step is transfer of cholesterol into mitochondria (StAR protein) and side-chain cleavage (desmolase, P450scc) to pregnenolone; ACTH stimulates it.
• Steroids are lipid-soluble and diffuse out of the cell as soon as they are made, so the cortex stores almost no hormone; secretion equals synthesis. (The thyroid is the only gland that stores large amounts of hormone, outside its cells as colloid.)
• Steroids act on intracellular receptors that alter gene transcription, so even IV hydrocortisone takes hours to work. In anaphylaxis adrenaline acts in minutes; steroids are not first-line.

Low cortisol removes feedback, ACTH rises and the glands become hyperplastic: congenital adrenal hyperplasia.

Cortisol

• Rhythm: peaks in the early morning around waking, lowest near midnight; the rhythm is lost in Cushing syndrome. Stress drives CRH, then ACTH, then cortisol.
• Metabolic: main action is gluconeogenesis (protein breakdown in muscle supplies amino acids); reduces peripheral glucose uptake (anti-insulin); permissive for glucagon and lipolysis; central fat redistribution. After major trauma, raised cortisol and catecholamines cause hyperglycaemia with insulin resistance, a stress response rather than diabetes.
• Anti-inflammatory and immunosuppressive: induces lipocortin (annexin-1), which inhibits phospholipase A₂ and so prostaglandin and leukotriene synthesis; reduces lymphocytes and eosinophils, raises neutrophils; stabilises lysosomes.
• Permissive action: cortisol must be present for catecholamines to produce their full vasoconstrictor and metabolic effects (it maintains adrenergic receptor expression). Without it, blood pressure falls.
• Other effects: bone loss, thin skin, poor healing, muscle wasting, mild mineralocorticoid action at high levels (kidney 11β-HSD2 normally inactivates cortisol to cortisone, protecting the mineralocorticoid receptor; liquorice inhibits it).
• Carrier: cortisol-binding globulin (transcortin). Oestrogen (combined pill, pregnancy) raises it, so total cortisol is high and an overnight dexamethasone test can be falsely positive. Enzyme inducers (carbamazepine) cause false positives by speeding dexamethasone breakdown.

Cushing syndrome

• Features: central obesity, moon face, buffalo hump, purple striae, proximal myopathy, thin skin and bruising, hypertension, diabetes, osteoporosis, hypokalaemia, infection.
• Commonest cause: exogenous steroids. Endogenous: pituitary adenoma (Cushing disease, about 70%; suppresses with high-dose dexamethasone), adrenal adenoma (low ACTH), ectopic ACTH (small cell lung cancer; very high ACTH, hypokalaemia, pigmentation).
• Screen with overnight 1 mg dexamethasone suppression, 24-hour urinary free cortisol or late-night salivary cortisol.
• After removing a cortisol-secreting adrenal adenoma, the other adrenal has atrophied from prolonged low ACTH, so glucocorticoid replacement is needed for months.
• Nelson syndrome: after bilateral adrenalectomy for Cushing disease, loss of cortisol feedback lets the pituitary adenoma enlarge: pigmentation from high POMC/ACTH, headache, bitemporal field loss. After bilateral adrenalectomy, lifelong glucocorticoid and mineralocorticoid replacement is needed.

Adrenal insufficiency

• Addison disease (primary): autoimmune in most developed countries; tuberculosis remains important in Pakistan. Low cortisol and aldosterone cause fatigue, weight loss, hypotension, hyponatraemia, hyperkalaemia, hypoglycaemia and pigmentation from high ACTH/POMC (palmar creases, buccal mucosa). Diagnose with the short Synacthen test.
• X-linked adrenoleukodystrophy: a boy with behavioural and school decline, visual and gait problems and Addison disease; very long-chain fatty acids are raised (peroxisomal defect).
• Waterhouse–Friderichsen syndrome: bilateral adrenal haemorrhage in meningococcal septicaemia.
• Adrenal crisis (vomiting, abdominal pain, BP 70/40, Na⁺ 122, K⁺ 6.1): IV hydrocortisone and 0.9% saline immediately.
• Sick-day rules: a patient on long-term steroids (for example prednisolone 7.5 mg) with fever doubles the dose during the illness; extra cover for surgery. Sudden withdrawal of long-term steroids can precipitate crisis because the HPA axis is suppressed.
• Secondary (pituitary) failure lacks pigmentation and hyperkalaemia because aldosterone is preserved.

Aldosterone

• Acts mainly on collecting duct principal cells: Na⁺ reabsorption (ENaC, Na⁺/K⁺-ATPase), K⁺ and H⁺ secretion. Increases K⁺ excretion.
• Stimulated by angiotensin II and directly by raised K⁺ (independent of renin), and in dehydration. Renin is inhibited by angiotensin II, ANP, high renal perfusion pressure and vasopressin; stimulated by sympathetic activity and prostaglandins.
• Primary hyperaldosteronism (Conn): hypertension, hypokalaemia, metabolic alkalosis, high aldosterone with low renin; oedema is rare (aldosterone escape). Screen with the aldosterone-to-renin ratio after stopping spironolactone, which raises renin and gives false negatives (use verapamil or doxazosin meanwhile).
• Secondary hyperaldosteronism (high renin): renal artery stenosis, heart failure, cirrhosis, diuretics.
• Liquorice mimics it with low renin and low aldosterone (11β-HSD2 inhibition).

Adrenal medulla and catecholamines

• Synthesis: tyrosine to DOPA (tyrosine hydroxylase, rate-limiting), dopamine, noradrenaline, then adrenaline by PNMT, induced by cortisol flowing from the cortex through the medulla.
• Breakdown by MAO and COMT to metanephrines and VMA.
• Low-dose adrenaline (beta-1 and beta-2): systolic rises (more contractility), diastolic falls (beta-2 dilatation in muscle), heart rate rises, mean pressure changes little. Noradrenaline (alpha-1) raises both with reflex bradycardia.
• Phaeochromocytoma (chromaffin cell tumour): episodic headache, sweating, palpitations, hypertension; plasma free or urinary metanephrines. Give an alpha-blocker (phenoxybenzamine) first, then a beta-blocker. Propranolol alone blocks beta-2 vasodilatation and leaves unopposed alpha vasoconstriction, provoking crises such as 240/130. Familial in MEN 2, von Hippel–Lindau, NF1.
• Neuroblastoma (small round blue cells, children under 4, N-myc amplification): raised urinary VMA and homovanillic acid.

Remember Salt, sugar, sex from outside in; cortisol is permissive and slow; alpha before beta in phaeochromocytoma.

Exam trap Aldosterone is controlled mainly by angiotensin II and potassium, so pituitary failure spares it.

Exam trap 21-hydroxylase deficiency causes salt wasting; 11β-hydroxylase deficiency causes hypertension.

How FCPS asks about this

• Main action of cortisol: gluconeogenesis; peaks early morning; permissive for catecholamines.
• Why cortisol is not stored: lipid-soluble steroids diffuse out as soon as they are made.
• Addisonian crisis: IV hydrocortisone and saline; sick-day rules double the dose.
• Marker of 21-hydroxylase deficiency: raised 17-hydroxyprogesterone; XX infant with male-looking genitalia.
• Remaining adrenal after adenoma removal: atrophied from low ACTH, so replacement for months.
• Low-dose adrenaline infusion: systolic up, diastolic down.
• BP surge when a phaeochromocytoma is given propranolol: unopposed alpha vasoconstriction.