Adrenal cortex: steroid synthesis and endocrine disorders
How the adrenal glands make cortisol, aldosterone and androgens, and how adrenal insufficiency, CAH and Cushing syndrome are recognised and managed.
The adrenal cortex has three zones that make aldosterone, cortisol and adrenal androgens from cholesterol under the control of angiotensin II and ACTH. Enzymes in the tissues switch cortisol on and off, which decides whether it reaches mineralocorticoid receptors. This page covers that physiology and the main endocrine uses of corticosteroids: replacement, sick-day rules, CAH and the dexamethasone tests for Cushing syndrome.
Steroidogenesis and the three zones
All adrenal steroids start from cholesterol, which is moved into mitochondria and cut by the side-chain cleavage enzyme (CYP11A1) to pregnenolone. From there the zones diverge according to the enzymes they express. The glomerulosa has aldosterone synthase and responds to angiotensin II and potassium; the fasciculata has 17alpha-hydroxylase and 11beta-hydroxylase and makes cortisol under ACTH; the reticularis makes DHEA and its sulfate. Cortisol feeds back to suppress CRH and ACTH. Cortisol circulates mostly bound to corticosteroid-binding globulin, which rises with oestrogen and pregnancy.
The 11beta-HSD shuttle
Cortisol and aldosterone bind the mineralocorticoid receptor equally well, and cortisol is far more abundant. In the kidney and colon, 11beta-HSD2 converts cortisol to inactive cortisone so that only aldosterone controls sodium. When the enzyme is missing (apparent mineralocorticoid excess) or blocked by glycyrrhizic acid in liquorice, cortisol activates the receptor and causes hypertension and hypokalaemia. 11beta-HSD1 does the reverse in liver, fat and other tissues; cortisone and prednisone are prodrugs that need it, so hydrocortisone or prednisolone are used where activation is impaired.
Adrenal insufficiency and sick-day rules
Primary insufficiency (Addison disease, usually autoimmune) loses both cortisol and aldosterone. Secondary insufficiency, from pituitary disease or abrupt withdrawal of long-term glucocorticoids, loses mainly cortisol. Replacement is lifelong: hydrocortisone or prednisolone, plus fludrocortisone in primary disease, guided by symptoms, blood pressure and electrolytes. Because the body cannot raise cortisol under stress, extra glucocorticoid is given during illness, surgery or major stress, patients carry an emergency injection kit and a steroid emergency card, and treatment is never stopped suddenly. Adrenal crisis, a rapid worsening often triggered by infection, injury or surgery, is an emergency treated with injected glucocorticoid in hospital.
Congenital adrenal hyperplasia
CAH is a group of autosomal recessive enzyme defects in cortisol synthesis. Low cortisol removes feedback, ACTH rises and the glands enlarge, and steroids made before the block are diverted to androgens. About 95% of cases are 21-hydroxylase deficiency.
- Classic salt-wasting form: cortisol and aldosterone deficiency with life-threatening sodium loss in early infancy; girls may be born with virilised genitalia.
- Classic simple virilising form: androgen excess without salt loss.
- Non-classic form: later, milder androgen excess (hirsutism, irregular periods, infertility, acne).
- Treatment: glucocorticoid replacement to restore cortisol and suppress ACTH-driven androgens, plus fludrocortisone and salt in salt-wasting disease.
Cushing syndrome and the dexamethasone tests
The commonest cause is long-term glucocorticoid treatment. Endogenous causes are a pituitary ACTH-secreting adenoma (Cushing disease, the most common), ectopic ACTH from tumours such as lung tumours, and cortisol-secreting adrenal tumours. Screening uses 24-hour urinary free cortisol, late-night salivary cortisol and the overnight low-dose dexamethasone suppression test: dexamethasone normally suppresses ACTH and cortisol, and failure to suppress supports Cushing syndrome. Two abnormal tests usually confirm it. A high-dose test, ACTH levels, imaging and petrosal sinus sampling then locate the source: pituitary adenomas often still suppress partly, ectopic and adrenal sources usually do not. Oestrogens, pregnancy and enzyme-inducing drugs can distort the test.
- Treatment is mainly surgical; cortisol-lowering drugs (metyrapone, ketoconazole, osilodrostat) or the receptor blocker mifepristone are used alongside or instead.
Test yourself
Think of the answer, then tap the question to see it.
Why does eating large amounts of liquorice cause hypertension and low potassium?
Glycyrrhizic acid blocks 11beta-HSD2, so cortisol is not inactivated in the kidney and activates mineralocorticoid receptors.
Why do people with adrenal insufficiency need extra glucocorticoid when they are ill?
Their adrenals cannot raise cortisol under stress; without extra doses, illness or surgery can precipitate an adrenal crisis.
Why does 21-hydroxylase deficiency cause androgen excess?
Low cortisol removes feedback, ACTH rises, and the precursors that cannot become cortisol or aldosterone are diverted to androgens.
What does failure to suppress cortisol after low-dose dexamethasone suggest?
Cushing syndrome: normal feedback would suppress ACTH and cortisol; a second abnormal test usually confirms it.
Example drugs
- Hydrocortisone
- Fludrocortisone
- Prednisolone
- Prednisone
- Dexamethasone
- Metyrapone
- Ketoconazole
- Osilodrostat
- Mifepristone
Connections
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: Addison's disease - Treatment (NHS, 2026); 21-hydroxylase deficiency: MedlinePlus Genetics (MedlinePlus (U.S. National Library of Medicine), 2026); Cushing's Syndrome (National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 2026).
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Representative model, for educational purposes only.