Adrenal steroidogenesis, the HPA axis and the adrenal medulla

At a glance

• The adrenal cortex has three zones, each defined by its enzymes: glomerulosa (aldosterone, driven by angiotensin II and potassium), fasciculata (cortisol, driven by ACTH) and reticularis (DHEA and androstenedione, driven by ACTH).
• All steroids start from cholesterol. StAR moves it into mitochondria; CYP11A1 makes pregnenolone. ACTH acts on both through the MC2 receptor and cAMP.
• CRH and AVP drive ACTH. Cortisol suppresses both, with fast (minutes) and slow (hours to days) feedback. Cortisol peaks at waking and is lowest around midnight.
• A block in one enzyme lowers cortisol, raises ACTH, and pushes precursors down the other open pathways. That logic explains every form of congenital adrenal hyperplasia (CAH).
• The medulla is a sympathetic ganglion. It makes adrenaline (about 80%) and noradrenaline, and needs cortisol from the cortex to make adrenaline.

The pathway

Enzyme (gene)	Step	Zone
StAR, CYP11A1	Cholesterol to pregnenolone	All
3β-HSD (HSD3B2)	Pregnenolone to progesterone; 17-OH pregnenolone to 17-OH progesterone; DHEA to androstenedione	All
17α-hydroxylase/17,20-lyase (CYP17A1)	Adds the 17-OH needed for cortisol; lyase activity makes androgens	Fasciculata, reticularis
21-hydroxylase (CYP21A2)	Progesterone to deoxycorticosterone (DOC); 17-OH progesterone to 11-deoxycortisol	Glomerulosa, fasciculata
11β-hydroxylase (CYP11B1)	11-deoxycortisol to cortisol; DOC to corticosterone	Fasciculata
Aldosterone synthase (CYP11B2)	Corticosterone to aldosterone	Glomerulosa only

DHEA sulfate (DHEAS) comes almost only from the adrenal, so a very high DHEAS points to an adrenal source of androgen excess. Adrenal androgens are the main androgen source in women and fall with age.

Cortisol transport and tissue access

About 90% of cortisol is bound to cortisol-binding globulin (CBG) and albumin. Oral oestrogen raises CBG, so total cortisol rises and can mask insufficiency or produce a false-positive dexamethasone suppression test. Nephrotic syndrome and critical illness lower CBG.

Tissues set their own exposure. 11β-HSD1 (liver, fat) reactivates cortisone to cortisol. 11β-HSD2 (kidney, colon, placenta) inactivates cortisol, protecting the mineralocorticoid receptor and the fetus. Liquorice blocks 11β-HSD2. Dexamethasone and betamethasone are poor 11β-HSD2 substrates, so they cross the placenta for fetal lung maturation; prednisolone mostly doesn't.

Worked examples

Following an enzyme block

A 3-week-old boy has vomiting, Na⁺ 124 mmol/L and K⁺ 7.1 mmol/L.

1. 21-hydroxylase is absent. Neither cortisol nor aldosterone can be made.
2. Low cortisol removes feedback and ACTH rises, so the adrenals enlarge (hyperplasia).
3. Upstream precursors build up. 17-hydroxyprogesterone is often over 300 nmol/L.
4. They are shunted through 17,20-lyase into androgens. A girl would be virilised at birth; this boy looked normal, which is why boys present later with salt-wasting crisis.

About 95% of CAH is 21-hydroxylase deficiency (1 in 15,000 births). Non-classic disease presents in adolescent or adult women with hirsutism and oligomenorrhoea that resembles PCOS; a raised early-morning follicular-phase 17-OH progesterone, confirmed with a Synacthen-stimulated level, makes the diagnosis.

Deficiency	Cortisol	Mineralocorticoid effect	Androgens	Picture
21-hydroxylase	Low	Low (salt wasting)	High	Virilised girls, salt-wasting boys
11β-hydroxylase	Low	High (DOC)	High	Virilisation plus hypertension, low K⁺
17α-hydroxylase	Low (corticosterone covers)	High (DOC)	Low	Hypertension, low K⁺, absent puberty
3β-HSD	Low	Low	DHEA high, potent androgens low	Salt wasting; undervirilised boys, mild virilisation possible in girls
StAR (lipoid CAH)	Low	Low	Low	Salt wasting, female phenotype in 46,XY

Glucocorticoid treatment in CAH has two jobs: replace cortisol and suppress ACTH-driven androgen excess, often needing supraphysiological doses. Crinecerfont, an oral CRH type 1 receptor antagonist, lowered androstenedione and allowed reduction to physiological glucocorticoid doses in the 2024 CAHtalyst trials; it was approved by the US FDA in December 2024.

Reading the axis with dynamic tests

Morning cortisol: under 100 nmol/L at 8 am strongly suggests insufficiency. Over about 350 to 450 nmol/L (assay dependent; lower cut-offs apply to newer monoclonal assays) usually excludes it.

Short Synacthen test: 250 µg tetracosactide IV or IM, cortisol at 30 and 60 minutes. A peak under about 450 nmol/L (roughly 420 to 500 depending on assay) means the adrenal cannot respond.

Pattern	8 am cortisol	ACTH	Synacthen	Renin
Primary adrenal insufficiency (Addison)	Low	High	Fails	High
Secondary (pituitary or exogenous steroid)	Low	Low or normal	Fails if chronic; may pass if under 2 to 4 weeks	Normal

Addison disease has hyperpigmentation (ACTH and its precursor POMC act on MC1R) and hyperkalaemia. Secondary insufficiency has neither, because aldosterone is preserved. Both can cause hyponatraemia: cortisol is needed to suppress AVP and excrete free water.

Dexamethasone suppression: 1 mg at 11 pm, cortisol at 8 am. A normal axis suppresses to 50 nmol/L or less. Failure suggests Cushing syndrome but has false positives from oral oestrogen (CBG), CYP3A4 inducers that speed dexamethasone clearance (carbamazepine, phenytoin, rifampicin), depression, alcohol and obesity. Once confirmed, ACTH separates ACTH-dependent disease (pituitary, ectopic) from adrenal adenoma (ACTH suppressed).

Exogenous glucocorticoids

A 68-year-old woman has taken prednisolone 10 mg daily for 4 months for polymyalgia rheumatica. Prednisolone suppresses CRH and ACTH, her fasciculata atrophies, and she cannot raise cortisol if she becomes septic. The 2024 ESE/Endocrine Society guideline advises assuming suppression with prednisolone 5 mg/day or more for 4 weeks or longer, giving sick-day rules and stress dosing, and tapering to physiological doses (prednisolone 4 to 5 mg) before testing the axis. Recovery can take 6 to 12 months. See glucocorticoid pharmacology and glucocorticoid therapy complications.

Steroid	Glucocorticoid potency (hydrocortisone = 1)	Mineralocorticoid effect	Equivalent dose
Hydrocortisone	1	Present (significant above 50 mg/day)	20 mg
Prednisolone	4	Small	5 mg
Dexamethasone	25 to 30	None	0.75 mg
Fludrocortisone	10	High (about 125 times hydrocortisone)	Used for mineralocorticoid effect only

The adrenal medulla

Chromaffin cells receive preganglionic cholinergic sympathetic fibres (nicotinic receptors). Synthesis runs tyrosine → DOPA (tyrosine hydroxylase, rate limiting) → dopamine → noradrenaline (dopamine β-hydroxylase) → adrenaline (PNMT). Cortisol arriving through the intra-adrenal portal blood induces PNMT, which is why extra-adrenal paragangliomas usually secrete noradrenaline only.

Catecholamines are cleared by reuptake, then by MAO and COMT. COMT converts adrenaline to metanephrine and noradrenaline to normetanephrine, and the end product is vanillylmandelic acid. Phaeochromocytomas express COMT and leak metanephrines continuously, so plasma free metanephrines (or urinary fractionated metanephrines) are the screening test. Tricyclics, SNRIs, phenoxybenzamine and levodopa can raise normetanephrine falsely.

In phaeochromocytoma, start α-blockade first (phenoxybenzamine or doxazosin) for 10 to 14 days. Starting a beta-blocker alone removes β2 vasodilation and leaves α1 vasoconstriction unopposed, causing a hypertensive crisis. See multiple endocrine neoplasia and autonomic nervous system physiology.

How it's tested

• Neonate or infant with salt wasting and raised 17-OH progesterone: 21-hydroxylase deficiency.
• Young person with hypertension, hypokalaemia and low renin and aldosterone: 11β- or 17α-hydroxylase deficiency, liquorice, or Liddle syndrome. See RAAS physiology.
• Collapse after stopping long-term prednisolone, with hyponatraemia but normal potassium: secondary adrenal insufficiency. See adrenal crisis.
• False-positive dexamethasone suppression on the combined oral contraceptive or carbamazepine.
• Normal Synacthen a week after pituitary apoplexy. See pituitary apoplexy.
• Hypertensive crisis after starting propranolol in an undiagnosed phaeochromocytoma.
• Drugs acting on the pathway: ketoconazole (mainly CYP17A1 and CYP11A1, plus 11β-hydroxylase, so androgens fall and gynaecomastia occurs), osilodrostat (CYP11B1 and CYP11B2), metyrapone (11β-hydroxylase), abiraterone (CYP17A1), etomidate (11β-hydroxylase, adrenal suppression after a single induction dose). See pituitary, adrenal and gonadal hormone drugs.

Pitfalls

• ACTH has little long-term effect on aldosterone. Hyperkalaemia and high renin point to primary adrenal failure.
• 11β- and 17α-hydroxylase deficiency cause hypertension; 21-hydroxylase deficiency causes salt wasting.
• Oral oestrogen raises CBG and total cortisol. Stop it for 6 weeks before cortisol testing where possible.
• A normal short Synacthen test does not exclude recent-onset secondary adrenal insufficiency.
• Dexamethasone is not measured by cortisol assays; prednisolone and hydrocortisone are. Test the axis on dexamethasone, or after a 24-hour gap from hydrocortisone.
• Abiraterone blocks CYP17A1, so ACTH rises and DOC accumulates. It is given with prednisolone to prevent hypertension and hypokalaemia.
• Alpha-blockade before beta-blockade in phaeochromocytoma.