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Biochemistry · Metabolic pathway

Adrenal cortisol synthesis !

In the adrenal cortex cholesterol is trimmed and hydroxylated step by step to make cortisol. A block at any step causes congenital adrenal hyperplasia.

Updated 2026-11-01

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Balance: nadph -6NADH +1

Key facts

  • StAR moves cholesterol into the mitochondrion and CYP11A1 cuts its side chain to make pregnenolone: the rate-limiting step, driven by ACTH.
  • The cortisol route of the zona fasciculata uses 3β-HSD, then 17α-hydroxylase (CYP17A1), 21-hydroxylase (CYP21A2) and 11β-hydroxylase (CYP11B1).
  • 21-Hydroxylase deficiency causes about 95% of congenital adrenal hyperplasia; 17-hydroxyprogesterone rises.
  • Without 17α-hydroxylation (zona glomerulosa) the same enzymes make aldosterone instead; the 17,20-lyase activity of CYP17A1 leads to adrenal androgens.
  • Each hydroxylation is a cytochrome P450 reaction that uses NADPH and O₂.
Also called
Adrenal steroidogenesis (glucocorticoid route)

Regulation

  • ACTH (cAMP–PKA) raises StAR activity within minutes and the amount of every enzyme over days.
  • Cortisol inhibits CRH and ACTH (negative feedback); when cortisol is low, ACTH rises and the adrenals enlarge (hyperplasia).
  • Angiotensin II and potassium control the aldosterone branch (CYP11B2), not the cortisol route.

The steps, one by one

  1. Step 1 · Cholesterol side-chain cleavage enzyme (CYP11A1, P450scc), with StAR irreversible Cholesterol + NADPH + o2 → Pregnenolone + Isocaproaldehyde + nadp + H₂OOn the inner mitochondrial membrane it hydroxylates carbons 22 and 20 and then cuts the side chain, leaving pregnenolone; StAR first brings the cholesterol in.If it fails: StAR or CYP11A1 defects cause congenital lipoid adrenal hyperplasia: no steroid hormones at all, with salt-wasting adrenal insufficiency. Adrenal insufficiency →
  2. Step 2 · 3β-Hydroxysteroid dehydrogenase type 2 (HSD3B2) irreversible Pregnenolone + NAD⁺ → Progesterone + NADHIn the endoplasmic reticulum it oxidises the 3-hydroxyl and moves the double bond from ring B to ring A (Δ5 → Δ4), giving progesterone.If it fails: 3β-HSD deficiency: a rare congenital adrenal hyperplasia with salt wasting; boys are undervirilised and girls may be mildly virilised by DHEA.
  3. Step 3 · 17α-Hydroxylase/17,20-lyase (CYP17A1) irreversible Progesterone + NADPH + o2 → 17α-Hydroxyprogesterone + nadp + H₂OAdds a hydroxyl at carbon 17; its second activity, the 17,20-lyase, would cut the side chain and lead to androgens instead.If it fails: 17α-Hydroxylase deficiency: no cortisol or sex steroids, but extra 11-deoxycorticosterone gives hypertension and hypokalaemia. Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency →
  4. Step 4 · 21-Hydroxylase (CYP21A2) irreversible 17α-Hydroxyprogesterone + NADPH + o2 → 11-Deoxycortisol + nadp + H₂OHydroxylates carbon 21 of 17-hydroxyprogesterone to give 11-deoxycortisol (and of progesterone in the aldosterone branch).If it fails: 21-Hydroxylase deficiency is the most common congenital adrenal hyperplasia: 17-hydroxyprogesterone piles up and is diverted to androgens; severe forms waste salt. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency →
  5. Step 5 · 11β-Hydroxylase (CYP11B1) irreversible 11-Deoxycortisol + NADPH + o2 → Cortisol + nadp + H₂OBack in the mitochondrion it adds the 11β-hydroxyl that makes cortisol active.If it fails: 11β-Hydroxylase deficiency: virilisation with hypertension, because 11-deoxycorticosterone accumulates. Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency →

Clinical notes

  • 21-Hydroxylase deficiency: ambiguous genitalia in girls, salt-wasting crises in newborns and high 17-hydroxyprogesterone on screening.
  • 11β-Hydroxylase deficiency: virilisation plus hypertension, because 11-deoxycorticosterone acts as a mineralocorticoid.
  • 17α-Hydroxylase deficiency: hypertension, hypokalaemia and no sex steroids (absent puberty, undervirilised XY infants).
  • Ketoconazole, metyrapone, osilodrostat and abiraterone block steps of this pathway and are used to lower cortisol or androgens.

Pathways

Test yourself

Think of the answer, then tap the question to see it.

Which step limits the rate of steroid hormone synthesis?

Delivery of cholesterol into the mitochondrion by StAR and its side-chain cleavage by CYP11A1, both driven by ACTH.

Which steroid rises in 21-hydroxylase deficiency and is used for newborn screening?

17-Hydroxyprogesterone, which cannot become 11-deoxycortisol and is diverted to androgens.

Why does 11β-hydroxylase deficiency cause hypertension while 21-hydroxylase deficiency causes salt wasting?

In 11β-hydroxylase deficiency 11-deoxycorticosterone, a mineralocorticoid, accumulates; in 21-hydroxylase deficiency neither cortisol nor aldosterone can be made.

Which drug blocks CYP17A1 in prostate cancer?

Abiraterone, which inhibits 17α-hydroxylase/17,20-lyase and therefore androgen synthesis.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: 21-hydroxylase deficiency: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); 3-beta-hydroxysteroid dehydrogenase deficiency: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1) - Homo sapiens (UniProt, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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