[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Biochemistry](https://durgical.com/en/biochemistry/) › Adrenal cortisol synthesis [Biochemistry](https://durgical.com/en/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 ## Interactive map **Balance:** nadph -6 NADH +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 - **Step 1 · Cholesterol side-chain cleavage enzyme (CYP11A1, P450scc), with StAR** irreversible [Cholesterol](https://durgical.com/en/biochemistry/molecules/cholesterol/) + [NADPH](https://durgical.com/en/biochemistry/molecules/nadph/) + o2 → Pregnenolone + Isocaproaldehyde + nadp + H₂O On 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 →](https://durgical.com/en/conditions/adrenal-insufficiency/) - **Step 2 · 3β-Hydroxysteroid dehydrogenase type 2 (HSD3B2)** irreversible Pregnenolone + [NAD⁺](https://durgical.com/en/biochemistry/molecules/nad/) → Progesterone + NADH In 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. - **Step 3 · [17α-Hydroxylase/17,20-lyase (CYP17A1)](https://durgical.com/en/biochemistry/enzymes/17-hydroxylase-17-20-lyase/)** irreversible Progesterone + [NADPH](https://durgical.com/en/biochemistry/molecules/nadph/) + o2 → [17α-Hydroxyprogesterone](https://durgical.com/en/biochemistry/molecules/17-hydroxyprogesterone/) + nadp + H₂O Adds 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 →](https://durgical.com/en/conditions/congenital-adrenal-hyperplasia-due-to-17-hydroxylase-deficiency/) - **Step 4 · [21-Hydroxylase (CYP21A2)](https://durgical.com/en/biochemistry/enzymes/21-hydroxylase/)** irreversible [17α-Hydroxyprogesterone](https://durgical.com/en/biochemistry/molecules/17-hydroxyprogesterone/) + [NADPH](https://durgical.com/en/biochemistry/molecules/nadph/) + o2 → 11-Deoxycortisol + nadp + H₂O Hydroxylates 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 →](https://durgical.com/en/conditions/congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency/) - **Step 5 · [11β-Hydroxylase (CYP11B1)](https://durgical.com/en/biochemistry/enzymes/11-hydroxylase/)** irreversible 11-Deoxycortisol + [NADPH](https://durgical.com/en/biochemistry/molecules/nadph/) + o2 → [Cortisol](https://durgical.com/en/biochemistry/molecules/cortisol/) + nadp + H₂O Back 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 →](https://durgical.com/en/conditions/congenital-adrenal-hyperplasia-due-to-11-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 - [Adrenal cortisol synthesis](https://durgical.com/en/biochemistry/pathways/adrenal-cortisol-synthesis/) ## Related conditions - [Adrenal insufficiency](https://durgical.com/en/conditions/adrenal-insufficiency/) - [Cushing syndrome](https://durgical.com/en/conditions/cushing-syndrome/) - [Congenital adrenal hyperplasia due to 21-hydroxylase deficiency](https://durgical.com/en/conditions/congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency/) - [Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency](https://durgical.com/en/conditions/congenital-adrenal-hyperplasia-due-to-11-hydroxylase-deficiency/) - [Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency](https://durgical.com/en/conditions/congenital-adrenal-hyperplasia-due-to-17-hydroxylase-deficiency/) ## Related - [Cholesterol](https://durgical.com/en/biochemistry/molecules/cholesterol/) - [Steroid hormone synthesis (overview)](https://durgical.com/en/biochemistry/topics/steroid-hormone-synthesis/) - [Cholesterol synthesis (mevalonate pathway)](https://durgical.com/en/biochemistry/pathways/cholesterol-synthesis/) - [LDL receptor](https://durgical.com/en/biochemistry/enzymes/ldl-receptor/) - [NADPH](https://durgical.com/en/biochemistry/molecules/nadph/) - [Classic bile acid synthesis pathway](https://durgical.com/en/biochemistry/pathways/classic-bile-acid-synthesis-pathway/) - [Cortisol](https://durgical.com/en/biochemistry/molecules/cortisol/) - [Aldosterone](https://durgical.com/en/biochemistry/molecules/aldosterone/) - [17-Hydroxyprogesterone (17-OHP)](https://durgical.com/en/biochemistry/molecules/17-hydroxyprogesterone/) - [21-Hydroxylase (CYP21A2)](https://durgical.com/en/biochemistry/enzymes/21-hydroxylase/) - [11β-Hydroxylase (CYP11B1)](https://durgical.com/en/biochemistry/enzymes/11-hydroxylase/) - [17α-Hydroxylase/17,20-lyase (CYP17A1)](https://durgical.com/en/biochemistry/enzymes/17-hydroxylase-17-20-lyase/) - [Adrenal enzymes and congenital adrenal hyperplasia](https://durgical.com/en/biochemistry/topics/adrenal-enzymes-and-congenital-adrenal-hyperplasia/) - [Aromatase (CYP19A1)](https://durgical.com/en/biochemistry/enzymes/aromatase/) ## 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. [Add to my cards (4)](https://durgical.app/estudiar/?add=/en/biochemistry/pathways/adrenal-cortisol-synthesis/) Educational information, not medical advice. For any symptom, see a health professional. Sources: [21-hydroxylase deficiency: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/21-hydroxylase-deficiency/) (MedlinePlus, US National Library of Medicine, 2026); [Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/congenital-adrenal-hyperplasia-due-to-11-beta-hydroxylase-deficiency/) (MedlinePlus, US National Library of Medicine, 2026); [3-beta-hydroxysteroid dehydrogenase deficiency: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/3-beta-hydroxysteroid-dehydrogenase-deficiency/) (MedlinePlus, US National Library of Medicine, 2026); [Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1) - Homo sapiens](https://www.uniprot.org/uniprotkb/P05108/entry) (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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