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USMLE Step 1EndocrinologyEP 09 of 14

Adrenal steroidogenesis: zones, enzymes and the 17α-hydroxylase fork

One gland and one cholesterol pool make three hormone families. Each cortical zone has its own driver and its own enzymes, and 17α-hydroxylase decides which path a steroid takes.

  • 5:29 video
  • 3 min read
  • 11 sources
  • Published 15 Nov 2026
Video lesson · 5:29 · Watch on YouTubeSeries: Endocrinology · @medservatory
Chapters (9)
By the end of this lesson

Trace the adrenal steroid synthesis pathway from cholesterol to aldosterone, cortisol and androgens by zone and enzyme.

The short version

  1. The adrenal cortex has three zones, outermost first: glomerulosa (aldosterone), fasciculata (cortisol), reticularis (androgens). Salt, sugar, sex.
  2. Angiotensin II and potassium are the main drivers of the glomerulosa; ACTH drives the fasciculata and the reticularis.
  3. Every adrenal steroid starts as cholesterol: StAR delivers it and CYP11A1 makes pregnenolone; in the glomerulosa and fasciculata, 3β-hydroxysteroid dehydrogenase then makes progesterone.
  4. 17α-hydroxylase is the fork: with it the cortex makes cortisol and androgens; without it, only aldosterone.
  5. A block piles up the steroid before it, lowers the hormone after it, and spills into any pathway still open.

Adrenal steroidogenesis: why removing the pituitary spares aldosterone

A woman has her pituitary gland removed, and her cortisol falls close to zero. Yet her aldosterone is fine and her potassium stays normal. The adrenal glands are intact, so the adrenal cortex still makes aldosterone.[2][6]

This lesson follows adrenal steroidogenesis from cholesterol to aldosterone, cortisol and androgens, by zone and by enzyme. The same gland and the same cholesterol give three different hormones, and the answer to the puzzle lies in which zone has which driver and which enzymes.

The three zones of the adrenal cortex: salt, sugar, sex

The cortex has three layers, outermost first. Salt, sugar, sex: from the outside in.[1][6][7]

Adrenal cortex zones, outermost first
ZoneMain productMain driver
Zona glomerulosaAldosterone (salt)Angiotensin II and potassium
Zona fasciculataCortisol (sugar)ACTH
Zona reticularisAndrogens, such as DHEA and androstenedione (sex)ACTH

Beneath the cortex, the medulla makes catecholamines. It is not part of this map.[1][7]

ACTH can also stimulate the glomerulosa acutely, but angiotensin II and potassium are its main drivers.[6][7]

The production line: from cholesterol to progesterone

Every adrenal steroid starts as cholesterol. A protein called StAR carries cholesterol to the inner mitochondrial membrane, where the side-chain cleavage enzyme, CYP11A1, makes pregnenolone.[3][6]

ACTH boosts cholesterol supply to this first step, which is one way it drives the whole line.[6]

Next, 3β-hydroxysteroid dehydrogenase turns pregnenolone into progesterone. This enzyme is expressed in the glomerulosa and the fasciculata, and is low in the reticularis.[6][8]

  1. CholesterolThe starting material for every adrenal steroid.
  2. PregnenoloneMade by CYP11A1 after StAR delivers cholesterol to the inner mitochondrial membrane.
  3. ProgesteroneMade by 3β-hydroxysteroid dehydrogenase in the glomerulosa and fasciculata. The reticularis, low in this enzyme, starts its androgen route from pregnenolone instead.

Three lanes by enzyme, and 17α-hydroxylase as the fork

Glomerulosa lane. This zone has no 17α-hydroxylase, so everything is steered one way. 21-hydroxylase turns progesterone into deoxycorticosterone; aldosterone synthase then makes corticosterone and finishes the job.[4][7][9]

Fasciculata lane. 17α-hydroxylase acts first, giving 17-hydroxyprogesterone. 21-hydroxylase then makes 11-deoxycortisol, and 11β-hydroxylase makes cortisol.[4][5][6] For Step 1 the lanes are drawn in the simplified exam order: 3β-HSD first, then 17α-hydroxylase.

The fasciculata also makes some deoxycorticosterone from progesterone, under ACTH. Keep that in mind for the next lesson.[6][10]

Reticularis lane. Here 17α-hydroxylase acts on pregnenolone, giving 17-hydroxypregnenolone. The same enzyme has a second activity, 17,20-lyase, which clips off the side chain to make DHEA, the parent of androstenedione.[6][10]

Zones, products and enzymes
ZoneEnzymes in the laneEnd product
Glomerulosa3β-HSD, 21-hydroxylase, aldosterone synthase (no 17α-hydroxylase)Aldosterone
Fasciculata3β-HSD, 17α-hydroxylase, 21-hydroxylase, 11β-hydroxylaseCortisol
Reticularis17α-hydroxylase and its 17,20-lyase activity, starting from pregnenoloneDHEA, then androstenedione

So 17α-hydroxylase is the fork in the road: with it you make cortisol and androgens; without it, only aldosterone.[6][8][9]

The block rule: pile-up, fall, spill

Cortisol suppresses ACTH, so when cortisol is low, ACTH is high.[3][11]

If an enzyme is blocked, the steroid before it piles up, the hormone after it falls, and the pile-up spills into any pathway still open.[3][4][5]

  1. Before the blockThe precursor accumulates.
  2. After the blockThe product falls.
  3. Open pathwaysThe pile-up spills into any pathway still open.

Picture 11β-hydroxylase missing. 11-deoxycortisol and deoxycorticosterone pile up, cortisol falls, ACTH rises, and the spill pushes out more androgen.[3][5][10][11]

The next lesson, congenital adrenal hyperplasia, asks what happens when each of these enzymes is missing.

Practice question

Original · USMLE style
Your turnQB-MS-S1-ENDO-005-01

A researcher incubates cells isolated from the outermost zone of a normal adult adrenal cortex with radiolabelled cholesterol. The cells produce pregnenolone, progesterone, deoxycorticosterone, corticosterone and aldosterone. They produce no 17-hydroxyprogesterone, cortisol or dehydroepiandrosterone.

The absence of which of the following enzymes best explains the missing products?
Pick one option. Your answers stay on this device.

Common questions

What are the three zones of the adrenal cortex and what do they make?

From the outside in: the zona glomerulosa makes aldosterone, the zona fasciculata makes cortisol, and the zona reticularis makes androgens. A memory hook is salt, sugar, sex.[6][7]

What drives each zone of the adrenal cortex?

Angiotensin II and potassium are the main drivers of the glomerulosa. ACTH drives the fasciculata and the reticularis, and can also stimulate the glomerulosa acutely.[6][7]

Why is 17α-hydroxylase the fork in adrenal steroid synthesis?

With 17α-hydroxylase the cortex makes cortisol and androgens; without it, as in the glomerulosa, steroid synthesis is directed to aldosterone only.[8][9]

Which enzymes make cortisol from progesterone?

17α-hydroxylase makes 17-hydroxyprogesterone, 21-hydroxylase makes 11-deoxycortisol, and 11β-hydroxylase makes cortisol.[4][5][6]

What happens upstream and downstream of a blocked adrenal enzyme?

The steroid before the block piles up, the hormone after it falls, and the excess spills into any pathway still open.[3][4][5]

Transcript

Read the full narration, by chapter598 words

0:00The case: pituitary removed, cortisol gone, aldosterone fine

A woman has her pituitary gland removed, and her cortisol falls close to zero. Yet her aldosterone is fine, and her potassium stays normal. Same adrenal gland, same cholesterol. So why does one hormone vanish while the other carries on? Today: trace adrenal steroid synthesis from cholesterol to aldosterone, cortisol and androgens, by zone and by enzyme.

0:25The three cortical zones: salt, sugar, sex

The adrenal cortex has three layers, outermost first. The zona glomerulosa makes aldosterone, the zona fasciculata makes cortisol, and the zona reticularis makes androgens. Salt, sugar, sex: from the outside in. Beneath the cortex, the medulla makes catecholamines, and it is not part of today's map.

0:49What drives each zone: angiotensin II, potassium and ACTH

Each layer has its own driver. Angiotensin two and potassium switch on the glomerulosa; ACTH drives the fasciculata and the reticularis. ACTH can nudge the glomerulosa too, but angiotensin two and potassium are its main drivers. So when the pituitary goes, cortisol and androgens collapse, but the glomerulosa keeps making aldosterone. That is our patient.

1:17The production line: cholesterol to pregnenolone to progesterone

Now the production line. Every adrenal steroid starts as cholesterol. A protein called StAR carries cholesterol to the inner mitochondrial membrane, where the side-chain cleavage enzyme, CYP11A1, makes pregnenolone. ACTH boosts cholesterol supply to this first step, which is one way it drives the whole line. Next, three beta hydroxysteroid dehydrogenase turns pregnenolone into progesterone.

1:47Three lanes by enzyme, and 17 alpha hydroxylase as the fork

Now the glomerulosa. It has no 17 alpha hydroxylase, so everything is steered one way. 21-hydroxylase turns progesterone into deoxycorticosterone, corticosterone follows, and aldosterone synthase finishes the job. In the fasciculata, 17 alpha hydroxylase acts first, giving 17-hydroxyprogesterone. 21-hydroxylase then makes 11-deoxycortisol, and 11 beta hydroxylase makes cortisol. The fasciculata also makes some deoxycorticosterone from progesterone, under ACTH. Keep that in mind for the next lesson. In the reticularis, that same 17 alpha enzyme has a second activity, 17,20-lyase, which clips off the side chain to make DHEA, the parent of androstenedione. So 17 alpha hydroxylase is the fork in the road: with it you make cortisol and androgens; without it, only aldosterone.

2:52The block rule: pile-up, fall, spill

One rule to carry into the next lessons. Cortisol suppresses ACTH, so when cortisol is low, ACTH is high. If an enzyme is blocked, the steroid before it piles up, the hormone after it falls, and the pile-up spills into any pathway still open. Picture 11 beta hydroxylase missing. 11-deoxycortisol and deoxycorticosterone pile up, cortisol falls, ACTH rises, and the spill pushes out more androgen.

3:26Your turn: a practice question

Your turn. A researcher incubates cells from the outermost zone of a normal adult adrenal cortex with radiolabelled cholesterol. The cells make pregnenolone, progesterone, deoxycorticosterone, corticosterone and aldosterone. They make no 17-hydroxyprogesterone, cortisol or DHEA. The absence of which enzyme best explains the missing products? A, three beta hydroxysteroid dehydrogenase. B, 17 alpha hydroxylase. C, 21-hydroxylase. D, aldosterone synthase. E, cholesterol side-chain cleavage enzyme. Pause here and decide.

4:15The answer, one option at a time

A is out: the cells make progesterone, and that step needs three beta hydroxysteroid dehydrogenase. C is out: they make deoxycorticosterone, so 21-hydroxylase is working. D is out: they make aldosterone, which only aldosterone synthase can do. E is out: pregnenolone appears, so cholesterol side-chain cleavage is present. So the answer is B. Without 17 alpha hydroxylase there is no 17-hydroxyprogesterone, and so no cortisol and no DHEA.

4:52Recap pocket card and next lesson

Three things to keep. One: salt, sugar, sex from the outside in; angiotensin two and potassium drive the glomerulosa, ACTH drives the other two layers. Two: 17 alpha hydroxylase is the fork between aldosterone and cortisol or androgens. Three: a block piles up what is before it, lowers what is after it, and spills into the open pathways. Next, congenital adrenal hyperplasia: what happens when each of these enzymes is missing.

Sources

Numbers in the text, e.g. [1], point here
  1. MSD Manual Professional Version. Overview of Adrenal Function. msdmanuals.com/professional/endocrine-and-metabolic-disorders/adrenal-disorders/overview-of-adrenal-function
  2. MSD Manual Professional Version. Secondary Adrenal Insufficiency. msdmanuals.com/professional/endocrine-and-metabolic-disorders/adrenal-disorders/secondary-adrenal-insufficiency
  3. MSD Manual Professional Version. Overview of Congenital Adrenal Hyperplasia. msdmanuals.com/professional/pediatrics/endocrine-disorders-in-children/overview-of-congenital-adrenal-hyperplasia
  4. MSD Manual Professional Version. CAH due to 21-hydroxylase deficiency. msdmanuals.com/professional/pediatrics/endocrine-disorders-in-children/congenital-adrenal-hyperplasia-caused-by-21-hydroxylase-deficiency
  5. MSD Manual Professional Version. CAH due to 11 beta-hydroxylase deficiency. msdmanuals.com/professional/pediatrics/endocrine-disorders-in-children/congenital-adrenal-hyperplasia-caused-by-11beta-hydroxylase-deficiency
  6. Kater CE. Arch Endocrinol Metab 2022 (adrenal cortex zones and steroidogenesis). pmc.ncbi.nlm.nih.gov/articles/PMC9991025/
  7. Front Endocrinol 2025 adrenal review. pmc.ncbi.nlm.nih.gov/articles/PMC12832385/
  8. Nature Genetics 2026 adrenal atlas. pmc.ncbi.nlm.nih.gov/articles/PMC13553300/
  9. Diagnostics 2026 steroid profiles review. pmc.ncbi.nlm.nih.gov/articles/PMC12896859/
  10. J Endocrinol Invest 2025. pmc.ncbi.nlm.nih.gov/articles/PMC12602608/
  11. JCEM 2026 cortisol feedback. pmc.ncbi.nlm.nih.gov/articles/PMC13183435/

The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.

Image credits. Illustrations: Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (recoloured, outlined, resized): woman, pituitary gland, kidney with adrenal gland, adrenal gland cell types (cortical zones), mitochondrion. The pathway lanes, slip, bars, cards and all handwriting are drawn in code (original). No AI-generated teaching images.

Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-ENDO-005.

For exam study only, not medical advice. Read the medical disclaimer.

In this series

Playlist on YouTube
← Previous · EP 08Calcium homeostasis: PTH, vitamin D and calcitonin
  1. EP 01Hypothalamic-pituitary axes and feedback: primary, secondary, tertiary5:05
  2. EP 02Primary vs secondary endocrine disorders: paired hormone levels5:13
  3. EP 03Insulin secretion in the beta cell: from glucose to granule5:06
  4. EP 04Insulin vs glucagon signalling: receptors and effects5:19
  5. EP 05DKA vs HHS pathophysiology: why only one makes acid5:58
  6. EP 06Diabetes drugs by mechanism: where each class acts5:58
  7. EP 07Thyroid hormone synthesis, step by step5:14
  8. EP 08Calcium homeostasis: PTH, vitamin D and calcitonin5:28
  9. EP 09Adrenal steroidogenesis: zones, enzymes and the 17α-hydroxylase fork5:29
  10. EP 10Congenital adrenal hyperplasia: three enzymes, three patterns5:44
  11. EP 11Cushing syndrome: the dexamethasone suppression test and ACTH5:29
  12. EP 12Primary hyperaldosteronism: high aldosterone, low renin5:27
  13. EP 13SIADH vs diabetes insipidus: central vs nephrogenic DI5:44
  14. EP 14MEN1, MEN2A and MEN2B: match the gene to its tumours5:13