ENDO / ADRENAL CORTEX
Congenital Adrenal Hyperplasia
When the adrenal cortex blocks the steroid assembly line, things pile up in unexpected places.
A 7-day-old male is brought to the ER with vomiting, poor feeding, and lethargy since day 4 of life. He was delivered at term with no complications and discharged with a normal newborn exam.
Vitals: BP 62/38, HR 185. Labs: Na+ 121, K+ 7.2, glucose 44. The father mentions "our daughter had genital surgery as a baby." Newborn screen for 17-hydroxyprogesterone: critically elevated.
Correct: 21-hydroxylase deficiency (most common CAH, ~90% of cases)
The 7-day salt-wasting crisis is the male tell. Girls get caught earlier because of ambiguous genitalia at birth. Boys look normal, go home, then collapse when mom's placental mineralocorticoids wear off around day 5-7. The elevated 17-OHP confirms the enzyme block.
Why NOT Addison? Addison is autoimmune adrenal destruction in adults. A 7-day-old doesn't have time to develop that. The family history of genital surgery + 17-OHP spike = CAH.
Na+ 121, K+ 7.2
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No aldosterone. Aldosterone keeps Na+ in and K+ out. Without it, Na dumps into urine and K builds up. It mimics Addison's but the context is a newborn with a family history.
17-OHP critical
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The backup product. When 21-OH is blocked, 17-hydroxyprogesterone piles up and diverts into the androgen pathway. Elevated 17-OHP is the newborn screen marker for CAH.
Sister had genital surgery
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Androgen overflow. The sister was a 46,XX female virilized in utero by excess androgens (clitoromegaly, labial fusion = "ambiguous genitalia"). Same enzyme deficiency in both siblings = autosomal recessive inheritance.
SECTION 2 OF 4
The Blocked Pathway
Tap each enzyme to see what gets blocked, what builds up, and what spills over.
Builds Up (trouble)
Progesterone
↓
17-OH-Progesterone
↓
Overflows to ANDROGENS
Missing (the damage)
21-OH ⛔ BLOCKED
X
DOC (no aldosterone precursor)
↓
ALDOSTERONE ❌
↓
CORTISOL ❌
Clinical result
Salt-wasting crisis (no aldo)
Virilization (androgen overflow)
High ACTH (no cortisol brake)
Adrenal hyperplasia
21-OH Deficiency at a glance
Salt-Wasting No aldosterone. Na+ dumps, K+ rises. Day 5-7 crisis in males.
Virilization Female newborns have ambiguous genitalia. Males look normal at birth.
No HTN Doesn't start with 1 in the mnemonic. No mineralocorticoid excess.
Treatment Hydrocortisone (cortisol) + Fludrocortisone (aldosterone replacement).
Builds Up (trouble)
11-deoxycorticosterone (DOC)
+
11-deoxycortisol
+
DOC acts as a mineralocorticoid
Missing (the damage)
11beta-OH ⛔ BLOCKED
X
Corticosterone
↓
ALDOSTERONE (low)
↓
CORTISOL ❌
Clinical result
HTN (DOC = mineralocorticoid)
Virilization (androgen overflow)
High ACTH (no cortisol brake)
No salt-wasting (DOC fills in)
11beta-OH Deficiency at a glance
HTN DOC piles up and acts like aldosterone. Na+ retained, K+ drops, BP rises.
Virilization Androgen overflow causes virilization in females, early puberty in males.
No Salt-Wasting DOC compensates for missing aldosterone. The patient retains salt.
Treatment Hydrocortisone only (no fludrocortisone - DOC already too mineralocorticoid-active).
Builds Up (trouble)
Pregnenolone
+
Progesterone
+
DOC/Corticosterone excess
Missing (the damage)
17alpha-OH ⛔ BLOCKED
X
17-OH intermediates
↓
SEX STEROIDS ❌
↓
CORTISOL ❌
Clinical result
HTN (DOC/corticosterone excess)
No sex steroids → female phenotype in 46,XY
Primary amenorrhea in 46,XX
No pubic / axillary hair
17alpha-OH Deficiency at a glance
HTN Progesterone builds up, shunts to DOC/corticosterone (both have mineralocorticoid activity).
No Virilization OPPOSITE problem - can't make sex steroids at all. 46,XY presents as phenotypic female.
No Salt-Wasting Excess mineralocorticoids prevent salt loss.
Treatment Hydrocortisone + sex hormone replacement at puberty.
Board trap: 17alpha-OH deficiency in a 46,XY karyotype presents as a teenage girl with primary amenorrhea, no pubic hair, and hypertension. The lab clue: very low testosterone + very high progesterone. The 17alpha enzyme is needed to make ANY sex steroid (androgens AND estrogens). No enzyme = no masculinization in males = female external phenotype.
SECTION 3 OF 4
The "1 Mnemonic" Game
Tap each cell to mark YES. Some enzymes hit multiple columns. Then submit.
The attending just taught you this: "If the enzyme number starts with 1 = HTN. If it ends with 1 = Virilization. If it does BOTH = 11."
Now prove you got it. Mark every correct enzyme-outcome pair.
| Enzyme | Hypertension | Virilization | Salt-Wasting |
|---|---|---|---|
| 21-OH | |||
| 11beta-OH | |||
| 17alpha-OH |
Starts with 1 = HTN: 17alpha-OH (17) and 11beta-OH (11) both start with 1. Both cause HTN via mineralocorticoid excess.
Ends with 1 = Virilization: 21-OH (21) and 11beta-OH (11) both end in 1. Both cause androgen overflow.
11beta-OH = BOTH: starts AND ends with 1. HTN + virilization. No salt-wasting (DOC fills in).
21-OH: ends with 1 = virilization. Doesn't start with 1 = no HTN. Salt-wasting because no aldosterone AND no DOC.
| Feature | 21-OH | 11beta-OH | 17alpha-OH |
|---|---|---|---|
| HTN | No | Yes | Yes |
| Virilization | Yes | Yes | No (anti-virilized) |
| Salt-wasting | Yes | No | No |
| Electrolytes | ↓Na, ↑K (hyper K) | ↓K (hypo K) | ↓K (hypo K) |
| Key backup | 17-OHP | DOC | Progesterone |
| Sex steroids | Excess (andro) | Excess (andro) | Absent |
| Treatment | HC + Fludro | HC only | HC + sex hormones |
Board trap: the potassium flip. 21-OH deficiency = hyperkalemia (no aldosterone, K+ can't be excreted). 11beta-OH and 17alpha-OH = hypokalemia (DOC/corticosterone act as mineralocorticoids, pump K+ out). A question that shows a CAH patient with LOW potassium is pointing you away from 21-OH and toward the HTN-causing deficiencies. Potassium is the tiebreaker.
Memory Hook
The "1 rule" is the number on the door.
Apartment 21: Ends in 1 = the tenant causes drama (virilization), but the building has no water pressure (no HTN, actually salt-wasting). Apartment 11: On both sides of the block (HTN + virilization). Apartment 17: At the start of the street (17 starts with 1 = HTN), but no drama inside (no virilization - actually quieter than normal).
Board trap: cortisol has no second messenger. Cortisol is a steroid (lipophilic). It crosses the cell membrane, binds the glucocorticoid receptor in the cytoplasm, and the complex moves to the nucleus to regulate gene transcription. Break it down: No second messenger - it IS the message. Don't confuse with ACTH: ACTH acts on a G-protein coupled receptor and uses cAMP as its second messenger. ACTH uses cAMP. Cortisol uses DNA.
THE FOUR VARIANTS
The Lineup
Four enzyme deficiencies. Tap each card to flip.
21-OH Deficiency
Most common (90%). Salt-wasting + virilization.
21-Hydroxylase Deficiency
- Frequency: ~90% of all CAH
- Blocks: cortisol + aldosterone synthesis
- Accumulates: 17-OHP, androgens
- Signs: salt-wasting crisis + virilization in females
- Screen: 17-OHP elevated on newborn screen
- HTN: No (salt-wasting instead)
- Board pearl: K+7 crisis in male newborn day 5-7 = 21-OH
11-beta-OH Deficiency
2nd most common. HTN + virilization. No salt-wasting.
11-beta-Hydroxylase Deficiency
- Frequency: 2nd most common CAH
- Blocks: cortisol synthesis
- Accumulates: 11-deoxycortisol, 11-deoxycorticosterone (DOC)
- DOC effect: acts as a mineralocorticoid, causes HTN
- Signs: HTN + virilization, NO salt-wasting
- Board pearl: "11 starts and ends with 1" = HTN + virilization
17-alpha-OH Deficiency
HTN, NO sex hormones. XY = phenotypic female.
17-alpha-Hydroxylase Deficiency
- Blocks: sex hormones + cortisol
- Accumulates: progesterone, DOC/corticosterone
- Signs: HTN + NO virilization + no sex hormone development
- 46,XY: phenotypic female (no androgens = default female)
- 46,XX: primary amenorrhea, no pubic hair
- Board pearl: teenager with HTN + no pubic hair + primary amenorrhea = 17-alpha-OH
3-beta-HSD Deficiency
Early pathway block. DHEA elevated. Ambiguous genitalia in both sexes.
3-beta-HSD Deficiency
- Block: early in steroidogenesis pathway
- Accumulates: DHEA (weak androgen)
- 46,XX: mild virilization from DHEA
- 46,XY: under-virilized (DHEA is too weak for full masculinization)
- Electrolytes: salt-wasting (no aldosterone)
- Board pearl: ambiguous genitalia in a male neonate + DHEA elevated = 3-beta-HSD
CLINICAL REASONING
Decision Tree: Which CAH Type?
Follow the clinical findings. Tap each branch to reveal the diagnosis.
Is virilization present (ambiguous genitalia in female, or androgen excess)?
Virilization narrows it to 21-OH or 11-beta-OH.
Now check sodium: is the patient salt-wasting?
Now check sodium: is the patient salt-wasting?
No virilization points away from 21-OH and 11-beta-OH.
Check for hypertension and absent sex hormone development (see 17-alpha-OH below).
Check for hypertension and absent sex hormone development (see 17-alpha-OH below).
Virilization present: is sodium LOW (salt-wasting)?
21-Hydroxylase Deficiency.
No aldosterone produced. Salt dumps into urine. Classic day 5-7 crisis in male neonates.
Confirm: 17-OHP markedly elevated on newborn screen.
Treatment: hydrocortisone + fludrocortisone.
No aldosterone produced. Salt dumps into urine. Classic day 5-7 crisis in male neonates.
Confirm: 17-OHP markedly elevated on newborn screen.
Treatment: hydrocortisone + fludrocortisone.
11-beta-Hydroxylase Deficiency.
DOC (deoxycorticosterone) builds up and acts as a mineralocorticoid. Sodium retained, potassium excreted, BP rises.
Patient still virilized (androgen overflow), but NO salt-wasting.
Treatment: hydrocortisone only (no fludrocortisone, DOC already fills the mineralocorticoid role).
DOC (deoxycorticosterone) builds up and acts as a mineralocorticoid. Sodium retained, potassium excreted, BP rises.
Patient still virilized (androgen overflow), but NO salt-wasting.
Treatment: hydrocortisone only (no fludrocortisone, DOC already fills the mineralocorticoid role).
No virilization + hypertension + absent sex hormone development?
17-alpha-Hydroxylase Deficiency.
Cannot make any sex steroids (blocks the entire sex steroid branch).
46,XY: phenotypic female (no androgens = default female development).
46,XX: primary amenorrhea, no secondary sex characteristics.
HTN from excess DOC/corticosterone (mineralocorticoid activity).
Treatment: hydrocortisone + sex hormone replacement at puberty.
Cannot make any sex steroids (blocks the entire sex steroid branch).
46,XY: phenotypic female (no androgens = default female development).
46,XX: primary amenorrhea, no secondary sex characteristics.
HTN from excess DOC/corticosterone (mineralocorticoid activity).
Treatment: hydrocortisone + sex hormone replacement at puberty.
Ambiguous genitalia in male neonate + elevated DHEA?
3-beta-HSD Deficiency.
Blocks early in the steroidogenesis pathway. Only weak androgen (DHEA) is produced.
DHEA is too weak to fully masculinize an XY fetus, but enough to mildly virilize an XX fetus.
Salt-wasting present (no aldosterone pathway).
This is the rare one: remember it by "DHEA = weak androgen = ambiguous in BOTH sexes."
Blocks early in the steroidogenesis pathway. Only weak androgen (DHEA) is produced.
DHEA is too weak to fully masculinize an XY fetus, but enough to mildly virilize an XX fetus.
Salt-wasting present (no aldosterone pathway).
This is the rare one: remember it by "DHEA = weak androgen = ambiguous in BOTH sexes."
ANATOMY + PATHOPHYSIOLOGY
Clinical Images
Scroll to browse. Key visuals for CAH and adrenal steroidogenesis.
Adrenal gland: cortex (CAH) vs medulla (pheo). Three cortical zones make cortisol, aldosterone, androgens.
Bilateral adrenal hyperplasia in CAH: excess ACTH drives adrenal enlargement when cortisol feedback is lost.
SECTION 4 OF 4
Board Questions
5 of 25 questions per load. They're different each time.
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