11-hydroxylase deficiency
Summary
11β-hydroxylase deficiency is a form of congenital adrenal hyperplasia (autosomal recessive, CYP11B1 mutation) that blocks conversion of 11-deoxycorticosterone (DOC) to corticosterone and 11-deoxycortisol to cortisol. It causes decreased cortisol with increased ACTH, androgen excess (virilization/ambiguous genitalia in females), and HYPERTENSION with low renin due to DOC accumulation (mineralocorticoid effect). Contrast with 21-hydroxylase deficiency (hypotension, hyperkalemia, salt wasting) and 17α-hydroxylase deficiency (hypertension, hypogonadism/ lack of sex hormones).
Detail
**Genetics/Enzyme:** Autosomal recessive; CYP11B1 gene (chromosome 8q24). Second most common cause of CAH (~5-8%) after 21-hydroxylase deficiency (~90%+). 11β-hydroxylase (mitochondrial P450c11) is found in the zona fasciculata and converts 11-deoxycortisol → cortisol and 11-deoxycorticosterone (DOC) → corticosterone (precursor to aldosterone in zona glomerulosa via aldosterone synthase, CYP11B2, which is intact).
**Pathophysiology:** - ↓ Cortisol → loss of negative feedback → ↑ ACTH → adrenal hyperplasia (bilateral). - Precursors shunted toward androgen pathway → ↑ DHEA, androstenedione, testosterone → virilization. - ↑ 11-deoxycorticosterone (DOC), a weak mineralocorticoid → sodium and water retention, volume expansion, hypertension, hypokalemia, metabolic alkalosis; this suppresses the renin-angiotensin system → ↓ renin, ↓ aldosterone (low-renin hypertension). - ↑ 11-deoxycortisol (the marker, also used for diagnosis; this is the basis of the metyrapone test, which blocks 11β-hydroxylase).
**Clinical features:** - Females (46,XX): ambiguous genitalia at birth (clitoromegaly, labial fusion) with normal internal female structures (uterus, ovaries), because of in utero androgen exposure. - Males (46,XY): normal genitalia at birth, precocious pseudopuberty (early pubic hair, penile enlargement, small testes) in childhood; accelerated growth with early epiphyseal closure → short adult stature. - Hypertension (often in childhood), hypokalemia, ± signs of cortisol deficiency (less severe than 21-OH deficiency). - Hirsutism, acne, and oligomenorrhea in non-classic forms.
**Labs:** ↑ 11-deoxycortisol, ↑ DOC, ↑ androstenedione/testosterone, ↑ ACTH, ↓ cortisol, ↓ renin, ↓ aldosterone, ↓ K⁺, alkalosis.
**Treatment:** Glucocorticoid replacement (hydrocortisone) to suppress ACTH and thus androgen and DOC production; antihypertensives/mineralocorticoid antagonists (spironolactone) if needed; surgical genital reconstruction for affected females as appropriate.
**High-yield comparison (CAH):** | Enzyme | BP | K⁺ | Androgens | Sex hormones/genitalia | |---|---|---|---|---| | 21-hydroxylase | ↓ (salt wasting) | ↑ | ↑ | Virilization in females; precocious puberty in males; ↑ 17-OH progesterone | | 11β-hydroxylase | ↑ | ↓ | ↑ | Virilization in females; ↑ 11-deoxycortisol/DOC | | 17α-hydroxylase | ↑ | ↓ | ↓ | ↓ sex hormones: XY → ambiguous/female genitalia, undeveloped testes; XX → lacks secondary sexual development (primary amenorrhea); ↑ DOC, corticosterone |
Mnemonic: "11 = hyper-11 (hypertension)"; 17 = "17 = hypertension too but no sex hormones"; 21 = "21 = low (volume/pressure) – lose salt". Also: both 11β and 17α cause hypertension; only 17α lacks androgens/estrogens.
**Note:** Don't confuse with 11β-hydroxysteroid dehydrogenase type 2 deficiency (apparent mineralocorticoid excess; cortisol acts on mineralocorticoid receptor → hypertension, hypokalemia, low renin/aldosterone, but without virilization), which can also be caused by licorice (glycyrrhetinic acid) ingestion.
Sources
- First Aid for the USMLE Step 1 (Endocrine: Steroid hormone synthesis / Congenital adrenal hyperplasia)
- Pathoma (Robbins/Sattar) – Endocrine: Adrenal cortex
- Robbins & Cotran Pathologic Basis of Disease – Adrenal cortex, Congenital adrenal hyperplasia
- Harrison's Principles of Internal Medicine – Adrenal cortex disorders
- Endocrine Society Clinical Practice Guideline: Congenital Adrenal Hyperplasia (Speiser et al.)
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