21-hydroxylase deficiency

Interpretation of stimulated 17-OH progesterone levels Steroid pathway showing effects of 21-hydroxylase deficiency

Screening by androgen measurements

In possible hyperandrogenic states without specific concern about CAH, Wallace & Sattar suggest it is probably adequate to test only those with total testosterone > 4nmol/l.

However, Kuttenn states that non-classical CAH is regularly diagnosed in 6% of hyperandrogenic women, and 20% of women with confirmed CAH have testosterone <2 nmol/L. (Conversion: 3.47 nmol/L = 1 ng/mL). Androstenedione is oversecreted by adrenals in CAH, with raised testosterone mainly the result of peripheral conversion - discrepantly elevated androstenedione is a hint to CAH diagnosis. (Conversion: 3.492 nmol/L = 1 ng/mL).

Diagnosis by 17-OH-progesterone

Speiser gives the following typical results and adjacent nomogram:

  • Salt-wasting disease: up to 3000 nmol/l (100,000 ng/dl)
  • Simple-virilizing disease: 300-1000 nmol/l (10,000-30,000 ng/dl)
  • Non-classical disease: 50-300 nmol/l (1500-10,000 ng/dl)

ACTH-stimulated 17-OH-progesterone is recommended. Random measurements in non-classical disease are often normal, unless taken in the early morning.

  • Conversion of units: 1 ng/mL = 3.026 nmol/L
  • Early morning baseline level: Bidet found a median baseline level of about 25 nmol/L, though 2 out of 161 confirmed patients had baseline levels <6 nmol/L. Escobar-Morreale found a mean morning baseline 17-OHP of about 35 nmol/L, and a minimum of 5 nmol/L, in 6 patients with non-classical CAH (of 270 hyperandrogenic women screened).
  • ACTH-stimulated level: a result greater than 30 nmol/L indicates CAH. From Bidet, median was about 120 nmol/L, minimum was 28 nmol/L. (Typical results of 6-9 in non-CAH but hyperandrogenic women according to Escobar-Morreale).
  • Unstimulated measurements at normal clinic times may be in normal range

Genetics etc

  • 95% of CAH are 21-OH deficiency
  • Gene is CYP21A2
  • Autosomal recessive
  • Most are compound heterozygotes (two different mutations), phenotype corresponds to least severe mutation
  • All children of classical CAH patients will be carriers
  • Sensible for partners of CAH patients to be genotyped - consider maternal dex if both are carriers of classical mutations
  • Nonclassical CAH patients may carry one classic mutation
  • Nonclassical CAH - mutations only impair 21-OH - no cortisol deficiency, but hyperandrogenism in females

Glucocorticoid therapy

  • Generally HC in children: growth suppression with longer-acting steroids
  • Normal circadian rhythm of cortisol and 17-OHP: low at night, rise from 0200, peak 0800
  • Reverse circadian pattern previously used suppress morning ACTH, e.g. hydrocortisone 10,5,15 mg, or dexamethasone at night (250-500 mcg/d, typically 375mcg)
  • Now rarely attempt to suppress morning ACTH as inevitably results in Cushing's syndrome. Typical UK practice is prednisolone 3+1mg, or HC 10+5+5mg
  • Dex is not inactivated by placental 11β-HSD, so crosses placenta. Use hydrocortisone or prednisolone in sexually-active females not using contraception
  • Lower dose ⁄ shorter-acting GC sensible in older women when osteoporosis bigger issue than fertility
  • In non-classical CAH, treatment for children with rapid skeletal aging ⁄ females with virilization
  • In non-classical CAH, adult males need no treatment, females may be OK with OCP + antiandrogen

Mineralocorticoid therapy

  • To maintain normal electrolyte/renin activity
  • Not required in non-classic CAH
  • Consider extra salt intake in hot weather ⁄ intense exercise

Monitoring

  • Androstenedione and PRA should be normalized
  • 17OH-P should not be normalized as this will tend to cause Cushing's syndrome
  • Suggested morning 17OH-P targets:
    • children 400-1200 ng⁄dl (12-36 nmol⁄l)
    • adult female wishing fertility <800 (<24)
    • adult male with no testicular adrenal rest <2500 (<75)

Associated conditions

  • Fertility impaired in women with classical CAH. Polycystic ovaries are common.
  • Sperm quality impaired in men with classical and simple virilizing CAH. Testicular adrenal rest is detected in about 1⁄3 of adult males. Sperm count correlates with functional testicular volume and inhibin B levels.
  • Adrenal rest = ectopic adrenal tissue, most common in untreated⁄poorly-treated classical CAH
  • Some experts recommend that sole use of dex is as temporary measure to suppress gonadal rest for temporary induction of fertility (e.g. sperm banking), accepting severe Cushingoid side effects in short term.
  • Longer-acting glucocorticoids needed to regulate menstrual cycle, but avoid dex in pregnancy unless father also a known carrier and fetal adrenal suppression desired

Other metabolic effects

  • Insulin resistance and obesity common
  • Impaired adrenal medullary function (NB cortisol and adrenaline def = hypo risk in DM)