Metyrapone Test

Metyrapone inhibits 11-beta-hydroxylase (CYP11B1), the final enzyme in cortisol synthesis, which blocks conversion of 11-deoxycortisol to cortisol. The fall in cortisol removes negative feedback, and a normal pituitary responds with a rise in ACTH that drives 11-deoxycortisol (the precursor) and 11-deoxycorticosterone up. The test therefore assesses the capacity of the pituitary to secrete ACTH in response to a fall in cortisol.

It is used to diagnose secondary (pituitary or hypothalamic) adrenal insufficiency when the insulin tolerance test is contraindicated, and in the past to separate pituitary from ectopic ACTH-dependent Cushing syndrome.

Metyrapone is a cheaper alternative to the insulin tolerance test in patients with cardiac disease or epilepsy, but it is hazardous in patients with adrenal insufficiency because it can precipitate an adrenal crisis. The short (overnight) version is used in practice. Metyrapone is difficult to obtain in many countries, and the glucagon and synacthen tests have replaced it in most centres. A reliable 11-deoxycortisol assay (liquid chromatography with tandem mass spectrometry) is needed.

Indications. Suspected secondary adrenal insufficiency (previous pituitary disease, surgery, irradiation, long term glucocorticoid therapy) when the insulin tolerance test cannot be done. Assessment of the hypothalamic-pituitary-adrenal axis recovery after pituitary surgery. Historically, differentiation of Cushing disease from ectopic ACTH syndrome.

Contraindications. Known or suspected primary adrenal insufficiency (morning cortisol under 100 nmol/L with high ACTH), severe untreated secondary adrenal insufficiency (morning cortisol under 100 nmol/L), pregnancy, acute illness, and use of drugs that interfere with the assay (spironolactone). Patients with a high pre-test probability of adrenal insufficiency are tested in hospital.

Overnight (single dose) test.

• Patient admitted, or in a day unit overnight. Glucocorticoids are withheld for at least 24 hours (hydrocortisone) or longer for synthetic steroids, unless unsafe.
• At 23:59 (midnight), give metyrapone 30 mg/kg orally (maximum 3 g) with a snack to reduce nausea. A common adult dose is 2 g for under 70 kg, 2.5 g for 70 to 90 kg, and 3 g for over 90 kg.
• At 08:00 the next morning, take blood for cortisol, 11-deoxycortisol and ACTH.
• The patient is monitored overnight for symptoms of adrenal insufficiency (nausea, abdominal pain, dizziness), and blood pressure and glucose are checked. Hydrocortisone is given immediately after the 08:00 sample, or at once if the patient becomes unwell.

Multiple dose (3-day) test. Metyrapone 750 mg every 4 hours for 6 doses, with 24-hour urinary 17-hydroxycorticosteroids measured. This version is rarely used now.

Validity. The test is valid when 08:00 cortisol falls to under 200 nmol/L (7 microg/dL), showing that the enzyme block was effective.

Normal response. 11-deoxycortisol over 200 nmol/L (7 microg/dL) at 08:00, with ACTH over 33 pmol/L (150 ng/L). An intact axis.

Impaired response.

• 11-deoxycortisol under 200 nmol/L (and ACTH not raised) with effective cortisol suppression: secondary adrenal insufficiency (reduced ACTH reserve).
• Partial response (11-deoxycortisol 200 to 350 nmol/L) is borderline, and repeat testing or another test (insulin tolerance, glucagon) is used.
• Failure of cortisol to fall under 200 nmol/L: inadequate drug absorption, drug interaction (inducers such as phenytoin, rifampicin) or cortisol excess, and the test is repeated with a higher dose.

Cushing syndrome (historical). In pituitary Cushing disease, ACTH and 11-deoxycortisol rise exaggeratedly (11-deoxycortisol increases by over 2 times the baseline), whereas in ectopic ACTH syndrome and adrenal tumours there is little or no increase. Inferior petrosal sinus sampling and imaging have replaced this application.

Medical treatment. Metyrapone is also used as a cortisol lowering therapy in Cushing syndrome (250 mg to 6 g daily in divided doses), with cortisol day curves for monitoring. 11-deoxycortisol and androstenedione rise on treatment, and cross-reactivity with the cortisol assay may overestimate cortisol, so mass spectrometry is preferred.

Critical values and findings needing immediate action.

• Hypotension, vomiting, abdominal pain, confusion or hypoglycaemia during the test: adrenal crisis, immediate intravenous hydrocortisone 100 mg, saline and glucose, and sampling for cortisol and 11-deoxycortisol before the steroid is given if possible.
• Cortisol at 08:00 over 200 nmol/L after the dose: ineffective block, and the 11-deoxycortisol result is not interpreted.
• 11-deoxycortisol under 100 nmol/L with ACTH low: definite secondary adrenal insufficiency, and glucocorticoid replacement is started.

Interferences and pitfalls.

• Cortisol immunoassays cross-react with 11-deoxycortisol, causing falsely high cortisol readings and an invalid test. Mass spectrometry or an assay with low cross-reactivity is used.
• Enzyme inducers (phenytoin, carbamazepine, phenobarbital, rifampicin) lower metyrapone effect, and oestrogens or other drugs alter binding proteins.
• Spironolactone, hydrocortisone and other steroids interfere with the 11-deoxycortisol result.
• Hypothyroidism and acute illness blunt the response.
• The test cannot be done in patients with untreated adrenal insufficiency, and adrenal crisis is a real risk.
• Nausea and vomiting can prevent drug absorption, and the dose is taken with food.
• Reference limits for 11-deoxycortisol depend on the assay, and local ranges are established.
• Pituitary recovery after surgery: results within 6 weeks may not reflect long term function.

Special groups.

• Children: used rarely, with a dose of 300 mg/m².
• Pregnancy: contraindicated.
• Older adults: caution with comorbidity and polypharmacy.
• Regions: availability of metyrapone is limited, and glucagon or synacthen testing is generally used.

Follow up tests. Synacthen stimulation test, morning cortisol and ACTH, insulin tolerance test or glucagon stimulation test, electrolytes, glucose, other pituitary hormones (TSH, free T4, prolactin, IGF-1, gonadotrophins), pituitary MRI, and 21-hydroxylase antibodies if primary adrenal insufficiency is suspected.