Insulin Tolerance Test

The insulin tolerance test (ITT) assesses the integrity of the hypothalamic-pituitary-adrenal axis and growth hormone secretion by inducing hypoglycaemia (plasma glucose under 2.2 mmol/L) with intravenous insulin. Hypoglycaemia is a potent stress that stimulates ACTH and cortisol and growth hormone secretion through central mechanisms.

It tests the whole axis from hypothalamus to adrenal cortex, and is considered the reference method for diagnosing adult growth hormone deficiency and for confirming secondary adrenal insufficiency, particularly after pituitary surgery or in hypopituitarism, where a synacthen test may be falsely normal in recent onset disease.

The test is accurate (sensitivity and specificity over 95% for cortisol and GH deficiency) but carries risk, and requires continuous supervision by an experienced doctor or nurse. It is used less now because of the availability of glucagon stimulation, macimorelin and synacthen tests, but it is still the reference comparison in many centres.

Indications. Suspected growth hormone deficiency in adults (hypopituitarism, pituitary tumour, cranial irradiation, traumatic brain injury, childhood onset deficiency re-testing at transition). Suspected secondary adrenal insufficiency with equivocal synacthen test or recent pituitary insult. Assessment of cortisol reserve before stopping glucocorticoid therapy in selected patients.

Contraindications. Ischaemic heart disease (history of angina, infarction, ECG abnormality), epilepsy or seizure history, cerebrovascular disease, severe untreated hypoadrenalism or hypothyroidism (baseline cortisol under 100 nmol/L or evident hypothyroidism), age over 65 years (relative), pregnancy, and severe hypopituitarism with a baseline 09:00 cortisol under 100 nmol/L (risk of profound hypoglycaemia). Glycaemia over 3.0 mmol/L is needed before starting. Other tests are used in contraindicated patients.

Preparation. Fast from midnight, test in the morning (08:30 to 09:00). Doctor present throughout. Written consent. A baseline ECG. Hydrocortisone replacement is withheld for 24 hours before (unless the patient is unstable), and thyroid hormone replacement is optimised first (hypothyroidism blunts responses). Glucose for intravenous administration (50% dextrose), hydrocortisone and glucagon are at the bedside.

Procedure.

• Insert an intravenous cannula. Baseline samples for glucose, cortisol and GH at 0 minutes.
• Give soluble insulin intravenously, usually 0.15 units/kg (0.1 units/kg in suspected hypopituitarism, 0.3 units/kg in obesity, Cushing syndrome or acromegaly).
• Take samples for glucose, cortisol and GH at 15, 30, 45, 60, 90 and 120 minutes. Bedside glucose is checked every 15 minutes.
• Adequate hypoglycaemia: plasma glucose under 2.2 mmol/L (40 mg/dL) with symptoms (sweating, tachycardia, tremor). If not reached at 45 minutes, repeat the insulin dose.
• At the end, give oral carbohydrate once the final sample is taken, and intravenous glucose if the patient is severely symptomatic or drowsy, and hydrocortisone if cortisol is low.
• The patient is observed until glucose is over 4 mmol/L and fed before discharge.

Validity. The test is valid only if plasma glucose falls to 2.2 mmol/L or less (and symptoms occur). Otherwise it is repeated.

Cortisol response.

• Normal peak cortisol: 500 nmol/L (18 microg/dL) or more, by assay (some laboratories use 450 nmol/L for newer, more specific immunoassays, or 500 nmol/L with older assays).
• Peak cortisol under 500 nmol/L: adrenal insufficiency (partial at 350 to 500 nmol/L, severe at under 350 nmol/L). Glucocorticoid replacement is considered at peak under 350 nmol/L.

Growth hormone response.

• Severe adult GH deficiency: peak GH under 3 microg/L (9 mU/L) with the glucose threshold met.
• Partial deficiency: 3 to 5 microg/L. Normal: over 5 microg/L (some centres use 5.1 or higher, with assay specific cut offs).
• In obesity, cut offs are lower (peak under 1 to 2 microg/L), and in children, GH deficiency is peak under 7 to 10 microg/L.
• Interpretation requires at least one other pituitary hormone deficiency or a high pre-test probability, since 10 to 20% of healthy people have peak GH under 3 microg/L by chance.

Prolactin and TSH. Prolactin response is not diagnostic. Other pituitary axes are tested by basal levels.

Critical values and findings needing immediate action.

• Neuroglycopenia (confusion, loss of consciousness, convulsion): immediate intravenous 50% dextrose (50 mL) or 10% dextrose 150 to 200 mL, glucagon 1 mg intramuscularly, and hydrocortisone 100 mg intravenously if severe adrenal insufficiency is suspected.
• Seizure during the test: airway protection, intravenous glucose and benzodiazepine.
• Arrhythmia or chest pain: stop the test, ECG, glucose and cardiology review.
• Baseline cortisol under 100 nmol/L: the test is not done, and replacement is started.
• Persisting hypoglycaemia after glucose: continuous glucose infusion, repeated checks for 2 to 4 hours, and observation.

Interferences and pitfalls.

• Failure to reach glucose under 2.2 mmol/L is the main cause of false negative or invalid tests. Insulin resistance (obesity, Cushing syndrome, acromegaly, diabetes) requires higher doses.
• Oestrogen (oral) raises cortisol binding globulin and total cortisol, giving falsely normal results. Oral oestrogens are stopped for 6 weeks before.
• Cortisol assay differences: newer monoclonal immunoassays and mass spectrometry give lower values than older polyclonal assays, so lower cut offs (370 to 450 nmol/L) are used locally.
• Hypothyroidism and untreated hypogonadism blunt GH response.
• Depression, antidepressants, antipsychotics and anticholinergics blunt GH responses.
• Glucocorticoid use suppresses the axis and is withheld before testing as safe.
• Recent pituitary surgery or radiotherapy: ACTH deficiency can evolve, and the test is delayed for at least 6 weeks after surgery (12 weeks in some centres) for reliable results.
• The test is unsafe in elderly patients, those with epilepsy and cardiovascular disease, and glucagon stimulation or macimorelin is used instead.

Special groups.

• Children: GH testing is done in specialist centres, often with sex steroid priming before puberty, and ITT in children is dose adjusted and rarely used.
• Older adults: avoided because of cardiovascular risk.
• Pregnancy: contraindicated.
• Transition patients: childhood onset GH deficiency is retested at final height, and ITT is the reference with peak under 5 microg/L indicating persistent deficiency.
• Regions: the test is available in few centres, and glucagon testing is more widely used.

Follow up tests. Synacthen stimulation test, morning cortisol and ACTH, IGF-1, thyroid function, gonadotrophins and sex steroids, prolactin, electrolytes, glucose, pituitary MRI, glucagon stimulation test, macimorelin test, and bone densitometry.