Endocrine dynamic function tests - insulin tolerance test

Principle

The reference standard for both the HPA axis (cortisol) and GH reserve in one test
Principle: insulin-induced hypoglycaemia is a potent, physiological central stressor -> hypothalamus -> CRH/GHRH -> ACTH and GH -> cortisol
- Tests the whole axis from hypothalamus down, which a Synacthen test does not
*The only stimulus that reliably detects recent-onset secondary adrenal insufficiency* - within ~4-6 weeks of pituitary surgery or apoplexy the adrenals have not yet atrophied, so Synacthen is falsely normal

Requires deliberate, symptomatic hypoglycaemia - which is why it is rarely done and why the contraindications matter more than the protocol

Performed only in specialist endocrine units with medical staff present throughout
Largely displaced in routine practice by the short Synacthen test (cortisol) and glucagon or arginine-GHRH testing (GH)

Neuroglycopenia -> hypothalamic glucose-sensing neurons -> CRH and AVP -> corticotroph ACTH -> adrenal cortisol
Simultaneously -> GHRH release and somatostatin withdrawal -> somatotroph GH
Adequate hypoglycaemia is essential: the stimulus must be glucose <2.2 mmol/L with autonomic symptoms
- A test that never reached 2.2 is uninterpretable - it does not exclude deficiency

Overnight fast; IV cannula; doctor present with 50% glucose and hydrocortisone drawn up
Soluble insulin 0.1-0.15 units/kg IV (0.05 if hypopituitarism strongly suspected; 0.3 if insulin-resistant - Cushing's, acromegaly, obesity)
Glucose, cortisol and GH at 0, 15, 30, 45, 60, 90, 120 minutes
Bedside glucose at each time point
Terminate/rescue with IV glucose if severe neuroglycopenia - but keep sampling: the axis has already been stimulated

Axis	Adequate response
Cortisol	Peak >500-550 nmol/L on older polyclonal immunoassays
	*Roche Elecsys Cortisol II and other monoclonal/LC-MS-aligned assays read lower - cut-offs of ~420-450 nmol/L apply*
GH	Peak >3-5 microg/L (severe adult GHD usually defined as <3 microg/L)

*Always check which cortisol assay your laboratory uses before applying a cut-off* - using the old 550 threshold with a modern assay over-diagnoses adrenal insufficiency
A rise in cortisol without adequate hypoglycaemia proves nothing

*Ischaemic heart disease or cerebrovascular disease (ECG in everyone over 40 or with risk factors*)
*Epilepsy or unexplained seizures*
Untreated hypothyroidism - blunts the GH and cortisol response (replace thyroxine first)
Basal cortisol already <100 nmol/L - the diagnosis is made; testing adds only risk
Age extremes, pregnancy

Test	Assesses	Notes
Short Synacthen (250 microg)	Adrenal cortisol reserve	*30-min cortisol >420-450 nmol/L on modern monoclonal assays (was 500-550)[[c2]]. Falsely normal within 4-6 weeks of pituitary insult*
Glucagon stimulation	GH and cortisol	1 mg IM (1.5 mg if >90 kg), samples half-hourly for 3-4 h. GH cut-off ~3 microg/L, BMI-adjusted (lower in obesity). Safe in IHD and epilepsy - the usual ITT substitute. Nausea is common
Arginine + GHRH	GH only	Samples half-hourly for 2 h; BMI-adjusted cut-offs. GHRH availability is limited
Macimorelin (oral ghrelin agonist)	GH only	Single oral dose; peak GH cut-off ~2.8 microg/L. Not available in all centres; prolongs QT
IGF-1	GH screen	A low IGF-1 with >=3 other pituitary hormone deficiencies is sufficient to diagnose adult GHD without provocation
Overnight/8 am cortisol	HPA screen	<100 nmol/L = deficient; >350-400 nmol/L = intact; between = test

Medical supervision throughout; never leave the patient alone
IV access with glucose and hydrocortisone at the bedside
Expect and document sweating, tremor, drowsiness - these confirm the stimulus was adequate
Feed a carbohydrate meal at the end and observe until fully recovered
Late hypoglycaemia can occur - do not discharge immediately

Secondary adrenal insufficiency -> hydrocortisone replacement (typically 15-25 mg/day in divided doses, weighted to the morning); no fludrocortisone needed (renin-angiotensin-aldosterone is intact)
- Sick day rules, emergency hydrocortisone injection, medical alert identification
Adult GH deficiency -> daily SC GH titrated to IGF-1 in the age-adjusted normal range; benefits are body composition, lipids, bone and quality of life
Replace glucocorticoid before thyroxine and before GH - GH increases cortisol clearance via 11beta-HSD1 and can unmask adrenal insufficiency

Post-pituitary surgery: assess at 6-12 weeks (and use the ITT rather than Synacthen if within ~6 weeks of the insult)
After cranial radiotherapy: axes fail progressively over years - retest periodically

Hypopituitarism from adenoma, surgery, radiotherapy, apoplexy, Sheehan syndrome, traumatic brain injury, hypophysitis (including checkpoint inhibitor), infiltrative disease
Order of hormone loss under compression: GH -> LH/FSH -> TSH -> ACTH
- GH is lost first, so isolated GH deficiency can be the earliest sign
Prolonged exogenous glucocorticoids - the commonest cause of secondary adrenal insufficiency overall
Untreated hypothyroidism and obesity both blunt the GH response - correct or account for them

Untreated secondary adrenal insufficiency -> adrenal crisis during illness or surgery; entirely preventable
Untreated adult GH deficiency -> central adiposity, dyslipidaemia, reduced bone density, impaired quality of life and exercise capacity
Recovery of the HPA axis after pituitary surgery does occur - retest rather than assume lifelong replacement
Post-radiotherapy hypopituitarism is progressive over 10+ years - a normal test today does not exclude deficiency later
The commonest error is not doing the test but applying the wrong cut-off to the local assay

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