Arginine Stimulation Test

The arginine stimulation test assesses pituitary reserve of growth hormone (GH) and, in some versions, prolactin, and it is also used for copeptin stimulation. Intravenous arginine, an amino acid, stimulates GH release by inhibiting hypothalamic somatostatin.

It is safe, does not cause hypoglycaemia and is well tolerated, but the GH response is less than with insulin induced hypoglycaemia and it is therefore less sensitive in adults, so it is usually combined with growth hormone releasing hormone (GHRH-arginine test) to increase accuracy. The arginine test is also used in children for diagnosing GH deficiency and, with copeptin measurement, for diagnosing central diabetes insipidus.

In adults, the GHRH-arginine test has sensitivity and specificity of 90 to 95% when body mass index specific cut offs are used. In children, GH deficiency is diagnosed from two different provocative tests (for example arginine and clonidine) because a single test gives false positives in 10 to 20% of healthy short children. In central diabetes insipidus, copeptin after arginine at 60 minutes with a cut off of 3.8 pmol/L separates it from primary polydipsia with an accuracy of about 93%.

Indications. Suspected GH deficiency in children with short stature and slow growth (second test after clonidine, glucagon or exercise). Suspected adult GH deficiency (with GHRH where available). Arginine copeptin test in suspected diabetes insipidus. Assessment of pancreatic beta cell reserve in research (arginine induced insulin secretion).

Contraindications and cautions. Severe renal or hepatic impairment (arginine accumulation and hyperkalaemia), electrolyte abnormalities, pregnancy, extravasation (arginine is irritant). Arginine can cause hyperkalaemia in renal impairment. Cautions in patients on potassium sparing diuretics.

Preparation. Overnight fast of 8 to 12 hours. Rest in bed. Baseline thyroid function is normal (hypothyroidism blunts GH), and sex steroid priming is given to prepubertal children over 8 years (girls) or 9 years (boys) with oestrogen or testosterone to improve specificity. Intravenous access, with arginine hydrochloride 10% prepared.

Procedure.

• Baseline blood for GH (and glucose) at time 0 (and for copeptin at time 0 in diabetes insipidus testing).
• Arginine hydrochloride 0.5 g/kg (maximum 30 g) in 100 to 200 mL saline, infused intravenously over 30 minutes.
• Take samples for GH at 30, 60, 90 and 120 minutes. For copeptin, a sample at 60 minutes is taken.
• GHRH-arginine test in adults: GHRH 1 microg/kg intravenous bolus together with the arginine infusion, and GH is measured at 15-minute intervals for 1 hour then at 30-minute intervals.
• The infusion site is observed for extravasation, and the patient is monitored for nausea, flushing and headache.

Growth hormone (children).

• Peak GH over 10 microg/L (some centres 7 microg/L for the newer assay): normal.
• Peak GH 5 to 10 microg/L: partial deficiency.
• Peak GH under 5 microg/L with an abnormal second test: GH deficiency, along with auxology, IGF-1 and bone age.

Growth hormone (adults, GHRH-arginine). Cut offs by body mass index: peak GH under 11.5 microg/L (body mass index under 25 kg/m²), under 8 microg/L (25 to 30 kg/m²), and under 4.2 microg/L (over 30 kg/m²) indicate severe GH deficiency. Arginine alone: peak under 0.4 microg/L in adults is severe deficiency (low sensitivity).

Copeptin after arginine. Copeptin at 60 minutes: over 3.8 pmol/L suggests primary polydipsia (excludes central diabetes insipidus), and under 3.8 pmol/L indicates central diabetes insipidus. The test is better tolerated than hypertonic saline but has slightly lower accuracy.

Prolactin. Arginine raises prolactin, and a blunted rise suggests pituitary lactotroph reserve damage (research use).

Critical values and findings needing immediate action.

• Extravasation of arginine causing tissue necrosis: stop infusion, elevate, and surgical review if severe.
• Hyperkalaemia (potassium over 6 mmol/L) in renal impairment: treatment is graded by severity.
• Anaphylaxis or severe flushing and hypotension: stop the infusion and give emergency treatment.
• Children with peak GH under 5 microg/L and growth failure: specialist assessment and consideration of GH therapy after a second test, MRI and exclusion of other causes.
• Central diabetes insipidus identified: pituitary MRI and desmopressin.

Interferences and pitfalls.

• A single stimulation test gives false positive GH deficiency in healthy children, particularly in prepubertal children, which is why sex steroid priming and two tests are used.
• Obesity, hypothyroidism, depression, hypogonadism and glucocorticoid excess blunt GH responses.
• GH assays differ in specificity, and cut offs depend on the assay (recombinant 22 kDa standardised assays give lower values than older polyclonal assays).
• The arginine test alone has lower sensitivity in adults, which is why the GHRH-arginine combination is used. GHRH is not available in all countries.
• GHRH-arginine can be falsely normal in recent hypothalamic damage (cranial radiation within 5 years) because the pituitary is still responsive to GHRH.
• Arginine infusions are bulky, and nausea is common.
• IGF-1 is a useful screening test in adults but may be normal in up to 40% of GH-deficient patients.
• Results are interpreted with auxology (growth velocity), bone age and IGF-1 in children.

Special groups.

• Children: pubertal status and priming are essential for interpretation, and cut offs are low in puberty.
• Obese adults: lower GH peaks, with BMI-adjusted cut offs.
• Older adults: peak GH falls with age.
• Pregnancy: avoided.
• Regions: availability of GHRH and GH assays is limited, and clonidine or glucagon tests are alternatives.

Follow up tests. IGF-1 and IGFBP-3, a second provocative test (clonidine, glucagon, insulin tolerance), thyroid function, bone age X-ray, pituitary MRI, other pituitary hormones, karyotype in girls with short stature (Turner syndrome), coeliac serology, and copeptin or hypertonic saline test where diabetes insipidus is suspected.