Growth Hormone and IGF-1

Growth hormone (GH) is a 191 amino acid hormone secreted in pulses from the anterior pituitary under hypothalamic control (stimulated by GHRH and ghrelin, inhibited by somatostatin). It acts on the liver and other tissues to produce insulin like growth factor 1 (IGF-1), which mediates most of its growth promoting effects.

GH is pulsatile, mostly nocturnal, and its level is very low between pulses in healthy adults, so a random value cannot show deficiency. IGF-1 is stable across the day and reflects integrated GH secretion. Both are measured by immunoassay.

IGF-1 is the screening test for acromegaly and, with dynamic tests, for GH deficiency. GH is measured during suppression and stimulation tests.

Acromegaly has an incidence of 3 to 4 per million each year and a prevalence of 40 to 125 per million, with a mean delay to diagnosis of 5 to 10 years. GH deficiency in adults affects about 2 to 3 per 10 000, most often after pituitary tumours or their treatment. Childhood GH deficiency affects about 1 in 4000 to 10 000 children.

Indications.

• Excess: enlarging hands and feet, coarse facial features, jaw prominence, sweating, headache, carpal tunnel syndrome, sleep apnoea, hypertension, diabetes, arthropathy, and gigantism in children.
• Deficiency: short stature or growth failure, slow growth velocity, neonatal hypoglycaemia with micropenis or midline defects, hypopituitarism, low energy, increased fat mass, and reduced bone density in adults with pituitary disease.

Specimen. Serum. For IGF-1, a random sample is used, and a fasting sample is not required. For GH dynamic tests, an indwelling cannula is placed, the patient fasts overnight, and samples are taken at fixed times. Samples are stable for days at 2 to 8 °C.

Reference ranges are assay specific, age specific and sex specific. IGF-1 is reported in microg/L (nmol/L, x0.131) or as a Z-score for age and sex.

IGF-1. Rises in childhood, peaks in puberty, then falls through adult life. Raised: acromegaly (over the age specific upper limit), puberty, pregnancy (late), and rarely hepatic or paraneoplastic production. Lowered: GH deficiency, malnutrition and anorexia nervosa, poorly controlled diabetes, hepatic failure, hypothyroidism, chronic illness, oral oestrogen (reduces hepatic production), kidney failure, and GH resistance (Laron syndrome).

A normal IGF-1 for age excludes active acromegaly. A low IGF-1 in a patient with high pre-test probability and multiple other pituitary deficits supports GH deficiency, though in isolated deficiency normal IGF-1 does not exclude it.

Random GH. Not diagnostic. Undetectable levels are normal between pulses. A random level under 1 microg/L (under 3 mIU/L) makes acromegaly very unlikely.

GH suppression test (oral glucose tolerance test). Diagnostic test for acromegaly. After a 75 g glucose load, GH is measured at 0, 30, 60, 90 and 120 minutes. A nadir under 1 microg/L (under 0.4 microg/L with sensitive assays) excludes acromegaly. Failure to suppress, with a raised IGF-1, confirms it. Paradoxical rise may occur. The test is less reliable in diabetes, liver or kidney disease, and puberty.

GH stimulation tests.

• Insulin tolerance test (reference test, hypoglycaemia to under 2.2 mmol/L, peak GH under 3 microg/L diagnoses severe adult deficiency, contraindicated in epilepsy, ischaemic heart disease and adrenal insufficiency)
• glucagon test (peak under 3 microg/L in normal body mass, with lower cut offs in obesity)
• arginine and GHRH-arginine tests
• macimorelin test (oral)

Childhood tests use clonidine, arginine, glucagon or insulin, with peak GH under 7 to 10 microg/L defining deficiency, usually after sex steroid priming in prepubertal children.

Other related tests. IGFBP-3 supports a diagnosis of GH deficiency in children, and prolactin, cortisol, thyroid and gonadal axes are tested in all.

Acromegaly. Raised IGF-1 and failure of GH to suppress under 1 microg/L on glucose. Pituitary macroadenoma in more than 75%, with prolactin co-secretion in 25%. Ectopic GHRH is rare. Complications include hypertension, diabetes, cardiomyopathy, sleep apnoea, colonic polyps and increased mortality. Treatment response is assessed by IGF-1 (age normal) and random GH under 1 microg/L.

Adult GH deficiency. A cause (pituitary surgery, radiotherapy, tumour, trauma, infiltration), at least one other pituitary deficiency, and a low peak GH on a provocation test. In adults with three or more pituitary deficits and a low IGF-1, a stimulation test is not required.

Childhood GH deficiency. Short stature, low growth velocity, delayed bone age, low IGF-1 and IGFBP-3, and a failed provocation test (two tests) in a child with no other cause for short stature. MRI excludes a structural lesion.

GH insensitivity. High or normal GH with low IGF-1 and low IGFBP-3 (Laron syndrome, GH receptor defects).

Gigantism. Excess GH before epiphyseal fusion in a tall child, requiring a pituitary tumour workup.

Critical values and findings needing immediate action.

• Acromegaly with visual field loss, severe headache, acute diplopia or pituitary apoplexy.
• Hypopituitarism with hypotension or hyponatraemia, needing cortisol replacement before further testing.
• Hypoglycaemia in a neonate with suspected combined pituitary deficiency (jaundice, micropenis).
• Insulin tolerance test with severe hypoglycaemia, seizures or ECG change.

Interferences and pitfalls.

• Assays differ widely, with different standards, and age specific normal ranges apply to each assay.
• IGF-1 is falsely low in malnutrition, liver and kidney disease, and with oral oestrogen. IGF-1 is falsely normal in obese GH-deficient patients.
• IGF-1 rises in pregnancy and puberty and is interpreted against age and Tanner stage.
• Random GH is not diagnostic of deficiency or excess.
• Obesity lowers GH response to stimulation, and cut offs must be adjusted.
• GH-binding protein, heterophile antibodies, and the injected recombinant GH can interfere.
• Untreated hypothyroidism, hypoadrenalism and hypogonadism are corrected before testing.
• Sex steroid priming is used in children before puberty.

Special groups.

• Neonates: GH is high at birth and falls over weeks, and deficiency presents with hypoglycaemia.
• Children: auxological data (height SDS, growth velocity, bone age) come before biochemical tests.
• Pregnancy: placental GH variant raises IGF-1, and acromegaly is monitored with symptoms and imaging.
• Older adults: IGF-1 falls with age and age adjusted limits are needed.
• Regions: malnutrition related low IGF-1 is common in children and must be excluded.

Follow up tests.

• Repeat IGF-1, oral glucose tolerance test with GH, IGFBP-3, prolactin, cortisol and ACTH stimulation
• thyroid function tests, gonadotropins and sex steroids
• MRI of the pituitary, visual fields, bone age radiograph in children
• colonoscopy, echocardiography, sleep study, glucose and HbA1c
• karyotype in girls with short stature, and growth hormone receptor gene testing