GH–IGF-1 Axis & Disorders of Growth

Regulation of GH secretion

Pulsatility. Somatotrophs, the most abundant anterior pituitary cells, release GH in bursts; the largest pulse comes in slow-wave sleep soon after sleep onset. Between pulses GH is nearly undetectable, and its half-life is about 20 minutes, so a random GH level can mimic excess at a peak or deficiency at a trough. IGF-1, carried by IGFBP-3, is steady and reflects integrated GH output, which makes it the screening test.

Stimulators. GHRH, ghrelin, hypoglycemia, exercise and stress, deep sleep, arginine, fasting and puberty, when sex steroids amplify pulse size.

Inhibitors. Somatostatin; IGF-1 feedback, which lowers GHRH and GH and raises somatostatin; hyperglycemia, the basis of the glucose suppression test; obesity; glucocorticoid excess and hypothyroidism, both causes of growth failure in children.

GH and IGF-1 actions

The IGF-1 route. GH binds a cytokine-type receptor; JAK2 phosphorylates STAT5, which drives hepatic transcription of IGF-1, IGFBP-3 and acid-labile subunit. IGF-1 acts on its receptor tyrosine kinase to make growth-plate chondrocytes proliferate (linear growth) and to promote protein synthesis and muscle and organ growth.

Direct GH effects. Independent of IGF-1, GH stimulates lipolysis and antagonizes insulin, lowering muscle glucose uptake and raising hepatic gluconeogenesis. It is therefore a counter-regulatory, diabetogenic hormone, while IGF-1 itself is insulin-like and can cause hypoglycemia when given as a drug.

Testing logic

Suspected deficiency. Low IGF-1 and IGFBP-3 are supportive but nonspecific, since both fall in malnutrition, hypothyroidism and liver disease. Diagnosis requires an inadequate GH peak on provocative testing with insulin-induced hypoglycemia, arginine, glucagon, clonidine or, in adults, oral macimorelin (a ghrelin agonist); children usually need two failed tests.

Peripubertal children with constitutional delay can fail stimulation tests because sex steroids are still low; brief sex-steroid priming before testing prevents this false positive.

GH excess

Gigantism vs acromegaly. Excess before epiphyseal closure produces gigantism with rapid linear growth; after closure it produces acromegaly. Features include enlarging hands and feet (ring and shoe size), coarse features, frontal bossing, prognathism with gapped teeth, macroglossia, sweating, carpal tunnel syndrome, sleep apnea, arthropathy, hypertension and diabetes. Concentric cardiomyopathy is the leading cause of death, and colon polyps warrant colonoscopy. Up to about 40% of somatotroph adenomas carry activating GNAS mutations.

A pharmacologic contrast. Pegvisomant, a GH-receptor antagonist, normalizes IGF-1 while GH stays high, copying Laron physiology.

GH deficiency, resistance and short stature

Newborns. Birth length is normal because fetal growth is largely GH-independent. Clues are neonatal hypoglycemia (worse with ACTH deficiency), micropenis when gonadotropins are also lacking, and prolonged jaundice. Midline defects (septo-optic dysplasia, cleft palate, single central incisor) and PIT1 or PROP1 mutations suggest combined pituitary deficiency.

Children. Proportionate short stature with height velocity falling across percentiles, rising weight-for-height, immature cherubic facies and delayed bone age. Recombinant GH (somatropin) can cause slipped capital femoral epiphysis, idiopathic intracranial hypertension and scoliosis progression.

Short and chubby suggests an endocrine cause (GH deficiency, hypothyroidism, Cushing syndrome); short and thin, with weight falling first, suggests undernutrition or chronic disease such as celiac disease or IBD.

Laron syndrome. An autosomal recessive GH-receptor defect blocks JAK2/STAT5 signaling, giving very high GH with low IGF-1, IGFBP-3 and usually GH-binding protein. Children have severe proportionate short stature, frontal bossing, midface hypoplasia and hypoglycemia. GH fails; recombinant IGF-1 (mecasermin) works but can cause hypoglycemia. Malnutrition and liver disease produce an acquired version of the same pattern.

Psychosocial deprivation. Severe neglect or abuse suppresses GH functionally: poor growth, delayed bone age and low stimulated GH, often with hyperphagia, food hoarding or foraging and disturbed sleep. A nurturing environment restores GH and brings rapid catch-up growth.

Normal variants. Familial short stature features short parents, normal velocity along a low percentile, bone age equal to chronological age, on-time puberty and short adult height on genetic target. Constitutional delay features a late-bloomer parent, early slowing then parallel growth, delayed bone age and late puberty, with normal adult height. Midparental target height is the parents' mean height plus 6.5 cm for boys or minus 6.5 cm for girls.