Growth Hormone Receptor (GHR)

The growth hormone receptor is a single-pass class I cytokine receptor with no kinase activity of its own. It sits at the membrane as a preformed dimer rather than being dimerised by ligand, and one growth hormone molecule engages both subunits asymmetrically, binding the first through high-affinity site 1 and the second through lower-affinity site 2, and the resulting rotation of the transmembrane domains brings the associated JAK2 kinases into productive alignment. JAK2 then phosphorylates STAT5b, which drives transcription of IGF-1, IGFBP-3 and the acid-labile subunit.

Two human situations anchor the model. Laron syndrome, from inactivating receptor mutations, produces severe short stature with high growth hormone and very low IGF-1, and is treated with recombinant IGF-1, since growth hormone cannot work. Long-term follow-up of the Ecuadorian Laron cohort found a near-absence of diabetes and remarkably little cancer, the strongest human evidence that growth hormone signalling is not uniformly beneficial. Pegvisomant is a growth hormone analogue with an intact site 1 and a disabled site 2, so it occupies the receptor without permitting rotation; approved in 2003, it normalises IGF-1 in most patients with acromegaly.

The two-site mechanism has a counterintuitive consequence in vitro: at very high concentrations growth hormone occupies site 1 on separate subunits without pairing them, producing self-antagonism and a bell-shaped rather than saturating dose-response curve.

The clinically important misconception is that receptor resistance is a rare genetic curiosity. Acquired resistance is common: malnutrition, poorly controlled diabetes, hepatic disease and systemic inflammation all reduce receptor expression or post-receptor signalling, producing a low IGF-1 alongside high growth hormone. A low IGF-1 therefore does not identify where in the axis the problem lies.