Structure
Molecular Composition
- 191-amino acid, single-chain, nonglycosylated polypeptide.
- Molecular weight: 22-kDa.
- Core comprised of four alpha-helices in parallel/antiparallel orientation.
- Structure stabilized by two disulfide bonds located between cysteines 53-165 and 182-189.
- Derived from 217-amino-acid precursor; signal peptide cleaved before secretion.
- 22-kDa form constitutes 75% to 90% of total pituitary growth hormone.
- 20-kDa form, resulting from alternative splicing, accounts for <10%.
- Remaining fraction includes desamidated, N-acetylated, oligomeric, and 17.5-kDa variant forms.
Genetic Basis
- Encoded by GH1 gene.
- Gene located on long arm of chromosome 17 (17q22-24).
- Located within cluster of five highly homologous genes.
Mechanism of Action
Receptor Characteristics
- Binds Growth Hormone Receptor (GHR) on target cell surfaces.
- GHR is 620-amino acid, single-chain transmembrane molecule.
- Member of class 1 hematopoietic cytokine receptor family.
- Comprises extracellular hormone-binding domain, single membrane-spanning domain, and intracellular signaling domain.
Receptor Activation
- Preformed GHR dimers exist on cell surface.
- Single growth hormone molecule binds sequentially to two GHR molecules (initially to stronger site 1, followed by weaker site 2).
- Binding induces receptor dimerization and conformational change.
Intracellular Signaling (JAK-STAT Pathway)
- Receptor dimerization repositions intracellular domains and associated Janus Kinase 2 (JAK2).
- JAK2 undergoes autophosphorylation and activation.
- Activated JAK2 cross-phosphorylates distal tyrosine residues on GHR.
- Phosphorylated sites recruit SH2-domain molecules, specifically Signal Transducer and Activator of Transcription (STAT) 5a and 5b.
- STAT molecules undergo phosphorylation, dimerization, and nuclear translocation.
- STAT dimers/tetramers bind DNA, activating transcription of target genes (e.g., Insulin-Like Growth Factor 1 [IGF-1]).
Biological Effects
- Stimulates hepatic synthesis of IGF-1.
- Promotes linear growth, bone thickness, soft tissue growth, and protein synthesis.
- Stimulates lipolysis and induces cellular insulin resistance.
Pattern of Secretion
Secretory Dynamics
- Synthesized, stored, and secreted by anterior pituitary somatotropes.
- Highly pulsatile secretion pattern.
- Normal young men average 12 secretory bursts per 24 hours.
- Between secretory bursts, baseline serum concentration remains < 0.2 ng/mL.
Circadian Rhythm
- Peak secretion occurs during night.
- Maximal secretion coincides with onset of first slow-wave sleep (stages III/IV).
- Rapid-eye-movement (REM) sleep associated with low secretion.
Regulatory Control
- Stimulated by hypothalamic Growth Hormone-Releasing Hormone (GHRH).
- Inhibited by hypothalamic somatostatin.
- Secretory peaks occur when GHRH peaks coincide with somatostatin troughs.
- Ghrelin (gastric enteroendocrine peptide) directly stimulates secretion via specific secretagogue receptors.
- Physiologic stimulators: sleep, exercise, physical stress, trauma, fasting, and hypoglycemia.
- Physiologic inhibitors: hyperglycemia, hypothyroidism, free fatty acids, glucocorticoids, and obesity.