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.

Isoforms

• 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.