Growth Hormone Stimulators and Inhibitors

Physiology of Growth Hormone (GH)

Human GH is a 191-amino acid, single-chain, nonglycosylated polypeptide with a molecular weight of 22-kDa,.
The structure comprises a core of four helices arranged in a parallel/antiparallel orientation, stabilized by two disulfide bonds.
The human GH gene (GH1) is located on the long arm of chromosome 17 (17q22-24) within a cluster of five closely related genes,.
Expression of GH1 is regulated by a highly polymorphic proximal promoter and a locus control region that ensures pituitary-specific, high-level expression.
While the 22-kDa form accounts for 75% of pituitary GH, alternative splicing yields a 20-kDa variant accounting for less than 10%, along with other minor variants.

GH binds to specific receptor molecules on the surface of target cells.
The GH receptor is a 620-amino acid, single-chain molecule belonging to the class 1 hematopoietic cytokine family, featuring an extracellular domain, a single membrane-spanning domain, and a cytoplasmic domain,,.
GH binding induces receptor dimerization, which is an absolute requirement for GH action,.
Dimerization leads to the activation of a receptor-associated tyrosine kinase known as Janus kinase 2 (Jak2),.
Jak2 autophosphorylates and cross-phosphorylates distal tyrosine residues on the GH receptor, allowing signaling molecules like Signal Transducer and Activator of Transcription (STAT) 5a and 5b to dock and become phosphorylated.
Phosphorylated STAT5 molecules dimerize, translocate to the nucleus, bind to target DNA, and regulate the transcription of genes, crucially including the gene for insulin-like growth factor 1 (IGF-1),.

GH is secreted in a highly pulsatile and episodic fashion throughout the day and night,.
In normal young men, there are typically an average of 12 GH secretory bursts per 24-hour period.
Between bursts of secretion, normal serum GH concentrations remain extremely low, typically less than 0.2 ng/mL.
The pulsatile rhythm is generated by the alternating secretion of two primary hypothalamic regulatory peptides: Growth hormone-releasing hormone (GHRH) and somatostatin,.
Peaks of GH occur when maximal GHRH release coincides with troughs of somatostatin secretion.

Growth Hormone-Releasing Hormone (GHRH): GHRH is a hypothalamic peptide that serves as the primary stimulator of GH synthesis and release,,.
GHRH binds to a specific G-protein-coupled receptor (GHRHR) on somatotropes, stimulating adenylate cyclase and increasing intracellular cyclic adenosine monophosphate (cAMP) concentrations.
Ghrelin: Ghrelin is a 28-amino acid peptide produced predominantly in the stomach, but also in the arcuate nucleus of the hypothalamus,.
Ghrelin acts as an endogenous ligand for the GH secretagogue receptor (GHS-R), stimulating GH secretion at both the hypothalamic and pituitary levels,.
Ghrelin and synthetic GH-releasing peptides (GHRPs) stimulate GH release synergistically with GHRH.

Sleep: Sleep is a potent physiologic stimulator of GH release.
Maximal GH secretion occurs during the night, specifically coinciding with the onset of the first slow-wave sleep (stages III and IV).
Exercise and Physical Stress: Physical exercise, trauma, and acute illness significantly stimulate the release of GH,.
Fasting and Starvation: Acute fasting and nutritional deprivation increase both the number and amplitude of GH secretory bursts, primarily reflecting decreased somatostatin secretion,,.
Hypoglycemia: A decrease in blood glucose levels stimulates the release of GH, which acts as a counterregulatory hormone to increase blood glucose,.

Excitatory Neurotransmitters: The release of hypothalamic GHRH and the subsequent stimulation of GH are enhanced by multiple neurotransmitters including serotonin, histamine, norepinephrine, dopamine, acetylcholine, and gamma-aminobutyric acid (GABA),.
Specific Adrenergic/Dopaminergic Inputs: Alpha-2-adrenergic and dopaminergic inputs stimulate the release of GHRH, thereby stimulating GH.
Neuropeptides: Peptides such as galanin, thyrotropin-releasing hormone (TRH), vasoactive intestinal peptide, gastrin, neurotensin, substance P, calcitonin, neuropeptide Y, vasopressin, and corticotropin-releasing hormone participate in augmenting the GH axis response under various physiological states,.

Sex Steroids: Puberty, characterized by the rising levels of gonadal steroids, stimulates the release of GH,.
Both androgens (like testosterone) and estrogens increase GH pulse amplitude, which is responsible for the characteristic rise in GH and IGF-1 secretion observed during the adolescent growth spurt.
Thyroid Hormone: Normal thyroid hormone levels are a prerequisite for normal GH synthesis and spontaneous episodic secretion.

Somatostatin (Growth Hormone-Inhibiting Hormone, GHIH): Somatostatin is a 14-amino acid hypothalamic peptide that serves as the principal inhibitor of GH release,.
The binding of somatostatin to its specific receptor on somatotropes results in the inhibition of adenylate cyclase activity and a reduction in intracellular calcium concentrations.
Somatostatin primarily regulates the timing and amplitude of pulsatile GH secretion, rather than inhibiting GH synthesis directly.

Insulin-Like Growth Factor 1 (IGF-1) Long-Loop Feedback: IGF-1 exerts negative feedback control on GH secretion at the pituitary level,.
IGF-1 inhibits GH secretion directly in multiple systems and has been shown to inhibit spontaneous GH secretion in humans when administered subcutaneously.
Growth Hormone Short-Loop Feedback: GH regulates its own secretion by acting directly on hypothalamic GH receptors via a short-loop negative feedback mechanism,.
This short-loop feedback involves the activation of somatostatin neurons in the hypothalamic periventricular nucleus, which directly synapse on arcuate GHRH neurons.
Free Fatty Acids (FFAs): Elevated levels of free fatty acids exert negative feedback control on GH secretion at the pituitary level.

Hyperglycemia: Elevated blood glucose levels strongly inhibit the release of GH.
Obesity: Obesity is characterized by decreased GH secretion, which is reflected by a decreased number of GH secretory bursts, a lower pulse frequency, and reduced amplitude,.
Rapid-Eye-Movement (REM) Sleep: In contrast to slow-wave sleep, periods of REM sleep are associated with low GH secretion.
Aging: GH secretion begins to decline by late adolescence and continues to fall throughout adult life, a phenomenon sometimes referred to as the somatopause.

Glucocorticoids (Excess): Elevated levels of glucocorticoids inhibit GH release and can blunt spontaneous and provocative GH secretion,.
Hypothyroidism: A state of thyroid hormone deficiency inhibits normal GH release and blunts spontaneous GH secretion,.
Specific Receptor Ligands: The secretion of somatostatin (which inhibits GH) is increased by beta-2-adrenergic stimuli and corticotropin-releasing hormone (CRH).
Conversely, the secretion of somatostatin is inhibited by muscarinic acetylcholine and 5-HT-1D receptor ligands.