Growth hormone (GH) synthesis and release are primarily regulated by two hypothalamic peptides: somatostatin, which inhibits GH secretion, and growth hormone-releasing hormone (GHRH), which stimulates its release (Fig. 1). A third endogenous hypothalamic GH stimulating factor has been hypothesized and called growth hormone secretagogue (GHS, also known as growth hormone releasing peptide). GHSs have been synthesized, and are small molecules that promote somatotroph growth hormone release independently of, but synergistically with, GHRH (6,7).
GHRH is produced by hypothalamic neurons located primarily in the arcuate nucleus (8,9). These neurons release GHRH into the hypophyseal-portal circulation, where it passes to the anterior pituitary gland with subsequent binding to somatotrophs. The GHRH gene is present as a single copy (10). Using fluorescent in situ hybridization and microsatellite markers, it has been localized to chromosome 20q12 in humans (11).
Growth failure secondary to perturbations in these hypothalamic factors could involve loss of function mutations in the ligands GHRH or GHS or gain of function mutations in somatostatin. Although no molecular abnormalities of GHRH, GHS, or somatostatin have been described to date, it has been hypothesized that functionally GHRH-deficient states account for the majority of cases of childhood GH deficiency (12). Chatelain et al. demonstrated that GHRH agonist treatment can stimulate endogenous GH secretion in 77% of patients with GH insufficiency (13).
Two animal models of GHRH deficiency have been described. In one, administration of monosodium glutamate (MSG) to mice causes a selective loss of arcuate nuclei neurons (14,15). MSG-exposed rodents have impaired growth, obesity, hypogonadism, and hypothyroidism (16). The other animal model of GHRH deficiency is the Gsh-1 homeobox gene knockout mouse (17). Homeobox genes encode a family of DNA binding proteins, and the Gsh-1 gene encodes a product necessary for GHRH gene transcription and translation. Gsh-1 knockout mice have extreme postnatal dwarfism, sexual infantilism, leukopenia, significant perinatal mortality, a shortened life span, and biochemical evidence of GHRH deficiency. Their anterior pituitary glands are one-third normal size and possess decreased numbers of somatotrophs and lactotrophs.
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