Production, secretion and regulation of the hormone inplicated in Dwarfism, Gigantism and Acromegalia

Growth hormone (GH) stimulates the postnatal longitudinal bone growth and its deficiency results in Dwarfism.
If excessive, GH causes Gigantism in children, when it occurs prior to the fusion of the epiphyseal growth plates, and Acromegaly in adults.
GH regulates cell growth and differentiation primarily by modulating gene expression and metabolism in target tissues that express the GH-receptor (GHR) like the bones.

Synthesis and Secretion
GH is synthesized in the somatotrophic cells of the Anterior Pituitary gland in the brain, as a precursor protein. GH is also produced in other tissue including placenta and lymphocytes.
In mammals, the endogenous secretion is regulated by the opposing actions of two hypothalamic hormones, the GH-releasing hormone (GHRH) and the Somatostatin, that regulate the synthesis and secretion of GH by the anterior lobe of the Pituitary gland. GH-releasing hormone (GHRH) stimulates and Somatostatin inhibits GH synthesis and secretion. These hormones are secreted by hypothalamic neurons into the hypophyseal portal blood, a direct vascolar communication between the Hypotalamus (that is a region of the brain no so far from the Pituitary gland) and the Pituitary gland, where bind the neuroendocrine somatotroph cells that concentrate GH in membrane-enclosed secretory granules.
Spontaneous and stimulates release of GH is sensitive to an organism's age, gender, nutritional status and physiological parameters including stress, exercise and sleep. For example, GH secretion is augmented by fasting and diminished in obesity and it declines with age.
GH release can be regulate by peripheral signals independent of GHRH from the Hypothalamus. GH secretagogues (GHSs) are synthetic compounds that stimulates the dose dipendent release of GH in vitro and in vivo.
Chronic exposure to elevated levels of GH inhibits the expression of the GHS-receptor, suggesting that it complements the down regulation in GHRH in the hypothalamus to decrease GH secretion. In contrast, intravenous infusion of GHRH stimulates a 10-fold increase in circulating GH levels and 2-fold induction of GHS-receptor in the pituitary.

GH-binding protein
Most plasma GH is associated with a GH-binding protein (GHBP). The circulating GH/GHBP complex is abundant in human serum but its exact role remains obscure. GHBPs "protect" or sequester GH and limit its association with the GH-receptor, thereby increasing the life of GH. This interaction may help differentially modulate the bioavailability of GH in response to specific stimuli.

Insuline-like factor-1
Many of the postnatal effects of GH are mediated by insuline-like factor-1 (IGF-1). GH mediates growth by binding to GH-receptors, which stimulate the production of IGF-1. IGFs are peptides that are structurally related to insulin, are sinthetized mainly by the liver but also in other tissues, and act in an endocrine and paracrine manner to stimulte cellular growth. Serum levels of IGF-1 correlate with the concentration of GH at peak amplitude. IGF-1 stimulates Somatostatin release and inhibits GHRH release from the Hypothalamus, ultimately decreasing GH synthesis and secretion from the pituitary. This negative feed back loop is a fundamental feature of the GH/IGF-1 axis. IGF-1 circulates in the plasma associated with IGF-binding proteins.

The Laron Syndrome
Circulating GH binds to the GH receptor (GHR) on target tissues. Mutation to the gene encoding the GHR result in insensitivity to the GH and is known as Laron syndrome.
Laron syndrome is clinically indistinguishable from a GH-deficiency except that serum levels of GH are high and IGF-1 is virtually absent. Digital image analysis shows decreased vascular branching points in the ocular fundus of patients with Laron syndrome supporting role for the GH/IGF-1 axis retinal vascularization.

Acromegaly is a chronic, debilitating disorder usually caused by GH hypersecretion in adults, from a pituitary somatotroph adenoma. In addiction to enlarged bones and organs, the disease is associated with increased morbidity including hypertension, insulin resistance and elevated triglycerides. With Acromegaly, the increased basal GH secretion and pulse frequently is accompanied by a disorganized pattern of secretion over 24 hours and results in abnormally high levels of IGF-1.


Peter A. Lee et al: Persistent Short stature, other potential outcomes, and the effect of Growth Hormone treatment in children who are born small for gestational age.
D.T. Kohn et al: Growth hormone receptor antagonist


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