Acromegaly pathophysiology: Difference between revisions
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==Pathophysiology== | ==Pathophysiology== | ||
Growth hormone is synthesized and stored in somatotroph cells, which account for >50% of pituitary hormone secreting cells. Growth hormone production and secretion is regulated by hypothalamic GH-releasing hormone, ghrelin and somatostatin. IGF-1 inhibits growth hormone secretion by both direct effect on the somatrophs and indirectly through stimulation of somatostatin that inhibits growth hormone secretion. Growth hormone is secreted in sporadic pulses with minimal basal secretion determined by sex, age, neurotransmitters, exercise and stress. | |||
Growth hormone action is achieved via its interaction with a single-chain transmembrane glycoprotein receptor (GHR). The growth hormone molecule interacts with a preformed dimer of identical GHR pairs, causing internalization of the receptor to initiate signaling. As a consequence, two Janus tyrosine kinase 2 molecules undergo autophosphorylation and in turn phosphorylate the GHR cytoplasmic domain. This activates intracellular proteins involved in signal transduction and transcription (STAT). | |||
The gene encoding the GHR is ubiquitously expressed, particularly in liver, fat and muscle. Growth hormone activation of the intracellular molecule STAT5b induces transcription of IGF-1. Systemic IGF-1 is synthesized primarily in the liver but also in extraheptatic tissues including bone, muscle and kidney and in the pituitary gland itself. IGF-1 circulates in serum bound to IGF-1 binding protein (IGFBP-3), or IGFBP-5, and acid-labile subunit in a 150-kD complex. Less than 1% of total serum IGF-1 circulates as a free hormone. The IGF-1 cellular effects are mediated by the IGF-1 receptor (IGF-1R), a heterotetrameric protein structurally similar to the insulin receptor. IGF-1 acts to mediate tissue growth or locally synthesized IGF-1 acts in a paracrine manner to regulate local GH target tissue growth<ref name="pmid26873451">{{cite journal| author=Dineen R, Stewart PM, Sherlock M| title=Acromegaly. | journal=QJM | year= 2016 | volume= | issue= | pages= | pmid=26873451 | doi=10.1093/qjmed/hcw004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26873451 }} </ref>. | |||
==References== | ==References== | ||
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Overview
Pathophysiology
Growth hormone is synthesized and stored in somatotroph cells, which account for >50% of pituitary hormone secreting cells. Growth hormone production and secretion is regulated by hypothalamic GH-releasing hormone, ghrelin and somatostatin. IGF-1 inhibits growth hormone secretion by both direct effect on the somatrophs and indirectly through stimulation of somatostatin that inhibits growth hormone secretion. Growth hormone is secreted in sporadic pulses with minimal basal secretion determined by sex, age, neurotransmitters, exercise and stress.
Growth hormone action is achieved via its interaction with a single-chain transmembrane glycoprotein receptor (GHR). The growth hormone molecule interacts with a preformed dimer of identical GHR pairs, causing internalization of the receptor to initiate signaling. As a consequence, two Janus tyrosine kinase 2 molecules undergo autophosphorylation and in turn phosphorylate the GHR cytoplasmic domain. This activates intracellular proteins involved in signal transduction and transcription (STAT).
The gene encoding the GHR is ubiquitously expressed, particularly in liver, fat and muscle. Growth hormone activation of the intracellular molecule STAT5b induces transcription of IGF-1. Systemic IGF-1 is synthesized primarily in the liver but also in extraheptatic tissues including bone, muscle and kidney and in the pituitary gland itself. IGF-1 circulates in serum bound to IGF-1 binding protein (IGFBP-3), or IGFBP-5, and acid-labile subunit in a 150-kD complex. Less than 1% of total serum IGF-1 circulates as a free hormone. The IGF-1 cellular effects are mediated by the IGF-1 receptor (IGF-1R), a heterotetrameric protein structurally similar to the insulin receptor. IGF-1 acts to mediate tissue growth or locally synthesized IGF-1 acts in a paracrine manner to regulate local GH target tissue growth[1].
References
- ↑ Dineen R, Stewart PM, Sherlock M (2016). "Acromegaly". QJM. doi:10.1093/qjmed/hcw004. PMID 26873451.