Human Growth Hormone Flashcards
hGH, somatotrophin
polypeptide hormone synthesized in the anterior pituitary
significant species specificity
direct stimulatory effects on bone, muscle, and cartilage
indirect effects through production of IGF-1
too little hGH during growth –> dwarfism
too high hGH during growth –> gigantism
too high hGH after growth –> acromegaly
Clinical use of hGH
approved use is limited to conditions of short stature
unapproved uses: induction of lactation, obesity treatment, induction of ovulation, anti-aging, body building
history of hGH
extracted mainly from cadavers thus low supply initially
in 1985 extracted use was halted due to prion diseases
protropin first recombinant form
hGH regulation
modulated by stress, exercise, sleep, nutrition, and GH
primary ctrlers:
hGH-releasing hormone - stim synthesis and secretion
somatostatin - inhibits release in response to GHRH and other stimulatory factors such as low blood sugar
GH stimulates IGF-1
How can we test hGH
rely on antibodies specific for 22kDa vs those that recognize all other and looking for changes in ratio
hGH receptor signaling
receptor is a dimer
binding of GH at site 1 & site 2 causes transmembrane helices to shift enabling JAK2 domains to phosphorylate one another and become active
result is increased transcription of IGF-1 and other genes
major substrate is STAT5b which dimerizes and intitiates transcription of 300+ genes involved in proliferation and growth (mutations in STAT5b that increase affinity for JAK2 are linked with certain cancers)
Effects of IGF1
promotes cell proliferation, cell survival, cell growth, and decreases apoptosis
low levels appear to be linked with longevity
artificially high levels of IGF-1 are linked with highest risk of cancer
hGH use
sterile vials for reconstitution
divided into 6-7 daily SQ injections, refrigerated
AEs: nerve, muscle, joint pain, edema, carpal tunnel syndrome, increased risk of insulin resistance, increased risk of some cancers
bacterial production and secretion of hGH
not glycosylated so suitable to use bacteria for host expression but there are problems with folding and most protein is found in insol inclusion bodies
DNA fragment from the pelB gene encoding a sequence for secretion of the protein is used
hGH is then translated and targeted for secretion into the periplasm
cytoplasmic proteins can then be centrifuged away
long acting hGH analogs
TransCon GH - modification attaches a biodegradable linker between hGH and PEG polymer which decreases renal excretion this increasing circulating time
hGH receptor antagonists
Octreotide: mimics SS and inhibits hGH for treatment of acromegaly
Bromocriptine: dopamine agonist that reduces production of GH. used to treat pituitary tumors
Pegvisomat: pegylated form of mutant GH, changes at site 1 to enhance binding, changes to site 2 to decrease binding. PEG added to decrease CL and immunogenicity
