growth hormone howell Flashcards
GH is somatotropin
single chain polypeptde. made in anterior pituitary.
- short half life of 20 minutes in circulation
- too much in childhood before bones fuse causes gigantism. deficiency in childhood causes dwarfism. too much GH/somatotropin after childhood after the bones have already fused causes acromegaly.
regulation of GH- GH is different from other hormones bc it has targets in most tissues of body. it increase cell size, number and differentiation.
- hypothalamus will release GHRH growth hormone releasing hormone onto the anterior pituitary. prototes release. somatostatin is inhibitory.
- bimodal regulation
- stomach and pancreas have GHRELIN. it’s affected by growth hormone releasing hormone and has a role in starvation.
- all of them act on g protein coupled receptors of somatotrophs in the anterior pituitary.
pulsatile secretions bc of: GHRH stimulating release and somatostatin inhibiting release of GH
SS is deep downward decrease of GH and GHSH is steady so you end up with pulse peaks
GHRH
increases GH transcription, and release.
- stimulates production of GHRH receptor on somatotrophs
- ** stimulates somatostatin release
somatostatin
decreases pulse freq and amplitude
- no impact on GH synthesis
- inhibits release of GHRH
ghrelin
made in stomach and pancreas and stimulates hunger. level increases right before a meal and drops after.
- ghrelin acts on growth hormone secreting receptor.
- important in feeding behavior, sleep, energy, and GH secretion. anti obesity drug possible
GH pulses over lifespan
- most pulses are at night during first few hours of sleep.
- # of pulses in the day in constant.
- amplitude of pulse is amt of GH released, has high amplitude in puberty
- exercise causes surge in GH
- a drug that disrupts sleep in kids like ritalin will effect their height. if normal nutrition is maintained, they’ll catch up.
GH secretion is stimulated by
deep sleep, exercise, sex steroids (accounts for growth spurts in puberty), fasting/hypoglycemia, amino acids (arginine and protein). stress, alpha adrenergic agonists, and dopamine agonists (supress in acromegaly)
- fasting increases number of pulses and duration of pulses
- in patients suspected of being GH deficient, you can induce hypoglycemia with insulin to provoke GH secretio since fasting causes GH release.
- AA increase GH release bc they inhbit somatosatin release
GH secretion is inhibited by
IGF1, obesity, glucocorticoids, hyperglycemia, free fatty acids, GH, bea adrenergic agonists
- obesity decreases number of GH pulses, and also decreases duration of each pulse
- somatostatin feedback on GHRH not GH
GH effects and regulation
GH act on liver to release IGF-1. Insulin like growth factor 1. IGF1 mediates effects of GH. essential for most GH activity.
-GHRH and SS act on separate receptors on somatotroph. GHRH g protein subunit increases cAMP, increases pkA, and increases Ca causing GH release.
GH receptor activation in tissues
GH binds. JAK stat dimerization tyrosine kinase activity, phospylate JAK then STAT . STAT translocates to numcleus and acts as transcription activators.
GH effects on body
GH has the opposite effects of inulin. ppl with too much GH will have insensitivity to insulin.
- liver: response to GH is release ig IGF1. stimulates hepatic glucose production.
- adipose tissue: release and oxidation of FFA, esp in fasting. reduce lipoprotein lipase activity and decrease lipogenesis
- skeletal muscle: anabolic effects. amino acid uptake and incorporation in proteins- supress protein degradation.
bone: during or before puberty: GH acts on prechondrocytes to increase IGF1 mRNA. IGF1 acts on early condrocytes in auto and paracrine manner in causing clonal expansion. osteoclasits and blasts then make this mature bone
GH, food and IGF1
if no GH, then no IGF1.
- but, if you dont have food, then regarless of how much GH you have you wont have IGF1 release. problem for growing malnourished kids.
- IGF1 circulates at constant level all day.
- iGF1 is primary screening test when considering GH deficiency since its levels are stable and reflective of GH levels.
- IGF1 is the actual thing causing growth spurts/height increase in puberty.
IGF1 signaling pathways
GHRH and SS were g protein. GH binding was JAK/STAT. IGF1 dimerizes, leads to autophosphorylation bc its tyrosine kinase, stimulates PI3 kinase (acts by IRS) and ras map (acts by ShC) pathways that regulate transription
GH deficiency and replacement
definciency can be caused by:
- defect in the pituitary stalk, affecting the hypothalamo pituitary function,
- mutation in GH1 gene. kids will have slow growth of less than 2 inches a year and severe post natal growth failure. mutation in GH1 gene cant be trated with rhGH bc body will make antibodies.
