- increases GH gene transcription - promotes GH release - stimulates production of GHRH receptor - stimulates somatostatin release

Unit 6 - Growth Hormone Flashcards by Annette Liem

GH structure, and halflife

single chain polypeptide with 20 minute halflife

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how is GH regulated?

hypothalamus: GHRH (activate) and somatostatin (inhibits)
stomach/pancreas: ghrelin (unknown how activates, but acts as segretagogue receptor)

all go to GPCRs, but integration leads to episodic, pulsatile secretion

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role of GHRH on GH

increases GH gene transcription
promotes GH release
stimulates production of GHRH receptor
stimulates somatostatin release

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role of somatostatin on GH

decreases pulse frequency
decreases pulse amplitude
no impact on GH synthesis
inhibits GHRH release

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what is ghrelin more important for, other than GH secretion control?

feeding behavior, energy regulation, and (possibly) sleep

-target for anti-obesity drugs

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pulsatile nature of GH over lifespan

pulses primarily at night

number stays nearly constant, but larger amplitude during puberty
strenous exercise causes surge in GH

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how does Ritalin (and other sleep-disrupting drugs) affect growth?

1 inch shorter and 4 pounds lighter than peers

-can catch up if good nutrition maintained

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what is GH secretion stimulated by?

deep sleep
exercise
sex steroids (growth sputs at puberty)
fasting/hypoglycemia (used as clinical test to provoke GH secretion if suspect deficiency)
AA (decrease somatostatiin release)
stress
alpha-adrenergic agonists
dopamine aconists (suppressed in acromegaly)

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what is GH secretion inhibited by?

IGF-1
obesity
glucocorticoids (cortisol)
hyperglycemia
FFA
GH
beta-adrenergic agonists

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how does obesity VS fasting affect GH?

obesity decreases number and duration of each pulse

fasting increases number and amplitude of each pulse

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how is GH related to somatostatin and IGF-1?

hypothalamus releases somatostatin and GHRH

somatostatin inhibits, while GHRH stimulates GH secretion (both via GPCR; stimulate with AC, cAMP, PKA, and Ca++)
GH inhibits GHRH release, and stimulates somatostatin release, then acts on liver to release IGF-1
IFG-1 stimulates target tissue effects, stimulates somatostatin release, and inhibits GHRH release and anterior pituitary activity

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how does GH activate its receptor?

transmembrane receptor in cytokine receptor family to activate JAK/STAT pathway

causes dimerization for signal transduction, and binding to 1+ JAK tyrosine kinases 1
induces phosphorylation of JAK kinases and receptor 2, then STATs dimerize and translocate to nucleus to act as transcription activators
increased expression of CISH (GH target gene)
major sites of action are bone, liver, and adipocyte (but also kidney, muscle, eye, brain, heart, and immune cells)

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what causes short stature in Pygmies?

severe underexpression of GH receptor

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what are the effects of GH on adipose tissue?

decrease glucose uptake and increase lipolysis

stimulated release and oxidation of FFA, especially during fasting
decreased LPL activity
decreased lipogenesis

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what are the effects of GH on muscle?

increased glucose and AA uptake

increased PRO synthesis

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what are GH effects on chondrocytes?

increased AA uptake, PRO synthesis, DNA/RNA synthesis, chondroitin sulfate, collagen, cell size and number

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what are GH effects on brain?

affects mood and behavior

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effects of GH on liver

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stimulates IGF-1 production, and stimulates hepatic glucose production

effects of GH on bone

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affects all phases and zones of GH

supports differentiation of mesenchymal stem cells (prechondrocytes) into chondrocytes
local IGF-1 induces clonal expansion of early chondrocytes and maturation of later chondrocytes
leads to synthesis of ECM proteins like collagen II, hyaluronic acid, and mucopolysaccharides
as cells move closer to already-formed trabecular bone, it becomes calcified and remodeled by osteoclasts and osteoblasts to form mature bone

where is IGF-1 made and what are its levels?

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some is from kidney/skin, but mostly is liver

circulates all day long at relatively constant level
inhibited by anorexia and other eating disorders

what happens if there’s GH without insulin?

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GH doesn’t induce growth

-also won’t stimulate growth w/o CHO

how does IGF-1 act?

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stimulates growth via endocrine, paracrine, and autocrine fashion
-negative FB to hypothalamus and pituitary to down-regulate GH secretion

how is IGF-1 used clinically?

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primary screening test when considering GH deficiency, since its levels in circulation are more stable and reflective of GH levels in normal individuals

how do insulin, IGF-1, and IGF-II differ?

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insulin, IGF-I and IGF-II share 3 domains (A, B, and C) with high degree of AA sequence homology

C region is cleaved from insulin (C-peptide), but not IGFs
IGFs also have short D domain
IGF-II secretion not significantly regulated by GH
insulin and IGF-I are heterotetramers joined by DS bonds, with cytoplasmic beta units with tyrosine kinase domains and autophosphorylation sites
IGF-II receptor (also M6P receptor) is single polypeptide chain w/o kinase domain, and poorly understood cellular function

how are signaling pathways activated by IGF-1?

dimerization of IGF-1 receptors leads to autophosphorylation - recruits 2 major phosphotyrosine binding PRO (IRS-1 and Shc) which are phosphorylated by IGF-1 receptor - recruits other PRO to membrane, leading to activation of phosphoinositol-3-kinase and Ras/MAP kinase pathways that regulate cellular transcription

when does the pubertal growth spurt happen?

peak rate of growth corresponds to peak serum concentrations of IGF-1 - both sex hormones contribute to rapid increase - in girls, begins at early puberty - in boys, occurs after puberty has begun

what are some causes of GH deficiency?

organic: congenital absence of pituitary stalk, TBI, or cranial radiation therapy idiopathic: functional of developmental state, which resolves in mid-puberty

can mutations in GH-1 gene be treated with rhGH?

no, because the individual will eventually make Abs VS what is perceived as a foreign PRO

what happens if you give extra GH in excess of normal during treatment of GH deficiency?

nothing; it doesn't increase the rate of growth above what is normal

Laron syndrome

autosomal recessive point mutation or deletion in GH receptor (heterozygotes have mild growth retardation) - markedly low IGF-1 - normal or elevated GH concentration (unable to respond to it) - severe post-natal growth failure - treatable with rhIGF-1 before puberty, but not rhGH - similar if have mutation of Stat5b gene

what does the insulin/IGF-1 pathway promote?

aging

what is gigantism?

exposed to too much GH throughout life (before puberty and bones fuse) -have hyperglycemia, and 10% of giants get full-blown diabetes due to degeneration of beta cells in islets of Langerhans

what is acromegaly?

GH-secreting adenomas after bones fuse (so don't cause bone growth, but width) - effects vary depending on size, growth rates, and invasiveness - large tumors cause destruction of pituitary and deficiency of other pituitary hormones - may affect optic chiasm and vision - protrusion of jaw, macroglossia (enlarged tongue), enlarged hands/feet, carpal tunnel, reduced strength, etc.

what does GH deficiency in adults cause? what are tests? treatment?

usually caused by pituitary problems, surgery, or radiation - increases visceral adipose tissue, carotid intima media thickness, inflammatory markers of CVD, clotting factors, insulin resistance, and LDL; also anxiety and depression - decreases myocardial function, HDL, and "get up and go"; also reduced strength and bone loss - test by insulin treatment, then GH test 20-30 minutes later, or glucagon and GHRH challengers - treated with rhGH

how do GH levels change over the years?

5-20 years: 6 ng/mL 20-40 years: 3 ng/mL 40-70 years: 1.6 ng/mL

what does GH replacement therapy do? side effects?

- restores muscle mass - reduces fat deposits - increased energy - side effects: insulin resistance, diabetes, edema, and carpal tunnel syndrome

where is therapeutic GH usage approved?

- GH deficiency - idiopathic short stature (ISS) - Turner syndrome - Prader-Willi syndrome (PWS) - chronic renal insufficiency (DRI) - small for gestational age (SGA)

what kinds of chronic diseases could a deviation from the growth chart percentile mean?

- IBS (like Celiac's disease) - Lupus and other collagen-vascular diseases - renal failure - thalassemia

what are the "general calculations" for midparental height?

girls: [(Father + Mother) - 13]/2 boys: [(Father + Mother) + 13]/2

what happens if celiac disease boy is given replacement doses of thyroid hormone?

thyroxin restored growth to normal - thyroid hormone response element is upstream of GH transcriptional start site - so hypothyroidism reduces GH with very dramatic consequences

what syndromes have short stature with normal hormone status?

``` Turner syndrome (missing 1 X) Down syndrome (trisomy 21) many others, but Turner and Down are the most common ```

how is short stature in Turner Syndrome?

haploinsufficiency of SHOX gene - SHOX PRO is developmentally regulated - concentrated in hypertrophic region of growth plate zone during childhood - locus is in pseudoautosomal (in both X and Y) region of Xp - have slower velocity during childhood, plus scant pubertal growth spurt - treated with GH, and given sex steroids, but height not completely restored

what happens in Klinefelter's syndrome?

XXY (have extra copies of SHOX) - taller than average b/c of extra SHOX and gonadotropin deficiency - don't go into puberty, and don't fuse bones, so grow for longer than normal

Unit 6 - Growth Hormone Flashcards

(43 cards)