Unit 6 - Growth Hormone Flashcards
GH structure, and halflife
single chain polypeptide with 20 minute halflife
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
role of GHRH on GH
- increases GH gene transcription
- promotes GH release
- stimulates production of GHRH receptor
- stimulates somatostatin release
role of somatostatin on GH
- decreases pulse frequency
- decreases pulse amplitude
- no impact on GH synthesis
- inhibits GHRH release
what is ghrelin more important for, other than GH secretion control?
feeding behavior, energy regulation, and (possibly) sleep
-target for anti-obesity drugs
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
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
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)
what is GH secretion inhibited by?
IGF-1 obesity glucocorticoids (cortisol) hyperglycemia FFA GH beta-adrenergic agonists
how does obesity VS fasting affect GH?
obesity decreases number and duration of each pulse
fasting increases number and amplitude of each pulse
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
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)
what causes short stature in Pygmies?
severe underexpression of GH receptor
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
what are the effects of GH on muscle?
increased glucose and AA uptake
increased PRO synthesis
what are GH effects on chondrocytes?
increased AA uptake, PRO synthesis, DNA/RNA synthesis, chondroitin sulfate, collagen, cell size and number
what are GH effects on brain?
affects mood and behavior
effects of GH on liver
stimulates IGF-1 production, and stimulates hepatic glucose production
effects of GH on bone
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?
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?
GH doesn’t induce growth
-also won’t stimulate growth w/o CHO
how does IGF-1 act?
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?
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?
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
