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Physiology > Unit 6 - Growth Hormone > Flashcards

Unit 6 - Growth Hormone Flashcards

1
Q

GH structure, and halflife

A

single chain polypeptide with 20 minute halflife

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2
Q

how is GH regulated?

A

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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3
Q

role of GHRH on GH

A
  • increases GH gene transcription
  • promotes GH release
  • stimulates production of GHRH receptor
  • stimulates somatostatin release
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4
Q

role of somatostatin on GH

A
  • decreases pulse frequency
  • decreases pulse amplitude
  • no impact on GH synthesis
  • inhibits GHRH release
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5
Q

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

A

feeding behavior, energy regulation, and (possibly) sleep

-target for anti-obesity drugs

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6
Q

pulsatile nature of GH over lifespan

A

pulses primarily at night

  • number stays nearly constant, but larger amplitude during puberty
  • strenous exercise causes surge in GH
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7
Q

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

A

1 inch shorter and 4 pounds lighter than peers

-can catch up if good nutrition maintained

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8
Q

what is GH secretion stimulated by?

A 
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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9
Q

what is GH secretion inhibited by?

A 
IGF-1
obesity
glucocorticoids (cortisol)
hyperglycemia
FFA
GH
beta-adrenergic agonists
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10
Q

how does obesity VS fasting affect GH?

A

obesity decreases number and duration of each pulse

fasting increases number and amplitude of each pulse

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11
Q

how is GH related to somatostatin and IGF-1?

A

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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12
Q

how does GH activate its receptor?

A

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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13
Q

what causes short stature in Pygmies?

A

severe underexpression of GH receptor

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14
Q

what are the effects of GH on adipose tissue?

A

decrease glucose uptake and increase lipolysis

  • stimulated release and oxidation of FFA, especially during fasting
  • decreased LPL activity
  • decreased lipogenesis
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15
Q

what are the effects of GH on muscle?

A

increased glucose and AA uptake

increased PRO synthesis

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16
Q

what are GH effects on chondrocytes?

A

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

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17
Q

what are GH effects on brain?

A

affects mood and behavior

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18
Q

effects of GH on liver

A

stimulates IGF-1 production, and stimulates hepatic glucose production

19
Q

effects of GH on bone

A

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
20
Q

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

A

some is from kidney/skin, but mostly is liver

  • circulates all day long at relatively constant level
  • inhibited by anorexia and other eating disorders
21
Q

what happens if there’s GH without insulin?

A

GH doesn’t induce growth

-also won’t stimulate growth w/o CHO

22
Q

how does IGF-1 act?

A

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

23
Q

how is IGF-1 used clinically?

A

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

24
Q

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

A

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
25
Q

how are signaling pathways activated by IGF-1?

A

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
26
Q

when does the pubertal growth spurt happen?

A

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
27
Q

what are some causes of GH deficiency?

A

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

28
Q

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

A

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

29
Q

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

A

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

30
Q

Laron syndrome

A

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
31
Q

what does the insulin/IGF-1 pathway promote?

A

aging

32
Q

what is gigantism?

A

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

33
Q

what is acromegaly?

A

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.
34
Q

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

A

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
35
Q

how do GH levels change over the years?

A

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

36
Q

what does GH replacement therapy do? side effects?

A
  • restores muscle mass
  • reduces fat deposits
  • increased energy
  • side effects: insulin resistance, diabetes, edema, and carpal tunnel syndrome
37
Q

where is therapeutic GH usage approved?

A
  • GH deficiency
  • idiopathic short stature (ISS)
  • Turner syndrome
  • Prader-Willi syndrome (PWS)
  • chronic renal insufficiency (DRI)
  • small for gestational age (SGA)
38
Q

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

A
  • IBS (like Celiac’s disease)
  • Lupus and other collagen-vascular diseases
  • renal failure
  • thalassemia
39
Q

what are the “general calculations” for midparental height?

A

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

40
Q

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

A

thyroxin restored growth to normal

  • thyroid hormone response element is upstream of GH transcriptional start site
  • so hypothyroidism reduces GH with very dramatic consequences
41
Q

what syndromes have short stature with normal hormone status?

A 
Turner syndrome (missing 1 X)
Down syndrome (trisomy 21)
many others, but Turner and Down are the most common
42
Q

how is short stature in Turner Syndrome?

A

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
43
Q

what happens in Klinefelter’s syndrome?

A

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

Physiology (60 decks)

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