Growth Hormone Flashcards
1
Q
growth hormone
A
- single chain polypeptide hormone
- produced in anterior pit
- half life of 20 minutes
- excess in childhood-gigantism
- adult- acromegaly
- deficiency during childhood-dwarism
2
Q
regulation of GH secretion
A
- hypothalamus- GHRH, somatostatin
- stomach and pancreas- ghrelin
- all activate G protein coupled receptors
- targets in most tissue
3
Q
hypothalamic control of GH secretion
A
- GHRH-dominant signal
- somatostatin inhibits
- integration results in episodic, pulsatile secretion
4
Q
GHRH
A
- increases GH gene transcription
- promotes GH release
- stimulates production of GHRH
- stimulates somatostatin release (brakes no out of control)
5
Q
somatostatin
A
- decreases pulse frequency
- decreases pulse amplitude
- no impact on GH synthesis
- inhibits GHRH release
6
Q
ghrelin
A
- stomach and pancreas
- stimulates hunger
- levels increase before meals and decrease after
- acts on growth hormone secretagogue receptor
- feeding behavior, energy regulation, sleep?
7
Q
pulsatile secretion of growth hormone over lifespan
A
- pulses primarily at night
- number of pulses per day stays nearly constant
- larger pulse amplitude during puberty
- strenuous exercise can cause surger
8
Q
ritalin
A
- can cause short stature
- because disrupts sleep and secretion of GH
- can catch up if good nutrition is maintained
9
Q
stimulation of GH secretion
A
- deep sleep
- exercise
- sex steroids
- fasting/ hypoglycemia
- amino acids
- stress-like severe stress/nutritional loss
- alpha adrenergic
- dopamin agonists (suppress in acromegaly)
10
Q
inhibitors of GH secretion
A
- IGF-I
- obesity
- glucocorticoids
- hyperglycemia
- free FA
- GH
- beta adrenergic agonists
11
Q
effect of nutrient state
A
- obesity decreases- number of GH pulses, duration of pulse
- fasting increases-number of pulses, amplitude of pulses
12
Q
insulin induced hypoglycemia
A
- used as a clinical test to provoke GH secretion in suspected GI-deficient individuals
- aa increase GH primarily by decreasing somatostatin release
- GH binds to GH binding protein which prolongs life
13
Q
GH Regulation/effects
A
- GHRH from hypothal increases GH, somatostatin decreases
- GH important in child development and metabolism
- some effects mediated by somatomedins-IGF1 produced by liver or target tissues
14
Q
actual release of GH
A
- GHRH stimulates Gs protein receptors in somatotroph cells
- increases cAMP and calcium, causes release of GH
- cAMP activates PKA, phosphorylates CREB, upregulates Pit-1 which upregulates GH
15
Q
paraventricular region
A
- synthesize somatostatin
- inhibits through Gi
16
Q
GH activation of its receptor
A
-transmembrane receptor in cytokine receptor family
-must dimerize for signal transduction
-major sites of action:
bone, liver adipocyte, muscle
-JAK/STAT
-binding causes dimerization of receptor and binding of JAK tyrosine kinase 1, induces phosphorylation of JAK kinases as well as receptor 2
-activated JAKs subsequently P the STATs- which go to the nucleus and act as TFs
-leads to expression of CISH and established GH target gene
17
Q
effects of GH
A
- postnatal longitudinal growth
- direct and indirect effects
18
Q
GH in liver
A
- stimulates IGF1
- stimulates hepatic glucose production
19
Q
adipose tissue
A
- GH stimulates release and oxidation of free FA, especially during fasting
- mediated by the reduction in activity of lipoprotein lipase
- lipogenesis reduced
20
Q
skeletal muscle-GH
A
- anabolic actions
- stimulates aa uptake and incorporation into protein
- suppresses protein degradation
- stimulates cell proliferation, increases metabolism and changes muscle fiber distribution
21
Q
brain effects of GH
A
-mood and behavior
22
Q
gh overall
A
counteracts action of insulin on lipid and glucose metabolism by decreasing skeletal muscle glucose use, increasing lipolysis and stimulating hepatic glucose production
23
Q
effect of GH on bone
A
- increase aa uptake
- increase protein syn
- inc DNA and RNA syn
- inc chondroitin sulfate
- inc collagen
- inc cell size and number
- supports differentiation of mesenchymal stem cells into chondrocytes
- local IGF1 induces clonal expansion of early chondrocytes and maturation of later
- leads to synthesis of ECM proteins including typ II collagen, hyaluronic acid and mucopolysaccharides
- as cells move toward trabecula they become calcified
24
Q
GH and food
A
- stimulate the liver to secrete IGF1
- some made by kidney and skin but don’t contribute to circulation
- circulates all day at relatively constant level
- GH doesn’t induce growth in animals that lack insulin, also wont work without carbs, anorexia will curtail IGF 1 and decrease growth
25
Q
IGF1
A
- stimulates growth
- endocrine, paracrine and autocrine
- negative feedback to hypothal and pit to downregulate GH
- clinical use-primary screening test fo GH def, more stable and reflective of GH
26
Q
IGF I and II
A
- share 3 domains, aa seq homology (with insulin too)
- C region is cleaved from insulin, but not IGFs
- IGFs have D domain
27
Q
IGF I and II receptors
A
- insulin and IGF1 are heterotetramers joined by disulfide bonds
- cytoplasmic portion of beta subunits have tyrosine kinase domains and auto-P sites
- IGFII-single polypeptide chain with no kinase domain, cellular function poorly understood
28
Q
signaling pathways from IGF1
A
- dimerization of receptor leads to auto-P
- recruits two major phosphotyrosine binding proteins IRS-1 and SHC
- phosphorylated by IGF1 receptor
- recruits other proteins to the membrane leading to activation of the phosphoinositol 3 kinase and Ras/MAp kinase pathways that regulate transcription
29
Q
pubertal growth spurt
A
- sex hormones contribute to rapid increase in stature
- girls earlier and boys later
- IGF peak in puberty
30
Q
GH def and replacement
A
- several rare causes of def
- any defect affecting HPA
- mutation ins GH1 gene (can’t treat because they’ve never seen it so they will have a rxn)
- children have extremely slow growth- less than 2 inches/year
- severe post natal growth factor
- giving extra hormone doesn’t increase rate of growth to above normal levels
31
Q
organic causes of GH def
A
congenital absence of pit stalk, TBI, cranial radiation therapy
32
Q
idiopathic causes of GH def
A
-can be functional of developmental state, which resolves mid puberty
33
Q
laron syndrome
A
- GH insensitivity
- point mutation/deletion in GH receptor
- low IGF concentration
- normal/elevated GH
- severe post natal growth failure
- treatable with IGF
- AR
- heterozygotes mild growth retardation
- out of 230 worldwide, none have cancer
- no diabetes/ acne
- mutation of Stat5b gene similar
- treatment with IGF before puberty can compensate for short stature
- ecuador
34
Q
gigantism
A
- pituitary giants
- exposed to too much GH throughout life
- hyperglycemia/ diabetes
- degeneration of beta cells
35
Q
acromegaly
A
- GH secreting adenomas
- effects vary depending on size and growth rate and invasiveness
- large tumors cause destruction of pit and deficiency of other pit hormones can affect optic chiasm and vision
- protrusion of jaw, macroglossia (big tongue), enlarged hands and feet, carpal tunnel, reduced strength
36
Q
GH def in adults
A
- usually caused by pit probs
- can be result of surgery or radiation
- causes increase in interstitial fat
- reduced strength and bone loss
- feelings of anxiety and depression
- treatment with GH remediates issues
- found by using insulin to stimulate secretion
- increases visceral fat-carotid intima media thickness, IF markers of CV disease, clotting factors, insulin resistance
- decreases myocardial function- HDL
37
Q
GH and aging
A
- 5-20, 5 ng/ml
- 20-40, 3
- 40-70, 1.6
- replacement therapy:
- restores muscle mass, reduces fat deposits, feeling of increased energy
- side effects include insulin resistance, diabetes, edema, carpal tunnel
38
Q
FDA approved use of GH
A
- GH def, idiopathic short stature, turner syndrome
- prader willi syndrome
- chronic renal insufficiency
- small for gestational age
- nutrition- first few generations in america are taller because parents weren’t nourished
39
Q
other causes of growth problems
A
- celiac, hypothyroidism
- reduced levels of IGF
- replacement of thyroxin restore growth to normal height
- thyroid response element upstream of GH transcriptional start site- hypothyroid reduces GH
40
Q
short stature with normal hormones
A
-turner, down syndrome
41
Q
tuner syndrom
A
- haploinsufficiency of SHOX gene
- SHOX is developmentally regulated
- concentrated in the hypertrophic region of the growth plate zone during childhood
- pseudoautosomal region of Xp
- missing 1 X
- 45, X in about 50%
- isochomosome Xp or q, or mosaic
- 45X, 46XX
- slower velocity during childhood, scant pubertal growth spurt
- treated with GH and sex steroids- height improved but not restored
42
Q
SHOX locus
A
- developmentally regulated
- expressed throughout fetal growth plate, concentrated in hypertrophic zone
- pseudoautosomal region of Xp
- can have mutation that causes short stature
