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MS 1 Unit VI Physiology > Growth Hormone > Flashcards

Growth Hormone Flashcards

1
Q

Growth Hormone

A
  • GH, somatotropin
  • single chain polypeptide hormone
  • produced in anterior pituitary
  • half time in circulation -20 min
  • excess during childhood-gigantism; during adult-acromegaly
  • deficiency during childhood-dwarfism
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2
Q

Regulation of GH Secretion

A
  • Hypothalamus:
  • growth hormone releasing hormone (GHRH)
  • somatostatin

Stomach and Pancrease
-ghrelin

-All activate G protein coupled receptors

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3
Q

Hypothalamic Control of GH Secretion

A
  • GHRH stimulates
  • somatostatin inhibits
  • integration results in episodic, pulsatile secretion
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4
Q

GHRH

A
  • increases GH gene transcroption
  • promotes GH release
  • stimulates production of GHRH receptor
  • stimulates somatostatin release
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5
Q

Somatostatin

A
  • decreases pulse frequency
  • decreases pulse amplitude
  • no impact on GH synthesis
  • inhitibts GHRGH release
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6
Q

Ghrelin

A
  • produced in stomach and pancreas
  • stimulates hunger
  • levels increase before meals and decrease after
  • acts on growth hormone secretagogue receptor

likely more important for: feeding behavior, energy regulation, possibly sleep, than control of GH secretion. Target for design of anti-obesity drugs

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7
Q

Pulsatile Secretion of Growth Hormone Over the Lifespan

A
  • pulses are primarily at night
  • number of pulses per day stays nearly constant
  • larger pulse amplitude during puberty
  • strenuous exercise causes a surge in GH

-typical variations in growth hormone secretion throughout the day, demonstrating the especially powerful effect of strenuous exercise and also the high rate of growth hormone secretion that occurs during the first few hours of deep sleep. Drugs that disrupt sleep in children can decrease growth, at least temporarily. Example include drugs ADHD (Ritalin). After 3 years on Ritalin, children are on average 1 inch shorter and 4 pounds light than their peers however they eventually catch up to a normal height if good nutrition is maintained

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8
Q

GH Secretion

A
  • stimulated by:
  • deep sleep
  • exercise
  • sex steroids
  • fasting/hypoglycemia
  • amino acids
  • stress
  • alpha- adrenergic agonists
  • dopamine agonists (suppress in acromegaly)

inhibited by:

  • IGF-I
  • obesity
  • glucocorticoids
  • hyperglycemia
  • free fatty acids
  • GH
  • beta-adrenergic agonists
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9
Q

Effect of Nutrient State and GH

A

Obesity decreases:

  • number of GH pulses
  • duration of each pulse

Fasting increases:

  • number of GH pulses
  • amplitude of each pulse
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10
Q

Insulin induced hypoglycemia

A
  • used as a clinical test to provoke GH secretion in suspected GH-deficient individuals
  • amino acids increase GH release primarily by decreasing somatostatin release
  • GH in the circulation is bound to GH-binding protein which prolongs it half-life
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11
Q

GH Regulation/Effects

A
  • growth hormone release by anterior pituitary is controlled by GHRH and somatostain
  • growth hormone has an important role in growth and development of children and regulation of metabolism. Some of its effects are mediated by somatomedins produced by the liver or by specific target tissues
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12
Q

Release of GHRH

A
  • small-bodied neurons in the arcuate nucleus of the hypothalamus secrete GHRH, a 43-amino acid peptide that reaches the somatotrophs to release GH stored in secretory granules by raising [cAMP]i and [Ca2+]i. cAMP activates protein kinase A to phosphorylate the transcription factor CREB, augmenting the transcription of Pit-1, a transcription factor that upregulates GH and GHRH receptor
  • increased Ca2+ levels lead to secretion of GH
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13
Q

Somatostatin

A
  • neurons in the periventricular region of the hypothalamus synthesize somatostatin, a 14 amino acid neuropeptide
  • travels to the anterior pituitary via the long portal vessels, is a potent inhibitor of GH secretion, through Gi-protein coupled receptor
  • somatostatin acts by inhibiting adneylyl cyclase and thus lowers (Ca2+)i
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14
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 (also some on kidney, eye, brain, heart, cells of immune system)
  • the receptors activate the JAK/STAT pathway for signal transduction- JAK tyrosine kinases 1 and 2
  • activated JAKs subsequently phosphorylate the STATs, which as dimers, translocate to the nucleus and act as transcription activators
  • leads to the increased expression of CISH, a well established GH target gene
  • severe under expression of the GH receptor is a contributing causes of short stature in Pygmies
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15
Q

Effects of GH

A
  • a major role of GH is regulation of postnatal longitudinal growth
  • GH has direct and indirect effects ( through somatomedians such as IGF-1)
  • Liver- stimulates the production of IGF-1 and stimulates hepatic glucose production
  • adipose tissue- GH stimulates the release and oxidation of free fatty acids particularly during fasting. This is mediated by the reduction of the activity of lipoprotein lipase, which clears lipoproteins and trigylcerides from the bloodstream. Lipogenesis is reduced.

-overall GH counteracts the action counteracts the action of insulin on lipid and glucose metabolism, by decreasing skeletal muscle glucose utilization, increasing lipolysis and stimulating hepatic glucose production

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16
Q

Skeletal Muscle and GH

A
  • anabolic actions on skeletal muscle
  • stimulates amino acid uptake and incorporation into protein– suppresses protein degradation
  • it also stimulates cell proliferation, increases metabolism and changes muscle fiber distribution
17
Q

Effect of GH on Bone

A
  • growth hormone supports the differentiation of the mesenchymal stem cells (prechondrocytes) into chondrocytes
  • local IGF-I induces the clonal expansion of the early chondrocytes and the maturation of later chondrocytes
  • this leads to the synthesis of extracellular matrix proteins including type II collagen, hyaluronic acid and mucopolysaccharides
  • as cells move closer to the already formed trabecular one it become calcified
  • soon after this it begins to be remodeled by the action of osteoclasts as osteoblasts to form mature bone
18
Q

IGF-1

A
  • overwhelming source of circulating IGF-1 is the liver. Some is made by kidney and skin but these sources do not contribute significantly to the circulation. IGF-1 circulates all day at a relatively constant level
  • GH does not induce growth in animals that insulin; it also won’t stimulate growth in the absence of carbohydrates. Anorexia and other eating disorders will dramatically affect the growth of a child by curtailing IGF-1 production
  • stimulates growth:
  • endocrine: classic systemic effect through circulation
  • paracrine: affects neighboring cells
  • autocrine: affects producing cell
  • negative feedback to hypothalamus and pituitary to down regulate GH secretion
  • IGF-1 - is primary screening test when considering growth hormone deficiency, since it levels in the circulation are more stable and reflextive of GH levels in normal individuals
19
Q

Insulin-like growth factor

A
  • insulin, IGF-I, and IGF-II share three domains (A,B and C) which share a high degree of amino acid sequence homology
  • the C region is cleaved from insulin (as the C peptide) during processing but not cleaved from IGF-I or IGF-II
  • in addition, IGF-I and IGF-II also have a short D domain
  • IFG-II secretion is not significantly regulated by GH
  • both insulin and IGF-I receptors are heterotetramers joined by disulfide bonds- for both the cytoplasmic portion of the beta subunits have tyrosine kinase domains as well as autophosphorylation sites
  • the IGF-II receptor is a single polypeptide chain with no kinase domain, its cellular function is poorly understood
20
Q

Signaling Pathways Activated by IGF-1

A
  • dimerization of IGF-1 receptor leads to autophosphorylation
  • this recruits two major phosphotyrosine binding proteins IRS-1 and Shc, which are phosphorylated by the IGF-1 receptor
  • this recruits other proteins to the membrane leading to the activation of the PI3K and the Ras/MAP kinase pathways that regulate cellular transcription
21
Q

Pubertal Growth Spurt

A
  • at puberty both sex hormones contribute to rapid increase in stature
  • for girls, growth spurts begin at the early stages of puberty, whereas for boys they usually occur well after puberty has begun
  • serum insulin like growth factor (IGF-1) levels and height velocity as a function of age
22
Q

Growth Hormone Deficiency and Replacement

A

-several rare causes of deficiency
-any defect affecting hypothalamo-pituitary function
-mutations in GH-1 gene
-children have extremely slow growth < 2 inches/year
-severe post-natal growth failure
Organic causes: congenital absence of pituitary stalk, traumatic brain injury, cranial radiation therapy
Idiopathic: can be functional of developmental state, which resolves in mid-puberty
-mutations in GH-1 gene cannot be treated with rhGH- the individual will eventually make antibodies to what is perceived as a foreign protein
-giving extra hormone (hormone levels in access of normal) during treatment does not increase the rate of growth above what is attained with normal levels

23
Q

Growth Hormone Insensitivity

A
  • Laron Syndrome
  • point mutation or deletion in GH receptor
  • markedly low IGF-I concentration
  • normal or elevated GH concentration
  • severe post-natal growth failure
  • treatable with rhIGF-1
  • autosomal recessive; heteroxygotes show mild growth retardation. The disease is rare
  • prevents cancer, diabetes, acne
  • treatment with rhIGF-1 before puberty can compensate for short statue
24
Q

Gigantism

A
  • pituitary giants, individuals who have been exposed to too much GH throughout life
  • typically has hyperglycermia and 10% of giants develop full blown diabetes mellitus due to degeneration of beta cells of the islets of Langerhans
25
Q

Acromegaly

A
  • growth hormone secreting adenomas cause acromegaly
  • the effects of growth hormone-secreting adenomas vary depending on size and growth rate as well as invasiveness
  • large tumors cause destruction of the pituitary and deficiency of other pituitary hormones and may affect the optic chiasm and vision
  • growth hormone excess produces acromegaly in adults and protrusion of jaw, macroglossia (enlarged tongue), enlarged hands and feet, carpal tunnel syndrome, reduced strength and other effects
26
Q

Growth Hormone Deficiency in Adults

A
  • usually caused by pituitary problems
  • can be result of surgery or radiation
  • causes increase interstitial fat
  • reduced strength and bone loss
  • feelings of anxiety, depression
  • treatment with rhGH remediates many of these issues

-identified by provocative pharmocological tests to stimulate GH secretion: insulin treatment to lower blood sugar is followed 20-30 min later with a blood test for GH. Other tests include glucagon and GHRH challenges

27
Q

GH- Deficiency for Cardiovascular Disease

A
  • increases: visceral adipose tissue- carotid intima-media thickness
  • inflammatory markers of cardiovascular disease- clotting factors
  • insulin resistance- LDL

decreases: myocardial function- HDL- get up and go
- GH- deficiency is not as impactful as being grossly over weight and sedentary but has the same trend

28
Q

Growth Hormone and Aging

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

replacement therapy: restores muscle mass, reduces fat deposits, feeling of increased energy, side effects include insulin resistence, diabetes, edema, carpal tunnel syndrome

29
Q

FDA approved uses for GH

A

-growth hormone deficiency, idiopathic short stature, Turner syndrome, Prader-Willi syndrome, chronic renal insufficiency, small for gestational age

30
Q

Target Height

A
  • Girls (F+M) - 6.5
  • Boys (F+M) + 6.5 cm
  • in families moving to the US from a developing country, the first two generations grow a little taller than predicted by the formula
  • growth retardation and reduced IGF-1 in Celiac disease
  • also hypothyroidism
31
Q

Short stature in Turner Syndrome

A
  • attributed to haploinsufficiency of the SHOX gene
  • SHOX protein is developmentally regulated
  • SHOX protein is concentrated in the hypertrophic region of the growth plate zone during childhood
  • SHOX locus is in pseudoautosomal region of Xp

-absence of one X-chromosome

32
Q

Klinefelter’s syndrome

A
  • patients with extra sex chromosomes have extra copies of SHOX and are taller than normal
  • for instance XXY individuals are taller than average partly due to an extra copy of SHOX and partly due to a gonadotropin deficiecny
  • in addition they don’t go into puberty and don’t fuse their bones and thus continue to grow for longer than normal

MS 1 Unit VI Physiology (12 decks)

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