Endocrine 9

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Growth hormone (GH, hGH)

aka Somatotropin

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GH is not highly conserved between species

GH in cows, pigs, sheep is not effective in humans

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hGH

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single polypeptide chain of 191 AA, with 2 intrapeptide disulfide bonds

Variants of growth hormone have been isolated from humans, produced by post translational modifications and distinct mRNA with seq ommited from the N terminal region

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GH: origin

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GH is synthesized in the anterior lobe of the pituitary gland; is stored in large dense granules and can account for up to 10% of the dry weight of the tissue

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GH: circulation

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GH circulates bound to a protein similar in structure to target cell growth hormone receptor

half life 20-30mins

aging not associated with dramatic decline in amt of circulating GH

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GH: effects

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- pulsatile GH is more effective than continuous GH
- growth hormone promotes growth in size of limbs and internal organs.

Net linear bone growth occurs near the ends of bones in epiphyses

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Epiphyses

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epiphyseal plate (cartilage) that proliferates, cartilage forms a matrix --> bone

faster rate of growth the larger the epiphyseal space

assays for GH measure ability to inc size of space

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GH: effects

metabolism

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- long term tx with GH makes tissue resistant to effects of insulin to stimulate gluocse uptake

-GH is diabetogenic
-- even though it promots release of insulin like GF that promote glu uptake

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Growth hormone

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1. spares glucose utilization
2. inc availability of free FA
3. promotes AA uptake and protein synthesis

Generally
- dec adiposity
- inc lean body mass

Acute administration of GH inc circulating gree FA and glycerole (acute promotion of lipolysis)

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Other effects (enrichment) of GH include

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1. Inc Ca absorption from the gut
2. Inc urinary Ca excretion
3. Inc urinary hydroxyproline excretion
4. Inc retention of phosphate, potassium, and Na (Na can be bc of aldosterone--> inc intersitial V --> HTN

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Syndromes of growth hormone excess:

Gigantism

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-hypersecretion of GH result from pituitary tumors

- if hypersecretion before bony epiphyses close--> inc linear growth --> long arms/ legs

- size of visceral organs inc, amt of adipose tissue dec

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Syndromes of growth hormone excess:

Acromegaly

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- if hypersecretion occurs after epiphyses close --> bone growth in fingers, toes, hands, feet, jaw, around eyes

- size of visceral organs inc, amt of adipose tissue dec

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Syndromes of growth hormone deficiency:

Dwarfism

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- lack of GH from failure of pituitary to release the hormone, or removal of gland

- lack of GH prevent kids from reaching normal stature

- mild obesity common, puberty delayed

-Adults- lack of GH is not known to cause any physical signs

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Laron type GH reistance

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defects with GH receptor or post recepto steps that mediate hormone action

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GH

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- two bindings sites (sites 1 and 2) that cause dimerization of GH receptors

- dimerization appears to be req for GH to produce a biological effect

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First research

Somatomedins

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growth hormone promoted the expression of a somatomedin (factor in serum)--> promotes bond growth

factors that mediated somatic growth

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Second research

MSA multiplication stimulating activity

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responsible for promoting the division of cells grown in culture

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Third research

Non suppressible insulin like activities NSILA

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Antibodies that blocked insulin action in bioassay failed to block the majority of insulin - like activity (activity taht promotes glu uptake and metabolism) in serum from fasted animals

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All three research -->

insulin like growth factor (IGF)

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IGF1- somatomedin A or C or basic somatomedin, GH inc level of IGF 1 mRNA in liver and peripheral tissues

IGF2 aka MSA

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IGF-1

IGF-2

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Molecular weights 7500

similar in structure to insulin, except that the C peptide (removed form insulin) remains

major site syn--> liver
mRNA coding for IGF also at other sites

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Circulation of somatomedins

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IGF-1 and IGF-2 circulate bound to larger proteins.

after dissociation they are more active

half life--> hours

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IGF's (somatomedins) effect

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similar to insulin

mediate effect of growth hormone

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IGF receptors

Type 1

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- preferentially binds IGF 1 compared to IGF-2
- binds insulin weakly
- has instrinsic tyrosin protein kinase activity and a structure similar to insulin receptor

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IGF receptor

Type 2

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- preferentially binds IGF-2 compared to IGF-1
- do not bind insulin
- structurally distinct from type 1 and insulin receptors

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Insulin and IGF-1

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-Insulin, inc amt of IGF-1
-Insulin deficiency dec IGF-1 (dec restored by admin of insulin not GH)
-Insulin act directly on liver to inc IGF-1 rather than by inc GH
- Admin IGF-1 to insulin deficient animals restores growth but does not restore blood glucose

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Hypopituitary dwards

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-have depressed IGF-1 and IGF-2

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Tx of hypophysectomized rates with IGF-1 not IGF-2

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restores growth

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Pygmies

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- normal amts of GH
- slightly depressed amts of IGF-2
- low amts IGF-1

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Standard, miniature, toy levels of GH

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IGF-1 highest in the standard strain, intermediate in the minature, lowest in the toy

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Clincal use of IGF's

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- cDNA coding for IGF-1 and IGF-2
- short kids fail to respond to GH therapy may fail to syn normal amts of IGF-1, tx with IGF-1
- if kids respond GH but have adverse side effects

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Glucoreceptors in hypothalamus sense changes in blood glucose

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--> a fall in blood glucose --> promotes secretion of GHRH

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GHRH

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- stimulates a pituitary adenylate cyclase--> cAMP --> promotes release of GH

- somatic mutations in pituitary (Gs- alpha) cause constitutively elevated cAMP--> cause GH releasing tumors

- age dec response to GHRH

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Somatostatin

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- acts via Gi and diminishes GHRH action bc its a general inhbitor of hormone stimulated (not basal) adenylate cyclase)

- somatostatin overrides GHRH stimulation of GH release

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Release of GH into circulation is pulsatile and periodic

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- Feeding dec daytime circulating levels of GH
- large peak 1-2 hrs after commencing nocturnal sleep

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Test for normal release response

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- insulin induced hypoglycemia

- basal levels of plasma GH are 1-5ng/ml

- after exercise rise 15-50ng/ml

- hormone assayed by RIA

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GHRH- Growth hormone release hormone

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- 44AA
- normal source of GHRH is in the brain
- pancreatic tumors produce and secrete GHRH --> lead to GH excess and cause acromegaly

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GHRH: circulation

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- little GHRH in the plasma
- if injected it effectively release GH

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GHRH: administration

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-GHRH used to treat slow glowing children w/ low amts of circulating GH

- effective for pts that lack effective regulation of normal pituitary

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Somatostatin refers to small peptide

Somatostatin: origin

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- 28AA precursor

- synthesized in brain but also in peripheral tissues (pancrease) where it suppresses insulin release

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Somatostatin: circulation

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- found free in plasma and is rapidly cleared

Half life- somatostatin 14 -->2-3 mins

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Somatostain: Administration

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- surgical removal of pituitary does not reduce excess GH production
- treat problem with somatostatin but
1. somatostain has short hlaf life
2. it inhibits adenylate cyclase in a variety of tissues

--> inhbition leads to inhbition of insulin release

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Growth hormone, insulin and growth

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--circulating levels of GH may be elevated during stress when there is little growth

-Insulin also influences production of IGF-1

- GH is critical factor regulating growth via IGF-1 --> should not be assumed that GH is sole regulator of the process.