Growth Hormone

Growth hormone:

Long arm chromosome 17 – GH –hCS cluster : There are five genes for GH - two are important

1. Normal GH (22K): 75% of circulating GH

2. hGH –V (20K): 10% of circulating GH

3,4,5 hCS (HPL) –supplies fetal need in absence of GH-N leads to normal growth of embryo even if GH genes are defective.

Chorio somato mamotrope hormone L, A and B (transcription factor).

Pit-1 binds to promoter region of gene there is no GH if it is absent.

Pit-1(tissue specific protein transcription factor) binds to promotor region of gene = mRNA = pre hormone = removal of signal peptide = active hormone

GH also has homology to prolactin: The three cousins: HGH, HPL and Prolactin

Plasma level, Binding, Metabolism:

GH binding protein (GHBP): binds GH in plasma protecting from degradation.

GHBP is equivalent to extracellular portion of GH receptor: about 50% of total is bound

Metabolism takes place in liver, 1/2t: 6-20min

Molecular Action:

Binds to receptor –member of cytokine receptor superfamily:

Dimerization of receptor (must bind two receptors) leads to activation JAK2 = self phosphorlyation = phosphorylation of STAT 1,3 and 5 ( STAT proteins are transcription factors) which then enter nucleus to DNA and lead to gene transcription. No receptor = Laron syndrome.

Pit-1 involved in creation of GH and STAT is involved in post-receptor defects

HORMONES ALWAYS HAVE RECEPTOR AND POSTRECEPTOR ACTION

After JAK there is downstream action activation of IRS1, IGF1 and others, Tyrosine phosphatases cut of the reaction, GH receptor induced by insulin and estrogen and repressed by fasting (both insulin and GH are phosphorlated and phosphorlates others).

REMEMBER: dimmerization, STAT and series of activation

GH leads to dimmarization activates JAK2 then tyrosine on JAK is phosphorlated leads to phosporlation of other proteins.

JAK2 ---- transcription factor stat activates G protein and genes

Series of events:

GHRH and Somatostatin have opposing effects, when one increases the other decreases. Hypothalamus receives stimulus form the brain such as neuroepi, seratonine, etc, effected by stress and sleep. Glucose and FFA also work on hypothalamus. Somatomedin= IGF-1

IGF-1 works on pituitary and hypothalamus this is the long loop

GHRH has a negative feedback to hypothalamus this is ultra-short loop

GH has negative feedback on hypothalamus this is short loop

Regulation of GH secretion – very important:

• Pituitary GHRH: Specific GHRH receptor 1. AC &CAMP + 2. PLC &DAG + IP3

• GHRELIN –GHRP found in stomach and hypothalamus (first found in rat stomach), other (hottest hormone – in research)

GH secretagogues

• Somatostatin (GHIH): 5 receptors (dec CAMP and intracellular calcium)

• Secretion of GH dependent on S/GHRH – one inc. the other dec. opposing action

• Opposing effects on IC (intracellular) Ca+ levels GHRH inc and GHIH drops IC Ca+ levels – then Pit 1 action inc or decreased

• GH = IGF 1 = negative feedback to GH

Nutrition and GH secretion: High protein meal ( Arginine), hypoglycemia and low FFA increase & hyperglycemia and high FFA decrease secretion

GH protects you from hypoglycemia

Obesity: inhibits - Leptin (167 AA) polypeptide secreted from adipose cell. Most people are resistant to leptin, thus does not control appetite any longer

Malnutrition: inhibits IGF 1 upgrading GH, lack of feedback

LOTS of regulation of GH

• Stress (fever, exercise, surgery ) – shuts off sex hormones

• Sex hormones (E & A) – women have higher GH than men

• Neuronal: Dopamine, norepi, serotonin all increase GHRH responses, AcH drops SS.

• Alpha adrenergic stimuli inc and B adrenergic stimuli diminish response of GH

• Excess steroids drop GH (inhibit growth)

Endocrinologist used to examine boys GH levels by giving them estrogen and beta blocker at the same time and check levels.

Pulsatile secretion GH

• About 10 pulses daily: GH levels low 50% of day – in order to measure GH you must show that it is not responsive to stimulus, give insulin cause a drop in glucose levels and then give FFA

• Low in 95% of samples in elderly & obese

• Highest in puberty

• 50% drop in GH level every 7 years

• Regular nocturnal peak 1 hr after stage 3 or 4 sleep.

GH secretion : Higher in childhood than adulthood peak during puberty, low before birth because you have IGF-2 and HPL instead.

GH Action:

• Production of IGF -1

• Enhances lipolysis and lipid oxidation (correct for low FFA)

• Enhanced protein synthesis (muscle growth / steroid)

• Antagonism of insulin action

• Phosphorous, sodium and water retention

• Enhance renin and aldosterone (cause sodium and water retention)

• Suppression ANF (arterial naturatic factor – drop sodium)

• Inc 1,25(OH)2 Vit D = inc Ca absorption gut (for bone growth by increasing active vitamin D and Ca++ retention).

• Need normal levels of GH for pancreatic development but too much GH = antagonism to insulin

• Increases cardiac muscle size and contractility and CO

• Sensitizes gonads to LH and FSH promoting pubertal sexual development

• Leads to tumor growth in excess – colonic polyps

IGF 1 (Somatomedin) - Its like “and Abraham beget Isaac”

If you were to treat Jaws from James Bond you will give him somatostatin to stop GH and measure IGF-1 levels, there is a new drug that interferes with dimmarization of GH receptor.

Liver major site of syntheses but other organs produce as well

• GH stimulates IGF 1 (Structurally related to Proinsulin but have unique C chain).IGF -1 levels in plasma change with levels of GH.

• IGF-1 levels correlate with progression of pubertal growth

• 6 binding proteins (IGFBP 3 most significant and also GH mediated)

• IGF receptor similar to IR

• Fasting & insulin deficiency drops IGF 1 (inc GH)

• Growth promoting effects mostly accounted for by IGF 1.

• Cortisol and large doses estrogens diminish IGF -1 (GH antagonism)

• Be prepared for developments: is it tissue IGF or plasma IGF which leads to growth?? Open area in progress!

Structure of Proinsulin that is similar to IGF-1, insulin receptor has two alpha and two beta chains and will cross react with IGF-1. Large amounts of IGF-1 can cause hypoglycemia.

IGF-1 Pathology

• Acromegaly - activity of disease correlates with IGF – 1 levels

• Pituitary dwarfism – low IGF levels

• Laron syndrome: Abnormal IGF receptor with low IGF and high circulating GH levels

• Anorexia Nervousa: high GH and low IGF

IGF-2

• Also similar to proinsulin as is IFG 1

• mRNA found in liver, cartilage and others

• Receptor is a monomer (binds IGF 1)

• IGF -2 less affected by GH and regulates growth in fetus,

• Found in trophoblast cells and enhances placental growth

• In excess can stimulate insulin receptor and cause hypoglycemia

Next slide was a depiction of IGF-2 sequence it is alpha, beta, and C chain

Prolactin: in hypothalamus dopamine will shut off prolactin and somatostatin. TRH leads to production of TSH and prolactin (influences gonads and mammary glands). Overproduction shuts of THRH and leads to infertility.

Prolactin receptor works on DNA leads to gene expression. Prolactin is higher during sleep and highest in the morning, patient must get up two hours before giving blood for checking prolactin levels.

Factors for PROL secretion:

Increase physiological: pregnancy, nursing, nipple stimulation, exercise, stress and sleep.

Increase Pharmacological: TRH, estrogen, dopamine antagonist, opioids, monoamine oxidase inhibitors, verapamil.

Increase pathological: Hypothyroidism and pituitary tumors increase prolactin secretion.

Decrease pathological: hypopituitarism and pseudo-hypoparpthyroidism

During pregnancy there is a 50% increase in the size of pituitary for increased prolactin production.

Category: Physiology Notes