Lecture 3 Growth Hormone and IGF-1

Somatomedin/insulin-like growth factors

secreted by liver and stimulate effects of growth hormone

Where is growth hormone synthesized

anterior pituitary cells called somatotrophs- make up 40-50% of the cells of the anterior pituitary, GH is stored in large granules within the cells

What hypothalmic hormones regulate the synthesis and secretion of GH

Growth hormone releasing hormone (GHRH)- induces synthesis and secretion

Somatostatin- inhibits synthesis and secretion

Stimulation of GH

GHRH Somatostatin

Ghrelin (also orexigenic*)

Sleep

Fasting, acute hypoglycemia

High protein meal

Exercise

Puberty

Estrogens and Androgens

Physiologic Stress

(i.e., trauma, surgery, infection, fever)

Inhibition of GH

Somatostatin

Somatomedins

Increased blood free fatty acids

Increased blood glucose

Administration of Exogenous GH

Obesity

Senescence (aging)

Sleep-wake cycle GH secretion

Increased when asleep, decreased when awake (higher secretion with slow-wave sleep)

Sex differences in GH secretion

GH secretion is greater in females than males

Estradiol stimulates GH secretion with a peak just before ovulation

Testosterone stimulates GH secretion in males

Life span differences in GH secretion

Plasma levels of IGF-1 are greatest in children and peak during puberty. IGF-1 levels decline with aging

Signal Transduction of GH

GH receptor is a receptor associated with tyrosine kinases IGF-1 receptor has  and  subunits 2 receptor monomers dimerize with GH binding

Signal Transduction of IGF-1

IGF-1 receptor has alpha and beta subunits- an example of a receptor tyrosine kinase

Metabolic effects of GH and IGF-1

Increase protein synthesis (synergistic action with Insulin)-

Increased amino acid transport into cells

Stimulation of transcription and translation

Inhibit protein catabolism

Mobilization of fatty acids and utilization of fatty acids

stimulates release of fatty acids from adipose cells, therefore there is an increase in plasma FFA and ketoacids

Increases oxidation of fatty acids by the body’s cells

Effect on Carbohydrate (CHO) metabolism

decrease utilization of glucose, therefore elevate blood glucose; an effect often called “anti-insulin effect”

Why is GH a diabetogenic hormone

it increases insulin resistance, especially in situations of high GH concentrations-

Decreased glucose uptake into muscle and adipocytes

Stimulates glucose production by the liver (gluconeogenesis)

How does GH-IGF stimulate linear growth in bones

stimulating all aspects of chondrocyte function-

Increased amino acid uptake, protein synthesis, collagen, chondroitin sulfate, cell size and number

Total bone mass and mineral content of bone are increased by GH- stimulate osteoblastic activity

GH effects on organs

Hypertrophy and hyperplasia of visceral organs-

increased growth of heart, lung, liver, pancreas, GI tract, adrenal glands, etc.

GH sensitizes the gonads to LH and FSH during puberty

Growth promoting hormones

GH – IGF1

Insulin

Thyroid Hormone

Testosterone

Estrogen

Other local factors

Hormones that inhibit growth

Cortisol

Childhood hypersecretion of GH

gigantism- the main symptom of children with gigantism is excessive height. Other features include thickening of facial features and extremities, sleep problems, and enlarged heart

Adulthood hypersecretion of GH

Acromegaly: the benign tumor arises after puberty when linear growth stops due to closure of the epiphyseal plates- excess growth hormone here causes bones, cartilage, body organs and other tissues to increase in size.

Characteristic changes in appearance include larger hands, feet, ears, lips and nose and a more prominent jaw and forehead. Other symptoms include deep voice, sleep apnea, and high blood pressure

What are patients with gigantism and acromegaly at risk for

Diabetes Mellitus

Acromegaly muscle changes

muscle weakness, muscle atrophy (although muscle mass may appear normal or increased), and vascular changes leading to vascular degeneration and muscle fiber degeneration

GH deficiency in children

decrease linear growth; short stature or pituitary dwarf