Growth Hormone & Acromegaly

Which factors stimulate growth hormone?

*hormonal*: growth hormone releasing hormone, glucagon, low levels of IGF-1 *metabolic*: hypoglycemia, fasting, amino acids *neurogenic*: sleep, stress, alpha-AR

Which hormonal factors inhibit growth hormone?

*hormonal*: somatostatin *metabolic*: hyperglycemia, obesity *neurogenic*: beta-AR

How does growth hormone excess impact pre-pubertal patients? What about post-pubertal?

*pre-pubertal*: gigantism...increase in body size, hyperglycemia, glucose intolerance, hyperinsulinemia, diabetes. *post-pubertal*: acromegaly...epiphyseal plates so no impact on long-bones, but soft tissues/bones and other tissues continue to grow. Lower jaw protrusion, forward slanting forehead, big feet, thick fingers

How does growth hormone deficiency impact pre-pubertal patients? What about post-pubertal?

*pre-pubertal*: leads to dwarfism (Laron Dwarfs have defects in GH receptor/IGF activity) *post-pubertal*: no impact on growth because epiphyseal plates have already fused, but prolonged deficiency increase in fat deposition, decrease in protein deposition and muscle mass

How do the affinities of insulin and IGF I compare at different receptors?

IGF > Insulin at the IGF I receptor Insulin > IGF at the insulin receptor IGF ~ Insulin at the IGFII Mannose-6-Phosphate receptor *all are tyrosine kinase receptors*

How many types of insulin growth like factors are there? What is another name for them?

IGF I (produced in adulthood by the liver) & II (produced in fetal stage) somatomedins

Which IGF has effects on chondrocytes? Which has effects on other tissues?

IGF I on bone, II on other organs and tissues like muscle

What are the clinical features of acromegaly?

aural enlargement, coarsening of facial features, myopathy, arthritis and arthralgias, macroglossia, spacing of teeth, protrusion of jaw hypertension, congenital heart failure, left ventricular hypertrophy, cardiomyopathy sleep apnea hyperhydrosis, acrochordons viseromegaly, colon polyps menstrual abnormalities, galactorrhea, decreased libido, erectile dysfunction

How does growth hormone achieve decreased adiposity?

combination of increased lipolysis with decreased glucose uptake

How are pituitary adenomas treated radiologically?

conventional, gamma knife or proton beam

How does growth hormone achieve gluconeogenesis and glucose sparing?

decreases glucose uptake, initiates ketogenesis via lipolysis and switches to that for energy instead of glucose, increases insulin secretion, decreases glycogen deposits

How is acromegaly diagnosed?

demonstrate excess growth hormone by checking random GH, glucose-suppressed GH, IGF-1 levels and MRI imaging

If growth hormone is meant to decrease glucose uptake, why would it cause increased insulin secretion in an acute setting?

eventually all this insulin secretion flooding the receptors causes down regulation of those receptors, so that you eventually get insulin resistance in the long term

What is the etiology of acromegaly? Gigantism?

excess growth hormone --> excess IGF-1 --> excess visceral/somatic growth *after bone fusion* in gigantism, this happens *before bone fusion*

How is growth hormone diabetogenic?

growth hormone decreases glucose uptake, which increases plasma glucose, which increases insulin secretion in the short term. increased insulin secretion in the long term causes involution of insulin receptors such that the patient becomes insulin resistant, hyperglycemic and eventually diabetic

How is growth hormone regulated?

growth hormone releasing hormone released by arcuate nucleus, which stimulates anterior pituitary to release growth hormone, while somatotropin released from paraventricular nucleus inhibits growth hormone release

What are some of the local effects of a pituitary adenoma?

headaches, visual field defects (like bitemporal hemianopsia aka tunnel vision), and cranial nerve palsy

How often is GH secreted and when?

in the early early morning in a pulsatile fashion. levels of GH in the body vary throughout the day from 0.1 to 3, so it's not the best measurement to assess acromegaly

What are short-term metabolic effects of growth hormone on the body?

increased lipolysis increased protein synthesis increased gluconeogenesis decreased glucose uptake in liver and muscle

How does growth hormone achieve protein synthesis?

increases amino acid intake, increases transcription, decreases protein degradation

How does growth hormone achieve lipolysis?

increases hormone-sensitive lipase to initiate lipolysis, thereby increasing plasma FFA levels, increasing FFA use for energy as ketogenesis to allow for glucose sparing, since it is decreasing glucose uptake

What is the characteristic clinical feature of acromegaly?

spacing of the teeth

Where is IGF-1 synthesized? What induces its synthesis?

synthesized by the liver, mostly (though 25% is autocrine/paracrine), and induced by GH

What are some endocrine and metabolic effects of acromegaly?

• Insulin resistance, IGT • HTN - increased aldosterone, low renin • Hypertriglyceridemia • Hypercalciuria • Low TBG

What is the half-life of IGF-1?

15 hours, which makes it a good screening test for acromegaly instead of GH

How is glucose used in diagnosis of acromegaly?

OGTT load of 75 gm given and then GH is evaluated (first baseline, then 1 hour and then 2 hours after bolus)

What kind of hormone is growth hormone? What is another name for it?

Peptide hormone Somatotropin

At what time of day do growth hormone levels spike?

just after falling asleep

When are growth hormone levels highest?

just before midnight

How is growth hormone synthesized?

like this!

What is the most common cause of acromegaly?

pituitary adenomas account for 99% but rare causes include GH carcinoma, Syndromes (MEN-1, Carney's syndrome McCune Albright), tumors producing GH or GHrH

What are the homologues to human growth hormone?

placental variant growth hormone, human chorionic somatomammotropin, human prolactin

At what stage of life is GH the highest? lowest?

puberty senescence

What is the nature of growth hormone secretions?

pulsatile

In what circumstances does GH increase?

sleep, stress, short-term fasting and exercise

How are pituitary macroadenomas managed?

trans-sphenoidal resection of pituitary tumor is preferred trans-frontal resection indicated for severe invasion

How are pituitary adenomas treated medically?

using somatostatin receptor ligands/agonists: ocreotide, lanreotide dopamine (because at high doses it acts similarly to somatostatin): bromocriptine and cabergoline growth hormone receptor agonist: pegvisomant

When is IGF active?

when it is NOT bound to IGF binding protein