Growth Hormone Physiology

Insulin Receptor

- Binds IGF-1 at ~100-fold lower affinity that insulin

Type 2 IGF Receptor

- Binds IGF2 with high affinity - Binds IGF-1 with low affinity - Clearance receptor for IGF-2 Most inactive with NO downstream signaling, therefore presumed to be a clearance factor.

Acromegaly

- Excess secretion of GH after closure of epiphyses - Usually caused by a GH- secreting pituitary tumor - Increase in facial structures, hands, feet, deepening voice - Soft tissues swelling internal organs (heart, liver and kidneys)

Pituitary Dwarfism

- Generalized deficiency of anterior pituitary GH secretion during childhood - Failure of IGF-1 formation (*African Pygmy or Levi-Lorain dwarf*) - Both are treatable today with replacement therapy

Ghrelin

- Ghrelin is made in the stomach. - It stimulates both GHRH and GH - Ghrelin causes GH secretion, feeding and weight gain

Gigantism

- Growth Hormone disorder. - Results from excess growth hormone in Childhood *(before epiphyses close)* - Often due to pituitary tumor - Cardiovascular side effects are very common

Type I IGF Receptor

- Heterotramer - Binds *IGF-1 and IGF-2* with high affinity - Structurally almost identical to Insulin Receptor - Present in almost ALL tissues (except liver) - Active second messenger signaling (TYR- Kinase) Phosphorylation through multiple pathways - SH2 (Src) pathway, PI3K/ PIP2 pathway, SH2 pathway

Factors inhibiting GH secretion

- Hyperglycemia - Elevated levels of insulin - Elevated levels of free fatty acids

Factors stimulating GH secretion

- Hypoglycemia - *High levels of amino acids (especially during starvation)* - Stress

IGF binding proteins

Also extends the half life of IGFs and regulate availability of IGFs. *IGFBP-3* is the major carrier in circulation. Other IGFBPs have paracrine effects throughout the body

Direct Effect of GH

Carbs and Lipids - Generally works in the opposite direction as insulin - Causes increases in plasma glucose and triglycerides Amino acids and overall growth - Acts in the same direction as insulin - Uptake of amino acids - Increased protein synthesis and growth - Decreased protein catabolism

Growth Hormone Signal Transduction

Cell surface, not intracellular -> Membrane bound dimer -> Requires binding of GH at two sites -> Receptor the dimerizes and activates cytoplasmic Janus Kinases -> Second messengers cascade from there, involving ERK 1/2 and STAT, *increasing transcription of target genes* -> Translation results in production of many *proteins associated with growth and metabolism*

IGF-1 vs IGF-2

IGF-1 is the primary functional IGF after birth, and its levels fluctuate with GH over the years. IGF-2 is important in fetal growth and development, and is present in higher concentrations in adult than IGF-1, but its role in adults is not clear

GH and IGF working in concert to Regulate growth

Stimulate growth in all tissues in the body capable of growing. Promote hyerplasia (increased proliferation) and hypertrophy (increase cell size). Both promote the development of greater numbers of cells and specific differentiation of certain types of cells, as chondrocytes and early muscle cells.

GH (Somatotropin) Release

Under Dual Control. GHRH stimulates somatotropes to release GH. GH then stimulates a number of cell types to secrete *Insulin-like Growth Factors* of which the liver is the main source. Release of GH is inhibited by the peptide somatostatin (SRIF or also known as GHRIH)

Insulin like Growth Factors

- IGF-1 has receptors that are much like insulin - Many of the growth- promoting effects of IGF- 1 also resemble those of insulin - Unlike insulin IGF-1 does not promote glucose uptake by muscle and adipose cells. - IGF-2 has a different receptor, that binds IGF-2 more than IGf-1 and clears IGF-2 - IGF-1 receptor binds both IGF-1 and 2 found in almost all tissues, *except the liver* - *IGF-1 can bind to the insulin receptor but at 100x les affinity than insulin*

Transport of GH

- Water soluble peptide hormone, BUT GH has a binding protein in the plasma (*Growth Hormone binding protein, or GHBP*) - as much as 50% of GH is protein bound. - half life of GH free hormone is only 20 minutes, but protein bound it is 12-16 hours.

GH-IGF axis multiple points of regulation

GH exerts primarily short loop feedback IGF exerts long loop feedback

Direct effect Summary

GH increase lipolysis in adipose tissue GH reduces glucose uptake in muscle GH increases hepatic gluconeogenesis

IGFBPs and their functions (FYI material)

IGFBP-1 - Paracrine growth factor in *amniotic fluid, inhibiting some insulin like action of IGF-1 and IGF-2* IGFBP-2 - Paracrine growth factor in the *cerebrospinal fluid*, as is IGFBP-6 (*these are both inhibitory*) IGFBP-3 - Paracrine growth factor in follicular fluid and as an endocrine agent, *potentiates IGF activity* IGFBP-4 - has low concentration in plasma- much more tissue specific expression. *inhibits IGF there* IGFBP-5 - Paracrine agent in *bone matrix*. Its action is *inhibitory outside bone but not inside bone matrix*

GH progression

Peaks during Puberty then slowly declines during adulthood. With GH and IGF levels increase in parallel during Puberty. After puberty, levels remain steady throughout most of adulthood, and then decline somewhat rapidly after 60. During adulthood, GH and IGF regulate and maintain body mass, and facilitate compensatory growth (e.g. growth of kidney to compensate removal of the other kidney.

Chronotropic and other Factors for Secretion of GH

Pulsatile secretion throughout the day. Stimulated by: - Hypoglycemia - Protein Deficiency - Exercise - Trauma - Peaks during sleep