Growth Hormone - Wright

IGF binding Proteins

Act to extend the half life of IGF and regulate Availabilty. IGFBP-3 Is the major Transporter in circulation.

Summary of How GH and IGF work together

1. GH and the IGFs promote hyperplasia (increases proliferation) and hypertrophy (increases cell size). 2. GH and the IGFs promote the development of greater numbers of cells and specific differentiation of certain types of cells, such as chondrocytes and early muscle cells. 3. GH is unique, because in contrast to other tropic hormones, GH does not function directly by stimulating a single target gland (e.g. ACTH stimulates the adrenal; TSH stimulates the thyroid, etc.), but rather this pituitary hormone exerts profound effects on the liver, muscle, and adipose and is known to exert lesser on most tissues in the body. 4. Recognize that the effects of GH are also mediated via the IGFs. (Which is discussed in the Regluation flash card) 5. GH and IGFs work in concert to regulate growth and development. The IGFs, like GH, also exert wide-spread effects on most tissues of the body.

When does GH production peak during your life?

During puberty, both GH and IGF1 (not shown here) levels increase in parallel. The levels of both GH and IGF1 correlate well with growth rates in children, and the pubertal peak rate of growth corresponds to levels of GH and IGF1. After puberty, the levels of both GH and IGF1 begin to fall, remain steady throughout most of adulthood, and then decline somewhat rapidly after approximately age 60. During adulthood, GH and IGF regulate and maintain body mass, and facilitate compensatory growth (e.g., after removal of a kidney, increased cell division in the remaining kidney lets it grow until its total mass comes to approximate the former mass of the two kidneys combined).

Gigantism

Excess production of Growth Hormone before Epiphyses Close Often can occur due to pituitary Tumor. Cardiovascular Side effects common. YOU ARE A GIANT

Acromegaly

Excess secretion of Gh after closure of Epiphysis. Usualy caused by GH secreting Pituitary Tumor Increases Facial stuctures, hands, feet, deeping voice. Soft tissue swelling in internal organ (heart, live, kidney)

Receptor Signaling Pathways

Receptor signaling: (he did not talk about the type of signals, was on slide) • TYRK phosphorylation • Multiple pathways: - SH2 (Src) pathway - PI3K/PIP2 pathway - SH2 pathway

Signal transduction for growth hormone

GH binds to two transmembrane GH receptors, Receptor then dimerizes and activates cytoplasmic Janus kinases and alters EXPRESSION of numerous GENES via activation of STAT and ERK; Translation results in production of many proteins associated with growth and metabolism

Pituitary Dwarfism

Generalized Deficiency of Anterior Pituitary GH secretion During Childhood, or Failure of IGF1 formation. (African pygmy or levi-lorain Dwarf) both are treatable. (extra) Panhypopituitarism first occurring in adulthood causes (1) hypothyroidism, (2) depressed production of glucocorticoids by the adrenal glands, and (3) suppressed secretion of the gonadotropic hormones. Thus, the picture is that of a lethargic person (from lack of thyroid hormones) who is gaining weight (because of lack of fat mobilization by GH, adrenocorticotropic, adrenocortical, and thyroid hormones) and has impaired sexual functions. GH deficiency in adults resulting from an age-related decline in GH production, is becoming recognized as a pathological syndrome. GH deficiency is one of many possible causes of chronic hypoglycemia. Recent studies have shown that extended deficiencies of GH lead to changes in body composition. The percentage of body weight that is fat increases, whereas the percentage that is protein decreases. In addition, muscle weakness and early exhaustion are symptoms of GH deficiency.

GH-IGF Regulation

High Growth Hormone inhibits release Via Short loop feed back. High Insulin-like Growth Factor Inhibits Growth Hormone Via Long loop. Low GH increases Growth Hormone Via Short loop. Low Insulin-like Growth Factor Stimulates Growth Hormone via Long loop. Also: GHRH - Stimulates Secretion and Synthesis. Ghrelin: Stimulates GHRH and GH secretion Somatostatin: Inhibits GH

Insulin Like Growth Factors

IGF-1 is the primary functional IFG 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 adults than IGF-1, but its role in adults is not clear.

Direct Effects of Growth Hormone

In adipose tissue: Stimulates Lipolysis Inhibits: Glucose uptake (preventing storage, causing increases in plasma glucose & triglycerides) In liver: Stimulates: Protein synthesis, Gluconeogenesis, Glycogenolysis, IGF production, secretion Inhibits: Glycogenesis In Muscle: Stimulates: Protein synthesis, Amino acid uptake, Glycogenolysis Inhibits: Glucose uptake

Indirect Effects of Growth Hormone via IGF-1

Increases growth of non-muscle cells Including cartilage-producing chrondrocytes On Chondrocytes: Stimulates: Amino acid uptake, Protein synthesis, RNA synthesis, DNA synthesis, Collagen production, Chondroitin sulfate, Hyperplasia, Hypertrophy On liver: None On Muscle: Stimulates: Protein synthesis, Amino acid uptake, *Glucose uptake (he is double checking this)

Growth Hormone transport

It is Water Soluble but has a binding Protien in the plasma, growth hormone binding protein. 50% bound. Half life of free homrone 20 min., 12-16 hours with Binding protein. GHBP is a cleaved derivative of target cell Growth Hormone receptors. - Clinical correlation: By measuring GHBP, you can estimate the number of GH receptors at target tissues.

What factors influence secretion of GH

Pulsatile secretion occurs throughout the day, stimulated by: Hypoglycemia Protein deficiency (high amino acid) Exercise Trauma Peaks during sleep Strenuous exercise has the property of stripping energy stores from the blood so it makes sense that increased GH with its ability to increase plasma glucose would join the other hormones secreted for this purpose. In children, most of the actual growth takes place during sleep, which for most children corresponds to the highest non-exercise associated peak over a 24 hour period.

Growth Hormone Releasing Factor

The release of GH is under dual control. GHRH stimulates somatotrophs to release GH. GH stimulates a number of cells types in various organs, to secrete Insulin-like-growth factors and also exerts direct effects on metabolism . Release of GH is inhibited by the peptide somatostatin (SRIF or also known as GHRIH).

IGF Receptors - Type 1 IGF Receptor vs insulin

Type 1 IGF Receptor: • Heterotetramer. • Binds IGF1 and IGF2 with high affinity. • Structurally almost identical to Insulin Receptor. • Present in almost ALL tissues (except liver). Insulin Receptor: • Binds IGF1 at ~100-fold lower affinity than insulin. (others receptors which he said he is not really interested in) Type 2 IGF Receptor: • Binds IGF2 with high affinity. • Binds IGF1 with low affinity. • Clearance receptor for IGF2 (?)