Hormonal control of growth
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Revision as of 13:50, 23 March 2011
Normal growth and development
- Normally the greatest growth rate occurs between zero and 20 weeks of gestation.
- Then there is a sharp decline in growth rate until birth and then a shallower decline until 40 weeks postpartum.
- After birth, one's growth rate is very high and decreasing rapidly until age 5, then is slowly decreasing, then goes back up for puberty (earlier for females), and then decreases rapidly before age 20.
Hormone regulation of growth
- At different stages of growth, different growth hormones are important to proper development.
- Recall that IGFs, GH, T3, Sex steroids, and insulin are all growth hormones.
- Insulin is important throughout prenatal and post-natal development.
- IGFs are the other important prenatal growth factor.
- Growth hormone (GH) and T3 become important for post-natal development.
- GH is the major stimulus for somatic growth.
- T3 potentiates GH's affect and is crucial for CNS development.
- Finally, sex steroids are important for growth at puberty.
- Androgens accelerate linear growth, close the epiphyseal plates, and increase muscle mass.
- Estrogens decrease linear growth, close the epiphyseal plates, and while they increase GH in the plasma, they decrease somatomedin levels
- Glucocorticoids inhibit somatic growth.
Control of GH
- The general axis for GH secretion is the hypothalamus, the pituitary (somatotropes), and the target organs (liver, muscle, bone, adipose).
- The hypothalamus releases growth hormone releasing hormone which acts on the somatotropes of the anterior pituitary to promote release of GH.
- GHRH = growth hormone releaseing hormone = GRF = growth-hormone releasing factor = somatocrinin.
- The hypothalamus releases somatostatin which acts on the somatotropes of the anterior pituitary to inhibit release of GH.
- The somatotropes of the anterior pituitary release growth hormone (GH) which act on the liver, muscle, bone, and adipose tissues.
- The liver releases IGFs in response to GH signaling.
- The muscle, bone, and adipose likely produce IGFs for local signaling, also, in response to GH signaling.
- Many tissues respond to GH and IGFs by growing: bones, soft tissues, gonads, viscera, etc.
- The hypothalamus releases growth hormone releasing hormone which acts on the somatotropes of the anterior pituitary to promote release of GH.
- GH feedback occurs at all levels: ultrashort feedback, short (direct), and long (indirect).
- Ultrashort feedback occurs when somatostatin and GHRH from the hypothalamus feedback on the cells of the hypothalamus to inhibit their actions (that is, somatostatin feedback will decrease release of somatostatin).
Is this autocrine or does it enter the blood stream and come back around? Does this feedback promote the production of the opposite factor? That is, does somatostatin feedback on the hypothalamus promote production of GHRH?
- Short (direct) feedback occurs when GH from the somatotropes of the anterior pituitary feeds back on the hypothalamus to decrease production of GHRH.
Does this short feedback also promote release of somatostatin?
- Short (direct) feedback also occurs when IGFs from the liver feedback on the somatotropes of the anterior pituitary to decrease production of GH.
- Long (indirect) feedback occurs when IGFs produced by the liver feedback on the the hypothalamus.
Example causes of pituitary dwarfism
- There are many reasons that GH signaling could fail and thus cause dwarfism.
- A defect in the GHRH receptor would mean that the somatotropes of the anterior pituitary would never get the signal to release GH.
- A pituitary development disorder would mean there are no somatotropes to generate GH.
- A GH defect would result in a signal that fails to produce the desired effect in target tissues.
- A GH receptor defect would result in failure to produce the desired effect in target tissues.
- A GH binding protein defect would result in failure to get the GH to the target tissues.
- A STAT defect would result in improper signaling at the target tissue and a lack of transcription regulation.
- IGF1 defects would result in target tissue response that was ineffective.
- IGF receptor defects would result in secondary target tissue response that was ineffective.
GH Axis diseases
- Short statures is the result of diseases of the GH axis.
- We know of diseases at every level of the axis.
Control of GH secretion
- Recall that the hypothalamus releases both somatostatin (anti-growth hormone) and GHRH (pro-growth hormone).
- Somatostatin signals through SRIF and SST receptors on somatotropes.
- GHRH signals through the GHRH receptor on somatotropes.
- Recall that GH and IGFs (from the liver and other GH target tissues) negatively feedback on somatotropes (receptors not given).
- Ghrelin is a pro-GH factor from the stomach.
- Ghrelin signals through the GHS receptor on somatotropes.
- GHRH
- Also called GRF and somatocrinin
- GHRH is a neuropeptide (44 amino acids).
- GHRH causes GH release at the somatotropes and also causes somatotrope proliferation.
- GHRH is related to secretin and glucagon
Why does this make sense?
- GHRH binds a 7-transmembrane helix receptor on the somatotrope.
- GHRH signals through elevation of cAMP levels.
- Somatostatin (SST)
- Somatostatin (SST) is also called somatotropin release-inhibiting factor (SRIF)
- Like GHRH, SST (somatostatin) is a neuropeptide (14 amino acids).
- Just as GHRH causes increased cAMP levels in the somatotropes, somatostatin (SST) causes a decrease in cAMP; this makes sense because GHRH and SST have opposite affects on GH release by the somatotropes.
- Somatostatin also has roles in the gut, pancrease, etc.
- Somatostatin arrests nearly every secretion of the gut.
Why does this make sense? Are the levels that affect the somatotropes similar to those that affect the gut? How much does eating correlate with growth?
- Ghrelin
- Ghrelin is released by endocrine neurons of the stomach.
- Ghrelin causes increased secretion of GH at the somatotropes of the anterior pituitary.
- Ghrelin signals through the GHS receptor (growth hormone secretagogue receptor).
- The growth hormone secretagogue receptor (GHS-R) signals through an IP3/DAG/Ca++ pathway to cause release of GH.
- The fact that the secretagogue receptor uses a separate pathway than the GHRH and SST pathway is significant.
GHRH receptor mutations
- The GHRH receptor is annotated as GHRH-R.
- Mutations in the GHRH-R cause short stature.
- These mutations are rare.
Growth hormone
- Growth hormone (GH) is also called somatotrophin (STH) or somatotropin (ST).
- GH is made by somatotropes in the anterior pituitary.
- Growth hormone is carried in the plasma by proteins called growth hormone binding proteins.
- Growth hormone is secreted in bursts.
Are these bursts dependent on eating or independent? (Think ghrelin and somatostatin.
- Growth hormone is also released on a 24 hour (circadian) rhythm and is high during sleep.
Growth hormone / Prolactin superfamily
- Growth hormone is a member of the prolactin superfamily.
- Both GH and PRL use JAK-STAT signaling mechanisms.
- Recall that prolactin is also made in the anterior pituitary (by lactotrophs) and stimulates lactation in post-partum females.
- There is only one copy of the prolactin gene in mammals.
- There are many copies of the GH gene in mammals.
- GH-N is the version expressed in the anterior pituitary; it is also called GH1.
- Copies of the growth hormone gene (including GH1) are found on chromosome 17.
- Some copies of the growth hormone gene are called chorionic somatotropin because they are expressed in the placenta.
- These paralogs to growth hormone are labeled "CS" as in "CS-A", "CS-B", etc.
- These paralogs are sometimes called "placental lactogens", too.
Do these placental lactogens come from the baby and signal the mother's mammary glands?
- Growth hormone promotes the growth of long bone and the closure of the epiphyseal plates.
- It is hypothesized that this effect occurs by GH signaling on the liver, the liver responding by producing IGF 1 and IGF 2, and IGF 1/2 signaling proliferation of the epiphyseal cartilage and subsequent sulfation.
- Sulfation can be followed (and thus experiments can measure the effect of GH / IGF 1/2 on bone formation) via incorporation of radioactive sulfur (S35).
- IFG1 and IGF2 are called somatomedins because they are the result of GH signaling.
Insulin-like growth factors (IGFs)
- Insulin-like growth factors are small peptides (as in insulin).
- IGFs (insulin-like growth factors) are bound to IGF binding proteins when circulating in the blood; these are called IGFBPs.
- IGF1 is an important growth factor for all stages of growth.
- The IGF1 receptors looks much like the insulin receptor.
- Recall that the insulin receptor uses a tyrosine kinase mechanims (as does the IGF1 receptor).
Is IGF1 important for tissue maintenance type growth or just growth as in pre-20 year old growth?
- IGF2 is primarily important for fetal growth.
- The IGF2 receptor (IGF2R) can bind IGF2 and mannose-6-phosphate.
- It has been observed that IGF2R knockouts are larger than their peers.
- Therefore it has been suggested that IGF2R may be responsible not only for IGF2 signaling but also for destruction of excess IGF2.
How does a receptor transduce a signal but also control excess signal?
GH signaling
- GH induces a JAK-STAT signaling pathway.
- Recall that JAK-STAT pathways use dimerization of receptors (in this case the GHR) to recruit janus kinases.
- JAK = janus autophophorylating kinase so remember that JAKs autophosphorylate.
- Upon autophosphorylation, STAT proteins are recruited, phosphorylated, and dimerized.
- Prolactin also uses JAK-STAT signaling.
Factors affecting GH release
- There are neurogenic, metabolic, and hormonal influences upon GH release.
- These can be either pro-GH release or anti-GH release.
- Stimulators:
- Neurogenic stimulators of GH release: non-REM sleep, stress
- Metabolic stimulators of GH release: hypoglycemia, low FFA levels, amino acids
- Hormonal stimulators of GH release: GHRH, estrogens
- Inhibitors:
- Neurogenic inhibitors of GH release: REM sleep, emotional deprivation
- Metabolic inhibitors of GH release: hyperglycemia, high FFA levels, obesity
Why does it make sense that high sugar should slow growth? Seems opposite.
- Hormonal inhibitors of GH release: somatostatin (SST), large doses of corticosteroids, somatomedins (like IGFs)
GH secretion during sleep
- Growth hormone levels are highest during sleep.
GH changes with age
- Growth hormone concentrations decrease with age (at 20 years old).
- Some have wondered if we should give GH replacement therapy to promote longer, better life.
Do IGF levels follow the same curve? Are there other factors that promote IGFs?
Physiological effects of human GH
- Growth hormone has prominent effects on adipose, liver, muscle, chondrocytes, bone, heart, and lung.
- In general, GH causes growth and generates free energy for the body.
- In liver, GH causes an increase of gluconeogenesis (generates free energy for the body) and IGF production (growth).
- Note that IGF production at the liver will go on to signal growth in muscle, bone, and cartilage.
- In adipose, GH causes decreased glucose use and increased lypolysis (generates free energy for the body).
- In muscle, GH causes decreased glucose uptake (generates free energy for the body) yet increases amino acid uptake and increased protein production (growth).
- In chondrocytes, GH causes proliferation, collagen production, and chondroitin sulfate production (growth).
- Note that GH induces growth of cartilage indirectly through IGFs produced by the liver.
- In bone, heart, and lung, GH causes increased cell size and number (growth).
- Note that GH induces growth of cartilage indirectly through IGFs produced by the liver.
- Finally, kidney, pancreas, intestine, and many other tissues respond to IGFs as the bone, heart, and lungs do--growth via IGF signaling.
Insulin-like versus "diabetogenic" effects of GH
- Growth hormones has some effects that are insulin like and some that oppose the actions of insulin.
- Recall that insulin generally tells the body that there is lots of energy and tissues should feel free to use glucose and to do what they are designed to do.
- Growth hormone is insulin-like in that it causes:
- increases amino acid uptake and protein synthesis by muscle
- Growth hormone opposes insulin's action in that:
- GH promotes lipolysis (GH frees up energy so the body can grow but insulin is correlated with glucose so it doesn't have to signal for freeing of energy)
- GH increases glucose production by the liver (again, GH frees up energy so the body can grow but insulin only comes along when glucose is present so it doesn't have to signal for free of energy at the liver via glycogenolysis)
- GH inhibits glucose uptake by muscle and fat
Since GH is telling the muscle to grow (make proteins) it is surprising to me that GH specifically tells the muscle not to use glucose. How does this make sense.
- GH makes muscle and fat resistant to insulin
See question from above
- GH--in excess--can cause diabetes like disease and acromegaly.
