Download 3-4 (Weigent)

Heme/Endo: 3:00-4:00
Tuesday, Nov 3, 2009
Dr. Weigent
IGF = insulin-like growth factor
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Growth Hormone
GHRH = growth hormone releasing hormone
Scribe: Andrew Treece
Proof: Dylan Vaught
Page 1 of 4
GH = growth hormone
[S1] Introduction
a. This is just a short outline.
b. There are many studies based on growth hormone now to help various types of people (short people, old
people, athletes).
c. You can become to short or too large from imbalances of growth hormone and we will talk about those.
[S2] Recent Developments Supporting the Importance of Growth Hormone
a. This slide has most of the take home information about growth hormone. ****This will be a question on the test.
b. Growth hormone is involved in linear growth. It has effects on chondrocytes.
c. It reduces adiposity. This is favorable to some people who want to take some pounds off. It breaks down lipids.
d. It enhances lean body mass. It stimulates protein synthesis and amino acid uptake in the muscle. It enhances
lean muscle through this process, so this could help an older person to protect bone if they fall.
e. It stimulates the immune system. As you age the levels of growth hormone decline and as a result the
incidence of leukemias go up. This is subtle but it is there.
f. The other thing here is that people that take growth hormone start to think better about themselves and their
wellbeing. It is unclear if it gets into the brain or not, but it is more likely that they have lost some weight and
gained a little strength and have a higher self confidence.
[S3] Growth Hormone diagram
a. Growth hormone is 191 amino acid polypeptide single chain. It is 22 kD. This is the major product out of the
pituitary. (There is a 20kD alternatively spliced product that is missing amino acids 32-45). Growth hormone has
a couple disulfide bonds.
b. There are over 100 forms of this protein found in the blood, with the predominant one being what is shown on
the slide. This protein is modified by almost anyway you can think of (phosphorylated, acetylated,
polymerization) and all of these things are found in the serum and pituitary extracts and they have modified
activity which could be good or bad.
c. Not only do you find growth hormone being produced by the pituitary, but you also find a significant amount
being produced by the cells of the immune system. Growth hormone has also been reported to be produced in
the brain. These last two are local, but when it comes out of the pituitary it floods the whole body.
[S4] Anterior Pituitary Cells and Hormones
a. This is review from the previous lectures.
b. The somatotroph is the cell of the pituitary that makes the growth hormone. It’s the most predominant cell.
c. Most adenomas in the pituitary are a result of the growth hormone, so you get overproduction of this cell type
and expansion and you get intrusion on other tissues.
[S5] Figure flow chart
a. There are several mechanisms of control for growth hormone.
b. This slide shows the hypothalamus, pituitary, and some other important target tissues.
c. Somatostatin is a negative regulator. GHRH is a positive regulator.
d. These two emerge from the hypothalamus and impact the pituitary through that blood vessel system. They
promote or inhibit the synthesis of growth hormone.
e. Then you have feeback inhibition that occurs primarily through the IGFs. These are 70 amino acid proteins that
are insulin-like. They are structurally similar to insulin. Their receptors form similar to insulin. They promote a
lot of the effects of growth hormone.
f. The predominant site of synthesis of IGFs is the liver. There are different IGFs (1 and 2 with the primary one
being IGF 1).
g. IGFs feedback and inhibit at the level of the pituitary and hypothalamus. What they do here is diminish the
sensitivity of the pituitary to GHRH. They stimulate the synthesis of somatostatin in the hypothalamus.
h. There is also a short loop in this system where growth hormone can feedback and inhibit in the hypothalamus.
i. When you get older your growth is for the most part done. An increase in glucose and free fatty acids stimulate
somatostatin and this in turn inhibits the growth hormone.
j. Stress and sleep also affect growth hormone. When you need glucose that is a stress and as a result of that a
lot of things happen in the body. One is that growth hormone levels increase under the stress conditions so
they are inhibited when the glucose is up in the blood. They play a role at puberty because the sex steroids and
thyroid hormone will promote the secretion of growth hormone.
[S6] Ying-Yang Control of GH Secretion
a. This just shows a view of what can happen at the somatotroph where you have GHRH and somatostatin both
acting at the same cell with one inhibiting and one stimulating.
b. It turns out that they both work through the adenyl cyclase receptor and influence the levels of cAMP.
Heme/Endo: 3:00-4:00
Scribe: Andrew Treece
Tuesday, Nov 3, 2009
Proof: Dylan Vaught
Dr. Weigent
Growth Hormone
Page 2 of 4
c. In the case of GHRH you have a channel phosphorylation resulting in a depolarization of the cell. It is the extra
calcium that plays an important role in secretion and release of granules and dumping of the hormone.
d. On the other hand, somatostatin inhibits Gproteins, and will influence the transport of potassium and you get a
hyperpolarization.
e. All things being equal, somatostatin probably dominates here.
VII. [S7] Typical variations in growth hormone secretion…
a. This shows the secretion and diurnal nature of lower levels during the day and a spike at night.
b. It is probably just metabolic. At night you are not eating, and when you aren’t eating your body feels like it is
being stressed and looks for ways to maintain glucose levels through these hormones.
c. Growth hormone modulates the effects of low glucose levels in the blood to spare the brain.
d. There is another spike in result to exercise which is another stressful situation.
VIII. [S8] Somatotrope diagram
a. Another important hormone involved in the synthesis of growth hormone is thyroid hormone, T3, triodothyronine.
b. T3 will increase the sensitivity of the somatotrope to GHRH. It will increase the synthesis of growth hormone. It
also modifies the growth hormone receptor and helps target cells express that receptor and become sensitive to
growth hormone. These are 3 quick ways that thyroid hormone plays a role in what’s going on with growth
hormone.
IX. [S9] Evaluation of Growth Hormone
a. Growth hormone is measured in the blood through various methods.
b. Basal levels are usually low (nanograms) unless you are at one of the peaks, so it is usually measured by
pulling it out of reserves from the pituitary. It also varies from person to person.
c. You can give people insulin. It stimulates cells to take the glucose up. In that process you become
hypoglycemic and that is a stress. Less glucose, more growth hormone. You can measure the response to
insulin.
d. Growth hormone is also induced by high levels of arginine. You can give them GHRH. You can make them run
on the treadmill.
e. Then there are individuals that are older and past the growing stages, yet they get a tumor in the pituitary and
now they produce growth hormone. One of the things it does is causes other changes in the body. In those
people you can give them glucose and it suppresses growth hormone.
X. [S10] Proteolytic Cleavage
a. This is a transport model of the growth hormone. The above picture is in the human and the lower picture is in
the mouse. The receptor is a single polypeptide chain. Under certain conditions (like an immune response) an
enzyme that is a metaloprotease acts at the site between the membrane of the protein and cleaves off the
extracellular portion of the receptor.
b. If the ligand binds to the piece that is released you have a binding protein. Although growth hormone is a 22kD
protein and most proteins don’t have binding proteins in this case it does to protect it and build it as a reservoir.
About 50% of the growth hormone in the blood is bound in this form.
c. On the cells that have lost their receptor, those cells become desensitized to growth hormone. Some people
with acromegaly could use some desensitization so this may be used as a therapy.
XI. [S11] hGh receptor
a. This is the growth hormone and the receptor. It is activated as a dimer with two sites. The growth hormone
binds to one piece then that interacts with another receptor in the membrane and forms a complex with one
growth hormone and two receptor pieces. When these come together they attract kinases and become
phosphorylated and now you have second messengers being sent into the cell to perform the biology of growth
hormone.
b. Always use the right amount of growth hormone in the lab because more is not better here due to the
mechanism. You can bind up the receptor sites and they can’t for the dimer.
XII. [S12] Mechanism of Growth Hormone Action
a. What happens after growth hormone binds and forms the dimer it activates Jak kinases (listed here as Jak2).
b. These are receptor associated kinases that are not part of the sequence of the growth hormone receptor. As a
result of the dimer formation from above these Jak kinases are attracted to that spot and a lot of phosphorylation
goes on. They phosphorylate themselves and the receptor and now they become attractive to other substrates
in the cell like STATs (signal transducer activators of transcription). STAT 5B is most prevalent in the growth
hormone system.
c. These STATs are normally in the cytoplasm in a latent phase, but once they are phosphorylated they aggregate
and move into the nucleus and act at a number of promoters. These are in a lot of systems.
d. There are other proteins activated in addition to STATs. MAP kinases become activated and protein synthesis
is increased.
Heme/Endo: 3:00-4:00
Scribe: Andrew Treece
Tuesday, Nov 3, 2009
Proof: Dylan Vaught
Dr. Weigent
Growth Hormone
Page 3 of 4
e. One of the mRNAs that comes out of this process is the IGF. Another protein that comes out is SOCS
(suppressor of cytokine synthesis) which is a negative inhibitor. The SOCS is able to feedback and disturb and
distract the actions of the Jak 2 kinases. Intracellularly you have an inhibitor that is induced by the growth
hormone.
XIII. [S13] Growth Hormone pathways
a. Basically you have three tissues. The muscle, liver, and fat are all anybody really cares about with growth
hormone. Each hormone has a specific effect on each of these tissues.
b. In the muscle, it increases muscle mass, increases amino acid uptake, increases protein synthesis, and
decreases glucose uptake. This is important.
c. In the adipose, it increases lipolysis. It also decreases glucose uptake here but probably by a different
mechanism than in the muscle. The important feature is that it spares the glucose utilization by the muscle and
fat so that the brain can be served.
d. In the liver, there are increases all around. There is increase in RNA synthesis, increase in protein synthesis,
increase in gluconeogenesis. There is also an increase in the somatomedin or IGFs.
e. The bottom line is the ability to decrease the glucose uptake earns growth hormone the nickname of being
diabetogenic agent. It elevates the levels of blood glucose.
XIV.
[S14] Catecholamines flow chart
a. The only thing to be said here is that growth hormone works on the adipose tissue to stimulate a number of
pathways but the most important is the one where it stimulates the hormone-sensitive lipase.
b. That is the enzyme involved in the breakdown of triglyceride. It also inhibits the lipoprotein lipase which is the
enzyme that allows adipose to take up the free fatty acids.
c. So growth hormone stimulates lipolysis.
XV. [S15] Insulin-like Growth Factors
a. Read this slide and the next on your on. He has said the important aspects of these slides, but he did say read
them. The text is listed below. Also he added that IGF1 is more growth hormone dependent than IGF2.
1. IGF molecules are 70 amino acid peptides that have 50% homology to insulin and are growth hormonedependent for synthesis.
2. Found in serum as 150kDa ternary complex with an IGF-binding protein and a glycoprotein called acid-labile
subunit (ALS).
3. At least six IGF-binding proteins are present that regulate transport, availability, and half-life of IGF molecules.
XVI.
[S16] Insulin-like Growth Factors (cont)
4. IGFBP can inhibit or enhance IGF induced growth as well as act independently to promote growth. IGFBP
proteases have been described.
5. Highest amount of IGF RNA found in the liver. Local production of IGF molecules may be important in that they
may act in an autocrine or paracrine manner (role in malignancy?).
6. IGF molecules are more stable than GH and feedback inhibit GH synthesis at pituitary (blocks GHRH action) and
hypothalamus (stimulates somatostatin release).
XVII. [S17] Somatomedins flow chart
a. This lists more details about what IGF hormones are doing.
b. For the most part the arrows are green and up in the bone and peripheral tissue.
c. The liver is the predominant source of IGFs, but all kinds of tissues have the ability to make small amounts at
local levels. Tumors upregulate the IGF1 receptors or their ability to make IGF and it acts in an autocrine
fashion and it pushes them along to a higher grade and metastasis.
d. The key feature here is that it is anabolic and building stores of glucose.
XVIII. [S18] Figure 4 flow chart
a. This shows what is called the dual effector hypothesis for growth hormone and IGF-1 in the bone
b. Growth hormone is thought to be more involved in the differentiation in the precursor cells. Once they
differentiate then IGF-1 that is produced in the bone is thought to be more involved in the clonal expansion of
those cells.
XIX.
[S19] Somatopause
a. Somatopause is related to changes in secretion like making too much growth hormone. It is thought to be
something wrong with the hypothalamus among other things.
b. As you get old cells start disappearing. The cells that are important but very few, when you lose those it has an
effect. When you lose cells in the hypothalamus you lose GHRH and somatostatin becomes a larger player in
the regulation so you lose growth hormone.
c. What happens is about the opposite of what we said growth hormone is doing. So you get an increased fat
mass, the bones become more brittle, and there is muscle mass loss.
XX. [S20] Relation between the integrated concentrations of growth hormone…..
a. This just shows the relation between age and the integrated level of growth hormone.
Heme/Endo: 3:00-4:00
Scribe: Andrew Treece
Tuesday, Nov 3, 2009
Proof: Dylan Vaught
Dr. Weigent
Growth Hormone
Page 4 of 4
XXI.
[S21] Growth Deficiency
a. This is a 9yo Peruvian girl that is only 2.5 feet tall. She has a growth hormone receptor defect.
b. She has a decrease in growth hormone. There is a lack of somatotrophs. Sometimes people are just born with
fewer cells. Otherwise there is an inability to respond to GHRH.
c. There are problems in the receptor.
d. Sometimes those post-receptor events are to blame like decreased IGF production or action.
e. There is also decreased GHRH release.
f. As people get older the second messengers have a tendency to show up at the wrong place at the wrong time
and end up doing the wrong thing.
XXII. [S22] Gigantism
a. In the opposite case, you can have a pituitary with growth hormone excess before closure of the epiphyses.
XXIII. [S23] Acromegaly
a. This man has features that are ballooning out. His jaw grows large and his fingers are thick.
b. There are other changes that take place as a result. They are often diabetic due to the elevated levels of blood
glucose.
XXIV. [S24] Man diagram
a. These are some of the changes that take place in some individuals when they get older and maybe develop an
adenoma in the pituitary from a somatotrope.
b. They can get this osteonecrosis-arthritic-vertebral changes.
c. They can get enlarged hands and feet.
d. There can be hirsutism which is hair growth on the chest. There can also be a situation with gynecomastia and
lactation when growth hormone acts at the prolactin receptor. Prolactin does not act at the growth hormone
receptor.
e. When you get this pituitary tumor causing an increase in growth hormone it is crushing other cells so they get a
bitemporal hemianopia where they lose the peripheral vision.
(end time 41:53)