Growth hormones Flashcards
Learning Outcomes
Growth Hormone
So when we think of growth hormone.
We know that it is regulated. Again, as we said, with all the other hormones up till now, almost by the hypothalamus.
And you can see in this diagram that this time the, um,
release of hormones from the hypothalamus impacts upon the cells in the anterior pituitary that are known as somatotrope cells.
And these cells generate, uh, growth hormone.
And growth hormone is released into the circulation, and it has two main, um types of effects.
So it will stimulate soft tissue growth, um, and bone growth.
And it will also influence metabolism. So we’re going to have a look at these two different things as we go through.
Now remember that anterior pituitary does contain other cells that are involved in the regulation of hormones.
And we talked about some of these already. But we’re going to focus today on the somatotrophe cells.
These are the most abundant, uh, cells in the pituitary.
It’s about 10% of its mass.
So most of the response that’s seen comes from here, there would be quite a high level of of expression of protein that’s released from here.
So the difference is in this case is that growth hormone is exerting its effect mostly directly on body tissues,
whereas often the hormones that are released from the anterior pituitary then go on to cause other hormones to be released.
How hypothalamus affects growth hormone
So when we think of growth hormone.
We know that it is regulated. Again, as we said, with all the other hormones up till now, almost by the hypothalamus.
And you can see in this diagram that this time the, um,
release of hormones from the hypothalamus impacts upon the cells in the anterior pituitary that are known as somatotrope cells.
And these cells generate, uh, growth hormone.
And growth hormone is released into the circulation, and it has two main, um types of effects.
So it will stimulate soft tissue growth, um, and bone growth.
And it will also influence metabolism. So we’re going to have a look at these two different things as we go through.
Now remember that anterior pituitary does contain other cells that are involved in the regulation of hormones.
And we talked about some of these already. But we’re going to focus today on the somatotrophe cells.
These are the most abundant, uh, cells in the pituitary.
It’s about 10% of its mass.
So most of the response that’s seen comes from here, there would be quite a high level of of expression of protein that’s released from here.
So the difference is in this case is that growth hormone is exerting its effect mostly directly on body tissues,
whereas often the hormones that are released from the anterior pituitary then go on to cause other hormones to be released.
Human Growth Hormone
So in terms of human growth hormone, it’s a large ish, protein that contains 191 amino acids.
And you can see a diagram at the bottom here.
And you can see it looks a little similar to insulin in terms of, um, its secondary structure.
Growth hormone signals through tyrosine kinase receptors
which generally, um, does stimulate not only body growth in terms of organ size, um, and things like that.
It increases those organ sizes by increasing the rate of mitosis that’s going on.
And it also influences it by allowing some bones in some tissue types to become more specialised through that process of differentiation.
Um, so an example of that is seen in bone.
It also stimulates the release or secretion of insulin like growth factor one,
which happens in the liver, and between, growth hormone and between insulin like growth factor one.
This increases the protein synthesis and metabolism of fatty acids.
So it stimulates, uh, lipid breakdown. Um, when the body is in a fasting state.
And this, of course, counteracts the actions of insulin.
So it drives for no uptake of peripheral glucose into the tissues and muscles, because this is usually a hormone that is released,
um, during periods of, low, glucose levels, to drive that blood glucose level to stay up.
So during, the embryonic phase.
growth hormone levels are relatively low and it increases shortly after birth.
And this continues to increase up to puberty.
GH Receptor signalling
So in terms of growth hormone signalling, we have our receptor on the cell surface this time.
And amino acid or protein, growth hormone will bind to its receptor.
And this then leads as a tyrosine kinase receptor to the recruitment of proteins that will then pass on the information.
by phosphorylation. And then this will lead to a cascade of proteins being activated.
And these will eventually be able to enter the nucleus and increase transcription.
Control of Growth Hormone Release
So in to in terms of our growth hormone, release what happens and when.
So up at the top here, we’ve got our hypothalamus.
And what happens is, is that we get growth hormone releasing hormone (GHRH) that is released by the hypothalamus.
And this is carried down in the hypophyseal circulation down to the anterior pituitary where it stimulates receptors,
growth hormone releasing hormone receptors on the somatotroph cells.
These cells then release growth hormone, which is this purple triangle, into the general circulation.
Of course, this may have its own effects through binding to growth hormone receptors in many tissues,
and that will usually result in an increase in mitosis, which leads to proliferation, but also an increase in cell size.
So an increase in the number of cells and an increase in the size, which is also known as hypertrophy.
In the liver. However, the exposure of growth hormone and binding of it to its receptor is shown here.
Then leads to the release of insulin like growth factor one.
Insulin like growth factor one is then released from the liver,
and it can go on to bind to insulin like growth factor receptors that are present on bone and soft tissue elsewhere.
there are additional roles for Insulin like growth factor one, which we’re not going to consider in this module
So it’s important just to know that there can be additional effects.
But there’s also the ability of IGF-1 to have other effects.
there are other stimulus that lead to the release of IGF-1.
It’s not just growth hormone.
Effects of Growth Hormone
So in terms of what effects growth hormone has, generally, as I mentioned before, there is an increase in tissue size,
and an increase in protein synthesis, RNA and DNA synthesis, which of course enables that mitosis rate to slowly etch up.
In the liver. Of course, that stimulates the release of IGF one because it transcriptionally turns this gene on,
which then leads to the creation of IGF one protein.
It’s important to know that growth hormone, although it is a peptide protein of 191 amino acids,
it’s actually small enough to be filtered by the kidney.
So it needs to be bound to a protein in the circulation to prevent it from being, filtered.
And that, of course, increases the half life of this hormone.
In terms of its effect on bone. this can increase protein deposition.
Um, it can increase the number of chondrocytes, and the size of chondrocytes
But it can also increase the number of osteogenic cells.
Osteo meaning bone. So there’s also the ability, to
Induce some differentiation of those osteogenic cells.
And the creation of osteoblasts and osteoblasts.
build bone is how I think of it.
Osteoblasts are able to increase the thickness of the very top layer of the periosteum by laying down deposits of calcium.
And this is really important throughout life because the thickness of the periosteum can also, relate to how strong these bones are.
Insulin-like Growth Factors (IGFs)
Now insulin like growth factor also has a role of its own.
it’s a peptide growth factor and it binds instead to G-protein coupled receptors.
And these act by adenylyl cyclase.
And there are two related factors IGF one, which is generally expressed during adulthood, and IGF two, which is only expressed in the foetus.
These are previously called somatomedins because it was thought that these mediated the effects of growth hormone.
But it’s actually now been found that these can have their own effects, and hence why they’re now called insulin like growth factors.
And generally they’re considered to
Induce growing tissues. So for example they have effects on bone adipose tissue and also the liver.
Peptide growth factors, act via G protein coupled receptor signalling (via adenylyl cyclase)
2 related factors, IGF-1 and IGF-2 (previously called somatomedins)
Synthesised in growing tissues e.g. bone, adipose & liver
So in terms of our, G-protein coupled receptor, you can see here that insulin like growth factors or other, peptide.
Hormones may bind to a G protein that’s here in the membrane.
It crosses the membrane seven times.
And this is associated with, a heterotrimeric G protein protein underneath and heterotrimeric meaning it has three parts a,
G alpha, a G beta and gamma subunit.
And what happens is, when this is bound to GDP.
It’s inactive, and when the GDP is swapped out for GTP, it then becomes active.
And this is able to activate this little enzyme here that’s in the membrane called adenylyl cyclase.
and this has the ability to convert ATP into cyclic AMP.
And that conversion, then allows cyclic AMP to bind as a cofactor to lots of different enzymes,
and then stimulate things other proteins to move into the nucleus.
Insulin-like Growth Factors (IGFs) functions and work in bones
So in terms of those interested in growth factors, the functions of course, are in part due to growth hormone.
And it has an important part in the feedback mechanism for growth hormone
it stimulates cell growth, as we mentioned.
And IGF two is the most active in the embryonic phase of development in terms of bone, which will be important next week.
it stimulates lots of different aspects of chondocyte function which are important, such as collagen production and bone matrix Lay down. It’s also important in the formation and differentiation or maturation of osteoblasts, which are the key generators of bone.
Effects on Metabolism
So in terms of what this looks like when we put this all together,
is that during a fasted state, the liver glycogen would be converted into glucose.
Because, remember, this is a place where glycogen can be stored not just in the muscle,
but that conversion of glycogen to, glucose also happens of course, in the muscles.
Where you would be generating, some more of this to generate energy production.
Also what would happen. the adipose tissue would begin stimulating.
We would start with our triglyceride stores, break them down into fatty acids and glycerol,
which can then go through gluconeogenesis to generate glucose.
So these two things are happening. via growth hormone and via also via cortisol as well.
And then in the muscle, we’re again getting the breakdown of some proteins.
If this low level of glucose or hypoglycemic period lasts for, even longer, that will generate amino acids,
which can then get broken down and used for energy production through gluconeogenesis.
And then our final one where there’s actually no effect.
But is the whole point of this exercise is that glucose levels are maintained so that your brain can still work.
And I think of it a little bit like this. If you’re lying in bed, you’re in a fasted state.
Okay. It’s 4:00 in the morning.
You’ve been asleep for a little while. Some of us longer than others.
And you’re lying that you desperately need a wee.
So you get up. Your body is also in a region where it shouldn’t need too much energy to move your muscles.
If you got out of bed but you didn’t have your brain working, then there would be no point having your muscles moving when you’re lying in bed.
You need to dream. You need to still maintain your brain function.
otherwise When you wake up in the morning, you won’t be able to think about anything.
You won’t be able to move. Okay, so this is what happens.
During that fasted state, your brain needs to still be active.
And the only, the only thing that can penetrate the barrier is glucose.
It can’t take up triglycerides.
It can’t take up pyruvate or lactate.
And this is why everything is converted into glucose.
So it’s easy to get it into the brain and to keep the brain working.
Metabolic effects of Growth Hormone
Now, I mentioned also that there are metabolic effects of growth hormone.
And when we looked at those functions earlier, we mentioned what the effects were in the fed state.
But actually growth hormone has quite a big effect on what happens during a fasted state as well.
And actually it works mainly.
Its main aim is to maintain the blood glucose levels so that the brain can still function okay in adipose tissue and in muscle.
This means that it decreases uptake because they’re the hungry ones.
They’re the ones that during times of when you’re awake, for example, and you’re moving about using your muscles, and as you might be Eating, anything excess and left over will be stored, as adipose tissue.
So both of these then we need to shut down if you have low glucose levels.
And we need to stop those things from happening because they will decrease the blood glucose levels.
Instead, in the liver and in adipose tissue, it drives for the generation of new glucose, So gluconeogenesis. And it also, drives glucogenesis as well.
And there’s lipolysis that happens in the adipose tissues, making sure that you generate new, glucose from the stored fats.
So the breakdown of triglycerides to generate some more glucose.
One of the main effects is on Bone
So you get up. Your body is also in a region where it shouldn’t need too much energy to move your muscles.
If you got out of bed but you didn’t have your brain working, then there would be no point having your muscles moving when you’re lying in bed.
You need to dream. You need to still maintain your brain function.
otherwise When you wake up in the morning, you won’t be able to think about anything.
You won’t be able to move. Okay, so this is what happens.
During that fasted state, your brain needs to still be active.
And the only, the only thing that can penetrate the barrier is glucose.
It can’t take up triglycerides.
It can’t take up pyruvate or lactate.
And this is why everything is converted into glucose.
So it’s easy to get it into the brain and to keep the brain working.
So this is in complete opposition to what happens in bone, of course.
Which is where our focus is going to be next week. So in terms of our growth hormone, growth hormone stimulates two effects on bone.
So its direct effect is that it makes the chondrocytes the are present in the end of the bone.
So this part up here at the top is the epiphyseal plate.
And underneath it are the cells that go through expansion when you’re getting long bone growth.
And the chondrocytes have to increase in their number and they extend the region of bone where the GH moves into.
And commitment to that chondrocyte lineage, the cells to which the GH is added, is what’s induced by growth hormone,
growth hormones effect through IGF one on chondrocytes however results in proliferation and hypertrophy that’s happening at those chondrocytes as well.
So not only we’re having an increase and committing to that lineage, there’s an increase in the number and an increase in size.
And this pushes the long bone growth. However, there’s also a paracrine effect of IGF one that’s independent of growth hormone.
So it happens within the bone not necessarily from outside.
And it will release IGF one.
In response to exposure of IGF one.
And again, that will increase the number and lineage of cells here.
IGF-1 can exert both endocrine and paracrine/autocrine effects. When discussing its paracrine effects within bone tissue, it means that IGF-1 is produced and acts locally, directly within the bone microenvironment.
Independent of Growth Hormone: While IGF-1 is typically associated with GH stimulation (systemically released by the liver), local production of IGF-1 within bone cells can occur independently of GH. This local production influences bone metabolism and growth in a more direct and tissue-specific manner.Response to IGF-1 Exposure: Cells within the bone respond to the presence of IGF-1 by upregulating signaling pathways that increase the number of osteoblasts and their activity, enhancing bone formation and mineralization
When do we need GH?
So in terms of regulation over from when you’re a foetus to
Very late on in life. Post 65 is considered to be this senescence region.
You can see that immediately after birth, there’s an increase of growth hormone that then peaks during puberty.
And if you think about it, this is when most of your growth is happening pre puberty.
And then after puberty this starts to drop off very quickly okay.
So there’s no further growth in bone length and things like that.
But this is relatively evenly maintained through adult life until you get older.
When do we need GH? in the day
Now the brain. Needs that growth hormone.
So this does also mean that there’s a daily
Regulation of the release of growth hormone.
Once you hit midnight, then there’s an increase of growth hormone up to about 2:00 in the morning of growth hormone release.
And of course, this is the bit where you might have had dinner, maybe about 7:00, maybe a little bit earlier, maybe a bit later.
So this is the point at which you have had your food.
You’re digesting it. Now we’re hitting low levels of glucose because this is a semi fasting state.
Okay. And so what happens is every four hours during those periods you will get a release of growth hormone.
So you can see almost periodically every four hours there’s release.
And it gets smaller towards the end here as you start to get a little restless.
So periods of stress when cortisol is high, such as sustained exercise, fasting or starvation.
These are all stimulants of the release of growth hormone.
so. I’ve given you some reference values.
Please do not memorise these. These are here for your reference to come back to.
When do we need GH? how is it regulated
So when do we need growth hormone? as I mentioned, it’s a stress hormone.
Increases with physiological stresses as in walking, jumping.
Okay. It also increases with neurological stress.
Then you know such as the perceived “oh my goodness I’m stressing!”.
it also is acutely triggered by hypoglycaemia.
and as we’ve just mentioned in the figure this will be used when we’ve got an increase in the amino acids that are in the blood.
And this stimulates growth hormone release and an increase in glucose concentration and fatty acids leads to the inhibition of growth hormone.
Feedback and Physiological stimulation of Growth Hormone
growth hormone is acutely triggered by hypoglycaemia.
and as we’ve just mentioned in the figure this will be used when we’ve got an increase in the amino acids that are in the blood.
And this stimulates growth hormone release and an increase in glucose concentration and fatty acids leads to the inhibition of growth hormone.
So how does that work. Remember we talked about the hypothalamus before.
And we’ve got growth hormone releasing hormone that is stimulated by those things you just talked about such as deep sleep.
also an increased level of amino acids in the bloodstream hypoglycaemia, decreased levels of fatty acids.
So all the things that would happen if you haven’t eaten for a while okay.
What you also notice is there’s a number of different hormones that stimulate this.
So this growth hormone releasing hormone stimulates the somatotrophes from the anterior pituitary,
which then leads to liver, bone and skeletal muscle metabolic effects.
But on the liver, this leads to the release of insulin like growth factors.
These also have a negative feedback to the anterior pituitary to reduce the release of growth hormone,
and also to reduce, growth hormone releasing hormone.
But there’s also circumstances under which there is release of growth hormone inhibiting hormone.
Also known as somatostatin.
so these stimulus, are all the opposite of these ones over here on the left that stimulate the release.
So ageing, obesity, high blood, levels of growth hormone and insulin like growth factors,
but also hyperglycaemia, high levels of fatty acids and low levels of amino acids.
So in these situations, you don’t need growth hormone to be stimulating the release of glucose, because they may already, have those high levels.
Okay. Again. I’ve given you the IGF ranges here.
They are different depending on what period of life you’re in.
Again, I don’t remember them. I’ve given you the reference.
Please come back and use this if you need to.
What happens when it all goes wrong?
Pituitary Dwarfism
So what happens when it all goes wrong? I’m not going to spend ages on this because I’ve been talking for a while already, and I’m aware of that.
But please do look at these slides to identify some of the deficiencies that may come.
Obviously, if we don’t have a lot of growth hormone that may be visualised as a form of dwarfism in this case there may be a deficiency or change in the receptor or other causes.
There is need for growth hormone in growth of height.
And that can mean if we don’t have a lot of those during, childhood, then we will end up with some dwarfism
And often this can be treated with growth hormone replacement.
before we could genetically engineered human growth hormone to be used.
there was a period of time where we tried porcine, growth hormone, which didn’t work.
It has to be primate growth hormone and part of the reason for then creating it via Genetic engineering was because prior to that, we used to take this growth hormone from cadavers, dead people.
Okay, so this was really important here.
Variants of Dwarfism
there are some cases where no more growth hormone is seen.
However, there is still dwarfism.
So an example of that is laron dwarfism where there’s a single base pair change in the growth hormone receptor or even larger sections removed,
which can lead to a reduced reduction in the growth hormone sensitivity.
Because there’s no receptor for it to be detected by.
And in this often you see low IGF one also.
The important thing to remember is up till now I’ve talked about dwarfism in childhood.
Pituitary Gigantism
if pituitary, production of growth hormone remains high in adulthood,
what we tend to see is that you start to get an increase in rapid bone growth.
And of course, normalmbody proportions change.
Uyou end up with someone much taller, usually about eight feet tall.
This is relatively rare, to see.
Acromegaly
However, if pituitary gigantism happens in adulthood,
of course you’ve gone through the phase of height increase already so instead you start to see changes to the
fingers so you get bony outgrowths around the joints and enlargement of the brow across the top here,
and sort of a very square jaw. Um, there’s also some changes in, uh, peripheral tissues and things like that.
So these changes are irreversible and can cause quite a lot of pain.
Summary- Describe the feedback control that occurs between the hypothalamus, pituitary and other organs in the control of hGHsecretion
Explain the physiological effects of both hGHand IGFs and relate this to their mechanisms of action.
Examine signs or symptoms of diseases where hormonal imbalance is occurring and link these to other regulatory systems that may contribute to these
Deficiency
Hormone imbalance
Receptor
