9. Endocrinology - 1

Whoops. Is the lighting okay for everybody? Yeah, okay. Well, good morning, everyone. Thank you for coming along to this 9 o'clock session on a Wednesday. My name is Sue Chan, and I will see you for three lectures this semester and then another three lectures. in the second semester on endocrinology. So we're going to be looking at endocrine system and hormones in the body. Okay? So as I said, three lectures this semester, the next three lectures, so that's today, 10 o'clock. and also next week at 9 a.m. We're going to be looking at basic mechanisms and the main endocrine systems within the body. There are a number of different endocrine glands within the body, and we'll have a look at each of those in turn. And then in the spring semester, we're going to start putting all these hormones together and start to look at disease as well. So those people who have just come in, if you wouldn't mind just quickly scanning the QR code. Thank you. Okay, so the very first lecture we're going to do is to review those hormone mechanisms, those principles behind how hormones work, how they bring about their actions within the body. But before then, we also have to understand how they are synthesized. and transported in the body. So we're going to start off with some terminology, firstly defining what intercellular messages mean. So essentially it's communication between cells as intercellular. And then to look at... at two main groups of hormones, peptide hormones and steroid hormones, compare and contrast in terms of the basic structure, synthesis, release, transport, and mechanism of action. Look at how hormone levels are regulated. Hormone levels are not static. They go up and down depending on the need of the organism. And then finally, we're going to look at a little bit about how endocrine disorders or diseases come about. and how we might treat those conditions. Okay. So starting off with some terminology then. So endocrine essentially means internal secretion. Endo meaning internal or inside. Crine meaning secrete. Okay. So the endocrine system essentially means that we've got endocrine glands, organs in the body that secrete hormone. The hormone itself is the chemical messenger involved in that communication. communication between cells. So it's the first of our inter-cellular communication systems. The hormone is that chemical messenger that's secreted by an endocrine gland, and that endocrine gland does not contain ducts, in other words, tubular systems within that organ itself. Now I'd like you to look at the bottom here. An exocrine gland is a gland that has ducts within so that the product... is then secreted to the external part of the body. Exo meaning outside crine secretion, okay? So we're talking about the salivary gland. So saliva is produced and then secreted along into these tubular connections to the external part of the body, which would be the mouth. Now you think it's the inside body, but actually if you think about opening your mouth, that's actually then outside the body, okay? So you're secreting saliva. via these exocrine duct-containing glands. Similarly, sweat, glands in the skin, and then lacrimal is the tear duct. So exocrine essentially means secretion outside the body, and we have some examples here. With endocrine, we've got hormones that are secreted into the circulation, into the blood, and then that hormone travels around some distance within the circulation to then reach... target cells and tissues. Everybody okay with the definitions there? Okay. All right. So let's have a look at these intercellular messengers in the body. We have four types that we need to, well, five types actually, that we need to concern ourselves with. We've got that endocrine. So again, it's a hormone, which is the intercellular messenger molecule from an endocrine gland secreted into the circulation, traveling some distance in the circulation. in the blood to reaching their target cells and tissue some distance away. So the example that I'd like to give to you and may be familiar to some of you is insulin. So insulin is a hormone secreted from the islets of lung hands within the pancreas. And then insulin... In the circulation, travel some distance to reach the three main metabolic organs in the body. That's the liver, the adipose tissue, fat cells, and skeletal muscle. And from there on, the insulin is able to affect the... metabolism within those organs. And you'll see that these organs are obviously some distance away from the pancreas. So the insulin, the hormone, has traveled some distance. Let's like to define to you auto-crime communication and para-crime communication. Again, looking at the words here, auto meaning self, crime, secretion or cell. We've depicted auto-crime with the letter A. This is when it's a substance secreted by the cell, and it's not secreted into the blood. It's just secreted into the interstitial fluid. That's the fluid that bathes the cell, okay? That autocrine substance travels a very short distance within the interstitial fluid to affect that same cell that secreted that substance. So it's a substance secreted by the cell, traveling a very short distance within the interstitial fluid, the fluid that bathes the cell, to then come back and affect that same cell that made that substance. A classical example here are your prostaglandins, which you'll learn in a moment. learn about later on in the module. And then we've got paracrine denoted here by the P. Para meaning alongside, adjacent, neighbouring. Okay? So hopefully you can see that a paracrine substance in terms of communication is one that's secreted by one cell into the interstitial fluid, travelling again a short distance to affect the adjacent or neighbouring cell. Okay? So here, We've got within the islets of Langerhans a number of different cell types. Some are able to secrete somatostatin, and this somatostatin can go on to affect insulin secretion from neighboring islet cells. So this is paracrine communication, where there's only a short distance of the molecule traveling within the interstitial fluid to affect neighboring cells. Next we've got neuroendocrine. So again, look at the name of this. Neuro relating to nerve cell. Endocrine we've just defined a moment ago. So this is where we've got a nerve cell that actually makes a whole... The hormone is stored in the axon terminus and then when required, that hormone is secreted into the blood, travelling some distance to reach its target cell. Now this nerve cell... can be known as a neuroendocrine cell or a neurosecretory cell. The hormone that's made can be known as a neuroendocrine hormone or a neurohormone. So this relates to endocrine cells that are also nerve cells and that upon the arrival of a nervous stimulation, the neurohormone is then secreted from the axon terminus into the blood, traveling some distance to the brain. to reach target cells and tissues. And examples here, we've got oxytocin and arginine vasopressin, which is also known as antidiuretic hormone. And these two hormones are secreted from the posterior pituitary gland. And we'll look at this again in our second lecture this morning. And finally, we've got neurotransmitter, which I believe you've had lectures on already. This is where it's a substance secreted by a neuron from the presynaptic membrane here. And this neurotransmitter crosses the synaptic cleft within that synapse to reach the postsynaptic membrane of this second neuron. And we have many examples of neurotransmitters. We've got no adrenaline. acetylcholine, glutamate, glycine, etc. Everybody okay at this stage? Okay, so we've defined intercellular messengers. We're particularly interested in endocrine communication and the communicating molecule. This chemical messenger is known as the hormone. We have several types of hormones based on the chemical makeup of hormones. Okay, so we have PET. hormones, steroid hormones, hormones derived from tyrosine, and then the last group here, the iodine. ...cosinoids, which are the prostaglandins. We're going to be focusing on the first three groups because you're going to be looking at prostaglandins in some more detail later on. So the peptide hormones, you're very well aware... They're made up of amino acids. They're simple chains of amino acids, such as with TRH, which is three amino acids in length, or much more complex with secondary and tertiary structure. such as in LH and FSH. The peptide hormones make up a large group of hormones, and they include those from the hypothalamus, the anterior and posterior pituitary glands, pancreas, and the gut. The steroid hormones, they're all based around cholesterol. This is that fatty substance that you find in the bilayer of plasma membranes. Cholesterol is also that fatty substance that we talk about, which can clog up blood. vessels in those who have high cholesterol levels. So cholesterol is a fatty substance and cholesterol is what is the starting material for the synthesis of steroid hormones. The steroid hormones include cortisol, aldosterone, both of these are from the adrenal cortex. And then we've also got the sex hormones such as testosterone, estrogen and testosterone from the gonads, the reproductive system. We then have the hormones derived from tyrosine, so that's the amino acid tyrosine. We've got the thyroid hormones and the catecholamines from the adrenal medulla. The catechol element is the phenolic... ring with the hydroxy groups of the tyrosine R group, the R chain. And so the catecholamines are those that have amines attached also. Okay. So we're talking about adrenaline and noradrenaline here. So those are from the adrenal medulla. So, maybe you're starting to see that with the chemical makeup of these hormones, that this difference in the chemical structure would therefore reflect on the way in which the hormones are synthesized, stored, transported and held. they act. So what we're going to do next is to compare and contrast peptide hormones with sterile hormones. Peptide hormones tend to be hydrophilic. They like aqueous environments. Okay? Whereas the steroid hormones, based around that molecule cholesterol, they are lipophilic. They like fatty lipid environments. So there's the marked difference in the chemical makeup of these hormone groups here. Okay. So let's start off with peptide hormone synthesis. So peptide hormone synthesis involves the same machinery in cells for any molecule or protein that's going to be secreted or exported. from a cell. So we're starting off with the gene of the peptide hormone. So we're starting off with DNA which is transcribed to messenger RNA. that then acts as the template for the synthesis of that peptide hormone. The messenger RNA is translocated or transported out of the nucleus, and then it's used as a template for the synthesis of the peptide. The very first molecule that's made, that's within the rough endoplasmic reticulum, is the pre-pro-hormone molecule. So the... protein synthesizing organelles in the body or in the cell here are the ribosomes. The ribosomes are attached to a tubular network known as the endoplasmic reticulum. So the ribosomes together with the endoplasmic reticulum form what's known as the rough endoplasmic reticulum. That's where the peptide hormone is made and the peptide hormone is made within the tubular network. The first molecule that's made is pre-prohormone. It's not yet the mature hormone. The pre part is a signal peptide that is telling the cell this particular peptide molecule needs processing, it needs packaging because it's going to be exported or secreted from the cell. Okay, so whilst the pre-pro hormone is transported along this tubular network, we've got some post-translational modification steps occurring, and the pre-signal is also... cleaved so that by the time it reaches the Golgi complex it's now in the form of pro hormone we've cleaved the pre signal away we've had some post translational modification in the RER and now with within the Golgi complex, there's just some additional processing, any additional cleavage of any extraneous segments to then package the hormone within the secretory granule. in the secreted granule, it's now in its mature form. So the hormone is now stored. The hormone is stored until released upon the arrival of a stimulus. Everybody okay? Does anybody need me to explain that process again? Have you covered this already anywhere else where on the degrees that you're doing? Does anybody need me to explain this again? Yeah? Fine? Okay. So what we're starting with, the peptide hormone... is the gene for that hormone. So the first step of making our peptide hormone is to transcribe that DNA into messenger RNA. That messenger RNA gets moved out of the nucleus. into the cytoplasm because that's where we're going to find the ribosomes. The ribosomes are that protein-synthesizing organelle, and these ribosomes are attached to a tubular network known as the endoplasmic reticulum. Together, they form the rough endoplasmic reticulum. The peptide hormone is made within the tubular network, and the first molecule that's made is known as pre-pro-hormone. The pre-part is this. hydrophobic signal to tell the cell that this particular peptide needs further processing, it needs packaging because it is going to be exported from the cell. So whilst it's moving through this tubular network of the RER, the rough endoplasmic reticulum, we've got the post-translational modification steps and the cleavage of that pre-signal so that by the time it reaches the next... The next tubular system known as the Golgi complex is now in the form of pro-hormone. It's not yet ready. It needs further processing and packaging as it travels through this, again, another tubular network known as the Golgi complex or the Golgi apparatus. By the time it reaches the secretory granules, which are vesicles, pinched off from the Golgi complex, we now have our hormone in its mature form and it's stored within these secreted granules until we're ready for the hormone to be released. Is that okay? Yeah? Everybody okay? Right then. So we've got our hormone made and it's stored in secreted granules. So when a stimulus arrives for hormone release, what we have is this process known as exocytose. Exocytosis is the movement of secretory granules towards the plasma membrane. The membrane of the secretory granule and the membrane of the plasma membrane fuse together. The content of the granule is then expelled out. So exocytosis is fusion of the secretory granule with the plasma membrane and then hormone release with the expulsion of the content of the granule. the secreted granule out of the cell. Okay. Steroid hormone synthesis does not involve genes. Remember, it's based around that molecule cholesterol. So I've shown you cholesterol with this pale-colored rectangle, and essentially... it's a series of enzymatic conversion of that cholesterol molecule. There's a number of enzymes involved in converting that steroid molecule into our steroid hormone. enzymes shown in this green oval and we then are able to reach our through the synthetic pathway our mature steroid hormone with this hatched rectangle okay now remembering that cholesterol is a lipophilic molecule, our steroid hormones are also lipophilic. You can't contain them in membranes because they're able to cross through the lipid bilayer of these membranes. So what happens is that that they pass through the plasma membrane by simple diffusion. Remember that the plasma membrane has its lipid bilayer that's also made up of cholesterol. And so these steroid hormones, being lipophilic, can easily just cross through by simple diffusion. And they are not stored, so you cannot contain your lipophilic hormones in membranes, because they just pass through those membranes very easily. And because they are lipophilic, they therefore are not able to be transported in the circulation easily. They don't readily dissolve in the circulation. inverted commas, in the aqueous environment of the plasma of blood. So they need to be bound to plasma proteins, which then helps their solubility within blood to then be transported around the circulation. Everybody understand that? So when you mix oil with water and you shake it, eventually they will separate. So the oil doesn't go into that aqueous environment very well. And similarly... We have that with our lipophilic hormones. And to overcome the transport issues here, we bind our lipophilic steroid hormones to plasma proteins, which increases the solubility of our steroid hormones so that we can transport this steroid hormone much more readily and much more easily within circulation. Based on what we know about the chemical structure then of these peptide hormones and steroid hormones, with the peptide hormones being hydrophilic and the steroid hormones, and I'm also going to include the thyroid hormones here as being lipophilic. their transport and their half-life are quite distinct and different. So with the peptide hormones being hydrophilic, they can dissolve, inverted commas, in the aqueous environment of plasma. They are circulated as free, unbound hormone, so they're not bound to plasma proteins. Whereas the lipophilic hormones, they are not readily soluble in the plasma, so they need to be bound to these plasma proteins, which act as carrier molecules, and there are these weak, reversible bonds. Okay? And in terms of the half-life, the half-life is the time taken. for the initial concentration to fall by 50%. Hydrophilic peptide hormones, their half-life is really short. And that's because there are protease enzymes within the plasma that will easily degrade the peptide hormones. So once a peptide hormone is secreted, it's not around for very long. It's just around for a few moments because there are protease enzymes within the blood. that then degrades, metabolizes the peptide hormone. So the half-life of your hydrophilic peptide hormones are low. Whereas the steroid and thyroid hormones, which are lipophilic, they are bound to plasma proteins, okay? And essentially, that protects the hormones from being metabolized, from being degraded. So there's an increase in the half-life of these. lipophilic hormones. So being bound to plasma protein protects the hormone from being broken down. So they are around for a lot longer, hours to days. So to summarize a little bit more here, unbound free hormone is what we regard as being biologically active. That is the form that can go to bind to receptors on target cells. However, as an unbound or free hormone, it is more susceptible to metabolic degradation because there are protease enzymes floating around in the blood. Binding to plasma carrier proteins delays that metabolism, as we've seen with the lipophilic hormones. So it provides a circulating reservoir of hormone. In other words, there's a lot of those lipophilic hormones around because there is delayed metabolism. There's decreased susceptibility to... to metabolic degradation. circulation. Everybody okay with that? Okay, so what have we done? We've talked about how hormones are made, how they're transported in the circulation. How about how they act then? Okay. We've started to talk about receptors. Receptors are what... mediates the effects of hormones. And again, the location of those receptors depend on the chemical makeup of the hormone. So with peptide hormones being hydrophilic, they cannot readily... cross the plasma membrane easily. Remember the plasma membrane is lipophilic because it's got the lipophilic bilayer. And so being hydrophilic and not being able to cross the plasma membrane easily, then we have plasma membrane located receptors for peptide hormones on target cells and tissues. Everybody understand that? Yeah? Okay, so hydrophilic peptide hormones cannot cross plasma membranes easily. Therefore, receptors for these are located on the plasma membrane. We have two types of plasma membrane receptors available depending on the hormone of interest. We have on the left G-protein coupled receptors and on the right tyrosine kinase linked receptors. Okay, when these receptors are activated, there is signal transduction. And what that means is that we've got the mediation of the signal from the hormone from the outside of the cell to the inside of the cell. There may be a number of second messengers involved, and that leads to, ultimately, the physiological response. That response might be changing the activity of enzymes, Could be changing the activity of ion channels, or we're changing the expression of specific proteins. And that means from the DNA to messenger RNA to protein synthesis of specific proteins. And that altered expression of that protein means that if it's an ion channel, you're going to get more ion channels expressed, therefore the activity associated, or if that specific protein is an enzyme, then it might be that increased or decreased. decreased activity of that enzyme. So once again, we've got G protein couple receptors, or tyrosine kinase linked receptors as peptide hormone receptors. Once activated, there may be signal transduction, and the physiological response may be one of these listed here, or a combination. It could be altered enzyme activity, ion channel activity, or even gene expression. An example of a hormone that's, its effects being mediated by a G-protein couple receptor is that for glucagon. And the G-protein is GS. The effector molecule is adenylate cyclase. And the second messenger here is cyclic AMP. An example of a tyrosine kinase-linked receptor for a peptide hormone is that for insulin. Okay, so steroid hormones mediate their actions via intracellular receptors. Remember, lipophilic easily pass across plasma membranes, so they're easily therefore... gain access to the inside of the cell. And much of the effects of these lipophilic hormones, steroid hormones, and new thyroid hormones are mediated by intracellular receptors. Now, these may be located in the cytosol or even in the nucleus. Okay? And when these receptors are activated, then what we have... Can you still hear me at the back? Yep. What we have is the binding of two, that is the hormone and the receptor, to the promoter region of specific genes. Okay? So intracellular receptors can be regarded as being hormone-regulated transcription factors. So when the hormone binds to its intracellular receptor, the complex binds to the promoter of a specific gene and able to either increase or decrease gene expression. In other words, it may activate gene expression by then allowing DNA to be transcribed to messenger RNA, and that messenger RNA to be translated into protein, or there could be a decrease in gene expression, decrease of this transcription and translation. So ultimately... The change in protein levels and its associated function would therefore be the consequence of this change in gene expression. Everybody okay with that? Yeah, so this is known as the genomic effect of hormones here. It's complicated in that these lipophilic hormones may have actions that are mediated by plasma membrane receptors. These plasma membrane receptor mediated effects are more rapid. okay the genomic mechanism can take a number of hours for the effects to be seen or even days whereas the much more rapid effects that we see with plasma membrane receptors can happen in seconds or minutes. Now, this concept here of plasma membrane receptors for these lipophilic hormones has only been around for a small number of years, and it's beyond the scope of these lectures to talk more about these. But we will talk about the genomic effects mediated by these lipophilic hormones. So what have we done here then? We've talked about intracellular receptors. and what they are, sorry, intercellular messages and what they are, and we understand what endocrine means. We've gone through peptide hormone and steroid hormone synthesis, release, transport. In terms of metabolism, we're not going to focus much on there. There's nothing particularly startling about metabolism of hormones, just that it's the same processes as other protein or lipophilic molecules within the body. going to move on to looking at the regulation of hormone release and then to finish off with endocrine disorders. So hormone levels do not stay static. There are times when we need a little bit more and other times when we don't need as much. But what we do need in biology is homeostasis. Homeostasis is basically the processes involved in maintaining the environment being external around us or the internal environment at an optimum level. A level that is relatively constant and steady but optimal. optimized for life. So that's homeostasis. And what we have here are some processes to maintain homeostasis, to maintain this almost equilibrium of optimized steady state. Okay? So what I'd like to describe to you first is feedback regulation. Now, you probably know a lot more about feedback regulation than you think. And I'm going to describe this to you. And then you can have, you know, a bit of a... a consideration about this afterwards. Feedback regulation, so it sounds complex but it's not. This is where the consequence of a process acts to regulate the rate at which the process occurs. So here's the process A, it leads to consequence B, but it's the consequence that then regulates how that process then goes on to work. So if process A gets activated, we get get consequence B. Yeah? Okay? And you know a lot about negative feedback. Negative feedback is where consequence here, B, is able to inhibit process A so that it's then decreased. consequence goes down, and the control of the process also diminishes. So we're trying to keep the system running at a relatively narrow set point. homeostasis. The consequence negatively controls the process so we maintain a set point. So this morning in your homes then, the thermostat, maybe you've got the central heating set lower, but thermostat is set 19 degrees. The room where the thermostat is, is about 16, 17 when you wake up. The central heating comes on. The central heating comes on because the thermometer in the thermostat has registered that it's below the set 19 degrees. degrees. The thermostat communicates to the central heating system and the central heating system then pumps heat to the radiator in that room. The radiator warms up. It warms the room up. The temperature goes from 17 to 18 to 19 degrees. And oh, it goes up to 20. The thermostat senses that. It's gone above 19 degrees. Talks to the central heating to then switch down the heat to that room. The radiator goes down. The temperature in the room comes back down from 20 to 19. It's very nice. It's very comfortable. But then it dips down to 18. again. The thermostat senses that and tells the boiler, the central heating, to put more heat to the room. So that is negative feedback with your central heating to try and maintain a narrow set point of that lovely, comfortable temperature of 19 degrees. Okay? Is everybody okay with negative feedback? We've got lots of examples in biology where we've got negative feedback because this is about homeostasis, about processes to try and... to maintain a narrow set point which is optimized, relatively constant, near steady state. So we have lots of examples of negative feedback in endocrine. But we also have positive feedback. Now positive feedback is when a consequence enhances or amplifies the process further. So process A gets activated, we get consequence B. Consequence B... amplifies or enhances process A, and that then leads to more consequence and greater activation here. This is not about homeostasis. This can be detrimental. There are very few examples of positive feedback in biology. So you can think about it. You've got some grazing animals. They're a little bit twitchy. Some of the animals... are raising their heads, looking out for predators. Suddenly, they all get a little bit more nervous, a little bit twitchy. It's a fantastic feeding ground. There's really lots of grass there. They all get very twitchy. They all get very nervous. And they start to stampede. There is no predator there. So the positive feedback is where you've got twitchiness and nervousness that's then led to a detrimental consequence. These animals leave in the really good feeding ground. So that's just my example of giving you some understanding of what positive feedback is in biology. There are very few examples of positive feedback in biology. We have two in endocrine. Everybody okay about negative and positive feedback? So what we have in endocrine here is just a simple feedback regulation. This is when a gland secretes a hormone. The target cell either gets stimulated or activated. There is a response, and that response would then feedback to affect that endocrine gland. This example is of the regulation of glucose by insulin. So we have the beta cells within the islets of Langerhans that secretes insulin. Insulin acts on those three metabolic organs. so the liver, adipose and skeletal muscle. The response is a change in blood glucose, and that blood glucose would then act to stimulate or inhibit the beta cell, so there's more or less insulin being... secreted. So that's our simple feedback regulation. But of course, it's not always simple, is it? Because what we have is an endocrine axis that we need to consider. This is when we have hormones from the hypothalamus and the pituitary involved. These are known as tropic hormones because they affect another endocrine gland. So this is what it looks like, okay? We will go through this slowly in the next lecture, so don't worry too much. So what we have is a series of endocrine glands with their hormones affecting each other. So we have the hypothalamic or hypothalamus releasing hormone here, which affects the anterior pituitary and then the release of its tropic hormone. The tropic hormone from the anterior pituitary affects a peripheral endocrine gland, and that peripheral endocrine gland is what gives rise to our target cell response. Okay? The negative feedback loops are shown here. The peripheral hormone can activate this long feedback loop. which acts on one level above on the anti-apotretic tropic hormone level or two levels above to the hypothalamus releasing hormone. We've also got a short feedback loop from... from the tropic hormone from the anti-aperture tree up to the hypothalamus. So it looks like this then. If this peripheral hormone, the levels here, go too high, it will activate this long feedback loop. It will decrease the level of the hyperflamic releasing hormone that may be stimulatory. It will decrease the levels of the tropic hormone from the anterior pituitary. There is now less stimulation of the peripheral endocrine gland and levels of the peripheral hormones come down. So we're now keeping it at this set narrow range. Okay? If the peripheral hormone here, levels go too low, there is little or no activation of these negative feedback loops. There's now more hypothalamic releasing hormone that is stimulatory on the anterior pituitary. There's more tropic hormone on the anterior pituitary. So there's greater stimulation of the peripheral endocrine gland, so levels of peripheral hormone comes up. So we're keeping levels within this set narrow... a range so this is homeostasis okay everybody see that so anybody need me to explain that again we also have in some instances feedback coming from the target cell response which is a very long feedback loop right up to the hypothalamus Okay, so this is what we're going to be looking at in the next lecture. We'll be going through this slowly. It's not as complex as you think, okay? But you can see there are a number of endocrine axes that lead to release of hormones from peripheral endocrine glands, which we'll be looking at in a little bit more detail later. Okay, so we've done feedback regulation. We also have neuroendocrine reflexes. This is where we've got higher centers in the brain that can markedly affect those endocrine axes. Okay, so there's input. from higher centers in the brain. The one that you're very familiar with is stress because you know about cortisol. Cortisol is the stress hormone. So let me introduce this axis to you. So here is cortisol. It's released from the adrenal cortex. It's regulated by this hormone ACTH from the anterior pituitary. And that hormone is regulated by CRH from the hypothalamus. So this is the hypothalamus, pituitary, adrenal cortex, endocrine axis for the control of cortisol release. Under acute stress situations, so we're talking about things like infection, trauma. injury, low blood glucose, fluid deprivation. Higher centers in the brain are activated, and this leads to a marked increase in CRH. increase in CRH leads to an increase in ACTH, and a lot of cortisol is made. This cortisol is then going to help you deal with that stress situation. Okay? So there's the neuroendocrine reflexes there, high centers of the brain being activated to switch on this endocrine axis. Then we've got diurnal and circadian rhythm. So this is about the biological clock. Diurnal means day to night, and circadian means around a day. So for humans, this is around 24 to 25 hours. Okay? So this is the typical diurnal variation that we have for cortisol. So what we have is in the light area we've got the day and then in a dark area it's the night so you'll be sleeping during that time and you can see this repetitive oscillating pattern of cortisol levels in the blood. You'll see that levels are highest first thing in the morning and then lowest at midnight. So during the course of your waking day you are actually using cortisol. You're using cortisol for your usual trials and tribulations of the waking day. So you're probably using a bit of cortisol now, trying to stay alert. You can use lots of cortisol first thing this morning, getting your body out of bed. getting into the bathroom before your housemates, grabbing some breakfast, running to the bus or walking very quickly or cycling to to uni and now you're using cortisol to stay alert. You're going to be using cortisol all the way throughout your life. the day. You are tired at night, partly because you've got very little cortisol left. You've not got cortisol to help you to do things, okay? But during the course of the night, you are sleeping, you're not using cortisol, and therefore levels go back up again for the next waking day. So that's the diurnal pattern for cortisol, and that's what I mean about diurnal or circadian rhythms associated with hormones. release. Okay, so let's finish off now talking about endocrine disorders. There are three causes of endocrine disease, okay. You can have too much hormone, hormone excess, that's hyper secretion. Hyper meaning elevated high. You can have deficiency or lack of a hormone, hyposecretion, low hormone secretion. And then the third process it's known as decreased target cell responsiveness. So there's almost like resistance developed to the hormone. And this can happen at the level of the receptor or downstream signaling in terms of enzymes. If we need to understand about disease, we'd need to obviously think about the causes then. So we need to think about whether it's a primary or secondary cause. A primary cause is if it's associated with the endocrine gland. that makes the hormone. So if we're talking about cortisol and it's a problem associated with cortisol, then there must be an issue with the adrenal cortex if it's a primary cause of disease. endocrine gland that makes that hormone of interest. So primary disease is the root cause, the endocrine gland that is responsible for that particular hormone. A secondary cause, if it's due to another condition altogether, unrelated, or there's abnormal hypothalamic pituitary secretion. In other words, there's something wrong with the endocrine axis that then leads to a condition called endocrine dysfunction. to problems to the peripheral endocrine hormone levels. Okay? So let me illustrate that to you now. So a condition that we'll look at in the spring is Cushing's syndrome. Essentially, it means just excess cortisol. So here's the axis once again, hypothalamic CRH, anti-epituitary ACTH, and adrenal cortical cortisol. This is Cushing's. Excess cortisol. Can you see? I've just made that oval shape much bigger, and I've made the cortisol word in bold. A primary cause is associated with the adrenal cortex. We've got perhaps a tumor in the adrenal cortex that's making too much cortisol. It is the root cause. It's associated with the endocrine gland that makes that hormone of interest. This is primary Cushing's. Secondary Cushing's next. is when there perhaps is a tumor in the anterior pituitary producing too much ACTH. That excess ACTH is stimulating the adrenal cortex to produce lots of cortisol. There's that secondary Cushing's. So secondary defect is when it's, in this example, illustrated where there's a problem associated with the hypothalamic or pituitary mechanism. And in this example... it's because perhaps we've got a tumour secreting too much ACTH, and that ACTH is stimulating the adrenal cortex to release lots of cortisol. Another form of secondary Cushing's is when it's due to something else altogether, and this is when it could be due to an ectopic ACTH-producing tumour. Ectopic essentially means abnormal location. Now, ACTH... It's normally only secreted by the anterior pituitary cells. But when it's secreted by other cell types, that only happens when it's due to a tumour. So it's tumour cells acquiring a different characteristic. This different characteristic is to produce and secrete ACTH. These cells may be derived from the lung, ovary or bladder. These cells don't normally make ACTH, yeah? But when there's a tumour there, some of these cells may acquire the ability to produce and secrete ACTH. And this ACTH is then... then what's responsible for the increase in cortisol in this secondary cause of Cushing's? Everybody okay with the definitions of primary and secondary disease? Yeah? Okay. Right then, so just to finish off then, if we have a deficiency of hormone, a hyposecretion, then what do we do? We want to replace it back, okay? So we give synthetic hormone. So classic example, of course, you know about menopause. Okay. giving menopausal women HRT, hormone replacement therapy. You're replacing estrogens, you may also replace progesterone. If there's hormone excess, hypersecretion, what do you want to do? You want to try and decrease production, and if available, maybe drugs to block hormone production, or you want to block the hormone receptor. If there is target cell responsiveness that is decreased and if available, then drugs to enhance cellular response. I've just been talking about tumours, a lot of endocrine conditions. due to tumours, then what you need to do is firstly to locate the tumour and then remove the tumour. So you would specifically use radiotherapy to destroy those particular cells or you would surgically remove the tumour. Okay? Alright? So that's the end of the first lecture. The time's now 5.02. We'll start in 10 minutes time at 5 past 10. Okay? Just to give you a break. Thank you, folks. Thank you.

Whoops. Is the lighting okay for everybody? Yeah, okay. Well, good morning, everyone. Thank you for coming along to this 9 o'clock session on a Wednesday.

My name is Sue Chan, and I will see you for three lectures this semester and then another three lectures. in the second semester on endocrinology. So we're going to be looking at endocrine system and hormones in the body.

Okay? So as I said, three lectures this semester, the next three lectures, so that's today, 10 o'clock. and also next week at 9 a.m. We're going to be looking at basic mechanisms and the main endocrine systems within the body.

There are a number of different endocrine glands within the body, and we'll have a look at each of those in turn. And then in the spring semester, we're going to start putting all these hormones together and start to look at disease as well. So those people who have just come in, if you wouldn't mind just quickly scanning the QR code. Thank you. Okay, so the very first lecture we're going to do is to review those hormone mechanisms, those principles behind how hormones work, how they bring about their actions within the body.

But before then, we also have to understand how they are synthesized. and transported in the body. So we're going to start off with some terminology, firstly defining what intercellular messages mean. So essentially it's communication between cells as intercellular. And then to look at...

at two main groups of hormones, peptide hormones and steroid hormones, compare and contrast in terms of the basic structure, synthesis, release, transport, and mechanism of action. Look at how hormone levels are regulated. Hormone levels are not static. They go up and down depending on the need of the organism.

And then finally, we're going to look at a little bit about how endocrine disorders or diseases come about. and how we might treat those conditions. Okay.

So starting off with some terminology then. So endocrine essentially means internal secretion. Endo meaning internal or inside. Crine meaning secrete. Okay.

So the endocrine system essentially means that we've got endocrine glands, organs in the body that secrete hormone. The hormone itself is the chemical messenger involved in that communication. communication between cells.

So it's the first of our inter-cellular communication systems. The hormone is that chemical messenger that's secreted by an endocrine gland, and that endocrine gland does not contain ducts, in other words, tubular systems within that organ itself. Now I'd like you to look at the bottom here. An exocrine gland is a gland that has ducts within so that the product... is then secreted to the external part of the body.

Exo meaning outside crine secretion, okay? So we're talking about the salivary gland. So saliva is produced and then secreted along into these tubular connections to the external part of the body, which would be the mouth. Now you think it's the inside body, but actually if you think about opening your mouth, that's actually then outside the body, okay? So you're secreting saliva.

via these exocrine duct-containing glands. Similarly, sweat, glands in the skin, and then lacrimal is the tear duct. So exocrine essentially means secretion outside the body, and we have some examples here.

With endocrine, we've got hormones that are secreted into the circulation, into the blood, and then that hormone travels around some distance within the circulation to then reach... target cells and tissues. Everybody okay with the definitions there? Okay. All right.

So let's have a look at these intercellular messengers in the body. We have four types that we need to, well, five types actually, that we need to concern ourselves with. We've got that endocrine.

So again, it's a hormone, which is the intercellular messenger molecule from an endocrine gland secreted into the circulation, traveling some distance in the circulation. in the blood to reaching their target cells and tissue some distance away. So the example that I'd like to give to you and may be familiar to some of you is insulin. So insulin is a hormone secreted from the islets of lung hands within the pancreas.

And then insulin... In the circulation, travel some distance to reach the three main metabolic organs in the body. That's the liver, the adipose tissue, fat cells, and skeletal muscle. And from there on, the insulin is able to affect the...

metabolism within those organs. And you'll see that these organs are obviously some distance away from the pancreas. So the insulin, the hormone, has traveled some distance.

Let's like to define to you auto-crime communication and para-crime communication. Again, looking at the words here, auto meaning self, crime, secretion or cell. We've depicted auto-crime with the letter A.

This is when it's a substance secreted by the cell, and it's not secreted into the blood. It's just secreted into the interstitial fluid. That's the fluid that bathes the cell, okay? That autocrine substance travels a very short distance within the interstitial fluid to affect that same cell that secreted that substance.

So it's a substance secreted by the cell, traveling a very short distance within the interstitial fluid, the fluid that bathes the cell, to then come back and affect that same cell that made that substance. A classical example here are your prostaglandins, which you'll learn in a moment. learn about later on in the module. And then we've got paracrine denoted here by the P. Para meaning alongside, adjacent, neighbouring.

Okay? So hopefully you can see that a paracrine substance in terms of communication is one that's secreted by one cell into the interstitial fluid, travelling again a short distance to affect the adjacent or neighbouring cell. Okay?

So here, We've got within the islets of Langerhans a number of different cell types. Some are able to secrete somatostatin, and this somatostatin can go on to affect insulin secretion from neighboring islet cells. So this is paracrine communication, where there's only a short distance of the molecule traveling within the interstitial fluid to affect neighboring cells. Next we've got neuroendocrine.

So again, look at the name of this. Neuro relating to nerve cell. Endocrine we've just defined a moment ago. So this is where we've got a nerve cell that actually makes a whole... The hormone is stored in the axon terminus and then when required, that hormone is secreted into the blood, travelling some distance to reach its target cell.

Now this nerve cell... can be known as a neuroendocrine cell or a neurosecretory cell. The hormone that's made can be known as a neuroendocrine hormone or a neurohormone. So this relates to endocrine cells that are also nerve cells and that upon the arrival of a nervous stimulation, the neurohormone is then secreted from the axon terminus into the blood, traveling some distance to the brain. to reach target cells and tissues.

And examples here, we've got oxytocin and arginine vasopressin, which is also known as antidiuretic hormone. And these two hormones are secreted from the posterior pituitary gland. And we'll look at this again in our second lecture this morning. And finally, we've got neurotransmitter, which I believe you've had lectures on already. This is where it's a substance secreted by a neuron from the presynaptic membrane here.

And this neurotransmitter crosses the synaptic cleft within that synapse to reach the postsynaptic membrane of this second neuron. And we have many examples of neurotransmitters. We've got no adrenaline. acetylcholine, glutamate, glycine, etc.

Everybody okay at this stage? Okay, so we've defined intercellular messengers. We're particularly interested in endocrine communication and the communicating molecule. This chemical messenger is known as the hormone. We have several types of hormones based on the chemical makeup of hormones.

Okay, so we have PET. hormones, steroid hormones, hormones derived from tyrosine, and then the last group here, the iodine. ...cosinoids, which are the prostaglandins.

We're going to be focusing on the first three groups because you're going to be looking at prostaglandins in some more detail later on. So the peptide hormones, you're very well aware... They're made up of amino acids. They're simple chains of amino acids, such as with TRH, which is three amino acids in length, or much more complex with secondary and tertiary structure.

such as in LH and FSH. The peptide hormones make up a large group of hormones, and they include those from the hypothalamus, the anterior and posterior pituitary glands, pancreas, and the gut. The steroid hormones, they're all based around cholesterol.

This is that fatty substance that you find in the bilayer of plasma membranes. Cholesterol is also that fatty substance that we talk about, which can clog up blood. vessels in those who have high cholesterol levels. So cholesterol is a fatty substance and cholesterol is what is the starting material for the synthesis of steroid hormones. The steroid hormones include cortisol, aldosterone, both of these are from the adrenal cortex.

And then we've also got the sex hormones such as testosterone, estrogen and testosterone from the gonads, the reproductive system. We then have the hormones derived from tyrosine, so that's the amino acid tyrosine. We've got the thyroid hormones and the catecholamines from the adrenal medulla.

The catechol element is the phenolic... ring with the hydroxy groups of the tyrosine R group, the R chain. And so the catecholamines are those that have amines attached also.

Okay. So we're talking about adrenaline and noradrenaline here. So those are from the adrenal medulla. So, maybe you're starting to see that with the chemical makeup of these hormones, that this difference in the chemical structure would therefore reflect on the way in which the hormones are synthesized, stored, transported and held. they act.

So what we're going to do next is to compare and contrast peptide hormones with sterile hormones. Peptide hormones tend to be hydrophilic. They like aqueous environments.

Okay? Whereas the steroid hormones, based around that molecule cholesterol, they are lipophilic. They like fatty lipid environments.

So there's the marked difference in the chemical makeup of these hormone groups here. Okay. So let's start off with peptide hormone synthesis. So peptide hormone synthesis involves the same machinery in cells for any molecule or protein that's going to be secreted or exported. from a cell.

So we're starting off with the gene of the peptide hormone. So we're starting off with DNA which is transcribed to messenger RNA. that then acts as the template for the synthesis of that peptide hormone.

The messenger RNA is translocated or transported out of the nucleus, and then it's used as a template for the synthesis of the peptide. The very first molecule that's made, that's within the rough endoplasmic reticulum, is the pre-pro-hormone molecule. So the...

protein synthesizing organelles in the body or in the cell here are the ribosomes. The ribosomes are attached to a tubular network known as the endoplasmic reticulum. So the ribosomes together with the endoplasmic reticulum form what's known as the rough endoplasmic reticulum. That's where the peptide hormone is made and the peptide hormone is made within the tubular network.

The first molecule that's made is pre-prohormone. It's not yet the mature hormone. The pre part is a signal peptide that is telling the cell this particular peptide molecule needs processing, it needs packaging because it's going to be exported or secreted from the cell. Okay, so whilst the pre-pro hormone is transported along this tubular network, we've got some post-translational modification steps occurring, and the pre-signal is also...

cleaved so that by the time it reaches the Golgi complex it's now in the form of pro hormone we've cleaved the pre signal away we've had some post translational modification in the RER and now with within the Golgi complex, there's just some additional processing, any additional cleavage of any extraneous segments to then package the hormone within the secretory granule. in the secreted granule, it's now in its mature form. So the hormone is now stored. The hormone is stored until released upon the arrival of a stimulus.

Everybody okay? Does anybody need me to explain that process again? Have you covered this already anywhere else where on the degrees that you're doing?

Does anybody need me to explain this again? Yeah? Fine? Okay. So what we're starting with, the peptide hormone...

is the gene for that hormone. So the first step of making our peptide hormone is to transcribe that DNA into messenger RNA. That messenger RNA gets moved out of the nucleus.

into the cytoplasm because that's where we're going to find the ribosomes. The ribosomes are that protein-synthesizing organelle, and these ribosomes are attached to a tubular network known as the endoplasmic reticulum. Together, they form the rough endoplasmic reticulum. The peptide hormone is made within the tubular network, and the first molecule that's made is known as pre-pro-hormone.

The pre-part is this. hydrophobic signal to tell the cell that this particular peptide needs further processing, it needs packaging because it is going to be exported from the cell. So whilst it's moving through this tubular network of the RER, the rough endoplasmic reticulum, we've got the post-translational modification steps and the cleavage of that pre-signal so that by the time it reaches the next...

The next tubular system known as the Golgi complex is now in the form of pro-hormone. It's not yet ready. It needs further processing and packaging as it travels through this, again, another tubular network known as the Golgi complex or the Golgi apparatus.

By the time it reaches the secretory granules, which are vesicles, pinched off from the Golgi complex, we now have our hormone in its mature form and it's stored within these secreted granules until we're ready for the hormone to be released. Is that okay? Yeah? Everybody okay?

Right then. So we've got our hormone made and it's stored in secreted granules. So when a stimulus arrives for hormone release, what we have is this process known as exocytose.

Exocytosis is the movement of secretory granules towards the plasma membrane. The membrane of the secretory granule and the membrane of the plasma membrane fuse together. The content of the granule is then expelled out. So exocytosis is fusion of the secretory granule with the plasma membrane and then hormone release with the expulsion of the content of the granule.

the secreted granule out of the cell. Okay. Steroid hormone synthesis does not involve genes.

Remember, it's based around that molecule cholesterol. So I've shown you cholesterol with this pale-colored rectangle, and essentially... it's a series of enzymatic conversion of that cholesterol molecule. There's a number of enzymes involved in converting that steroid molecule into our steroid hormone. enzymes shown in this green oval and we then are able to reach our through the synthetic pathway our mature steroid hormone with this hatched rectangle okay now remembering that cholesterol is a lipophilic molecule, our steroid hormones are also lipophilic.

You can't contain them in membranes because they're able to cross through the lipid bilayer of these membranes. So what happens is that that they pass through the plasma membrane by simple diffusion. Remember that the plasma membrane has its lipid bilayer that's also made up of cholesterol.

And so these steroid hormones, being lipophilic, can easily just cross through by simple diffusion. And they are not stored, so you cannot contain your lipophilic hormones in membranes, because they just pass through those membranes very easily. And because they are lipophilic, they therefore are not able to be transported in the circulation easily. They don't readily dissolve in the circulation.

inverted commas, in the aqueous environment of the plasma of blood. So they need to be bound to plasma proteins, which then helps their solubility within blood to then be transported around the circulation. Everybody understand that?

So when you mix oil with water and you shake it, eventually they will separate. So the oil doesn't go into that aqueous environment very well. And similarly... We have that with our lipophilic hormones.

And to overcome the transport issues here, we bind our lipophilic steroid hormones to plasma proteins, which increases the solubility of our steroid hormones so that we can transport this steroid hormone much more readily and much more easily within circulation. Based on what we know about the chemical structure then of these peptide hormones and steroid hormones, with the peptide hormones being hydrophilic and the steroid hormones, and I'm also going to include the thyroid hormones here as being lipophilic. their transport and their half-life are quite distinct and different. So with the peptide hormones being hydrophilic, they can dissolve, inverted commas, in the aqueous environment of plasma.

They are circulated as free, unbound hormone, so they're not bound to plasma proteins. Whereas the lipophilic hormones, they are not readily soluble in the plasma, so they need to be bound to these plasma proteins, which act as carrier molecules, and there are these weak, reversible bonds. Okay? And in terms of the half-life, the half-life is the time taken. for the initial concentration to fall by 50%.

Hydrophilic peptide hormones, their half-life is really short. And that's because there are protease enzymes within the plasma that will easily degrade the peptide hormones. So once a peptide hormone is secreted, it's not around for very long. It's just around for a few moments because there are protease enzymes within the blood. that then degrades, metabolizes the peptide hormone.

So the half-life of your hydrophilic peptide hormones are low. Whereas the steroid and thyroid hormones, which are lipophilic, they are bound to plasma proteins, okay? And essentially, that protects the hormones from being metabolized, from being degraded. So there's an increase in the half-life of these. lipophilic hormones.

So being bound to plasma protein protects the hormone from being broken down. So they are around for a lot longer, hours to days. So to summarize a little bit more here, unbound free hormone is what we regard as being biologically active.

That is the form that can go to bind to receptors on target cells. However, as an unbound or free hormone, it is more susceptible to metabolic degradation because there are protease enzymes floating around in the blood. Binding to plasma carrier proteins delays that metabolism, as we've seen with the lipophilic hormones. So it provides a circulating reservoir of hormone. In other words, there's a lot of those lipophilic hormones around because there is delayed metabolism.

There's decreased susceptibility to... to metabolic degradation. circulation. Everybody okay with that? Okay, so what have we done?

We've talked about how hormones are made, how they're transported in the circulation. How about how they act then? Okay.

We've started to talk about receptors. Receptors are what... mediates the effects of hormones.

And again, the location of those receptors depend on the chemical makeup of the hormone. So with peptide hormones being hydrophilic, they cannot readily... cross the plasma membrane easily. Remember the plasma membrane is lipophilic because it's got the lipophilic bilayer. And so being hydrophilic and not being able to cross the plasma membrane easily, then we have plasma membrane located receptors for peptide hormones on target cells and tissues.

Everybody understand that? Yeah? Okay, so hydrophilic peptide hormones cannot cross plasma membranes easily.

Therefore, receptors for these are located on the plasma membrane. We have two types of plasma membrane receptors available depending on the hormone of interest. We have on the left G-protein coupled receptors and on the right tyrosine kinase linked receptors.

Okay, when these receptors are activated, there is signal transduction. And what that means is that we've got the mediation of the signal from the hormone from the outside of the cell to the inside of the cell. There may be a number of second messengers involved, and that leads to, ultimately, the physiological response. That response might be changing the activity of enzymes, Could be changing the activity of ion channels, or we're changing the expression of specific proteins.

And that means from the DNA to messenger RNA to protein synthesis of specific proteins. And that altered expression of that protein means that if it's an ion channel, you're going to get more ion channels expressed, therefore the activity associated, or if that specific protein is an enzyme, then it might be that increased or decreased. decreased activity of that enzyme.

So once again, we've got G protein couple receptors, or tyrosine kinase linked receptors as peptide hormone receptors. Once activated, there may be signal transduction, and the physiological response may be one of these listed here, or a combination. It could be altered enzyme activity, ion channel activity, or even gene expression. An example of a hormone that's, its effects being mediated by a G-protein couple receptor is that for glucagon.

And the G-protein is GS. The effector molecule is adenylate cyclase. And the second messenger here is cyclic AMP.

An example of a tyrosine kinase-linked receptor for a peptide hormone is that for insulin. Okay, so steroid hormones mediate their actions via intracellular receptors. Remember, lipophilic easily pass across plasma membranes, so they're easily therefore...

gain access to the inside of the cell. And much of the effects of these lipophilic hormones, steroid hormones, and new thyroid hormones are mediated by intracellular receptors. Now, these may be located in the cytosol or even in the nucleus. Okay?

And when these receptors are activated, then what we have... Can you still hear me at the back? Yep. What we have is the binding of two, that is the hormone and the receptor, to the promoter region of specific genes.

Okay? So intracellular receptors can be regarded as being hormone-regulated transcription factors. So when the hormone binds to its intracellular receptor, the complex binds to the promoter of a specific gene and able to either increase or decrease gene expression. In other words, it may activate gene expression by then allowing DNA to be transcribed to messenger RNA, and that messenger RNA to be translated into protein, or there could be a decrease in gene expression, decrease of this transcription and translation.

So ultimately... The change in protein levels and its associated function would therefore be the consequence of this change in gene expression. Everybody okay with that? Yeah, so this is known as the genomic effect of hormones here.

It's complicated in that these lipophilic hormones may have actions that are mediated by plasma membrane receptors. These plasma membrane receptor mediated effects are more rapid. okay the genomic mechanism can take a number of hours for the effects to be seen or even days whereas the much more rapid effects that we see with plasma membrane receptors can happen in seconds or minutes. Now, this concept here of plasma membrane receptors for these lipophilic hormones has only been around for a small number of years, and it's beyond the scope of these lectures to talk more about these. But we will talk about the genomic effects mediated by these lipophilic hormones.

So what have we done here then? We've talked about intracellular receptors. and what they are, sorry, intercellular messages and what they are, and we understand what endocrine means.

We've gone through peptide hormone and steroid hormone synthesis, release, transport. In terms of metabolism, we're not going to focus much on there. There's nothing particularly startling about metabolism of hormones, just that it's the same processes as other protein or lipophilic molecules within the body. going to move on to looking at the regulation of hormone release and then to finish off with endocrine disorders. So hormone levels do not stay static.

There are times when we need a little bit more and other times when we don't need as much. But what we do need in biology is homeostasis. Homeostasis is basically the processes involved in maintaining the environment being external around us or the internal environment at an optimum level. A level that is relatively constant and steady but optimal.

optimized for life. So that's homeostasis. And what we have here are some processes to maintain homeostasis, to maintain this almost equilibrium of optimized steady state.

Okay? So what I'd like to describe to you first is feedback regulation. Now, you probably know a lot more about feedback regulation than you think. And I'm going to describe this to you.

And then you can have, you know, a bit of a... a consideration about this afterwards. Feedback regulation, so it sounds complex but it's not.

This is where the consequence of a process acts to regulate the rate at which the process occurs. So here's the process A, it leads to consequence B, but it's the consequence that then regulates how that process then goes on to work. So if process A gets activated, we get get consequence B. Yeah?

Okay? And you know a lot about negative feedback. Negative feedback is where consequence here, B, is able to inhibit process A so that it's then decreased. consequence goes down, and the control of the process also diminishes.

So we're trying to keep the system running at a relatively narrow set point. homeostasis. The consequence negatively controls the process so we maintain a set point. So this morning in your homes then, the thermostat, maybe you've got the central heating set lower, but thermostat is set 19 degrees.

The room where the thermostat is, is about 16, 17 when you wake up. The central heating comes on. The central heating comes on because the thermometer in the thermostat has registered that it's below the set 19 degrees. degrees.

The thermostat communicates to the central heating system and the central heating system then pumps heat to the radiator in that room. The radiator warms up. It warms the room up. The temperature goes from 17 to 18 to 19 degrees.

And oh, it goes up to 20. The thermostat senses that. It's gone above 19 degrees. Talks to the central heating to then switch down the heat to that room. The radiator goes down.

The temperature in the room comes back down from 20 to 19. It's very nice. It's very comfortable. But then it dips down to 18. again. The thermostat senses that and tells the boiler, the central heating, to put more heat to the room. So that is negative feedback with your central heating to try and maintain a narrow set point of that lovely, comfortable temperature of 19 degrees.

Okay? Is everybody okay with negative feedback? We've got lots of examples in biology where we've got negative feedback because this is about homeostasis, about processes to try and... to maintain a narrow set point which is optimized, relatively constant, near steady state.

So we have lots of examples of negative feedback in endocrine. But we also have positive feedback. Now positive feedback is when a consequence enhances or amplifies the process further.

So process A gets activated, we get consequence B. Consequence B... amplifies or enhances process A, and that then leads to more consequence and greater activation here.

This is not about homeostasis. This can be detrimental. There are very few examples of positive feedback in biology.

So you can think about it. You've got some grazing animals. They're a little bit twitchy. Some of the animals... are raising their heads, looking out for predators.

Suddenly, they all get a little bit more nervous, a little bit twitchy. It's a fantastic feeding ground. There's really lots of grass there. They all get very twitchy. They all get very nervous.

And they start to stampede. There is no predator there. So the positive feedback is where you've got twitchiness and nervousness that's then led to a detrimental consequence.

These animals leave in the really good feeding ground. So that's just my example of giving you some understanding of what positive feedback is in biology. There are very few examples of positive feedback in biology.

We have two in endocrine. Everybody okay about negative and positive feedback? So what we have in endocrine here is just a simple feedback regulation. This is when a gland secretes a hormone. The target cell either gets stimulated or activated.

There is a response, and that response would then feedback to affect that endocrine gland. This example is of the regulation of glucose by insulin. So we have the beta cells within the islets of Langerhans that secretes insulin.

Insulin acts on those three metabolic organs. so the liver, adipose and skeletal muscle. The response is a change in blood glucose, and that blood glucose would then act to stimulate or inhibit the beta cell, so there's more or less insulin being... secreted.

So that's our simple feedback regulation. But of course, it's not always simple, is it? Because what we have is an endocrine axis that we need to consider. This is when we have hormones from the hypothalamus and the pituitary involved.

These are known as tropic hormones because they affect another endocrine gland. So this is what it looks like, okay? We will go through this slowly in the next lecture, so don't worry too much.

So what we have is a series of endocrine glands with their hormones affecting each other. So we have the hypothalamic or hypothalamus releasing hormone here, which affects the anterior pituitary and then the release of its tropic hormone. The tropic hormone from the anterior pituitary affects a peripheral endocrine gland, and that peripheral endocrine gland is what gives rise to our target cell response.

Okay? The negative feedback loops are shown here. The peripheral hormone can activate this long feedback loop. which acts on one level above on the anti-apotretic tropic hormone level or two levels above to the hypothalamus releasing hormone. We've also got a short feedback loop from...

from the tropic hormone from the anti-aperture tree up to the hypothalamus. So it looks like this then. If this peripheral hormone, the levels here, go too high, it will activate this long feedback loop. It will decrease the level of the hyperflamic releasing hormone that may be stimulatory. It will decrease the levels of the tropic hormone from the anterior pituitary.

There is now less stimulation of the peripheral endocrine gland and levels of the peripheral hormones come down. So we're now keeping it at this set narrow range. Okay? If the peripheral hormone here, levels go too low, there is little or no activation of these negative feedback loops. There's now more hypothalamic releasing hormone that is stimulatory on the anterior pituitary.

There's more tropic hormone on the anterior pituitary. So there's greater stimulation of the peripheral endocrine gland, so levels of peripheral hormone comes up. So we're keeping levels within this set narrow...

a range so this is homeostasis okay everybody see that so anybody need me to explain that again we also have in some instances feedback coming from the target cell response which is a very long feedback loop right up to the hypothalamus Okay, so this is what we're going to be looking at in the next lecture. We'll be going through this slowly. It's not as complex as you think, okay?

But you can see there are a number of endocrine axes that lead to release of hormones from peripheral endocrine glands, which we'll be looking at in a little bit more detail later. Okay, so we've done feedback regulation. We also have neuroendocrine reflexes.

This is where we've got higher centers in the brain that can markedly affect those endocrine axes. Okay, so there's input. from higher centers in the brain.

The one that you're very familiar with is stress because you know about cortisol. Cortisol is the stress hormone. So let me introduce this axis to you. So here is cortisol. It's released from the adrenal cortex.

It's regulated by this hormone ACTH from the anterior pituitary. And that hormone is regulated by CRH from the hypothalamus. So this is the hypothalamus, pituitary, adrenal cortex, endocrine axis for the control of cortisol release.

Under acute stress situations, so we're talking about things like infection, trauma. injury, low blood glucose, fluid deprivation. Higher centers in the brain are activated, and this leads to a marked increase in CRH.

increase in CRH leads to an increase in ACTH, and a lot of cortisol is made. This cortisol is then going to help you deal with that stress situation. Okay?

So there's the neuroendocrine reflexes there, high centers of the brain being activated to switch on this endocrine axis. Then we've got diurnal and circadian rhythm. So this is about the biological clock. Diurnal means day to night, and circadian means around a day. So for humans, this is around 24 to 25 hours.

Okay? So this is the typical diurnal variation that we have for cortisol. So what we have is in the light area we've got the day and then in a dark area it's the night so you'll be sleeping during that time and you can see this repetitive oscillating pattern of cortisol levels in the blood. You'll see that levels are highest first thing in the morning and then lowest at midnight.

So during the course of your waking day you are actually using cortisol. You're using cortisol for your usual trials and tribulations of the waking day. So you're probably using a bit of cortisol now, trying to stay alert. You can use lots of cortisol first thing this morning, getting your body out of bed.

getting into the bathroom before your housemates, grabbing some breakfast, running to the bus or walking very quickly or cycling to to uni and now you're using cortisol to stay alert. You're going to be using cortisol all the way throughout your life. the day. You are tired at night, partly because you've got very little cortisol left. You've not got cortisol to help you to do things, okay?

But during the course of the night, you are sleeping, you're not using cortisol, and therefore levels go back up again for the next waking day. So that's the diurnal pattern for cortisol, and that's what I mean about diurnal or circadian rhythms associated with hormones. release.

Okay, so let's finish off now talking about endocrine disorders. There are three causes of endocrine disease, okay. You can have too much hormone, hormone excess, that's hyper secretion. Hyper meaning elevated high.

You can have deficiency or lack of a hormone, hyposecretion, low hormone secretion. And then the third process it's known as decreased target cell responsiveness. So there's almost like resistance developed to the hormone. And this can happen at the level of the receptor or downstream signaling in terms of enzymes. If we need to understand about disease, we'd need to obviously think about the causes then.

So we need to think about whether it's a primary or secondary cause. A primary cause is if it's associated with the endocrine gland. that makes the hormone. So if we're talking about cortisol and it's a problem associated with cortisol, then there must be an issue with the adrenal cortex if it's a primary cause of disease. endocrine gland that makes that hormone of interest.

So primary disease is the root cause, the endocrine gland that is responsible for that particular hormone. A secondary cause, if it's due to another condition altogether, unrelated, or there's abnormal hypothalamic pituitary secretion. In other words, there's something wrong with the endocrine axis that then leads to a condition called endocrine dysfunction.

to problems to the peripheral endocrine hormone levels. Okay? So let me illustrate that to you now. So a condition that we'll look at in the spring is Cushing's syndrome. Essentially, it means just excess cortisol.

So here's the axis once again, hypothalamic CRH, anti-epituitary ACTH, and adrenal cortical cortisol. This is Cushing's. Excess cortisol.

Can you see? I've just made that oval shape much bigger, and I've made the cortisol word in bold. A primary cause is associated with the adrenal cortex.

We've got perhaps a tumor in the adrenal cortex that's making too much cortisol. It is the root cause. It's associated with the endocrine gland that makes that hormone of interest. This is primary Cushing's.

Secondary Cushing's next. is when there perhaps is a tumor in the anterior pituitary producing too much ACTH. That excess ACTH is stimulating the adrenal cortex to produce lots of cortisol.

There's that secondary Cushing's. So secondary defect is when it's, in this example, illustrated where there's a problem associated with the hypothalamic or pituitary mechanism. And in this example... it's because perhaps we've got a tumour secreting too much ACTH, and that ACTH is stimulating the adrenal cortex to release lots of cortisol. Another form of secondary Cushing's is when it's due to something else altogether, and this is when it could be due to an ectopic ACTH-producing tumour.

Ectopic essentially means abnormal location. Now, ACTH... It's normally only secreted by the anterior pituitary cells.

But when it's secreted by other cell types, that only happens when it's due to a tumour. So it's tumour cells acquiring a different characteristic. This different characteristic is to produce and secrete ACTH. These cells may be derived from the lung, ovary or bladder. These cells don't normally make ACTH, yeah?

But when there's a tumour there, some of these cells may acquire the ability to produce and secrete ACTH. And this ACTH is then... then what's responsible for the increase in cortisol in this secondary cause of Cushing's?

Everybody okay with the definitions of primary and secondary disease? Yeah? Okay. Right then, so just to finish off then, if we have a deficiency of hormone, a hyposecretion, then what do we do? We want to replace it back, okay?

So we give synthetic hormone. So classic example, of course, you know about menopause. Okay.

giving menopausal women HRT, hormone replacement therapy. You're replacing estrogens, you may also replace progesterone. If there's hormone excess, hypersecretion, what do you want to do?

You want to try and decrease production, and if available, maybe drugs to block hormone production, or you want to block the hormone receptor. If there is target cell responsiveness that is decreased and if available, then drugs to enhance cellular response. I've just been talking about tumours, a lot of endocrine conditions.

due to tumours, then what you need to do is firstly to locate the tumour and then remove the tumour. So you would specifically use radiotherapy to destroy those particular cells or you would surgically remove the tumour. Okay?

Alright? So that's the end of the first lecture. The time's now 5.02. We'll start in 10 minutes time at 5 past 10. Okay? Just to give you a break.

Thank you, folks. Thank you.

Transcript for:9. Endocrinology - 1

Transcript for:
9. Endocrinology - 1