So welcome back. So today we want to talk about the endocrine system. And we only wanna talk about it in general concepts or general terms. And then when we actually go through the endocrine system a little later in the course, we're gonna look at very specific endocrine glands. But today we're gonna look over the entire, sort of an overview of the entire system. So the first things we wanna talk about is to contrast the endocrine reflex loop with local control. And then secondly, we want to characterize hormonal classes. And this is gonna be classified according to their chemical nature. Third, we wanna explain the role of the carrier proteins in the cases where we have a hydrophobic molecule and it has to be delivered through the blood through an aqueous system to the tissues. Four, we wanna explain the differences among the receptor types for the different classes of these hormones. And then we wanna explain the differences in their stimuli. And then lastly, explain differences in their regulation. Okay, so there's quite a bit of things to go over, so let's start. So the first thing is that this is one of the major homeostatic control systems of the body. The other one, of course, is the nervous system. But you have also local control systems. And the local controls systems are occurring at the target cells themselves. And target cells are the cells that have receptors, that is, a protein that can recognize a specific chemical. And we said in the homeostasis lectures that we have a situation where a chemical can be secreted from the first cell and it works on its neighboring cell, and that chemical is called a paracrine. But we can also have the cell secreting a chemical that works on itself, and that's then called an autocrine. But these are not considered to be hormones. They are secreted into the interstitial space, and they work locally. The homeostatic controls that we're talking about when we're talking about the endocrine system is that we have a cell that's going to secrete it's chemical into the blood. And then the blood is going to deliver it to the target cells. Those are the cells that have receptors for the hormone or for that chemical. All of the cells of the body will be bathed by these hormones. They're all gonna see the hormone. But unless they have a receptor for the hormone, they can't recognize the hormone and will not respond to the hormone. The second thing that we have to remember about this system is that these chemicals are being secreted into the blood. And the blood is effectively three and a half liters of plasma, so you have three and half liters of fluid. And the chemical then is going to be diluted into this very large volume. Because of that, the chemicals will be at very, very, very low concentrations. And because they're at low concentrations, picomolar or nanomolar range concentrations, they have to have very, very high affinity receptors sitting on their cell surfaces. So the target cell has a high affinity receptor. And the chemical, the hormone in the blood, the concentration of the hormone is going to be very low or very dilute. So we have very low concentration or very dilute signals. This is in contrast to the nervous system, which is our other major communication system of the body. In here, the nerve is going to secrete its chemical into a very tiny space, which is called the synapse. And that's almost butting up against its target cell. So it's a very, very small space. And so the amount of neurotransmitter being released will be in very high concentration at the target cell's receptors. So the target cell receptors then will have low affinity. They have low affinity. It means that the binding of neurotransmitter to that receptor is very rapid, but it'll come off very quickly from that receptor. So we have in the nervous system then, we have a high concentration of the neurotransmitter. And the receptor on the target cell is going to have a low affinity receptor. The other thing we need to remember about the endocrine system is that these are ductless glands. So the secretions from these hormones is going to go straight into the capillary beds that are profusing all of these cells. There are no ducts that are taking the material, then, away from the gland and depositing it at a distance. The second thing is that the endocrine glands are going to regulate many of the homeostatic missions of the body. So they're going to regulate the sodium and water balance, the calcium balance, energy balance, processes that cope with stress, growth and development, and processes that are associated with reproduction. And as we go through the course, we're going to talk about each of the endocrine systems that are, in fact, mediating each of these different homeostatic functions. That other thing about the endocrine system is that the concentration of the hormone is critical. If we have too high of a concentration, then we have too much of a stimulus, we have too great of a stimulus. We can down-regulate the receptors so that the receptors then on the target cells are not available. On the other hand, if we have too low of a concentration, not enough of the receptors are activated on the target cells, and we don't get a big enough biological response. So the concentration of the hormone in the blood, you wanna have it at what's called a u concentration. And this is where it is at the normal concentration, where we will get an adequate response from the receptor. The rate of the production of the hormone is gonna be our most regulated aspect. And it is going to be regulated by both positive and negative feedback loops. The other thing about the hormone system is that the hormones are delivered by the blood. And because they're delivered by the blood, it is a very, very slow delivery. With the nervous system, the nerve is butting right up against its target cell, so the response is immediate. It's within seconds. But with the hormonal system, the response can be minutes to hours. So it's a much, much slower type of a response. The other thing about it is that the delivery of these hormones can be dependent on mass action because some of these hormones are bound to carriers. So, if the hormone is bound to its carrier, which is what's shown here, then that hormone can come off from the carrier and become a free agent. So, it's free within the bloodstream. And then it's able to bind to its receptor, which is going to be on the cell or within the cell. In the case of the hormones that are bound to carriers, these are usually steroid hormones. These are usually lipid soluble hormones. And so they have to be bound to a carrier in order to be able to move through the blood stream. So they're bound to a protein carrier, and this protein carrier then has to have low affinity so that the hormone can be pulled off the carrier to bind to the target cell receptor. Cuz we want the hormone to be released from the carrier to bind to its receptor, which has high affinity. So the equation then is pulled towards the receptor, and this is what's known by mass action laws. And then lastly, the concentration of the hormone will be governed by its rate of degradation or removal from the body. And it can be degraded either in the liver or by the kidney, excreted by the kidney. Okay so we have actually three different types of hormones and we can classify them by their chemical nature. But first are the peptide or protein hormones. These can be anywhere from three amino acids or bigger. These hormones are first synthesized on ruffin to plastic reticulum as what as known as the preprohormone this is an inactive species. And the preprohormone then, this protein, will be further cleaved, as it's packaged and moved to the Golgi. And once it's in the Golgi, which is another organelle system within the body, then it's cleaved to a prohormone. In some cases, the prohormone is active, but in most cases the prohormone is also inactive. And in the Golgi, then, these hormones will be packaged into secretory vesicles. And the secretory vesicles, then with the stored hormone inside, the hormone is now cleaved one more time to form the active species. So the pro hormone then is cleaved to give us the active hormone and that's occurring within the secretory vesicles. In these cells that are secreting the peptide or protein hormones, the secretory vesicles packaged with the hormone these secretory vesicles can sit in the cytoplasm for long periods of time and they'll sit there until there's a secretagogue, that is a signal that comes to the cell and tells the cell to secrete it. The cell then will have an increase in calcium, in the intercellular calcium, or an increase in cyclic AMP. And either of those signals, will cause, then, the secretion of these hormones from the cells. But these hormones are pre-packaged. And because they're pre-packaged, they can be released as needed. So they're synthesize, and they're waiting for the signal. To be secreted. The other thing about these is that they are proteins, and so once they're into the blood they have a very short half life. So we have a short half lives. They do not require a carrier because they are soluble within the plasma, and they are synthesized and stored. An example of one of these hormones would be insulin. So insulin for instance, is made as a preprohormone. Insulin is packaged, is then cleaved as it moves from the rough endoplasmic reticulum to the Golgi, and there it's packaged into vesicles. And then once it moves into the vesicle, the insulin then becomes cleaved. The cleavage section from the insulin molecule is called a c peptide. And it turns out that the c peptide also has biological activity, and the two are going to be present in equal molar ratio within the vesicle. When the insulin is secreted the c peptide is also released into the blood. The second type of hormones are the hormones that are derivative of cholesterol and these hormones are called steroid hormones. They are made by the adrenal glands, by the gonads, and by the placenta of the pregnant female. These steroid hormones are not soluble in plasma. They are lipid soluble, so they have to be transported in the blood on carrier proteins. These hormones have to be synthesized on demand. They can not be stored within membrane bound vesicles within the cytoplasm. Because they're able to go past the little membrane vesicles. They're soluble and lipid. So when you need any of these hormones then, they have to be synthesized. Once they're synthesized then they have to be secreted. So these hormones take a little bit more time for them to increase in tighter or increasing amount within the blood. The other thing is that they have to be transported on carrier proteins. So they are bound to the carrier protein, the carrier protein is made in the liver, they're bound to the carrier protein and then delivered to the tissues. Then pulled off from the carrier protein and then used within the tissues. Many times, these steroid hormones are converted to a more active species within the target tissues and we'll talk about that when we get to the specific instances. For instance, the testosterone, which is made in male. This is the male sex hormone. The testosterone can be converted to a much more higher active form, which is dihydrotestosterone, which is DHT. Testosterone can also be converted from the male hormone, can be converted to estrogen within the tissue as well. So testosterone can be converted by an enzyme, either to DHT, or to estrogen, depending upon the target tissue. The last of these hormones is the amino acid derivatives and what's shown here are derivatives of tyrosine. So we have epinephrine as one of these hormones. It's made in the adrenal gland. The epinephrine is soluble in plasma and has a very short half-life of seconds to minutes. The epinephrine will bind to the same receptors that, the adrenergic receptors that the neuroepinephrine binds to. So it's sort of a backup system for the sympathetic nervous system. Tyrosine derivatives can also be made into thyroxine or into T3. Thyroxine, which is shown here, is the thyroid hormone. These are insoluble in plasma. They are transported via carriers to their target tissues. And they have a very long half life, because they are bound to the carrier. Their half lives are on the order of hours to days. And in fact, these hormones have a half life, T4 has a half life of seven days. Interestingly enough, these hormones are converted in the target tissue. So, T4, which is what's shown here, cuz it has four iodine residues on it, can be converted to T3, which is the other active species, by removing one of the iodines. So let's talk a little bit about the transport carriers. The transport carriers as I said, extend the life of the hormone in the blood and that the thyroid hormones is several days, the steroid hormones, testosterone and estrogen is on the order of 60 to 90 minutes. They also importantly, they sequester the hormone from its target cell. As long as the hormone is on the carrier and is bound to the carrier, it's not able to enter and to engage into the receptor. So, the only hormone that's actually active of these is going to be the free hormone, and the free hormone is going to be very, very small concentrations within the blood. Because it's not very soluble within the blood. So, it's being released from the carrier just locally at the tissue, and that will be the carrier, that will be the hormone that's able to bind to its' receptor. The total concentration of the hormone is going to reflect the free plus the bound. So as you look at the total concentration then by saying antibody you will see what's bound as well as what's free. But it's only the free that's going to be active. So why is this important? You could have an instance where you have an individual who is put on birth control pills. So she's taking estrogen. And as she's taking estrogen, estrogen causes a secretion of a hormone, of a carrier from the liver. For the thyroid hormone. So her total amounts of thyroid hormone which is circulating within the blood, can rise. This hormone is then bound to this new carrier, to this extra carrier, and even though you have a large amount of material that's bound to the carrier it's the free hormone that's the important amount. So the person could have normal amounts of free hormone, but very high amounts of hormone bound to a carrier, and be perfectly normal. And we'll talk about this some more when we talk about the thyroid gland. Now these different classes of hormones also differ in their receptor types. So the hormones which are soluble in plasma, they're the ones that are hydrophilic material, so peptide derivatives. They bind to receptors which are present on the cell's surface, and that's what's shown here. And there are essentially three different types of receptors that they can bind to. These receptors are integral membrane protein, so they're inserted within the plasma membrane. The first is one where you have a tyrosine kinase linked situation, and this is the receptor for growth hormone. What this means is that the hormone, when the hormone binds to this receptor, that an enzyme, which is tyrosine kinase, kinase means it puts a phosphate group on something, is recruited to the receptor. And then that second messenger signaling then starts a cascade of events which changes the metabolism of the cell. In the second case which is the case of insulin, the insulin binds to its receptor, that receptor itself is a tyrosine kinase. So binding the insulin to its receptor activates the tyrosine kinase and you now get a phosphorylation cascade where we change again the metabolism of the cell. And again, it's a very rapid second messenger signaling within the cell. And the last one is the G coupled receptors. And the G coupled receptors are using, in some cases, adenosine cyclase to cause changes, metabolic changes within the cells. And again, we're activating second messenger cascades, which will then rapidly change the metabolism of the cell and this is the type of receptor that we see for glucagon. We also have the steroid hormones and the thyroid hormone, and they're both soluble in lipids. And so these two types of hormones can cross the plasma membrane and enter directly into the interior of the cell. And because they can enter into the interior of the cell, their receptors are inside the cells. So these receptors are receptors that are going to bind to the DNA, and activate gene transcription. That is they're gonna change the type of messenger RNA, and proteins that are gonna be made by this particular cell. They're changing the activity of the DNA. In every case, we can have multiple types of receptors on a target cell. For instance, the beta cell of the pancreas has receptors on it that regulate its activity. And those receptors they can be receptors for epinephrine on it. There's also receptors for acetylcholine on that same cell. So it's going to the net effect of these receptors and whether they're activated and how active they are, will be determine what the outcome is from that given cell. The other thing is you should remember are that there are large numbers of these receptors on the cell surface, there's not just one receptor on the cell surface, but many, many, many copies of receptors on the cell surface. And also many copies of the transcription factors, that is the nuclear receptors which are within these cells. First, binding the steroid hormones or for binding the thyroid hormones. The target cell sensitivity is depends on its receptor. So, the affinity of the receptors, as we said, has to be high affinity for these hormones because we have very low concentrations of the hormone. Secondly, the receptor number, the target cells that have very high numbers of receptors on its cell surface for a given hormone, are very, very sensitive to that particular hormone. And then third, competition. Competition is that some of these hormones are very similar in structure, and they can bind to the receptors. So for instance, the mineral corticoid receptor can cortisol combined to it and aldosterone combined to it. And to prevent cortisol from binding to the that mineral corticoid receptor then the cell has a protective mechanism for inactivating the cortisol. And lastly, saturation and again this is when all the receptors that are present on the cell's surface are bound by the hormone. All the receptors are occupied. So we'd have maximal activity at that time or maximal response from the target cell. So it's sort of difficult to think about this. This is all abstract and I'm giving you sort of laundry lists of things to remember. And they're the type of things where it's difficult to think about, because we're not talking about a particular hormone or a particular activity. So let's go through and look at these different kinds of stimuli that can activate the hormones or the endocrine systems, and the first of these would be that we have neuron that's going to become targeted by a stimulus, and so this neuron then is going to secrete a hormone, and it's called a neuroendocrine cell. This neuron can sense the concentration of sodium that's within the blood. And by sensing the concentration of sodium, as sodium rises within the blood, this particular neuron becomes activated and secretes a hormone called anti-diuretic hormone. This hormone works on the kidney, and causes the kidney to move water from the presumptive urine back into the blood so it dilutes down the amount of sodium that's within the blood. So this is called a neural control and the neuron is secreting from what's called a posterior pituitary, a part of the brain. In the second kind of a situation, we have a hormone, which is regulating a hormone, which is regulating a hormone, which is regulating a hormone. So, under this conditions are stimulus could be that we have low plasma glucose. If we have low plasma glucose then the hypothalamus, again, the portion of your brain can sense that from the blood, and it will secrete the first hormone which is growth hormone releasing hormone. That works on the pituitary cell to secrete growth hormone. And the growth hormone then works on the liver, which is its target cell, and the liver then, or the bone which are its target cells. So here we have one hormone, which is controlling another hormone, which is controlling a third. So we have a series of hormones, and this is a complex negative feedback loop. And in the last case, we have the stimulus directly activates the final gland, and that is, is that if we have low blood calcium levels. So we have low blood calcium levels, we can activate the parathyroid gland. And the parathyroid gland secretes the parathyroid hormone, and the parathyroid hormone works on bone. And this bone then will release calcium. And the calcium then is the negative feedback loop which removes our original initiating signal. So this can be very complicated, the other illustration I could have given for this last one is the pancreas and that is where we are secreting insulin, glucose rises in the blood, insulin is secreted from the pancreatic beta cell. This then would be insulin, and the insulin works on the target cell which is the muscle or fat to take the glucose back up into the body. So we're gonna have very complicated systems and we're gonna deal with each of these systems separately at a later time in the course. That's how we turn on the system. So how do we turn off the system? We can turn off the system both locally and systemically. So we can turn off the system locally at the gland itself. This would be through receptor desensitization. If we simply remove the receptor for the hormone in the target cell, from the cell surface for instance. If it's an insulin receptor, and we remove it from the cell's surface, then the target cell which is a skeletal muscle, cannot see the insulin, does not bind the insulin, and won't respond. The alternative is that you can degrade the actual receptor. So you can remove it from the target cell surface and degrade it. The type two diabetic is a situation where we had receptor desensitization. So the type two diabetes is where that individual does not respond correctly to insulin. Insulin is present in the system, but the receptor is desensitized. And so, you don't get the movement of glucose from the blood into the skeleton muscle cells correctly. To hide it, to remove this rise in blood glucose due to feeding. The other way of controlling this is through the negative feedbacks and that's obviously what we were just talking about, where if you have the stimulus, and that was if you had a high sodium within the blood and then we move water back by this hormone, anti diuretic hormone, then move water back to the kidney to dilute that sodium. Then we remove that initiating signal and that's simply a regular negative feedback system. Okay. So one of our general concepts then. So the first is that we have peptide hormones, and they're soluble in plasma. They bind to cell surface receptors. They're fast-acting and they're gonna have short half lives. Secondly, we have thyroid hormones and steroid hormones, and these are insoluble in plasma, the act by intercellular receptors to change transcription, that is to change the DNA expression, or the gene expression. They're slow acting, and they're gonna have long half lives. Third, we have binding proteins, that are called carriers, that regulate the hormone availability to the target cell. They'd regulate the physiologic function and the half lives. The carriers extend the half lives of these hormones. Fourth, the hormone releases under neural control, hormonal control, nutrient control, or ion control. So, we can have different types of signals which are going to regulate whether or not the hormone is going to be secreted, or be synthesized and secreted. Five, signaling is regulated by changing the plasma hormone concentration This is, by far, the most common site for regulation. But you can also change the target cell sensitivity. You can do so by removing the receptors from the cell surface, or, you can simply uncouple the receptors so that you combine the hormone to the receptor. But, it doesn't activate the second messenger signalling within the cell. So, it's effectively turned off, so it's a desensitized. By its receptor. Okay, so we will come back and look at all of these different points, when we are dealing with the endocrine systems themselves, with all the different individual endocrine glands, much later in the course, okay. So see you then.
