Greetings. So today we going to talk about the hypothalamus pituitary adrenal axis. This is the axis that governs your response to stress, and the stress can be psychological stress. Or it could be physical stress such as trauma, surgery or some type of internal problem where you are dehydrated, for instance. So the, so the, this particular axis is going to get the body ready for what's known as fight or flight response. And it's going to work with the sympathetic nervous system To to mobilize fuel. The other thing that this axis does is that, one of the hormones is secreted from the axis. Is able to dampen the immune system. And so, this particular hormone cortisol is used pharmacologically by the medical field to dampen in, inflammation or to prevent some type of immune re, reaction. So we're going to talk about then this complex complex organ. So the adrenals, the adrenal gland is what is shown here. They're fairly small organs, they're sitting on top of the kidneys. And so you have two adrenals as you have two kidneys in your body. The adrenal gland itself has a cap connective tissue capsule that surrounds the entire gland. And, the gland has no ducts, because this is an endocrine gland. The gland itself is going to be divided into two zones. The outermost zone is called the cortex, and it's going to secrete steroid hormones. And we will have three types of steroid hormones coming from this region. The inner portion of the gland, which is shown here, it's called the medulla, this is an area which is going to be secreting tyrosine derivatives, and these are epinephrine and norepinephrine. And in humans it's predominantly epinephrine. Now as I want to, as we go through this particular this particular lecture, what I first want to do is concentrate on the hormones that are coming from the cortex. And then we'll very briefly talk about the hormones that are coming from the medulla. And then how the hormones from the cortex and the medulla actually work in a synergistic manner. The hormones from the cortex then, as I said, are steroids which means that they have to be they're insoluble in plasma so that they are delivered to their target cells by carriers. And secondly that they are able to pass through plasma membranes, and so they cannot be stored within their, within the tissue that's generating them. So, these are hormones that are going to be synthesized on demand. And thirdly, because they can pla, pass through plasma membranes, they're soluble in lipid. Then they have receptors which are found within the cells, with inside the target cells. And these receptors are going to be what we call transcription factors. These are, these are proteins that bind to DNA and will cause the specific gene to be to be made into RNA. And then that RNA will be made into protein. And so that whole process takes several minutes, at least 30 minutes, to make a new protein. So the response to these hormones will be slow. First we have to synthesize them. And then we have to deliver them by the blood, have them pulled off of their carriers. And then they have to change transcription of the gene. That is to change the, the type of proteins that will be expressed within these cells. So it's going to be a slow, slow response, but the response will be long lasting. Because we change proteins within the target cells. The cortex itself is going to be secreting three separate steroid hormones. And as, and as you can see here, this cortex is divided into three zones. In the first zone we are secreting aldosterone. In the second zone, we're going to secrete cortisol, and in the third zone, we're, and it's secreting something which is called DHEA for our purposes, and this is a weak androgen. So it's a sex steroid. A sex hormone which is a very weak male sex ster sex hormone. The way to remember what these hormones are doing in the body is to remember that aldosterone is going to be affecting the salt balances of the body. The cortisol is going to be effecting sugar balances in the body, and DHA, DHEA is, is affecting your sex sex, secondary characteristics. So it's salt, sugar and sex. Alright, so let's talk about then this first, the first hormone which is aldosterone. Now aldosterone is not going to be regulated by the hypothalamus-pituitary axis. Aldosterone has, is secreted by the zone one from the adrenal cortex in response to two separate stimuli. The first stimulus is when we have an increase in blood potassium concentration. As blood potassium concentration rises, aldosterone will be secreted by the adrenal gland. Aldosterone works on the kidney to cause reabsorption of sodium and water from the presumptive urine space back into the blood. And in exchange, it is causing the potassium to move from the blood into the urine space. So we're removing potassium from blood, and we're moving sodium and water back into, into blood from the urine space. This, this simply means that we are going to increase the excretion of potassium in the urine. And this will correct then, our high or elevated so, potassium levels in the blood. The second signal that works for to trigger the release of aldosterone from the adrenal is angiotensin two. This is a vasoconstrictor that is released by the body in response to low blood pressure. So low blood volume or low blood pressure. Is sensed by the kidney, and the kidney then will trigger a cascade of events which lead to an elevation in angiotensin two, this very potent vasoconstrictor. This vasoconstrictor will cause the adrenal cortex to secrete aldosterone. And again, aldosterone is going to work on the kidney tubules, and we're going to have a reabsorption of sodium and water. So we're going to move sodium and water back into the body. And in exchange, we will lose potassium into the urine. By moving sodium and water back into the body then we effectively are going to increase the blood pressure because we're increasing blood volume. Again, this, these two signals are independent of a hypothalamus-pituitary axis. And the aldosterone is not going to be regulated by the hypothalamus-pituitary axis. The second hormone that we want to talk about is cortisol. That's the one that's going to govern our sugar level. So cortisol is also called a glucocorticoid. Cortisol is the dominant glucocorticoid in, in humans. Cortisol is going to be regulated by the hypothalamus-pituitary axis, and that's what's shown here. So we have then a circadian rhythm and pulsatility and secretion because the hypothalamus pituitary axis is governing the, the release of cortisol from the adrenal gland. So the pulsatility occurs throughout the day, and then, in late sleep, that is just before you wake in the mornings, then cortisol levels will rise. And so the, the highest am, amplitude of cortisol is going to be in very early just before you're waking up, early in the morning. And then, cortisol falls during the day to about half maximum, at about four o'clock in the afternoon. So, cortisol, then, has this circadian peak. But, in addition to that, the cir, cortisol can increase in response to stress. And the increase is superimposed on the circadian rhythm. So, if we have an individual who's highly stressed, that individual may be secreting cortisol at such, at this level. So, the, the circadian rhythm is maintained, but we just have a higher amplitude in the secretion of cortisol. Cortisol is going to be mobilizing fuel sources. And the, we're going to talk about that in just a few minutes. So let's look at the, at the actual regulation of of cortisol. And this is as I said, by the hypothalamus pituary axis. In this particular case, I've diagrammed a low plasma glucose. So this is going to be our, our stressor for this axis. That's going to be perceived by the hypothalamus. The hypothalamus secretes, secretes this hormone, this small peptide, neuropeptide, which is CRH, or corti, corticotropin. Corticoptropin works on the an, anterior pituitary [COUGH] Excuse me. To cause it to secrete ACTH which is adrenocorticotropin. [COUGH] And ACTH, in turn, works on the adrenal cortex. In that zone two, which is going to secrete then cortisol. Cortisol is released from into the blood. It's synthesized on demand. It's released into the blood. It binds to a carrier. And, and, and it's delivered to the target tissues within the body. And cortisol is going to work on essentially all target, all cells of the body. And we'll talk about that in just a few minutes. In addition cortisol itself mediates the long access negative feedback loop to both the, the anterior pituitary to govern the levels of ACTH. Into the hypothalamus to govern the levels of CRH. So this is a, the normal, complex negative feedback loop that we've always seen with a hypothalamus pituitary axis. ACTH can also mediate a negative feedback loop. And this is our short negative feedback loop, which is then, Also dampening the release of CRH from the hypothalamus. And of course, CRH can mediate the ultra short, which is a paracrine loop and that's what's shown here. So, that's the ultra short negative feedback loop. When cortisol is, this access is first matured within the body. It takes about the first, one whole year of life before this access is, is working under normal conditions. But once it's matured. Then if cortisol is, is depressed, by giving pharmacological doses to an individual, the endogenous axis can be depressed, and then when you rel, you remove the drug, the cortisol that has been given exogenously. This axis takes about four to six weeks to come back on board. So the axis can be suppressed by giving cortisol as a drug, and then it takes a long time for it to actually come back and to be functioning in its normal manner. And so therefore individuals who are put on cortisol are always weaned off the drug in a very slow manner. The other thing about this axis is that ACTH is going to increase the secretion of DHEA, which we said was our weak androgen. And this weak androgen, oh if we have high levels of ACTH and we have high levels of cortisol we will have high levels of DHEA. If we have a situation where we have low levels of cortisol, then ACTH will rise and DHEA will rise even though the cortisol levels are low. So the synthesis of DHEA is independent of cortisol synthesis, but they are both being driven by ACTH. DHEA does not mediate a negative feedback loop to ATCH or to CRH, so. DHEA can rise under certain conditions, but it will not mediate a negative feedback loop. Why is this important? There are certain conditions where you may have a insufficiency of cortisol. The individual's not able to synthesize cortisol because specific enzymes are missing, and under these conditions, ACTH will rise. DHEA will rise. If this individual is a male, it doesn't make much of a, of a difference in the phenotype, because it's male hormone. It's a wer, a very weak androgen, and so the maleness of the individual doesn't really change. But if the individual is a female, then the amount of male hormone, that is, the amount of DHEA, can be sufficient to masculinize the female, so the female is then virilized. So under certain conditions, then, when we cannot make cortisol, we can make excess amounts of DHEA and virulize the individual, if the individual is a female. So what are these meta, metabolic effects then, of cortisol itself? As I said, cortisol is going to mobilize fuel sources and that's to raise blood glucose. And what it's doing, is it's moving fuel from very long lasting sources such as muscle, bone, fat and it's degrading those tissues to mobilize it into a plasma glucose and also into glycogen. So the liver is going to be making glycogen and well as glucose. Glycogen is a very labile form of stored fuel. In addition to that, cortisol is going to cause the beer belly fat to grow. This, all the fat that is found in the periphery, that's on your arms and on the legs, is going to be degraded by cortisol. But the, the fat then, is going to be deposited into the beer belly region. And this is called omental fat. And in this area, it's a very labile fat, it's a different type of fat than what you find within the, within your arms and within your legs for instance. So it's mobilizing fuel and it's putting the fuel into much more labile storage, storage storage forms. Cortisol itself has made major pharmacological effects and as I said the first use is that it's anti-inflammatory and can suppress the immune response. Invdividuals who are being treated for chemotherapy for instance are often given cortisol. And this is to dampen the immune response so that it doesn't attack the tissues of the body. Secondly, cortisol will degrade bone muscle. Peripheral fat is essentially where, it's a very a very catabolic hormone so it's going to degrade all of these tissues. Immobilize these tissues. So that we could then raise plasma glucose labels. And thirdly cortisol directly inhibits the growth hormone thyroid hormone actions, insulin, and sex hormones at their target tissues. So it has profound effects upon the body, not only to mobilize fuels. But it also effects other other hy, hypothalamus pituitary axes. What are some of the pathologies that, I would like to just talk about two major adrenal pathologies. The first one is hyposecretion. So this is where we have an insufficiency of hormone. And this particular, particular disease is called Addison's disease. We have an insufficiency of aldosterone and of cortisol. Because, in this particular disease, the entire adrenal cortex is being degraded. This is an autoimmune disease where the body is attacking the cells of the adrenal cortex. The phenotype of these individuals is that they will have a low blood pressure, they will have low concentrations of sodium within the blood, and they're going to have very high concentrations of potassium. So why is this an important point? They, high concentrations of potassium, if potassium concentrations get too high, you can affect the resting membrane potentials of, of tissues which are active. Which are electrically active, such as, neurons in the heart and skeletal muscle. And you can, you can cause profound hyperexcitability within the individual by having the by having the potassium levels moving, moving the threshold. That is moving the resting membrane potential toward threshold. Under these conditions the lethal this is actually, can be a lethal condition if the, the amount of potassium in the blood rises too high. So that, so, well the problem is predominantly the missing aldosterone. But we also have a problem with fuel, and that is that the cortisol itself is missing, and so we're going to have an inability to mobilize fuel and to mobilize glucose in order to respond to stress. So I want you to predict what the level of ACTH in the blood would be. What do you think? That's right. Because cortisol is dec, is decreased in these individuals, ACTH is going to be very high. The negative feed back to the hypo, to the pituitary is missing, and so we will rise, the ACTH levels will rise in the blood. Now, the second condition that we want to consider is, is the hypersecretion, but this is going to be hypersecretion of cortisol alone. And and this is due to an excess of ACTH. And the disease that we're talking about is called Cushing's disease. Cortisol rises and of course, our DHEA will rise because ACTH is at very high levels. Under these conditions, as the individual will have hyperglycemia, you'll have high blood glucose levels. There will again be wasting of the muscle, of bone, of fat. But we're going to increase our beer belly fat. And the individual also can, can form what's called a moon face. That is a very rounded face because we get deposits of fat within the, within the face. So these are individuals that are moving their, their fuel sources to very labile deposits of glycogen, and to the omental fat or the beer belly fat, under the drive of cortisol. In order to test whether or not this, how this axis is misbehaving, then you can give a drug called dexamethasone. Dexamethasone inhibits the synthesis of ACTH from the pituitary. If you give dexamethasone and then wait 60 minutes, the ACTH levels should fall, and in response to a fall in ACTH levels, we should then also see a fall in cortisol, and obviously a fall in DHEA. So, this is called a suppression test. And the dexamethasone is used to find out whether or not the tumor that's, that's causing excess expression of, or synthesis of ACTH is present within the pituitary. All right, and just in the last few minutes I want to talk about the medulla. So we're going to switch gears slightly. Remember I told you that the medulla is going to be secreting a tyrosine derivative. The tyrosine derivative is predominantly epinephrine, but it can also be secreting norepinephrine. In the human, it's, it's predominantly epinephrine. It's like an 80 to one 80 to 20 ratio. So this is the adrenal medulla. The adrenal medulla is innervated by the sympathetic nervous system. And when we increase the activity of the sympathetic nervous system, secretion from the adrenal medulla increases. And we will have circulating, rise in circulating levels of epinephrine. Epinephrine is a derivative of tyrosine. It's soluble in water. It does not have to be bound to a carrier, has very short half lives. And it's cleared from the body very quickly. Epinephrine, you have an increase in, in the sympathetic drive when you have an increase in stress. And an increase in stress then, the epinephrine, feeds back and modulates the, the perception of stress. This particular hormone is going to be working in conjunction with Cortisol. So the two pieces are actually working together. The two parts of the adrenal gland, are, are going to be working together to, to govern the response to stress. And that's what's shown here. So our metabolism in stress. So, let's say that we have a situation where our plasma glucose levels are falling. The plasma, the drop in plasma glucose level is perceived as stress. This will cause the hypothalamus to secrete our CRH. It works on the corticotrophs of the pituitary to secrete ACTH, and that causes an increase in cortisol. The cortisol works on fat, to degrade the fat and then while degrading the fat, we will then release free fatty acids and glycerol. And they're delivered to the liver and plasma glucose levels will rise. In addition, the sympathetic nervous system is activated because this is a stressful condition. And the sympathetic innervation to the medulla causes an increase in epinephrine. Epinephrine is circulating within the blood, and its target is fat. It causes lipolysis of fat, the breakdown of fat, just like we had with cortisol. Again, free fatty acids and glycerol are then dumped into the blood and it's delivered to the liver which converts this into, into glucose. In addition to these two hormones, that is, cortisol and epinephrine, the sympathetic nervous system also acts on the pancreas. And this is a, this is an axis that we haven't yet discussed, but, but what it is, is in your pancreas, there are two cells which are endocrine cells. One which is called beta, and these cells secrete insulin. And the other cell, which is the alpha cell, secretes glucagon. The sympathetic nervous system directly inhibits the secretion of insulin. And in the absence of insulin glucagon secretion is increased. So we now have a third hormone. That, that rises when we have a stressful situation. So we have epinephrine, we have cortisol and we have glucagon. Glucagon also works on the liver to cause an increase in plasma glucose. And the three hormones together, that is, epinephrine, cortisol and glucagon. Together, make a very large rise in plasma glucose levels. And this is called synergy, because the rise is bigger than the, than what each of these individual hormones can do by itself. So we have a synergistic action of three hormones in response to stress. And that is from two from adrenal, and one from the pancreas. [BLANK_AUDIO] So what are our general concepts? So the first is is that our adrenal glands are comprised of two glands, that are regulated separately, and they produce different hormones. The cortex produces steroid hormones, and the, the first of these is aldosterone, and aldosterone governs the balance of sodium and potassium within the blood. As well as the blood volume. The second is cortisol, and cortisol is a very catabolic hormone that's going to degrade all tissues, including bone within the body to increase plasma glucose levels. It's mobilizing fuel sources. And the third is, is that we have a very weak androgen called DHEA which affects secondary sex traits and in, particularly in the female. In the male, as I said, they have, they have testosterone and they have androgens which are stronger male sex hormones. And so the, the DHEA effects are not as dramatic. The, the adrenal medulla secretes primarily epinephrine. And the epinephrine acts to increase oxygen to the tissues. That is, epinephrine will bind to adrenergic receptors just like norepinephrine binds to adrenergic receptors. So it binds the beta twos in the lung. So it causes a dilation or an opening of the airways within the lung so that we can get air into the lung easier. Secondly, it will mobilize fuel and that is it's going to degrade lipids. So we're going to have a higher amount of glucose, plasma glucose levels. And importantly, it's going to inhibit insulin secretion. So the insulin is not going to be taking the, the glucose that we're trying to increase in the plasma and stuffing into the, into the skeletal muscle to store it back into fat and to skeletal muscle. And instead, the insulin is going to, to be absent and we're going to have glucagon. So we're going to have a rise in plasma glucose levels. The net effect of the adrenal hormones. That is, cortisol and epinephrine plus glucagon, is to respond to stress. And this is getting the body ready, then, for fight or flight response. So the next time we come in here we're going to actually talk about how we, we, we are using the, the hypothalamus pituitary access to regulate reproduction. See you then. Bye bye. [BLANK_AUDIO]
