Greetings. So today we going to talk about the hypothalamus pituitary adrenal axis. This is the axis that governs your response to stress. 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. This particular axis is prepares the body for what's known as fight or flight response. It works 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. This particular hormone, cortisol, is used pharmacologically by the medical field to dampen inflammation or to prevent some type of immune reaction. We will discuss this complex organ system. The adrenal, the adrenal gland, is shown here. They are fairly small organs which sit on top of the kidneys. You have two adrenals just as you have two kidneys in your body. The adrenal gland itself has a connective tissue capsule that surrounds the entire gland. The gland has no ducts because this is an endocrine gland. The gland itself is divided into two zones. The outermost zone is called the cortex, It secretes steroid hormones. We 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 secretes tyrosine derivatives. These hormone are epinephrine and norepinephrine. In humans it is predominantly epinephrine. Now as we go through this particular, I will first concentrate on the hormones that are coming from the cortex. Then very briefly we will talk about the hormones that are coming from the medulla. Lastly then we'll consider how the hormones from the cortex and the medulla actually work in a synergistic manner. The hormones from the cortex as I said, are steroids. This means that they are insoluble in plasma. They are delivered to their target cells by carriers. Secondly these hormones are able to pass through plasma membranes. So they cannot be stored within the tissue that's generating them. These are hormones synthesized on demand. And thirdly, because they can pass through plasma membranes, they're soluble in lipid, Then their receptors are found within the cells, with inside the target cells. These receptors are what we call transcription factors. 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. 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. 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 change the type of proteins that are 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 secretes three separate steroid hormones. As you can see here, the cortex is divided into three zones. In the first zone we secrete aldosterone. In the second zone, we secrete cortisol, and in the third zone, and it secretes something called DHEA. For our purposes, DHEA is a weak androgen. It is a sex steroid. A sex hormone which is a very weak male sex hormone. The way to remember what these hormones do in the body is to remember that aldosterone affects the salt balances of the body. Cortisol alters sugar balances in the body, and DHEA, DHEA is, your sex which alters secondary sex characteristics. It is salt, sugar and sex. Alright, so let's talk about this in more detail. First, consider the first hormone which is aldosterone. Note that aldosterone is not be regulated by the hypothalamus-pituitary axis. Aldosterone is secreted by zone one from the adrenal cortex in response to two separate stimuli. The first stimulus is an increase in blood potassium concentration. As blood potassium concentration rises, aldosterone will be secreted by the adrenal gland. Aldosterone works in the kidney to cause reabsorption of sodium and water from the presumptive urine space back into the blood. In exchange, it causes potassium to move from the blood into the urine space. So we remove potassium from blood, and we move sodium and water back into blood from the urine space. This simply means that we increase the excretion of potassium in the urine. This process correct the high or elevated potassium levels in the blood. The second signal that trigger the release of aldosterone from the adrenal is angiotensin two. This is a vasoconstrictor released by the body in response to low blood pressure. Low blood volume or low blood pressure is sensed by the kidney. The kidney triggers 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. Again, aldosterone works in the kidney tubules to promote reabsorption of sodium and water. We move sodium and water back into the body. In exchange, we lose potassium into the urine. By moving sodium and water back into the body then we effectively increase the blood pressure because we increase blood volume. Again, these two signals are independent of the hypothalamus-pituitary axis. Aldosterone is not regulated by the hypothalamus-pituitary axis. The second hormone that we want to talk about is cortisol. That's the one that governs our sugar (glucose) level. Cortisol is also called a glucocorticoid. Cortisol is the dominant glucocorticoid in humans. Cortisol is regulated by the hypothalamus-pituitary axis. That is what is shown here. Cortisol has a circadian rhythm and pulsatility of secretion because the hypothalamus pituitary axis is governing the release of cortisol from the adrenal gland. The pulsatility occurs throughout the day, and in late sleep. Then just before you wake in the morning, cortisol levels rise. The highest amplitude of cortisol is very early just before you're waking up, early in the morning. Cortisol level falls during the day to about half maximum, at about four o'clock in the afternoon. Cortisol, then, has this circadian pattern. But in addition to that circadian rhthym, cortisol can increase in response to stress. The increase is superimposed on the circadian rhythm. If we have an individual who's highly stressed, that individual may be secreting cortisol at this level. The circadian rhythm is maintained, but we have a higher amplitude in the secretion of cortisol. Cortisol acts to mobilize fuel sources. We're going to talk about that in just a few minutes. Let's look at the actual regulation of cortisol. It is regulated by the hypothalamus pituary axis. In this particular case, I've diagrammed a low plasma glucose. This will be our stressor for this axis. That is perceived by the hypothalamus. The hypothalamus secretes this hormone, this small peptide, neuropeptide, which is CRH, or corticotropin. Corticoptropin works on the 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 cortisol. Cortisol is released into the blood. It is synthesized on demand. It is released into the blood. It binds to a carrier. And, then it is delivered to target tissues within the body. Cortisol works on essentially all cells of the body. We'll talk about that in just a few minutes. In addition cortisol itself mediates the long access negative feedback loop to both the anterior pituitary to govern the levels of ACTH. In the hypothalamus it governs the levels of CRH. This is a normal, complex negative feedback loop that we've always seen with the hypothalamus-pituitary axis. ACTH can also mediate a negative feedback loop. This is our short negative feedback loop, which dampens the release of CRH from the hypothalamus. And of course, CRH can mediate the ultra short loop which is a paracrine loop. That's what's shown here. That's the ultra short negative feedback loop. Interestingly this axis must first mature within the body. It takes the first, whole year of life before this access is working under normal conditions. But once it's matured. then if cortisol is depressed, by giving pharmacological doses of cortisol to an individual, then the endogenous axis can be depressed. When you remove the drug, cortisol, that has been given exogenously then 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 come back and to be functioning in its normal manner. 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 governs the secretion of DHEA, which we said was a weak androgen. If we have high levels of ACTH and high levels of cortisol, then we will have high levels of DHEA. In the pathological situation of low cortisol, then ACTH will rise and DHEA will rise even though the cortisol levels remian low. The synthesis of DHEA is independent of cortisol synthesis, but they are both driven by ACTH. DHEA does not mediate a negative feedback loop to ACTH or to CRH. DHEA can rise under certain pathologic 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. Under these conditions, ACTH will rise. DHEA will rise. If this individual is a male, it doesn't make much of a difference to the phenotype, because DHEA is a male sex hormone. It's a very weak androgen. 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. 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. What are the metabolic effects of cortisol itself? As I said, cortisol mobilizes fuel sources. It raises blood glucose. And what it is doing, is moving fuel from very long lasting sources such as muscle, bone, and fat. I degrades those tissues to raise plasma glucose and also to make glycogen. The liver makes glycogen and well as glucose. Glycogen is a very labile form of stored fuel. In addition to that, cortisol causes the beer belly fat to grow. 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. The fat then is deposited in the beer belly region. This is called omental fat. Fat in this area is a very labile fat. It is a different type of fat than what you find within your arms and within your legs for instance. So cortisol mobilize fuel and stores the fuel in much more labile storage, storage forms. Cortisol itself has many major pharmacological effects. As I said the first use is that it's anti-inflammatory. It can suppress the immune response. Invdividuals who are being treated for chemotherapy for instance are often given cortisol. This is to dampen the immune response so that it doesn't attack the tissues of the body. Secondly, cortisol will degrade bone, muscle and peripheral fat. It is essentially a very catabolic hormone. It can promote degradation of all of these tissues. It mobilizes these tissues in to fuel. Cortisol then raise plasma glucose levels. And thirdly cortisol directly inhibits the growth hormone and thyroid hormones, insulin, and sex hormones at their target tissues. It has profound effects upon the body, not only to mobilize fuels. But it also effects other other hypothalamus-pituitary axes. What are some of the pathologies? I would like to talk about two major adrenal pathologies. The first one is hyposecretion. This is where we have an insufficiency of hormone. This 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 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? The high concentrations of potassium is critical. If serum potassium concentration get too high, you can affect the resting membrane potentials of tissues which are electrically active. Cells that are electrically active such as neurons, heart, and skeletal muscle. You can cause profound hyperexcitability within the individual by changing the potassium levels in blood. This can cause the resting membrane potential to move towards threshold. These conditions can be lethal. This can be a lethal condition if the, the amount of potassium in the blood rises too high. That problem is predominantly the missing aldosterone. But we also have a problem with fuel. That is the cortisol itself is missing. These individuals will have an inability to mobilize fuel and to mobilize glucose in respond to stress. 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 decreased in these individuals, ACTH is going to be very high. The negative feed back to the hypothalamus, to the pituitary is missing, So we will have ACTH levels rise in the blood. Now, the second condition that we want to consider is hypersecretion. But this is hypersecretion of cortisol alone. This condition is due to an excess of ACTH. The disease that we're talking about is called Cushing's disease. Cortisol rises and of course, DHEA will rise because ACTH is at very high levels. Under these conditions, the individual will have hyperglycemia, They have high blood glucose levels. There will again there will be wasting of the muscle, of bone, of fat. But there is an increase in beer belly fat. The individual also can form what's called a moon face. That is a very rounded face because of fat deposits within the face. These are individuals move 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 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. In response to a fall in ACTH levels, we should then also see a fall in cortisol, and obviously a fall in DHEA. This is called a suppression test. The dexamethasone is used to find out whether or not the tumor that's causing excess expression of, or synthesis of ACTH is present within the pituitary. All right. 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 secretes a tyrosine derivative. The tyrosine derivative is predominantly epinephrine, but it can also secrete norepinephrine. In the human, it's, it's predominantly epinephrine. It's like an 80 to 20 ratio. This is the adrenal medulla. The adrenal medulla is innervated by the sympathetic nervous system. When we increase the activity of the sympathetic nervous system, secretion from the adrenal medulla increases. We will see a rise in circulating levels of epinephrine. Epinephrine is a derivative of tyrosine. It is soluble in water. It does not have to be bound to a carrier, and has very short half lives. It is cleared from the body very quickly. Epinephrine increases when the the sympathetic drive increases in stress. An increase in stress then, the epinephrine, feeds back and modulates the perception of stress. This particular hormone is going to be working in conjunction with Cortisol. So the two regions of the adrenal are actually working together. The two parts of the adrenal gland, cortex and medulla, are working together to govern the body's response to stress. That's what's shown here. Consider our metabolism in stress. Let's say that we have a situation where our plasma glucose levels are falling. The drop in plasma glucose level is perceived as stress. This will cause the hypothalamus to secrete 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. They're delivered to the liver. 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. 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 delivered to the liver which converts them into glucose. In addition to these two hormones, that is, cortisol and epinephrine, the sympathetic nervous system also acts on the pancreas. This is an axis that we haven't yet discussed. What it is, is that in the pancreas, there are two cells which are endocrine cells. One is called a beta islet cell. These cells secrete insulin. The other cell type, is the alpha islet cell. They secrete glucagon. The sympathetic nervous system directly inhibits the secretion of insulin. In the absence of insulin, glucagon secretion is increased. So we now have a third hormone 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. The three hormones together, that is, epinephrine, cortisol, and glucagon. Together, cause a very large rise in plasma glucose levels. This is called synergy because the rise is bigger than what each of these individual hormones can do by itself. We have a synergistic action of three hormones in response to stress. Two from adrenal gland and one from the pancreas. [BLANK_AUDIO] So what are our general concepts? The first is is that our adrenal glands are comprised of two glands. They are regulated separately, and they produce different hormones. The cortex produces steroid hormones. The first of these is aldosterone. Aldosterone governs the balance of sodium and potassium within the blood, as well as the blood volume. The second is cortisol. Cortisol is a very catabolic hormone that degrades all tissues, including bone, within the body to increase plasma glucose levels. It mobilizes fuel sources. The third is a very weak androgen called DHEA which affects secondary sex traits In particular it virilizes the female. In the male, as I said, they have testosterone. They have androgens which are stronger male sex hormones so DHEA effects are not as dramatic. The adrenal medulla secretes primarily epinephrine. The epinephrine acts to increase oxygen delivery to the tissues. That is, epinephrine will bind to adrenergic receptors just like norepinephrine binds to adrenergic receptors. It binds the beta two receptors in the lung. So it causes a dilation or an opening of the airways within the lung. We can get air into the lung easier. Secondly, it mobilizes fuel. Epinephrine degrades lipids. This raises the amount of glucose in the blood, plasma glucose levels. And importantly, epinephrine inhibits insulin secretion. Insulin will not oppose raising the plasma glucose by stuffing the glucose into the skeletal muscle Insulin stores glucose in fat and in skeletal muscle. Instead, the insulin is absent. We have glucagon. 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. This is getting the body ready for the fight or flight response. So the next time we meet we're going to actually talk about we use the hypothalamus pituitary axis to regulate reproduction. See you then. Bye bye. [BLANK_AUDIO]
