Greetings. So today we're going to talk about the hypothalamus pituitary axis and how it regulates the basal metabolic rate of the body. It does so by regulating the thyroid gland. The thyroid gland secretes two hormones which are called thyroxine and triiodothyronine. These two hormones work on every cell of the body. These hormones are not only necessary for regulating basal metabolic rate of all the cells of the body, but they also are necessary for the expression of other endocrine hormone receptors within specific tissues. They will affect reproduction, they will affect growth and so forth, through their permissive acts. The thyroid hormones also are absolutely required for the development of the central nervous system. A baby that is developing with inadequate amounts of thyroid hormone at birth will have profound mental retardation. That child cannot be corrected by giving proper amounts of thyroid hormone post birth. So that child has profound mental retardation throughout life. So let's look at the thyroid gland. The thyroid gland sits like bow tie across the front of your throat. It has two lobes which are connected by an isthmus. That's what shown here. The thyroid gland is an unusual structure. It has what are called follicles within the gland itself. These are essentially balls of cells. That's a single layer of cells. They secrete the hormones into the capillary beds which surrounds all of the balls. If I took it a section through the gland, it would look like this. The cells which are secreting the hormone are here. Surrounding the cells is a network of capillaries. There are no ducts because again this is an endocrine gland. In the interior of the ball we have what's known as a colloid. The colloid is the extracellular storage form of the pre-pro-hormones. This pre-prohormone is called thyroglobulin. it is a 330,000 molecular weight protein. This is an inactive protein. It's the storage form of the hormones. In any given time you have about three months worth of stored thyroglobulin within the follicles. Outside of the follicles, we have cells which are called C cells. These are C or clear cells. These C cells secrete a second hormone called calcitonin. Calcitonin is used for calcification of bone. It's not very important in the human, but it is very important in other species. One other point about this gland. It is dynamic. Under stimulation, the thyroid gland can grow in size. That's what's shown here. It can grow in size by having the cells actually getting very tall and making a lot of the colloid. They're making a lot of the hormone. With high stimulation, this would be a very active gland. The growth of the gland can be so large that it's actually palatable, or you can see it, as a growth across the neck. The other time when you can see a growth of the gland is when we have a very inactive gland. And under these conditions, then there's a lot of colloid which is being stored within the gland but we're not releasing the hormone. This will be a hyposecretion condition. In both of these cases, this growth of the gland will be very large. An enlargement of the gland is called a goiter. We'll talk about goiters a little bit later in this lecture. The thyroid gland makes two hormones; both are active species. The hormones themselves are ether conjugates of tyrosine residues. That's what's shown here. They are iodinated ring structures of these tyrosines. There maybe four iodines on the two rings. Then, we have T4 which is thyroxine. If we remove one of the iodine residues from the outer ring, then we have what is called triiodothyronine, T3. Triiodothyronine and thyroxine are both active species. The thyroxine, T4, is a prohormone for T3. And in relative activity, the T3 is more active than the T4. We can also release from this gland an inactive species. The inactive species is shown here, where one of the inner rings is missing an iodine. If the iodine is missing on the inner ring, this would be called a Reverse T3, This is an inactive species. If both iodines are missing on the inner ring, it would be a Reverse T2, again an inactive species. If you recall from our lecture on the endocrine concepts, the thyroid hormones are insoluble in plasma. They are secreted from the gland,and then are bound to carrier proteins. The carrier proteins are made by the liver. The carrier protein delivers the hormones to the target tissues. At the target tissue, the carrier protein has low affinity, and the target tissue has high affinity receptors. So the hormone is pulled off from the carrier which has low affinity to bind to the high affinity receptors. The higher affinity receptors are present within the nucleus of the target cells. The thyroid hormones bind to transcription factors and activate transcription in the target cells. Let's just look at these folicular cells for a little bit longer. The folicular cells, as I've told you are secreting the pre-prohormone, the colloid, into the center of the follicle. It is present here. The cells themselves are what's diagrammed here. There is an apical surface of the cell which is facing the colloid or our storage form of the hormone. And on the basal surface, the cells are facing the blood. This will be the capillaries which are perfusing these cells. On the basal surfaces of these cells, we have a sodium- iodine co-transporter. So the iodine is being delivered from the diet through the blood. It's being picked up, and moved into the cells by this symporter. We are using the sodium gradient, established by the sodium- potassium ATPase, to move the iodine into the cells. The iodine can move into the cell such that we can have 25 to 1 ratio of iodine within the cells versus what's within the plasma. So these cells then actively store iodine, or taking up iodine from the blood. As the iodine enters the cells, it is converted to iodide, and then this peroxidase, which is an enzyme. Anything that has an ase, A-S-E at the end of it, is an enzyme. This peroxidase binds attaches the iodide to the thyroglobulin, which has been secreted and stored into this colloid. The colloid itself will be iodinated. Under conditions where we are synthesizing this hormone. This colloid is the pre-prohormone, We're also going to release thyroid hormone from the cells. To do so, the colloid is taken up into the cells. It fuses with lysosomes where it is degraded to the free hormnes which are then released from the cell at the basal surface. Both T4 and T3 are released. More T4 is released than T3. The ratio is about 11 to 1 from the cells. As the T4 and T3 are released, they bind to the carrier protein, which is present within the plasma. Then they are delivered to their target cells within the body. The thing that you should notice about these thyroid cells is that they are regulated, They are regulated by TSH, thyroid stimulating hormone. Thyroid stimulating hormone is secreted by the pituitary. So these thyroid hormones are regulated by the hypothalamus pituitary axis. The receptor for TSH is present on the basal surface facing the blood stream. TSH is a peptide hormone. It binds.to these membrane-bound receptors. Under the conditions where TSH is binding to the receptors we will synthesize the colloid and also synthesize and release from these cells T4 and T3. Because the thyroid hormone is bound to carrier, there is a large amount of hormone present within the plasma, but it's in an inactive state. Remember that only the free hormone is actually able to enter into the cells and bind to their receptors within the cells. We have a very large amount then of stored hormone that's circulating within the plasma, up to as much as seven days worth of hormone can be circulating within the plasma. Because we have a lot of stored hormone that's circulating within the plasma, we often use TSH levels to tell us what the activity of the gland is. TSH, within the blood, is used to monitor the activity of the thyroid gland. What does the H-P axis actually look like? This is what's diagramed here. The hypothalamus releases TRH, which is thyroid releasing hormone. It works on the thyrotophs of the anterior pituitary to secrete thyroid simulating hormone. Thyroid stimulating hormone works on the thyroid gland to release T3 and T4. They in turn feedback in a negative feedback manner both to the anterior pituitary as well as to the hypothalamus. Again a complex negative feedback loop. This would be the long negative feedback loop. Just as we describe for the other hormones secreted by this axis, TSH will mediate a short axis negative feedback loop. That's shown here. The ultrashort loop is mediated by TRH. So, there's a complex negative feedback loop which is regulated at multiple levels by the circulating hormones. The entire axis is also regulated by thermal signals coming from the body. When the body temperature is perceived as cold, the axis is activated. Under these conditions, the amount of TRH secreted from the hypothalamus is increased. This inturn, increase TSH levels which will increase T4 and T3. They will drive the metabolic rate of the tissues of the body. In addition to the thermal signals which coming into this axis we have caloric signals. The caloric signal is a hormone coming from fat. The fat stores secrete this hormone called leptin. Leptin activates the axis. When we have high amounts of leptin, the body is perceived to have fuel storage. We're then able to drive the metabolic rates of all of the cells of the body. So high leptin will cause an increase in TRH, and in turn it will increase TSH levels. TSH in turn increases T4 and T3 levels. Leptin at the same time regulates feeding behaviours. At high leptin levels the body perceives high storage forms of fat. This turns off the feeding axis. Under these conditions we drive metabolic rate but turn off feeding behavior. The converse, of course, is true. When we have low leptin levels, we will turn off the thyroid hormone axis. We turn down that axis to turn down basal metabolic rate. This is to conserve our fuel. We will drive feeding. Thyroid hormones are also regulated within the periphery by the peripheral tissues. This is done by conversion. The thyroid hormone T4, as I said, is the pro hormone for T3. So, T4 can be converted to T3 by removal of one of the iodines. This removal is done by a deiodinases an enzyme. Note the ase at the end of the term. Deiodinases are present within the peripheral tissues. THese deiodinases are able to convert T4 to T3. There are multiple forms of deiodinases. The formes that we are interested in are deiodinase one and two. Deiodinase 1 is present on the surfaces of the cells. And as T4 enters into the cell, it can be converted to T3 by this deiodinase. This enzyme also makes reverse T3. About 50% of T4 will be made into a reverse T3, which is inactive. And 50% into T3, which is the active species. The active T3 moves to the nucleus and activates transcription. In particularly, two genes that are turned on are the beta one adrenergic receptors and the sodium-potassium ATPase. And particularly, we turning on beta one adrenergic receptors in the heart. If you recall that drives heart rate. Okay, we will come back to that point in a little bit. Deiodinase 1 is a regulated enzyme. It's expression is regulated in different tissues, and it is regulated by energy levels. Under starvation, deiodinase 1 is down-regulated, We lose deiodinase 1 activity when starving, or during starvation. Or a restriction of fuel. The second deiodinase that's present within the body is distributed in very specific locations. It is i the CNS, the heart, the thyroid gland, and skeletal muscle. This deiodinase is Deiodinase 2. It is not regulated by starvation. This deiodinase is always active in those cells. Deiodinase 2 is present on the nuclear envelope. It's located internally in the cell, inside the target cells. It sits on the nuclear envelope. It converts T4 to T3. So cells which have Deiodinase 2 have very high occupancy of the transcription factor such as in the brain. So what happens then when we have changes in our feeding state? That's what's shown here. When we have a mild fast, let's say you are traveling. and you only have enough money for one meal a day. That means restricting your caloric intake. Normally you need about two thousand calories a day to maintain your normal metabolic rate. Under these conditions, say you're taking in 1500 calories a day. So under these conditions, the free T3, this very very small amount of free T3 that's present within the plasma, can decrease to up to 50%. But if we look at the free T4 in this individuals, we would see that it's normal. That means that the TSH levels, the thyroid stimulating hormone levels are also normal. Now, why are they normal? The negative feedback loop from T4 is still active and it's mediating negative feedback to the pituitary and to the hypothalamus. So the axis looks as a normal axis, but we are running at a lower metabolic rate within the body. The reason we're running at a lower metabolic rate is that the deiodnase 1 has been down-regulated. The expression of that enzyme within the kidney, liver, and so forth is now lower. If we extend our fast, then we go into a severe fast where we restrict our caloric intake. Let's say, to 1,000 calories a day and for several days or for a week. Under these conditions, we can decrease the free T3 so that it's less than 1% or 1%. And we will also decrease the free T4. We are decreasing the total amount of the thyroid hormones available to the body. We will decrease the TSH. Why is it that the negative feedback did not automatically kick in and cause the TSH levels to rise? The reason it did not is because under conditions of severe dieting, we have used up our leptin depots. And by using up the leptin depots, the fat depots, the signaling of leptin has dropped. By having leptin decrease, the TRH signal is also decreased, TSH is decreased. The entire axis is now decreased. What's the advantage to the body? The advantage to the body is that under these conditions, where we have restricted fuel coming into the body, you want to be able to maintain the CNS activity and to maintain the contraction of the heart. The fuel that is actually present in the body for use is being used by those specific tissues rather then being used by other tissues within the body. So, we go to a lower metabolic rate. The consequence is, is that these individuals would feel very cold. They're not able to generate as much heat within the body. Their metabolic rates have been decreased. In addition to that, they would feel very tired and they would not have a lot of energy, sometimes they get sort of foggy. They don't think very clearly. It's a body running on low fuel. So, what's our pathology for this system? One of the pathologies that we talked about is that we can develop a Goiter. The Goiter can develop under different circumstances. The first is that the Goiter which is an enlargement or growth of the gland itself, can occur when we don't have enough iodine in the diet. So we cannot make thyroid hormones. In condition of iodine deficiency in a diet, Goiters will form. A lot of colloid is made because the HP axis is being driven. We have high levels, circulating levels of TSH because we do not have our negative feedback loop which suppresses the axis. Goiters used to be very prevalent within the population at large across the world. Then, they added iodine to salt. When they added iodine to salt, iodinized salt, the presence of Goiters decreased dramatically. The other condition where we can have two little hormone or hyposecretion of the hormone, as we already mentioned, can occur during development. When that occurs, then we have what's called Congenital Hypothyroidism. Under these conditions, the CNS fails to develop. Ther is a problem with CNS development. There is mental retardation. This will also affect growth. But once the baby is born and the thyroid hormone levels are corrected, then growth can be corrected despite it's retardation throughout development in utero. But the CNS is not able to develop. There is a condition which is an autoimmune disease which leads to Hypothyroidism. This is called Hashimoto's disease. In Hashimoto's disease, the gland is actually being degraded or a lost. So in Hashimoto's disease, an autoimmune disease, the cells, the follicular cells enter into apoptosis. We are losing the cells which are make the hormone. A Goiter can form under these conditions, even though we're losing the cells. This is because a colloid will be made by the cells that are present. They're trying to make up for the loss of the hormone. But, the total effect is that there is going to be too little thyroid hormone being made. The conditions of Hypothyroidism, again, will give you a feeling of cold, being very cold, the skin turn over is affected so that we get flaky skin. The hair gets very brittle,and the individual has low energy levels. The individual just doesn't feel like they're thinking very well, they feel like they're a little foggy in the way they're able to address problems. And these individuals can be helped by giving them then a T4 or T3. Usually, T4 was given but in some instances both T4 and T3 are given. In the condition where we have too much thyroid hormone, this called hypersecretion. In hypersecretion, the gland again can grow because we're having a strong stimulation, either because we have a tumor that's growing within the thyroid gland or there is a strong stimulation by TSH of the gland itself. One of the most common of these hypersecretion conditions is called Grave's Disease. Again, this is an autoimmune disease. Here, the antibody IgG actually recognizes or binds to the TSH receptor. It mimics the binding to that receptor of TSH and activates the receptor. Under these conditions, we will stimulate the TSH receptor. This increases the secretion of T4 and T3, but will decrease TSH levels. THS levels fall because the negative feedback loop is working. We have very high levels of circulating thyroid hormone, but we don't have proper negative feedback regulation of that gland. This is a very common disease and it turns out to be one in those common of all of the endocrine diseases for the human. There's one other condition in which we have hypersecretion from the gland. This is called Thyroid Storm. In the Thyroid Storm, we now have a condition which is a medical emergency. In thyroid storm, the individual has a very, very fast heart rate. This tachycardia is extremely fast. It is difficult to fill the heart because the heart is beating so rapidly. The individual will have a high fever, because they're generating a lot of heat. They are driving their metabolism. One thing that the thyroid hormone does is upregulating a protein called an uncoupling protein. And this uncoupling protein is causing the mitochondria to generate heat rather than to generate ATP. Foe these individuals, the main problem is with the cardiovascular system. If you cannot fill the heart then the cardiovascular system will collapse. They present with a high fever, and a very fast heart rate, tachycardia. You give them a beta blocker to protect the heart. And then you give them a blocker for the deiodinase 1, which is up regulated in hyperthyroid conditions. When you block that particular enzyme, then T3 levels decrease in content throughout the body. The body will then drop the amount of T4 and T3 that's being made and that's driving the the metabolic rate within the body. So what are our key concepts? Key concept number one is that T3 and T4 are synthesized and secreted by the thyroid gland in response to TSH which is coming from the pituitary. Second, that the thyroid hormones are formed from the hydrolysis of iodinated thyroglobulin, and the thyroglobulin is our pre-prohormone. And that normally we have about three months supply of the preprohormone within the thyroid gland. Third, we need dietary iodine in order to be able to synthesize the hormones. So we have to iodinate the thyroxine residues in order to have an active species. Four, under normal conditions, the majority of T3 is made from T4. T4 is our prohormone, and this T3 is usually made in the peripheral tissues by an enzyme which is called deiodinase. This is an important site for regulating the basal metabolic rate of the tissues. And 5, the thyroid hormones are essential for development of the nervous system, and particularly the central nervous system for normal body growth and to regulate basal energy and temperature within the body. So the next time we come in here we're going to talk about how the hypothalamus, pituitary axis can regulate our metabolism in stressful situations. This is where we regulate the adrenal glands, so see you then.
