Greetings, today we start our discussion of the endocrine system proper. In particular, we want to address one of the major endocrine systems which is the hypothalamus-pituitary axis. We're going to talk about this in the next four lectures, which are dealing with homeostatic control. And then next week, we will discuss how it controls reproduction. This is a dominant axis for the entire body. The pituitary regulates energy and water balances. It also regulates growth, response to stress, and, as I said, reproduction. The pituitary secretes 8 hormones. And some of these hormones act directly on non-endocrine tissues such as bone, where it regulates the growth of the bone. In other cases, these hormones modulate the activity of endocrine glands, which are located within the periphery of the body. When it does so, these pituitary hormones are called trophic peptides or trophic hormones. Trophic because they are regulating the secretions from peripheral endocrine glands. The pituitary itself is regulated by the hypothalamus. This a region of the brain. The pituitary is a portion of the brain, and so is the hypothalamus. Th is system integrates afferent signals from the rest of the body and from the brain. Because the pituitary sits outside of the blood brain barrier is able to receive signals from the blood. It is able to integrate both the electrical activity of the body, that is what's coming back from the nervous system to the brain, with that signaling which is coming back through the blood. This is a very complicated scenario. The easiest way to understand the communication between these two systems or these two regions of the brain is to look at how they developed. That's what's shown here. In embryonic development there is a down-growth of the brain. This is shown here. This downgrowth remains attached to the base of the brain in an area which called the infundibulum. The downgrowth expands and becomes what is known as the pars nervosa. This entire region, the infundibulum plus the pars nervosa is called the posterior pituitary. The posterior pituitary, then, is going to be neural tissue. It retains its connection to the brain throughout life. The second portion of the pituitary, the other lobe, is called the anterior lobe. This arises from the roof of the mouth as an extension from the roof of the mouth. It becomes severed during development. It forms a little cuff around the infundibulum. It aligns directly besides the posterior lobe. This is called the anterior lobe. It consists of the pars tuberalis, which is this little cuff-like region, and the pars distalis, which is the larger portion, aligned next to the pars nervosa. Between the two lobes, there is a region called the pars intermedia. This pars intermedia is also part of the anterior pituitary, This is also glandular tissue. In the human, the pars intermedia is not of major importance. But in lower animals, it actually has a major function in regulating the change in the coloring of the skin to stress and signaling. We then have two lobes, the anterior lobe of the pituitary and the posterior lobe of the pituitary. What I want to talk about today is the activity of the anterior lobe, and then in the next lecture we'll talk about the activity of the posterior lobe. As I said, there are eight hormones which are coming from the pituitary. Six hormones are going to come from the anterior lobe, and two hormones are going to be secreted by the posterior lobe. In this diagram, we see again, our hypothalamus which is the neural tissue connected to the infundibulum and down into the posterior lobe. This is all neural tissue. Surrounding that is a little cuff which is the pars tuberalis. Then the pars distalis which is here. So the grayed region is the anterior lobe. The anterior lobe is regulated by the hypothalamus. It is done so through a portal system, which are blood vessels THese vessels pick up small peptides which are secreted from the brain and deliver them into the pars distalis to regulate the cells within the pars distalis. This system is called a portal system. Blood enters from the superior hypophyseal artery into the region of pars tuberalis and the upper region of the infundibulum. This is also known as the median eminence. The blood vessel breaks up into a capillary bed within this region and then forms a vein. The veins then deliver the blood to a second capillary bed which is located within the pars distalis itself. All of the cells within the pars distalis are bathed by the second capillary bed. Because we have two capillary beds connected by veins, this is called a venous portal system. The peptide secretions from the hypothalamus come from an area known as the paraventricular nucleus. The region is where the somas, the cell bodies of these neurons live. They extend their axons down to the first capillary bed. These axons terminate on the first capillary bed. These hypothalamic neurons secrete little neuropeptides, anywhere from three amino acids to ten amino acids in size, into this first capillary bed. Theses peptides are picked up by the venous drainage and then delivered to the second capillary bed within the pars distalis. Here, they regulate the secretions of their target cells within the pars distalis. The pars distalis target cells then secrete hormones. Those hormones enter into the vein which is draining from the pars distalis to be delivered then to the systemic circulation. There's a couple things that we have to pay attention to. One is, is that, these little neuropeptides are delivered to the pars distalis, the cells of the pars distalis, their target cells, in very high concentrations. As we all recall, when you deliver peptides to cell surface receptors in high concentrations, these receptors will down-regulate. To prevent the down-regulation, these small peptides are released in a pulsatile manner. So pulsatility is critical for the activity of the system. The second thing that we have to remember is that these secretions coming from the hypothalamus are going to be episodic. In most cases it's a circadian rhythm. So they're going to be secreted on a regular timed basis throughout the day. But in one particular instance, and that is in the adult female reproductive tract, we actually have a monthly cycle rather than a daily cycle. So we have both pulsatility in secretion of this neuropeptides, and we have an episodic secretion of the neuropeptides. The target cells will have low affinity receptors because they're seeing high concentrations of the neuropeptides. So low affinity receptors within the pars distalis cells themselves. Now this is a complicated system because we're dealing with six different hormones. These hormones coming from the hypothalamus are called releasing factors That's what's shown here. Each releasing factor is going to work on a target pituitary cell. That target pituitary cell will secrete a hormone. These are called trophic factors or trophic hormones because they will regulate the activity of the target organ within the periphery. So for instance, TRH is a thyroid releasing hormone. It works on the thyroid tropes at the pituitary. It causes them to secrete thyroid stimulating hormone. When thyroid stimulating hormone enters into the systemic circulation, it works on the thyroid gland. The thyroid gland will secrete the thyroid hormones, which are T3 and T4. In some instances, we have more than one hormone being secreted by the pituitary cells. In this particular instance, we have the gonadotrophic releasing hormone, which is coming from the hypothalamus. It's target cells are within the pituitary. They will secrete two hormones, luteinizing hormone or LH, and follicle stimulating hormone or FSH. These two hormones work on the gonads of both males and females. To control the production of the gametes as well as the secretion of the steroid hormones or the sex hormones. So in each case then, we have a positive factor, a releasing factor, which causes the release of a hormone from the pituitary cells. But there are two instances where we also have an inhibitory factor. This occurs in control of growth hormone and prolactin. Growth hormone and prolactin actually have negative regulatory factors. The negative factor for growth hormone is somatostatin. The negative factor for prolactin is dopamine. For these two hormones then, the net effect of the positive factor and the negative factor on pituitary cell determines whether or not we get secretion of the trophic hormone. So, let's look at this axis regulation of the hypothalamus to the pituitary in a conceptual manner. What is shown here is that the hypothalamus secretes a factor which is releasing hormone. This is a positive factor. It releases this factor, XRH, to work on the target cell within the pituitary. The target cell releases its hormone, in this case XTH. That XTH hormone works on its peripheral target cells. So XTH goes into the systemic circulation and activates a cell, which is within the periphery. In turn that target cell secretes a hormone which in this case we call X. Now this hormone X will feed back from the periphery to the pituitary in a negative feedback manner. It also feeds back to the hypothalamus in a negative feedback manner. So we have a negative regulation by the periphery of both the hypothalamus and the pituitary. This is called the long negative feedback loop. In addition to this, we have a feedback from the pituitary factor XTH itself. That XTH factor feeds back to inhibit the hypothalamus. This is called the short negative feedback loop. Both of these loops are negative. That is they will dampen the release of the hypothalamic peptides XRH. There is a third loop. This is called the ultra-short loop. This is mediated by the hypothalamic peptide XRH itself. This is a paracrine feedback. Again, it's a negative feedback. This is called the ultra-short loop. So what we've just described is a complex negative feedback loop where we have multiple levels of regulation. Where there are negative feedbacks controlling each level of secretion. As I said, in the condition of growth hormone or prolactin, we also have feedback to a negative factor. That's what's shown here. In this case, we turn on the secretion of the negative factor. That negative factor then, adds to the inhibition of the target cell within the pituitary. Let's consider growth hormone because it demonstrates this entire system. The is growth hormone. If we look at growth hormone secretion in the adult during the day, then we can see that it is pulsatile. We have a pulsatile secretion throughout the day. In addition, secretion is in a circadian rhythm. That is, the maximum amplitude occurs in the early sleep hours, during early sleep. Then as we approach waking, secretion of the growth hormone precipitously drops. Growth hormone secretion in the aged individual shows the same circadian rhythms. But growth hormone secretion amplitudes will be smaller. There will be less growth hormone being secreted in the elderly. Conversely in the very young, we observe much higher amplitudes of growth hormone being secreted. But again, it's going to be secreted on a sleep wake cycle. So in the young we would have higher amplitudes. Two other things about growth hormone. and In addition to circadian rhythm and its pulsatility, it can also be regulated by stress. It will increase in response to stress and as we said, it increases to response to sleep. Growth hormone decreases in a response to an increase in blood glucose. When we see this drop in growth hormone in the early hours just before waking, this is due to a rise in cortisol. The rise in cortisol increases blood glucose levels which shuts off the release of growth hormone. Let's look at the H-P axis then for growth hormone. The hypothalamus secretes GHRH, or growth hormone releasing factor. This works on the somatotropes which are the target cells within the pituitary. They, in turn, secrete growth hormone. Growth hormone works in the periphery on the liver, as well as a few of the other organs which we'll talk about in just a few minutes. But at the liver, it causes secretion of a second hormone. This is called insulin like growth factor, 1, insulin like growth factor one. Insulin like growth factor 1 mediates the long loop negative feedback, not only to the hypothalamus but also to the pituitary. This long negative feedback loop, dampens the secretion of growth hormone from the pituitary and GHRH from the hypothalamus. Growth hormone also mediates a negative feedback loop. This is the short negative feedback loop. GH comes from the pituitary to the hypothalamus. Then GHRH mediates the ultra short loop. That's shown here. Again, that's a paracrine loop, where neighboring cells regulate their adjacent cells. Insulin-like growth factor-1 which comes from the liver in a positive manner turns on the secretion of somatostatin from the hypothalamus. This is an inhibitory hormone. In fact, somatostatin in anywhere in the body is always an inhibitory hormone. It shuts down the secretion or the release of growth hormone. So the somatotropes receive information from the hypothalaums, the positive factor which is GHRH. And they receive somatostatin. The net effect determines whether or not they should secrete growth hormone, and how much growth hormone should be secreted. For many years, it was thought that growth hormone was the only hormone that regulated growth of the body. And then with the advent of transgenic mice, we were able to knockout the growth hormone receptor in the transgenic animals. When they did so, they found that the fetus actually developed quite normally, but that soon after birth the animal was not able to grow correctly. So, growth hormone is really important for the growth of the individual after birth. But before birth, growth hormone didn't seem to have much of an effect on the growth of the fetus or the embryo. When they did a similar study with IGF-1 and knockout of the IGF-1 receptor, then what they found was that, that the animal was not viable. So, IGF-1 was identified as being absolutely required for the development of the fetus. So we have two growth factors, IGF1, which is necessary for the growth of the fetus and we have growth hormone, which governs growth of the body after birth. So, what are the roles of growth hormone? Growth hormone is a hormone, which works on many tissues to the body. It moves glucose into the plasma from fat depots. It decreases fat depots and it increases muscle size. So growth hormone builds a lean muscular body, a lean muscular phenotype. It prevents glucose storage. It mobilizes the glucose to be used then for growth. Growth hormone increases not only to stress, but also to instances when we have high amino acids circulating within the blood. That will turn on growth hormone. Those amino acids are what's being used to build muscle size. The growth hormone also works on the long bones of the body. It increases the long axis of the body until we have closure of the hypophyseal plates. At that time, then the bones can no longer grow in length, but the growth hormone can cause the bone to grow in width. In addition, we have growth hormone activating IGF-1 secretion from the liver. IGF-1 works not only on the long bones in concert with the growth hormone, but it also acts to keep the size of all the internal organs commiserate with the growth of the long axis of the body. So the growth of the lungs, the liver, the heart, these are all directed by IGF-1. IGF-1 causes the growth of the internal organs. What happens when we have growth hormone excess? If we have a tumor that's within the anterior pituitary, it can driving the secretion of growth hormone. If this occurs in the young before we have closure the hypophyseal plates, we can get what is called gigantism. These are individuals can get to be greater than eight feet tall. So until the closure of the hypophyseal plates, then we will have an elongation of the long bones of the body. After puberty, if excess GH occurs in an adult after closure of the epiphyseal plate, then this is called acromegaly. Under these conditions,there is coarsening of the facial features with growth of the flat bones of the body. The hands will grow, the feet will grow. The iindividual has a prominent eyebrow ridge and jaw. Commensurate to this growth, all of the organs will increase in size. They increase in size because the high secretion of growth hormone causes a high increase in circulating IGF-1. So certain bones of the bodies are growing, Bt in addition, there is growth of the heart, growth of the liver and so forth. What has happened in recent years is that many athletes used growth hormone or abuse growth hormone, because it can give a muscular lean, muscular body. A very strong muscular body, but the problem with that gain in muscle mass, is that they cause the internal organs to grow. Often, these individuals die an early age, in their thirties, because they have an enlarged heart or an enlarged liver. So, there's a downsize then to the use of growth hormone. What also happens if we have insufficiency of growth hormone? One instance where we actually have normal secretion of growth hormone, but the IGF-1 levels are restricted. This occurs in pygmies. In the pygmy, the entire structure of the body is normal. It's all proportionate. It's just that the individual is much smaller. The individual is smaller, because of the restriction of IGF-1. IGF-1 is made, but it's not made at the normal levels that you would see in an individual who doesn't have this condition. So under conditions where IGF-1 is restricted, body size is also limited or restricted. So, what are our general concepts? The general concepts is first that the hypothalamus regulates hormone secretion from the pituitary. It regulates water and energy balances, which we haven't directly talked about, but we will in the next couple of lessons as well as reproduction and growth. The pituitary consist of two lobes, the anterior lobe and the posterior lobe. They have different embryological origins. They're regulated separately and they produce different hormones. The anterior pituitary is regulated by negative feedback by hormones from its target organs which are in the periphery of the body. there are four major feedback loops for the anterior pituitary. One which we discussed was growth hormone, the next is the thyroid. The thyroid hormones will feedback and regulate the anterior pituitary. The third is from the adrenal glands. The adrenal grand hormone will feedback and regulate the secretion from the anterior pituitary, and then LH and FSH, which are going to be regulated by the sex steroids, which emanated from or secreted from the gonads. And lastly, many of the pituitary hormones are called trophic for their target cells, because they increase the secretion of the hormone from their target endocrine cells. In addition to that, they increase the size of the target cells and the number of the target cells. So it is a dynamic system where we can actually increase the amount of hormone being made as well as the number of cells, which are producing these hormones. So the next time we meet, we will discuss the posterior pituitary and how it regulates both the ionic composition as well as fluid balances within the body. So, see you then.