Greetings, today we're going to start a discussion of the endocrine system proper. And particularly, we want to be addressing 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 we're going to, next week, talk about how it controls reproduction. So 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 is going to secrete 8 hormones. And some of these hormones are going to act directly on non-endocrine tissues such as bone, where it's going to regulate the growth of the bone. And in other cases, it's going to modulate the activity of endocrine glands, which are located within the periphery of the body. When it does so, these hormones are going to be called trophic peptides or trophic hormones, because they're regulating the secretions from these peripheral endocrine glands. The pituitary itself is regulated by the hypothalamus, and this a region of the brain. So the pituitary is a portion of the brain, and so is the hypothalamus. And that the hypothalamus is going to integrate afferent signal from the rest of the body and from the brain. And the pituitary because it's sitting outside of the blood brain barrier is able to receive signals from the blood. So that it's able to then 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. So this is a very complicated scenario. So the easiest way to understand the communication between these two systems or these two regions of the brain is to look at how they develop, and that's what's shown here. So in embryonic development we have a downgrowth of the brain, which is shown here. And this downgrowth remains attached to the base of the brain in an area which is called the infundibulum. The downgrowth expands and becomes what is known as the pars nervosa. And this entire region, the infundibulum plus the pars nervosa is called the posterior pituitary. So the posterior pituitary, then, is going to be neural tissue, and it retains its connection to the brain throughout life. The second portion of the pituitary, the other lobe, is going to be called the anterior lobe. And this arises from the roof of the mouth as an extension from the roof of the mouth, and it then becomes severed during development. It sort of forms a little cuff around the infundibulum. And it aligns directly besides the posterior lobe. And 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, which is aligned next to the pars nervosa. Between the two lobes, there is a region which is called the pars intermedia. And this pars intermedia is also part of the anterior pituitary, this is also a 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. So we then have two lobes, anterior lobe of the pituitary and the posterior lobe of the pituitary. And 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, here's our hypothalamus which is the neural tissue which is connected to the infundibulum and down into the posterior lobe. So this is all neural tissue, and surrounding that is a little cuff which is our pars tuberalis, And then the pars distalis which is here. So the grayed region is the anterior lobe. Now the anterior lobe is regulated by the hypothalamus. And it's done so through a portal system, which is a blood vessels which are picking up small peptides which are secreted from the brain and delivering them into the pars distalis to regulate the cells which are sitting within the pars distalis. This system is called a portal system because as the blood enters it 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. We break up into a capillary bed within this region and then form a vein. And the veins then deliver the blood to a second capillary bed which is located within the pars distalis itself. So all of the cells which are 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 secretions from the hypothalamus from an area which is known as the paraventricular nucleus, And these are where the somas, the cell bodies of these neurons live. They're going to extend their axons down to the first capillary bed, and they're going to terminate on the first capillary bed. These neurons are going to secrete little neuropeptides, anywhere from three amino acids to ten amino acids in size, into this first capillary bed. They're going to be picked up by the venous drainage and then delivered to the second capillary bed within the pars distalis. And here, they're going to regulate the secretions from their target cells within the pars distalis. And the pars distalis those cells then, will secrete hormones. And those hormones will then enter into the vein which is draining from the pars distalis and be delivered then to the systemic circulation. There's a couple things that we have to pay attention to. And one is, is that, these little neuropeptides are going to be delivered to the pars distalis, the cells of the pars distalis, their target cells, in very high concentrations. And as we all recall, when you deliver peptides to cell surface receptors in high concentrations, these receptors will down-regulate. And to prevent the down-regulation these small peptides are going to be 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 and secretion of this neuropeptides, and we have an episodic secretion of the neuropeptides. The target cells are going to have low affinity receptors because they're seeing high concentrations of the neuropeptides. So low affinity receptors within the pars distalis themselves. Now this is a complicated system because we're dealing with six different hormones. And these hormones, coming from the hypothalamus are called releasing factors and that's what's shown here. And each releasing factor is going to work on a target pituitary cell. And that target pituitary cell will secrete a hormone and these are going to be 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. With thyroid stimulating hormone enters into the systemic circulation and it works on the thyroid gland. And the thyroid gland will secrete the thyroid hormones, which is T3 and T4. In some instances, we have more than one hormone being secreted by the pituitary cells, and in this particular instance, we have the gonadotrophic releasing hormone, which is coming from the hypothalamus. It's target cells are the which are within the pituitary, and they will secrete two hormones, luteinizing hormone or LH, and follicle stimulating hormone or FSH. These two hormones work on the gonads of both the males and the females. To control the production of the gametes as well as the secretion of the steroided 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. And this in control of growth hormone and prolactin. So growth hormone and prolactin actually have negative factors. The negative factor for a growth hormone is somatostatin, and then the negative factor for prolactin is dopamine. These two hormones then, the net effect of the positive factor and the negative factor on pituitary cell is what's going to determine whether or not we get secretion of the trophic hormone. So, let's look at this axial regulation of the hypothalamus to the pituitary axis in a conceptual manner. So, what we see then is the hypothalamus has a factor which is releasing hormone, this is a positive factor, it releases this to work on the target cell which is within the pituitary. The target cell will release its hormone, in this case X, and that hormone works on its peripheral target cells. So it goes into the systemic circulation and activates a cell, which is within the periphery. It in turn secretes a hormone which in this case we call X. Now this hormone will feed back X feeds back from the periphery to the pituitary in a negative feedback manner. And 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. And this is called the long negative feedback loop. In addition to this, we have a feedback from the pituitary factor itself and that factor feeds back to inhibit the hypothalamus and this is called the short negative feedback loop. So both of these loops are negative and that is they will dampen the release of the hypothalamic peptides. There is a third loop and this is called the ultra-short loop and that is mediated by the hypothalamic peptide itself and this is a paracrine feedback. And again, it's a negative feedback and this is called the ultra-short loop. So what we've just described then is a complex negative feedback loop where we have multiple levels of regulation, where we have negative feedbacks controlling each of these levels of secretion. And then as I said, in the condition of growth hormone or prolactin, we also have feedback to a negative factor, and that's what's shown here. And in this case, we're turning on the secretion of the negative factor. And that negative factor then, adds to the inhibition of the target cell within the pituitary. So let's consider growth hormone because it is a demonstration of this entire system. The growth hormone, if we look at a growth hormone secretion in the adult during the day, then we can see that it is posital. So we have a posital secretion throughout the day and that it is in circadian rhythm. And that is, is that its maximum amplitude is going to be in the early sleep hours, so it's early sleep. Then as we come towards waking, then the growth hormone precipitously drops. Growth hormone in the age individual is actually going to show the same circadian rhythms. But the growth hormone the amplitudes will be smaller. So we will have less of growth hormone being secreted in the elderly. And then conversely in the very young we'll have much higher amplitudes of growth hormone being secreted. But again, it's going to be secreted on a sleep wake cycle, and so in the young we would have higher amplitudes. Two other things about the growth hormone, and that is 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. And when we see this drop in blood glucose in the early hours just before waking, this is due to a rise in cortisol. And the rise in cortisol then is increasing blood glucose levels and is shutting off the growth hormone release. So let's look at the HP axis then for growth hormone. The hypothalamus is secreting GHRH, or growth hormone releasing factor, and this is working on the somatotrose which are the target cells within the pituitary. And they, in turn, will 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 a secretion of a second hormone, and this is called the insulin growth factor, insulin growth factor one. Insulin growth factor 1 mediates the long loop negative feedback, not only to the hypothalamus but also to the pituitary. So this is the long negative feedback loop, it going to dampen the secretion of growth hormone from the pituitary and from the hypothalamus. Growth hormone also mediates the negative feedback loop, and this'll be the short negative feedback loop, coming from the pituitary to the hypothalamus. And then GHRH will mediate an ultra short loop, and that's shown here. And again, that's a paracrine loop, where its neighboring cells are regulating their adjacent cells. Insulin-like growth factor-1 which is coming from the liver in a positive manner will turn on somatostatin 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 and it's going to then shutdown the secretion or the release of growth hormone. And so the somatotose then are going to take in the information from the positive factor which is GHRH. And the amount of the somatostatin and determine whether or not they should secrete growth hormone, and how much growth hormone should be secreted. Now 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 the growth hormone receptor in the transgenic animals. And when they did so, they found that the fetus actually developed quite normally, but that soon after birth that the animal was not able to grow correctly. So, that the growth hormone then was 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 the similar study with IGF-1 and knockout the IGF-1 receptor, then what they found was that, that the animal is 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 is governing them the growth of the body after birth. So, what are the roles of growth hormone. So, the growth hormone is a hormone, which is going to work on many tissues to the body. It is moving glucose into the plasma and from fat depots, so it's decreasing fat depots and it's increasing muscle size. So it's going to build a lean muscular body, a lean muscular phenotype. It's preventing glucose storage. It is mobilizing the glucose to be used then for growth. Growth hormone increase not only to stress, but also to instances when we have high amino acids circulating within the blood. So, that will turn on growth hormone and those amino acids are what's being used to build muscle size. The growth hormone also works on the long bones of the body and will increase 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 then have growth hormone activating IGF-1, secretion from the liver. And the IGF-1 works not only on the long bones in concert with the growth hormone, but it is working 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 and the IGF are the ones, which are causing 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, which is driving the secretion of growth hormone and this occurs in the young before we have closure the hypophyseal plates, we can get what is called gigantism and these are individuals that 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 this occurs in an adult when we have closure of the epiphyseal plate, then this is called acromegaly. And under these conditioning, you have coarsening of the facial features of the flat bones of the body. The hands will grow, the feet will grow. You have a prominent eyebrow ridge and jaw. Commensurate to this, all of the organs will increase in size and they're increasing in size, because the high secretion of growth hormone is causing a high increase circulation of IGF-1. So, both certain bones of the bodies are growing. But in addition to that, we have 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. So very strong muscular body, but the problem with that is as they're gaining muscle mass, they're also causing the internal organs to grow. And often, these individuals will die an early age in the 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? So one instance where we actually have normal of growth hormone, but the IGF-1 levels are restricted and this occurs in pygmies. And 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? So the general concepts is first that the hypothalamus regulates hormone secretion from the pituitary and it's going to regulate 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 from hormones, from its target organs which in the periphery of the body and 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 are going to feedback and regulate the anterior pituitary. The third is from the adrenal glands and the adrenal grand 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 are emanated from or secreted from the gonads. And lastly, many of the pituitary hormones are called tropic 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 cells and the number of the cells. So it's 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, then we're going to talk about the posterior pituitary and how it regulates both the ionic composition as well as fluid balances within the body. So, see you then.
