Welcome, today we want to continue our discussion of the Endocrine system. The general concepts of the Endocrine system. Today we want to talk about two specific things that is, the assessment of the system and its pathology. The way you classify the pathology. So first, we want to explain the principles and the limitations of how we measure the hormones. This is done in two ways. One is by actually quantitating them and secondly asking whether or not they're active. Then we want to explain classification of the endocrine pathologies. How to assess functions? We said the last time that if we have too much hormone. We have a hyper- secretion of the hormone. We have hormone excess. The problem with this situation is that you can have down regulation of the target cell receptor. We could desensitize the biological system. Such that it's not recognizing the hormone. It is not giving us the biological activity. Or we could have a really, really strong response. This would be an excessive response to the amount of hormone that's available. The second problem is that we have too little concentration of the hormone, We have hypo-secretion of the hormone. This would be hormone insufficiency, where not enough of the receptors on the target cells are occupied. We don't get the biological effect that we need, or the biological response that we need. Then we said we could also have target cell resistance. This is a problem where the receptors on the target cells are unresponsive. They could be unresponsive because they're uncoupled. and still present on the cell surface. This is what we see with Diabetes Type 2 individuals often. Or we have the receptors actually removed or degraded. It's not even present on the cell surface. And then lastly, we have just right or a normal, eu-secretion. And that's where the hormone, the endocrine system is working correctly. We have two assays for measuring our hormones. One of them is called competitive binding assay. Remember that the hormones are a very, very small concentrations within the blood. So we have to have a very sensitive assay to find the amount of hormone, that's within our sample. And to do this we use a specific antibody. This antibody recognizes the hormone. We have in our system, in the assay, we put in a labelled hormone. So we have a known amount of labelled hormone that would bind up all of the antibody that's within the system. We mix this with a hormone that's from our patient or from the unknown. We don't know the amount of hormone that's here, so this is our x amount. We mix this then with the known or labeled hormone and our antibody. And then assay for how much of the labeled hormone has been brought down. And the unlabeled hormones should compete a finite amount of the labeled hormone. And then by subtraction we know how much should have come down. By subtraction we can figure out how much of the unlabeled hormone we have present in the sample. This is high sensitivity because of the antibody and is high specificity because of the antibody. But it doesn't tell you if the hormone is active. So when could this give us a false reading? So let's say you have an individual who presents as if they are a diabetic type I. These individuals have very high circulating levels of plasma glucose. Yes, high circulating of plasma glucose, but when you assay for the insulin in their bloodstream. You find that insulin is also present. So by this competitive binding assay, the insulin is present. The question is, is the insulin they're making functional? The way you test that, would be that you give this individual some insulin that you know is functional. And see whether or not the amount of glucose that is circulating in the plasma decreases. If it does, then you know that the insulin that the individual is making, is an insulin that's not biologically active. It can not bind to the receptor, or it has some problem in its structure. So we have to have a second assay then which tells us whether or not our hormone is functional. These are called bioassays. So what I've diagrammed here is a complex negative feedback loop of one of the hormones. That we'll talk about later on in the course. But this particular hormone is cortisol and it's secreted by the adrenal gland. This hormone is secreted in response to low plasma glucose. With low plasma glucose, the hypothalamus, an area of your brain, secretes a hormone called CRH, or corticotropin. This hormone binds to a second area of the brain called the anterior pituitary to secrete ACTH, adrenal cortocotrophin. ACTH works on the adrenal cortex to cause secretion of cortisol. That's our regular (typical) stimulation of the cortisol from the adrenal gland. Cortisol happens to be a steroid hormone so it takes about 30 to 60 minutes before cortisol will rise in the blood. And the reason for the delay is that cortisol is has to be synthesized on demand. Then cortisol is secreted into the blood, binds to a carrier and then is delivered to its target tissue. The cortisol will feed back in a negative manner to turn off the secretion from the anterior pituitary and the hypothalamus. This is a complex negative feedback loop. This the axis that we considered when ee were talking about homeostatic controls in the first lecture. What happens if the cortisol in particular individual is very very high? Now we have very high level of cortisol. Because we have high level of cortisol. We will actually have very high levels of plasma glucose. The affected individual is coming in to the physician's office. because of the symptoms that this very high cortisol is causing within his body. So, this high cortisol should have fed back and turned off ACTH and turned off CRH. But it doesn't seem to be, it's too high. The question is do we have a tumor that's making this cortisol, or do we have too much of this ACTH which is pushing the synthesis of cortisol? Is the problem occurring here, at the ACTH level, or is the problem occurring here at the cortisol level, at the adrenal itself? To test this axis, we run a suppression test. To do so we give a drug called dexamethasone, which inhibits the synthesis of ACTH by pituitary cells. When we give this drug, if we administer the drug, the ACTH levels should fall. When the ACTH level fall, then the cortisol levels should also fall. So, if we had a very high amount of ACTH, and we turn off the ACTH, the cortisol should fall. If the cortisol does not fall under these conditions, then the question is whether or not the ACTH has gone down? You can assay for the ACTH. If on the other hand, the cortisol does fall and the ACTH, under these circumstances also falls. but the cortisol stays high. That would tell you that there's a problem with the adrenal glands. Or that there's a problem with a tumor someplace in the body that's secreting cortisol that's not under the regulation of ACTH. So this is a way then that we can sort of parse the axis to find out exactly where in the axis our problem lies. Let's look at a case where we have the opposite. Where we have low cortisol, we have low cortisol levels. The hypothalamus secretes CRH due to the low plasma glucose. And we should have also ACTH, but low cortisol. We can give this individual ACTH, so exogenous ACTH to push the axis. To see whether or not the adrenal is working. When we do that then the cortisol levels should rise. We wait 30 to 60 minutes and we should see rise in cortisol. If the gland, the adrenal gland is working correctly, then the exogenous ACTH should correct this situation. We should see a rise in cortisol. That then tells us that there was a problem with the anterior pituitary, that it was not secreting ACTH correctly. Or there may have been a problem with the CRH, which if low would cause a decrease in the ACTH. So at that level then, you would have to go back and look to see whether ACTH and CRH levels are appropriate. So how do you classify these endocrine pathologies? The endocrine pathologies then in this situation where we have this complex negative feedback loop. We have a primary pathology if the last endocrine organ is not working correctly. So in our case we had low cortisol. And that endocrine organ was the adrenal cortex. If we have low cortisol, what we should have seen if the problem is at the adrenal, then we should have seen ACTH levels high and CRH levels high. The system would try to push the gland to get an increase in cortisol. On the other hand, we don't have a negative feedback loop to decrease the ACTH or the CRH. because the cortisol level is low. If the problem was secondary, then we'd have a low cortisol but we would also have low ACTH. The ACTH is the problem, and that means that the problem is sitting here at the pituitary. The CRH then could be high because the CRH is trying to push the ACTH. But the ACTH is not being secreted correctly, it's low and therefore cortisol is low. That would be classified as a secondary pathology. And if the problem is occurring at the level of the hypothalamus then this is a tertiary problem. Where we have low cortisol, we will have low ACTH, we will have low CRH. The entire axis is down-regulated. And the entire axis is down-regulated, we are missing CRH. In these individuals then the individual can be given ACTH. By giving them ACTH we then can move the cortisol levels up. Because the adrenal gland was working correctly. So our task is to identify the pathology as you're looking through different problems. We want to identify whether there is a pathologiy and be able to classify at what level the pathology is occurring. This is a misspelling. So one of our general concepts, then, first of all we have, pathology in endocrinology. occurs when there is either too little or too much hormone. or we have a resistance to the hormone due to a receptor dysfunction. and secondly, we can interpret the hormone levels. and as we're interpreting the hormone levels, we have to consider the trophic hormones that are above it. and or the level of the nutrients which are controlled by the hormone. and so in the case of the complex negative feedback loop. We have to consider all of the hormones. Which are within that negative feedback loop as to whether or not they may be the problem. And you start with the primary and then work backwards. But you have assays where you can assay the amount. For instance, we could assay the amount of ACTH. We can assay the amount of cortisol. But you start with assaying the amount of cortisol. And then go back and see whether or not there was a problem with the ACTH. So I hope this makes sense to everybody. You should go ahead and try the problem sets. Because this will allow you to apply what you've learned from these various concepts in endocrinology. Two actual cases and see whether or not you can think through these cases. Okay, so see you next time. Bye bye.
