Chapter 17: the endocrine system. Before we move on, you just have to take a look at this comic, it's the best thing ever. Thank you Saturday morning breakfast cereal. I hope you got that, if not go back and hit pause. Today we're going to be talking about what breastfeeding, petting a cat and having an orgasm all have in common, and it turns out it's oxytocin... oops. Spoiler alert! We're going to talk about the difference between paracrine and endocrine signaling. We've already discussed a couple examples of paracrine signaling, such as tanning and inflammation. So today you need to understand why that's different from endocrine signaling, and why we care. We'll talk about type 2 diabetes, and the major concept today will be receptor down-regulation, which is common to a lot of other conditions besides type 2 diabetes, but this is probably the most common one. We'll talk about second messenger systems today, which is something that hormones frequently use. We'll talk about a lot of negative feedback loops today, and of course when I say that word you're thinking "homeostasis" when you really should be thinking "the homeostatic regulation of hormone levels". So we'll talk about why testing for a thyroid hormone or testing for testosterone levels is not a good idea-- that's not the most useful metric that we have at our fingertips. We'll talk about goiter today-- this is a symptom of both hyper- and hypo-thyroidism. We'll talk about stress. And we'll also talk about the pill, around which there's a lot of misinformation and lies that circulate in the media. To do all of that, we'll start off the way that we normally do, with some basics some things that a lot of hormones share in common. We'll just define endocrine signaling at the start, talk about lipid- versus water-soluble hormones, the second messengers that they use ,how there can be changes to the amount of receptor levels, and we'll talk about changes to the amount of hormone levels. So we're going to be regulating things on multiple levels. To add to that, we're going to add even more levels! Sometimes hormones will work in permissive, synergistic, and antagonistic ways with other hormones. Once we're done with all of the basics, we can move on to the specifics. We'll talk about the HPA axis, and there's a large number of hormones involved in this, so that'll take some time. We'll move on to the thyroid, the parathyroid, and then a few other random endocrine glands. I've always had a little bit of an issue with the endocrine system, despite studying endocrinology, and that is almost every tissue in the human body dumps hormones into the extracellular fluid or into the bloodstream. For instance, we've seen muscle tissue producing testosterone and growth hormone, and we've seen the skin producing melanocyte stimulating hormone, so these organs listed here really only have one thing in common, and that is it's their major job to dump hormones into the bloodstream, rather than just something else that they do. These organs are not connected to each other the way that the circulatory system or the skeletal system maintains direct physical connections-- with a couple exceptions, the hypothalamus and the pituitary are connected to each other structurally, and the pituitary is connected to the adrenals chemically, otherwise these are all just a bunch of random organs whose primary job it is to produce chemicals an.d release them into the bloodstream The endocrine system is useful for when we need signals to spread to distant part of the body, regulating different processes that all need to be coordinated. For instance, I don't want to wind up like this guy here. When we are growing, we need things to grow at the same rate. That not only means growing in size, but it might also mean maturing at the same rate. We don't want babies with beards and really long arms and really big ears. Well, okay, I was a baby with really big ears, but that's beside the point. Hormones allow very different processes to be regulated and to be coordinated with one another, so that's the basic function of the endocrine system. It typically regulates really big and broad processes, like growth and development and reproduction, and it does so by dumping chemicals into the extracellular fluid or into the bloodstream. And these chemicals are signals that we call hormones. The nervous system can use chemicals as signals. We've already seen one example where a neuron can use the chemical acetylcholine to activate all of the muscle cells that it's connected to. But these chemicals only diffuse a very short distance away, and really we only signal to the cells that were connected to. On the other hand, the endocrine system can send signals to very distant targets, ones whose only connection is the bloodstream. Just a refresher, the endocrine system includes a bunch of endocrine glands which dump chemicals into the extracellular fluid or into the bloodstream, whereas exocrine glands secrete substances through a duct to a surface of the body or outside the body. So there's a number of ways that chemicals can be used as messengers. There are I think maybe one example that I know of (in Bi231-233) chemicals being transmitted through gap junctions, we won't talk about that this term. Sometimes, though chemicals can be released in a paracrine fashion. That just means a short distance away. Tanning and inflammation were examples of this. If you slap me in my face, the place that got slapped turns red, not other places. The inflammatory molecules don't diffuse a significant distance away. On the other hand, the endocrine system can release some of these same chemicals into the bloodstream where they travel far and wide, causing different reactions in very distant target locations. The response that a cell has to a hormone depends on whether or not it has a receptor for that hormone, and which type of receptor. The hormones themselves don't really matter, they're a signal. What really matters it's that there is a receptor there for them. For instance, my car key doesn't start all cars. The only car that it can start is the one whose lock is programmed to fit my car key. There's nothing special about my car key other than it fits in that particular lock, it's not some sort of magical door opening and car starting signaling mechanism. So how a cell responds to the hormone depends upon the receptors to that hormone. An endocrine gland can release a hormone, and many different targets can respond, and they can respond differently based off of which hormone receptor they have and what it's linked up to within the cell. These responses may be very quick changes in electrical activity, these changes may be a bit slow such as changes in DNA transcription, and these changes may be even slower than that, changes in growth and shape. Back when I was learning about the endocrine system, there was a relatively limited number of hormones that we knew about, so we simply memorized all 30 or 40 of them and classified them based off of their chemical formula. It turns out this doesn't matter for the same reason it doesn't really matter what your car key or your house key is made of, as long as it is rigid and maintains its shape when you put it in a lock. It could be steel, it could be iron, it doesn't really matter, it could even be a really dense plastic. What matters is the shape. So I'm going to skip over classifying hormones based off of their chemical formula, that's something that might be interesting to a chemist but not to a physiologist, with one exception. The one exception is the difference between steroid hormones (or the lipid-soluble hormones) and water- soluble hormones. Water soluble hormones typically exert their effects over the course of hours. If I have diabetes, I will need to inject myself with insulin when I have breakfast, and then again at lunch, and then again at dinner. On the other hand, thyroid hormone and the steroid hormones exert their effects on the order of days. If, well, if I were a female and I took a birth control pill, I could have sex in the morning in the afternoon and the evening without having to take more pills, and that's because the hormones in those pills stick around inside of the body for a significantly longer period of time than water-soluble hormones like insulin. So that's the one major difference that we're going to care about: how long these things last in the human body. In addition to that, the lipid- soluble hormones are going to be able to move across plasma membranes, so where their receptors are located can also be different from the water-soluble ones. So those are the two major differences between hormones based off of their chemistry, and I think the only reasons that we should really care about what molecules they are made of. Water-soluble hormone receptors must be at the surface of target cells, because these hormones are water-soluble they cannot diffuse across the plasma membrane, so the receptors for these molecules must be transmembrane proteins. These frequently activate second messengers inside of the cell. A second messenger would be like somebody ringing the doorbell, and the sound of the doorbell gets my dog barking, which gets my cat scared, who launches himself off of my legs, scratching me in the process, and then I get up to answer the door. That was a second messenger system. The doorbell was at the surface of my home, but my dog and cat were inside. Those were the second messengers. One of the most common forms of second messenger systems includes transmembrane proteins called g protein-coupled receptors. Let's take a moment and dissect that large name. The last letter R here stands for receptor, they can receive the hormone at the cell surface. And then inside the cell they will activate a second messenger system, and that second messenger system is a g protein. So let's go through this fairly common second messenger system. When we activate a G protein-coupled receptor, either with a hormone or in this case a drug, we activate a g protein, which activates an enzyme called adenylate cyclase, which makes a molecule called cyclic AMP. cAMP can go on to activate any number of things inside of the cell. The g protein, adenylate cyclase, and cyclic AMP are all examples of second messengers-- messages that occur inside of the cell. This will take a little bit of memorization, but I do have a few slightly helpful tips. If you take a look at AMP, and then think of something that might have three phosphates rather than just one, you might recognize this as being similar to ATP. It turns out if you take ATP, get rid of two of the phosphates, and then attach the third one back to itself in a circle, you get cyclic AMP. And the enzyme that makes that is called Adenylate cyclase. You're on your own for the rest of the stuff. This will just take some memorization, but it will be useful because we're going to be seeing the second messenger pathway quite a bit next quarter and a little bit this quarter. One important thing that happens when a second messenger system is activated is that we get amplification of the signal. This is important because many hormones exist in the femtomolar range in the bloodstream. If you don't know what a fempto-mole is, let's see if I can remember.... let's see, we've gotten molar, millimolar (which is one one thousandth of a mole), micromolar (which is one one thousandth of a milimole), nonomolar (which is another one one thousandth) and then I believe femtomolar. Did I get that right? I hope so. Anyhow, hormones exist at very minute concentrations in the bloodstream, but we often want to have very big responses inside of the cell, so we need to amplify those responses. A hormone activating just one receptor, that receptor could activate a number of G proteins, in turn those could activate a number of adenylate cyclase enzymes, which in turn could make thousands and thousands of molecules of cyclic AMP every second, and now we've got a very big response in the cell. Let's go through one example of how hormones can function, and what second messengers can do. Insulin is secreted by the pancreas in response to high blood glucose. The rest of my body has no idea what blood glucose levels are, that's the job of the pancreas. And when the pancreas detects high blood glucose levels, this will trigger the secretion of insulin. And insulin is just a signal, it's like a key if you will, it travels throughout the body and binds to insulin receptors which we find on many target organs. The binding of insulin activates a second messenger pathway, we amplify the signal, and it can lead to the movement of a lot of vesicles to the plasma membrane that contain glucose transporters. And these transporters will start moving glucose out of the blood and into the cell. This should stop the problem of high blood glucose by reducing blood glucose. Furthermore, we're going to activate enzymes that can metabolize some of that glucose, like this glucose 6 kinase down here, which will begin the process of breaking down glucose into energy. Steroid hormone receptors are frequently located inside of the cell, that's because lipid-soluble hormones can freely cross the plasma membrane to bind to these receptors. When that happens, the receptors typically dimerize, move into the nucleus, and then bind to DNA and alter gene transcription. So those are some of the basics of hormone signaling. We'll come back to paracrine versus endocrine, and we'll definitely see some lipid-soluble hormones versus some water-soluble hormones. And we'll definitely have some chances to look at second messengers in action. Next up, we need to consider factors that affect the amount of a hormone signal that's present in the body. The first may seem straightforward: how much hormone is there. You might assume that doubling the amount of hormone will double the effect, and sometimes you'd be right, but sometimes you'd be wrong. The endocrine system is just that complicated. Next up, we need to consider the number of receptors and how good those receptors are at binding the hormone. For instance, we'll see in the case of type 2 diabetes that patients actually have very high levels of insulin in their bloodstream, but very low levels of the insulin receptor. And for this reason-- even though they have high levels of the hormone-- they are not capable of properly regulating blood glucose levels. Lastly, we'll need to consider what other hormones might be present at the same time. It turns out that hormones can interact with each other, either positively or negatively. So we'll see examples of all three of these. Let's start by going into more detail about hormone levels. Some hormones are produced by their glands in response to humoral stimuli. This doesn't mean jokes, it means levels of chemicals in the bloodstream. For instance, the pancreas regulates the amount of insulin it produces based off of blood glucose levels. Next up, some endocrine glands respond to the nervous system. The pituitary can get signals from the hypothalamus in order to release hormones into the blood. The pituitary also responds to other hormones that, oddly enough, also come from the hypothalamus. So we will see instances where hormones are produced in response to other hormones. In general, as we produce more of the hormone, there's often a negative feedback loop that blocks its own production. This is called an endocrine reflex. Some endocrine reflexes are simple, meaning the endocrine gland that produces the hormone also measures the amount of hormone. Others are complex, meaning the endocrine gland that produces the hormone is not the one measuring it. The measurement might be done elsewhere, by a different gland. For instance, the hypothalamus decides how much testosterone to make, but it doesn't actually make the testosterone, it controls the production of testosterone by the testes. We not only have to worry about how much hormone is being produced when determining the levels in the blood stream, we have to worry about how quickly it's being removed. One very common metaphor that you will see for this is trying to fill up a kitchen sink by turning on the tap while the drain is still open. The amount of water in your sink at any given time would be dependent both on the fill rate and the empty rate. Hormones are emptied from the body by the liver and kidneys predominantly, others might be removed by enzymes in various tissues. This will become a factor if your patient is in liver or kidney failure. This could put their hormone levels out of whack. In addition to worrying about levels of the hormone, we're also going to worry about the receptors. Having just a few Receptors would make the cell relatively insensitive, but having more receptors would increase its sensitivity to the hormone. We're also going to have to worry about the types of receptors. Some are more sensitive than others. Just like hormone levels, receptors undergo up- regulation and down-regulation based on the amount of hormone. Typically, with increasing levels of a hormone this will lead to a decreased amount of receptors. Conversely, take away the hormone, receptor levels can go back up. Not every hormone receptor does this, but a number of them do, and this is a fairly common pattern. Hormone receptors are proteins-- often a transmembrane protein-- that can bind to the hormone, and because there are different types of hormone receptors for the same hormone, we have to worry about which types of receptors are on any given type of cell. It may be that for the same level of hormone, one cell may have a very strong response, another may have a very mild response, one may have a minimal response, and one may not respond at all, and this is all due to which type of hormone receptor that these cells have. We must also consider the effect that a second hormone may have on the first. Here are three basic patterns that we will see. Sometimes a hormone will have no effect, unless there's a second one allowing it to have that effect. Sometimes two hormones may work together synergistically, often much lower doses of both hormones lead to a greater effect than a larger dose of just one hormone. Lastly, we'll see a number of hormones that antagonize one another. We've already seen an example of this with PTH and calcitonin. So that wraps up the main mechanisms by which hormone signals are regulated. Next up, we're going to cover some specific hormone signaling pathways. The first is the hypothalamic-pituitary-adrenal axis, or the HPA axis. The word "axis" means that the hypothalamus controls the pituitary, which in turn can control the adrenals. The hypothalamus is part of the brain, but it can produce a number of hormones that all end in the letters -RH. This is unique to the hypothalamus, so it makes your job a little easier. It can also synthesize the hormones ADH and oxytocin. Lastly, it can also control the release of epinephrine and norepinephrine from the adrenals, but that's something I'll cover in bi 232. The pituitary, on the other hand, is a gland below the brain. Half of it is epithelial and it produces a large number of hormones. Here's the list of them right here, we'll go over them one at a time. And it also releases ADH and oxytocin. So here's our first little question here: why do these two show up on both sides the list? The pituitary is a small gland that sits in the sella turcica, and it's just below the hypothalamus and they're connected to each other. That connection is a portal vessel, which means a vein that travels just from the hypothalamus down to the pituitary. This is unique for an endocrine gland, usually endocrine glands dump their hormones into the general circulatory system and they travel throughout the body. Here, the hypothalamic hormones travel first to the pituitary where they exert their effects. So the hypothalamus secretes a large number of releasing hormones, and these are the hormones that control the pituitary. There's also a group of inhibitory hormones, but those aren't going to be on the exam. The pituitary, on the other hand, secretes a large number of hormones in response to these releasing hormones. So, the pituitary itself is really half a gland and half part of the brain. The posterior part, which is what releases oxytocin and ADH, can really be considered an extension of the hypothalamus, whereas the anterior portion is truly glandular-- meaning it's made of epithelial cells, not neural tissue. So here's my cartoon that should hopefully illustrate that a little bit better. Neurons that begin up in the hypothalamus have long extensions, and the ends of these cells are in the pituitary. The hypothalamus synthesizes ADH and oxytocin, but sometimes we say it's secreted from the posterior pituitary. On the other hand, the hypothalamus also makes a large number of releasing hormones that are dumped into that portal circulatory system, and they travel to the anterior pituitary. This really is a separate structure, a different cell type. The releasing hormones will trigger the production and release of the pituitary hormones. Our first annoyingly tricky detail is that a couple of these pituitary hormones are synthesized together. The hypothalamic hormone CRH instructs the anterior pituitary to make POMC or pro-opio melanocortin. This is just one gene that, when translated, is then snipped into three parts, one of which is the hormone ACTH, another is the hormone MSH, and the third is an endogenous opiate that we will not be concerned about this term. This detail will become important when we discuss Addison's disease. Every time you increase ACTH levels you have to increase MSH levels at the same time, because they're part of the same gene. Melanocytes stimulating hormone or MSH is a hormone we already discussed. It can be produced locally by the skin in response to UV damage and it leads to increased darkening of the skin (or tanning). MSH production by the pituitary doesn't play a big role in skin color. Instead, the MSH from the pituitary seems to regulate weight gain. This is one of the annoying details of the endocrine system. Frequently, hormones will have different jobs when they're produced in different locations. MSH levels in the bloodstream don't vary much between person to person except in a few instances. One will be Addison's disease coming up later, and the next is pregnancy. This can increase melanin production in a few key areas of the body, namely the nipples and portions of the external genitalia. The function of that melanin is different from how we think of it in the skin, except possibly to increase the visibility of the nipples following pregnancy, making it easier for a newborn to find them and breastfeed. Next up, we also talked a little bit about growth hormone. It can be produced locally by skeletal muscle tissue when it's undergone exercise. It can also be produced by the pituitary and dumped directly into the bloodstream. This is regulated by growth hormone- releasing hormone (or GHRH) from the hypothalamus. This should regulate the production of a growth hormone. Growth hormone affects most tissues in the human body, especially muscle and bone tissue. It increases protein synthesis and the burning of fat. Technically, the effects of growth hormone are indirect, it increases the expression and release of another hormone, but that's a level of detail that won't be terribly important to us. As we previously mentioned, growth hormone can increase bone growth, especially at the epiphyseal plates prior to puberty, which is why if the pituitary secretes an abnormally large amount of growth hormone prior to puberty it leads to the condition gigantism, whereas after puberty-- when there's no more cartilage there-- it can lead to the condition acromegaly .We can only add bone tissue by appositional growth when there's no more growth plate. If gigantism is not treated, it will develop into acromegaly later in life. It is possible, however, to only develop acromegaly-- for instance, getting a tumor on the pituitary after puberty. Conversely, growth hormone deficiency can lead to one type of dwarfism called proportional dwarfism. Our most common form of dwarfism was caused by a condition called achondroplasia. However, this condition affects the growth of cartilage, and therefore affects long bones not the other bones of the skull and thoracic cage. Next up, the pituitary releases a number of other hormones that are new to us: TSH, ACTH, FSH, and LH. We'll be talking about their functions in a moment, but these are all regulated by hypothalamic releasing hormones. Their names are fairly understandable. TRH triggers the release of TSH, CRH triggers the production and release of ACTH, and then Gonadotropin releasing hormone (or GnRH) triggers the release of the two hormones that affect our gonads, FSH and LH. TSH is thyroid stimulating hormone. When the hypothalamus tells the pituitary to make TSH, this TSH will enter the general circulation, and when it reaches the thyroid gland, it instructs the thyroid gland to produce more thyroid hormone. There is a complex negative feedback loop here: increasing levels of thyroid hormone should shut down production of TRH. ACTH, made by the pituitary, targets the adrenals to make corticosteroids, including glucocorticoids and mineralocorticoids. This was under the control of CRH from the hypothalamus. I will talk about those corticosteroids in more detail coming up. Once again, though, there should be a complex negative feedback loop. Next up, the gonadotropins include LH and FSH. They have the same basic function in men and women, just they target a different gonad. FSH triggers follicles in women to produce eggs, in men it triggers spermatogenesis. Luteinizing hormone, on the other hand, drives the production of sex steroids. Ovaries should produce estrogen and progesterone in response to LH, whereas testes will generate testosterone in response to LH. Prolactin increases the growth of glandular tissue in the breasts and triggers them to start producing breast milk. Keep in mind this is only the production of breast milk, we'll add one more layer of complexity to this in a moment. Prolactin is under the control of estrogen receptor elements, meaning that when estrogen binds to the estrogen receptor, the estrogen receptors can enter the nucleus and bind directly to the promoter of prolactin and increase its production. Estrogen won't do this all the time. Typically it requires a very high amount of estrogen that we only see towards the end of pregnancy or shortly after childbirth. Next up are the posterior pituitary hormones. Of course these were made in the hypothalamus and released from the posterior pituitary. The first is oxytocin and the second ADH. Oxytocin does a number of things in the body, including triggering the letdown reflex as well as trigger smooth muscle contractions in the uterus, whereas ADH targets the kidneys to hold on to water which should lead to an increase in blood pressure The first function of oxytocin is involved in child delivery. Oxytocin triggers smooth muscle contractions in the uterus, which in turn signal for increased levels of oxytocin to be produced. This should trigger more frequent and stronger contractions until childbirth occurs. This was one of our few examples of a positive feedback loop. For this reason, synthetic oxytocin can be given to women to speed up delivery. One form of synthetic oxytocin is called pitocin. Our second function for oxytocin is in triggering the letdown reflex. Stimulation of the nipples can signal the pituitary to release oxytocin, which will trigger the glandular tissue to squeeze and release breast milk. The breasts had to be primed beforehand by the hormone prolactin. Otherwise, if there's no breast milk in the breasts, oxytocin cannot trigger the letdown reflex. We say therefore that prolactin has a permissive role when it comes to oxytocin. On the same note, a midwife may stimulate a pregnant woman's nipples to increase oxytocin production, which can in turn increase uterine contraction strength to speed along a difficult delivery process. That might be done if the female does not want to use the artificial form of oxytocin. Oxytocin has more jobs, though. It is also released in response to an orgasm. For these little critters here, these voles, that can help lead to what's called "partner preference", which is homologous to saying falling in love in humans. It turns out there's two types of highly related voles. There are prairie voles which mate for life, and meadow voles which do not. It turns out if you block oxytocin receptors in the prairie voles, they will no longer mate for life. On the other hand, if you genetically engineer the meadow voles to have the correct oxytocin receptor, these will now mate for life. We'll talk more about the location of where these oxytocin receptors are next quarter when we talk about the nucleus accumbens-- part of the brain responsible for drug addiction. Oxytocin is frequently referred to as the "love hormone", however, when people do this it shows they're either ignoring all of its other effects, or they're just ignorant of those effects. It's true that oxytocin levels increase when we have an orgasm, and that seems to play a role in partner preference or falling in love. Oxytocin levels also increase at childbirth and this may very well help form a bond between mother and child, and oxytocin levels can even increase after petting a cat or a dog, this leads to a milder form of pair bonding behavior. However, oxytocin is also involved in other interpersonal relationships like hatred and mistrust. It seems to play a role in very strong emotional connections between people, either positive or negative ones, and for that reason I do not refer to this hormone as the "love hormone". To review, the major effects of oxytocin include triggering labor contractions and the letdown reflex during breastfeeding, it can also play a role in falling in love, in sexual arousal and orgasm. So how can one hormone do all of these things? Well, I think the easiest way is just with a difference in hormone levels. We could imagine that a lot more oxytocin is released during childbirth or during sex than it would after petting a cat. Oxytocin can only trigger the letdown reflex when prolactin permitted it to do so. I had a student once who said "ooh, is that why whenever I had sex while I was pregnant I would start lactating?" and everybody in the room got that question correct on the midterm. Yes, indeed, oxytocin produced during an orgasm could trigger the letdown reflex if the breast tissue had been primed with prolactin ahead of time, which happens during pregnancy. Oxytocin can also have effects just in the brain, locally released rather than having effects on the uterus and breast tissue. That would be a paracrine signal rather than an endocrine signal. The other posterior pituitary hormone was antidiuretic hormone. This hormone blocks the formation of urine, hence its name anti diuresis. It is produced in response to elevated solute levels. The brain interprets this as not enough water in the body, so it produces ADH, which tells the kidneys to retain that water rather than release it in the form of urine. Alcohol inhibits ADH function, and therefore causes people to need to urinate frequently when they drink. Just a heads up, ADH gets multiple names. It can also be called vasopressin. It turns out there were two groups of people working on the same hormone and they didn't realize it. One group noticed that this hormone affected the kidneys and how much urine they produced, another group noticed that it affected blood pressure, hence the name vaso for veins and pressin for pressure. I will try and call it ADH throughout the year. But just like oxytocin, ADH plays multiple roles throughout the body, not just in water retention from the kidneys. In addition to oxytocin, ADH is also included in a number of behavioral issues, including people on the autism spectrum and other conditions. So those were the hormones involved in the HPA axis. Right now would be a good time to take a break and come back when you're rested. Welcome back! Let's talk about the hormones from the neck down, starting with the thyroid gland, which is located in the neck, close to the trachea. Under the microscope, the thyroid gland is made predominantly of simple cuboidal epithelial cells surrounding a central area called the colloid. Another name for these simple cuboidal epithelial cells is follicle cells. Between the follicles, you can find para-follicular cells, which make different hormones. The follicle cells make thyroid hormone, which comes in two basic flavors: T3 and T4. The difference between these two is the number of iodine atoms, otherwise they are fairly interchangeable, at least to the point where we don't have to worry. It's true one of them is a little bit stronger than the other, but they both bind to the thyroid hormone receptors, so we're going to consider both of these molecules "thyroid hormone". The production of thyroid hormone is regulated by the hypothalamus and pituitary. The hypothalamus produces TRH, which tells the pituitary to make TSH, which tells the thyroid gland to make thyroid hormone. And then we have our negative feedback loop reducing TRH production. Most cells in the human body will respond to thyroid hormone. The receptors for thyroid hormone are located inside of the cell. That's because thyroid hormone is one of our lipid-soluble molecules, so the hormone can get directly across the plasma membrane to bind to its receptors, which can then alter DNA transcription. The responses to thyroid hormone usually involve an increase in the metabolism of the target cell. When thyroid hormone signaling is too high or too low, we call that hyperthyroidism or hypothyroidism. One example of hyperthyroidism is Graves disease, where the immune system makes antibodies that bind to the TSH receptor found on the thyroid cells. For this reason, these cells think they are constantly being stimulated by the pituitary, and they release elevated levels of thyroid hormone. On the other hand, hypothyroidism is caused by a deficiency in thyroid hormone signaling. Commonly, this can be caused by an iodine deficiency. Without iodine you can't make the molecules T3 and T4. A condition called goiter is a symptom of both hyper- and hypo- thyroidism. Hopefully it should be fairly easy to understand that if a person's thyroid gland was this large, it could be over-producing thyroid hormone. But what about hypothyroidism, why would that lead to a goiter? Let's imagine a person has an iodine deficiency, and for that reason they can't produce thyroid hormone. With the drop in thyroid hormone levels, the negative feedback loop on the hypothalamus would be removed, and the hypothalamus would increase its production of TRH, which will tell the pituitary to make more TSH, which will tell the thyroid gland to make more thyroid hormone. Of course, with an iodine deficiency it doesn't matter how much TSH is in the bloodstream, the thyroid gland cannot produce thyroid hormone. And as a result, it will continue to grow larger to try and compensate for the issue, without ever fixing the problem. The only place where iodine atoms are used in the human body is in the thyroid gland to make thyroid hormone. Therefore, radioactive iodine can be used as a tracer. Just enough radiation is added that we can follow it in the body. Radioactive iodine should accumulate within the thyroid gland. If we find that radioactivity elsewhere in the body, that could be a sign that a thyroid tumor has metastasized to other places in the body. Luckily, we can just up the dose of radioactive iodine to a toxic level. The only cells that should gobble up that iodine are the thyroid gland and any thyroid cells that have metastasized to other parts of the body. This is a highly treatable metastatic cancer, at least compared to other cancers that have metastasized. The thyroid gland is the only place in the human body that stores and utilizes iodine atoms. For that reason, if a person is exposed to radioactive iodine-- such as the case with nuclear meltdowns-- we worry about their increased risk of developing thyroid cancer. Surprisingly, following the Three Mile Island disaster there was no increased rate in thyroid cancer. This report was so surprising another group repeated it, and came to the same conclusions. This isn't to say it was no big deal, people did die earlier near the disaster, but from results other than cancer. Our next question asks how do we test for hyperthyroidism or hypothyroidism? It turns out that while we could test for thyroid hormone levels, there are better tests. And the same pattern will be true for any of the hormones we've discussed that have complex negative feedback loops. So while it is possible to test for thyroid hormone levels, it's actually better to test for TRH and TSH. Let's go through a hypothetical scenario where we've got three patients who have three different levels of sensitivity to thyroid hormone based on their receptor levels. We have got one patient who has an average number of receptors, another one who has very low levels, and a third person who has very high levels. Keep in mind that these same levels of thyroid hormone receptor are not only found in the target cells but also in the hypothalamus. If all of these patients start from scratch, they will have to produce TRH and TSH to tell the thyroid to start producing thyroid hormone, and it will begin to do so. For our very sensitive patient number three, this low amount of thyroid hormone might be enough to activate some of those receptors, causing the effects of thyroid hormone throughout the body, as well as initiating the negative feedback loop in the hypothalamus. This patient would stop producing TRH and TSH, and therefore this is the amount of thyroid hormone that they would make. The other patients would have to make more TRH and TSH to stimulate their thyroid glands to produce more thyroid hormone. Let's say for the average person this amount of thyroid hormone level here was enough to have effects in the body, and to induce the negative feedback loop in the hypothalamus. Now this person would stop producing thyroid hormone. Our patient in the middle, however, would have to keep producing thyroid hormone. They are relatively insensitive, so the hypothalamus would have kept churning out TRH and TSH, until finally their thyroid hormone levels were enough to activate their relatively insensitive receptors. We now have three patients who have the correct amount of thyroid hormone, even though it's very different for each patient, based off of their sensitivity. This is one reason why simply testing for hormone levels is not the best way to determine whether somebody is hyper- or hypo-thyroid. It's one metric, but there's a much better metric. Let's make patient number two hypothyroid, let's say they've got a bit of an iodine deficiency, and their thyroid gland is only producing half the amount of thyroid hormone that it should. They may have the exact same amount of thyroid hormone in their blood as patient number one, but because their receptors are relatively insensitive, it's not enough. That means the negative feedback loop on the hypothalamus will be removed, and they will start churning out TRH and TSH to try and fix the problem. Patient number three, let's say they've got an antibody that binds to their thyroid gland and causes it to over produce thyroid hormone. When they over produce thyroid hormone, we now have extra signaling in the body as well as in the hypothalamus. Their levels of TRH and TSH should now drop even lower. So here we have three different patients with the exact same amount of thyroid hormone, but one of them has hypothyroid syndrome, and the other hyper thyroid syndrome. So what's different about these three patients if it's not thyroid hormone level? Well, the patient who is hypothyroid has elevated levels of TRH and TSH, whereas the patient who is hyperthyroid has diminished levels of TRH and TSH. This is a much better marker. We can't be sure how sensitive a patient is to thyroid hormone levels-- at least not yet. What we can do is ask whether the hypothalamus thinks that the amount of thyroid hormone is okay or not, and the way that we do that is looking at TRH and TSH levels. For any patient who is not producing enough thyroid hormone, no matter what that level is, they will have elevated levels of TRH and TSH. And then we would find the exact opposite pattern for a patient who's producing too much thyroid hormone. The same pattern will be true for any hormone that has one of these complex negative feedback loops. Instead of thyroid hormone, I could be talking about testosterone and then GnRH and LH. It's very common for people to be diagnosed as low-testosterone by a simple blood testosterone test. That test is not a very good one, in fact, what it probably tells us more about the patient is how sensitive their receptors are to testosterone, not whether their body is producing the correct amount of testosterone. If your goal is simply to sell testosterone supplements, you'll be fine with that inadequate sort of test! But if you really want your patients to get healthier, looking for the hypothalamic and pituitary hormones is a much better metric. The thyroid gland also produces calcitonin. That comes from these para- follicular cells here that are in between the follicles. This is, of course, the mirror hormone for PTH. PTH comes from the parathyroid gland. You will be amazed how many students miss the question of "where does parathyroid hormone come from?" on their final exam. So please don't be one of those students! I'm going to keep putting that question on there until everybody starts getting it right. (it really should be an easy question, at least I think). PTH and calcitonin were of course mirror hormones, we should only see one of these in the bloodstream at any given time. PTH is produced when blood calcium is too low and it will activate osteoclasts, as well as decrease kidney excretion and increasing gut absorption. Calcitonin does the exact opposite. The adrenal glands also produce a number of hormones. The outer portion of the adrenal glands, called the cortex, is the endocrine portion for the adrenals. The deeper medulla actually produces neurotransmitters epinephrine and norepinephrine, and I consider that more part of the autonomic nervous system, so we'll talk about that in Chapter... oh I think 15 . Let's focus today on the hormones that come from the adrenals. The first ones are the mineralocorticoids like aldosterone. These regulate blood pressure by regulating the reabsorption of sodium from our urine. Sodium, as you may know, affects blood pressure. Aldosterone can trigger more reabsorption of sodium, and this can happen in response to a drop in blood pressure. By stimulating the reabsorption of more sodium, more water will follow by osmosis, therefore because there's now more water in the blood stream, our blood pressure should be higher. The glucocorticoids, like cortisol, are the next group of hormones.Tthese can regulate blood glucose. They do so by stimulating the movement of glucose out of organs like the liver, therefore cortisol tends to counteract insulin, and can lead to hyperglycemia if there's too much cortisol in the system. The other major effect of cortisol is to block the inflammatory response. Both of these things are really good if you're trying to run away from a saber-toothed tiger. The extra glucose gives you more energy, and if you happen to twist your ankle we don't want to stop because of all of the pain and swelling, we want to keep running. Even if we damage our ankle further, we can worry about healing the ankle when we're away from the saber-toothed tiger. So both of these effects are very good in stressful situations. Cortisol has a number of other effects, and so many of these things you may recognize as being associated with the stress. The effects of the stress hormone cortisol are very different whether we're discussing short-term stress or long-term stress. Mobilizing glucose and blocking the inflammatory response, as I just mentioned, were really good from running away from saber-toothed tigers. On the other hand, these things are not good long-term. Prolonged elevated blood glucose will increase our risk of type 2 diabetes, and blocking inflammation long term can increase damage to the body and increase risk of infections. Unfortunately, our brain does not really understand the difference between short- term and long-term stress. The stress of having to listen to this lecture, for instance, might be increasing your cortisol levels, and whether you know it or not you, might be sick right now, and the moment that you finish your final exam, the cortisol will go away. Your immune system will suddenly realize that you've had an infection for the past few days, and now you're going to get sick right at the time that your break should have been starting. Furthermore, stress can either be physical or psychological. Physical stresses include injury and pain and disease. Psychological stresses include pressure and frustration and conflict. Both of these can induce the release of cortisol into the body. That cortisol really isn't doing anything to fix these problems over here, in fact, chronic cortisol production is doing harm to the body by elevating blood glucose levels and by inhibiting the inflammatory response, which is an important part of the healing process. Nevertheless, we use corticosteroids in medicine, hopefully only short-term. We might use them as an immunosuppressant for people who have autoimmune disorders like rheumatoid arthritis. And we can use them as a powerful anti-inflammatory. Sometimes inflammation, when it goes out of control, does more harm to the body than good, so we might need to use a corticosteroid to put the damper on the inflammatory response. Furthermore, CRH levels are not in their normal range for people on the autism spectrum, and this can cause a number of symptoms throughout the rest of the body. For instance, it can make the skin hypersensitive to clothing and watches and whatnot, and may cause it to break out in hives. It can also affect the digestive tract as well. The adrenal glands also produce androgens, such as testosterone. This is the case for both men and women. In men, the majority of testosterone comes from the testes, only a small amount comes from the adrenal glands. Lastly I will cover the production of epinephrine and norepinephrine from the medulla when we discuss the autonomic nervous system. Next, one disease that affects the adrenal glands is called congenital adrenal hyperplasia, where the adrenal glands produce too much testosterone. In men, most of the testosterone comes from the testes, so even if you doubled or tripled the amount of testosterone from the adrenals, that would just inhibit GnRH production from the hypothalamus, and the testes would wind up making that much less, bringing us right back to our regular homeostatic set-point, and no symptoms. On the other hand, for women, that excess testosterone can cause masculinizing events. For instance, for children this can disrupt the formation of the genitalia, and can lead to problems with puberty and fertility. Addison's disease is another disease that affects the adrenal glands. The symptom that we're going to notice is hyperpigmentation of the skin, which has nothing directly to do with the adrenal glands. But if the adrenal glands aren't producing enough mineralocorticoids and glucocorticoids, that can lead to dangerously low blood pressure and blood sugar, which have their own symptoms. It's just this one is going to be the most noticeable. That comes about because if the adrenals aren't producing enough adrenal hormones, that will increase production of CRH from the hypothalamus, which tells the pituitary to make ACTH, and then ACTH would tell the adrenals to make more of these glucocorticoids and mineralocorticoids. However, we don't make ACTH directly, we made that precursor molecule POMC. So for every ACTH that you get, we also get some MSH, and that can cause the skin to get darker, despite your patient not being in the Sun. So that's the thyroid the parathyroid and the adrenals. We've got just a few more random organs to discuss. The pineal gland is a little area of epithelial cells located deep in the brain, and these cells produce melatonin. Melatonin can have effects on the reproductive system, although trying to predict what those effects are would be difficult. It may raise or lower or have no changes to LH and FSH hormone levels. Nevertheless, if somebody's having a problem with their melatonin, this is something that you might also take a look at, ensure that their reproductive hormones are in the normal ranges. We produce melatonin at night. It binds to melatonin receptors found throughout the brain, and this can induce drowsiness. Sunlight (or the light from your cell phone that you're watching this video on right now) can also inhibit melatonin production. Melatonin is also a popular supplement. For instance, many people will use melatonin to help them fall asleep, especially when traveling by airplane. The pineal gland synthesizes melatonin from the amino acid tryptophan. This has led some people to hypothesize that the reason that you get sleepy after a Thanksgiving meal is that turkeys have a lot of tryptophan. They do not have any more tryptophan than any of the other amino acids, and there's lots of foods that are rich in amino acids besides just meat. The reason that you feel sleepy after a Thanksgiving meal is because you ate too much and now more of your blood is going to the digestive tract to aid in the absorption of nutrients, and less of it is going to your muscles, so you feel tired. You would expect to have the same results if you ate too much tofurkey at your Thanksgiving meal. (Jamie, you promised me five dollars for every time I mention your product). Next up, when we don't produce enough melatonin, it can cause us to have problems falling asleep, but producing too much has its own problems as well. This is associated with a form of depression called seasonal affective disorder. This is just one type of depression, and really has nothing to do with any of the others. This one is easily treatable, though, with broad-spectrum lights. So that's a very cheap and non-invasive treatment. But this would be something that a patient should worry about if they have become reliant on melatonin for sleep, we don't want to overdo it, because it could be affecting their mood as well. This slide here is just to represent how complicated hormones can be. If anybody ever tells you that the human body is simple, or they make it sound simple, they don't know what they're talking about. Melatonin has been shown to lower blood pressure in patients with hypertension, and that's great because it's a very cheap product. On the other hand, in your patients who are on blood pressure drugs and they heard that melatonin lowers their blood pressure, it actually works in an antagonistic fashion and raises blood pressure. So it's important to discuss which supplements your patients are on in addition to which medications they may be taking. The pancreas is a digestive system organ. The bulk of this organ is composed of exocrine cells which are connected to ducts, and they produce digestive enzymes and juices which get dumped into the small intestines to aid in digestion. There are small pockets of endocrine cells, however, and these are the ones we are going to focus on. The endocrine cells lie within these pancreatic islets-- or the more old-fashioned name that I learned was the islets of Langerhans. The two most important cell types are the Alpha and the beta cells. The alpha cells produced the hormone glucagon, the beta cells produce the hormone insulin. The reason that these two hormones aren't as important is simply because they're not on the test. Glucagon and insulin are mirror hormones, similar to the way that calcitonin and PTH counteracted one another.. When blood glucose levels are too low, the alpha cells of the pancreas detect this and secrete glucagon. Glucagon can travel throughout the body, binding to glucagon receptors on target tissues, which will then dump glucose into the bloodstream, bringing blood glucose back up to its homeostatic set-point. It would be dangerous to have too little glucose in the blood, for instance the brain would not function properly. On the other hand, if blood glucose levels go too high, the beta cells in the pancreas detect this and they secrete the hormone insulin. Insulin travels through the bloodstream to bind to insulin receptors on target tissues, which then remove the glucose from the blood, bringing it back down to our homeostatic set-point. So these two hormones are mirror hormones, so if you memorize what insulin does, then glucagon just does the opposite. Some of their main target tissues include the liver, skeletal muscle, and adipose tissue. Let me focus on insulin action and how it lowers blood glucose. If there is elevated blood glucose, the only cells in the body that recognize this are the beta islet cells in the pancreas. They can detect this high blood glucose, and that will stimulate them to release the hormone insulin. This hormone travels throughout the body, and it can bind to insulin receptors on our target cells. Most cells in the human body have insulin receptors, and they will respond by moving glucose transporters to the plasma membrane. These glucose transporters can now transport glucose out of the blood and into the cell. The second messenger system that the insulin receptor activates will also activate enzymes which can begin to metabolize this glucose. If this were a liver cell, it might convert some of that extra glucose into glycogen, whereas if this is adipose tissue we might convert that extra glucose into a triglyceride molecule. Diabetes mellitus is a condition where insulin signaling is insufficient. For type 1 diabetes, we call this an insulin deficient diabetes. This is an autoimmune disease where the immune system attacks the beta islet cells, therefore the pancreas cannot produce enough insulin. Without enough insulin, blood glucose levels get dangerously high. This can be treated by injecting insulin into the bloodstream. This patient still has insulin receptors. Type 2 diabetes typically arises later in life, so you might call it adult-onset diabetes. We can also call it insulin- resistant diabetes. One of the main risk factors for this type of diabetes is obesity. The main risk is actually elevated blood glucose for prolonged periods of time, which can happen when people's diets are not healthy. If there is chronically elevated levels of insulin because a person has a high- glycemic diet, that extra insulin can induce receptor down-regulation over time. So too much insulin leads to a removal of insulin receptors, and now our patient is resistant to the hormone insulin. In either case, we do not have enough insulin signaling, but for type 1 diabetes it's caused by too little insulin, and for type 2 diabetes it's caused by too much insulin. So this illustrates very well receptor sensitivity as being a very important factor when it comes to being in a diseased state versus a healthy state. As mentioned, type I diabetes can be treated with insulin injections. There's other ways to inject insulin besides a needle, for instance there are pumps that can be used. Once upon a time we had to get insulin by grinding up pig pancreases, and there just aren't enough pig pancreases to meet the demand, so this drug was very expensive. But with the invention of gene cloning and genetic engineering, we now have E. coli that can produce human insulin. this made Genentech very rich at the time. Unfortunately now it's generic and so other companies are trying to invent new types of insulin that are synthetic, that they can have a patent on and sell for a higher price.Ttype-2 diabetes, on the other hand, is caused by too much insulin, and so if we were to give a patient with type 2 diabetes an insulin injection, it would only be making their disease worse. However, insulin injections are still the number one treatment. The "best" option would be monitoring their diet and increasing their amount of exercise to get their blood glucose levels under control, but you're going to find it very infrequent that your patients listen to you when you tell them they need to diet and exercise. So we're frequently going to have to come up with drugs to give these patients to keep their symptoms under control. Now insulin is the only one I'm going to talk about, there are other drugs, like metformin, which have an entirely different target, and are optimal, but we can't really discuss that in this class. So if more insulin is only going to make a patient with type 2 diabetes even worse, why would we ever consider giving it to them? And that's because while, yes, insulin injections could make the disease progressively worse over time, the short- term effects of hyperglycemia are more dangerous, and we need to get those under control as quickly as possible. Ideally, diet and exercise and that metformin drug might begin to work on their own, but we need to worry about the effects of elevated blood glucose. So why could too much sugar be bad? I mean, we need to eat this stuff, so how could it be bad for us? Well it's all about the correct amount in the correct place. And if I have too much glucose in the bloodstream, then water will be attracted to the blood, and that means water may leave my cerebral spinal fluid, and this can affect how my brain functions, causing drunken-like behaviors, for instance. It'll also affect the kidneys. Excess of glucose winds up in the filtrate of my kidneys, pulling water along with it, which further dehydrates me. Lastly, glucose is sticky, and it can stick to our blood vessel walls, causing them to harden and become damaged. This can be especially bad for our very delicate blood vessels found in the eyes and in our toes, and so one of the symptoms of type 2 diabetes-- if it's left out of control-- is progressive blindness and requiring amputation due to gangrene of the extremities. On the right hand side of this page are some symptoms of hypoglycemia. Now somebody with diabetes suffers from hyperglycemia, but if they forgot to inject with insulin, and they became hyperglycemic and then noticed it and injected with insulin, well it takes a while for that insulin to work, and five minutes later they may have forgotten that they just injected themselves with insulin, and then noticing the symptoms of hyperglycemia, inject themselves again. With double the dose of insulin, that could cause too much glucose to leave the bloodstream, leading to hypoglycemia. This is not a symptom of the disease, but a symptom of the treatment. It's iatrogenic. There are dogs in Great Britain who have been trained to make sure that they can alert their owner if this has happened to them. A treatment for hypoglycemia is fairly simple, get carbohydrates back into the bloodstream. Optimally, this is in a liquid form, such as orange juice. Lastly, we've got a few more endocrine organs to cover. The testes produce testosterone. It turns out there's more than one chemical that is considered a type of testosterone, so we call them all together androgens. The ovaries produce estrogen and progesterone, hence women are twice as complicated as men (but maybe you didn't need to come to anatomy class to figure that out). They both have a negative feedback loop, GnRH is produced by the hypothalamus, which tells the pituitary to make LH, which tells the testes in this case to produce testosterone. More testosterone would feed back on the hypothalamus to decrease GnRH production. When people abuse anabolic steroids, they may inject androstenedione directly into the bloodstream, greatly elevating their testosterone levels in the blood. But this will shut down GnRH and LH production, which shuts down production of testosterone in the testes. So while the rest of the body has really high levels of testosterone, the testes actually have much lower levels of testosterone than are normal, and this can lead to testicular shrinkage and loss of fertility. Luckily, this is reversible. If somebody stops juicing and takes away the androstenedione, everything should eventually go back to the original homeostatic setpoint. There are other conditions that have been associated with anabolic steroid abuse, however the evidence for these is anecdotal at best, and just outright ridiculous at worst. For instance, the idea that anabolic steroids would increase the risk of committing suicide, there's just no science to back that up. The risk of elevated stroke or heart attacks is serious. However, we also see evidence that testosterone inhibits stroke and protects against heart attacks, so we're just not really clear on what the risks of abuse really are for this class of drugs. So testosterone, being made from cholesterol, is a steroid. So are estrogen and progesterone, it's just those two do not affect skeletal muscle, therefore we do not consider them anabolic steroids. There are a number of other chemicals that people might abuse to improve their athletic performance. We already discussed growth hormone-- this can increase both muscle mass and bone density. Next quarter we'll talk about erythropoietin, which can increase red blood cell production, which increases endurance. Even insulin can be abused, and that's because insulin will cause muscle cells to move glucose out of the bloodstream and into the muscle-- it turns out it also tells muscle cells to do the same with amino acids, and then we convert those molecules into glycogen and myofibrils, and muscles get larger in size. Even stimulants can be abused to increase athletic performance, but none of these molecules are steroids, hence the term "performance-enhancing drug" is a better blanket term. The birth control pill-- or combined oral contraceptives-- also work because of this negative feedback loop. While there are many different brands of birth control pills, what they all have in common is that they contain progesterone (or something that mimics progesterone). When there are progesterone levels in the blood, this will block production of GnRH, which blocks LH and FSH, and those two hormones are required for ovulation. Without ovulation, there can be no pregnancy. There are many different delivery methods for progesterone, and different doses, but they all take advantage of the same negative feedback loop. You will find that there's a lot of misinformation out there surrounding birth control I'll go into it in a lot more detail when we learn about the reproductive system later, but I would like to go through a few risks right now. One risk, which is not really a health risk but a comfort risk, is in breakthrough bleeding. We'll get a better understanding of that when we learn how estrogen and progesterone affect the uterus. Next up is the more serious risk of thromboembolism and stroke, and this was absolutely true back in the 50s and 60s. These days, the doses of estrogen and progesterone found in birth control is much much lower, and the risk has been reduced to effectively zero. Nevertheless, you will find people that go data mining to look for reasons to scare people into not using birth control pills. I could do the same thing with seatbelts, I could find data from the 50s that said if children wear seatbelts they're more likely to get harmed, it would be safer just to throw them in the backseat and call it good. We now know that lap belts do more harm than good in many situations, that's why we have shoulder harnesses and children's seats. Another thing that can be used to scare young women especially is the risk of increasing acne with the use of birth control pills. Luckily, there's enough brands out there on the market that if excessive acne is caused by one brand, you can just switch to a different one, and you might even see a reduction in acne-- estrogen can do that. We definitely know that birth control pills are not linked to cancer, this is clear as day. So there should be no scare for an increased risk of breast or cervical cancer despite the fact that estrogen can promote the growth of these cancers. To understand that we'll need to go into more detail, but what I can tell you really quickly is that even though you're taking a pill containing estrogen and progesterone, it's probably lowering your overall dose of estrogen and progesterone because you're not cycling (and especially you're not getting pregnant where estrogen and progesterone levels skyrocket), and what we know there is that pregnancy absolutely does not increase the risk of breast cancer or cervical cancer-- just the opposite in fact despite having massive levels of estrogen and progesterone. So we should not be worried about any cancer risk with birth control. Even so, if our only worry was lifespan, what we should be telling all women of reproductive age to do is to take birth control pills-- just automatically give birth control to every woman once she goes through puberty. And of course that would be stupid, because nobody would be able to have children. Nevertheless birth control pill usage increases life expectancy, most likely because there is a risk of death during childbirth. With fewer child births, you will get fewer child birth-related deaths. So the benefits of birth control greatly outweigh the risks. Nevertheless, we shouldn't just be thinking in terms of longevity. Quality of life is always important, too, so if a woman wants to get pregnant she should not really be worried about the risks associated with it. We need to we need to weigh the risks and benefits of any question. Next up, Leptin can be produced by adipose tissue. Aah-ha! Adipose tissue is not a gland, it's a connective tissue, not epithelial tissue. But this just goes to show that our outmoded idea of what the endocrine system is needs to be changed. Lots of tissues produce hormones, not just glands. Leptin affects body weight, and if you were a mouse given all the food that you could eat, you would get pretty darn fat. But if you were given leptin injections, leptin would reduce your appetite. It doesn't work that way in people, and if you ask me why, I just have to tell you if I knew the answer to that, I would have fixed it by now and I'd be freaking rich! Leptin has a different job when you were growing up than it does when you're an adult. It seems that leptin might actually control how your brain gets wired as you are developing in the womb. The amount of leptin that you're exposed to in the womb might be influenced by your mother's diet at the time, and so what your mom eats may influence how hungry or how not hungry you are for the rest of your life this. Ts known as an epigenetic event, something that you inherited from your mother (or maybe even your grandmother) that wasn't DNA. This was first noticed during World War II, after the nazis had barricaded holland and nearly starved many of their people to death. Those that survived had lifelong health issues. Those that survived and were pregnant during that time, their children also had issues throughout their lives, and their children's children - all linked to metabolism - and it could be due to the hormone leptin. So I bring that up to illustrate a very important concept, and that is many hormones have one job in our childhood, and a different job in adulthood. For instance testosterone and estrogen helped us to go through puberty when we were younger, but we are not continually going through puberty as we are older, even when we keep producing these hormones. Their roles have changed. Furthermore we worry about chemicals in our environment mimicking or altering hormone levels. The one that I hear about the most often are BPA's, which can act as endocrine disruptors. That's because BPA's can mimic estrogen, so if you had more of this chemical in your bloodstream it might inhibit GnRH production from the hypothalamus. Of course, if you're a female and your ovaries are churning out a ton of estrogen to begin, with a little bit more from plastic will just cause your ovaries to produce that much less. And even you men you are producing estrogen, some of your testosterone gets converted into estrogen, so a little bit of environmental estrogen really will not have significant effects, at least not from these BPA's, and that has been fairly well tested. Nevertheless they are illegal, and had been replaced with a new chemical called BPS's, which are even more estrogenic. And that's just what happens when we ban chemicals without asking "what's going to replace it?" Nevertheless, children-- very young children-- should not be producing any estrogen at all, at least not very young female children, and therefore you might be concerned about estrogen exposure in baby bottles. So a BPA-free baby bottle might be a good safe bet, as long as it doesn't have BPS's, and that's where glass can come into play. The last one, and this is the last slide of the term, are the Eicosanoids. Wwe've actually already learned about these-- or at least the ones that I want you to know about. There are a few enzymes which can take phospholipids and convert them into short-range signaling hormones known as inflammatory molecules. The one that I have said over and over are the prostaglandins, but there are other inflammatory molecules. And the reason that these are so important is that we often treat inflammation, we limit inflammation by providing drugs that inhibit these enzymes. For instance, aspirin, ibuprofen and acetaminophen can block this enzyme over here. This is important because sometimes the inflammatory response is too strong, and may be causing more pain and discomfort than we are okay with. So that's the last lecture of the term (depending on how many of those concept reviews that you still have to watch). Good luck studying for the final!