the endocrine system like the nervous system integrates and coordinates the functions of organs and organ systems in general the endocrine system regulates specific body functions such as fluid and electrolyte balance reproduction and metabolism endocrine glands secrete molecules into the bloodstream endocrine glands can be either unicellular or multicellular and they can develop from either epithelial or neural tissue the endocrine system involves complex interactions between endocrine glands hormones and the cells controlled by the hormones let's start with the hormones they are chemical messengers that are secreted by endocrine glands into the blood then they are transported by the blood throughout the body the cells that hormones eventually encounter and bind to are called target cells a particular cell is a target for a hormone if the cell contains a specific receptor for that hormone binding of a hormone to the correct receptor results in a change of activity of the target cell each combination of hormone and receptor can cause a different change in a cell a cell is a target for a hormone if and only if it contains a receptor for that hormone hormone receptors are proteins located either in the cell membrane or inside the cell in the cytosol or in the nucleus a shape match between the hormone and its receptor ensures that the hormone is controlling the correct cell each cell type in the body contains receptors for different sets of hormones some hormones like thyroid hormone control every cell in the body that means that all cells have receptors for thyroid hormone but other hormones control more specific sets of cells for example the hormone fsh controls only specific cells in the ovaries and testes i'm going to summarize that information in this drawing i'll start with an endocrine cell this could be any cell in any endocrine gland and i also need a blood vessel and i also need some target cells so i will draw two different target cells and i'm going to give these cells some hormone receptors and i'm using simple shapes for these hormone receptors to indicate that they would be binding to different hormones the hormones don't actually have simple shapes like this so you can see in target cell one i've got um one receptor that would bind with a triangle one with a circle and one with a square and target cell 2 only has the triangle and the square receptors okay so now it's time for a hormone so in the endocrine cell it's been making hormone molecules and secreting them into the blood and those hormones are being carried throughout the body by the bloodstream and whenever they go through capillaries which we'll cover in chapter 19 some of the hormones leave the blood and go out into the tissue fluid and if they encounter a cell that has a receptor whose shape they match they bind to that cell and notice that the hormone cannot bind to target cell 2 because there's no receptor and as a result of the hormone binding to a target cell there is a change in the cellular activity so here i've summarized the main points about how hormones work they come from endocrine glands they're carried in the bloodstream a cell is only a target if it has a receptor for a specific hormone and each cell in the body each type of cell in the body contains different sets of hormone receptors within a target cell the number of receptors for hormone may vary over time because the number of receptors determines the cell's sensitivity to the hormone changing the number of receptors changes the cell's sensitivity a phenomenon called up regulation occurs when a cell increases the number of hormone receptors making it more sensitive to the hormone on the other hand down regulation occurs when a cell decreases the number of hormone receptors making it less sensitive to the hormone amino acid-based hormones except thyroid hormone are large and polar so they cannot diffuse through the plasma membrane that's why their receptors are transmembrane proteins that have a binding site for the hormone on the outside of the cell when the hormone binds with its receptor it causes a change on the inside of the cell even though the hormone did not actually enter the cell this process of conveying information from the hormone by way of the receptor to the inside of the cell is called signal transduction there are two main categories of hydrophilic hormone receptors one of them is called a kinase receptor kinase receptors are transmembrane proteins that have a receptor on the extracellular side of the membrane and a kinase enzyme on the intracellular side of the membrane when a hormone binds to the receptor on the outside of the cell it activates the kinase enzyme on the inside of the cell then the kinase enzyme produces the cellular response for example insulin receptors belong to this category and we will discuss them later in the chapter here i'm going to summarize how a kinase receptor works and i'm going to start by drawing the kinase receptor protein so it's a transmembrane protein and then i'm going to draw the cell membrane this is not exactly to scale and i'll identify that on the top part of the cell membrane we have extracellular fluid so that's the outside of the cell and on the bottom side of the membrane intracellular fluid for the inside of the cell so i'm going to use a triangle to represent a hormone molecule and that hormone molecule is able to bind with the receptor part of this protein because there's a match between the shape of the receptor and the hormone molecule once that happens that triggers communication within the protein and that activates the enzyme which is on the intracellular end of the protein so now the enzyme is active and the enzyme will proceed to catalyze a chemical reaction and that reaction is the cellular response to the hormone the other kind of hydrophilic hormone receptor is part of a second messenger mechanism these have a complex transmembrane protein receptor when the hormone binds to that receptor on the outside of the cell membrane it activates a g protein located on the inside of the cell membrane so that's the first step binding of the hormone to the receptor and then the second step is activation of the g protein in the third step part of the g protein detaches and moves along the inside of the membrane until it reaches and activates a membrane bound enzyme in the fourth step that enzyme catalyzes the formation of a second messenger molecule on the inside of the cell fifth the second messenger molecule causes some change in cell activity the types of changes that are caused by second messenger mechanisms fall into three categories one is smooth muscle contraction or relaxation two is the opening or closing of ion channels and three is activating or deactivating intracellular enzyme systems you will need to be familiar with a specific second messenger mechanism called the cyclic amp system in this system the g protein activates a membrane-bound enzyme called adenylate cyclase adenylate cyclase then catalyzes the conversion of atp into cyclic amp which is the second messenger cyclic amp then activates the intracellular enzyme called protein kinase protein kinase then phosphorylates one or more other proteins in the cell to activate them and to cause the cellular response to the hormone and finally another enzyme called phosphodiesterase inactivates cyclic amp to stop the cell's response to the hormone i'm going to summarize how the cyclic amp second messenger mechanism works and i'm starting with the cell membrane and i'll just represent that by a line and i'm going to indicate extracellular fluid above the line meaning the outside of the cell and intracellular fluid below the line meaning the inside of the cell so the first thing i'm going to add to this is the receptor for the hormone and these receptors look a lot like snakes and they go through the membrane several times the actual hormone receptor is on the extracellular side of the membrane and the whole thing is called the receptor molecule or you could call it the receptor protein on the inner side of the receptor molecule is a set of molecules called the g-protein complex another thing located on the inside of the cell membrane is the enzyme adenylate cyclase so here's how the system works i'm going to start with a hormone and that hormone is going to bind to the hormone receptor and activate it so activation is carried through the molecule to the inside of the cell that activates a g-protein component which then travels along the inside of the membrane until it gets to the adenylate cyclase and then it activates adenylate cyclase once adenylate cyclase is activated it converts atp which is already in the cell into a related molecule called cyclic into cyclic amp and that's also written just with a plane c amp same molecule cyclic amp then activates a different enzyme called protein kinase and it's abbreviated pk and usually there would be some designation that that's the inactive form the little i stands for inactive so what cyclic amp does is to convert protein kinase to active protein kinase and that's written pka and then protein kinase the activated form is the cellular response to the hormone hydrophobic hormones are lipid soluble so they can easily diffuse through the cell membrane to get into the cell the first step in this process is binding between the hormone that's already gone into the cell and its specific intracellular receptor which is either in the cytosol or the nucleus and together they form a hormone receptor complex second the hormone receptor complex binds to a specific place on dna that triggers the third step which is the activation of a gene and its subsequent transcription to a molecule of messenger rna fourth the messenger rna leaves the nucleus goes out into the cytosol and is translated into a protein by ribosomes the proteins made by the ribosomes are the cellular response to this hormone also please note there are some hydrophobic hormones that also have additional ways of affecting their target cells okay so i'm going to summarize how the hydrophobic hormones work and i'll just start out by making a cell and so this is going to be the cell it's got extracellular fluid on the outside and intracellular fluid on the inside and here i have a steroid hormone which is hydrophobic i'm going to add a nucleus and in the nucleus there's dna there's also receptor and this particular example i will put the receptor inside the nucleus to start with okay so i'm going to start back with the steroid hormone which is going to diffuse into the cell because it's not stopped by a lipid bilayer so it can diffuse straight in and once it gets into the cell it goes into the nucleus and then it binds to the hormone receptor the hormone plus receptor then attached to a section of the dna and that causes that section of dna to be transcribed onto a molecule of messenger rna messenger rna goes out into the cytosol so now i'll draw out messenger rna molecule and it is sort of clamped between the two components of a ribosome and as a result of that a protein is made i'm just trying to make it a different color and the new protein is the cellular response to the hormone if our bodies needed an individual hormone molecule for each cellular response our endocrine glands would have to be about a million times bigger than they are to be able to make enough hormone molecules fortunately we are more efficient than that because of a process called amplification amplification occurs at the target cell when just one hormone molecule binds to one receptor molecule it doesn't just produce one response it may cause a kinase enzyme to activate hundreds or thousands of intracellular responses or in a second messenger mechanism the membrane-bound enzyme may make hundreds of second messengers each of which may cause thousands of responses so amplification allows us to use very little energy in making hormones but still creates a huge response in the target cell hormones are not secreted at a constant rate instead their secretion is constantly readjusted to meet the current needs of the body as we talk about the individual hormones and subsequent lectures we'll cover the specific mechanisms that control each one this section is intended to introduce you to the three basic secretion control mechanisms the secretion of a specific hormone may be controlled by one or more of these mechanisms the secretion of many hormones is controlled by simple negative feedback between the hormone and some other molecule in the blood insulin is a good example when blood glucose concentration is high it causes insulin secretion then insulin helps cells remove glucose from the blood which decreases blood glucose now the low blood glucose level suppresses insulin secretion so low blood glucose reduces insulin secretion by negative feedback other examples of negative feedback control involve the interaction between hypothalamic pituitary and peripheral hormones for example if the thyroid hormone level is low it will increase the secretion of thyroid stimulating hormone if the thyroid hormone level is high it will suppress the secretion of thyroid stimulating hormone in this case thyroid hormone reduces thyroid stimulating hormone secretion by negative feedback generally negative feedback inhibits a hormone secretion when the hormone's blood concentration is high and it increases a hormone's secretion when that hormone's blood concentration is low i'm going to show you how you would diagram negative feedback between hormones so let me go with my first example of high blood glucose so i'm using an up arrow to indicate high and the high blood glucose will trigger an increase in the secretion of insulin and as a result of insulin acting on target cells in the body those target cells will take glucose out of the blood and that will lower the blood glucose and now it is the decrease in blood glucose that will suppress further insulin secretion by negative feedback so when you see a minus sign in a circle it's usually a symbol for negative feedback another simpler example is thyroid stimulating hormone don't worry we'll catch that in the second part of chapter 16 which causes an increase in the secretion of thyroid hormone and then that increase in thyroid hormone has a negative feedback effect to suppress further tsh secretion in neural control the nervous system stimulates hormone secretion in response to a specific stimulus for example high blood osmolarity is detected by neurons in the hypothalamus and those neurons cause the secretion of antidiuretic hormone often hormone secretion is part of a neuroendocrine reflex in which the efferent limb of the reflex is a hormone traveling through the blood instead of an action potential propagated along an axon i'm going to use something called the milk let down reflex to summarize and illustrate both neural control of hormone secretion and a neuroendocrine reflex so i have to draw some parts in to get this started i'm going to have the central nervous system and i'll just let this box represent the central nervous system that would be the brain and spinal cord and i need to have a target organ and that is going to be the myoepithelial cells of the mammary gland so i'm going to come over here and add i'll just add one secretory unit and part of a duct and so these are the cells that are making milk so let's assume they've already made some milk and that milk is going to be located inside the lumen of that secretory unit and on the outside of each secretory unit there's a layer of cells called myoepithelial cells so if you remember what myo means it's muscle and epithelial tells you that these are epithelial cells that are modified to contract okay so because we're talking about hormones we have to find a way to get the hormones from one place to another and so that's going to be by way of blood vessels so here i've got a blood vessel which is going through the central nervous system and then it's also going to go i mean it's not the same blood vessel but blood will eventually circulate through the brain and then eventually through the mammary gland i have a neurosecretory cell in the central nervous system and this is actually going to be it would be in the hypothalamus but we don't have to worry about that right now and it makes a hormone called oxytocin which is abbreviated capital o capital t and so now i'm going to have oxytocin represented by i think blue dots so here's oxytocin and it's going to be secreted into the bloodstream by the endocrine gland and the blood will carry it throughout the body and whenever it gets into a capillary some of it will diffuse out into the tissue fluid so it's going to go out all over the body but it will only manage to affect those target cells that it comes into contact with and have and that have receptors for it okay so there's our oxytocin just continuing throughout the blood okay so to put this all together i'm going to start with the beginning of the reflex there are mechanoreceptors things like lamellated or pacinian corpuscles located in the nipple and so i'll just draw a little mechanoreceptor there and that's a sensory neuron so it's going to carry information from the nipple into the central nervous system when it gets there it will synapse with a neurosecretory cell and so the synapse between the sensory neuron and the neurosecretory cell plus the place where the hormone is released constitute the integrating center for this reflex so the signal coming in through the sensory neuron tells the neurosecretory cell to release oxytocin into the blood and oxytocin released into the blood eventually diffuses over to the mammary gland and i'm not going to draw individual receptors on these cells just because they're so small but it binds to the near the myoepithelial cell and it causes them to contract and when the epithelial cells contract they push milk out into the duct system and it gets pushed all the way to the nipple which is where the baby can get access to it so we've got the parts of a reflex which are first of all the receptor which is going to be the mechanoreceptor then we have the afferent pathway which in this case is a sensory neuron we have the integrating center we have the efferent pathway which in this case is a hormone in the blood and we have the effector organ which is the mammary gland many hormones are at least partly controlled by rhythmic release patterns generated in the brain the most common type of rhythmic release is circadian or diurnal which means a 24-hour cycle the body's main biological clock is in the suprachiasmatic nucleus of the hypothalamus that nucleus's name is abbreviated s c n the scn suprachiasmatic nucleus contains cells that exhibit self-induced rhythmic firing during the day they manufacture clock proteins as more and more clock proteins accumulate the clock proteins begin to block their own production and existing clock proteins begin to be broken down when they're all gone about 24 hours have passed since this clock is not very accurate it has to be updated by signals from the eyes specific ganglion cells in the retina contain a photopigment called melanopsin instead of sending messages to the visual pathway these cells send information about the amount of light directly to the suprachiasmatic nucleus and the supracosmetic nucleus uses that information to reset the clock to 24 hours then information from the biological clock the supracosmetic nucleus is used to set cyclic patterns all over the body the supracosmetic nucleus itself is connected by neurons to other parts of the brain and controls their cyclic activity an example would be the sleep centers the supracosmetic nucleus also controls melatonin secretion from the pineal gland melatonin goes through the blood to organs throughout the body and keeps their clocks on schedule so i'm going to summarize what happens in the supracosmetic nucleus here and i'll start with the suprachiasmatic nucleus itself and in that i'm going to make up a little pretend clock and so this is going to represent a period of 24 hours and i'll say that the top part is going to represent the daytime and the bottom part represents night and i'm just going to designate 6 p.m as the end of day and 6 a.m as the beginning of the day so when we wake up in the morning we don't have any clock proteins but the genes that make clock proteins automatically start up and they begin to make clock proteins which build up inside the cells of the supracosmetic nucleus and so the red dots are going to represent clock proteins and then let me try to rewrite that part when we go to sleep once the clock proteins stop being made existing enzymes in these cells begin to break them down and so as you sleep the amount of clock proteins decreases until before you wake up they disappear altogether and so this process is automatic once we reach a certain level of clock proteins they shut off the clock protein genes and no more clock proteins are made and not one of my more successful diagrams and on the other hand at 6 a.m the lack of clock proteins turns the clock protein genes back on and so this automatically clicks on or clock protein formation clicks on in the morning and clicks off in the evening and so the cycle repeats about every 24 hours however it's not 100 accurate and so the supracosmetic nucleus gets some help from cells in the retina and in the retina there are non-visual ganglion cells they contain a photopigment called melanopsin which is sensitive to dark and light just like the opsins were when you learned about vision in amp1 only these cells are sending their information to the supracosmic nucleus to tell the brain when it's dark outside and when it's light outside and so unless you're exposed to a lot of artificial light you're going to get a good idea from these cells about when it's daytime and when it's nighttime and this process is called entrainment so in addition to having this input that helps to keep the clock on a 24-hour cycle the supracosmetic nucleus sends output to various parts of the body one of those being output to neurosecretory cells to control hormone secretion another output goes to the pineal body and so it's controlled by the supracosmetic nucleus and it secretes melatonin and melatonin goes through the blood throughout the body and it coordinates the clocks of other organs so organs that are outside of the nervous system and so there you have the main inputs and outputs to the supracosmetic nucleus and the basic mechanism by which it works when more than one hormone acts on a cell they can sometimes affect each other's level of activity there are two such types of interactions permissiveness and antagonism in permissiveness one hormone first acts on a cell to increase the number of receptors for a second hormone making the cell more responsive to the second hormone for example thyroid hormone acts on cells in the heart to increase their number of beta 1 receptors making those heart cells more sensitive to the effects of catecholamines in antagonism one hormone first acts on a cell to decrease the number of receptors for a second hormone making the cell less responsive to the second hormone for example during pregnancy progesterone acts on uterine myocytes to reduce the number of estrogen receptors making the uterus less sensitive to estrogen there are four factors that affect the concentration of a hormone in the blood at any given time a the first one is the rate of secretion and we've covered that in the previous section the second one b is metabolic activation some hormones must be chemically altered to activate them after they have been secreted but before they combine to a receptor in their target cells examples of this are thyroid hormone and testosterone the third factor c is binding of the hormone to a transport protein those are also called binding proteins and in this case they're going to mean the same thing transport protein means the same thing as binding protein most hydrophobic hormone molecules are attached to transport proteins while they're being carried by the blood that's because they don't really mix easily with water and of course plasma is mostly water so anyway the hormone molecules that are attached to the transport proteins are called bound and the hormone molecules that are not attached to transport proteins are called free there's a chemical equilibrium between the amount of bound and free hormone only the free hormone molecules are biologically active meaning only the free hormone molecules can leave the blood and attach to receptors in target cells the number of free hormone molecules depends on two things first is the amount of hormone in the blood and second is the amount of transport protein in the blood for example more than 99.5 percent of thyroid hormone is bound to transport proteins leaving less than 0.5 percent free to act on target cells the fourth factor is inactivation and excretion hormones don't stay in the blood forever many of them are lost in urine just because the kidneys cannot or will not retain them other enzymes sorry hormone molecules are broken down by enzymes in the liver and after that they're no longer able to bind to their receptors or affect their target cells hormone disorders are a major health problem over 10 percent of americans are diabetic and over 5 percent have a thyroid disorder whether or not they know about it diabetes mellitus is still a major cause of death in the united states all health professionals will deal with hormone disorders on a regular basis to understand hormone disorders you need to know a few terms hypocrite means not secreting enough of a hormone hyper secretion means secreting too much of a hormone either of these conditions may have several causes when the problem with a hormone secretion is the gland itself the disorder is called primary hypo or primary hyper secretion for example a tumor in the thyroid gland causes primary hyper secretion autoimmune destruction of the adrenal cortex causes primary hypo secretion when a hormone disorder is caused by a different organ than the endocrine gland it is called secondary hypo or secondary hypersecretion damage to the pituitary gland might fail to stimulate the thyroid gland to secrete thyroid hormone in this case it's not the thyroid gland's fault so that's called secondary hypothyroidism in addition to abnormal hormone secretion problems with the number of hormone receptors in the target cells can also cause disorders for example part of what causes type 2 diabetes mellitus is a decrease in the number of insulin receptors in target cells so even if the amount of insulin in the blood is normal cells cannot respond and their physiology becomes abnormal you