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The endocrine system is a system of glands that produce hormones.This system is one of the two major systems that are involved inthe control of physiological function in vertebrate animals. Theother system is the nervous system. So all of the variousphysiological systems of the body are going to be controlled byone or the other or in many cases controlled by the interactionbetween the two. I am going to take as an example of a systemwhich is controlled by the endocrine system, the malereproductive system. I'll start by talking about some generalprinciples of endocrinology. What are hormones? What areendocrine glands? How do hormones influence the activities of thecells that they are controlling? Then I will go onto a specificexample of the male reproductive system and how it is controlledby the endocrine system.
We can start by defining the word endocrine. An endocrine glandis a gland that does not have a duct. Endo means inside and crinerefers to releasing, so the translation of this word would be agland that releases its product inside the glands; specificallyone that releases its products into the capillaries that aregoing through the gland. This is distinctive from an exocrinegland which means outside releasing and would be something like asweat gland that has a duct and releases its product through thatduct onto other surfaces of the animal's body. Salivary glands,tear glands, and sweat glands are all examples of exocrineglands.
But we are talking about endocrine glands and the product of anendocrine gland is a hormone. A hormone is a chemical substancesynthesized by the cells of the endocrine gland secreted into theblood pulling through the capillaries in the endocrine gland.After it gets secreted into the blood, the hormone circulatesthroughout the body, comes into contact with all of the cells ofthe body because the hormone is able to exit the capillaries anddiffuse around in the interstitial fluid, comes into contact withall of the cells of the body and it influences the activity ofparticular populations of cells that are called the Target cells.So a hormone is a chemical substance produced by an endocrinegland, enters the circulation (within that gland), comes intocontact with all of the cells of the body and it influences theactivity of its target cell which are the specific cells that arecontrolled by the hormone.
One of the first questions that we need to address is how is itpossible for a hormone (which is coming into contact with all ofthe cells of the body) to influence the activity of onlyparticular groups of cells of the target cells. This basic issueis what's called Hormone Target Cell Specificity. In other words,there is a specific relationship between a hormone and it'starget cells. How is it possible for a hormone to influence theactivity of only particular target cells? Another aspect of thisquestion is that different target cells may respond in differentways to the same hormone. For example one of the hormones thatI'll be talking about in terms of male vertebrate reproductivesystem is testosterone - the male sex steroid hormone. It hastarget cells within the gonad and the testis, so the hormone isnecessary for the production of sperm. Testosterone has influenceon skeletal muscle and that's why males tend to be (on average)stronger than females. That's why many athletes take anabolicsteroids (which are similar to testosterone) to build muscle. Butit has an impact on other cells as well. It influences the depthof voice and it influences the distribution and quality of hair.It even has impact strictly in lower vertebrates on theirbehavior. So a single hormone can have a whole variety ofdifferent target cells.
How is it possible for one hormone to produce different responsesin these different target cells? Now there are 2 separate answersto that question. And the reason for that is that there are 2fundamentally different groups of hormones. The two groups ofhormones are:
PEPTIDE HORMONES STEROID HORMONES
Receptor MBP Receptor: Cytoplasmic Protein
The exact details of hormone target cell specificity aredifferent for these 2 different groups of hormones because these2 hormones have a fundamentally different chemical nature.
Peptide hormones are like very short proteins. They are composedof perhaps as few as 6 or 7 amino acids that are joined togetherin a linear sequence by peptide bonds. The exact same kind ofbond that holds amino acids together when they make up a protein,only it's very, very short. As a consequence of the fact that itis made up of a fairly small number of amino acids, it is still amuch too large of a molecule to ever be able to get through themembrane. And it's also a water soluble molecule so that itcannot dissolve in the membrane to get through. It has charges onit and it's too big. So peptide hormones cannot enter the cell.
Steroid hormones are based upon the basic structure of a complexmultiple ringed molecule called cholesterol. Cholesterol can leadto the hardening of the arteries but you don't want to eliminateit completely because the molecule is necessary for theproduction of steroid hormones. There are quite a few steroidhormones in addition to the sex steroids, testosterone andprogesterone. And steroid hormones, (based upon cholesterol) arefat soluble. Even though it's a large complex molecule, it candissolve in the lipid component of the cell membrane andtherefore it can go into the cell. In fact, when I said thathormones come into contact with all of the cells of the body,what's true of steroid hormones is that they enter the interiorof all of the cells of the body and yet they still only influencethe activity of their target cells.
Let's talk first about the mechanism of hormone target cellspecificity in a peptide hormone. Since the peptide hormone isnot fat soluble and it's too big to enter the cell, the peptidehormones have to have receptor molecules that are located on theoutside surface of the cell membrane. So we might say, here is acell that's going to be a target cell for a peptide hormone.There's going to be a receptor molecule that is exposed on theoutside of the cell. So the receptor, in both types, is going tobe a membrane bound protein. There are 3 basic classes ofmembrane bound proteins: receptor, catalyst, and transporters. Sothis receptor is like the acetylcholine receptor in aneural-muscular junction. It's a complex 3-dimensional moleculeexposed on the outside of the cell. And so the hormone comesalong, it's just floating around at random in the exterior fluidand it comes into contact with it's receptor. The hormone is notgoing to enter the cell. What's going to happen next is thatthere is another membrane bound protein and in this case it is acatalyst which has it's active site on the interior of the cell.This catalyst is called adenylate cyclase and it catalyzes achemical reaction that converts ATP into a compound called cyclicAMP (cAMP) - means it has a ring structure. Now, we're used toATP being consumed in energy utilizing chemical reactions likemuscle contraction but in this case it is actually being used asa substrate for a reaction.
The cAMP will then trigger a complex series of reactions and Iwon't go into the details of that complex series of reactions.But what's important is that the cAMP will cause an inactiveprotein to become activated. What do I mean by that? Well we knowthat messenger RNA (mRNA) goes to a ribosome and leads to theproduction of a protein which is a string of amino acids and ithas some complex structure. Well in some cases this protein maybe an enzyme that is a catalyst capable of catalyzing aparticular chemical reaction but it may have a sequence of aminoacids that are produced when the enzyme is made by the ribosomethat inactivated the enzyme. In other words, you make an enzymebut it has something that may be physically blocking it's activesite and preventing this enzyme from being able to catalyze thechemical reactions. That would be an enzyme in an inactive form.The cAMP comes along and it may trigger a sequence of severaldifferent reactions but the net effect is that it removes thatinactivator and then this enzyme will start catalyzing it'schemical reaction which it is uniquely designed to catalyze. Andthat chemical reaction that is catalyzed by this activated enzymeis going to constitute the cell's response to the hormone.Whatever the cell does in response to this hormone is going to bea chemical reaction of some sort which is catalyzed by thisactivated enzyme. Now that's a very general statement ordescription of what happens and there are many peptide hormonesproduced by the bodies of vertebrate animals. There are 6 or 7 ofthem produced by the anterior pituitary alone and there areothers produced in other places and the remarkable thing is thatthis general explanation of hormone target cell specificity in apeptide hormone applies to all of those different peptidehormones. All of them lead to the activity of adenylate cyclaseand to the production of cAMP in the cell. The recognition ofthat remarkably uniform intracellular mechanism was really quitea surprise to the people that first discovered it.
The cAMP is referred to as the 2nd messenger. If we consider thehormone to be a message that's sent from the endocrine gland tothe target cells, then it makes sense to call cAMP the 2ndmessenger because it carries that message within the cell. Soadenylate cyclase is an enzyme found in the membrane and it willnot be active. It will not be catalyzing the production of cAMPunless there is a hormone attached to the receptor. So thereceptor for the hormone and the adenylate cyclase have to appearright next to each other in the membrane and the hormonesfloating around bumps into the receptor. The receptor combinedwith the hormone produces some kind of a conformational change orsomething that turns on the adenylate cyclase, cAMP starts beingproduced within the cell and the cAMP within the cell triggersthe sequence of reactions that causes an enzyme to be active.There has to be a mechanism to turn all of this off so there'ssomething in the cell that's breaking down the concentration orbreaking down cAMP and lowering the concentration of cAMP. Therealso has to be some place in the body where the hormone itself isbeing broken down. So what we have here is a very dynamic processwhere the concentration of the hormone in the system is variable.It's always being broken down at some rate and if the endocrinegland increases the amount of hormone that it produces per dayand the rate of degradation stays constant, then theconcentration of hormone in the system will go up and when thathappens, the receptors for that hormone will spend a largerfraction of their time with that hormone combined with them. Thatmeans the adenylate cyclase will spend a larger fraction of thetime producing cAMP and so the concentration of the hormone goesup in the blood of the animal and the concentration of cAMP goesup inside the target cells and therefore it's possible to producea variable response where the target cells can respond to theconcentration of the hormone in the system.
For a steroid hormone, there is also a receptor. Target cellshave receptors and the non-target cells don't have the receptorsso even though the steroid hormone is floating around in thecytoplasm of all the cells, the cells that are not target cellsin effect don't even know it's there because they don't have areceptor. In the case of the steroid hormone, the receptor is acytoplasmic protein. It may not be a simple protein. It might bea glycoprotein but the important idea here is that floatingaround in the cytoplasm of the target cells is a complex moleculewhich is a receptor which has a specific stereospecificlock-and-key capacity to combine with the steroid hormone as thesteroid hormone comes into the cell. The same target cell couldeasily be a target cell for both the steroid and the peptidehormone, so in this case we're going to have the receptor sittinghere in the cytoplasm, the steroid hormone which is this complexring structure has 3 or 4 rings. It's going to come into thecell, it's going to diffuse right through the membrane and it'sgoing to combine with the receptor in the cytoplasm. Then thereceptor in the hormone stays bonded to one another and thereceptor hormone forms a complex which then through this randomdiffusion ends up in the nucleus. The nuclear membrane has largepores in it so that large molecules can get from the cytoplasminto the nucleus of the cell and this receptor hormone complexmoves into the nucleus where it interacts with a particular areaon the DNA which is probably a regulator gene and when thereceptor hormone complex through random molecular movement comesinto contact with that regulator gene, then that appropriatesequence of
DNA will be the transcribed production of mRNA. So a veryspecific sequence of the genetic material will be read out andthe messenger RNA will be produced. What happens then is the mRNAis going to exit the cell, it's going to go find a ribosome andit's going to lead to the production of some new protein. Thatnew protein might be an enzyme that catalyzes a chemical reactionor it might be a structural protein so that the cell grows butthat new protein is going to be the critical step in the cell'sresponse to the hormone. Whatever the target cell is supposed todo in response to that hormone, it's going to hinge upon theproduction of this new protein that is being fabricated by themRNA.
So in both cases the same hormone can have different target cellsand different target cells will have their own peculiar responseto the hormone and the reason that the same hormone can producedifferent responses is that each target cell has it's ownprotein. It either gets activated or produced. Different targetcells have their own protein. If it's a peptide hormone,different target cells will activate a different protein and thatprotein will allow them to respond differently in the case of thedifferent target cells for a steroid hormone. The cell willproduce a different mRNA in response to the receptor hormonecomplex entering the nucleus and you end up with a differentprotein that is the basis for their response. Now that's a verygeneral statement. A very general explanation of the differencesin hormone target cell specificity for these 2 major classes ofhormones.
Let's take a specific example of a physiological system that iscontrolled by the endocrine system; the case of the malereproductive system.
Male Reproductive System:
An example of how this biochemistry and cell physiology relatesto the whole animal might be the following very common sequenceof events in the life of a little bird. It's a generalizationthat applies not only to birds but also to a variety of differentspecies of reptiles as well as some species of mammals. The birdis a good example because we get to see them and we can observetheir behavior. In the winter time you'll see flocks of birdsflying around with the males and females of the species hangingout together, looking for food and cuddling together to keep warmat night. At some time during the spring, the behavior responsesof these individuals to each other changes dramatically. Andassociated with that, the males birds may molt losing some oftheir old drab camouflage feathers and grow some brightly coloredpatches of feathers in specific places. Those brightly coloredpatches of feathers are going to be used as signals in courtshipand in territorial defense. The male birds that were all having agood time together looking for something to eat for months on endwill suddenly be very agnostic towards each other. They will notget along at all. The males will set up a territory in thehabitat which is appropriate to that species and the males willexclude all other males of their species from that section of thehabitat. Then the female birds who they had just been buddy withwill become courting targets for the males. And the females willbe receptive to that courtship behavior. The males will courtthem for some period of time and then they will copulate. Theymight make a nest before they copulate, but she will lay eggswithin a short period of time and then the male and the femalemight take turns incubating the eggs in order to produce theyoung.
Now, we can see that the behavior of the animal is influenced bysomething changing in the environment. Experiments have shownthat what is happening in the environment to produce that changeis a change in the number of hours of continuous daylight. In thewintertime here in Southern Calif., we have about 10 hours ofdaylight and about 14 hours of dark. And then at the time ofspring in March, there's 12 hours of dark and 12 hours of lightand from that point, it goes into the situation in the middle ofsummer when there's only 14 hours of light and only 10 hours ofdark. Sometime during Spring, something happens in terms of theinterior physiology of the animal and the hormone/endocrinesystem kicks into gear. All of these physiological behavioral andanatomical changes will contribute and be controlled by thehormone.
The animals have to do that well ahead of the time of the yearwhen they want to be producing young. This whole system ofenvironmental control has evolved so that when the young havehatched out of the eggs and are being fed by the parents, theyare then beginning to start looking for food themselves. Thatwill happen when there's the maximum availability of food and thetotal period of time from the start of molt through courtshipthrough laying eggs and incubating them, and the eggs hatching.That whole period of time takes a couple of months. So theanimals have to anticipate the arrival of the great abundance offood that's going to happen in the summertime. They have toanticipate that by a couple of months so they use thephoto-period, that is the number of hours of continuous light.
Environmental Signals:
So let's talk about how this system operates. We can deal withthis in terms of considering this as being a sequence of piecesof information. We start with the environment. That in this casemight mean photo-period but it also could include the behavior ofanimals and the environment will include a variety of differentkinds of signals. Those signals will be perceived by the sensorysystems of the animals. So the eyes, ears, and the nose are allthe various sensory systems that can be involved. Now the nose orthe sense of olfaction is not going to be involved in birds butit's very important in mammals where pheromones are importantsignaling devices. This information from the sensory systems ofthe animal will travel through nerve tracts and are going to goto the outer parts of the brain of the animal which is called thecortex. It's going to go to very specific populations of nervecells in the cortex that we call the higher centers. These arepopulations of cells in the cortex that interpret theenvironmental information, that major photo-period for examplewhich interprets the behavior that the eyes are perceiving orwhich interpret the olfactory signals that are coming from thesense of smell. Now these higher centers after they recognize theenvironmental signal as being a signal that says it's time tostart reproduction will transmit information down to a deeperlayer in the brain which is called the hypothalamus. So thesensory systems are transmitting information to higher centers inthe form of action potentials (nerve impulses) and the highercenters are transmitting information to the hypothalamus in theform of standard nerve impulses that are action potentials andthey go to special nerve cells within the hypothalamus that arecalled neurosecretory neurons.
Neurosecretory neurons are the nerve cells within thehypothalamus that receive the action potentials from the highercenters. And as the name implies they are neurons, they are nervecells but they are neurosecretory. In a sense, they are like theneuron that we've already talked about. They have an axonterminal and they have what looks like synaptic vesicles in theaxon terminal. There is a chemical located within the synapticvesicles, but there's no neuron on the other side of the synapse.In fact, what happens when the synaptic vesicles fuse and dumpthat chemical out, that chemical then diffuses into a capillary.It travels in the blood and it goes to an organ which is locatedimmediately below the hypothalamus which is called the anteriorpituitary. There's a very short blood vessel that goes fromcapillary beds in the hypothalamus to capillary beds in theanterior pituitary and this is called the hypophyseal portalvessel. The hypophyseal portal vessel is a very short vein thatconnects a capillary bed in the hypothalamus to the capillary bedin the anterior pituitary.
Now these chemicals that are released by the neurosecretoryneuron wasn't even suspected originally. And then after awhile,there began to be some accumulating evidence thatendocrinologists came up with what suggested to be somethingcoming from another part of the body that was causing hormones tobe released by the anterior pituitary. If you took endocrinologyor just general zoology 3 decades ago, you would have heard theanterior pituitary referred to as the "master gland of thecell" because the endocrinologists thought that the anteriorpituitary was the boss in charge of everything. What they learnedwas that the anterior pituitary was not the boss and it was infact controlled by the hypothalamus. The hypothalamus producedthese things that were called releasing factors and they didn'tknow what they were. But there was some factor that caused theanterior pituitary to release hormones so they called themreleasing factors.
Then they realized that these things were just hormones. That theneurosecretory neurons produced what we now call releasinghormones. That chemical that was located in the synaptic vesicleand the neurosecretory neuron is what we would call a releasinghormone and when it is released from the end of the neuron,synaptic vesicles fuse. It diffuses into the hypophyseal portalvessel and then travels a very short distance where it goes intothe anterior pituitary with capillary beds and it will exit thecapillary bed where the target cells are located. These targetcells in the anterior pituitary will produce 2 hormones. Onegroup of target cells produce one hormone, the other one producesthe other.
The general name for these hormones that are involved in thecontrol of reproduction is gonadotropins. That term is a verygeneral term that endocrinologists use. The translation is ahormone that causes growth of gonads. Now as I said, there are 2gonadotropins that are found in vertebrate animals and these arecalled follicle stimulating hormone (FSH) and luteinizing hormone(LH).
If you were to have learned your basic endocrinology a long timeago when I did, you would have been told that these were thenames of the hormones in a female vertebrate but that there wereanother couple of hormones in male vertebrates. It turned outthat they were chemically identical. They were exactly the samehormones in both males and females. The names come from thefunction of the hormones in a female mammal but exactly the samehormones are found in male mammals and in fact, male and femalevertebrates of all vertebrate classes produce the same hormones.
The general functions of these hormones, these gonadotropins, arethe following and the target cells are different. They are goingto go to the gonad but each of the hormones has a differenttarget cell. FSH is going to go to the cells in the gonad whichundergo miosis and produce and develop the sperm. These arecalled the primary spermatogonia. So FSH is going to stimulatethe primary spermatogonia. The target cells for LH are cells thatare located outside of the seminiferous tubules and they arecalled interstitial cells. When LH comes into contact with theinterstitial cells, the interstitial cells produce testosterone.
So let's go back and identify what types of hormones the ones Ihave listed are. Releasing hormones are peptides. So when they goto their target cells (the 2 different populations of cells inthe anterior pituitary) they are going to operate through thepeptide hormone mechanism. And FSH and LH are also both peptides.So when they go to their target cells, the primary spermatogoniaand the interstitial cells are going to operate via that peptidehormone mechanism. Testosterone is a steroid hormone and thetestosterone is going to do a bunch of things and one is thatit's going to go to the primary spermatogonia because both FSHand testosterone are necessary for the primary spermatogonia tobe able to produce sperm. The testosterone is also going tofeedback on the hypothalamus, and the hypothalamus is going tomeasure the concentration of testosterone in the blood. If theconcentration of testosterone in the blood is too low, thehypothalamus is going to produce more releasing hormone and causethe anterior pituitary to produce more FSH and LH and that'sgoing to cause the interstitial cells to produce moretestosterone. So this is going to be regulated. The testosteroneis also going to go to different higher centers in the brain.Remember I said that the male birds' behavior towards the othermales and towards the females change. The reason that thisbehavior changes is because of the testosterone in it's system.He becomes aggressive and intolerant of other males and hebecomes amorous towards the females because of the testosteronein his system. Of course the testosterone is also going to beinvolved in the molt that causes him to grow the speciallycolored feathers as well. So there are a whole bunch of othertarget cells that the testosterone is going to be impacting inthe system.
Now one interesting ramification of this system as it's found inhumans is in the case of human athletes who take anabolicsteroids to bulk up. An anabolic steroid functions becausechemically it's very similar to testosterone and it has theeffect on skeletal muscle that testosterone has on skeletalmuscle. And so when these guys are weight lifting or exercising,they take these steroids and it causes them to put on muscle massand increase in strength. But all the other effects of theanabolic steroids will also happen. One of them is this feedbackon the hypothalamus. The hypothalamus is going to measure thatanabolic steroid and think that the testosterone concentration istoo high. And what does the hypothalamus do? It stops releasingthe releasing hormone which means that the target cells in theanterior pituitary stop producing FSH and LH. When there is noFSH being produced, even though the primary spermatogonia aregoing to think there's lots and lots of testosterone around,there's no FSH around so there won't be any sperm production. Sothose big buff dudes are in fact reproductively incompetentbecause they are not producing any sperm. It will also feedbackon their higher centers and it's widely acknowledged thatathletes that are taking anabolic steroids are aggressive andhave short tempers and that's a manifestation of this feedback onbehavior and addition to that of course, it also causes livercancer which is another good reason not to take anabolicsteroids.