ZOO 138, Wednesday, February 19, 1997, 12:00 p.m.
Now, today's lecture is on endocrinology. And it is not goingto be covered on the second midterm. It will be covered on thethird midterm, the one that you take during the final exam period.
You need to pay attention to this lecture, but you do not needto study this material for the exam on Friday.
Obviously, the reason that we're having a lecture today is becauseto have midterm on the day following your practical would probablyviolate the Constitution's new prohibition against cruel and unusualpunishment.
I'm going to talk about endocrinology. We need to start withsome definitions. The endocrine system, translation of that endocrinemeans -- "crine" means releasing and "endo"means inside or within.
And this is in reference to the fact that the glands that makeup the endocrine system release their product, which is calleda hormone. They release their product into the capillaries intothe blood that is flowing through the gland. And that is in contrastwith other glands.
Like as well as glands that are called exocrine glands. An exocrinegland releases its product, whatever it is, through some kindof a duct. And it exits the glands through the duct and is releasedon the body's surface.
So endocrine means releasing inside and referencing to the factthat the hormones are released into the blood.
What is a hormone?
A hormone is a chemical produced by an endocrine gland whichis a released into the blood and circulates throughout the entirebody of the animal, and it comes into contact with or enters;some hormones do one and some do the other. It comes into contactor enters every cell in the body and it influences the activityof some of those cells.
So it is produced by the endocrine gland, goes into the blood,comes into contact with or enters every cell in the body and influencesthe activity of some cells. Those cells which have their activityinfluenced by a particular hormone are called the target cellsfor that hormone.
They are the targets of the hormone. And there are basically2 different types of hormones. Some of them are peptide hormones,which means that they are like very very short proteins they arecomposed of maybe six or seven amino acids connected to one anotherby peptide bonds, the same bonds that connect amino acids inprotein, but they are very, very short proteins.
The other type of hormone are called steroid hormones. And steroidhormones are based upon a fairly complicated multi ringed moleculecalled cholesterol. The same evil stuff that you want to get outof your diet so it doesn't give you heart disease. It is an essential-- absolutely an essential molecule in your body because not onlyis it used in the production of steroid hormones, but it's alsofound in your membranes.
A significant amount of lipids in the membranes of all the cellsin your body are composed of cholesterol which is why when youeat meat you get cholesterol, a multi-ringed structure is modifiedto produce this steroid hormone. And the reason that some cellscontact all the cells in the body and other cells enter all thecells in the body is that steroid hormone is being modified.
Cholesterol molecules are fat soluble, therefore even thoughthey are pretty good sized they actually move through the membraneof every cell in the body. And they enter every cell in the body.
But peptide hormones, being not fat soluble, modest sized molecules,six or seven amino acids long, they cannot enter any cell. Butthey contact every cell in the body. So these hormones eithercontact or enter every cell in the body. But only particularcells in the body respond to a particular hormone.
And the cells that respond are the target cells. And one ofthe most important insights in the field of endocrinology that'sbeen gained in the last 20 years is the mechanism of what it isthat allows a particular cell to respond in one way to a particularhormone. It might respond in a different way to a different hormoneor a different is cell might respond in a different way to thecell same hormone.
And this general problem is called "hormone target cellspecificity." That refers to the very specific relationshipbetween particular populations of target cells and the hormoneswhich influence their activity.
To give you an example, testosterone is the male sex steroidhormone. It contacts all of the cells in the body. It might causeskeletal muscle cells to be more responsive to exercise. So thestrength of a muscle which is reflected in the number of actinand myosin, thick and thin filaments present in the cell, canrespond and is increased by exercise.
It might influence other cells in the body. It can influencebrain cells. In the bodies of some vertebrates it produces matingbehavior, an aggressive behavior. It can influence the distributionof hair follicles on the body producing the male distributionof hair follicles. It influences where fat deposits appear onthe body, which males deposit fat in different places than femalesdeposit fat.
So this single hormone is contacting all the cells in the bodyand influencing different populations of target cells to do differentthings. And the question is, how is that possible? How can thesame hormone cause some cells to react and some cells are totallyoblivious?
The testosterone in other cells respond in one way, and anothergroup responds in another way. But how is that possible? That'sthe question of hormone target cell specificity, some respondto 2 different hormones or more. So how is that possible? Theanswer to the question is different for peptide hormones and forsteroid hormones because of this business of the fat solubility.Where the cell -- where the hormone gets at the cell is goingto be different depending upon whether it's a peptide or hormoneor steroid hormone.
The most basic answer to the question of what makes a cell atarget cell is that it has a receptor for that hormone. In otherwords, it has a molecule. It's a peptide protein molecule or maybea glycoprotein that has the proper stereo specific or lock andkey and vernacular, the proper stereo specific configuration thatallows it to combine with the hormone.
If you are going to have a target cell for a hormone, you haveto have a receptor for the hormone. And if is hormone is a peptidehormone, then the receptor is a membrane-bound protein facingthe outside of the cell. That's my abbreviation for a membrane-boundprotein. It means that's it's one of the 3 classes of membrane-boundproteins.
In this case it's the one that is exposed on outside of thecell because the peptide can never get inside the cell. That iscell the target. The cell has to have a receptor that is exposedon the outside of the cell. On the other hand, if the hormonein question is a steroid hormone, then the receptor is a proteinor it can be a glycoprotein that is in the cytoplasm.
So that's the first part of the answer of what makes a cella target cell? It has to have a receptor for the particular hormonein question.
What happens after the receptor combines with the hormone isalso different in both of these cases. And the surprising thingis because there are probably a couple of dozen different peptidehormones that are known in the bodies of vertebrate animals.
One of the surprising discoveries, which actually got its discoverya Nobel Prize, is the fact that what happens after the receptoris stimulated is the same thing in a large percentage of thosecases. There is another membrane-bound protein which is found,if the membrane immediately adjacent to the receptor, which iscalled "adenylate cylcase."
Adenylate cyclass is a reaction that converts ATP, which wenormal expect ATP to be used for energy, but in this case ATPis converted into another compound, which is a ring structurewith only a single phosphate which is called "cyclic AMP."Cyclic AMP or that's abbreviated c AMP. "C" is lowercase and "AMP" is upper case.
So cyclic AMP is a produced within the cell when the receptoris combined with a hormone. And when the receptor does not havea hormone attached to its receptor site, then the enzymes adenylatecyclase is inactive and not catalyzing this reaction.
Now, somewhere else in the cell is a reaction which breaks downthis cyclic AMP. So you have a cell and it is has a receptor moleculein the membrane, and immediately adjacent to that is adenylatecyclase and when a hormone comes along and combines with the receptor,the adenylate cyclase is making cyclic AMP. So somewhere elsein the cell that cyclic AMP is being broken down.
So the concentration of cyclic AMP in the cell is a productof the difference between the rate at which it's being producedand the rate of being broken down. If there is a lot of hormone,then a lot of time the receptor is going to have a hormone boundto it. So a lot of time the adenylate cyclase is going to be active.So the rate of production of AMP is going to be high, and theconcentration is going to be high.
If there isn't a lot of hormone around then the adenylate cyclasewill be inactive and maybe no cyclic AMP will be present in thecell. So the concentration of the hormone gets translated directlyinto a concentration of cyclic AMP within the cell. A high concentrationof hormone produces high concentrations of cyclic AMP in the cell.
Now, the cyclic AMP is called the "second messenger."In other words, the endocrinologists who were studying this werethinking of the hormone as being a messenger sent from the endocrinegland to its target cell doing whatever you are supposed to dowhen I push your button. And since the peptide hormone cannotget inside the cell, the cyclic AMP is the second messenger carryingthat message within the cytoplasm of the cell.
Now, what that cell does in response to the increased concentrationof cyclic AMP is different for every different population of targetcells and for every hormone. But as a generalization, what happensis that some proteins, which is inactive enzymes, become activated.And this may be a new idea to you, but, you know, the way proteinsare made the messenger RNA comes out of the nucleus, goes to theribosome, the messenger gets translated into a protein, the proteinfolds up into its proper structure because of the weak molecularstructures between the amino acids.
Well, sometimes that protein which is fabricated, actually hasnot only an active enzyme but it has another little tail sectionthat blocks the active site on the enzyme and prevents the enzymefrom catalyzing any chemical reactions. And what happens whenthe cyclic AMP comes into the cell is that a sequence of reactionsis triggered where it removes that little cap, so you are actuallyactivating a pre-existing inactivated enzyme. You're allowingit to start catalyzing whatever chemical reaction those enzymeswould normal catalyze.
So that's a fairly fast response. This cascade of enzymaticreactions can happen pretty quickly. You activate an enzyme, andthe enzyme catalyzes some check reaction, which is important tothe cells or the response to the presence of the hormone on theoutside. That's the mechanism of hormone target cells specificityfor a peptide hormone.
For a steroid hormone it can enter the cytoplasm of the cell.And the receptor, which also has to have a proper lock and keyconfiguration for that particular steroid hormone is present floatingaround in the cytoplasm of the cell. And through random molecularmovement, when that receptor hormone complex is formed just throughrandom molecular movement, the complex -- some will find themselvesinside the nucleous of the cell because it's a nuclear membrane.
The nuclear membrane is a phospholipid membrane, but it hashuge pores in it, big enough for huge molecules like messengerRNA to go in and out. It has to have that kind of capacity.
So this receptor hormone complex is floating around inside thecytoplasm and by chance it floats into the nucleous and by chanceit bumps into some section of DNA. That's a regulator gene. Sothe receptor itself not only has one part that recognizes thehormone but another part that recognizes a particular sequenceof DNA.
And the net result is that you get the transcription of a DNAinto M RNA. So the receptor hormone complex connects to the appropriateparticular receptor and causes a particular gene to get translated.You have M RNA produced, and then the M RNA goes back out througha new clear pore, finds a ribosome and leaves the production ofnew protein. And that new protein is then
specific to the particular cell. It constitutes that targetcell's response to the hormone.
It might be an enzyme catalyzing a particular reaction. It mightbe structural proteins so that muscle cell builds for actin andmyosin. It takes a little bit longer for a cell to respond toa steroid hormone because we have to go through this entire processof making messenger RNA and finding ribosomes and making protein.We're not just activating a pre-existing protein, we're fabricatingnew protein when the steroid hormone is present.
So somehow is it possible for 2 different populations of cellsto respond in different ways to this same steroid hormone? Theyhave to have a receptor that recognizes the hormone, so that parthas to be the same. But the other part of the receptor that recognizesa particular sequence in DNA is different. So just as a differentpopulation of cells can respond to different peptide hormonesin different ways because different proteins are activated, differentcells can respond to the same steroid hormone in different waysbecause their receptors are specific to different sequences ofthe gene.
Any questions about that?
Now, what I want to do is give you specific example of the endocrine system so we can see the kind of complexitiesand how control occurs in the endocrine system. And I'm goingto take a fairly simple example, believe it or not. Because thisis a complicated system we're going to look at the male reproductivesystem in vertebrate animals. Part of this information is thecontrol of reproduction and part of it is to give you a specificexample of one of these control systems. And the I selected thisparticular one because there are both peptide and steroid hormonesinvolved in the control of the male reproduction.
And I selected male reproduction because, at least, for mammalsit's much simpler than females because it doesn't go through thecycles. Cycles involve a second hormone and a lot more complexity.
Don't be a offended that I'm talking about males here becausethey are simple. I'm sure some of you would agree with that.
Here is the situation I'm talking about. I'm not going to talkabout human beings, I'm going to talk about a species, it coulda mammal, a bird, or a reptile for that matter, which exhibitsthe kind of seasonal reproduction. I like to use examples frombirds because I like birds. If you watch what goes on around youin the environment here, even in the next month or so, you willsee some of the following kinds of changes taking place.
There will be flocks of birds where the males and females areall hanging out in a big group flying around together lookingfor food at night. They all huddle together, help keep each otherwarm. It's very, very platonic, kind of like a bunch of collegestudents just having a real good time. No sex. No courtship. Everybodyis just friends. No animosities between members of the same sexor anything like that. It's just a big platonic group.
And then as the number of hours of continuous daylight increases-- in other words, you are, more or less, generally aware it reachesa minimum on the 22nd of December, when there is ten hours ofdaylight and 14 hours of dark.
And that increases up to exactly the opposite condition on thelongest day of summer in June. On the 22nd of June when thereis roughly 14 hours of daylight here in Southern California andonly ten hours of night or dark.
But the number of hours of daylight increases, and the speciesof animals living in the temperate regions use that change totrigger reproduction. And when the number of hours of daylightgets to be more than about 12, the birds start to physiologicallyprepare themselves for reproduction. That's the mechanism I want to talk about. How does that happen?
If you look at different species of animals it wouldn't alwaysbe something that's triggered by daylight, and even if you lookthe males and females, if we study a male bird, if we just takea male bird and put him in a cage and give him an artificial lightcycle, 12 or 14 hours of light, the male bird will be totallyready to produce. Testosterone is produced. They might mulch newfeathers. The male becomes ready to produce.
Female birds under the same circumstances will get about halfwaythere in terms of being physiologically ready to start courtshipand lay eggs. What they need is some courtship from the male bird.In many species the male bird has these specie specific displays,showing color patterns and singing songs.
And the female bird not only responds the photo period, butalso from the behavior from the male bird in order to physiologicallycompletely get ready to reproduce. And in some species there mightbe pheromones involved. Maybe the pheromones of one or the otherwill be involved. Maybe in some species, it's a courtship by awhole bunch of birds.
And flamingos have wonderful group courtship displays. And theyall do this bizarre dance together for any of them to be ready to reproduce.
In some places it's just the rising in the rivers in some ducts.In Australia is rising of the rivers represents the beginningof the wet season. Sometimes it's sound.
So anyway, we have various kinds of sensory information, environmentalinformation. I'm going to break this down as though we have abunch of different areas, different parts of the body of animalsand communication between those parts.
This environmental information, what is going to be perceivedby the sensory systems. So we have eyes, ears and a nose. Thesensory system of an animal perceives this environmental informationdepending on what form it comes in.
And this sensory information gets transmitted to the top tothe cortex of the brain, to the higher areas of the brain in theform of action potentials. Nerve impulses are transmitted alongoptic nerves and so forth. And again, these are what we call highercenters of the brain.
These are areas of the brain where information can be processed.In other words, where a female bird can recognize the behaviorof a male of her species or where a bird, a male bird's biologicalclock can tell him, well, we have more than 12 hours of photo period now. So these arehigher centers of the brain, not the kind down at the bottom ofthe brain, housekeeping areas. We'll get to those in a minute.These are higher areas from the brain where some kind of processingand interpretation of information can take place.
And there are lots of different higher centers of the brain,only some of them are going to be involved in this, other highercenters will be involved in the behavioral like the male reptilewho becomes aggressive towards other males. The male birds, oncehe starts to get physiologically turned on, he starts his territorialdisplay and he will have a very different response to other malesthan he did before.
Before they were always pals, hanging out together and lookingfor food and staying warm at night. Now, all of a sudden theyare hate each other. And that male won't allow that male to comeanywhere near his territory. There is a big change in behavior.And that change is due to some different higher centers in thebrain of the animal that have become activated as a result ofthis process. And we'll see where that comes in later.
But these higher centers in the brain that have interpretedthis environmental information are going to send information inthe form of action potentials to one of these deeper down, lower, towards the spinal cord, areasof the brain, house keeping areas of the brain. And this one iscalled the "hypothalamus."
The "hypothalamus" is a very, very important partof your brain because it contains a whole bunch of different centers,little localized populations of cells that take care of differentbasic processes, regulation of blood pressure, thirst, hunger,body temperature, regulation. You have different local nucleoli,or cells within the brain, neurons within the brain that do differentthings.
And one of those groups of cells is composed of a very weirdcell, a very special cell, it's called "neurosecretory neuron."
So neurosecretory neurons are located within the hypothalamus.They receive these action potentials that are coming from highercenters of the brain that interpreted this environmental information.And these neurosecretory neurons, what is weird about them isthat they look like a basic neuron. They have a soma. They havean axon.
But the axon terminal, they do not form a synapse with anothernerve cell or muscle cell. They, in effect, have a synapse ora capillary. And they have synaptic vesicles that contain a chemical.And the synaptic vesicles fuse like in a neuro muscular junction, but when thechemical is dumped out it goes into the blood. And, in fact, it'sa hormone.
That's why they are called neurosecretory neurons. It's a neuron.It's a nerve cell but it secrets a chemical. And that's chemicalisn't called a neuro transmitter, which up this point you mighthave that it was called that because it is produced in the sameway. It's released from synaptic vesicles. This thing is calleda releasing hormone. These things produce a releasing hormone.
And that releasing hormone is put into a capillary which islocated in the hypothalamus and travels through a very short bloodvessel, which is one of a small number of blood vessels that connectsone capillary bed to another capillary bed.
Most blood vessels, as you know, connect the heart to the capillarybed. What do we call those blood vessels that connect the heartto a capillary bed?
Artery. And there is another capillary bed that goes back tothe heart, and we call those veins.
But this is one that goes a very short distance from the capillarybed. And then there is a blood vessel and another capillary bed,and that's called a portal vessel. When you look at the circulationof a rat, they have a hepatic part of the vessel. They have capillaries inthe gut and liver, this is another kind of portal vessels. Thisis called hypo hypophyseal. And hypophyseal vessels connect thehypothalamus to the endocrine gland called the "anteriorpituitary."
So the anterior pituitary is a pretty good sized gland. It'son the under side of the brain. You'll be able to see it you lookat the sheep brain in lab at the end of the quarter. And the anteriorpituitary produces I think 7 different peptide hormones. But 2of those peptide hormones are involved in the control of reproduction,and we need to know about that.
Now, this releasing hormone by the way is a peptide hormone.It's a very short peptide. And it's called a releasing hormonebecause it causes the anterior pituitary to release these 2 otherhormones that we're interested in.
So these 2 hormones because they control reproduction, theydo so by having their target cells be located in the reproductiveorgans of the animal in the gonads of the animal. The male gonadis the testes; in the female it is the ovaries.
Many different types of animals and in vertebrate animals aswell as have hormones that control their gonads. So there is ageneral name for a hormone that controls the gonads, and that's called "gonadotropin.""Tropin" refers to making it grow. So this hormone causesthe growth of a gonad.
The specific gonadotropins may be different in different groupsof animals. In vertebrate animals, the kind of animals that we'restudying here there are 2 gonadotropins.
These are called luteinizing hormone. It's a peptide hormoneand follicle stimulating hormone. So you get to the distinctionI'm drawing here. Gonadotropin is a general class of hormone,luteinizing and follicle stimulating.
The gonadotropin in vertebrate animals, interesting enough,the names of those hormones come from the function in female mammals.Follicle stimulating hormone stimulates the graffian folliclethat produces ovum. Luteinizing maintains the corpus luteum, whichis a structure on the gonads, and after ovulation it helps maintainpregnancy in the early stages.
When I was an undergraduate they thought there were 2 differentgonadotropins in males. And then they sequenced the isolated hormones,and they sequenced them and found out they are exactly the samemolecule.
So males have luteinizing hormone and follicle stimulating hormonein them as well, exactly the same molecule. But the target cells are different and so the effectis a little bit different.
Follicle stimulating -- luteinizing hormone is the message thatgoes to the testes. And in the testes luteinizing hormone combineswith cells that are called interstitial cells.
The interstitial cells are cells that are located outside ofseminiferous tubules. You have probably in basic biology lookedat a cross section of grasshopper testes and looked at a maturationof sperm. Those occur in tubules called seminiferous tubules.Located in between are these interstitial cells. And what theydo when LH, as it's called, what LH causes interstitial cellsto do is produce a hormone called testosterone, which is in facta steroid hormone.
So here is a hormone causing a cell to produce another hormone.Follicle stimulating hormone goes to the testes and it combineswith the cells that are going to make the sperm, those are calledthe primary spermatogenia. And the primary spermatogenia undergomeiosis. It results in the reduction of chromosomes, that processof meiosis causes primary spermatogenia to mature into sperm.
The testosterone produced by the interstitial cells must alsobe present for the primary spermatogonia to undergo spermatogenesis. Here the cell which requires 2 hormonesin order to be activated. It must have FSH, the gonadotropin producedin the anterior pituitary, and it also received testosterone.And the testosterone is produced by interstitial cells that arelocated outside of the seminiferous tubules, which is the maturationprocess taking place.
The testosterone itself is going to be involved in some otherimportant activities. It is going to be floating around in theblood contacting all the cells of the body. And it is going tobe sensed by these neurosecretory neurons and by the cells andthe anterior pituitary in the process. That's called feedback.
These controllers, the neurosecretory neurons and the anteriorpituitary cells that produce the gonadotropins are monitoringthe concentration of testosterone in the cell. If the concentrationgets to be too low then these cells increase their productionof the gonadotropins and stimulate more testosterone production.
If the concentration of testosterone gets to be too high, thenthese cells decrease the production of gonadotropins to get thatconcentration back down to where it needs to be. And that's afeedback mechanism, where the product of one things feeds backon its controller in order to maintain that concentration constant. Now, we know that testosterone also has a variety of differentactions. It acts on skeletal muscle, and it feeds back on otherhigher centers in the brain that are responsible for behavior.
So that male bird that starts courting females, his behaviorcenters for courtship are triggered his testosterone. His aggressivecenters which cause him to be aggressive to other males are triggeredby this testosterone. Skeletal muscle, hair follicles, fat cells,all these different cells are affected by testosterone.
Now, that's a very complicated picture. It has lots of differentcenters. We can think of these -- this anatomical place here isa form of communication to another anatomical place. Here is aform of communication to another anatomical place. Here is a formof a communication to another anatomical place. Here is anotherform of communication that feeds back and influences differentactivities. It's very tricky and dangerous to mess with a systemthat's this complicated.
But there are people who do it because of this, right? Anabolicsteroids which weight lifters take and other athletes who aretrying to enhance their physical performance are taking an artificialhormone that emulates the affect of testosterone.
That's why they take it is because it has the same effect on the skeletal muscle as testosterone does. But it alsohas the same effect everywhere else. It feeds back on behavior.So people taking anabolic steroids frequently have really badtempers because they have way too high a concentration of testosteroneand are producing aggressive behaviors.
It also feeds back on the neurosecretory neurons and the anteriorpituitary. If those glands think there is way too much testosteronein the system they are going to decrease the production of gonadotropins,which means there are less luteinizing hormones, so interstitialcells stop producing testosterone. But the anabolic steroid isdoing the job, but they also proceed less FSH, less follicle stimulatinghormone, than these cells need to have both.
So that big muscle-bound dude is probably not reproductivelycompetent. And the other thing is that very high concentrationsof a nonphysiological effect can induce liver cancer which isnot really a good thing good. It's probably a major reason thatit's not a good idea to use anabolic steroids.