Transcribed by Erica Manion 5.5.14Organ Systems Lecture 50

Physiology of the male reproductive System by Dr. Schiff

[Dr. Schiff] OK, so now that you know all of the cellular biology and anatomy and everything of the reproductive system, we are going to talk about the physiology of it and how it works and stuff like that. And were back to the hypothalamic-pituitary axis. Because what you basically have is something thats regulated up through the hypothalamus and the pituitary. But I should make a point that we are going to be discussing two different categories of people, which some may argue is an oversimplification. But todays hour is going to be devoted to male-type people. And then Thursday morning, I guess, is going to be devoted to female-type people. Notice that takes up two hours compared to the one hour for males, because women are more complicated. Jay Leno once said that studies have shown that women speak three times as many words per day as men, but men only hear one word out of three so it balances out. Ok. [writes on board]. The hypothalamus releases a gonadotropin releasing hormone or two, or more. Generally they are lumped together as one hormone. But they act on two different pituitary gonadotropes. There are gonadotropes that release LH, and those that release FSH, which Ive been told by some histologists, they look alike, but what do I know? To me all cells are rectangles. And this fellow releases LH, luteinizing hormone. And this releases FSH. These are the gonadotropes. And eventually you reach your target organ, and since this is males today, we are talking about the testes. In which, there are two different types of cells we are concerned with, in terms of hormonal feedback and regulation. The leydig cells, and the sertoli cells. And basically, the leydig cells release a hormone, testosterone from the testes, and it is a steroid which inhibits here (hypothalamus) and there (pituitary). There is some local circuitry however, where the testosterone also acts, possibly in a paracrine manner, on the sertoli cells. The sertoli cells main function is acting as nurse maids to developing sperm, as you saw, because a sperm cell is a tail attached to something that is essentially a nucleus, and theres not much in the way of organelles there, so they need to be spoon fed. But the sertoli cells also produce a hormone of their own called inhibin. Inhibin specifically inhibits the FSH releasing gonadotropes, whereas testosterone inhibits both. So there is a sort of de-coupling between the gonadotropes releasing LH and the gonadotropes releasing FSH, in that you can inhibit one more than the other in this feedback loop. Inhibin does not appear to act on the hypothalamus.

TestosteroneOk, this is all very nice. And then the question is, what does testosterone do? And a lot of what, theres some of what testosterone does, it does rather early in life, during fetal life in fact, because testosterone in the male fetus promotes formation of the external male genitals and also promotes the descending of the testes into the scrotal sac. And all this generally takes place in utero. The testes generally remain descended into the scrotal sac because they live more comfortably at below body temperature. Its a matter of keeping them cool by getting them outside the body. In fact, things can go wrong in the testes when they are warmed by being kept inside the body undescended, but Ill get back to that. So thats what the testosterone does early in life. And one point I should make is, remember the thyroid secretes T4 and T3, T3 is actually a stronger hormone than T4, but the thyroid secretes both. The testes secrete testosterone, but that can be converted by an enzyme 5-reductase to dihydrotestosterone, or DHT, which is a much stronger agonist on testosterone receptors in most cases. Interestingly, not these receptors (referring to the receptors on the pituitary and the hypothalamus). These receptors are sensitive only to testosterone and not to DHT. But in most of the body, DHT is a stronger androgen, a stronger hormone, than testosterone itself. And it is responsible as the male child grows, for the onset at puberty, and Im going to get back to that, for the secondary male sexual characteristics. The adult male has more upper body strength, more muscle mass, generally more height, growth of the long bones, more body hair, and deeper voice, stuff like that. Plus, less hair on the head after a period of time. Thats called male pattern baldness. Loss of hair on the top of the head thats characteristic only of males.

But none of these even start happening until something happens at puberty. And what happens at puberty is this. And this appears to apply in females, girls as well as boys lets say. Up to the first 10, 12, 13, 14 years, whatever, of life, the hypothalamus releases a steady level of gonadotropin releasing hormone, secretes it. Something happens. Some alarm clock goes off or something, we really dont know. At about age, whatever. Lets just say 12 to pick a number. And the gonadotropin releasing hormone, instead of being steady, begins to oscillate. Now this is not a fast, you know, nnnnn oscillation. Were talking about every 20-minutes cycle. Slow cycle. Up down up down up down. But, what happens is that the receptors for GnRH on the gonadotropes are much more sensitive to this oscillating, back and forth, up and down levels of gonadotropin releasing hormone than they are to a steady level of gonadotropin releasing hormone. So once this oscillation sets in, these fellows are much more stimulated and they secrete much larger quantities of LH and FSH. And in particular in the male, the larger quantities of LH lead to much larger production of testosterone, and in various parts of the body, conversion of the testosterone to DHT, and thats what causes the masculinization of the physical appearance. The puberty age physical growth in height, the growth of body hair, deepening of the voice, and stuff like that. And growth of pubic hair and pigmentation of the genitals. Alright, thats the whole package.

This all seems to be reasonably regulated because as you secrete more testosterone and DHT as a result of the conversion from testosterone, that testosterone then provides negative feedback here, and you (mic cut out). Ok. So you reach a new level of higher testosterone levels in the plasma, and thats what brings about the body changes and characteristics of puberty. But except for this jump up that happens at this early teenage age or sooner. This is just a perfectly normal feedback loop, you might as well be talking about the thyroid or the adrenal cortex or something. Nothing in particular thats very special is going on. One of the things that you have to remember though is that LH and FSH are, in addition to promoting the secretion of these hormones, promote growth and maturation of the testes. So this really begins to occur at puberty as well, the testes get larger and they go into their full adult form where you have your spermatogenesis and development of sperm cells and all of that. As a side comment, by birth, generally the testes have descended out of the body into the scrotal sac. If they dont, there may be a problem because undescended testes, those that remain at body temperature one of the reasons you want to keep them cool, so to speak, is that testes that remain inside the body at body temperature have a significant incidence of cancer. So undescended testes are dangerous to the person that has them. And second, they wont be producing sperm so its an anti-fertility so after all remember the male is a sperms way of making another sperm if you look at the cycle that way. So what generally happens is, if testes are undescended at birth they sort of watch them for a while, but by 6 months, attempts are made to bring about the descent of the testes. And one approach that is frequently used, well one is a surgical approach. But much more common is the use of a hormone, an exogenous hormone, HCG, which usually appears in a whole other context in women. But HCG, as you will see when we discuss women in a few days, is an LH mimic. So effectively you give hCG, human chorionic gonadotropin, its a gonadotropin and it stimulates the testes to grow, to produce testosterone. But also in this particular context, to descend into the scrotal sac. And if that doesnt work, then surgery is left because you dont want to leave testes inside the body because of the danger of malignancy.

What can go wrong?Ok. So, it looks like a well regulated system. What could possibly go wrong? There are a number of things.

One is, suppose you have an adult male who wants to be a better football player or to hit a large number of home runs or to get more muscular in some way. So he decides, or his trainer decides, that administration of testosterone-like compounds would be a way to go. No sane person would ever do that to himself, but they do, because the lure is money. And what youre basically doing by injecting testosterone-like hormones, or testosterone itself, but thats so primitive after all nowadays, is you are promoting the production of all these DHT type things, type effects, youre getting more body hair, youre getting more muscle, which is the whole point of it all in these cases. If youre effectively increasing the concentration of testosterone around, whats gonna happen here? The tropic hormone secretion is diminished, which will lead to testicular atrophy because of the tropic effect. So basically the person who takes the extra testosterone has more muscles, might get taller, if he still hasnt sealed his epiphyseal plates on his long bones, gets stronger, gets hairier, have a deeper voice, everything gets bigger except for two little things. Hahah. Which is why its not a good thing to do. Ok. So thats one thing that can go wrong, people doing strange things to themselves.

Theres another syndrome that is unusual. And that is generally called androgen insensitivity syndrome. Or, AIS. Endocrinologists, like all other doctors, nothing to do with our dean of academic affairs, but androgen insensitivity syndrome. And what happens is, sometimes a genetically male child is born with defective or missing entirely testosterone receptors. Now these are the testosterone receptors that also respond to DHT, they are responsible for all of the secondary male characteristics, in infancy and as a fetus and before birth, they are responsible for the formation of the external male genitalia and the descent of the testes. But suppose you are lacking in the receptors for testosterone. All of them. What is going to happen? Well, the first thing that happens, or doesnt happen, is this feedback inhibition. So the levels of LH go up, up, up, up, up, which cause more and more secretion of testosterone from leydig cells in the testes. But that testosterone is not doing anything masculinizing because there are no receptors for it to act on. But meanwhile the testosterone concentration is going up through the roof. So then what? This enzyme, has a limited rate at which it can convert testosterone to DHT. Its working at its maximum, its converting a lot of that testosterone to DHT, which in the absence of androgen receptors doesnt do anything. But as I mentioned in terms of the hydroxylation of vitamin D, if you have a substrate, a precursor, that builds up enough so that it cant go the way it would normally go through the enzymatic pathway, it can find itself a different enzyme. And in this particular case it is referred to as an aromatase, because it converts one of the saturated rings of the testosterone molecule into an aromatic ring, thats why it is called an aromatase. And what it basically produces is estradiol.

So what do you have in this androgen insensitivity syndrome? You have no receptors for testosterone, so you dont get the masculinization, you dont get the formation of the external genitalia with descent of the testes, the testis stay inside the body producing large amounts of testosterone. That testosterone is making, either making something that has no receptors for it, and therefore it cant do anything, or converting to estradiol. So what have you got now? This genetically XY person, does not have external male genitals. And then at puberty when the testosterone levels and therefore the estradiol levels go up enormously, starts developing female sexual characteristics. Breast growth, things like that. So now we have what looks like a perfectly normal teenage girl. Except with less than normal pubic hair growth, because that is driven by testosterone even in women. Or by androgens in general, not necessarily testosterone but the adrenal cortical androgens can handle that. So here you have this person who for all intents and purposes looks female, who come age 14, 15, even 16, begins to really panic because she is amenstrual. And so she seeks a physicians advice and assuming the physician has a little hint of suspicion or has seen this syndrome before, the physician checks for estradiol and testosterone levels in the plasma and does an ultrasound of the abdomen, and doesnt see a uterus and ovaries, instead sees two masses that sort of look vaguely like testes. So, what do you do. Youre the physician, what do you advise? You cant do nothing, why not? Because those testes might become cancerous. They cant descend because there is no scrotal sac or any other structure for them to descend into. They have to be removed. So basically, you have this person who then has the testes removed and has to take hormones to maintain the female body habits. Just, its unusual. Its sometimes referred to, especially in the older literature, as testicular feminization. But, the current terminology is androgen insensitivity syndrome, and it can be complete or partial. Sometimes you find all sorts of inter-sex type configurations. Partial masculinization, partial feminization, and so on and so forth. Ok.

What else can we talk about? Theres really not all that much to say about men because we are simple creatures. One interesting thing is whether or not there is a difference between male and female brains. Those who argue that there is, and those who argue that there isnt. Ok. In a woman, where the predominant hormone is an estrogen of some sort, estradiol or one of the other estrogen type hormones. Estrogen doesnt cross the blood-brain barrier. So the developing nervous system is not exposed to any steroid hormone, and that develops into, if there is such a thing, a female-type brain. Testosterone on the other hand does cross the blood-brain barrier. But once it gets there, there is an aromatase that can convert it to estradiol. So apparently the quote male brain, if there is such a thing, results from the presence of estradiol inside the cerebrospinal fluid. So the choice is estradiol which causes a male brain, or no hormone which produces the female brain, if there is such a thing. Which I am not going to mention at all. Or discuss at all. Ok, so, I guess Im finished kind of early. [Question]. No I dont, but I could check on it. But, there are partial forms where you have defective testosterone receptors. Theres also another interesting syndrome that does occur, and this is kind of odd. In the normal male, most of the male sexual characteristics are brought about by DHT, which is the stronger androgen. Now, DHT is formed by a 5-reductase from testosterone. And it turns out that there are two different 5-reductase enzymes that are present in the male body. Theres one that is present from before birth. And that one is probably responsible for the formation of the DHT that does the early modeling of the external genitals of the fetus and leads to the masculinization of the newborn baby. Theres another one that becomes apparent, or appears, at puberty. And thats why, after puberty, the male child or teenager or whatever, has even more DHT than usual. And as a result of this additional 5-reductase, you carry out all this major masculinization of the body, the bone growth, the muscle growth, the voice deepening, and so on and so forth. Body hair. Theres a genetically mapped syndrome that appears in some areas of Central America and northern parts of South America, plus a few other isolated places around the world, where the first 5-reductase is missing. So, certain numbers of genetically male children are born with no apparent external genitalia and sometimes pass for female, but then at puberty, masculinize. And what was assumed to be a clitoris enlarges and actually becomes a functioning penis. Now, this is a genetic syndrome that is prominent among certain small clusters of people, and they are used to it. And they are not surprised when it happens. It is sometimes casually referred to as penis at 12 syndrome. Hahaha. But again, most of the world, unusual but in a few hot spots, relatively common. And these males are fertile. They are. At puberty the testes descend and the whole process goes on. What should have happened 12 years earlier happens. Ok. So, alright. There you have it. For the most part, as I said, males are simpler.