Hypothalamic–Pituitary–Gonadal (HPG) Axis Differentials

by Carlo Raj, MD

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    00:00 We have an important table here. I really need you to know about the HPG Axis: H, hypothalamus; P, pituitary; G, gonadotrophic. Are we clear? The table here is going to show us testosterone and a couple of other parameters in which it’s going to move left or right. On the X axis represents age of your male. Let’s first focus upon the green line. That green line represents testosterone. Fetus, let me ask you a few questions embryologically. Are you ready? You can do this. We have testosterone. This testosterone is going to help the fetus obviously turn into a male. Genotypically, everything is great. Normal by the way, normal? Important to pay attention here because I will give you a table coming up in which I’ll walk you through differentials such as androgen and sensitivity syndrome. Then in female, things like Müllerian agenesis will become important. Pay attention. So here, everything is perfectly normal.

    01:13 Testosterone is being properly supplied to the fetus. We have a genotype of XY. The Y, the Y chromosome is going to give the male two things by default, by default. The Y is going to give the fetus, the male fetus the proper gonad. What’s a proper male gonad? Testis, that’s what the Y chromosome is going to give your male. Where is it located? Well whatever. Up in the abdomen and then we talked about the migration. Next, what else is that Y going to give you? Obviously the Y is not going to give you vagina. The Y is not going to give you the uterus. The Y wants to get rid of all that or not or regress, correct? But remember, all of us in the fetus, we were all ladies. We were all unisex.

    02:04 We’re all females. We were born with female or it was really non-specific, non-gender. But the Y chromosome changed everything. The Y chromosome gave you the male and Müllerian inhibiting factor.

    02:21 Someone called this Müllerian inhibiting hormone. Others would call this anti- Müllerian hormone.

    02:28 It’s all the same thing. You’re knocking out the Müllerian. The Müllerian is going to give the female what? The internal or external female structures, good, internal female structures. These include the fallopian tube, the uterus, the cervix, and the upper 2/3 of the vagina. What business does a male have those structures normally? We don’t, right? So therefore, the Y chromosome has given you by default a hormone called anti- Müllerian hormone. This male, the fetal male requires quite a bit of testosterone. There’s going to be an anti- Müllerian hormone in which none of those internal female structures have give rise to.

    03:15 Testosterone, fetus, the first branch of our topic here is going to give rise to what male structures? Internal or external male structures? Internal, internal, what do I mean by internal? The gonad was already given by the Y chromosome. That was the testis. That is not what I’m referring to. But it will give rise to seminiferous tubule, the vas deferens, and the seminal vesicle. That’s your testosterone.

    03:43 Are we done? No. The fetus requires a penis. The male fetus requires a prostate. What’s the name of that hormone? DHT. Do you think I’m giving you too much information? Am I giving you a review of physiology just because I’m trying to show off? No, no, I’m giving this information because when we talk about important tables for us to differentiate between Klinefelter, androgen insensitivity syndrome later on in female with Müllerian agenesis, if you haven’t understand this, it becomes a very challenging learning experience. So make this the most important point of learning, so that when we talked to you about pathologies, I can move through things much, much, much quicker.

    04:28 Testosterone, DHT, make sure you know what that gives rise to. In a male fetus, understand what the Y chromosome is going to give you. That’s the fetus. In the meantime, let’s say that the fetus have been delivered a boy, new-born, neonate child. Let’s move into puberty, shall we? Do you see the spikes in puberty, identify that, the yellow bar? What does that spike refer to? What’s the most effective way for us as an adolescent, or as a male, or as adult in general to release GnRH? Is it pulsatile or constitutive? Pulsatile. Do you notice during puberty, when the male is about to now go through puberty: deepening of the voice, hair-like structure, so on and so forth. That the GnRH is boom, boom, boom, boom, pulsatile, increasing in nature. During this time, you’ll notice please that the green line which represents testosterone, a second spike. How long does a spike rise and how high is testosterone in this male? Just about forevermore. Also, you’ll notice the following that all through adulthood, the testosterone is being increased. It correlates with proper spermatogenesis. Picture this. Your sperm is where? Your sperm is in your seminiferous tubule. It matured where? In the Sertoli cell. What is it that influences spermatogenesis? Oh yeah, the testosterone. You put all that together, you’re in good shape.

    06:05 In the meantime with that testosterone, what kind of feedback does it have on the hypothalamus and the pituitary? Negative feedback. So I want you to compare the testosterone, the green line in adult.

    06:17 Compare that to the blue line, the GnRH. Testosterone is high. GnRH is low. Do you see as to how you’re understanding this graph now? You’re not just sitting there memorizing it because you’ve actually understood physiology. We’re going to plug in pathology. What then happens in senescence? It depends as to when this occurs in males but you’ll find this in your practice. It’s called low-T syndrome.

    06:42 At some point in time, there is really no average age at this point in terms of when this occurs.

    06:48 But you kind of want to think of this as being post-menopausal in a male. So now the testosterone starts declining. Do you see the green line? It’s dropping. It correlates with what? Oh sperm production.

    07:01 Both are dropping. What’s the feedback mechanism? GnRH. Do you see the blue line? You find that to be rising. What do we call this? At this point, when you find that the gonads aren’t working properly, we call this primary hypogonadism. We’ll be dealing with that quite a bit. In fact, with primary hypogonadism, We’ll talk about this as being what’s known as your hypogonadotropic hypogonadism. It might sound a little foreign to you right now. But trust me, all of this, this table, this graph is ridiculously important for us to lay down the precedence and foundation of pathology. Let’s begin by looking at some serious pathologies.

    About the Lecture

    The lecture Hypothalamic–Pituitary–Gonadal (HPG) Axis Differentials by Carlo Raj, MD is from the course Reproductive Hormone Disorders.

    Included Quiz Questions

    1. FSH is under the negative feedback of inhibin and is not affected.
    2. Causes infertility due to Leydig cell atrophy
    3. LH is low
    4. Testosterone is high
    5. Commonly seen in athletes
    1. Inhibin is secreted by Leydig cells.
    2. Inhibin infusion will cause decrease spermatogenesis.
    3. Inhibin infusion will cause decrease FSH.
    4. Inhibin infusion is experimental.
    5. FSH is high in patients with Inhibin Deficiency due to testicular failure.

    Author of lecture Hypothalamic–Pituitary–Gonadal (HPG) Axis Differentials

     Carlo Raj, MD

    Carlo Raj, MD

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