Video: Testosterone production, action, and symptoms of hypogonadism

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Nelson Vergel


Testosterone production, action, and clinical manifestations of testosterone deficiency.

In the male body, the hypothalamus secretes gonadotropin-releasing hormone, or GNRH in a pulsatile fashion to stimulate the release of follicle-stimulating hormone, or FSH and luteinizing hormone or LH from the pituitary gland. LH travels in the bloodstream to the leydig cells of the testes, where it binds to the LH receptor and initiates a series of biochemical events that convert low-density lipoprotein or LDL cholesterol to testosterone. Testosterone secreted from the testes is carried by the bloodstream to target tissues where it produces its biological effects.

Failure of the testes to make physiological levels of testosterone is called hypogonadism. Hypogonadism due to abnormalities of the testes themselves is called primary hypogonadism, whereas a defect in the hypothalamic pituitary axis is termed secondary hypogonadism. Dual or mixed forms can also occur. If an insufficient amount of testosterone reaches the target tissues, manifestations of testosterone deficiency may appear in liver, muscle and adipose tissue. Testosterone binds directly to the androgen receptor. In the liver, testosterone enhances protein synthesis while in muscle, testosterone enhances muscle mass. Given its role in muscle, men with reduced levels of testosterone may complain of muscle weakness, lethargy or decreased energy.

In other tissues, testosterone must first undergo conversion before becoming biologically active. In the brain and bone, testosterone is converted by aromatization to estradiol, which then binds the estrogen receptor. Testosterone enhances bone development by promoting bone accretion. Men with reduced testosterone levels may develop osteoporosis. Testosterone acts in the brain to stabilize mood, enhance libido and may even have a positive effect on cognition. As a result, men with testosterone deficiency can experience mood changes, a lack of motivation, and reduced libido. To bind to the androgen receptor on skin, hair, gonadal and prostate tissues, testosterone is converted by 5-ᾳ-reductase to dihydrotestosterone, or DHT. Testosterone supports the growth of facial, body, axillary and pubic hair in the adult.

However, in some genetically susceptible men, testosterone may also inhibit hair growth in some areas of the scalp, leading to baldness. In the sexual organs, testosterone contributes to penile growth, spermatogenesis and prostate growth and function. Profound hypogonadism interferes with the vascular function of the penis, or corpora, and may lead to erectile dysfunction, and a decrease in orgasm quality. Other effects of testosterone include promotion of erythropoiesis and regulation of immune function. In summary, testosterone production plays a key role in many body tissues and testosterone deficiency can result in a myriad of clinical manifestations.
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Let's meet testosterone. We produce chemical signals in our bodies that allow one part of our body to communicate with other parts of our bodies, and these signals are called hormones. Testosterone is one of these hormones.

Testosterone is produced by our testes here, so let me draw a zoomed in view of one testis. After the testes make testosterone in cells that they have called Leydig cells, that testosterone is transported to other parts of the body via the bloodstream. I'm drawing red blood cells in red and I'll show you the little molecules of testosterone in green. These blood vessels carry testosterone all over the body so that it can carry out all of its biological functions.

Let me just point out that testosterone isn't only produced in men. It's actually produced in men and women, but males past the age of puberty, about 12 or 13 years old, have about seven or eight times the testosterone that women of the same age as them do. We still refer to it as the primary male sex hormone. To clarify, I'm just calling it a sex hormone because it's produced primarily by some of the male sexual organs, i.e. the testes.

I've told you that it's made in the testes and that it travels around in the blood vessels to every part of the body, but once it gets to its target, what exactly happens? How does it work? To show you this, I'll blow up a little cell here in the thigh. Here you have a cell, and up here, lining the cell or just beside the cell, you have that bloodstream that testosterone is floating around in. I'll draw back in those red blood cells. Let's just say the blood is going that way. Here's our testosterone.

When testosterone sees a cell that it wants to enter, it crosses through the cell membrane, which is sort of the cell's barrier to things outside the cell, almost like a selectively permeable gate. Then once the testosterone gets inside the cell, it sort of meets this carrier protein, and the carrier protein is something that will bind the testosterone and take it to its next destination within the cell. We'll draw that carrier protein as a taxi.

You have testosterone sitting right here in the backseat of the taxi, and then that carrier protein just drives it a little short way to something called the nucleus. The nucleus contains our DNA, and those are the blueprints of how we're made. In red, I drew a specific part of our DNA called a gene, and our DNA is made up of millions of genes. Genes are little segments of the DNA and some hormones interact with our genes to change our characteristics. That's exactly what testosterone does. It jumps out of the cab once it gets into the nucleus and it sort of binds onto that gene. I'll just label that that's a gene.

When testosterone binds the gene, it's able to influence its function. For example, if the gene told the body to make more muscle, then testosterone interacting with that gene would increase the rate of muscle production. In fact, that is one of testosterone's functions, and we'll touch on that a little bit later.

One more note on this topic. Depending on the type of cell that testosterone enters, it can be converted into a different hormone before going to the nucleus to interact with a gene, so the two possibilities are dihydrotestosterone, or DHT, and estrogen. That may sound a little counterintuitive because I think most people think of estrogen as a female-only hormone, but actually, males need estrogen as well and we have a little bit of it. It comes from testosterone. Even in the female, testosterone is converted to estrogen and that's how estrogen is made. It just happens a lot more often in the female. Having said that, in men, only about 7% of testosterone is converted to DHT, and less than 1% is converted to estrogen, so it's primarily testosterone that's exerting all of the hormonal effects.

You're probably wondering what some of the roles of testosterone are, so let's cover those. Testosterone actually starts working when you're really young, when you're still in development in your mother's womb, and what it does there is it induces your reproductive organs to differentiate into male reproductive organs. When males and females start out in development in the womb, they have the same precursor reproductive structures, so the presence of testosterone actually pushes the reproductive organs to turn into masculine ones.

Another really important thing testosterone does ... Remember how we said that testosterone is made in the Leydig cells here, and the Leydig cells are one of the cells in the testes? When testosterone starts to be released in higher quantities from those Leydig cells once you hit puberty, around age 12 or 13, that testosterone signals other cells in the testes to start the process of making sperm, a process called spermatogenesis. After sperm productions starts, having a baseline level of testosterone in the testes keeps sperm production going.

These are the major functions that testosterone has on the male reproductive tract, but testosterone actually has a lot of other functions around the body. It's responsible for what we call secondary sex characteristics. These are just physical traits that we typically think of of being masculine or feminine. For example, it stimulates the growth of facial hair, armpit hair, pubic hair, and hair on your arms and legs, and your chest, just to name a few areas. It's also responsible for the deepening of your voice that happens as you develop as a male, and that happens because testosterone induces growth of the voice box, or the larynx, and some people know that as the Adam's Apple. That's why you see a prominent sort of bulge in the throats of males.

Another thing it does is it induces male pattern fat distribution. That's sort of fat distribution around the central part of the body. It also has some structural effects on our bodies. It stimulates the process of anabolism, and what that means is taking smaller components in our bodies, like proteins, and building them up to bigger components or aggregates of those components, like muscles. Muscles are basically a big aggregate of proteins. That eg just means for example. Testosterone also stimulates bone growth, so it will make your bones bigger in diameter and longer, but it also stimulates the termination of bone growth once your bones can't grow anymore.

Those are the major secondary sex characteristics that testosterone stimulates. It effects your behavior, increasing your sex drive, and has been thought to possibly cause higher levels of aggression. Testosterone can increase the number of red blood cells that we have, and it does that by stimulating our kidneys to produce another type of hormone called erythropoietin, or EPO. EPO's role is to cause the creation of more red blood cells.

That all sounds pretty awesome, right? Except for maybe the possible link to aggression. It turns out there's a limit to the testosterone that you want floating around in your blood at any given time. If you have too much, bad things can start to happen. It's been theorized that the prostate has cells that are stimulated by DHT, or dihydrotestosterone. Do you remember that metabolite of testosterone we talked about earlier? The idea is that they grow bigger when there's too much DHT around and increase the risk of developing prostate cancer. The jury is still out on that one though.

One thing we do know is that male pattern baldness, that is, baldness on the top of the scalp, is actually promoted by excess DHT in the blood. This tells us that we don't want too little or too much testosterone traveling around in our blood and affecting our cells. How do we control how much testosterone is in our body?

It turns out that testosterone, to a large extent, self-regulates how much is produced, but how can it do that? It actually does that through something called a feedback loop. This concept of a feedback loop is by far how most hormones work. Again, a feedback loop is a method of self-regulation. An example of a feedback loop would be something like a thermostat. Let's say you set the temperature in your room to a nice 25 degrees celsius. Let's say it's 20 degrees in the room now. The thermostat will sense the temperature of the current air in the room and heat the room another five degrees until it gets to 25 degrees, and once it sensed that 25 degrees has been reached, it will turn off the thermostat.

Testosterone in the body is regulated in a similar way. There's a part of the brain called the hypothalamus that acts similar to that thermostat. It's actually sometimes referred to as the body's thermostat because it regulates most of our feedback loops, and the testosterone feedback loop is one of them. The hypothalamus will sense the amount of testosterone that's floating through your blood. If it's not enough testosterone, the hypothalamus will send a signal to another gland in the brain called the anterior pituitary, and that actually just sits right underneath the hypothalamus, and then the anterior pituitary sends more hormones to the testes that increases their testosterone production.

Conversely, if there's too much testosterone in the blood, the hypothalamus will sense that and it'll stop sending signals to the anterior pituitary, and then the anterior pituitary will stop sending signals to the testes. When that happens, you actually get a decrease in testosterone. Overall, this negative feedback loop is used to control the amount of testosterone in the blood. That control of blood testosterone levels is actually referred to as testosterone homeostasis, homeostasis meaning to remain constant.
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