256 ‒ The endocrine system: exploring thyroid, adrenal, and sex hormones | Peter Attia, M.D.

1. 0:00 – 1:02

   Intro

   1. PAPeter Attia0:00

      [whooshing] Hey everyone. I wanted to put together a video that answers a lot of the questions we get about hormones. Now, many of our podcasts cover hormones, and they cover them in really great detail, but a lot of times we kind of skip the basic physiology and frankly, even some of the treatment implications. So the purpose of this video is to cover four hormone systems: the thyroid system, the sex hormone system, both male and female, and the adrenal system. And basically what I'm going to do is talk about how these hormones come about, how they're regulated, what the feedback cycles are, and then talk a little bit about how we treat deficiencies in these hormones. Now, this will all be available in this video, but we're also gonna chop them up and you can, if you're only interested, for example, in female sex hormones, we'll have just a shorter video that covers that. But it will be the exact same content that's shown here. So let's dive in, and I'm gonna start with the thyroid system, if for no other reason than I'm just gonna go head to toe. [whooshing]

2. 1:02 – 15:02

   The thyroid system

   1. PAPeter Attia1:07

      Okay, so let's start with the thyroid system. Um, I've drawn a little bit of a schematic here. It's a bit oversimplified, and it's also at the same time a little bit messy, so I'm gonna try to explain it and hopefully it makes sense. You have, uh, the thyroid gland. This is the thing that sits in front of, uh, your larynx. Uh, you can actually feel the thyroid gland, and, uh, it's shaped as a shield, which is how it gets its name. And the thyroid gland is regulated directly, uh, via a hormone called TSH. So TSH is stimulated from the anterior portion of the pituitary gland, and it tells the thyroid gland to make T4 and T3. And the pituitary gland is regulated upstream by the hypothalamus, which stimulates it via a hormone called TRH. Now, I'll come back to the regulation of these in a moment, but let's just go back to the thyroid gland. So the thyroid gland makes mostly T4 and a little bit of T3. Now, where do the three and the four come from? What are they referring to? Well, they're referring to the number of iodines that are in the molecule. So not surprisingly, T4 has four iodines, T3 has three iodines. What's the difference between them? The difference has to do with their biologic activity. When you think of all the things that the thyroid hormone does, for example, how it keeps you warm, aids in metabolism, uh, controls things like the brittleness of your nails, your hair, uh, bowel function, all sorts of things, all of the thyroid promoting functions are controlled by the active version, which is T3. T4 conversely is the inactive version of the hormone. So if you're paying attention to what I just said, you'll note I just said that basically most of what comes out of the thyroid is T4, which is inactive. Now, it's not entirely clear what the ratio is between these, but it's directionally about four or five to one. I think it's almost just as easy to imagine that virtually everything the thyroid is producing is T4. So if the thyroid's producing T4, which is inactive, it needs to be converted into an active hormone in the body, and that's where these enzymes called deiodinases come in. And as their name suggests, deiodinases remove one of the iodines from T4 to create T3, which is the active hormone. Now the story gets a little bit more complicated because there are different types of deiodinases, but the three most relevant are D1, D2, and D3. So let's talk for a moment about these three deiodinases. D1 and D2 are quite similar in that they both convert T4 into T3. More about that in a moment. It's just where they do it that's slightly different. D1 is extracellular. It's on the cell membrane facing outward, whereas D2 is on the membrane of the endopa- endoplasmic reticulum, and it's facing internal to the cytosol. But put that aside for a moment and just keep in mind that D1 and D2 both convert T4 into the active hormone T3. This is the one that has all of the, you know, positive effects of thyroid hormone. Now, D3 is different in that D3 takes T4 and makes something called reverse T3. Reverse T3 is very similar to T3 except for a very important difference, which is it doesn't activate the receptor that T3 activates. So it occupies the receptor without activating it. So in effect, you can think of reverse T3 as anti-T3. It basically blocks the effects of T3. Now, it sounds like a very bad idea to have reverse T3 floating around, and unfortunately in the modern world it often is. It usually is a sign of inflammation, illness, or things of that nature. But I think that the reason it probably exists is to cope with shortage of nutrients. In other words, when nutrients are scarce, when you need to slow down metabolism, one of the first things that the body does is it increases the production of reverse T3 to block the effects of T3. In fact, one of the things I used to notice when I did frequent fasting, 'cause I would fast for, say, a week at a time, and I would always check my blood pre and post, is how much my thyroid function deteriorated during that period of time. And it wasn't just a deterioration in the usual metrics such as TSH, uh, and T4. It was how much my free T3 and reverse T3 changed. In fact, the ratio of my free T3 to reverse T3 might go from 0.25, which is pretty normal, to 0.05 or less in just a five to seven-day fast. And you know, I would say about half of that was due to the reduction in T3, and the majority of that was due to the increase in reverse T3. So the body is going to regulate these three enzymes in response to various physiologic circumstances, and that's effectively at the cellular level how the body is controlling thyroid function. Now, this creates a bit of a problem when you want to evaluate a patient for their thyroid status, because the traditional way to think about a patient's thyroid status is actually just to look at their TSH. And on the surface, this kind of makes sense because if everything is working perfectly, the TSH should give you the answer. If the TSH is very high, what must be true? Well, there must not be much T3 around because it would be inhibiting TSH. If TSH is very, very low, you would be getting a lot of inhibition from these things. You would be in a hyperthyroid state. But the reality of it is you can sometimes have a normal TSH and still have the symptoms of hypothyroidism. If, for example, you have very high amounts of reverse T3 and very low amounts of T3, in other words, if your T4 is being preferentially shunted into reverse T3 instead of T3, you might feel like you have the symptoms of hypothyroidism. You could be cold, your metabolism might be slow, you'd have difficulty sleeping. If it were really extreme, your nails might even get brittle. You'd be constipated. These sorts of unfortunately nonspecific, uh, symptoms which make it difficult to make such a diagnosis at times. So where does this matter when it comes to how we treat hypothyroidism? And to be clear, hypothyroidism is far more common than hyperthyroidism. I'm not gonna talk about hyperthyroidism. I'm gonna talk about hypo. The standard treatment for hypothyroidism is to give T4. We give a synthetic version of this hormone, the inactive thyroid hormone, and we do that with the knowledge that most patients will convert that T4 via D1 and D2 into T3. The T3 will go on to have all the biologic effects, and it will also suppress TRH and TSH, and the body will come back into line. So for example, if a patient shows up to see you and they have the classic symptoms of hypothyroidism and their TSH is elevated, for example, it's six or seven, you might give them, say, 75 micrograms of T4, and you might expect to come back and see that TSH at two or three and them feeling better. And many times it works out that way, but unfortunately, it doesn't always work out that way. And in fact, what you see sometimes is that you give a patient T4 and they start to feel worse, and sometimes their TSH actually improves. And the reason it improves is T4 does have some inhibition of TSH, not as much as T3, but some. But what if, for physiologic reasons, their D1 and D2 are being down-regulated while their D3 is being up-regulated and they're taking that T4 that you're giving them, and they're just making more and more reverse T3? Now, again, a, a person who's insulin resistant, a person who has low-grade inflammation, these are typically things that we, we might see drive that state. And that patient, even though their TSH improves, doesn't necessarily feel better. And for those patients, it might make more sense to actually give them T3 because if you give T3, you're basically bypassing the system altogether. You're still getting the feedback that's appropriate, but you bypass the step where the body might erroneously turn the T4 into reverse T3. Now, there's a bit of a problem in giving T3 because the, uh, regular version of T3, a drug called Cytomel, is a very difficult drug for patients to tolerate. When I was in training, uh, we would give T3 to patients after we did thyroidectomies on them for thyroid cancer, and patients could rarely tolerate it. Uh, we had to give it to them because we would immediately take all of their thyroid out in one moment, and they needed a big dose of T4 but a hefty dose of T3 to get them over the hump, and oftentimes they would feel pretty lousy from that. Now, since that time, uh, I think T3 has largely fallen out of favor. Not many doctors use Cytomel, uh, which is the, uh, trade name for T3 because it is so rapid in its onset. Instead, uh, people are typically using two other formulations. The first is a compounded control release T3. So it's the exact same hormone, T3, but it's just compounded in a way to be slowly released. This seems to be much more well-tolerated, and the doses can be pushed a little bit higher. A typical dose might be anywhere from 10 to 25 or even 30 micrograms of control release T3, and that seems to last a patient throughout the day. Of course, they have to take this generally in the morning to make sure that it's out of their system by evening, or at least it's reduced in potency. There's another way that patients, uh, often receive T3, and that's in combination with T4 vis-a-vis a formulation known as desiccated thyroid. Now, desiccated thyroid is basically whole thyroid gland, and therefore it contains T4, T3, and even some T2, but we're not gonna talk about that. So the two most common versions of desiccated thyroid are a formulation called Nature-Throid and Armour Thyroid. So if you're watching this video and you're interested in this topic, you've undoubtedly heard of these things. Now, I'm not gonna get into the religious debates about this stuff. There are really competing schools of thought, and there are some people that believe that the only thing that should ever be given to any patient with hypothyroidism is a desiccated formulation. Similarly, there are other people who think all of that desiccated stuff is total crap, and it should never be given, and we should only be giving T4, or we should only be giving T4 with a little bit of T3, or you should only be giving control release T3. I've interacted with people from all of these schools, and all I can say is if you're really interested in treating hypothyroidism, you better know all of them because there are some patients in whom one way works and another way doesn't. I've had patients who came to me on desiccated formulations, and I thought, "You know, I don't really like these desiccated formulations. I'm going to switch them over to T4 plus control release T3," and I could never get them right, and I ultimately end up putting them on desiccated and getting them right. Similarly, I get patients that show up on desiccated, and they sort of feel okay, but they're not quite right, and we get them feeling right in other ways. Now keep in mind, if you're giving desiccated thyroid, and this is kind of the reason why I don't generally like to use it except when it works, uh, you're giving a fixed amount of T4 and T3. You don't get to control it. The ratio is set, and it's something like 1 to 4.2 or something like that, meaning for every unit of T3 you're giving, you're giving 4.2 units or micrograms of T4. And again, for some patients, that's just right, but there are other patients who need more or less of one or the other, and that's why I tend to use T4 and T3 separately. But again, you're here to fix the symptoms more than you're here to fix the numbers, and you'll ultimately end up using whatever works. Finally, a word on half-life. T4 has a very long half-life. It's a matter of days. And for that reason, a patient shouldn't panic if they miss a day of T4. So if they forget their dose of T4, it's okay, just take it the next day and don't double up. Conversely, T3 has a much shorter half-life, and therefore, you do need to stay on top of your T3 when you give it. Now of course, remember, the control release and the immediate release T3 also have very different half-lives, but what I'm referring to is endogenous T3 as well. So there you have it, a pretty hopefully simple overview of the thyroid system. I guess one of the takeaways from this is that it's a little more complicated than you might be led to believe if your doctor is only looking at your TSH. And unfortunately, when you go to the doctor's office, a lot of the times that's the only lab they've ordered. I prefer to order not just the TSH, but the free T4, the free T3, and the reverse T3 if I have any concerns about hypothyroidism. I don't always order this blood test. So if the TSH is normal, the T3, T4 are normal, and the patient is asymptomatic, I'm not looking at their reverse T3. But if a patient has symptoms and you need to investigate them, I think you have to understand all of these. And what you're basically doing is using the amounts of T4 or free T4, T3 or free T3, reverse T3 to impute what the action is of these diod- deiodinases, and therefore, what your treatment strategy needs to be. [air whooshing]

3. 15:02 – 26:57

   The adrenal system

   1. PAPeter Attia15:07

      Okay. Next, we're gonna talk about the adrenal system. Personally, I find this to be the most confusing of the systems. It's also the one for which we can get virtually no information from a blood test. So when you think about the thyroid test, when you think about the sex hormones that we're gonna talk about later, we can get so much information from blood tests. When it comes to this system, we can't get anything from a blood test. So when people, you know, say, "Hey, I just got a blood test and my cortisol level was high, what does that mean?" Or, "My cortisol level was low. What does that mean?" I say, "I don't know. It doesn't mean anything," because what those tests are measuring are total cortisol. And total cortisol, just as we'll talk about when we talk about testosterone, is actually kind of unhelpful because it's all of the cortisol, including that which is bound, and the majority of cortisol is bound to a carrier protein known as cortisol binding protein. It's also bound to albumin and other proteins as well. So we really need to understand how much cortisol is unbound, uh, what's called free cortisol, and it's this free cortisol that exerts its biologic activity. Now, the really two main ways that you can do that, one is through a saliva test, and the other is through a urine test. I prefer the urine test, uh, and we use a test called the Dutch test. We have no affiliation with them. Uh, you can find out anything you want about the, the Dutch test online. You can probably order directly through them. I, I, I don't really know to be honest with you. But, uh, we order these for our patients when we think there's something worth investigating here. We don't do these tests on everybody. [lip smack] The reason we like the Dutch test is, first of all, it is measuring free cortisol. Uh, secondly, it's measuring cortisol metabolites. And cortisol metabolites are very helpful when it comes to understanding what cortisol production looks like. I'll explain that in a moment. Okay. So let's start with the basics. You have two adrenal glands, one on top of each kidney, and the adrenal glands produce cortisol. If you wanna go high enough on the chain, you'll know that this comes as a precursor via cholesterol. So cholesterol is the precursor that ultimately results in cortisol production just as it does androgens. Okay. Go back to what I said a moment ago. If you go and get a blood test for cortisol, all it's doing you is telling you the total amount of this you have in your system, but understanding that most of that is bound to carrier proteins. What we care about is how much of that is free, because it's only the free cortisol that does the important job of a glucocorticoid. [lip smack] So what we do when we take a look at a Dutch test is over time, typically four times over 24 hours, we get a snapshot of how much free cortisol exists, how much free cortisone exists, and equally importantly, how much of their metabolites or breakdown products exist. So alpha tetrahydrocortisol, beta tetrahydrocortisol, and tetrahydrocortisone. Now again, you can't get these from a blood test, and why they're important is because the sum total of these is how I learn what the total adrenal output is. There's a term that you hear thrown around a lot called adrenal fatigue. The suggestion is that if a person feels lousy, it's because their adrenal gland isn't making enough cortisol because it's fatigued, and of course, these people may indeed have low levels of cortisol. They may even have low levels of free cortisol, but doesn't mean their adrenal glands are fatigued. I would say the answer is in most cases probably not. In fact, in most of those patients, if you look at the total metabolized amount of cortisol and cortisone, you would in fact see that they have ample amounts of production. What might be happening is that they are degrading too much of their cortisol and/or turning too much of their cortisol into the inactive cortisone and instead of maybe converting it back, actually just metabolizing it here. So what regulates all of these things? Well, first of all, the regulation of turning cortisol into its metabolites and cortisone into its metabolite is regulated by enzymes called reductases. Again, I think the names of these enzymes are not really that important, but for the, uh, you know, people who really care, five alpha reductase, five beta reductase, five beta reductase. We're gonna talk about these later with sex hormones. Never mind. You basically have some, uh, enzymes that will turn cortisol into these and cortisone into this, and inflammation, obesity, and factors that are generally associated with poor health accelerate that conversion. So if a person is feeling lousy and their free cortisol is low and their free cortisone is low, and yet they have ample amounts of these, you really need to reverse the factors that are driving these things here. You really need to address the obesity, the insulin resistance, the leptin resistance, the underlying inflammation. A far more common problem, frankly, is in people who have very high or very low levels of free cortisol, and they may have symptoms associated with those things, and then you have to look at what's going on with their cortisone. So I always check in my mind these things first. So I always look to make sure adrenal output is appropriate, and as I said, it's virtually always appropriate. Um, the second thing I'm asking is, is the rhythm normal? Meaning, do they have... Do they wake up with a low level of free cortisol? [sighs] So do they wake up about here? Do they have a nice rise a couple hours after waking? Does it fall in the afternoon? And is it down here at bedtime? So that's about what we want to see. Now, if the answer is yes, then we're all done. If the answer is no, and let's assume that the person is really low, so they wake up here, they stay kinda low, they stay kinda low, they stay kinda low, and they're symptomatic, so they say, "Boy, I just can't, I just can't get going during the day," then I ask the question, well, how much cortisone do they have? And they might actually have plenty of cortisone. Uh, well, in that case, what we have to do is flip the way this enzyme's working because there's an enzyme, 11-beta-HSD, that converts cortisol to cortisone and back. But here's what's interesting is the dir- the direction of travel is determined by various things. So cortisone gets converted to cortisol preferentially when you have in- insulin resistance, obesity, inflammation, low thyroid function, leptin resistance. The other direction, cortisol being turned into cortisone, is, uh, facilitated when you have glucocorticoids. So for example, if a patient is taking steroids, understandably the body says, "We don't need any more cortisol. Let's turn it into cortisone." Hyperthyroidism, progesterone, PCOS, and even supplements like curcumin. So, um, what we like to do and what I think is one of the most potent things to do in the patient who doesn't have enough of this, has plenty of this, looks like this, and is symptomatic, is try to address these issues. And frankly, one of the most potent things to do is use something like an adrenal support. So adrenal support is a supplement that's usually made up of a number of things, the most potent of which, by the way, is licorice root. It's actually kind of a funny story, but high enough amounts of licorice will render a person functionally, uh, basically high in cortisol. So, um, I remember a story in medical school of a person that showed up looking like they had Cushing's disease. So Cushing's disease is a con- is a condition of excess cortisol production and nobody could figure out how it was happening until the, uh, nephrologist [lip smack] who was involved in this patient's care noticed that the patient was constantly eating licorice while seeing him. And the nephrologist said, "Hey, by the way, I noticed you're eating licorice. How much of that do you eat?" And he's like, "Oh, you know, about 10 packs a day." And so he was eating like 10 packs of black licorice a day, and he was basically shutting off this system and driving his cortisol through the roof. So you can actually use that to your advantage using licorice root if indeed that's part of the problem. [lip smack] The other thing we tend to look at is are there ways to suppress this system? So let's say you have a person who wakes up here and, um, you know, they shoot up to here, and then they just stay high, and they tell you, "I'm really having a difficult time sleeping." So in those people, I like to use something like phosphatidylserine, which suppresses the, uh, cortisol production in the evening and that actually helps facilitate sleep. In fact, this is something I use for myself if I'm jet lagged or if I need to be doing a big time zone jump. So if I need to go to bed at, say, noon functionally, right? If I'm, you know, putting myself in the time zone of where I'm going and it's nighttime there and it's only noon in my home time zone, but I need to go to sleep on the plane, one of the most important things I'll take is, you know, anywhere from four hundred to six hundred milligrams of phosphatidylserine because what that's doing is dropping the, um, dropping the cortisol. By the way, it's not clear what the mechanism of action is, uh, at least to me it's not. So we- we've looked at this and we- we- we can't quite figure out what the mechanism of action is, but we see the result. [lip smack] So, um, what's the take home here? Okay. The take home here is very difficult, if not impossible, to impute what's going on with adrenal function by looking at a blood test because it's looking at total cortisol, and if that weren't bad enough, it's just one snapshot in time. You really do need to see what's going on in total. Secondly, to- free cortisol and free cortisone by themselves still don't tell you a total picture. You do need to have some sense of what their metabolites are because that's what's actually telling you total adrenal output. Next thing you need to understand is the balance of cortisol and cortisone. How much do they have of each? This is inactive, so we think about this, at least I think about this, as kind of a repository for which I can put excess cortisol if I don't need it, if not down here, and where I can draw cortisol if I do need it. Remember, these are one-way streets, so once you go down to here, you're not reversing those, you're just slowing those enzymes. But here we can go back and forth between the two. Okay. I hope you can probably see why I find this to be the most complicated system out there, and in large part it's complicated because when a person has low free cortisol and they're symptomatic, you really do not want to give them hydrocortisone or prednisone or any glucocorticoid replacement. You would only reserve such treatment for a person who's truly in distress. And obviously, if a person has an Addisonian crisis, which is what happens when the adrenal gland completely shuts down, and of course, that is absolutely something that can happen. That happens in the face of an overwhelming infection, for example. By all means, those people need glucocorticoids or they will die. But for the average person who's walking around kind of dragging, feeling like blah, and indeed they have low free cortisol, I certainly wouldn't favor using glucocorticoids as a treatment for that. Instead, what you favor are addressing the underlying issues that are either extracting cortisol into its metabolites or turning cortisol into cortisone. And the problem is there are very few pills that fix that. A lot of that comes down to this word we all hate, lifestyle management. But unfortunately, that is the key. Again, licorice root's probably one of the best things you can use there, and of course, in the flip side, you can use other sort of adrenal supports as well. Anyway, hope that's helpful. [air whooshing]

4. 26:57 – 40:21

   The female sex hormone system

   1. PAPeter Attia27:01

      Okay, so the next system we're gonna talk about is the female reproductive system. Now, this looks pretty complicated, but let me tell you why I'm gonna make it less complicated. Uh, I think to understand female sex hormones, the easiest way to do it is to understand it during the reproductive cycle. In other words, to understand what's happening, uh, with women's sex hormones during her menstrual, uh, cycle and during her reproductive years. So this looks a heck of a lot more simple when you look at it in a woman who's outside of menopause, but let's start with this. Okay. So the first thing is, for the sake of simplicity, I'm going to assume a 28-day cycle. I realize, of course, that is not always the case. There are some women who might have a slightly shorter cycle or a longer cycle. But for the purpose of illustration, let's assume a 28-day cycle, which is about where most women are. The cycle is divided into two phases. Technically three, because there's a menstrual phase here, but let's just ig- acknowledge that the menstrual phase which starts at day zero, that's the first day of bleeding, even if it's just spotting and it's not a heavy period, that's day zero. That's the shedding of the endometrial lining, which we'll talk about. Then you move into a follicular phase, and the purpose of that phase, which is really driven by follicle-stimulating hormone and estrogen, is to ripen the follicle for ovulation. Ovulation takes place mid-cycle. After ovulation, we move into the luteal phase. The luteal phase is dominated by luteinizing hormone and progesterone, and the purpose of the luteal phase is to prepare the endometrial lining for implantation. Of course, this is something that doesn't occur most of the time. That only occurs during pregnancy, and therefore, when the body realizes, "Hey, we're not pregnant," the endometrial lining gets shed, and that's what results in this crashing progesterone level, and that is the shedding of the lining is, of course, what is the period, which brings us back to here and the cycle begins again. So let's talk about how these things work from the beginning. So follicle-stimulating hormone, along with luteinizing hormone, are secreted from the pituitary gland, the same place that makes TSH, uh, that we talked about in the thyroid system. And again, the purpose of follicle-stimulating hormone is to get the follicle ready for ovulation. So the follicular phase is really dominated by estrogen and FSH. And of course, the purpose of this is to prepare the body for ovulation. Now, we're very particular about when we like to do a blood test here, especially when a woman is approaching a perimenopausal state. So as a woman is getting closer and closer to menopause, we will really be, uh, monitoring the level of FSH and estradiol in about day three, four, or five. And the, kind of the canary in the coal mine as a woman is getting close to menopause from a biochemical standpoint is a rising FSH during that phase. So FSH should normally be very low during day three, four, five, which is usually when a woman is still in her period. If FSH starts to climb, especially if estradiol is low, you can be pretty sure that she's heading towards menopause. In fact, menopause is, you know, chemically, uh, demonstrated by a high FSH, typically north of twenty-five, thirty-five, 40, and low estradiol. In fact, a woman who's been in menopause for many years, uh, would easily have an FSH level of 50 or higher and unmeasurable levels of estradiol. So again, back to this situation here. FSH is rising. It has a little bit of a peak just before ovulation. Estrogen really rises now, so peak estradiol occurs right at or just before ovulation. The follicle comes out, and away it goes to see if indeed, uh, it's going to be, uh, met with a sperm, and if so, is it going to attach to the endometrium, et cetera. Now, the- This is where we enter the second half of the phase, the luteal phase. This is dominated by luteinizing hormone. So the purpose of luteinizing hormone is to prepare the endometrium for this implantation. Now, what I haven't drawn here, because it's just too complicated, is, um, what the thickness is of the endometrial lining as we go from here to here. So of course, just as a woman is finishing her period, so call it about here, the endometrium is at its thinnest, right? You've just shed that lining. And it's slowly, slowly, slowly building up. And of course, at about day 14, it really starts to build up that lining because it's preparing, again, for that implantation. Progesterone is rising, again rising, and by about day 21, when progesterone peaks, the body figures out if it's pregnant or not. And again, in most cases, it's not. And so because it's not pregnant, it begins to rapidly drop that progesterone level. Estrogen has also risen for a second peak. So this is the absolute peak of estrogen, but this is a second peak. And both of these hormones come crashing down, and the body begins to shed that endometrium at the end of that cycle. So there are a bunch of things I think I want to say about this. Um, the first is that, um, you know, any point in time when you get a blood draw on a woman and you are looking at FSH, LH, estradiol, and progesterone, you have to sort of know where you are. Now, once you do a lot of this, you're pretty good at guessing. So it's not rocket science when you're drawing a woman's levels and you see that she has a sky-high luteinizing hormone and estradiol to figure out that you probably drew the blood right around the time that she was ovulating. But in cases where it gets a little bit more complicated, when women's periods are irregular, when they're becoming appro-- when they're approaching perimenopause, it helps to have some sense of what's going on. And of course, in the case where a woman is not menstruating at all, it tends to be pretty easy because you're going to see very high levels of FSH or LH. Now, it becomes more complicated when a woman has an IUD, and as a result of that, she's not menstruating, but I'm not going to get into those complex situations right now. I just kind of want to go over the basics of the hormone system. The second thing I want to point out, and this point has been made in my podcast before, but I think if you're only coming to this now, it's worth understanding. Um, for many women, what's happening between, between day 21 and day 28 is really profound physiologically. So I, you know, we talk about this thing called PMS, and I think any woman who's experienced it knows it's a real thing. I certainly can't say I've experienced it, but I've spoken to enough women who have that, um, I have a real sense of why it's probably happening. Now, it's not entirely clear if it's the drop in progesterone that's driving this, but it likely is. Uh, I don't know how well this has been investigated, but we certainly suspect that there are central, uh, receptors for progesterone, and that in a susceptible woman, when progesterone levels are withdrawn so quickly, that can easily result in mood alterations. So for women who do experience significant, uh, and unwanted side effects of progesterone withdrawal, known as, you know, PMS, a very simple and effective way to treat it is with a low dose of progesterone that is administered starting at day 21 to 28. So how does that work? So again, if a woman has, has a fairly regular cycle, she'll know when she ovulates, and she'll know about a week after ovulation to take a low dose of progesterone. Typically, this is done at about 50 milligrams orally. That's just taken for seven days until she has her period. And what it does is it completely blunts this effect. So this effect is still happening, but her total levels of progesterone are not nearly as dramatic in the reduction, and this tends to ameliorate symptoms. So what's the drawback of that approach? Well, from a physiologic perspective, none. The biggest drawback is just the logistics of having to remember that seven days out of every 28, you have to take progesterone. This is an entirely safe thing to do, and I've used this with a number of women in the past. It seems to work very well. Uh, alternatively, women can stretch that out and take progesterone for the entire 14 days following their follicular, uh, pardon me, following their ovulation. And of course, they can take oral contraceptives throughout. But again, now that's creating a whole new set of issues around oral contraceptives, uh, which many women simply don't want to do. So I just point that out to say, one, um, I think when you look at a graph like this, hopefully you get an appreciation for what a profound level of, uh, withdrawal a woman is experiencing during the end of the luteal phase. And secondly, that there are lots of hormonal ways to address that. Now, the other hormone I haven't drawn on here is testosterone. I haven't drawn it for two reasons. The first is it doesn't change that much during the cycle. It changes a little bit. Um, I've read a number of different studies that have looked at it. Most of them suggest a peak testosterone about here when you have peak estradiol, but the fluctuation is so minor that I don't think it adds any value to this. Secondly, if I were to draw testosterone to scale on this graph, you'd have to look at the ceiling. That's how much more testosterone a woman has in her body than estrogen. Yes, I just said that. It sounds very counterintuitive, but it's true. A woman has, even at peak estradiol level, which is during ovulation, a woman has five to 10 times more testosterone in her body than she does estradiol. It's just that it's not changing all that much. It is unfortunately going away when she enters menopause, which is what I want to talk about next. So as a woman leaves her reproductive years, what's happening? Well, her body is less able to make estradiol and progesterone. And as estradiol and progesterone production go down, just as testosterone production goes down in a male, although it happens far less abruptly The pituitary gland senses this because there's a negative feedback loop, and it says, "I want more." So it starts making more FSH and more LH. And of course, the higher those go, at s- initially, the body responds, and you'll see a period where the cycle does continue. Sometimes it spreads out, it gets a little bit longer, but the body is able to compensate until, of course, it isn't. So when a woman is in menopause, what you'll see is no estrogen, no progesterone, very high LH, very high FSH. And so when we initiate hormone replacement therapy, and by the way, we never wanna wait until a woman is in that state where she has flatline estradiol, flatline progesterone, sky-high FSH, sky-high LH. We wanna do it long before that. We wanna do it as she's transitioning from this into that, and that could be literally a year or two years prior to that state. And what we're doing is we're giving her enough estradiol that her FSH usually ends up hovering around twenty to thirty. Again, that's still a pretty high level of FSH, um, meaning that's still got the brain thinking, "I want more estradiol," but you don't need to give maximum amounts of estradiol. We're simply trying to, um, control the vasomotor symptoms, so the hot flashes, the night sweats, the vaginal symptoms, atrophy, dryness, and perhaps most importantly, cardiovascular risk factors and, uh, bone risk factors. So e- estrogen being the most important hormone both in men and women as it regulates, uh, sending the signal of b- uh, tension on the bone into bone building via osteoblasts. So in summary, that's the look at the female endocrine system. Again, it's much more complicated than the male endocrine system, uh, sex endocrine system because of both the cyclic nature of it and the abruptness with which it goes away. Um, but again, I think it's something that everyone needs to understand because if you're a woman, you should understand this, and frankly, if you know a woman and you care about a woman, you should understand this. And it certainly would hopefully give empathy to, um, women who are struggling during that last portion of their luteal phase. Again, uh, men don't have an equivalent of this. We don't have a scenario whereby we're having a tenfold reduction in a major sex hormone that occurs over the course of a week. Uh, so I think it's understandable why that can pose issues for some women. So in summary, I think you can see that the female sex hormones are a little bit more complicated than what you're going to see in a moment, which is the male equivalent. Um, but I think it's also actually a more interesting system. Um, by understanding how this works, you have a sense of whether a woman is typically getting closer to menopause, which is generally one of our considerations as we're looking at these hormone levels. And as a woman is entering that perimenopausal period, you wanna be especially attentive to the time in which you draw. Again, day three, four, five become the most important blood draws as a woman is becoming perimenopausal because it's that FSH level at day three, four, and five that becomes your canary in the coal mine. If that level starts creeping up and it's over ten, eleven, twelve, even though she's not in menopause, I'm going to tell her she's probably getting close, and that's when we start to have our discussion about what hormone replacement therapy looks like. [whooshing sound]

5. 40:21 – 57:35

   The male sex hormone system

   1. PAPeter Attia40:25

      Okay, this brings us to the final, uh, hormone system we'll talk about today, which is the male sex hormone system. [smacks lips] Um, this system I think is a little bit simpler than the female system, but it still has its nuances. So let's kinda go back to a very similar pattern we saw with the thyroid system, which is upstream regulation at the hypothalamus, vis-à-vis GnRH, gonadotropin-releasing hormone, that tells the pituitary to secrete LH and FSH. Again, if you just watched me go over the female system, you'll realize we have the exact same thing happening there. I just didn't draw all of this because we had so many other complicated things to talk about. So [smacks lips] luteinizing hormone and follicle-stimulating hormone are speaking to the testes, and yes, I realize as I drew this, I didn't need to draw two of them. That was a bit gratuitous. Uh, but nevertheless, the testes have different cells in them, uh, Sertoli cells and lading, Leydig cells. The testes make testosterone. Now, there's a little more complexity to this that I will come back to in a moment, [smacks lips] but let's just start with the fact that the testes are making testosterone. We should also point out that testosterone is mostly bound. So just as I discussed with cortisol, most cortisol is bound, so is most testosterone. It's primarily bound to two hormones, sex hormone binding globulin, or SHBG, and albumin. But a relatively small amount, and it depends on how much albumin and SHBG you have, remains free. So we call that free or unbound testosterone, and it's anywhere from one to three percent of the total testosterone. Now, there are two things that are siphoning testosterone away that are very important. The first is 5-alpha reductase, which is the same enzyme we talked about back when we were going over cortisol. It's siphoning off some of that testosterone, uh, to make dihydrotestosterone. Now, not huge amounts, sort of, you know, a couple of percent, but dihydrotestosterone is a very important sex hormone. In fact, it has anywhere from two to ten, some studies would suggest even higher, uh, potency, two to ten X potency for the androgen receptor than testosterone. So I'm gonna talk about the androgen receptor in a minute, but I just want you to keep in mind that DHT has a much higher binding affinity for the androgen receptor than testosterone does. The other thing that is siphoning off testosterone is the aromatase enzymes that are converting testosterone into estradiol. Yes, that's the very same estrogen that women have as well. And estrogen turns out to be a very important hormone for men. I think this is something that hasn't been always appreciated, uh, but we now understand that, of course, estrogen is important in the male for mood, for body composition. for bone mineral density. So, um, I'll talk about this in a moment, but things that suppress estrogen have to be considered judiciously because of the negative side effects of having low estrogen. Okay. Not surprisingly, there is a feedback loop. So the feedback loop works, uh, as follows. Testosterone levels, as they rise, will inhibit both the hypothalamus and the pituitary, which slows down GnRH and LH and FSH. This is actually much more complicated than I've drawn it here, and I realize that there's gonna be some purist out there who says, "Oh my God, you forgot to mention this." Yeah, so it turns out that the hypothalamus does not have an overwhelming number of androgen receptors. So this is not happening directly, but rather indirectly. So testosterone is inhibiting a slightly different neuron that is then speaking to the hypothalamus. But I think for the purpose of this discussion, this is sufficient. The other thing to point out is that estrogen also inhibits luteinizing hormone secretion via the pituitary. So this becomes really important when we talk about, uh, certain drugs that are used to replace testosterone or to increase testosterone. Okay, so let's just summarize what we've learned so far. In the normal functioning system, GnRH tells the pituitary to make LH and FSH. They tell the testes to make testosterone. Small amounts of that are siphoned off to make DHT, and even smaller amounts, i.e., less than 1%, are siphoned off to make estrogen, and the system is in perfect balance. Now, how much of that testosterone is actually exerting its biologic effect on the androgen receptor? Well, it turns out very little is, because as I said, you have this thing over here, SHBG plus albumin, and it's soaking up most of the testosterone so that really the free testosterone, which is the biologically active, represents only about 1 to 3% of total testosterone. But the good news is that's all you need. This stuff's pretty darn potent. So testosterone binds to an androgen receptor. DHT also binds to an androgen receptor. It just does so in a way more potent fashion. And this happens inside the nucleus of a cell, and that's what affects transcription. Okay. Now we're gonna talk about a subject that is way more complicated than I think it's being led, uh, than people are being led to believe it is, and that's testosterone replacement therapy. It's not as simple as looking at the total testosterone or even the free testosterone and determining if a person has low testosterone or low T. And the reason for that is when you are measuring total testosterone, you don't really know what the free T is. The free T is a calculated lab value, so they don't really measure free T by most lab assays. They measure tost- total testosterone, they measure SHBG and albumin, and they calculate free T. But let's assume that the calculation is fairly accurate, and even if you don't rely on a lab to do that calculation, there are calculators online that can do that for you. So let's say you now know the free T, and we'll talk about what some ranges are in a moment. The question becomes, is the patient's low level, because let's just say they're at the 30th percentile, uh, for what their level is, does that explain their symptoms? Well, it's not entirely clear because what we don't know is what's happening here. So we don't know how many androgen receptors a person has, and therefore, we don't know how saturated their androgen receptors are with either testosterone or dihydrotestosterone. So we have to sometimes treat these things empirically, meaning we're treating symptoms, but we're using numbers as a guide to do so. So the most common symptoms of actual low testosterone, of androgen deficiency, in no particular order, 'cause they're gonna vary significantly by men, would be low libido, erectile dysfunction, low mood, difficulty putting on muscle mass, and insulin resistance. Tho- those are the big ones that I see. Now, there are, there are others to be sure, but those are really the big ones. And we know from clinical trials that when you give a group of insulin-resistant men testosterone, their insulin resistance improves. We know that if you give men testosterone and you provide them with a training stimulus, muscle mass increases, strength increases, body composition improves, which means adipose tissue goes down. We know that mood improves. We know that a whole bunch of factors move in the right direction. But despite all of that, I'm still pretty cautious when giving testosterone because I think it is an overused hormone. I think too many people are being given testosterone, and they probably don't need it because they're just being treated on their total testosterone level without necessarily considering these other factors, such as free testosterone, and of course, without understanding these things, which none of us can outside of a lab. So we have to really treat based on symptoms. Now, what are the treatment options? Um, there are, broadly speaking, two ways to think about this. The first is a direct way to do it, which is giving testosterone, and this can be done in many formats. Uh, the most common formats would be topical testosterone or injectable testosterone, but there's also an intranasal formulation. There are pellets that can provide sort of a slow release over a period of months. And then there are indirect ways to give testosterone, which are basically tricks that mimic these hormones. So, uh, the first of these is something called HCG, and HCG is a mimetic of luteinizing hormone. So an injection of HCG will tell the body to make testosterone just as you were giving luteinizing hormone. There is also a, um, synthetic FSH. It's far more expensive, and it's virtually never used. So the typical use case for synthetic FSH is in men who have been on testosterone replacement therapy for many years, who have now lost the ability to make testosterone. Because if you are given enough exogenous testosterone, you will shut down the capacity to make testosterone in very short order, and within a year, two years, you will permanently lose that ability, w- minus some Herculean doses of synthetic LH and synthetic FSH. So we should make sure we never lose sight of that. The other way to do this is to gl- give a drug that has become very popular called Clomid. Clomid, or clomiphene, is a drug that has been used historically by women using it for fertility purposes. Um, and what Clomid is doing is effectively tricking the brain via, uh, stimulation of GnRH by blocking the estrogen receptor, um, to make more LH and FSH. Now, the reason I'm not a fan of Clomid, there are several reasons, but one of the most important reasons is that it blocks the effect of estrogen in the brain, and that turns out to be a negative thing. Turns out we want the feedback of estrogen in the brain because it has many beneficial effects for mood. And there are some men who actually, when they're on Clomid, even though their testosterone levels soar, don't feel any better. We wonder if, in fact, that's because of Clomid. So not every man. There are some men that are on Clomid that feel great on it, but there are some who don't. Alternatively, you give testosterone, and when you give testosterone, you have to be mindful of the fact that your LH and FSH are going to go to zero because your body is going to stop making testosterone. This is a very potent feedback loop. When you give testosterone, these hormones will go up. Now, they go up depending on a number of factors. 5-alpha reductase has quite a strong genetic component, so some men are very strong 5-alpha reductase producers, and they're going to make a lot of DHT. By the way, this is responsible for one of the side effects of testosterone, which is hair loss. So a lot of hair loss is driven by DHT and the androgen receptor. And therefore, if you're susceptible to that and you give 5- if you give testosterone and you make more DHT, you're gonna accelerate hair loss. Similarly, aromatase activity varies genetically, but it also varies by factors such as insulin resistance, obesity, and factors like that. And therefore, the more adipose tissue you have, typically the more aromatase you have. So a person who's overweight is going to make more estradiol, all things equal, from a given amount of testosterone than a person who is lean. Are there side effects of having too much estradiol? Yes, there are. At some point, estradiol levels can become counterproductive. And of course, if they get very high, although I've never seen a case of this in 10 years of prescribing testosterone, um, we can see gynecomastia. So that's when a man will develop breast tissue. Again, these are typically things that are only seen in people who are using excessive amounts of testosterone, usually not under the care of a doctor, unfortunately. But if estradiol levels do get a little too high, they can be managed with a drug that blocks that conversion. The drug is known as anastrozole. Again, I personally am not a big fan of using it because I find you really don't need to use it in most men. In fact, it's nice to have the estradiol levels go up because you want it for bone health, you want it for mood, you want it for all of those other reasons. So we will typically not use anastrozole unless the estradiol level is in excess of 50, 55, or even 60, unless we are seeing symptoms that we would attribute to that. My general philosophy on testosterone replacement is that there has to be a biochemical case for it, i.e. free testosterone needs to be relatively low, at least below the 50th percentile, and there needs to be, more importantly, a symptomatic case for it. If both of those conditions are met, and of course the patient understands the risks and benefits, we would give TRT for a period of eight to 12 weeks. We would determine that we've fixed the biochemical issue, so they go from being at, say, the 30th percentile to being at the 80th percentile, and then we assess the symptoms. And sometimes the man says, "I don't feel any better." So you've fixed the number, but you haven't fixed the symptoms. And with very few exceptions, at that point I would say, "It doesn't make sense to continue this. We should stop doing it." Now, one exception to that would be if you were doing it for bone health. So if a man has osteopenia and he has low estradiol and low testosterone, we don't really care about symptoms at that point. We want his testosterone high, we want his estradiol high, because those are gonna be two of the most important steps we can take in combination with heavy training to increase or at minimum maintain his bone mineral density. But for most men, we care about the symptoms more than we care about the numbers. And if we don't fix the symptoms, we don't- we take it off, and we also watch, "Hey, do your symptoms get worse when we remove the testosterone?" Oftentimes they don't. And again, I can't answer what's going on there. I suspect that these might be men who have either low amounts of estrogen receptors, or their estrogen receptors are just highly saturated with the little bit of testosterone that they have in the first place. All right, so there you have it. That's, uh, sort of the quick overview of the male sex hormone system. Again, I think this system has its own nuances and complexities vis-a-vis how to make the diagnosis and then, of course, how to treat it. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the price of the subscription. Now, to that end, membership benefits include a bunch of things. One, totally kickass comprehensive podcast show notes that detail every topic, paper, person, thing we discuss on each episode. The word on the street is nobody's show notes rival these. Monthly AMA episodes or ask me anything episodes, hearing these episodes completely. Access to our private podcast feed that allows you to hear everything without having to listen to spiels like this. 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Episode duration: 57:35