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

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.760 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.780 here's today's episode. Welcome to a special episode of the drive. In many of our previous

00:00:54.760 podcasts, and as we'll see in upcoming episodes, we have spoken about and will speak about various

00:01:00.120 hormones. And while in these conversations, we can get into some of the details, a lot of times

00:01:05.240 we skip some of the basic biology and treatment implications around these hormones. As such,

00:01:10.640 I wanted to do an episode that answers a lot of these questions we get around the various hormones.

00:01:15.540 When thinking about the best way to do this, I reflect back on how I used to do this in pre-COVID

00:01:20.160 days. I always used a whiteboard or a piece of paper, and I would draw sketches of the systems.

00:01:26.420 As such, I've recorded a video series here where I go about these various endocrine systems,

00:01:32.720 the thyroid system, the adrenal system, and the sex hormone system for both men and women. In these

00:01:38.520 videos, I'll talk about how these hormones are regulated, what their feedback cycles are, and then

00:01:43.240 talk a little bit about how we treat deficiencies of these hormones. So while we will be releasing this

00:01:48.820 episode in audio format, with all the videos combined into one audio, I really can't recommend

00:01:54.780 highly enough that if you find this topic interesting, you really will need to watch the

00:01:59.080 videos. Watching these videos instead will provide much more understanding around the topics that we're

00:02:04.440 going to cover, and of course, as the cliche goes, a picture says a thousand words. So without further

00:02:10.080 delay, I hope you enjoy this special episode of The Drive.

00:02:18.040 So let's start with the thyroid system. I've drawn a little bit of a schematic here. It's a bit

00:02:23.660 oversimplified, and it's also at the same time a little bit messy, so I'm going to try to explain it,

00:02:27.000 and hopefully it makes sense. You have the thyroid gland. This is the thing that sits in front of

00:02:32.820 your larynx. You can actually feel the thyroid gland, and it's shaped as a shield, which is how it gets its

00:02:39.540 name, and the thyroid gland is regulated directly via a hormone called TSH. So TSH is stimulated from

00:02:46.820 the anterior portion of the pituitary gland, and it tells the thyroid gland to make T4 and T3, and the

00:02:54.800 pituitary gland is regulated upstream by the hypothalamus, which stimulates it via a hormone called

00:03:01.080 TRH. Now, I'll come back to the regulation of these in a moment, but let's just go back to the thyroid

00:03:05.500 gland. So the thyroid gland makes mostly T4 and a little bit of T3. Now, where do the three and the

00:03:12.820 four come from? What are they referring to? Well, they're referring to the number of iodines that are

00:03:17.580 in the molecule. So not surprisingly, T4 has four iodines. T3 has three iodines. What's the difference

00:03:25.040 between them? The difference has to do with their biologic activity. When you think of all the things that

00:03:30.500 the thyroid hormone does, for example, how it keeps you warm, aids in metabolism, controls things like

00:03:37.160 the brittleness of your nails, your hair, bowel function, all sorts of things, all of the thyroid

00:03:42.520 promoting functions are controlled by the active version, which is T3. T4, conversely, is the inactive

00:03:50.020 version of the hormone. So if you're paying attention to what I just said, you'll note I just

00:03:55.160 said that basically most of what comes out of the thyroid is T4, which is inactive. Now, it's not

00:04:01.740 entirely clear what the ratio is between these, but it's directionally about four or five to one.

00:04:07.760 I think it's almost just as easy to imagine that virtually everything the thyroid is producing

00:04:11.700 is T4. So if the thyroid's producing T4, which is inactive, it needs to be converted into an active

00:04:19.820 hormone in the body. And that's where these enzymes called deiodinases come in. And as their name

00:04:27.460 suggests, deiodinases remove one of the iodines from T4 to create T3, which is the active hormone.

00:04:37.060 Now, the story gets a little bit more complicated because there are different types of deiodinases,

00:04:41.860 but the three most relevant are D1, D2, and D3. So let's talk for a moment about these three

00:04:49.500 deiodinases. D1 and D2 are quite similar in that they both convert T4 into T3. More about that in

00:04:56.720 a moment. It's just where they do it that's slightly different. D1 is extracellular. It's on the cell

00:05:02.100 membrane facing outward, whereas D2 is on the membrane of the endoplasmic reticulum, and it's facing

00:05:08.240 internal to the cytosol. But put that aside for a moment, and just keep in mind that D1 and D2

00:05:13.260 both convert T4 into the active hormone T3. This is the one that has all of the positive effects of

00:05:21.380 thyroid hormone. Now, D3 is different in that D3 takes T4 and makes something called reverse T3.

00:05:27.720 Reverse T3 is very similar to T3, except for a very important difference, which is it doesn't

00:05:34.280 activate the receptor that T3 activates. So it occupies the receptor without activating it.

00:05:40.840 So, in effect, you can think of reverse T3 as anti-T3. It basically blocks the effects of T3.

00:05:48.700 Now, it sounds like a very bad idea to have reverse T3 floating around, and unfortunately,

00:05:53.360 in the modern world, it often is. It usually is a sign of inflammation, illness, or things of that

00:05:59.220 nature. But I think that the reason it probably exists is to cope with shortage of nutrients.

00:06:06.280 In other words, when nutrients are scarce, when you need to slow down metabolism, one of the first

00:06:11.400 things that the body does is it increases the production of reverse T3 to block the effects

00:06:17.200 of T3. In fact, one of the things I used to notice when I did frequent fasting, because I would fast for,

00:06:22.780 say, a week at a time, and I would always check my blood pre and post, is how much my thyroid

00:06:28.020 function deteriorated during that period of time. And it wasn't just a deterioration in the usual

00:06:34.520 metrics such as TSH and T4. It was how much my free T3 and reverse T3 changed. In fact, the ratio of my

00:06:43.020 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

00:06:55.140 day fast. And I would say about half of that was due to the reduction in T3, and the majority of that

00:07:00.960 was due to the increase in reverse T3. So the body is going to regulate these three enzymes in response

00:07:07.940 to various physiologic circumstances. And that's effectively, at the cellular level, how the body is

00:07:14.140 controlling thyroid function. Now this creates a bit of a problem when you want to evaluate a patient

00:07:19.700 for their thyroid status. Because the traditional way to think about a patient's thyroid status is

00:07:25.580 actually just to look at their TSH. And on the surface, this kind of makes sense, because if

00:07:30.820 everything is working perfectly, the TSH should give you the answer. If the TSH is very high, what must be

00:07:38.780 true? Well, there must not be much T3 around, because it would be inhibiting TSH. If TSH is very,

00:07:47.900 very low, you would be getting a lot of inhibition from these things. You would be in a hyperthyroid 1.00

00:07:53.780 state. But the reality of it is, you can sometimes have a normal TSH and still have the symptoms of

00:08:02.120 hypothyroidism. If, for example, you have very high amounts of reverse T3 and very low amounts of T3.

00:08:10.920 In other words, if your T4 is being preferentially shunted into reverse T3 instead of T3, you might

00:08:17.740 feel like you have the symptoms of hypothyroidism. You could be cold, your metabolism might be slow,

00:08:23.600 you'd have difficulty sleeping. If it were really extreme, your nails might even get brittle,

00:08:27.780 you'd be constipated. These sorts of, unfortunately, non-specific symptoms, which make it difficult

00:08:33.580 to make such a diagnosis at times. So where does this matter when it comes to how we treat

00:08:39.660 hypothyroidism? And to be clear, hypothyroidism is far more common than hyperthyroidism. I'm not going

00:08:46.340 to talk about hyperthyroidism. I'm going to talk about hypo. The standard treatment for hypothyroidism

00:08:53.300 is to give T4. We give a synthetic version of this hormone, the inactive thyroid hormone. And we do that

00:09:01.200 with the knowledge that most patients will convert that T4 via D1 and D2 into T3. The T3 will go on to

00:09:11.500 have all the biologic effects, and it will also suppress TRH and TSH, and the body will come back

00:09:17.960 into line. So, for example, if a patient shows up to see you and they have the classic symptoms of

00:09:22.320 hypothyroidism, and their TSH is elevated, for example, at 6 or 7, you might give them, say,

00:09:29.080 75 micrograms of T4, and you might expect to come back and see that TSH at 2 or 3, and them feeling

00:09:36.900 better. And many times it works out that way. But unfortunately, it doesn't always work out that way.

00:09:41.820 And in fact, what you see sometimes is that you give a patient T4, and they start to feel worse.

00:09:47.700 And sometimes their TSH actually improves. And the reason it improves is T4 does have some

00:09:54.260 inhibition of TSH, not as much as T3, but some. But what if, for physiologic reasons,

00:10:01.060 their D1 and D2 are being down-regulated while their D3 is being up-regulated, and they're taking

00:10:06.880 that T4 that you're giving them, and they're just making more and more reverse T3. Now, a person who's

00:10:12.780 insulin-resistant, a person who has low-grade inflammation, these are typically things that

00:10:18.260 we might see drive that state. And that patient, even though their TSH improves, doesn't necessarily

00:10:23.860 feel better. And for those patients, it might make more sense to actually give them T3. Because if

00:10:30.080 you give T3, you're basically bypassing this system altogether. You're still getting the feedback

00:10:34.980 that's appropriate, but you bypass the step where the body might erroneously turn the T4 into reverse

00:10:40.920 T3. Now, there's a bit of a problem in giving T3, because the regular version of T3, a drug called

00:10:48.140 Cytomel, is a very difficult drug for patients to tolerate. When I was in training, we would give

00:10:53.640 T3 to patients after we did thyroidectomies on them for thyroid cancer, and patients could rarely

00:10:59.540 tolerate it. We had to give it to them because we would immediately take all of their thyroid out 1.00

00:11:04.820 in one moment, and they needed a big dose of T4, but a hefty dose of T3 to get them over the hump,

00:11:10.260 and oftentimes they would feel pretty lousy from that. Now, since that time, I think T3 has largely

00:11:16.220 fallen out of favor. Not many doctors use Cytomel, which is the trade name for T3, because it is so

00:11:23.760 rapid in its onset. Instead, people are typically using two other formulations. The first is compounded

00:11:31.740 control release T3. So, it's the exact same hormone T3, but it's just compounded in a way

00:11:38.540 to be slowly released. This seems to be much more well-tolerated, and the doses can be pushed a

00:11:44.400 little bit higher. A typical dose might be anywhere from 10 to 25 or even 30 micrograms of control release

00:11:50.640 T3, and that seems to last a patient throughout the day. Of course, they have to take this generally in

00:11:55.140 the morning to make sure that it's out of their system by evening, or at least it's reduced in

00:11:59.980 potency. There's another way that patients often receive T3, and that's in combination with T4,

00:12:07.660 vis-a-vis a formulation known as desiccated thyroid. Now, desiccated thyroid is basically whole thyroid

00:12:14.740 gland, and therefore it contains T4, T3, and even some T2, but we're not going to talk about that.

00:12:20.380 So, the two most common versions of desiccated thyroid are a formulation called naturethroid

00:12:25.900 and armor thyroid. So, if you're watching this video and you're interested in this topic, you've

00:12:29.460 undoubtedly heard of these things. Now, I'm not going to get into the religious debates about

00:12:33.580 this stuff. There are really competing schools of thought, and there are some people that believe

00:12:37.400 that the only thing that should ever be given to any patient with hypothyroidism is a desiccated

00:12:42.140 formulation. Similarly, there are other people who think all of that desiccated stuff is total crap, 0.95

00:12:47.100 and it should never be given, and we should only be giving T4, or we should only be giving

00:12:50.820 T4 with a little bit of T3, or you should only be giving control release T3. I've interacted with

00:12:56.880 people from all of these schools, and all I can say is, if you're really interested in treating

00:13:01.360 hypothyroidism, you better know all of them, because there are some patients in whom one way works and

00:13:07.160 another way doesn't. I've had patients who came to me on desiccated formulations, and I thought,

00:13:12.440 I don't really like these desiccated formulations. I'm going to switch them over to T4 plus control

00:13:17.540 release T3, and I could never get them right, and I ultimately end up putting them on desiccated and

00:13:22.660 getting them right. Similarly, I get patients that show up on desiccated, and they sort of feel okay,

00:13:27.200 but they're not quite right, and we get them feeling right in other ways. Now, keep in mind,

00:13:31.380 if you're giving desiccated thyroid, and this is kind of the reason why I don't generally like to use

00:13:36.340 it, except when it works, you're giving a fixed amount of T4 and T3. You don't get to control it.

00:13:41.520 The ratio is set, and it's something like 1 to 4.2 or something like that, meaning for every unit

00:13:48.140 of T3, you're giving 4.2 units or micrograms of T4. And again, for some patients, that's just right,

00:13:56.520 but there are other patients who need more or less of one or the other, and that's why I tend to use

00:14:02.480 T4 and T3 separately. But again, you're here to fix the symptoms more than you're here to fix the

00:14:09.100 numbers, and you'll ultimately end up using whatever works. Finally, a word on half-life.

00:14:16.460 T4 has a very long half-life. It's a matter of days, and for that reason, a patient shouldn't panic

00:14:25.320 if they miss a day of T4. So if they forget their dose of T4, it's okay, just take it the next day

00:14:32.020 and don't double up. Conversely, T3 has a much shorter half-life, and therefore, you do need to

00:14:39.160 stay on top of your T3 when you give it. Now, of course, remember, the control release and the

00:14:44.500 immediate release T3 also have very different half-lives, but what I'm referring to is endogenous

00:14:49.420 T3 as well. So there you have it, a pretty hopefully simple overview of the thyroid system.

00:14:57.720 I guess one of the takeaways from this is that it's a little more complicated than you might be

00:15:02.820 led to believe if your doctor is only looking at your TSH, and unfortunately, when you go to the

00:15:08.920 doctor's office, a lot of the times, that's the only lab they've ordered. I prefer to order not just

00:15:14.960 the TSH, but the free T4, the free T3, and the reverse T3 if I have any concerns about

00:15:22.360 hypothyroidism. I don't always order this blood test. So if the TSH is normal, the T3, T4 are

00:15:28.980 normal, and the patient is asymptomatic, I'm not looking at their reverse T3. But if a patient has

00:15:33.380 symptoms and you need to investigate them, I think you have to understand all of these. And what you're

00:15:37.340 basically doing is using the amounts of T4 or free T4, T3 or free T3, reverse T3,

00:15:44.560 to impute what the action is of these diodinases, and therefore what your treatment strategy needs

00:15:52.580 to be. Okay, next we're going to talk about the adrenal system. Personally, I find this to be the

00:15:58.860 most confusing of the systems. It's also the one for which we can get virtually no information from

00:16:06.160 a blood test. So when you think about the thyroid test, when you think about the sex hormones that

00:16:10.360 we're going to talk about later, we can get so much information from blood tests. When it comes

00:16:15.160 to this system, we can't get anything from a blood test. So when people say, hey, I just got a blood

00:16:20.280 test and my cortisol level was high, what does that mean? Or my cortisol level was low, what does that

00:16:24.640 mean? I say, I don't know. It doesn't mean anything. Because what those tests are measuring are total

00:16:31.020 cortisol. And total cortisol, just as we'll talk about when we talk about testosterone,

00:16:35.480 is actually kind of unhelpful because it's all of the cortisol, including that which is bound. And

00:16:43.240 the majority of cortisol is bound to a carrier protein known as cortisol-binding protein. It's

00:16:49.360 also bound to albumin and other proteins as well. So we really need to understand how much cortisol is

00:16:54.600 unbound, what's called free cortisol. And it's this free cortisol that exerts its biologic activity.

00:17:01.440 Now, there are really two main ways that you can do that. One is through a saliva test,

00:17:06.440 and the other is through a urine test. I prefer the urine test. And we use a test called the Dutch 0.98

00:17:12.520 test. We have no affiliation with them. You can find out anything you want about the Dutch test

00:17:17.200 online. You can probably order directly through them. I don't really know, to be honest with you. But

00:17:21.280 we order these for our patients when we think there's something worth investigating here. We don't do

00:17:26.200 these tests on everybody. The reason we like the Dutch test is, first of all, it is measuring free

00:17:32.120 cortisol. Secondly, it's measuring cortisol metabolites. And cortisol metabolites are very

00:17:38.760 helpful when it comes to understanding what cortisol production looks like. I'll explain that in a moment.

00:17:44.880 Okay, so let's start with the basics. You have two adrenal glands, one on top of each kidney, 0.97

00:17:50.280 and the adrenal glands produce cortisol. If you want to go high enough on the chain,

00:17:56.360 you'll know that this comes as a precursor via cholesterol. So cholesterol is the precursor

00:18:01.520 that ultimately results in cortisol production, just as it does androgens. Go back to what I said

00:18:06.920 a moment ago. If you go and get a blood test for cortisol, all it's doing you is telling you the

00:18:11.820 total amount of this you have in your system, but understanding that most of that is bound to carrier

00:18:17.880 proteins. What we care about is how much of that is free, because it's only the free cortisol that

00:18:23.720 does the important job of a glucocorticoid. So what we do when we take a look at a Dutch test is over

00:18:31.720 time, typically four times over 24 hours, we get a snapshot of how much free cortisol exists, how much

00:18:39.060 free cortisone exists, and equally importantly, how much of their metabolites or breakdown products exist.

00:18:46.960 So alpha-tetrahydrocortisol, beta-tetrahydrocortisol, and tetrahydrocortisone. Now again, you can't get

00:18:54.520 these from a blood test, and why they're important is because the sum total of these is how I learn what

00:19:03.720 the total adrenal output is. There's a term that you hear thrown around a lot called adrenal fatigue.

00:19:11.280 The suggestion is that if a person feels lousy, it's because their adrenal gland isn't making

00:19:16.880 enough cortisol because it's fatigued. And of course, these people may indeed have low levels

00:19:22.240 of cortisol. They may even have low levels of free cortisol, but doesn't mean their adrenal glands

00:19:27.120 are fatigued. I would say the answer is in most cases, probably not. In fact, in most of those

00:19:32.260 patients, if you look at the total metabolized amount of cortisol and cortisone, you would in fact

00:19:39.060 see that they have ample amounts of production. What might be happening is that they are degrading

00:19:44.840 too much of their cortisol and or turning too much of their cortisol into the inactive

00:19:50.400 cortisone, and instead of maybe converting it back, actually just metabolizing it here.

00:19:56.200 So what regulates all of these things? Well, first of all, the regulation of turning cortisol

00:20:01.240 into its metabolites and cortisone into its metabolite is regulated by enzymes called reductases.

00:20:08.500 Again, I think the names of these enzymes are not really that important, but for the people who really

00:20:12.880 care, 5-alpha reductase, 5-beta reductase, 5-beta reductase, we're going to talk about these later

00:20:17.120 with sex hormones. Never mind. We basically have some enzymes that will turn cortisol into these

00:20:23.260 and cortisone into this. And inflammation, obesity, and factors that are generally associated

00:20:29.680 with poor health accelerate that conversion. So if a person is feeling lousy and their free cortisol

00:20:39.860 is low and their free cortisone is low, and yet they have ample amounts of these, you really need

00:20:48.160 to reverse the factors that are driving these things here. You really need to address the obesity,

00:20:55.120 the insulin resistance, the leptin resistance, the underlying inflammation. A far more common problem,

00:21:00.260 frankly, is in people who have very high or very low levels of free cortisol, and they may have

00:21:06.780 symptoms associated with those things. And then you have to look at what's going on with their

00:21:10.560 cortisone. So I always check in my mind these things first. So I always look to make sure adrenal

00:21:14.920 output is appropriate. And as I said, it's virtually always appropriate. The second thing I'm asking is,

00:21:21.260 is the rhythm normal? Meaning, do they have a nice rise a couple hours after waking? Does it fall in

00:21:28.500 the afternoon? And is it down here at bedtime? So that's about what we want to see. Now, if the answer is

00:21:34.700 yes, then we're all done. If the answer is no, and let's assume that the person is really low.

00:21:39.800 So they wake up here, they stay kind of low, they stay kind of low, they stay kind of low.

00:21:45.680 And they're symptomatic. So they say, boy, I just can't get going during the day. Then I ask the

00:21:53.020 question, well, how much cortisone do they have? And they might actually have plenty of cortisone.

00:21:58.440 Well, in that case, what we have to do is flip the way this enzyme is working. Because there's an enzyme,

00:22:04.420 11-beta-HSD, that converts cortisol to cortisone and back. But here's what's interesting, is the

00:22:10.800 direction of travel is determined by various things. So cortisone gets converted to cortisol

00:22:16.920 preferentially when you have insulin resistance, obesity, inflammation, low thyroid function,

00:22:22.880 leptin resistance. The other direction, cortisol being turned into cortisone, is facilitated when

00:22:29.160 you have glucocorticoid. So for example, if a patient is taking steroids, understandably,

00:22:33.200 the body says, we don't need any more cortisol, let's turn it into cortisone. Hyperthyroidism,

00:22:38.040 progesterone, PCOS, and even supplements like curcumin. So what we like to do, and what I think

00:22:44.100 is one of the most potent things to do in the patient who doesn't have enough of this, has plenty

00:22:49.020 of this, looks like this, and is symptomatic, is try to address these issues. And frankly, one of the

00:22:55.400 most potent things to do is use something like an adrenal support. So adrenal support is a supplement

00:23:00.580 that's usually made up of a number of things, the most potent of which, by the way, is licorice

00:23:05.580 root. It's actually kind of a funny story, but high enough amounts of licorice will render a person

00:23:11.000 functionally basically high in cortisol. So I remember a story in medical school of a person

00:23:16.840 that showed up looking like they had Cushing's disease. So Cushing's disease is a condition of

00:23:21.820 excess cortisol production. And nobody could figure out how it was happening until the nephrologist who was

00:23:29.620 involved in this patient's care noticed that the patient was constantly eating licorice while

00:23:34.120 seeing him. And the nephrologist said, hey, by the way, I noticed you're eating licorice. How much

00:23:37.620 of that do you eat? And he's like, oh, you know, about 10 packs a day. And so he was eating like 10

00:23:41.400 packs of black licorice a day, and he was basically shutting off this system and driving his cortisol

00:23:46.760 through the roof. So you can actually use that to your advantage using licorice root, if indeed that's

00:23:52.860 part of the problem. The other thing we tend to look at is, are there ways to suppress this system?

00:23:58.300 So let's say you have a person who wakes up here, and they shoot up to here, and then they just stay

00:24:05.380 high. And they tell you, I'm really having a difficult time sleeping. So in those people, I like

00:24:10.940 to use something like phosphatidylserine, which suppresses the cortisol production in the evening,

00:24:16.860 and that actually helps facilitate sleep. In fact, this is something I use for myself

00:24:20.860 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

00:24:27.000 at, say, noon functionally, right, if I'm putting myself in the time zone of where I'm going,

00:24:33.160 and it's nighttime there, and it's only noon in my home time zone, but I need to go to sleep on the

00:24:37.520 plane, one of the most important things I'll take is anywhere from 400 to 600 milligrams of

00:24:42.200 phosphatidylserine, because what that's doing is dropping the cortisol. By the way, it's not clear what

00:24:47.620 the mechanism of action is. At least to me, it's not. So we've looked at this, and we can't quite

00:24:51.840 figure out what the mechanism of action is, but we see the result. So what's the take-home here?

00:24:56.820 Okay, the take-home here is very difficult, if not impossible, to impute what's going on with

00:25:02.340 adrenal function by looking at a blood test, because it's looking at total cortisol, and if that weren't

00:25:08.220 bad enough, it's just one snapshot in time. You really do need to see what's going on in total.

00:25:13.420 Secondly, free cortisol and free cortisone by themselves still don't tell you a total picture.

00:25:19.880 You do need to have some sense of what their metabolites are, because that's what's actually

00:25:23.960 telling you total adrenal output. Next thing you need to understand is the balance of cortisol and

00:25:29.300 cortisone. How much do they have of each? This is inactive. So we think about this, at least I think

00:25:35.100 about this, as kind of a repository for which I can put excess cortisol if I don't need it, if not down

00:25:41.020 here, and where I can draw cortisol if I do need it. Remember, these are one-way streets, so once you go

00:25:46.240 down to here, you're not reversing those, you're just slowing those enzymes, but here we can go back

00:25:51.220 and forth between the two. I hope you can probably see why I find this to be the most complicated

00:25:56.140 system out there, and in large part it's complicated because when a person has low free cortisol and

00:26:02.440 they're symptomatic, you really do not want to give them hydrocortisone, or prednisone, or any

00:26:08.900 glucocorticoid replacement. You would only reserve such treatment for a person who's truly in

00:26:14.200 distress. And obviously, if a person has an Addisonian crisis, which is what happens when

00:26:19.760 the adrenal gland completely shuts down, and of course that is absolutely something that can

00:26:23.760 happen, that happens in the face of an overwhelming infection, for example, by all means, those people

00:26:28.240 need glucocorticoids or they will die. But for the average person who's walking around kind of dragging,

00:26:34.120 feeling like blah, and indeed they have low free cortisol, I certainly wouldn't favor using

00:26:40.960 glucocorticoids as a treatment for that. Instead, what you favor are addressing the underlying issues

00:26:46.700 that are either extracting cortisol into its metabolites or turning cortisol into cortisone.

00:26:52.680 And the problem is, there are very few pills that fix that. A lot of that comes down to this word we

00:26:57.980 all hate, lifestyle management. But unfortunately, that is the key. Again, licorice roots, probably one of the

00:27:03.660 best things you can use there. And of course, in the flip side, you can use other sort of adrenal

00:27:07.940 supports as well. Anyway, I hope that's helpful. Okay, so the next system we're going to talk about

00:27:13.820 is the female reproductive system. Now, this looks pretty complicated, but let me tell you why I'm

00:27:19.580 going to make it less complicated. I think to understand female sex hormones, the easiest way to 1.00

00:27:25.100 do it is to understand it during the reproductive cycle. In other words, to understand what's happening

00:27:30.580 with women's sex hormones during her menstrual cycle and during her reproductive years. So this

00:27:36.940 looks a heck of a lot more simple when you look at it in a woman who's outside of menopause. But let's 0.63

00:27:42.540 start with this. Okay, so the first thing is, for the sake of simplicity, I'm going to assume a 28-day

00:27:48.160 cycle. I realize, of course, that is not always the case. There are some women who might have a slightly

00:27:52.500 shorter cycle or a longer cycle. But for the purpose of illustration, let's assume a 28-day cycle,

00:27:57.520 which is about where most women are. The cycle is divided into two phases. Technically three, because 1.00

00:28:05.320 there's a menstrual phase here. But let's just acknowledge that the menstrual phase, which starts at

00:28:10.340 day zero, that's the first day of bleeding. Even if it's just spotting and it's not a heavy period, that's

00:28:15.620 day zero. That's the shedding of the endometrial lining, which we'll talk about. Then you move into a

00:28:21.080 follicular phase. And the purpose of that phase, which is really driven by follicle-stimulating

00:28:26.540 hormone and estrogen, is to ripen the follicle for ovulation. Ovulation takes place mid-cycle.

00:28:34.900 After ovulation, we move into the luteal phase. The luteal phase is dominated by luteinizing hormone

00:28:40.840 and progesterone. And the purpose of the luteal phase is to prepare the endometrial lining for

00:28:46.620 implantation. Of course, this is something that doesn't occur most of the time, that only occurs

00:28:51.040 during pregnancy. And therefore, when the body realizes, hey, we're not pregnant, the endometrial

00:28:56.900 lining gets shed. And that's what results in this crashing progesterone level. And that is the

00:29:02.940 shedding of the linings, of course, what is the period, which brings us back to here, and the cycle

00:29:06.480 begins again. So let's talk about how these things work from the beginning. So follicle-stimulating

00:29:10.560 hormone, along with luteinizing hormone, are secreted from the pituitary gland, the same place that makes

00:29:15.440 TSH that we talked about in the thyroid system. And again, the purpose of follicle-stimulating hormone

00:29:21.260 is to get the follicle ready for ovulation. So the follicular phase is really dominated by estrogen

00:29:27.740 and FSH. And of course, the purpose of this is to prepare the body for ovulation. Now, we're very

00:29:35.240 particular about when we like to do a blood test here, especially when a woman is approaching a 0.99

00:29:41.040 perimenopausal state. So as a woman is getting closer and closer to menopause, we will really be 0.79

00:29:46.540 monitoring the level of FSH and estradiol in about day three, four, or five. And kind of the canary in

00:29:54.020 the coal mine, as a woman is getting close to menopause from a biochemical standpoint, is a rising 0.97

00:29:59.620 FSH during that phase. So FSH should normally be very low during day three, four, five, which is usually

00:30:06.800 when a woman is still in her period. If FSH starts to climb, especially if estradiol is low, you can be

00:30:13.760 pretty sure that she's heading towards menopause. In fact, menopause is chemically demonstrated by a 1.00

00:30:19.280 high FSH, typically north of 25, 35, 40, and low estradiol. In fact, a woman who's been in menopause for

00:30:25.640 many years would easily have an FSH level of 50 or higher and unmeasurable levels of estradiol.

00:30:30.940 So back to this situation here, FSH is rising. It has a little bit of a peak just before ovulation.

00:30:38.800 Estrogen really rises now, so peak estradiol occurs right at or just before ovulation. The follicle comes

00:30:45.600 out, and away it goes to see if indeed it's going to be met with a sperm. And if so, is it going to attach

00:30:52.980 to the endometrium, etc. Now, this is where we enter the second half of the phase, the luteal phase. This is

00:30:57.820 dominated by luteinizing hormones. So the purpose of luteinizing hormone is to prepare the endometrium

00:31:02.800 for this implantation. Now, what I haven't drawn here, because it's just too complicated, is what

00:31:08.560 the thickness is of the endometrial lining as we go from here to here. So, of course, just as a woman 1.00

00:31:14.740 is finishing her period, so call it about here, the endometrium is at its thinnest, right? You just

00:31:20.660 shed that lining. And it's slowly, slowly, slowly building up. And of course, at about day 14,

00:31:27.040 it really starts to build up that lining because it's preparing, again, for that implantation.

00:31:32.180 Progesterone is rising, again rising. And by about day 21, when progesterone peaks, the body figures out

00:31:38.600 if it's pregnant or not. And again, in most cases, it's not. And so, because it's not pregnant, it begins 0.84

00:31:44.000 to rapidly drop that progesterone level. Estrogen has also risen for a second peak. So, this is the absolute

00:31:50.880 peak of estrogen, but this is a second peak. And both of these hormones come crashing down,

00:31:55.620 and the body begins to shed that endometrium at the end of that cycle. So, there are a bunch of

00:32:00.680 things I think I want to say about this. The first is that any point in time when you get a blood draw

00:32:06.120 on a woman, and you are looking at FSH, LH, estradiol, and progesterone, you have to sort of know where

00:32:12.280 you are. Now, once you do a lot of this, you're pretty good at guessing. So, it's not rocket science

00:32:16.980 when you're drawing a woman's levels, and you see that she has a sky-high luteinizing hormone,

00:32:22.680 an estradiol, to figure out that you probably drew the blood right around the time that she

00:32:26.780 was ovulating. But in cases where it gets a little bit more complicated when women's periods are 1.00

00:32:30.960 irregular, when they're approaching perimenopause, it helps to have some sense of what's going on.

00:32:36.260 And of course, in the case where a woman is not menstruating at all, it tends to be pretty easy 1.00

00:32:40.220 because you're going to see very high levels of FSH or LH. Now, it becomes more complicated

00:32:45.000 when a woman has an IUD, and as a result of that, she's not menstruating. But I'm not going to get 0.56

00:32:49.840 into those complex situations right now. I just kind of want to go over the basics of the hormone

00:32:54.520 system. The second thing I want to point out, and this point has been made in my podcast before,

00:32:59.040 but I think if you're only coming to this now, it's worth understanding. For many women,

00:33:03.560 what's happening between day 21 and day 28 is really profound physiologically. So, we talk about

00:33:09.580 this thing called PMS, and I think any woman who's experienced it knows it's a real thing. I certainly

00:33:13.720 can't say I've experienced it, but I've spoken to enough women who have that I have a real sense

00:33:18.660 of why it's probably happening. Now, it's not entirely clear if it's the drop in progesterone

00:33:24.680 that's driving this, but it likely is. I don't know how well this has been investigated, but we

00:33:30.920 certainly suspect that there are central receptors for progesterone, and that in a susceptible woman,

00:33:36.940 when progesterone levels are withdrawn so quickly, that can easily result in mood alterations.

00:33:42.620 So, for women who do experience significant and unwanted side effects of progesterone withdrawal,

00:33:49.680 known as PMS, a very simple and effective way to treat it is with a low dose of progesterone

00:33:57.300 that is administered starting at day 21 to 28. So, how does that work? So, again, if a woman 1.00

00:34:03.360 has a fairly regular cycle, she'll know when she ovulates, and she'll know about a week after

00:34:09.580 ovulation to take a low dose of progesterone. Typically, this is done at about 50 milligrams

00:34:14.500 orally. That's just taken for seven days until she has her period, and what it does is it completely 0.86

00:34:20.420 blunts this effect. So, this effect is still happening, but her total levels of progesterone

00:34:25.900 are not nearly as dramatic in the reduction, and this tends to ameliorate symptoms. So, what's the

00:34:30.780 drawback of that approach? Well, from a physiologic perspective, none. The biggest drawback is just the

00:34:35.580 logistics of having to remember that seven days out of every 28, you have to take progesterone. This is

00:34:42.160 an entirely safe thing to do, and I've used this with a number of women in the past. It seems to work

00:34:47.100 very well. Alternatively, women can stretch that out and take progesterone for the entire 14 days 0.98

00:34:53.980 following their ovulation, and of course, they can take oral contraceptives throughout. But again, now that's

00:35:00.280 creating a whole new set of issues around oral contraceptives, which many women simply don't 0.98

00:35:04.920 want to do. So, I just point that out to say, one, I think when you look at a graph like this, hopefully

00:35:09.540 you get an appreciation for what a profound level of withdrawal a woman is experiencing during the end

00:35:16.760 of the luteal phase, and secondly, that there are lots of hormonal ways to address that. Now, the other

00:35:22.580 hormone I haven't drawn on here is testosterone. I haven't drawn it for two reasons. The first is it doesn't

00:35:29.680 change that much during the cycle. It changes a little bit. I've read a number of different studies

00:35:35.980 that have looked at it. Most of them suggest a peak testosterone about here when you have peak

00:35:41.120 estradiol, but the fluctuation is so minor that I don't think it adds any value to this. Secondly,

00:35:47.660 if I were to draw testosterone to scale on this graph, you'd have to look at the ceiling. That's how much 0.81

00:35:53.840 more testosterone a woman has in her body than estrogen. Yes, I just said that. It sounds very

00:35:59.840 counterintuitive, but it's true. A woman has, even at peak estradiol level, which is during ovulation,

00:36:08.080 a woman has five to ten times more testosterone in her body than she does estradiol. It's just that 0.70

00:36:14.520 it's not changing all that much. It is, unfortunately, going away when she enters menopause, which is what I

00:36:21.220 want to talk about next. So as a woman leaves her reproductive years, what's happening? Well, 0.90

00:36:28.480 her body is less able to make estradiol and progesterone. And as estradiol and progesterone 1.00

00:36:36.500 production go down, just as testosterone production goes down in a male, although it happens far less

00:36:42.180 abruptly, the pituitary gland senses this because there's a negative feedback loop and it says,

00:36:47.220 I want more. So it starts making more FSH and more LH. And of course, the higher those go,

00:36:55.140 initially the body responds and you'll see a period where the cycle does continue. Sometimes it spreads

00:37:01.000 out, it gets a little bit longer, but the body is able to compensate until, of course, it isn't.

00:37:05.700 So when a woman is in menopause, what you'll see is no estrogen, no progesterone, very high LH,

00:37:13.780 very high FSH. And so when we initiate hormone replacement therapy, and by the way,

00:37:20.340 we never want to wait until a woman is in that state where she has flatline estradiol, 0.96

00:37:25.580 flatline progesterone, sky high FSH, sky high LH. We want to do it long before that. We want to do it

00:37:31.940 as she's transitioning from this into that. And that could be literally a year or two years prior to

00:37:39.020 that state. And what we're doing is we're giving her enough estradiol that her FSH usually ends up 1.00

00:37:46.920 hovering around 20 to 30. Again, that's still a pretty high level of FSH, meaning that's still

00:37:54.120 got the brain thinking, I want more estradiol, but you don't need to give maximum amounts of

00:37:58.480 estradiol. We're simply trying to control the vasomotor symptoms. So the hot flashes, the night

00:38:04.040 sweats, the vaginal symptoms, atrophy, dryness, and perhaps most importantly, cardiovascular risk

00:38:10.660 factors and bone risk factors. So estrogen being the most important hormone, both in men and women,

00:38:16.260 as it regulates sending the signal of tension on the bone into bone building via osteoblasts.

00:38:23.700 So in summary, that's the look at the female endocrine system. Again, it's much more complicated 1.00

00:38:29.540 than the male sex endocrine system because of both the cyclic nature of it and the abruptness with

00:38:34.600 which it goes away. But again, I think it's something that everyone needs to understand

00:38:38.840 because if you're a woman, you should understand this. And frankly, if you know a woman and you

00:38:43.500 care about a woman, you should understand this. And it certainly would hopefully give empathy to

00:38:48.020 women who are struggling during that last portion of their luteal phase. Again, men don't have an

00:38:55.080 equivalent of this. We don't have a scenario whereby we're having a tenfold reduction in a major sex

00:39:01.940 hormone that occurs over the course of a week. So I think it's understandable why that can pose

00:39:06.840 issues for some women. So in summary, I think you can see that the female sex hormones are a little

00:39:12.940 bit more complicated than what you're going to see in a moment, which is the male equivalent.

00:39:16.960 But I think it's also actually a more interesting system. By understanding how this works,

00:39:21.280 you have a sense of whether a woman is typically getting closer to menopause, which is generally

00:39:27.180 one of our considerations as we're looking at these hormone levels. And as a woman is entering 1.00

00:39:32.120 that perimenopausal period, you want to be especially attentive to the time in which you draw. Again,

00:39:38.400 day 3, 4, 5 become the most important blood draws as a woman is becoming perimenopausal because it's 0.99

00:39:44.680 that FSH level at day 3, 4, and 5 that becomes your canary in the coal mine. If that level starts

00:39:50.840 creeping up and it's over 10, 11, 12, even though she's not in menopause, I'm going to tell her

00:39:56.700 she's probably getting close. And that's when we start to have our discussion about what hormone

00:40:00.740 replacement therapy looks like. This brings us to the final hormone system we'll talk about today,

00:40:06.620 which is the male sex hormone system. This system, I think, is a little bit simpler than the female 0.50

00:40:11.540 system, but it still has its nuances. So let's kind of go back to a very similar pattern we saw with

00:40:18.420 the thyroid system, which is upstream regulation at the hypothalamus vis-a-vis GNRH, gonadotropin

00:40:25.120 releasing hormone that tells the pituitary to secrete LH and FSH. Again, if you just watched me

00:40:30.740 go over the female system, you'll realize we have the exact same thing happening there. I just didn't 0.99

00:40:35.460 draw all of this because we had so many other complicated things to talk about. So luteinizing

00:40:40.880 hormone and follicle stimulating hormone are speaking to the testes. And yes, I realized as I drew this,

00:40:46.880 I didn't need to draw two of them. That was a bit gratuitous. Nevertheless, the testes have different

00:40:51.420 cells in them. Sertulli cells and Leydig cells, the testes make testosterone. Now, there's a little

00:40:57.360 more complexity to this that I will come back to in a moment, but let's just start with the fact that

00:41:02.160 the testes are making testosterone. We should also point out that testosterone is mostly bound. So just

00:41:09.340 as I discussed with cortisol, most cortisol is bound, so is most testosterone. It's primarily bound

00:41:16.180 to two hormones, sex hormone binding globulin, or SHBG, and albumin. But a relatively small amount,

00:41:24.660 and it depends on how much albumin and SHBG you have, remains free. So we call that free or unbound

00:41:31.420 testosterone. And it's anywhere from 1 to 3% of the total testosterone. Now, there are two things that are

00:41:39.540 siphoning testosterone away that are very important. The first is 5-alpha reductase, which is the same

00:41:45.560 enzyme we talked about back when we were going over cortisol. It's siphoning off some of that

00:41:49.820 testosterone to make dihydrotestosterone. Now, not huge amounts, sort of a couple of percent,

00:41:55.020 but dihydrotestosterone is a very important sex hormone. In fact, it has anywhere from 2 to 10,

00:42:02.240 some studies would suggest even higher potency, 2 to 10x potency for the androgen receptor than

00:42:08.920 testosterone. So I'm going to talk about the androgen receptor in a minute, but I just want

00:42:12.140 you to keep in mind that DHT has a much higher binding affinity for the androgen receptor than

00:42:18.000 testosterone does. The other thing that is siphoning off testosterone is the aromatase enzymes that are

00:42:24.420 converting testosterone into estradiol. Yes, that's the very same estrogen that women have as well. And

00:42:30.880 estrogen turns out to be a very important hormone for men. I think this is something that hasn't been

00:42:35.400 always appreciated, but we now understand that, of course, estrogen is important in the male for mood,

00:42:41.620 for body composition, for bone mineral density. So I'll talk about this in a moment, but things that

00:42:47.080 suppress estrogen have to be considered judiciously because of the negative side effects of having low

00:42:53.480 estrogen. Not surprisingly, there is a feedback loop. So the feedback loop works as follows.

00:42:59.340 Testosterone levels, testosterone levels, as they rise, will inhibit both the hypothalamus and the

00:43:05.680 pituitary, which slows down GNRH and LH and FSH. This is actually much more complicated than I've

00:43:13.300 drawn it here, and I realize that there's going to be some purist out there who says, oh my god,

00:43:16.760 you forgot to mention this. Yeah, so it turns out that the hypothalamus does not have an overwhelming

00:43:22.000 number of androgen receptors. So this is not happening directly, but rather indirectly. So

00:43:28.880 testosterone is inhibiting a slightly different neuron that is then speaking to the hypothalamus.

00:43:34.580 But I think for the purpose of this discussion, this is sufficient. The other thing to point out is

00:43:39.580 that estrogen also inhibits luteinizing hormone secretion via the pituitary. So this becomes really

00:43:46.620 important when we talk about certain drugs that are used to replace testosterone or to increase

00:43:53.260 testosterone. So let's just summarize what we've learned so far. In the normal functioning system,

00:43:59.840 GNRH tells the pituitary to make LH and FSH. They tell the testes to make testosterone. Small amounts of

00:44:05.920 that are siphoned off to make DHT. And even smaller amounts, i.e. less than 1%, are siphoned off to make

00:44:11.500 estrogen, and the system is in perfect balance. Now, how much of that testosterone is actually

00:44:17.420 exerting its biologic effect on the androgen receptor? Well, it turns out very little is,

00:44:22.740 because as I said, you have this thing over here, SHBG plus albumin, and it's soaking up most of the

00:44:31.900 testosterone so that really the free testosterone, which is the biologically active, represents only about

00:44:41.240 one to three percent of total testosterone. But the good news is that's all you need. This stuff's

00:44:46.420 pretty darn potent. So testosterone binds to an androgen receptor. DHT also binds to an androgen

00:44:55.320 receptor. It just does so in a way more potent fashion. And this happens inside the nucleus of a

00:45:01.440 cell, and that's what affects transcription. Now we're going to talk about a subject that is way

00:45:07.380 more complicated than people are being led to believe it is, and that's testosterone replacement

00:45:10.840 therapy. It's not as simple as looking at the total testosterone or even the free testosterone

00:45:17.360 and determining if a person has low testosterone or low T. And the reason for that is when you are

00:45:26.180 measuring total testosterone, you don't really know what the free T is. The free T is a calculated

00:45:32.560 lab value. So they don't really measure free T by most lab assays. They measure total testosterone,

00:45:41.080 they measure SHBG and albumin, and they calculate free T. But let's assume that the calculation is

00:45:46.700 fairly accurate. And even if you don't rely on a lab to do that calculation, there are calculators

00:45:52.160 online that can do that for you. So let's say you now know the free T, and we'll talk about what some

00:45:57.100 ranges are in a moment. The question becomes, is the patient's low level, because let's just say

00:46:03.180 they're at the 30th percentile for what their level is, does that explain their symptoms? Well, it's not

00:46:08.940 entirely clear, because what we don't know is what's happening here. So we don't know how many androgen

00:46:15.060 receptors a person has, and therefore we don't know how saturated their androgen receptors are with

00:46:21.260 either testosterone or dihydrotestosterone. So we have to sometimes treat these things empirically,

00:46:27.980 meaning we're treating symptoms, but we're using numbers as a guide to do so. So the most common

00:46:34.800 symptoms of actual low testosterone, of androgen deficiency, in no particular order, because they're

00:46:41.780 going to vary significantly by men, would be low libido, erectile dysfunction, low mood, difficulty putting

00:46:49.260 on muscle mass, and insulin resistance. Those are the big ones that I see. Now there are others to be

00:46:54.960 sure, but those are really the big ones. And we know from clinical trials that when you give a group

00:47:01.000 of insulin resistant men testosterone, their insulin resistance improves. We know that if you give men 0.80

00:47:06.620 testosterone and you provide them with a training stimulus, muscle mass increases, strength increases,

00:47:11.760 body composition improves, which means adipose tissue goes down. We know that mood improves. We know that a

00:47:17.040 whole bunch of factors move in the right direction. But despite all of that, I'm still pretty cautious

00:47:23.080 when giving testosterone, because I think it is an overused hormone. I think too many people are being

00:47:29.500 given testosterone, and they probably don't need it because they're just being treated on their total

00:47:35.180 testosterone level without necessarily considering these other factors, such as free testosterone. And of

00:47:40.540 course, without understanding these things, which none of us can outside of a lab. So we have to really

00:47:45.960 treat based on symptoms. Now, what are the treatment options? There are, broadly speaking, two ways to think

00:47:52.200 about this. The first is a direct way to do it, which is giving testosterone. And this can be done in many

00:47:58.080 formats. The most common formats would be topical testosterone or injectable testosterone. But there's also an

00:48:05.520 intranasal formulation. There are pellets that can provide sort of a slow release over a period of months. And then there are

00:48:11.880 indirect ways to give testosterone, which are basically tricks that mimic these hormones. So the first of

00:48:19.620 these is something called HCG. And HCG is a mimetic of luteinizing hormone. So an injection of HCG will tell

00:48:28.720 the body to make testosterone just as you were giving luteinizing hormone. There is also a synthetic FSH.

00:48:35.940 It's far more expensive and it's virtually never used. So the typical use case for synthetic FSH is in men

00:48:43.640 who have been on testosterone replacement therapy for many years who have now lost the ability to make

00:48:49.160 testosterone. Because if you are given enough exogenous testosterone, you will shut down the

00:48:55.220 capacity to make testosterone in very short order. And within a year, two years, you will permanently lose

00:49:01.940 that ability minus some Herculean doses of synthetic LH and synthetic FSH. So we should make sure we never

00:49:09.820 lose sight of that. The other way to do this is to give a drug that has become very popular called

00:49:17.140 Clomid. Clomid or Clomiphene is a drug that has been used historically by women using it for fertility

00:49:24.080 purposes. And what Clomid is doing is effectively tricking the brain via stimulation of GnRH by blocking

00:49:34.900 the estrogen receptor to make more LH and FSH. Now, the reason I'm not a fan of Clomid, there are

00:49:43.220 several reasons, but one of the most important reasons is that it blocks the effect of estrogen

00:49:49.000 in the brain. And that turns out to be a negative thing. Turns out we want the feedback of estrogen

00:49:55.520 in the brain because it has many beneficial effects for mood. And there are some men who

00:50:01.120 actually, when they're on Clomid, even though their testosterone levels soar, don't feel any better,

00:50:07.040 we wonder if, in fact, that's because of Clomid. So not every man, there are some men that are on

00:50:11.800 Clomid that feel great on it, but there are some who don't. Alternatively, you give testosterone,

00:50:16.120 and when you give testosterone, you have to be mindful of the fact that your LH and FSH are going

00:50:22.320 to go to zero because your body is going to stop making testosterone. This is a very potent feedback

00:50:28.200 loop. When you give testosterone, these hormones will go up. Now, they go up depending on a number 0.85

00:50:35.100 of factors. 5-alpha reductase has quite a strong genetic component. So some men are very strong 5-alpha

00:50:42.640 reductase producers, and they're going to make a lot of DHT. By the way, this is responsible for one

00:50:48.260 of the side effects of testosterone, which is hair loss. So a lot of hair loss is driven by DHT and

00:50:55.180 the androgen receptor, and therefore, if you're susceptible to that and you give testosterone and

00:50:59.360 you make more DHT, you're going to accelerate hair loss. Similarly, aromatase activity varies

00:51:05.240 genetically, but it also varies by factors such as insulin resistance, obesity, and factors like that,

00:51:10.540 and therefore, the more adipose tissue you have, typically the more aromatase you have. So a person

00:51:15.920 who's overweight is going to make more estradiol, all things equal, from a given amount of testosterone

00:51:21.080 than a person who is lean. Are there side effects of having too much estradiol? Yes, there are. At some

00:51:27.780 point, estradiol levels can become counterproductive, and of course, if they get very high, although I've

00:51:32.780 never seen a case of this in 10 years of prescribing testosterone, we can see gynecomastia. So that's when a

00:51:39.540 man will develop breast tissue. Again, these are typically things that are only seen in people who

00:51:44.760 are using excessive amounts of testosterone, usually not under the care of a doctor, unfortunately.

00:51:50.160 But if estradiol levels do get a little too high, they can be managed with a drug that blocks that

00:51:56.920 conversion. The drug is known as anastrazole. Again, I personally am not a big fan of using it,

00:52:02.960 because I find you really don't need to use it in most men. In fact, it's nice to have the estradiol

00:52:08.620 levels go up, because you want it for bone health, you want it for mood, you want it for all of those

00:52:14.840 other reasons. So we will typically not use anastrazole unless the estradiol level is in excess

00:52:21.620 of 50, 55, or even 60, unless we are seeing symptoms that we would attribute to that.

00:52:27.620 My general philosophy on testosterone replacement is that there has to be a biochemical case for it,

00:52:33.740 i.e. free testosterone needs to be relatively low, at least below the 50th percentile,

00:52:39.220 and there needs to be, more importantly, a symptomatic case for it. If both of those conditions

00:52:43.760 are met, and of course the patient understands the risks and benefits, we would give TRT for a period of

00:52:50.240 8 to 12 weeks. We would determine that we've fixed the biochemical issue, so they go from being at,

00:52:55.940 say, the 30th percentile to being at the 80th percentile, and then we assess the symptoms. And

00:53:01.620 sometimes the man says, I don't feel any better. So you've fixed the number, but you haven't fixed

00:53:06.180 the symptoms. And with very few exceptions, at that point I would say it doesn't make sense to continue

00:53:11.320 this, we should stop doing it. Now, one exception to that would be if you were doing it for bone

00:53:16.340 health. So if a man has osteopenia, and he has low estradiol and low testosterone, we don't really care

00:53:23.080 about symptoms at that point. We want his testosterone high, we want his estradiol high,

00:53:26.960 because those are going to be two of the most important steps we can take in combination with

00:53:31.360 heavy training to increase or at minimum maintain his bone mineral density. But for most men,

00:53:37.180 we care about the symptoms more than we care about the numbers. And if we don't fix the symptoms,

00:53:41.760 we take it off. And we also watch, hey, do your symptoms get worse when we remove the testosterone?

00:53:46.540 Oftentimes they don't. And again, I can't answer what's going on there. I suspect that these might be men

00:53:51.540 who have either low amounts of estrogen receptors, or their estrogen receptors are just highly

00:53:57.080 saturated with a little bit of testosterone that they have in the first place. All right,

00:54:00.780 so there you have it. That's sort of the quick overview of the male sex hormone system. Again,

00:54:06.840 I think this system has its own nuances and complexities vis-a-vis how to make the diagnosis,

00:54:12.260 and then of course, how to treat it. Thank you for listening to this week's episode of The Drive.

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The Peter Attia Drive - May 29, 2023

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

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