What's the Deal with Cortisol?

Perry: [00:00:01] Emily, we're talking about cortisol today, which people say is a stress hormone. And yeah, we'll get there. But I've been thinking a lot about stress this week. And one thing I wanted to tell you is that my fitness tracking watch, which is a Samsung watch, periodically pings me just to be like, hey, you're feeling very stressed right now. And this is.

Emily: [00:00:23] That sounds so annoying.

Perry: [00:00:24] It's not helpful. Samsung. Um, I have no idea why. Like it'll come up and I as a doctor, you know, I'll take my pulse and be like, is something weird happening? And I think I feel fine. But then of course it gets in your head. It's like, what? Well, am I stressed? And then I decide, well, I must be stressed and then I'm stressed. Does this happen to you?

Emily: [00:00:46] No, because my fitness tracker, of which I have two, uh, give me different kinds of inputs. But I will say at the end of the day, every day I get a message that's like, today you spent blah, blah, blah minutes in the high stress zone. [00:01:00] And then it tells me whether those are like part of my actual exercise or other things. Sort of like today, you spent two hours and nine minutes in the high stress zone. The majority of which came from activities outside of strain. And then it's like, oh, well, what, what else was I what else was I doing? And then it's usually like, usually this came from sleep. Then I'll be like, why did you drink alcohol? That's like, it's like, so it gets a little more judgmental. But yeah, people don't like the judgment aspects of watches. It's like, do you ever do you run with a watch? I do exercise. Do you notice that when you start running, it beeps a number like plus one plus two, negative one. Does your watch do this?

Perry: [00:01:40] My watch doesn't do that.

Emily: [00:01:41] This is the worst thing. You're like running along and you're like, I feel pretty good. And then your watch beeps and it's like negative six and that's.

Perry: [00:01:48] You suck at.

Emily: [00:01:48] This. You're you're bad. And so I think they should dial down the amount of information our watches are pushing at us.

Perry: [00:01:54] I think telling someone, hey, you're you're stressed Man is more or less [00:02:00] the equivalent of me telling my 16 year old daughter, like, you seem like you're in a bad mood. Like it's just just it's not going to go well.

Emily: [00:02:08] One step up from like, are you getting your period? But like still pretty bad.

Perry: [00:02:13] Okay. Having three older sisters, I know not to ask that question.

Emily: [00:02:17] You know, you learn that you learn that.

Perry: [00:02:19] Uh, maybe we need a more objective readout of stress. Maybe that objective readout is cortisol. Maybe not. Let's figure it out.

Emily: [00:02:26] Find out. I'm Emily Oster, I'm an economist and a data expert.

Perry: [00:02:32] And I'm Perry Wilson. I'm a medical doctor.

Emily: [00:02:34] It's Thursday, July 9th, 2026. And this is Wellness, Actually.

Perry: [00:02:39] Because you're getting a staggering amount of health and wellness information nowadays from every source imaginable. And some of it is awesome.

Emily: [00:02:47] And some of it is, well, actually bullshit. Fortunately, we're both people who know how to read studies, how to parse the data and can tell you what's worth thinking about and what you can [00:03:00] safely ignore.

Perry: [00:03:01] But before we dig in, a note that this podcast is for educational purposes and should not be construed as medical advice. We don't know your unique situation, so talk to your doctor for personal health decisions.

Emily: [00:03:12] This week we're asking what's the deal with cortisol? Perry and I will give the official smash or pass, and then we'll get to your question of the week. But first, let's do the health news roundup after the break.

Perry: [00:03:34] And we are back with the health news of the week. Emily, the FDA is allowing Zyn pouches to market their relative health benefits compared to other tobacco products like cigarettes. What's going on here? What's up with Zyn?

Emily: [00:03:54] So Zyn is a tobacco product. It is a nicotine product in particular, [00:04:00] and people like it. A lot of people like it a lot. Uh, it's become very popular with like tech bros because there's this sense that nicotine increases your focus and people like Andrew Huberman are kind of into the health benefits of, of nicotine, but they also understand that smoking is bad for you. And so this is like a way to get your nicotine without smoking. And okay, so the FDA has now allowed zyn to make what I would describe as health statements. So the claim is things like using zyn instead of cigarettes puts you at a lower risk of mouth cancer, heart disease, lung cancer, stroke, emphysema, and chronic bronchiolitis. That statement is, I would say, broadly true. So these products are definitely safer than cigarettes. I think what many people are concerned about is that children will see this and be like, hey, Zinn's a health food. And like I can do. And this is like, not bad for me at all. And on top of an atmosphere [00:05:00] in which you can also get, as we talked about in an earlier episode, like fruit flavored vapes, we're kind of entering a place where somehow we've come up with this idea that there's like health, health benefit opportunities to things that are not cigarettes, but still have this nicotine. And I think that's pretty dangerous in part because, um, if you get addicted to nicotine and then there's no zyn around, you got to move to something else like cigarettes, which are bad for you.

Perry: [00:05:28] Yeah. Or just zyn. I mean, this is or.

Emily: [00:05:31] Just zyn is bad for you. We don't really.

Perry: [00:05:33] Know. Right. I mean, this is true that smoking, like lighting something on fire and inhaling the smoke that comes out of it is worse for your lungs than sucking on a nicotine pouch. This is you're you're at less risk of lung cancer. But nicotine is a highly addictive substance. It binds to a receptor in your brain called the NMDA receptor. It makes you feel certain good things. And like all physically addictive substances, when it's taken away from you, you feel much worse than [00:06:00] you did at baseline. The psychological impact of that may be substantial. Certainly, the economic impact is substantial because these things cost money and being addicted to something that you need to take, even if it had like absolutely no ill health effects, if it was just like, oh, man, I've got to buy this every day and keep sucking on it imposes a cost. So it's an interesting shift at the FDA where they're kind of being accurate. But I think from a public health standpoint, they're not doing a great job telegraphing that like this still isn't a good idea.

Emily: [00:06:29] Yeah. I also think we're actually, in terms of the health benefits or costs of, of nicotine, you know, there's some research that nicotine kind of increases focus, but I don't know that we have anything that would tell us about the health potential health costs of consuming quite a lot of nicotine, which is effectively what people are doing when they're consuming many, many zyn pouches in a day. So we're getting kind of a dose that's even a bit different probably than we would tested in, say, mice. Yeah. Anyway, um all right. Something else that's going on [00:07:00] is an outbreak of explosive diarrhea. Uh, Cyclospora outbreak is happening throughout the U.S., especially in places in the Midwest. Perry, what can you tell us about the explosive diarrhea and where it's coming next and why?

Perry: [00:07:17] Uh, okay. Cyclospora is a parasitic amoeba that causes a really bad gastrointestinal illness. Voluminous watery non-bloody. For what it's worth, diarrhea. People are going dozens of times per day can lead to pretty severe dehydration, including the need for IV fluids, etc.. Current numbers there are 700 reported cases. This is a, you know, one of the, uh, reportable outbreaks. So like if you get a positive test and you if you run a clinical lab and a positive test comes through, you're required to report it. So we catch those. But there are likely people who are suffering in silence at home and drinking [00:08:00] their Gatorade and not getting officially tested for this. It's predominantly in the Midwest. The concern is that we actually don't know the source. So it's clear that, you know, where Cyclospora usually lives is on, um, produce and particularly like, uh, like mint and parsley, like the sort of garnish we produce as well as berries, which gets into my head because the berries are so good right now. And I like am getting blueberries and strawberries and raspberries and blackberries all the time at my grocery store. But so far, testing has not revealed a particular source. It is certainly out there.

Emily: [00:08:38] Yeah, it's I should say it's a it's actually a hard thing to test exact sources for because it takes the incubation period is not immediate. So if there's something which makes you sick in, you know, three hours. It's actually quite easy to say, okay, you know, a group of people got sick within three hours. We know exactly what they ate three hours ago. Okay. It was spinach or whatever. Here. It takes a while. People don't remember what they [00:09:00] ate. They ate a lot of different things. It's been hard to pinpoint.

Perry: [00:09:03] Yeah. One thing I was looking into about this, because my daughter gave me a hard time the other day because I made her a hamburger, and she said it was undercooked. And she's very afraid of gastrointestinal illnesses. And you sure. But, you know, yes, I guess you should cook your meat adequately. But like, come on, a rare hamburger is just the best thing in July. Um, so I did dig into this to see like gastrointestinal illnesses in the United States, what percent come from meat and poultry versus produce. And actually 46% of the foodborne illnesses come from produce and 31% from meat and poultry, which leaves, I don't know, whatever percent for I'm not sure what else, but more often, more often from produce. Yeah, it could be things like that. But produce is the most common source for foodborne illnesses in the US. You should wash your produce and guys, it's watermelon season like you should be washing the outside of your watermelon. I know you think that you're cutting into it, but you know you cut through [00:10:00] the skin and it goes through. That's my own. You can suffer your.

Emily: [00:10:06] Safety pennies here for ruining everything. Wash your watermelon.

Perry: [00:10:09] I'm not ruining it. Just wash it and then it's delicious. Um, all right, let's talk about, um, a new secret shopper study of these GLP one websites. So as you know, there are multiple websites online that market GLP one and a new study actually out of Yale, although I wasn't affiliated with it, um, set up a fake persona and called 49 of these websites and was able to get a prescription from 45 of the 49. And two of them issued a prescription in under five minutes. Emily. Problem or solution?

Emily: [00:10:49] I would say problem. I mean, look, I, I, we've talked about this before. I'm, I'm a smash broadly on GLP one as a treatment for many things. And I think this is an incredible [00:11:00] technology. However, it is a medication. Injectable medication or now oral. But it's a medication that has significant effects on people and should ideally be prescribed by a doctor who has had some interaction with the patient. And I do worry about people who are really don't need this or for whom. Maybe it's it's even kind of damaging in the sense that, you know, we have seen some, some concerning at least anecdotal evidence about people have suffered from eating disorders in the past, this kind of this environment re-upping those. And I would worry about people in that category calling an online pharmacy and saying, hey, I feel like I need a GLP one similar to an article I saw come across my Instagram feed. It's just a clip of someone saying that the way that she got a GLP one was by wearing ankle, £20 ankle weights to the doctor so she could weigh the required £160 [00:12:00] to get on GLP one, even though she was only £120, which probably does not necessitate needing a GLP one. So that feels bad to me.

Perry: [00:12:10] Yeah, that should feel bad. Um, just over 50% of the site's asked about eating disorders at all in their intake surveys. Um, so there is some, uh, potential missed opportunities there. And I should say that almost all the sites are selling compounded GLP ones. They do this by making custom preparations. They take bulk amounts of like Ozempic or mounjaro, dissolve them in their own water, and then you have to add something to personalize it to the patients. They usually add like some B12 or something, so that it's not exactly the same as the branded pharmaceutical. So it's in this very regulatory gray Grey zone. You got to be careful. I mean, you know, again, there's a flip side of this. And I actually wrote about this this week, which is like, if it's this easy, then should there be prescriptions at all? Like, like this middle road of, oh yeah, they're prescriptions, but everyone can fake it seems [00:13:00] sort of dumb. So you either close these loopholes and you actually have to see a doctor and discuss it, or you don't. And you just let let people buy the things and the libertarians win, right?

Emily: [00:13:10] Yeah. And I'm.

Perry: [00:13:10] Open to.

Emily: [00:13:11] Either. Yeah. We haven't made that choice with most other medications. And I think most people would not make the argument that we should be allowing people to, you know, take statins whenever or, you know, just get on different. But maybe, maybe people would argue that.

Perry: [00:13:26] All right, that's it for the health news of the week after the break. What's the deal with cortisol?

Emily: [00:13:36] All right Perry. I am delighted to talk about cortisol, something I've heard a lot about as a woman in her, let's say, mid to late 40s, I'm aware that raising my cortisol too high will lead to the dreaded belly fat, and I'm sure we'll get later to the many ways in which my bones are turning to dust due to my high cortisol belly fat combo. [00:14:00] It's terrible. But before we get into this, just for people who are getting all their information about cortisol from the same Instagram that I'm getting it from, let's start by defining what is cortisol and what are we actually talking about here? Overall. So you're a doctor. Tell me.

Perry: [00:14:21] Yeah. Oh man, cortisol gets such a bad rap online and it's such a critical hormone. It's so important. So cortisol is a steroid hormone. We've talked about these several times before. And wellness actually steroid hormones are really interesting because the site that they act on is in the nucleus is with the DNA of a cell. So all the steroid hormones, including things like testosterone and estrogen, get into the nucleus and change how DNA is transcribed so it can fundamentally change what cells are doing, which means all these things can do a million different things. It's not like, you know, this one protein is responsible for, [00:15:00] you know, increasing your sugar level or decreasing your sugar level. It does a million things. And I think the best way to sort of think about cortisol is that it is there primarily to save your life in the next ten minutes at the expense of the next ten years. So cortisol is a hormone that's present to keep you moving and alive after something really bad has happened to you. Like you got mauled by a saber toothed tiger, or you are, you know, running from something that is trying to eat you.

Emily: [00:15:34] Wait, can I, I'm going to pause you there because I think for most people, the hormone, the thing they think is driving that is adrenaline. So when you tell me you were you were chasing by a tiger, I think adrenaline. Yeah. They're not the same.

Perry: [00:15:48] They're not the same. And cortisol is secreted by the adrenal glands, which is where adrenaline comes from to. And and they are by all means related and evolutionarily follow similar paths. [00:16:00] But adrenaline is much more cardiovascularly active in terms of like flogging your heart and whatnot, whereas cortisol, um, is more focused on sugar levels. So when you're being chased by a tiger, you want there to be plenty of sugar in your blood for your muscles to use and for your brain to use. And you really don't care about whether there's energy for your gut or your liver or your bones or for your immune system, even, which is a very energetic, energy intensive thing. So you're kind of like shutting everything down and focusing all that glucose into muscle and brain. And so when you give someone cortisol or when they're endogenous, when their own cortisol goes up, their blood sugar goes up, their immune system ramps down. That's why glucocorticoids, which are cortisol derivatives, are immunosuppressants, things like prednisone. Many people may have [00:17:00] used hydrocortisone cream, like for itches and stuff like that. So hydrocortisone is cortisol the exact same molecule. There's no difference between hydrocortisone and cortisol that your adrenal gland secretes. I mean, they put it in a cream, obviously, but but that's what it is. The problem that people attribute to cortisol and sometimes incorrectly, as we'll go into is like, what if that stressor lasts longer than 20 minutes? Right? You're running away from the tiger. Oh, you made it away from the tiger. Great. You're good. Everything's safe. Everything can go back to normal. What if your whole what if your whole life is stressor? What if you're constantly feeling like you're being chased by a tiger and your cortisol levels are high all the time, and it tells a really nice story that like, oh, that would do a lot of bad things. But as I said, cortisol gets a bad rap. And, um, it might not be as bad as you think.

Emily: [00:17:54] So in terms of just sort of people thinking about like the way that their cortisol [00:18:00] moves throughout the, the day, because cortisol is a, it is a hormone and it's, it's would be a mistake to think of it as just always flat, except when you're chased by a tiger. Yeah, yeah. It is something which is fluctuating through through the day. It's highest in the morning. So when you first wake up in the morning, your cortisol tends to be tends to be higher and it's lowest sort of in the middle of the night when you are asleep. Is my sense, like on average for most people. And then it will spike at times during the day. This is something that's quite hard to measure, but in principle it would spike when you are doing either physically or emotionally stressful activities like running from a tiger. Is that true?

Perry: [00:18:39] Yeah, yeah, yeah. The morning cortisol spike is well described. It is one of the reasons why heart attacks are more common in the early hours of the morning, for example, because your body is sort of revving up to get ready to wake up the day. And we will get to this is a circadian rhythm, [00:19:00] like one of our fundamental circadian rhythms. It's about five times higher in the morning than it is at night. I mean, it's a real it's a real shift over time. And if you really dig into the data, you'll find that the level of cortisol might not be as important as the circadian rhythm of cortisol. So one of the things we see in the truly chronically stressed are actually not high cortisol levels. It's a loss of that fluctuation. It's flat cortisol levels.

Emily: [00:19:28] Yeah. So I think that's a good that's a good pivot into what I the first piece of what's tough about this entire discussion is going to be really hard about the data, which is like, what are we measuring and when are we measuring? So this is not there are some things we measure in people where I think we can say, you know, maybe you want to do some repeat measurements, but like we have a good sense, like something like, you know, like a one C levels for like a diabetic, you know, you test people, you test if fasting, not fasting. But we have a good sense. We have a stable sense of like how we test that. And we could use that [00:20:00] to say, you know, you're a diabetic, you're not a diabetic. Measurements of cortisol, which are done typically through through your blood, although actually they can also do saliva. You can also do hair. You have many different ways to test this. They don't all test the same thing. And because there's this fluctuation, it's actually a really, really hard thing to hit. If you wanted to say, what's the number that's going to tell me? I'm chronically stressed in some dangerous way. There's sort of no number like that.

Perry: [00:20:27] Yeah. And actually, it's a lab test that's pretty bad. So there are some there are some lab tests, like sodium level. That's just it's been figured out. And we can do it really quickly and it's highly accurate. And you test the same blood sample twice and you get the same number and like, it's really nice. And cortisol just isn't one of those things. I mean, one of the major issues is that 95% of cortisol in your blood is bound to proteins and is inactive. So these are just chaperone proteins that carry it around. And then the free fraction, the 5% is the thing that does stuff in your cells. But almost all the lab [00:21:00] tests out there are measuring the total. So you know, that's is it correlated with the free. Yeah. But not great. And it's hard to know. There's obviously the timing of measurement that's really important. So you know, you really want to if you actually needed to measure cortisol, for example, to, to tell if you have a disease of excessive cortisol production and these diseases exists called Cushing's syndrome or Cushing's disease, you get a test early in the morning when you've got the best chance of capturing things high. The assays that they use for cortisol have a lot of false positives. So there's cross-reactivity with a bunch of other hormones and other substances that people are taking in. It's just like, I mean, I'll say right now, like getting your cortisol measured. If you don't have symptoms of a cortisol, excess disease is you're unlikely to get any useful information.

Emily: [00:21:54] So a thing. Okay. So when we talk about the ways to to measure cortisol, actually measuring your [00:22:00] blood has both the total and free fraction issue. It also has the issue that when you take someone's blood, it raises their cortisol. Oh yeah. Yeah. Because it's stressful. It's like, it's stressful. Like somebody's sticking a needle in your arm and you're like, it's a tiger. Like, I better get ready to run away. It's not a tiger. You asked for that. But as a result, like saliva is in some sense the sort of best metric of this at a moment, because it's not stressful to take someone's saliva. But the thing that I wonder is why, you know, we have continuous glucose monitors. Why has someone not made something that I stick in my. You could put it on a zyn pouch, something I stick in my mouth and leave in my mouth all the time on like the side of my cheek. And then it constantly measures my cortisol. Don't you think Brian Johnson would buy that in, like one hot second? Like, why is the market not delivering that? Perry. What's the problem?

Perry: [00:22:49] No doubt people are pitching that in Silicon Valley right now.

Emily: [00:22:54] Um, call me call me VC funds. We're going to measure cortisol with our mouth sticky [00:23:00] mouth stick.

Perry: [00:23:02] I think two things. One, cortisol is complicated to measure. It's, uh, you know, it's a, it's a hormone. It's, it's, it's a bigger molecule than something like glucose, which is small and easy to measure. And then the second thing is that nobody knows what to do with the answer. I could tell you what your cortisol.

Emily: [00:23:18] That's not the answer. I'm sorry. That's not the answer to why they're constantly. People love to measure stuff. There's nothing to do it. The first answer was right. You should have stopped at that one.

Perry: [00:23:26] Okay, we will erase the second. No. It's fine. I can be wrong sometimes.

Emily: [00:23:30] Okay, so this is very hard to measure, and we'll get into why. That probably means you shouldn't you shouldn't measure it. But despite its difficulty in measuring, there is actually a fair amount of research on the relationship between cortisol measured in some way we will get to and various health outcomes. And I will just like spoiler. I think most of this literature is really bad and it is observational and not causal. And I have a lot of complaints about it, [00:24:00] and I've been practicing my complaints. But before we get into them, uh, I do think it's worth talking a little bit more. You alluded to to Cushing's disease, but a little bit more about the places where high cortisol can actually be very damaging. Or we know that this is a this is a problem.

Perry: [00:24:20] Yeah. We should talk about Cushing's disease because actually a lot of the influencer Work is taking what people see in Cushing's disease, where cortisol levels are through the roof and saying therefore mildly elevated cortisol levels in normal people also do this thing. And so, so what Cushing's disease is, is a benign tumor, typically on the adrenal gland that secretes cortisol. It is unregulated. So it just it's sitting there and it's just secreting cortisol, secreting cortisol, secreting cortisol. And that is quite bad for you. The the syndrome of Cushing's syndrome is characterized by pretty dramatic moon facies, what they call it, the very [00:25:00] round face that you may be familiar with. If you see people on very high dose of other corticosteroids like prednisone. Sorry about these terms, but this is what the medical terms are. A buffalo hump, which is like a collection of fat on the upper part of the back at the bottom of the neck striae, which are really violaceous, like deep purple stretch marks in the abdomen, a lot of accumulation of visceral fat, diabetes, high blood sugar, and so on and so forth. The treatment is removal of the cortisol secreting tumor.

Emily: [00:25:34] And I think it is it's actually very important to note, because some of the things we see in the sort of wellness influencer claim space are things that seem like, well, if you have this Cushing's disease, you will have this. And therefore, if you have a mildly elevated level of cortisol in the normal range, you also get less, maybe less belly fat, but still some belly fat.

Perry: [00:25:56] Right, right. And that, that has that nice sort of logical, [00:26:00] like step by step ring to it. But if you've been listening to wellness, actually, you know, you actually have to prove these things with data. So let's talk about data. I mean, I, you know, there are clearly cases where cortisol, high cortisol levels are, are bad for you. I mean, maybe the most dramatic one is in sepsis and septic shock, where it is fairly well established that if people are coming in with very high cortisol levels. In the setting of sepsis, they're more likely to die. It's a nice study in PLoS One. In 2019 that took 139 patients with severe sepsis or septic shock, and those who had cortisol levels that were high by their definition, had a ten fold higher mortality risk, which is a pretty large effect size. Now, Emily, that's that's not a causal study, as you said, that's observational. So walk me through like, why? Yeah. Is it the cortisol that's bad? Or what are you thinking when you hear, okay, high cortisol, ten fold risk of death in septic shock?

Emily: [00:26:58] Yeah. So I do, [00:27:00] I think sort of two things in that case, which come up again later. So, so one is that, yeah, this is not a randomized. The cortisol. Some people came in with a higher level of cortisol than others. It seems plausible to me that that is measuring something else about, you know, how stressful, like what else is going on in your life? Or even like, how bad is this sepsis? I realize all sepsis is bad. Um, sepsis is not good, but sort of like, could you read this as this is, is kind of a metric itself of how much is the body struggling in other ways. And this is just one measure of that. I will say in this particular case, the fact that the odds ratio is ten, which means like the mortality risk is ten times as high, that's actually a quite that's a very big effect. It is therefore the kinds of biases I have in my mind, like differences in other things that could be going on in people's lives and so on, probably aren't driving a ten fold increase in mortality. So the, the combination [00:28:00] here of the particular outcome, which is so extreme and how large the effect size is, would makes me more confident in that result, even though I think it would be better to have a randomization, although this is a case in which I cannot imagine how you would randomize people to different cortisol levels. That's not that's not really an available randomization, which is why we're going to Generally need to rely on observational data.

Perry: [00:28:24] Yeah, yeah. And for the medical people listening who trained back when I did, there was a time when we gave people cortisol or other glucocorticoids when they had sepsis, because we thought, oh, all this inflammation is the bat like their, their immune systems going crazy. We need to suppress their immune system a little bit. That was standard of care for a while. We no longer really do that except in rare circumstances. And so it is quite complicated. And I think, you know, it's certainly possible that a large amount of that observed effect size is just due to the fact that really sick people have really high cortisol, potentially. Um, but most people who are listening to us are not currently [00:29:00] having sepsis or septic shock.

Emily: [00:29:01] Yeah. Stop listening. If that's you.

Perry: [00:29:03] Stop hanging in.

Emily: [00:29:04] There and do. Yeah.

Perry: [00:29:07] Maybe we're the one thing keeping them sane in the hospital bed.

Emily: [00:29:10] We're not. All right.

Perry: [00:29:12] We believe in you.

Emily: [00:29:13] Most people are worried about the idea that a chronically elevated or frequently elevated level of cortisol, or just having high cortisol. Whatever people seem to mean by that is bad for some health outcome, like heart disease being the sort of the one we should start with. It's the one that comes up the most. And so this is a place where there is some data. And I want you to describe the data. And then I'm going to tell you my feelings on it.

Perry: [00:29:40] Yeah. Why it's wrong. I'll set you up in the best way I know how. Okay. I'm going to give you two studies here. One is sort of a prototypical. There's other studies in this space looking at urinary cortisol. Gosh, we didn't even mention that. There's yet another place you can measure cortisol. You can measure it in the urine. And [00:30:00] then the risk of cardiovascular mortality. This was from the Journal of Clinical Endocrinology and Metabolism. That's a good journal. 2010 861 participants above age 65. They got 24 hour urine cortisol levels at baseline and followed them for six years. Over the course of that time, people in the highest tertile to the highest third of urinary cortisol levels, had five times the risk of dying of cardiovascular disease, but there was no difference in deaths from other causes. So there's a big effect size five fold from higher cortisol levels. I told you I'd give you one other study just to give you something to to talk about. So nope. I'm not. I'm going to wait on the Mendelian randomization because it's going to require some explanation. So let's start with this. My urinary cortisol is in the top third of people's urinary cortisol. I have five fold the risk of dying from cardiovascular disease in the next six years. Sounds pretty bad. Got to get my cortisol down.

Emily: [00:30:56] Okay. I mean, look, here are some things that [00:31:00] raise people's cortisol. Being poor, working at night, having few resources, having a stressful family life, having other diseases, things like that. All of those things are independently associated with death from heart disease. We know that like a million different ways. Exercise causes you to be less dying. It lowers your cortisol overall. All of these things are like going on in the background. And if you look at the people in the study and you look at the terciles, they differ in a bunch of different ways from each other. And it is therefore extremely difficult to imagine that we are attributing this difference in the risk of death to these levels of cortisol, as opposed to attributing them to these other things. Now, this is a case in which actually the whole thing is very complicated because, well, maybe it's these [00:32:00] other things raising your cortisol, which is then causing you to, you know, have a higher risk of death. That's an interesting mechanism. But if you ask like, what's the like, what's the action item here? What's the like thing that would fit? It's changing these other things. It's not like if you gave someone a shot that magically lowered their cortisol. That would have this positive impact on them. These results are also the sample is quite small. Not that many people died, which is good, and the. Therefore, this sort of hazard ratio of five is like incredibly noisy. It's consistent with an effect that's too. It's consistent with an effect of 13 times, which is definitely not true. It's just this is a statistically noisy, very potentially biased effect. I just I don't think we learn anything from studies like this. I just think we learn nothing.

Perry: [00:32:50] So I, I completely agree that there's all this stuff that can affect your cortisol that might also independently affect your risk of death, right? [00:33:00] We know in America at least being poor dramatically increases your risk of dying from cardio.

Emily: [00:33:04] And also dramatically increases your cortisol.

Perry: [00:33:06] So yeah, so, so, okay, that's classic confounding. The problem is, you know, we all love a randomized trial, but no one's going to do a randomized trial of supplemental cortisol on people. That's not going to happen, probably would be considered unethical. So we're left with some other options. And I think I think we need to talk about Mendelian randomization. Okay. So let's put on our genetic hats for a second. I, I sort of believe in Mendelian randomization as an approach. And Emily, I think you are more skeptical of it. So I'm going to let me tell you how I view it and then you tell me why I'm wrong. Okay, here's the idea. There are certain genes that increase the amount of cortisol you make independent of other things, genes that have to do with hormone synthesis and stuff. And everyone has little variations in their genes, and some are just a bit more active than others. And so all else being equal, [00:34:00] there are people who genetically live at a higher cortisol level than a similar person who had a different genetic background. So, you know, and this is true of everything, not just cortisol, right? There are some people who just genetically have a higher LDL than other people, and some people have genetically lower LDL.

Perry: [00:34:17] Okay. Because your genetics are assigned at birth, not know at conception, um, that exposure happens before you know that you're poor, before you know, you have stress in your life before anything else. It cannot be related to that. The genetics are not related to those things. Being poor doesn't change your DNA. Right. And therefore, we can use those genetic signals and say, okay, here's a person whose genes have them exposed to a higher level of cortisol than they otherwise would have been, given everything that's going on in their life. And here's a person whose genes have their cortisol lower than they otherwise would [00:35:00] have been giving everything that's going on in their life. And if the person with the genes that predispose them to high cortisol has a higher risk of cardiovascular disease than the person whose genes predispose them to low cortisol, I conclude, therefore, there is a causal link between cortisol level and cardiovascular disease.

Emily: [00:35:19] The term Mendelian randomization implies that something is being randomized. And so I think when we think about this technique, we want to think about the word random. So what you are suggesting is that the genes are allocated randomly, that when you are given genes, you are there's a piece of the genetics that are coming randomly to you. That is not true when comparing across people in the population overall. So let me give you a more direct example of this. Imagine that instead of cortisol, we were thinking about eye color [00:36:00] and you said there's a gene that determines your that determines your eye color. In fact, there is a gene that determines your eye color. There's a set of genes. We understand how those work, but it is not. When we look across the population, those genes are not randomly distributed. It's not like randomly. When you're conceived, you are given one of the eye color genes. It's random, only conditional on the genes that your parents have. So you have a set of parents and you have your mom has a set of 23 chromosomes. She has two copies of each. And at conception in the egg, you get one of those.

Emily: [00:36:37] And which one you get is random, but who your mother is, the genetics that she starts with is not random. So when we talk about Mendelian randomization, there's something cool, a cool idea in here. I want you to imagine two children born to the same set of parents, and mom has two copies of each chromosome. And [00:37:00] on one of those chromosomes, she's got like the high cortisol gene. And on the other copy, she's got the low cortisol gene and her children. Let's say one of them gets the high cortisol. One of them gets the low cortisol. That's random. And so then we have two siblings who are effectively everything is, you know, the same. Except that in this case, this particular thing is randomly allocated weight. And so you could then get many sibling pairs like that and say, conditional on your family controlling for your parentage, comparing you to your siblings. We're going to see whether the sibling who was randomly allocated the high cortisol gene has worse outcomes than the sibling that was not randomly allocated. That's a really cool idea that uses genetics and randomizes. Do you agree?

Perry: [00:37:53] Yeah. All I wanted to say was that in my mind, one of these kids is named Gene and the other is named Eugene. [00:38:00]

Emily: [00:38:01] I love that so much. Okay. But what? Okay, so that technique.

Perry: [00:38:07] Just trying to.

Emily: [00:38:08] Techniques works like it works sort of in concept the way I've described it. And there are some actually some issues with using that technique in practice, but at least in principle, there is a real randomization there. Here is the problem. The studies that are being done that are using a technique they are referring to as Mendelian randomization, do not actually do what I just described. Instead, what they do is they don't look within sibling pairs. They look just across people in the population. And that is ridiculous because genetics are not randomly allocated across people in the population. I mean, an equivalent thing is if you said, well, I'm interested in the impact of race on something, and I don't think I can just look at people's race because that's confounded with all kinds of other things. But I'm going to look at a gene for skin color, and I'm going to relate that to the outcome. [00:39:00] Well that's stupid. That's not like doesn't make any sense. It doesn't work. And so this, this technique is not being. It's not that it's conceptually poor. It's being used in a way that makes no sense.

Perry: [00:39:12] Well, so there is a caveat to Mendelian randomization. So to take your skin color example, which says that in order to use this technique, you have to show that the gene is associated with the phenotype. Right? So the gene is associated with skin color let's say. And the gene is associated with the outcome. But the gene is not associated with the outcome through any plausible path outside of the phenotype. So there is like some statistical testing you can do for that.

Emily: [00:39:43] Yeah. That's called the exclusion restriction. And in the cases that you've described where we're comparing, say two people with different genetics across different families, where, for example, one of them is born to a set of parents who have high cortisol, and one of them is born to a set of parents with [00:40:00] low cortisol. Now you're exclusion restriction is failed. And so that just doesn't work. So I think you're right. There is a thing and it's totally failing. And these guys don't seem to understand that. I just don't understand. I fundamentally, Perry, this is like drives me crazy because people in medicine use this technique all the time. And I just think they don't understand what they're doing. And I can't understand why they don't understand.

Perry: [00:40:23] Let me give you the results of the cortisol Mendelian randomization because maybe this is a moot point. Okay. So in the observational framework, we've seen that a high level of cortisol increases your risk of cardiovascular death by 500%. Okay. In the Mendelian randomization analysis, genes predisposing to high cortisol increased the risk of cardiovascular death by 8%.

Emily: [00:40:46] Right. I mean, okay. So one thing is if you think what Mendelian randomization is doing is fixing your causality problem, then I think what you would say, okay, now we've got a better result and it's basically zero. [00:41:00]

Perry: [00:41:00] Like it's basically.

Emily: [00:41:00] Zero. It basically doesn't matter.

Perry: [00:41:02] Does not suggest causality.

Emily: [00:41:03] I will say I think counter counterexample. As I've noted, I don't think the Mendelian randomization really makes any sense at all. And part of the reason that the effect I think is much smaller is because the genes they're identifying have very little predictive power on actually having high cortisol. And so like just these, these genes are not have very high penetrance. And so this may be failing and giving you a very small number for reasons that kind of have nothing to do with getting rid of bias. They may just be generating noise. I hate this technique. I understand that I'm being pedantic and annoying and talking about I hate this technique.

Perry: [00:41:45] I just, I, that's fine. We can't randomize people to high cortisol. We can't supplement them with cortisol or placebo. So we're stuck. We have to make some inferences. But I will say that based on this data, there's not a compelling argument that [00:42:00] high cortisol level in and of itself is causal of cardiovascular disease.

Emily: [00:42:04] I totally that that I think we totally agree on. I think your question about give me a better technique is an interesting one. I mean, I do think a true Mendelian randomization with a sort of a sibling pair study would be an interesting thing to explore. It could have some other problems, but I think that would be something interesting to to explore. I agree this is a very difficult problem. I think one thing you could imagine randomizing if you sort of, at least in a short term way, is some of the kind of behavioral techniques that might lower people's cortisol, like meditation. You can imagine running a study where you're like, one group gets like a lot of meditation support or some other, you know, therapy, something that would lower their cortisol. They probably have other effects. So it's not like a great study, but, you know, like it's something like that to try to affect people's cortisol. I agree, we're not going to find anything, but it doesn't mean it's not interesting to, to try.

Perry: [00:42:58] To at least look. So [00:43:00] all right, let's go.

Emily: [00:43:01] Sorry I got to exercise, guy. I feel like people are going to be like, why are you so exercised about this? But it's like, this is my job. This is like a thing. This is like the core of my of my like professional life. Other than parenting, writing is like statistical methods.

Perry: [00:43:15] What you guys don't know is that Emily. Emily's first boyfriend was a Mendelian randomization study. So, uh, okay, I want to move rather quickly through the other stuff that, um, the other stuff that people say that high cortisol does if we're going to write off cardiovascular disease. Um, and again, guys, we're not saying that there's no association between higher cortisol levels and these things. We're asking, is it the cortisol, not the like life stress and the other stuff. So I think, you know, a big one is diabetes, metabolic disease, right? Like we, we certainly know that people with Cushing's syndrome, much higher risk of diabetes. We know that when you put people on steroids like prednisone or [00:44:00] hydrocortisone, their blood sugar goes up. I was surprised here, Emily. Like there's a nice meta analysis of 21 studies. This is appearing in Psychoneuroendocrinology in 2018. 11,000 people or almost 12,000 people. No significant difference in basal cortisol levels between subjects with and without the metabolic syndrome, which I just wouldn't have. And that's like, that's not even a causal study. It's just.

Emily: [00:44:25] I mean, I think.

Perry: [00:44:26] There's no link.

Emily: [00:44:27] What's so interesting there is I might have, I would have thought that that we would see an association there just because of all of these other factors. Totally. But it seems like even, you know.

Perry: [00:44:38] Even the confounding can't.

Emily: [00:44:40] Even the confounding can't get you there somehow. Yeah. Maybe that's because it's hard to measure.

Perry: [00:44:44] Um, let's do stubborn belly fat.

Emily: [00:44:48] Yes. So much of it. Okay.

Perry: [00:44:51] How do I mean, I have so much stubborn belly fat. I don't think you do.

Emily: [00:44:54] It's so stubborn. I'm always arguing with it. It's always making these terrible points.

Perry: [00:44:59] Our [00:45:00] producer, Tamar just rolled her eyes like Emily saying she has belly fat.

Emily: [00:45:04] How do you describe stubborn? Well, okay.

Perry: [00:45:08] Anyway, I as a as a as a middle aged man. Stubborn belly fat is, I get it. It's stubborn because it's like I work out, I try to eat right and it's still there. And that's annoying. So, uh, I did look into this for us once again in Cushing's syndrome and Cushing's disease, there is a substantial increase in visceral adipose tissue. That's what belly fat is as opposed to subcutaneous fat, which is kind of all over your body. Belly fat is visceral fat and it's not good for you. Higher amounts of visceral fat are associated and potentially causally with cardiovascular disease. Um, but in a study appearing in clinical endocrinology in 2024, they looked at visceral fat and subcutaneous fat among people, just regular Joes with varying cortisol levels. And there was no association between higher cortisol level [00:46:00] in the non-pathologic range in the non Cushing's disease range and belly fat. So that's not it, folks.

Emily: [00:46:06] I also think it's worth saying like when people are chronically stressed it actually isn't. We said this at the top. It's worth saying again, it's not that chronic stress means you always have a high cortisol level. It actually means your cortisol is very flat as opposed to moving up and down, like it's sort of supposed to typically. And so like your cortisol is supposed to be responsive to like events and to the day, which of course is evolutionarily valuable because you want to really be able to respond when the tiger, when the tiger comes, when people are chronically stressed, they can get a sort of flattening of, of the cortisol, but it's not that it's higher. And so this sort of whole narrative is kind of.

Perry: [00:46:43] Yeah, it can even burn out. So there's some nice studies in PTSD in patients with PTSD that actually shows your typical patient with PTSD has lower cortisol levels than controls who don't have trauma. Um, so yeah, this whole idea that like your cortisol is so high and because you're [00:47:00] so stressed, if anything, it's blunting the cortisol response or your cortisol might even be low.

Emily: [00:47:06] So you don't need to detox your cortisol. Not that we have any like people will sell you a lot of stuff. Gummies. Oh, yeah. Drinks.

Perry: [00:47:13] Yeah. I mean, I did, I did look into it in case people want to make their cortisol. You know what? There are some things that will make your cortisol lower that I think are good for you anyway. So there's a pretty large meta analysis of randomized control trials. You had talked about, you know, randomizing people to interventions to lower cortisol, which of course have off target effects. This is once again, Psychoneuroendocrinology 2020 458 randomized trials, just about 3500 patients looking at different ways to reduce cortisol levels and mindfulness meditation relaxation techniques both reduce cortisol levels by about a third or so. Not bad. Um, interestingly, the studies of yoga and tai chi didn't have a significant effect. And the talk therapies like [00:48:00] cognitive behavioral therapy and counseling did not have a significant effect.

Emily: [00:48:03] So maybe mindfulness.

Perry: [00:48:04] Meditation. Yeah.

Emily: [00:48:06] Exercise is good for your cortisol lowers your cortisol. We also see that in, in randomized controlled trials, like.

Perry: [00:48:13] Uh, absolutely exercise. And we've hit on this several times, but sleep, you guys, especially, especially if you want to maintain that diurnal variation, which does appear to be an important thing for your overall health. Um, getting adequate amounts of sleep gets the cortisol into the right place at the right time.

Emily: [00:48:31] So is it worth, I think, an interesting question. Is it worth measuring cortisol at all? So we just gave you know, there are these are recommendations to that will in reduce your cortisol, but also things which you should probably be doing for general health maintenance regardless. Would you recommend someone measure their cortisol.

Perry: [00:48:52] If they had moon facies, a buffalo hump or violaceous striae, I would recommend that they have cortisol levels measured.

Emily: [00:49:00] Do [00:49:00] you want to know? My cortisol level is because I looked it up while we were here, because I had it measured in the last time I had a blood test.

Perry: [00:49:06] What time of day was it?

Emily: [00:49:08] Um, it was in the morning.

Perry: [00:49:11] It was 15 micrograms per deciliter.

Emily: [00:49:15] 19.

Perry: [00:49:16] Okay.

Emily: [00:49:16] It only got in the in the sufficient range for my.

Perry: [00:49:21] Um we should say I can't believe. Yeah. Sufficient. You know, you die without enough cortisol, right. Like that's the other the flip side of this is that your adrenal glands can stop producing cortisol. This is called Addison's disease, which JFK had. Um, and it causes like severe hypotension, sodium wasting death. You need to supplement. That's bad too. So I think cortisol is just like not something if you're into interested in your health and wellness, it's just not worth your time. It's like, don't you're not going to change your life based on it. And yes, you should de-stress, but not because of cortisol.

Perry: [00:49:57] I mean, look, I think. Every time we talk about hormones, [00:50:00] I am more and more impressed with the endocrine system. I feel like, you know, the human endocrine system is so like tight and it's so well thought out. And there's so much of the wellness space that's about like, give yourself more of this hormone and more of that hormone. Do this. And most of the time, like your endocrine system, like it's thinking about that, like it thought about when the cordless, when it should be low, like how much you need. It's like it's estrogen, like we're all kind of moving, moving together. And I just, I don't think it's a system we want to be messing with too much.

Perry: [00:50:35] With the exception of hormone replacement therapy and.

Emily: [00:50:37] With the exception of. Yeah, no. Yeah. Okay.There are some things, but like, like our tendency to want to get inside the endocrine system and mess around with it, I think is, is over. I think we're doing, we're doing too much of that outside of I agree. Hormone replacement therapy.

Perry: [00:50:52] Yeah, yeah. Cortisol too high is bad. Cortisol too low is bad. It needs to have a specific pattern. You're not going to get this right with like ashwagandha, which [00:51:00] does lower your cortisol a little bit, by the way. But like, this is one, trust your body a little bit and be zen.

Emily: [00:51:06] Trust your body, but don't trust Mendelian randomization because it's stupid.

Perry: [00:51:14] It can be done very well.

Emily: [00:51:16] It can be, but it's not. Okay. Enough of that for me. All right. Perry, smash or pass cortisol.

Perry: [00:51:22] Um, I mean, I'm a pass in terms of cortisol as a wellness metric. Obviously I love the hormone. I die without it. So do you. But I'm a pass. Emily. Smash or pass.

Emily: [00:51:33] I am a pass on anything that involves detoxing or detoxing. Changing gummies adapt to this and that. Uh, just trust your endocrine system. Unless you have buffalo hump and then get it looked at.

Perry: [00:51:48] All right. That's it for cortisol, your mailbag. Question of the week after the break.

Mailbag: [00:51:57] Hi, Emily and Perry. This is Celeste in Detroit. My [00:52:00] question is more personal to both of you. Is there anything that you felt certain about, like ten years ago that now you look back on and cringe? We all have them, and I'm dying to know yours. Thanks.

Perry: [00:52:13] Oh, this is such a good question. I'm sure there are many things that if I that I've suppressed and I have convinced myself that I never believed that really I did. But the one I am quite sure I believed strongly. And I think I'm going to just cheat a little bit and say, this was more like 15 years ago, maybe even pushing 20 years ago. But I was a hardcore fluid resuscitation vigilante when I was in medical training. So when someone came into the ICU with sepsis, I was it was like a contest, like how much IV fluid can I put into this person in the next 12 hours? Um, and back then we thought this was the right thing to do. This totally makes me cringe now. Like there's been a lot of evidence in the past 20 years that suggests that overly [00:53:00] aggressive fluid resuscitation can cause major problems down the road. And, you know, people get volume overloaded and their lungs don't work anymore and stuff like that. But it was like it used to be a contest among the residents. Like, oh, I gave that guy 15l last night and like high five. Like, yeah, that's how you treat sepsis. Um, and I cringe a little bit thinking about that now. How about, um.

Emily: [00:53:20] Um, I, that's amazing. Okay. Mine is more, mine is more personal. Um, it actually vaguely relates to, to cortisol. So I used to be very sure that you should exercise in the morning before you eat and that you should not eat anything before you should exercise fasted. But it turns out that's really stupid. And, uh, it's really bad for your cortisol. I think it raises your cortisol a lot to exercise fasted, and I don't do that anymore. And I think it was part of this space of like, you know, like diet culture that I find now, uh, very [00:54:00] cringey.

Perry: [00:54:00] It's okay. We're all entitled to change.

Emily: [00:54:03] I can't believe you guys were high fiving. That's like, that's so nerdy and weird. Oh, yeah. Yeah, it makes me. Yeah. Okay. Nerdy feelings. I'm not going to comment.

Perry: [00:54:17] Thanks.

Emily: [00:54:20] All right. That's it for us today. Stick with us next week when we'll ask what's the deal with pregnancy brain. And we'll have a special guest. Well, this actually is produced in association with iHeartMedia. Our senior producer is Tamar Avishai. Our executive producer at iHeart is Jennifer Bassett. Our theme music is by Eric Deutsch, and our content is for educational purposes only.

Perry: [00:54:43] If you like the show, help other people find us. Leave a rating and review on Apple Podcasts or your podcatcher of choice and help us spread the word about the show. You can follow us on Instagram at Wellness Pod. And don't forget, we want to hear from you. Head over to wellness.fm [00:55:00] and leave us a question for our mailbag or suggest a topic for a future show.

Emily: [00:55:05] We'll let the influencers have the last word.

Influencer: [00:55:07] When your cortisol levels are elevated, you can hang on to a lot of fat around your middle. And this can be really frustrating because it seems like you're doing everything right, but it's not budging. The first thing I want you to do is get rid of the high intensity interval training. The second thing is intermittent fasting. Get rid of it, eat 30g of protein within 30 minutes of waking up. And the third one is the least fun. And that is to stop drinking coffee first thing in the morning on an empty stomach. This third one might piss you off.