In this episode, we discuss:
- How our stress-response system works
- The concepts of resilience and metabolic reserve
- The origins of “adrenal fatigue”
- The problems with the adrenal fatigue model
- Why an accurate understanding matters
- The causes of HPA axis dysfunction
- How to treat HPA-D
- The Role of Stress and the HPA Axis in Chronic Disease Management by Dr. Thomas Guilliams
Chris Kresser: Hey, everybody, Chris Kresser here. Welcome to another episode of Revolution Health Radio. Today, we have a question from Mary. Let’s give it a listen.
Mary: Hi, Chris. I’m Mary from Oregon, and I heard that you recently did a presentation at a symposium in California with more information about evidence-based research addressing adrenal fatigue. And I think you’re going to focus of course on using diet to remedy those things. So I’m especially interested in that, and I know you’ve done some recent podcasts about over-exercising and adrenal fatigue. But I would appreciate it if you would do an updated podcast on adrenal burnout, or HPA axis dysfunction, or whatever you want to call it. So I appreciate it. Thank you.
Chris: Thanks for that question, Mary. It’s really an interesting topic. Adrenal fatigue has become a popular diagnosis amongst both patients and practitioners, at least within the functional and integrated medicine worlds. It’s really used to describe a wide range of symptoms from fatigue, insomnia, and brain fog to things like joint pain, allergies, and weight gain. If you search for adrenal fatigue online, you’ll see usually a bullet point list of pretty much every symptom that you could possibly ever experience, so very nonspecific and associated with a lot of problems.
Proponents of the adrenal fatigue concept will suggest that it affects hundreds of millions of people around the world and may be at the root of most modern disease. But the question is, does adrenal fatigue really exist? Is it an accurate representation of stress-related pathology? What happens to us when we experience chronic stress, and is it in alignment with current scientific evidence? These are questions I’ve been exploring for a very long time.
Can your adrenals really become fatigued?
When I started studying functional medicine and getting involved in this world, I heard the term “adrenal fatigue” thrown around a lot, and it’s one of those things that I think a lot of us as health care practitioners just accept, at least those of us in the functional and integrated medicine world. It’s certainly true that we see a lot of patients with stress-related issues and that chronic stress is associated with numerous health problems, so I didn’t doubt that because I had seen that both in my own experience and also with many patients. There is tons of research correlating stress with many different symptoms and diseases, but I did wonder if this idea that the mechanism that explains all of that is because our adrenals become drained and unable to produce cortisol anymore, which is kind of the fundamental idea behind the adrenal fatigue hypothesis.
I did a really deep dive into this issue in preparation for my clinician training program, and what I learned might surprise you. It definitely surprised a lot of the practitioners that I trained who have been like I was: just kind of accepting the adrenal fatigue idea without a lot of critical thinking and just assuming that it was true because it does make sense on the surface in many ways. I’ve been doing presentations for practitioners to dispel this what I call the “adrenal fatigue myth” and replace it with a more accurate conception of what’s really happening. I realized, Mary, when you asked me that question, that I haven’t actually shared this information with the general public and people that aren’t healthcare practitioners. So I wanted to take the opportunity to do that here, and thanks for giving me that excuse, Mary.
How Our Stress-Response System Works
In order to really understand this, we have to get a little bit geeky and take a closer look at some of the basic physiology and concepts here, otherwise it won’t really be possible for me to explain why the adrenal fatigue idea isn’t consistent with our current understanding of the body and how it responds to stress.
Our stress-response system consists of two primary components. There’s the sympathoadrenal medullary system (SAS) that primarily governs our immediate or short-term response to stress, and then there’s the hypothalamic–pituitary–adrenal axis (HPA axis), which governs our intermediate- to long-term stress response. These are both really complex systems, so I’m not going to bore you with all the details, but the key concept to understand here is that mechanisms that protect us in the short term from acute stress can actually become harmful or damaging over the long term. For example, let’s say you’re a hunter–gatherer and you’re out walking on the savanna and you’re confronted by a lion. Well, in that case, it’s a really good thing that your heart rate, blood pressure, blood sugar all go up, your muscles tense and your digestive and reproductive systems shut down because those immediate changes that happen help you to survive that threat.
But what happens if that system that helps us survive the short-term threats is continually activated, as it often is in the modern world? We’re stuck in traffic. We’re working two jobs, eating an inflammatory diet or using electronic media late at night. All of these things activate that same stress-response system, but those changes that all happen like, when you’re confronted by a lion, for example, that are adaptive in the short term can become maladaptive, or harmful, over the long term. The constant activation of that stress-response system erodes resilience and it depletes metabolic reserve. These are really, really important concepts to understand when it comes to understanding the effects of stress on our physiology.
The Concepts of Resilience and Metabolic Reserve
Resilience is defined as the immediate capacity of our body to respond to changes in physiological need—or to stress, to put it more simply. Metabolic reserve is basically the long-term capacity of our body to withstand stress. What happens is if we’re under a lot of stress, initially that resilience will drop. But if we have sufficient metabolic reserve, if you can think of it like a battery that’s charged, if our battery has a lot of charge, we should be able to withstand those changes fairly well or at least bounce back from those changes.
Another analogy that could be helpful is like a bank account. If you have a good balance between making withdrawals and making deposits and you’ve got a lot of deposits in a big bank account, you can withstand a period where you’re making more withdrawals because you’ve got that reserve there to back you up. But if you’re constantly making withdrawals over a long period of time and you’re not replenishing with deposits, then over time that account is going to be overdrawn.
That’s really a similar thing that happens with stress. There are a lot of things that we can do that build our resilience and metabolic reserve. Eat a healthy diet, get plenty of sleep, get adequate amounts of exercise (not too little, not too much), manage our stress, spend time in nature. All of the things that we talk about, those are metaphorical deposits into our metabolic reserve account and our resilience account. But if we’re constantly drawing that down with an inflammatory diet, not getting enough sleep, not getting enough exercise or getting too much exercise, the converse of everything that I just said, then that’s going to deplete our resilience and our metabolic reserve.
What we know when we look at the research is that there are a huge number of conditions that are associated with the loss of resilience and the depletion of metabolic reserve, and it is true that I think this is a key driver of the epidemic of modern disease. I’m just going to tell you a few of them. This is only a partial list, but:
- obsessive–compulsive disorder
- chronic fatigue syndrome
- premenstrual tension syndrome
- rheumatoid arthritis
These have all been associated with an activation of the HPA axis and that stress response and then the progressive loss of resilience and depletion of metabolic reserve.
The Origins of “Adrenal Fatigue”
Now let’s get back to this adrenal fatigue idea. It really comes from something called the general adaptation syndrome, which is a theory advanced by a pioneering doctor and researcher, Hans Selye. He was trying to describe the effects of stress on physiology, particularly in the animals that he was studying. This general adaptation syndrome that he suggested predicts what happens to the body when it’s exposed to stress. He basically argued that first you see rising cortisol, DHEA and pregnenolone hormones, stress hormones that are produced by the adrenal glands. When you’re first exposed to stress, you see all those things go up, and then over time they begin to decline as the stress is chronic or lasting. You have high cortisol at first, and then cortisol drops. It might even fall into the normal range in stage 2, and then in stage 3, cortisol and DHEA are falling below the normal range, until finally you reach adrenal exhaustion or failure, where cortisol, DHEA, and pregnenolone are all very low. That’s the typical idea.
This isn’t what Hans Selye argued, but people who saw Selye’s model and kind of took it and ran with it advanced the idea that what happened in that situation was that the adrenal glands, which normally produce cortisol, lost the ability to continue producing cortisol. The adrenal glands become fatigued, hence the name “adrenal fatigue,” and they were just over time, because of the exposure to chronic stress, they become less and less able to produce cortisol.
That’s the basic idea behind adrenal fatigue, and certainly we hear many people now saying, “Oh, my adrenals are shot.” “I’ve got adrenal fatigue. I can’t make cortisol.” People are taking supplements to increase cortisol levels because of this, including some medications like hydrocortisone to actually increase cortisol levels in the body.
The Problems with the Adrenal Fatigue Model
But there are really three primary problems with the adrenal fatigue hypothesis, and I’m just covering these very briefly because it gets pretty technical pretty quickly. I think for most people listening to this podcast, you’re mostly concerned with how this affects you and what you can do about it, maybe not so much about the terminology and why that’s important, but bear with me because I think it is meaningful and it does make a difference in terms of how we approach this, so I want to just quickly go over these three reasons that I think the adrenal fatigue concept is not accurate.
Number one, many, if not most, people with adrenal fatigue don’t really have low cortisol levels. Mary, I’ll talk about each of these in a little more detail. Number two, even when cortisol is low, it’s rarely because the adrenals are fatigued and unable to produce it. Number three, adrenal fatigue as a concept isn’t really supported by our current scientific understanding of the stress response.
1. Most people don’t really have low cortisol
Let’s go back to number one, which is that most people don’t actually have low cortisol. People with so-called adrenal fatigue don’t actually have low cortisol. Adrenal fatigue is often diagnosed by using a saliva cortisol test, and the cortisol that’s measured in saliva is in the unbound or free form. It means it’s not bound to a protein carrier. If you’ve heard of “free testosterone” or “free T3” or “free T4,” we’re talking about the same thing. It’s the free unbound form of the hormone. That is the most potent form of cortisol, but it only represents about 3 to 5 percent of the total cortisol in the body at any given time, and the rest of the cortisol is cleared by several different metabolic pathways before it’s excreted in the urine.
Again, this can get complex, but the key thing to understand here is that when we measure saliva cortisol, it’s not necessarily representative of the total cortisol levels in the body. When studies have looked at total cortisol levels in addition to free cortisol levels, they found that when people have low free cortisol, they don’t necessarily have low total cortisol. In fact, it’s more common when people have low free cortisol for them to have either normal total cortisol or even high total cortisol.
One of the reasons for this is that this constellation with low free cortisol and high total cortisol is common in obesity. Now we know that one-third of Americans are obese, two-thirds are overweight, so that’s not an uncommon thing to see. Again, the first thing is we need to be clear about what we’re actually measuring, and when we are clear about that, we see that free cortisol is not as common as is typically assumed.
Another issue is that some of the functional labs that are testing saliva cortisol in saliva have ranges that I believe are actually too narrow. I’ve often argued that the lab ranges are too broad, but in some cases, I think they’ve been revised in a way that isn’t totally supported by the evidence. That can lead to false diagnosis of low cortisol.
Another problem is how saliva is collected. When the saliva test is done in the morning, it’s really important in terms of determining the cortisol levels. Before we even wake up, cortisol levels are beginning to rise, and then right when we wake up and open our eyes and light hits our eyeballs, that leads to a dramatic rise in cortisol within the first 15 to 30 minutes after we wake up, and that’s called the cortisol awakening response. That accounts for over 50 percent of the total cortisol production during the day. It’s a major event in terms of cortisol production. What happened was that a lot of the labs that were doing this testing didn’t instruct people to take the first sample within that first half-hour period. If someone wakes up and then they wait for an hour or even two hours to do that first sample, they missed that entire cortisol awakening response—that surge of cortisol that happens early, first thing in the morning. The level that they get back will miss that surge of cortisol and it will lead to a falsely low morning level of cortisol, and they’ll be falsely diagnosed with low cortisol.
As you can see, there are a lot of problems with how we’ve been doing this. When you do the testing correctly, far fewer people actually do have low total cortisol and even low free cortisol than the testing initially led us to believe.
2. Even when cortisol is low, it’s rarely because the adrenals are fatigued
The second thing is that I mentioned was that even when cortisol is low, it’s rarely because the adrenals are fatigued and unable to produce it. Now this gets very technical very quickly too. But the first thing, I think, to say is that there certainly is a condition that does lead to the adrenal glands being unable to produce cortisol, and that’s called Addison’s disease. Addison’s is pretty rare. There are fewer than 200,000 cases a year. Even though stress is probably a factor, it’s an autoimmune disease, so it’s not a stress condition that’s wholly caused by stress.
It’s also important to note that the low levels of cortisol that are observed in Addison’s are way, way lower than what are observed in so-called adrenal fatigue. If you don’t have Addison’s, but you do have low cortisol, it’s not because the adrenals are not able to produce it. There are actually several other mechanisms that determine cortisol levels in the body and can lead to low cortisol levels, and they have nothing to do with the adrenals’ ability to actually produce cortisol.
I’m not going to go into detail on all these, but I’m just going to mention a few of them. One is downregulation of the HPA axis. When we’re exposed to stress over a long period of time, the body has some mechanisms that it uses to try to protect us from the effects of that high cortisol that would result from that stress. It essentially decreases the sensitivity of some receptors that are involved in this pathway, and that again is a protective mechanism. The body’s trying to prevent any harm coming from this exposure to high cortisol from stress, but unfortunately, that ends up leading to a decreased ability to produce cortisol in the face of future stress. That has to do with the brain. It doesn’t have to do with the adrenals not being unable to or not being able to produce it.
The second thing that can happen is cortisol resistance. If you’re familiar with the concept of insulin resistance, this is very similar. Chronically high cortisol levels can lead to cortisol resistance, and that’s caused by a decrease in cortisol receptor sensitivity. The receptors become insensitive to cortisol, and it can also be caused by a decrease in the number of receptors for cortisol. Again, that’s a protective response. The body’s trying to protect against the effects of high cortisol, but it ends up leading to low cortisol over time.
The third reason would be decreased bioavailability of cortisol at the tissue level. That can be caused by increased levels of the binding protein that carries cortisol throughout the body, and that can be also caused by an increase in the conversion of cortisol, which is the active form of the hormone into cortisone, which is a less active form of the hormone.
Those are just three of many other mechanisms that lead to low cortisol that have nothing to do with the adrenals being unable to produce it.
3. The adrenal fatigue concept isn’t really supported by our current scientific understanding of the stress response
The third reason is that adrenal fatigue is just really not supported by scientific understanding and the stress response. If you go on to PubMed, which is the clearinghouse of scientific studies database where you can search for various topics, and you type in “adrenal fatigue” in quotation marks, which means it will just search for that phrase, you’ll find about 10 results, and they’re not really impressive results either. But if you then search for “hypothalamic pituitary adrenal axis,” you’ll find about 18,000 results. The difference there is, as I said in the beginning of this podcast, there is tons of research connecting stress and disease showing that the effects of stress-related physiology are profound and can cause numerous symptoms and numerous health problems. But again, it’s because of brain or central nervous system or tissue-specific regulatory mechanisms that govern the availability of cortisol, not because the adrenals can’t produce enough of it.
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Why an Accurate Understanding Matters
Okay, so let’s talk about why this matters a little bit. The first reason is that if we want to really, truly understand how to address the signs and symptoms that were previously known as “adrenal fatigue,” if you will, then we need to understand what it actually is and then what causes it, which I’ll get to in a second. In functional medicine, of course, we’re always trying to address the underlying cause of disease. If we don’t know what the cause is, we can’t be as effective in our treatment.
Second is it brings us into alignment with the current scientific evidence, and that means we can leverage the vast amount of research that’s been done on stress and the HPA axis and disease outcomes to figure out better treatments and better ways of approaching things.
Third, it leads to better treatment outcomes for the two reasons that I just mentioned and can prevent harm. For example, let’s say we falsely diagnose a patient with adrenal fatigue because we’re not using saliva hormone testing properly, and we don’t collect the sample well, and it comes back with low cortisol, and we prescribe hydrocortisone or some some herbal treatment that raises the cortisol levels. Well, if they actually have high cortisol levels instead of low, then that might not be a good idea and may make them worse and potentially cause harm. There are real reasons why this is important, and it’s not just a question of terminology and splitting hairs.
The Causes of HPA Axis Dysfunction
Let’s talk a little bit about the causes of HPA axis dysfunction. That’s really what we’re talking about here. We’re talking about a dysregulation of the hypothalamic–pituitary–adrenal axis and possibly the SAS, sympathoadrenal medullary system. It’s not as sexy as adrenal fatigue. It’s not as easy to say. We could call it “HPA axis maladaptation.” That actually is probably even more accurate because most of the changes that occur, as I mentioned, are the body’s attempt to adapt to a chronically high cortisol, but in doing so, it overshoots the target and we end up with low cortisol. We can call it “HPA axis dysregulation,” which I have argued for. HPA-D is a way we could say it in shorthand, but we can also name a specific abnormality. If the patient actually has high cortisol rather than low, we could call it “hypercortisolism,” or just “high cortisol.” Or if the patient has normal cortisol but they’re producing not enough in the morning and too much at night, we could call it “disrupted diurnal cortisol rhythm.” Again, these terms are not as user friendly, not easy to say, but they’re important in terms of improving our understanding of what’s going on.
Okay, so what causes HPA axis dysfunction? Well there are four primary causes, and if anyone is interested in reading more about this and diving into this in much more detail, especially if you’re a health care provider, Dr. Tom Guilliams wrote a fantastic book. He’s with the Point Institute, and the book is called The Role of Stress and the HPA Axis in Chronic Disease Management. It’s oriented towards clinicians and practitioners, but if you’re interested, that’s what I would suggest.
Okay, so let’s talk about the four triggers of HPA axis dysfunction as Tom describes in his book.
- Perceived stress
The first is perceived stress, and that is what we all think about when it comes to stress. It’s financial stress, job stress, relationship stress, and there’s a lot more to say about that, and maybe we’ll do a separate thing on that. Perceived stress is an important term because it highlights the fact that people perceive stress in different ways. Something that’s stressful for one person may not be stressful for another. There are actually positive forms of stress called “eustress” and negative forms of stress called “distress,” but we can group this together in this category called perceived stress. Then inflammation is number two, blood sugar dysregulation is number three, and circadian disruption is number four.
Most people, I think, when they think of adrenal fatigue, think of stress as being the major cause, and it’s true that it is a major cause. But part of the problem there is we tend to neglect these other three causes that can be just as significant when it comes to HPA axis disruption.
- Anything that causes inflammation
Anything that causes inflammation—if you have SIBO and gut issues, even if you have no perceived stress in your life, that can still cause HPA axis problems—obesity, inflammatory diet, any other issues that we know can cause inflammation or will trigger HPA axis dysfunction.
- High or low blood sugar
High blood sugar or low blood sugar will also trigger that, and it’ll cause problems with insulin and leptin signaling, and that can affect the HPA axis in a negative way, so that’s another issue.
- Circadian disruption
Circadian disruption, that refers to not getting enough exposure to light at the right time during the day and then the morning in particular, and getting too much exposure to light at the wrong times, like at night. I’m sure you’ve heard me talk about this a lot. It’s in my book. This is a growing problem in the modern world, and it contributes really significantly to HPA axis dysfunction.
We’re running out of time, and we won’t have time to go into a really detailed treatment of what to do about this, but I’ll come back to that in a future podcast. For the purposes of this show, I just really wanted to give you an idea of why the adrenal fatigue hypothesis is … it’s not really correct and what we should replace it with, and then I’m just going to briefly mention what we can do about it.
How to Treat HPA-D
Hopefully, that’s obvious now because you know what the four triggers are. We need to of course address those four triggers as the primary way of reversing HPA axis disruption.
- This means reducing perceived stress. This is reducing our exposure to stress when that’s possible and then taking steps to manage stress when it’s not. I’ve written a ton about stress management, so we can provide some links in the show notes to help you get started with that, to keep going with that, because it’s so important. I can’t say enough about it. If a patient comes to me and they have significant HPA axis disruption, what I tell them is there is no way to supplement or eat yourself out of this alone. Those things are really important, but you really, really have to address the stress piece, the behavioral and lifestyle management part of it, or else you won’t get well.
- Number two would be to address root causes of inflammation. Again, if you have gut dysbiosis, SIBO, parasites or fungal overgrowth, and that’s contributing to an inflammatory picture, then you have to address that before the HPA axis will improve.
- Number three would be to regulate blood sugar. If your blood sugar is too high, taking steps to lower it like a Paleo-type of diet, possibly lower, low carb, and even keto, if necessary, would be helpful if you’ve got more of a hypoglycemic picture. Those steps still might be helpful, or you might need to eat smaller, more frequent meals, so whatever needs to be done to regulate blood sugar.
- Then what we would call circadian entrainment, which means bringing yourself more into alignment with the natural rhythm of light and dark, making sure to get some light exposure first thing in the morning if you can, but certainly during the day, and then reducing your exposure to artificial light at night. All of those things are really important for reducing that circadian disruption that can cause HPA axis problems.
Okay, I know that probably ended up being pretty sciencey and geeky. I hope that wasn’t overwhelming or confusing, but I just really felt like it was important to give you the overview of why the adrenal fatigue hypothesis is not supported by current scientific understanding of stress and how stress affects our physiology. Hopefully this leads to a broader investigation into the causes of the symptoms known as adrenal fatigue, if you’re exploring that yourself on your own as a patient, and I’m certainly passionate about training practitioners through my ADAPT program to better understand this condition and be able to more clearly diagnose, more accurately diagnose it and then more effectively treat it.
That’s it for today, everybody. Thanks for listening. Please keep sending your questions in to chriskresser.com/podcastquestion, and I’ll talk to you soon.
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