Adrenal Testing, Stress & the HPA Axis, Asking the Tough Questions with Dr. Tom Guilliams
The hypothalamic-pituitary-adrenal axis (or HPA axis) is a complex subsystem in your body that organizes and responds to threats (and perceived threats). The concept of “adrenal fatigue” has become popular in some functional medical circles, but it’s a misleading term for describing what’s really happening in stress-induced change to the HPA axis, which does not involve the adrenal glands. Dr. Tom Guilliams, an expert on stress and the HPA axis, discusses adrenal fatigue and adrenal testing, including the limits of the four-point salivary cortisol test and the DUTCH test. Adaptogenic herbs can be helpful, but the most high-impact actions for your health may still be addressing intense stressors. Learn the four root causes of stress to your HPA axis in this episode.
Dr. Michael Ruscio, DC: Hey everyone. Welcome to Dr. Ruscio Radio. This is Dr. Ruscio. Today I’m here with Dr. Tom Guilliams and we’re going to be talking about adrenal testing, for lack of a better term. As the audience knows, I’ve been critical of the whole term “adrenal fatigue,” as I think a growing number of clinicians and researchers are. And Tom had written a great paper and a book on this, actually, a number of years ago. I’ve been wanting to have this conversation for a little while. And finally, here we are. So Tom, welcome to the show and thank you for being here.
Episode Intro … 00:00:40 Origins of Four-Point Salivary Cortisol Test … 00:03:13 Four Causes of HPA Axis Stress … 00:08:40 Stress Perception & HPA Axis Response … 00:17:30 Data on Adrenal Supports? … 00:22:03 Cortisol Awakening Response & Diet … 00:28:20 Challenging the Concept “Adrenal Fatigue” … 00:33:31 Interpret CAR Test with Caution … 00:40:45 What to Know About the DUTCH Test … 00:44:25 Tips to Manage Your HPA Axis Stress … 00:48:42 Episode Wrap-Up … 00:51:28
Dr. Tom Guilliams, Ph.D.: Thank you for having me. I enjoy it.
DrMR: So tell us a little bit, just in brief, about your background and how you got into your research in—again, for lack of a better term—adrenal fatigue.
DrTG: I live in Central Wisconsin, and actually received my Ph.D. at the Medical College of Wisconsin. So I’ve been a Midwest Wisconsin boy for a long time. Received my Ph.D. in the mid-90s in molecular biology. So I didn’t exactly come into this field directly, I came in through the dietary supplement world. And from there I connected with the integrative functional medicine world as a whole. And as a Ph.D., I’m scrutinizing, I’m listening to things. I’ve heard a lot of interesting things in the last 20 years of being in this field.
But over the last five or six years, I’ve really focused in on the evidence for lifestyle medicine, integrative medicine, functional medicine paradigms—the testing behind what we do—and because of my background, the supplementation and the use of, let’s say, herbs, phytonutrients, vitamins, minerals, etc. So that’s really where I’ve emerged.
And of course, one of the big areas I was involved with for a long time was this idea of stress, or this term adrenal fatigue, which we can talk about. It has been adopted by a lot of people in the integrative functional medicine community, oftentimes without scrutinizing all the details of it. And even though I think we clearly know that stress is a major factor in chronic disease, we don’t always go back and look at the details. So that’s one of the things I did over probably the last 10 years. But in 2015 when I published the book, The Role of Stress and the HPA Axis in Chronic Disease Management, I tried to really hone in on the functional medicine approach to this and decide what is real and maybe what is not real.
Origins of Four-Point Salivary Cortisol Test
DrMR: Mm-hmm. And from what you have written on this—from what I’ve read—I think we’re in agreement on the broader points: we have to be careful in terms of looking at a four-point salivary cortisol test. And just for the audience, if you haven’t heard of this, adrenal fatigue can be tested with a take-home test. Essentially, morning, early afternoon-ish or pretty much right at noon, and then mid-afternoon and evening, you do a spit sample. And depending on how the hormone levels in the saliva read, you may or may not have adrenal fatigue. And one of the challenges I faced early in my career was the correlation between what we were seeing on the tests and the person in front of me were very, very poor. That was one of the first tests, actually, that got me to start challenging the assumptions in functional medicine, and was one of the inceptions that really led me to be a bit more critical.
Now, that does seem to be fairly well agreed upon in the research literature, that a four-point cortisol test is non-optimal. And Tom, where do you come into this conversation? Is there a background here that you’d like to arm people with about the four-point cortisol test and maybe how we got down that erroneous road? Or where do you pick this up?
DrTG: Yeah, I think there are a lot of things in that question. I think going back even to the notion of adrenal fatigue, we measure cortisol because it’s one of the major hormones that comes from the adrenal cortex. So we know that there is information when it’s extremely high or it’s extremely low. We know we have something going on. Typically, we’re talking about something, on the one hand, when it’s extremely low, like an Addison’s disease. We have something wrong with the adrenal gland itself, sort of an autoimmune situation where it cannot produce cortisol. The cells have died, as it were. Or you have some sort of overproduction, either an adenoma or typically something going on in the brain where you’re producing too much ACTH which is triggering that. So those extremes are out there and that’s where the endocrinologist lives.
But people started talking about the idea of stress creating changes in adrenal hormone output, the notion of adrenal fatigue. Think of the pancreas. The pancreas does actually begin to fatigue based on the long-term need to produce insulin. The same thing was thought to be occurring in the adrenal gland. That the adrenal gland—because long-term stress is producing all this cortisol—eventually just begins fatiguing, and not being able to produce much cortisol. And the theory is we could measure this in the blood, the urine, or the saliva. And, it turns out—we can get back to this later—that that’s not what’s happening. The adrenal gland is not just getting tired. It’s the brain that’s actually downregulating the stress response as a protective mechanism for the rest of the body. So we can get into that later.
But probably 20, 25 years ago, people started realizing that you could take saliva—which was a good measure of free cortisol, which is an important marker, not the total cortisol, but the free active part, which gets into saliva—and we can measure that throughout the day. And we knew that it was highest in the morning and lowest right before bed.
The problem was the instructions, as I discovered. I looked at every single lab that did this test. The instructions for the first test in the morning were all different, and none of them were done correctly. And when I went into the literature, I found out that the most common tests used to correlate saliva cortisol with some sort of stress-related phenomena, burnout, acute stress, or these kinds of things, was measuring what we call it the cortisol awakening response. That is the change in cortisol that you see in the saliva from the time you wake up until about 30 to 40 minutes later.
And that jump, that cortisol awakening response and then subsequent drop, can’t be done unless you take a 0.0 time of awakening and a point 30 or 40 minutes later (and then perhaps add those other points that you were mentioning late morning, late afternoon, and perhaps going to bed). That data that tells us about the plasticity of, essentially, the hypothalamus, or the anticipatory stress of the day, was the most commonly used clinical biomarker for stress research. And nobody was doing it.
So it just happened that I just went to the labs and I said, “Hey, you guys have been forgetting this big component of the literature.” Thankfully, as you know, several of the labs are now incorporating the cortisol awakening response and/or the cortisol awakening response with the diurnal test, which is helping clinicians to connect what they’re seeing in their patient with the broader literature that’s out in this research.
DrMR: So a few things there that we should clarify for people. One, the cortisol awakening response test is the most well-studied test, and that’s really what we should be doing. And then also, it’s more quantifying a brain regulation problem than it is literal fatigue of the adrenal glands.
Four Causes of HPA Axis Stress
DrMR: Okay. So, there are a few things here that I want to dig into. And I think the thing that I’m most curious to dig into—and try to arm our audience with better information regarding—is the clinical utility of this test. I’d like to just give you my thoughts and I’m certainly open to any challenges or commentary on these. But essentially I’ve not been doing cortisol testing now for probably close to five to six years, because it doesn’t seem that it’s telling me anything about what’s causing the source of the stress.
I would rather look at someone’s sleep, someone’s exercise, look for a chronic inflammatory burden, as the audience knows. Obviously, the gut is my primary area of focus. Not to say it’s the only area to focus on, but I’ve certainly been absolutely shocked at how many cases of fatigue, brain fog, poor sleep, and these loose constellations of symptoms that we’ll often associate with HPA dysfunction—which is the more contemporary way of diagnosing adrenal fatigue—have been responding beautifully in patients as we’ve been looking at their gut health, dietary problems, looking at their sleep.
If we think they might be exercising too much, we’ll just do a simple experiment: “Okay, for the next two to four weeks, we’ll scale back your exercise volume by one to two sessions per week.” And that’s gotten me very far. So, I’m wondering where do you fall on this argument? Are you still recommending the same amount of testing? Do you think it’s something that’s more quantifying a symptom rather than a cause?
DrTG: Well, I think there are two things going on. I think finding out why a certain thing occurs is sometimes different than finding what is occurring. So, the way that I teach the HPA axis stress is, the root cause of the stress usually comes from one of four categories. Perceived stress. And that’s a whole area of the perception of the stress and what we call lack of control and/or the way the brain perceives signaling. So it could be neurotransmitters, neurosteroid imbalance in the brain. And there are a lot of questionnaires that allow you to let a patient describe what it is that they believe is stressing them. Because what they believe is stressing them… obviously, their perception is what’s stressing them, because that’s how the brain works.
Circadian disruption. Like you mentioned, sleep is a big component of that jetlag, night shift. Anything that causes a chain in circadian disruption is going to create an HPA axis stressor. Inflammation. Cortisol is the body’s main anti-inflammatory. So we know that the brain is very sensitive to inflammatory signals like IL-1 beta, IL-6, TNF alpha. There are the classic signals and they trigger the brain to produce cortisol as an anti-inflammatory. And lastly, glucose control. So remember, cortisol is a glucocorticoid. The reason it got that name is because it actually manages glucose, which manages energy. So any time you have somebody who’s going hyperglycemic, hypoglycemic, they’re not regulating their blood sugar correctly, the brain sees that as a major stressor and tries to regulate that or fix that with the stress response.
So all of those things that I just mentioned can’t be diagnosed specifically with the salivary cortisol. However, I think one of the things that I’ve been coming to realize is the importance of circadian control on all kinds of factors in the body, including many things like metabolic issues and turning on and off genes in a circadian fashion. I was just at a conference where I lectured on the role of the stress response, circadian rhythm, and the role of nutrients or feeding on circadian rhythm. And the stress response, circadian rhythm and nutrient intake are very tightly controlled.
So two things that I like about the salivary cortisol test are—especially when you add the cortisol awakening response to it—one, you can tell by that whether you have a plastic or a very responsive awakening response, which tells you you still have robustness in the HPA axis. If that’s flat, that is usually not a good sign. Meaning it’s going to be much more difficult to deal with those individuals. For instance, a person with PTSD has a very flattened cortisol awakening response. The other thing is, you’ll be able to tell whether it has a circadian flow to it. So you want it to have a circadian change between morning and evening. And if you don’t, then that’s also a signal that something bigger is going on from a circadian standpoint. So it’s not something that I think you can use to diagnose the patient with on a single salivary cortisol, on a single day. But I think it adds to the picture of what you’re doing and chronic disease management.
In fact, my view is that the HPA axis is one of the global regulators of chronic disease management. It is actually being injured along with any other chronic disease pathway that’s going on, and it will show a change. So it can be used to confirm some issues. And you’ll see a lot of different things change over time. When you start treating, let’s say, sleep apnea or PTSD or depression or seasonal affective disorder or other neurotransmitter issues, you will see a change in the HPA axis as well. So it’s certainly not a test that’s going to diagnose everything. But I think along with other things, it can be helpful to understand how the body is affected by chronic disease.
DrMR: Okay, and I think that’s a fair compromise that maybe we can come to here. And I’ll try to restate that for the audience. Because I do think there are a few caveats here that the audience needs to be armed with when going to a doctor’s office. Unfortunately, the state of testing and functional medicine has gotten way too excessive. And I think patients now need to be a bit more of their own advocates in reigning back some of these tests that you could make a case for, but may not be essential. So if someone is on a budget, and they’re saying, “Well, let’s focus on the essentials testing,” just to throw an arbitrary ballpark figure, that might be, in my opinion, anywhere from $500 to maybe $1,200. I think that’d be reasonable, depending on the extent of what some person has going on. That’s a good ballpark. It’s not going to fit every case.
And then if you wanted to be more extensive with your testing, then you can start seeing some of these quotes that we hear coming in where the doctor wanted three thousand, five thousand, seven thousand dollars worth of lab testing. And I think we could put the adrenal testing in that camp, of a test that you can make a case for. And I believe, as you were saying, Tom, that this could help you quantify the success of other therapies. I agree, I think we could have some utility there. But we should draw this line, for the patient who thinks, “I’m feeling terrible, this test will tell me exactly why.” I think we need to make a clear distinction there so that the patient who has limited resources can focus on where to put their money. Would you agree with that, Tom?
DrTG: Yeah, certainly, of all testing. A good test in the hands of the wrong clinician is a waste of time and money. Because they may not know how to interpret it and they may not be able to treat it anyway. As you know, my rule of thumb is, you should only do tests where they’re going to change the course of therapy.
Thankfully, the salivary cortisol test is on the low end of costs compared to a lot of the other tests that are out there. So, I think it’s something you talk with your clinician about, and decide where along the path this is. Most people can tell you, if you talk to them long enough, if stress is involved in their life. Are they having sleep issues, are they having perceived stress issues? Do they have inflammation? Do they have glycemic dysregulation?
And clean those things up first, if you’re not sure what’s going on. But if you have somebody who you suspect really has a flatline cortisol level because of some major burnout or stress long term, it would be nice to have that catalog. And then follow that along perhaps every once in a while to see what’s going on.
Stress Perception & HPA Axis Response
DrMR: Mm-hmm. And just to shift to a parallel topic, but I’m curious to get your thoughts on this, if you’ve looked into this at all, for patients who have this high perceived stress—or you could maybe even make the argument that they’re not necessarily perceiving it as stress until you probe into it—who seem to be stuck in this fear of illness. It’s been described by Ashok Gupta as a conditioned defense response, Annie Hopper’s also described it and has her DNRS training to help these patients who might be starting to heal physiologically, but psychologically they’re stuck in a loop of feeling sick in this chronic facilitated stress response. Are you finding therapies like that can be helpful for these patients? They maybe have addressed sleep, circadian health, inflammation, and glucose control and they’re starting to improve, but they have this high-stress burden that needs to be unwound with some therapies to un-facilitate this otherwise facilitated circuitry.
DrTG: Yeah. There are several different questionnaires that you can use, perceived stress questionnaires. And they focus on one particular word. (I mean, it’s not used in everything.) It’s called “control.” When a person feels out of control with their relationships, out of control with their finances, their health is a big one, obviously. In fact, most of the questions are to try to gauge their sense of control of various components of their life. The more out of control someone feels, the more the perception of that stress. So, this has been looked at. There’s actually a little acronym called NUTS, which talks about the novelty and the uncertainty of certain events, how they threaten, or the sense of threatening.
So anything that’s new, anything that’s unpredictable, anything that threatens us, anything that doesn’t allow us to have a sense of control, will put us under stress. And beyond that, we’re now learning that neurotransmitters and something called neurosteroids (some steroids that are produced in the brain) actually modulate the way the brain perceives events. And when we say it’s all in your head, that’s kind of a euphemism. But actually, in some cases, it is in our head, meaning the way that the certain parts of the brain remember events or perceive something they’re seeing as a stressor is different in certain people. And it’s different over time, based on the experiences they’ve had. So these are real things, and your body can respond.
The HPA axis can respond to a stressor that has not even happened. Meaning, you’re anticipating it into a memory of an event, just as if the event is happening. So those are the complicated factors that many clinicians aren’t prepared to deal with in their patients. And obviously, they may need to be sent to individuals who can help them get through those issues, in a way that maybe a clinician who’s used to using adaptogens for adrenal conditions may not be familiar with.
DrMR: Okay. So just to recap really briefly here, there are these four pillars. There’s stress, there’s sleep and circadian health, there’s inflammation, and there’s glucose control. And I wholeheartedly agree that these are fundamental pillars that people need to address and optimize for in order to feel healthy, whatever the complaint is. Anything. You could make a case from sleep to potentially even joint pain.
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Data on Adrenal Supports?
You just mentioned something I definitely want to touch on, which is using adrenal adaptogens. There’s this older canard that seems to have permeated into some circles of functional, natural, integrative medicine (whatever you want to call it), that is, you need to do a test to figure out what adrenal supports that you need. And I haven’t found any evidence, other than one study out of, I think, over a hundred—I may have that number slightly off—that has used various forms of adrenal support.
This has usually been done based upon someone’s presentation. They’re tired, they’re not sleeping well, whatever it is. And I think it’s a fallacy for clinicians to be saying, “Well, we can put you on adrenal support, but we need to know what your adrenal rhythm is first so we can personalize the dose.” And it just doesn’t seem that there’s any good data to support that. What are your thoughts there?
DrTG: Well, I don’t know of any really good data… Part of the problem is, we don’t follow people long enough. So we can follow animals. And you can go back to the studies Hans Selye did with animals, where he took an unstressed animal and took them through various stages of stress and created what he considered this acute all the way to this chronic exhaustion phase, which is kind of where people get the idea of adrenal fatigue from. Well, when you look in humans, we don’t find those long-term studies. We do have some studies in chronic burnout subjects, where you end up getting hypocortisol and a flattened cortisol awakening response. This also occurs with mothers taking care of chronically ill children for a long time. It creates this burnout of their HPA axis.
So when you start looking at data—and of course, salivary cortisol is often used to try to pigeonhole somebody who’s in stage one or stage two or stage three—I think the problem with that is we only have one timepoint, oftentimes, or maybe two time points in this person’s life, and we’re guessing at what happened before that. So I typically don’t like using the term “supporting the adrenal gland,” because I don’t think most of the things that we do that influence the HPA axis are actually doing anything for the adrenal gland, per se. There might be a few things like vitamin C or whatnot that have been shown to change adrenal function or improve adrenal cell activity or whatnot. But most of what I teach are ways of helping the brain.
All of this adaption is going on in the brain, to help the brain better understand or better signal when cortisol comes to the brain. It should act as a signal to either turn up or turn down the HPA axis. Often that is not working, in PTSD people or individuals with depression or things like that. So we know the feedback inhibition can be modulated. And there’s actually a little bit of data to suggest that things like phosphatidylserine—which actually probably modulates this by changing the fluidity of the membranes in the brain—can help the signaling of cortisol in the brain, which gives you better feedback control. But most of the other data, like you said, doesn’t exist.
We don’t have a lot of data. There are some suggestions. For instance, the use of adaptogens. Most of the adaptogenic herbs have been thought to help the adrenal gland. As it turns out, we don’t know how they work. There’s a little bit of data to suggest that they can modulate heat shock proteins, which are really important for protein folding, and as it turns out, also very important for the glucocorticoid or cortisol receptor. So it’s possible that what’s going on with certain adaptogens like Rhodiola, Schisandra and these kinds of things is that they’re able to upregulate the body’s cortisol signaling capacity and therefore give a better response. But again, we don’t have enough data to correlate with specific salivary cortisol patterns with certain therapies. We have a lot of anecdotal evidence, a lot of doctors who’ve got things that they’ve seen, but we don’t have any published data to really accumulate like we’d like.
DrMR: I know at least, gosh, probably five years ago there were some being published—and I don’t know how speculative this was or how literal this was—that the adaptogenic herbs may help rectify an otherwise aberrant HPA dysfunction. And so some of these things like holy basil and Rhodiola and ginseng may partially act through helping to—I believe, for lack of a more specific description—kind of sensitize some of the hypothalamic and pituitary receptors to cortisol. Has that been proven? Disproven? Is there any update there?
DrTG: Well, we know that there is some effect on heat shock proteins. There’s actually some interesting data coming out on a series of chaperones, which are not heat shock proteins, but they’re very involved. They’ve got a very long name, which I won’t mention, but that are involved in the stress response itself. So there are people looking into those kinds of things. Licorice, of course, is a traditional adaptogen. We actually know how it works: it blocks the conversion of cortisol to cortisone. So you have a preservation of cortisol. And typically people use licorice in a low cortisol situation and it seems to preserve those levels. Obviously, people with really high cortisol levels don’t want to take licorice because it could exacerbate that problem.
So, we have some evidence for some of the things that are being used, but overall, like we talked about, we don’t have definitive biomarkers or ways of measuring what we’re trying to change. So we don’t necessarily have a way to do a clinical trial like we’d like, because we don’t have the definitive biomarkers like we do with, let’s say, cholesterol or high blood pressure. Or some other area where there’s a definitive agreement on some biomarker that everyone likes to change up or down. We don’t really have that with what we’re doing with HPA axis function.
Cortisol Awakening Response & Diet
DrMR: Sure. There’s another issue I was curious about. When we look at people who are going on lower-carb diets, in some of the research where they’ve tracked expanded thyroid panels in patients who were going on ostensibly healthier diets—oftentimes lower in carb than their baseline diet—the subjects would see reductions of body weight, better sleep, better energy. But they would see a skewing of a decrease of their T3 and an increase of their reverse T3. And this led some people to, I think, erroneously conclude that lower-carb diets were bad for your thyroid health. And it seemed that the best way to read that was this was a metabolic adaptation to a change in food substrates that wasn’t in any way pathogenic.
Now, of course, a long-term ketogenic diet where someone was going too low-carb for too long… we have to be careful about that extreme. But extreme cases aside, it seemed that that was a pretty tenable way to read that situation. Do you feel that there could be some kind of confounding of the cortisol awakening response testing, or points in the four-point cortisol rhythm testing, if someone was following a low-carb diet? Or is there some kind of dietary input that may be skewing things there?
DrTG: Most definitely. Remember the HPA axis is your body’s surveillance for any threat.
“Is Adrenal Fatigue real? Is the testing legitimate? In this episode, we’re asking Dr. Tom Guilliams the tough questions.”
Whenever you go on a low-carb diet and you start changing the dynamics of the way the body perceives nutrient availability, it is a stressor. And so, just generally, weight loss is a stressor. And not only will it raise cortisol levels, but it will also actually decrease cortisol-binding globulin. Now, we didn’t talk about this, but this is the reason that only a small amount of cortisol gets in the saliva, because most of it is bound to a binding protein. When obese subjects or people with elevated fat all of a sudden began losing that, the body sees that as a stressor. And not only does the HPA axis respond, but it also reduces the cortisol binding so that you have more free cortisol available. And of course, free cortisol alters the conversion of T4 to T3. And so there’s some effect of that there.
So it wouldn’t surprise me at all if, as the body was adapting to changes in available carbohydrates, the brain saw this as a stressor for a while until there was metabolic adaption to that. Not only that, but you’ll also see people go to bed hungry because, let’s say, they’re on a low-carb diet in the afternoon and the evening and they go to bed hungry. Remember, hypoglycemia is one of the classic HPA axis triggers. That’s how they actually do that in the lab. They use a euglycemic clamp to create hypoglycemia. And that’s the best way to test whether your HPA axis is functioning: give somebody insulin, make them hypoglycemic and their cortisol shoots through the roof.
So your brain is there to protect you. And when you start doing things that you think are helpful for you, the brain has to adjust to that. And all these things have to be adjusted, and the brain will always see those as stressors initially.
DrMR: And this is why, again, we should be careful—more my opinion here—with how literally we interpret these tests results. I could see a scenario wherein someone was using some type of intermittent fasting or shortened feeding window, and they could be seeing better sleep, weight loss, better energy, because they weren’t eating so late at night. But because of that, they may have a higher cortisol in the morning. I think, again, as you said earlier, Tom, the right test in the wrong hands is not going to be very helpful. So we have to be careful not to be overly literally interpreting test results and make sure we contextualize it so we get the appropriate read.
DrTG: And that’s certainly true of all tests. I think I wouldn’t use a salivary cortisol test in the middle or certainly at the beginning of a ketogenic diet or anything like that. And also we know—I talk about this in my book—when people haven’t eaten, you see a spike in cortisol. When people exercise, you see a spike in cortisol about half an hour after the exercise begins. And those are all healthy things. You actually want a cortisol spike when you exercise. When you get older and when you’re less fit, you get less of a spike. But knowing that you have to be able to do your salivary cortisol test, you have to know when the person exercised in order to interpret that.
In fact, I have a good friend of mine who runs a lab. He just did a salivary cortisol before and after he sent one of his office managers down a Six Flags water slide. They saw an 80% increase in their cortisol when they got off the slide. Which is a good thing. Obviously, the person didn’t want to die and their threat system went up. But you have to know what you’re testing. And once you know what you’re testing, it’s much easier to interpret it later.
Challenging the Concept “Adrenal Fatigue”
DrMR: So, I think people in the audience may have heard of this paper published a couple of years ago, entitled “Adrenal fatigue does not exist: a systematic review.” Again, I agree with that conclusion, in terms of, the notion of adrenal fatigue needs to be challenged. And one of the things that they cite in this paper is what looked like the cortisol awakening response showing aberrancies, or being positive in fatigued populations. It seemed that there was only about a 50% corollary between someone being fatigued and having what was termed as a positive cortisol awakening response test.
Now, as some context, that was the best out of all the other tests that were assessed in this systematic review. So again, I do agree that the data seem to support that the cortisol awakening response test is probably the best. But maybe not highly accurate. Or would you criticize that at all, or do you think 50%…?
DrTG: Well, that’s another whole area of that we can get into. The Endocrine Society and the groups that have written some of these papers that “Adrenal fatigue does not exist,” have completely misunderstood… So, let’s put it this way. I also agree that adrenal fatigue is the wrong nomenclature for describing stress-induced changes in adrenal function. Let’s just say that. But, the Endocrine Society has wrongly concluded that what adrenal fatigue means is that hypoadrenal function causes fatigue, and as it turns out in some studies, chronic fatigue syndrome.
When you actually have a diagnosis of chronic fatigue syndrome, you do typically have a blunted cortisol awakening response. Although like you said, it’s not true in every single subject. But the issue that the Endocrine Society is arguing against is completely mistaken. They’re creating a straw man that what adrenal fatigue means has to do with fatigue. And almost none of the wrong use of adrenal fatigue in the functional medicine community is on fatiguing, or these kinds of things. So it’s hard to explain in just a few minutes here, but it’s like everyone is trying to throw potshots at something that they don’t understand. Really, the Endocrine Society is to trying to prevent any patient from going to anybody in integrative or functional medicine, because they believe the endocrinologist is the only one to diagnose any sort of adrenal dysfunction.
So I’m actually writing kind of a nuanced article to basically describe the fact that those shooting holes in adrenal fatigue have probably more holes in their pocket than they think. But that doesn’t mean I’m defending adrenal fatigue either, if that makes any sense.
DrMR: Sure. And I can appreciate that nuance. So, is what you’re saying that fatigue is not often a symptom of adrenal fatigue?
DrTG: The two concepts, because of the word “fatigue,” are mistakenly brought together. If you want to get into the bigger question, does chronic stress create problems with mitochondrial energy? Yes, there’s plenty of data to suggest that mitochondria function poorly at a certain point during chronic stress, whether it’s psychosocial stress, etc. We’ve got a lot of data to suggest that.
So at what point does the mitochondrial function overall create lethargy or fatigue from other standpoints? And I think the answer is, there’s probably a threshold that’s different in every individual, their ability to be able to withstand that, the use of caffeine and other substances that people use to get around that. It’s a complicated question because we don’t have definitive biomarkers really, for a lot of these things. Fatigue itself is not a definitive diagnostic criterion either. So I do believe there’s a connection between chronic stress and fatiguing, let’s say mental and emotional fatigue, maybe even physical exhaustion and fatigue. But where a patient crosses that threshold is probably very difficult to figure out.
DrMR: I agree with the general point that not all fatigue may have a cortisol mechanism that underlies it. And I think one shining example of that is the fact that we’ve seen increased fatigue scores in those with gastrointestinal inflammation, most namely published in the model of IBS. When we do IBS studies, there have been a number of papers now that have shown that IBS patients have higher reported fatigue. So it’s possible that this is more of gut-brain inflammatory fatigue than it is a cortisol fatigue. That’s one of the reasons why I haven’t been a huge advocate of the adrenal testing, I think, because I’ve seen so many GI cases where their fatigue cleared completely from just resolving that chronic gut inflammation.
DrTG: I don’t consider cortisol the driver, cortisol or the HPA axis. And I like to think of the HPA axis rather than just cortisol.
DrTG: The HPA axis is the monitor. It’s the one that’s surveilling the whole process. So if the inflammation is coming from the gut—as you know, a lot of inflammation is coming from the gut, in many of these people—it is going to be affecting the HPA axis. Why? Because the HPA axis is affected by everything, including, and maybe especially, inflammatory signaling. Actually, there are a lot of gut-brain linkages between the stress response and CRH, which is what the hypothalamus produces. But also CRH and the immune system in the gut. And it changes gut motility. There are actually CRH receptors in the gut.
So what I’m saying is this is a highly complex system, and the HPA axis is one of the quintessential thermostats and organizers of threat in the body. And so as big as the gut is, I’d say it’s as big as the HPA axis is, as far as managing that signaling capacity going to the immune system. Because obviously cortisol is actually an immune regulator as well. So I don’t think you can say one is different than the other. They are all complimentary.
In fact, I consider the HPA axis, the immune system, and the gut as really the controllers of the interfaces. They are the surveillance of our interfaces, and they’re highly regulated together. So I like to know what they’re doing and how they influence one another. The more information I have, the better. But where you start and where you end… that’s the clinical judgment that needs to happen.
DrMR: Sure. So I think we have some overlap here in terms of how we’re looking at these things. I think what I prefer a patient to do—just working with enough patients who’ve had that bill that has just totally decimated their financial lives—is try to be a bit more conservative here.
Interpret CAR Test with Caution
And there’s a follow-up question here, which is, why would there not be a better agreement between the cortisol awakening response test and cortisol levels, if there’s always this tight correlation between the HPA axis and the cortisol awakening response in fatigued individuals?
DrTG: Well, I don’t know exactly what you’re asking specifically, but most clinical trials that look at these things look at groups of people. And so you see a trend in certain individuals a certain way. But the individual in front of you, depending on what is going on… Remember, most clinical trials take out a lot of outliers to get some sort of semblance of an answer. Obviously, patients coming into your office and other offices are the outliers. They may have multiple things going on, they may not be sleeping, they may not be doing things with the diet correctly, and they may have a GI issue. And those are more complicated. So you may see some anomalies in those individuals.
But there’s a pretty clear correlation that the salivary cortisol level is telling you what the free cortisol level is being produced by the serum. And that is really what’s going on with the HPA axis. How to correlate that is the challenge. And that’s what clinicians are challenged with all the time, with complex patient histories and complex patient presentations.
DrMR: Sure. And we can make a parallel to SIBO breath testing, where SIBO breath testing does have merit and it does have a correlation to symptoms, but it’s not 100% correlation. Again, coming back to this, that the test should be used by a competent provider so it can be contextualized appropriately is very important. One of the reasons why I’m not a big advocate of direct-to-consumer lab testing is because I oftentimes see patients come in, and they’ve just made themselves more confused when they’ve wondered something, rather than clarifying things.
DrTG: And I’ve just recently written a paper on SIBO and breath testing as well. And I agree. What I say is “breath test positive” has a meaning, but breath test positive doesn’t mean SIBO. Meaning, having a positive breath test means something. It usually correlates with symptomology, but it may not correlate with specific overgrowth in the small intestine.
DrMR: Yeah, we had Richard McCallum on recently, who’s a gastroenterologist who is challenging this concept. And what he’s found in one of his research studies was that it may more be dysbiosis than it is frank SIBO. So there’s something there that the clinician can modulate. It’s just we don’t want to, again, be overly literal with how we interpret these results.
Now, Tom, what about the DUTCH test? This is something that people tend to have a lot of questions regarding. I haven’t done a deep dive into vetting it because I just haven’t found the utility in this camp of testing, although I remain open to it. And I think you can make a case for it, as you are. The DUTCH testing is reporting to be more accurate, for reasons I don’t have at the tip of my mind right now. What should people know about the DUTCH test and what do you think about it?
DrTG: Well, full disclosure, I’m good friends with almost all the lab people, including Mark Newman, who is president at the lab who comes out with the DUTCH test. So that should be said with a caveat. I believe all of the labs are doing good analysis. But since you specifically asked about the DUTCH, it stands for a dried urine test. And I forget what all five letters stand for, but essentially it’s the D-U-T, the dried urine test, to look at hormones. And I’ll give credit to David Zava at ZRT, who is also using urine testing a little bit differently than the way Mark is using it in the DUTCH test. But they both are advocates for the idea of cortisol metabolites—so you can look at cortisol, cortisone, both of them have various metabolites—that come in the urine. And by measuring the timing and the types of metabolites in the urine, you increase the ability to look at other things.
Now, I’ll be honest, I’ve challenged Mark at DUTCH to gather enough data and begin publishing the correlations for when these unique metabolites change the diagnosis, and when in the literature we’re seeing different things. Actually, I would just recommend going to his website and looking, he’s just recently published some correlations. To be honest, I convinced him to go back and use saliva and the CAR, because he had abandoned that and I convinced him that that was something that he needed to add on. But to be fair, BioHealth Diagnostics, ZRT, Genova, and the DUTCH test, I’m familiar with all of them and they all do very good work, including Rocky Mountains up in Canada.
So I don’t want to leave the impression that I think the DUTCH test is the way to go. And because I don’t want to give a biased approach, I interact with all these labs. But I think there’s some data that I think they’re going to begin generating to suggest that maybe urine metabolites, in addition to salivary cortisol, may help distinguish some certain situations like women on birth control, or obese patients versus non-obese patients, or thyroid patients that have some unique characteristics that may be deciphered with some of these additional tests.
DrMR: Sure. And I think that sounds like a reasonable conclusion. From what I did check when that lab first came across my radar, it seemed—and I’ll just be fully candid here for our audience so I can be to the point—like they were making some interesting claims that there wasn’t really any data yet to support. And what I prefer to do there is wait on the sidelines until the data come in. Because if the claims aren’t supported, then I haven’t dragged my patients through the mud for years, using a test that ends up being invalidated or not supported. And if we do obtain the data, then great, I’ll be more than happy to use those if there seems to be this clinical need or clinical utility. So that’s the way I tend to approach these things.
And again, more for the audience, the reason why I do that is because if you’re not aiming to keep things simple, you can very easily drift into this model that unfortunately seems to be somewhat commonplace in functional medicine, which is lots of testing, lots of mechanisms, lots of cost, and unfortunately not as much result. Again, more my opinion here, but because you’re looking at the exotic many rather than the vital few. But to your point, Tom, hopefully, they’ll produce some data and that will be able to join the crop of tests that I would consider fundamental.
DrTG: Right. Okay.
Tips to Manage Your HPA Axis Stress
DrMR: So, as we move to a close here, is there anything that you want to leave people with? Any pearls or actionables where you would say, ‘Okay, here’s what you should do if you’re trying to get this whole HPA axis stress issue moving in the right direction?”
DrTG: Well, I agree with you, in the sense that I think it’s simpler. I think there are a lot of people who know what it is that’s stressing them and the types of things they need to do to change that. But they’re looking for some magic bullet, a supplement or a drug or some therapy, so that they don’t have to deal with really changing their diet or dealing with relationships that are stressing them out or a financial situation.
In fact, I had one doctor say, the best advice he gave to a woman under stress was to get a financial advisor because her finances were a mess, and it was stressing her out literally every single day. Really, it’s sitting back and saying, people have known for thousands of years that stress causes chronic disease. It’s just that we didn’t have the mechanisms, but we knew that. So dealing with those things that are sort of the obvious are going to really reduce what the brain sees as stress. And they’re going to lengthen what I call the adaptive capacity or the buffering capacity of our stress response system. It’s trying to deal with everything. Anything that goes awry in the body, the stress response has to kick in and try to stabilize and bring us back.
So if that’s happening every single day… what I tell people is, the stress response has to use the same mechanisms as the normal response. Like when there’s a fire truck coming down the road, everyone has to get off the road and let the fire trucks come through. That’s what happens to your metabolism. Every time you’re under stress, all your metabolic processes have to be on pause until you’re stabilized. It causes insulin resistance, it causes your bone mineral density to go down. All of these different chronic things that occur are put on pause, every time you’re under stress.
So I think generally just sit down and be honest with yourself. What are those things that you really need to change to reduce the stress in your life? Sometimes they’re little things, but sometimes they’re big things and those are the most difficult. The things that people know they need to change sometimes are the hardest for them to change. If they can start there, I think they’re going to be able to have big levers of change in their life.
DrTG: Yeah, I think that’s incredibly well said and I wholeheartedly agree. Tom, is there a website or anywhere that you’d like to point people online if they want to hear more from you?
DrMR: Yeah, I’ve got my own website, pointinstitute.org. And I’ve got the books, they’re available online. There are some downloadable white papers and other standards. So they can get ahold of me there or get some of our materials there.
DrTG: And Tom, I just want to say, from the work of yours that I’ve seen, it seems like you’re doing a very good job of striking that balance of being progressive and trying to get people solutions, but then not getting pulled into these fictitious solutions that are just really Hail Mary prayers without any evidence to support them. And so want to commend you here quickly, on towing what I think is a reasonable balance there.
DrMR: Trying to walk the tightrope is always fun.
DrTG: Right. Well, thank you again, Tom. It’s been a pleasure chatting.
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