Cortisol and the HPA Axis with Mark Newman of Precision Analytical: Rational Wellness Podcast 232

Mark Newman of Precision Analytical speaks about Cortisol and the HPA Axis with Dr. Ben Weitz.

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Podcast Highlights

2:04   The adrenal glands release cortisol, which is your stress response.  This is directed by the brain. The hypothalamus in the brain releases Cortisol Releasing Hormone (CRH) that goes to the pituitary gland, which releases ACTH and both the hypothalamus and the pituitary are in the brain.  ACTH then finds your adrenal gland and it stimulates the release cortisol, as well as aldosterone, DHEA, and your catecholamines like adrenaline.  Cortisol secretion is an important component of our normal circadian rhythm along with melatonin. ACTH starts going up before you wake up and when you wake up and the light hits the back of your eye, that is the signal to make ACTH, which make cortisol. Waking up is is a stress event, so you get the stress hormones secreted.

5:17  When testing the salivary cortisol upon awakening and throughout the day, if you are not making enough cortisol, it could be related to COVID. The antibodies for COVID can cross react and attack your ACTH and make it more difficult to produce cortisol.   And this could persist for a long period of time, which could be one factors in the symptoms that long haulers with COVID have, such as fatigue and brain fog.

8:47  Supporting the adrenal glands could be an important component of helping people recover from COVID.  We know now that the adrenal glands never actually become fatigued and unable to produce cortisol. The problem has to do with the signaling from the brain to the adrenal glands that gets disrupted.  This has led the conventional medical community to dismiss this concept of adrenal fatigue caused by long term stress, first described by Dr. James Wilson in his book Adrenal Fatigue. Allopathic medicine tends to see Addison’s Disease if you don’t make any cortisol and Cushing’s Disease if you make excessive levels of cortisol and nothing in between, but this is not true and this dysfunctional stress response is what those of us in the Functional Medicine community are helping patients deal with.

13:11  Salivary cortisol testing. To test for adrenal function, serum testing is not very helpful. This is why salivary testing for cortisol that can be done at various parts of the day is much more accurate and helpful.  The comprehensive DUTCH complete test includes not only cortisol testing at various parts of the day, but it also looks at the sex hormones, since if a guy has low testosterone, that can cause fatigue. And this test also looks at a marker for B12, and a B12 deficiency will cause fatigue. 




Mark Newman, MS is a recognized expert and international speaker in the field of hormone testing. Mark spent nearly 25 years developing and directing urine, blood, and saliva-based hormone testing along with other biomarkers like organic acids. His unique experience led him to pursue a revolutionary way to test hormones; so Mark began his own lab, Precision Analytical Inc., to create the latest innovation in hormone testing, the DUTCH Test® (a Dried Urine Test for Comprehensive Hormones).  The website is DUTCHtest.com. 

Dr. Ben Weitz is available for nutrition consultations specializing in Functional Gastrointestinal Disorders like IBS/SIBO and Reflux and also specializing in Cardiometabolic Risk Factors like elevated lipids, high blood sugar, and high blood pressure and also weight loss and also athletic performance, as well as sports chiropractic work by calling his Santa Monica office 310-395-3111. Dr. Weitz is also available for video or phone consultations.


Podcast Transcript

Dr. Weitz:            Hey, this is Dr. Ben Weitz, host of the Rational Wellness Podcast. I talk to the leading health and nutrition experts and researchers in the field to bring you the latest in cutting edge health information. Subscribe to the Rational Wellness Podcast for weekly updates. And to learn more, check out my website, drweitz.com. Thanks for joining me and let’s jump into the podcast.

Hello, Rational Wellness Podcasters. Today, I’m excited that we’re going to have an interview with Mark Newman about cortisol and hypothalamic-pituitary-adrenal axis. I know that’s a mouthful of words, but we’re going to put some meaning to that and explain it a bit better once we get started. Mark Newman, Masters of Science, is a recognized expert and international speaker in the field of hormone testing. Mark spent 25 years developing and directing urine, blood, and saliva-based hormone testing, along with other biomarkers like organic acids.

His unique experience led him to pursue a new revolutionary way to test hormones, so Mark began his lab, Precision Analytical, which offers the Dutch Tests, which stands for Dried Urine Testing for Comprehensive Hormones. In order to develop the most accurate evidence-based testing practices, Mark has written multiple peer-reviewed research papers highlighting the accuracy and clinical utility of dried urine hormone testing. Mark’s primary educational goal is to find and communicate truths about hormone replacement therapy monitoring to help providers care for their patients. He understands why each form of testing has its own strengths and weaknesses, which is why he encourages clinicians to follow the evidence, even when lab testing isn’t clinically helpful. Thank you so much for joining us, Mark.

Mark:                    Thanks for having me. Good to be here.

Dr. Weitz:            Great. So to set up the discussion for listeners who are not really familiar with what the adrenal glands are and do and what would be the point of testing for cortisol as a measure of adrenal function, perhaps you can give us a little information about that.

Mark:                    Sure. My area of expertise is really limited to reproductive and adrenal hormones, and when we focus in on the adrenal hormones, a lot of what we’re talking about is just your stress response. You’ve got stuff that goes on in your brain, CRH getting released from the hypothalamus, which goes to the pituitary, which we’re still in the brain there, which releases ACTH. And ACTH, is that stimulating hormone that cruises around in your blood, and when it finds most tissues, they don’t care. But when it finds your adrenal gland, it stimulates the release of among other things, cortisol. So it’s also involved in aldosterone and DHEA, and your catecholamines like adrenaline. But that’s a big part of the story is getting cortisol to do what it’s supposed to do, which is you want to make a whole bunch of it, but not too much in the morning, and then it comes down fairly rapidly. So you get this up and down, up and down pattern from day to day if things are functioning properly, and-

Dr. Weitz:            So, let me just stop you for a second. So what you’re saying is, is that this cortisol secretion is a really important component of our normal circadian rhythms, our wake/sleep cycle, along with say melatonin?

Mark:                    Yeah, so yin and yang for cortisol and melatonin. So, we want to make melatonin when it’s dark and we want to make cortisol when it’s light. And it’s literally the light is involved in when the light hits the back of your eye, that is the signal. And it’s a pretty amazingly complex system that I’m still learning about where you’ve got ACTH that stimulates the adrenal gland, but ACTH starts going up before you wake up.

Dr. Weitz:            So what is ACTH?

Mark:                   ACTH is the stimulating hormone that I’d have to spell it out to actually get the name exactly right.

Dr. Weitz:            Okay.

Mark:                   It’s the hormone that your brain makes that is the signal to the adrenal gland that it is time to make cortisol. So when you get stressed you make ACTH, and that helps you make cortisol. And when you wake up in the morning, waking up is actually the same biochemistry goes on when you wake up as when you get stressed. So essentially, like awakening and arousal for the day is your first stress event of the day so that your brain starts making ACTH. It’s this really fascinating biochemistry where the brain is making the ACTH, so you say, “Well, make cortisol.” Well, not yet. There’s this sort of braking mechanism that the body has to wear the ACTH builds up. And as soon as the light hits the back of your eye, it sort of releases the brake, and boom, you make a whole bunch of cortisol right when you wake up so that you’re moving from being awake to being alert. And light, actually, is the mechanism or the trigger that sends that on its way.

And that’s a lot of what we do is measuring cortisol at those different time points to say, “Hey, is this functioning the way that it’s supposed to?” And if it’s overfunctioning and you’re making too much, you’re going to have issues. And if it’s not functioning enough, which we’re starting to see a lot of, interesting little fact that I just learned from reading some papers on COVID is that the antibodies for COVID can recognize ACTH and sort of steal that from you, which can become part of this issue of not making enough cortisol as you’re recovering from COVID. So it’s pretty relevant to our lives every day and-

Dr. Weitz:            Well, hold it. Explain that quickly.

Mark:                    So the antibodies for the COVID virus can actually reduce your ACTH. So your brain says, “Time to make cortisol.” ACTH gets released. It’ll have to find its way to the adrenal gland. And this hasn’t actually been proven yet. It’s been shown with the other SARS. So, SARS-CoV-2 is COVID. With the other SARS viruses, we know that those antibodies actually recognize ACTH, and they can sort of steal that away from your cortisol production biochemistry.

Dr. Weitz:            So this is like a cross-reactivity phenomenon.

Mark:                    Yeah. Right. Right. And so one of the things that we see sometimes in COVID cases where they’re recovering and struggling to do so is a lack of cortisol production. And part of that story, which it’s early for COVID, right? There’s still research going on all over the place to try to figure out exactly why do some people become long haulers? Why do some people not? But part of that story can be a lack of cortisol production. And part of that story, is this interesting interaction between the antibodies from a SARS virus, and how much ACTH you have to stimulate cortisol production, so-

Dr. Weitz:            Interesting. So this could account for the fatigue and maybe the brain fog and some of the other symptoms related to long COVID symptoms?

Mark:                    Yeah. And it’s I don’t want to overstate that because it is a complex story that is still being told, and it’s they have to piece it together. Some of it’s old research from other SARS viruses, and some of it’s more specific to COVID, where we do see a fraction of those people even up to a year later are still struggling to make cortisol, and the why of that probably has something to do with that, but that’s still being kind of worked out by people who are knee-deep in COVID data.

Dr. Weitz:            So, but that might indicate that part of a workup for a patient with long COVID would be to do cortisol stress testing as offered by Precision Analytical or other labs.

Mark:                    Yeah, I just went back through a handful, couple dozen patients now that we’re getting beyond COVID for people by number of months, and just looked at people eight months out and 12 months out, and then looking at what the literature is saying. And yeah, there’s a subset of those people that’s pretty sizable, that struggle to regain their normal stress response, their normal cortisol production. So if you have people struggling with COVID, it’s not that well defined yet what the causal factors there are, and goodness knows it’s probably more than one thing, but not making cortisol as they used to.

Dr. Weitz:            Supporting the adrenal glands. Yes, supporting the adrenal glands could be an important component in helping people recover faster.

Mark:                    Well, yeah, and I think that’s as we were talking about before, I think the language that we use it depends if we want to speak very generally for the sake of our patient to make it simple, but when we’re studying it from a scientific standpoint it’s brain signaling is probably the bigger factor than… And that’s been this long going sort of, I don’t know if it’s a debate, but in our industry that we’re both in is that there’s this catchy phrase, adrenal fatigue, that really well describes what patients feel, which is that they don’t have enough of the hormone that their adrenal gland makes. And for years, our industry, I think without discriminating very well, used the phrase adrenal fatigue, but as we’ve really gotten into the biochemistry and figured out, “Okay, adrenal fatigue tells me a story about a gland that’s on top of my kidney that is really tired of making cortisol and it cannot.”  And when you really get in and look at it, what’s going on in most of those cases is that their adrenal gland works just fine, but it’s that brain chemistry that gets messed with in terms of your negative feedback and all of that, that is typically sort of at fault when the stress response gets screwed up is that it’s more of a brain issue and less of a… Adrenal gland is a little bit more like your knee when you hit the patella tendon there, it responds. And usually when you hit the adrenal gland with ACTH, which is its go signal, it goes. Making that cortisol…

Dr. Weitz:            But I think that concept maybe comes from diabetes and the pancreas and constant consumption of sugar and other things that stimulate the pancreas to produce insulin. Over time, the pancreas gets burned out, the cells can’t produce it, and then at some point, diabetics end up needing injections of insulin. And I think that concept has been applied to the adrenal glands.

Mark:                    Yeah. And I think not rightly so. I mean, it’s a reasonable theory, but I think when people went in and really looked at the biochemistry, it’s not actually what’s going on. The challenge is in on the scientific side you start talking about things like allostatic load, and all of these, resilience and some of these words that, let’s be honest, they’re just not as interesting to Google in terms of like being sticky. And that phrase, adrenal fatigue, it was sticky.  And Dr. Wilson, who’s a good friend of mine wrote the book on adrenal fatigue, and it really got the concept that if your cortisol is low because of long term stress, that’s an issue and we should deal with it, right? Because allopathic medicine tends to say, “Listen, you have Addison’s disease if you don’t make any cortisol. You have Cushing’s disease if you’re making gargantuan levels of cortisol that never come down. And everyone in between, you’re fine, have a nice day.” Right? Which is that’s why you’re in business, right? Because it’s not true. And so-

Dr. Weitz:            Oh, yeah. Absolutely.

Mark:                    …dysfunction in the cortisol space outside of disease is an issue. And the phrase, adrenal fatigue, brought that to the forefront. The problem is when you want to go and have credibility with what you’re doing to allopathic peers, and just generally, right? We want to be right. The phrase is actually it’s not correct in terms of what’s going on. And it does matter because when you look at Dr. Wilson’s work, who I have a lot of respect for, one of just the random things you’ll find is that the adrenal gland needs a lot of vitamin C.  So part of the solution for adrenal fatigue is a lot of vitamin C.  And I’m not saying you do or don’t need a lot of vitamin C, but if you’re fixing the wrong problem, you’re probably not going to have a lot of success.  And when you really look at the biochemistry, the stress response and the things that go on in your brain that help regulate that, that is where your dysfunction lies in most people who have a cortisol issue. And if we’re going to fix that problem… And fixing the problem is not my expertise. When you start talking about adaptogens and things, hopefully we’re starting with lifestyle, but fixing a problem, I’m more on the analytical side of how do we well-define this problem? And that’s why we developed our testing, is to say, “Listen, this is a complex problem. And if we want to well-define the patient’s dysfunction, we need more data than just…” And then that depends on how you fill in that blank. If you go all the way back to a serum test, I mean, serum works really well for a lot of hormones. It’s the default, right? But for cortisol, it’s not a great tool.

Dr. Weitz:            Right. Which is why we’ve been using salivary cortisol testing.

Mark:                   Right.  And a lot of traditional doctors will just sort of shrug and be like, “Well…”  Actually I spent last week at NAMS, which is a very conventional group, and we were talking to them about some of our research as it relates to hormone replacement.  But when you talk to those types of people about cortisol, it’s just like, “You know what, I look at the patient, I see what’s wrong with them.  I know what’s going on.”  And I’ll tell you what, when you do that and then you start testing, and you see how often that story that’s going on with their stress response does or doesn’t match up, there you can guess wrong a lot because there’s such an overlap, right?  That’s why we’re in the game of comprehensive testing with what we do is if you take something like fatigue.  Well, we have a number of stories that intersect with that, right? As a guy, if your testosterone is low, that’s going to be an issue. We’ve got a B12 marker on our DUTCH Complete and our DUTCH Plus. If you have an overt B12 deficiency, you’re going to have some fatigue. And but also, if your cortisol is low, you’re going to have fatigue, and certainly if you have a combination of those things. But we want a well-define what’s going on with that patient. And with cortisol, you really can’t do that with blood testing. The best example I always give people is that if you look at the studies where people are healthy, like a woman’s healthy and then she gets on birth control. The cortisol and serum will double as women get on birth control without anything happening to their stress response, because the birth control happens to stimulate the binding protein that gobbles up cortisol. Your body responds by making more cortisol. But the free cortisol that’s able to do something, those levels just hang out in the same level.

So when you’re looking at urine-free cortisol like with our DUTCH Complete, or salivary cortisol like with our DUTCH Plus, those things don’t change unless your stress response changes, unless your cortisol truly changes. But the serum cortisol, you can double it, again, just by putting a woman on birth control and then letting things resettle. So stress will double your cortisol, and that doubles your cortisol, but it’s not a meaningful change, right? Then what we’re looking for, the words I like to use with lab testing is we’re looking for meaningful differentiation. And serum does not meaningfully differentiate people with cortisol dysfunction and people without. And then beyond that, we want to look at the up and down patterns-

Dr. Weitz:            Because you’re seeing total cortisol levels versus free cortisol levels, correct?

Mark:                   Right. And when you look at things like estradiol, progesterone, testosterone, it’s not as important of a distinction. But when you look at cortisol, that up and down pattern of free cortisol is so much more differentiating between function and dysfunction. And so, for us, we look at that up and down pattern. So we can look at that in urine, and we can look at that in saliva. The reason that saliva is the king of cortisol when it comes to free cortisol is that you can measure the cortisol awakening response, which is something we all ignored until I don’t know, six or seven years ago, when the data just became overwhelming that that is another variable that’s important for us to look at, which is that rise you see in the early morning. And you can really only see that from looking at saliva.


Dr. Weitz:            Interesting. I’ve really been enjoying this discussion, but I’d like to take a minute to tell you about a new product that I’m very excited about. I’d like to tell you about a new wearable called the Apollo. This is a device that can be worn on the wrist or the ankle, and it uses vibrations to stimulate your parasympathetic nervous system. This device has amazing benefits in terms of getting you out of that stressed out sympathetic nervous system and stimulating the parasympathetic nervous system. It has a number of different functions, especially helping you to relax, to focus, to concentrate, get into a deeper meditative state, even to help you sleep, and there’s even a mode to help you wake up. This all occurs through the scientific use of subtle vibrations.

                                For those of you who might be interested in getting the Apollo for yourself to help you reset your nervous system, go to apolloneuro.com and use the affiliate code, Weitz10. That’s my last name, WEITZ10. Now, back to the discussion.



Dr. Weitz:            What you’re talking about is for a number of years, the way we would measure the salivary cortisol is we would measure it in the morning, noon, afternoon and evening. And was not necessarily right when they got up, it was sometime in the morning. And then the cortisol awakening response is that response that occurs in the first 30 minutes after waking up, right?

Mark:                   Right. I’ve got an interesting… For those of you that are actually viewing maybe I’ll show you this here. Let me share it.

Dr. Weitz:            Mark’s going to show us a slide to illustrate this, the cortisol when you’re waking.

Mark:                   We did a really neat test on this with our assistant medical director, bless her heart. So when we look at… So I’m showing you now the data we published that shows that the up and down pattern in urine from our dried urine samples and from saliva are statistically very similar. The up and down pattern that you see. But when you look at urine, the first two samples that we measure, that’s not a cortisol awakening response, because cortisol awakening response is right when you wake up and 30 minutes later. And right when you wake up in saliva is right when you wake up, but right when you wake up in urine is of course what you’ve been collecting all night.  So it’s an interesting measurement. It’s a good measurement, but it doesn’t help you with the CAR. So the CAR is saliva right when you wake up, right? And then 30 minutes later. So let me show you. This is called a mini-stress test a lot of times. So, what you’d like to have in your office is a bear, right? You could test your patients’ cortisol and then let the bear chase them, and then you could test them 30 minutes later and you’d know their response to a stress, right? But that obviously doesn’t work very well. So here’s what we did is my-

Dr. Weitz:            Yeah, it turns out that feeding the bear is very expensive, and you got security issues.

Mark:                   That’s the whole reason why we don’t do that, right? Is that’s too expensive. So, but this is the thing, waking and a stress response are the same biochemistry. So what I had Dr. Rice do is we went to the IFM Conference, and they have this slide where I’m showing a picture of it here, where you stand and the floor drops out from under you, right? And so if you don’t like heights, it’s sort of an unpleasant experience.  So I had her do a cortisol panel throughout the day. So what I’m showing now is when she woke up, her cortisol went up by about five, and then it comes back down. So then on this alternate day, in the middle of the afternoon when her cortisol has already gone down, she collected a saliva sample, she bravely got up on the death-defying water slide apparatus, and down the slide she went. And then she collected another saliva, and then another one a half an hour after that, and so on and so forth. What you can see is that the response to stress for her, it doesn’t always work out exactly this well. But her response to stress was five, and her response to waking was five.

So basically, when we freaked her out, her stress response kicked in, and that’s just not a practical test to do, right? But that’s the whole magic, if you will, of the cortisol awakening response is testing within five minutes of waking, catches you before you rise. And then catching you at 30 minutes says how dynamic is that stress response? And the word resiliency is used a lot when we talk about this is… And I’ll stop sharing my screen. I just wanted to show you that. I thought it was kind of fun data.

Dr. Weitz:            By the way, can I just ask a quick question?

Mark:                   Yeah.

Dr. Weitz:            The question has come up from patients doing this test, “I hit the snooze on my alarm. So I rolled over, I hit the snooze, and then I went back to bed. Does that mess it all up?”

Mark:                   I think it’s important that your waking time is normal-ish, because you got to remember, your cortisol starts to go up around 2:00 or 3:00 AM, right? So if for example, you wake up at 3:30, and you normally wake up at 7:00, then your CAR can be exaggerated because it’s got to makeup that ground a little bit, right? So you want to wake up at a normal time, but it really is the light that is the trigger for the cortisol awakening response. So you can get away with that. It’s probably better to just get up and do it, but what happens is the light hits the back of your eye, the change is rather instantaneous, but it takes five minutes for that change to find its way into your saliva. So you’ve got this five minute window.

So what’s best to do is I mean, if you can spend some money and get the test, I’d get your butt out of bed and get the light on, get your sample collected within five minutes, and then get the other one right around half an hour. And that’s going to give you some really good data. And I think you don’t have to do it perfectly, but the more you screw around with the collection, then the more sort of ambiguity can come into those results. So we do want it to be as precise as we can, but it is the light. So that would be why you also wouldn’t want to collect your sample, and then sit up in bed in the darkness and then wait half an hour. You want to get up and be active and get up and see what happens to my chemistry as I move again, from awake to alertness? That’s that whole point of that going on in our chemistry is to get us ready for the day.

Dr. Weitz:            And we should point out that the way your company tests the saliva is beneficial because other labs you have to spit into this tube, and sometimes when you first get up in the morning that alone can be a stressful event.

Mark:                   Well, it’s honestly it’s people asking too much of what you’re trying to do. So here’s the challenge is we test all the sex hormones in urine because I think they’re more accurate that way. We’ve published data that shows the serum correlation is really nice with estrogen and progesterone, et cetera, right? The challenge is if we use cotton swabs for cortisol because you can get a collection easily within two minutes.

Dr. Weitz:            So, in other words for those who don’t know, you just put this cotton swab in your mouth, get it wet, and then you stick it in a tube?

Mark:                   Yeah, you chew on it lightly a little bit. When I do it it takes me about 60 seconds, but it would never take you more than two minutes, right?

Dr. Weitz:            As opposed to spitting, because spitting can be-

Mark:                   Right. The challenge is if I want cortisol, and I want my sex hormones out of saliva, I have to give you a whole bunch. The problem is those cotton swabs absorb progesterone. So if you try to have a test that does cortisol and progesterone at the same time, you cannot use the cotton swabs. And as soon as you can’t use the cotton swab, then I have to ask you for two to three milliliters of saliva before you’ve even had any water to drink. And it just becomes a little bit of a nightmare, because if it takes you 15 minutes, guess what? Those second five and third chunk of five minutes, your cortisol has already doubled, right? Potentially. So you’ve just sort of screwed up the mechanism of how it works.  So it’s better to get the cortisol out of saliva. And then for us, we get all the sex hormones and their metabolites out of urine, where it’s a lot easier to measure accurately. I mean, measuring that’s a whole nother story, but measuring estrogen in saliva is just not a very good idea because it’s hard to do analytically, and then you can’t look at the metabolites. So for us, we’re using saliva for the cortisol. And then in the urine we’re measuring sort of everything else. So if you want just a urine only test, you can do the cortisol in urine also, you just don’t get the CAR, but you get everything else.

But for us, the reason we want to use the urine is A, it’s better for sex hormones. But the other thing is getting back to the adrenal picture is… And this was actually what led to our entire company is realizing that measuring cortisol without looking at its metabolites can really lead you in the wrong direction a lot of times. So we’re measuring cortisol, which is free, active, the most important thing you can measure, but then we’re also measuring the metabolites, which is essentially like it’s the bucket that catches all the cortisol you make so that you know how much glandular output you have. Which at first glance sounds like, “Well, I already know cortisol because I have free cortisol,” but as we’ve looked at the research, and looked at so many cases, it adds a dimension of understanding that really is helpful in a lot of cases.

Dr. Weitz:            When I hear that only 5% of the cortisol that’s produced is free, meaning not bound to proteins like cortisol binding protein. Why would the body produce all this cortisol and only leave a small percentage of it to be active?

Mark:                   That’s an interesting question. Because 5% is probably the highest quote you’ll find.

Dr. Weitz:            Oh, okay.

Mark:                   Most of them are around one to 2%. And some will say as high as five. I mean, that’s on the high end. So you’re right, most of it is free. And then there’s the whole hormone cascade that comes after that. So it’s a complex system and it’s fascinatingly complex, but it makes it difficult because it’s sort of like we want easy two dimensional pictures, but it’s this three-dimensional thing where you’ve got this up and down pattern of free cortisol. But then if you say, “Okay, that tells me my stress response,” true. But then when you say, “That tells me how much cortisol I quote, produce,” that’s actually not true. Well, in some cases, it’s not true, right? You need the metabolites to tell that part of the story.

The place I found that first that was so interesting is in obese people. In obese people you’ve got this, essentially, this organ of fat or gland or whatever. It’s this whole thing. It’s a whole system, and it loves hormones. And so cortisol, as you make it is going to get sucked up by fat. And then it gets metabolized and ends up in a toilet and your adrenal gland’s like, “Oh, well, I guess I’ll make a little bit more.” And as you get into obesity, the difference there is massive. So you’re making literally, to keep your stress response and that salivary cortisol in the same place, a skinny person and an obese person will make three times, like three times more cortisol in an obese person to sort of keep up with that sequestering metabolism excretion. And that’s where the story gets kind of complicated, and you can go in a lot of different directions with that, but we want to tell that story well.

And so there are a number of factors that can impact how the cortisol is cleared. So thyroid is probably the biggest space where we see that, where… And I’ve got a nice example of a patient who had low free cortisol, and then high metabolites. But see, that doesn’t finish the conversation because you have to ask why? Because usually that’s because they’re obese. And you say, “Oh, that makes sense. You have your free cortisol just is what it is, and the metabolites are going to move as you gain weight, and so that’s interesting.” But in this case, the person wasn’t obese and you continue to ask questions and say, “Okay, well what else makes me get rid of my cortisol at a fast rate?” Well, hyperthyroidism. Well, this person’s hypothyroid. Well, okay, that doesn’t make sense.  And then you keep digging and realize, “Oh, hold on now. We have our blood testing that shows the thyroid results are high. So this patient’s being overdosed. Oh, okay.” Now you keep digging at the problem and you realize that hyperthyroidism makes your body just zip through cortisol. So you get this gargantuan amount of metabolites and low free cortisol, and this story starts to make sense. So before you go fix a cortisol problem, obviously, you don’t want a patient hyperthyroid on accident, right? So with this patient, they said, “Oh, well drop the dose.”

I had a friend who had that same exact scenario, and it turned out the doctor said, “Here’s your medicine, take it once a day.” And she heard, “Here’s your medicine, take it morning and tonight.” And so she was inducing hyperthyroidism just by not following instructions. And so once they tapered that dose back, the thyroid results came where they belong. And now there’s no longer this imbalance of essentially burning through your cortisol faster than you’re supposed to. And the free cortisol went from low to high. So it’s like all this cortisol she was trying to make that her body was just zipping through. And she actually had a stress response, a stress situation that was hyper, but because of this concurrent thyroid problem, it just created this really complex situation. And that’s kind of our mantra is that complex problems need comprehensive solutions.

And so for cortisol, we want to see the up and down pattern, yes, but we also want to see the metabolites because we really don’t know the full story until we see both of those things so that we know what’s your stress response? And then but also, what is your cortisol production? When they tell the same story, it’s boring. You got a guy who’s on fire, he’s inflamed, whatever. His free cortisol is high, his metabolites are high, and you say, “Yeah, well, the metabolites didn’t help anything, but to confirm,” right?  And I can look at another case where a person has low cortisol, low metabolites, all it’s doing is confirming. And in that sense, you have more confidence, but it hasn’t really told you anything new. But when those things tell opposite stories where free cortisol is low, metabolites are high, that’s interesting. When it’s the opposite, that was actually one of the early cases I found in the literature, is that when you look at cortisol and anorexia in the literature, you get opposite stories depending if you’re looking on a urine story or a saliva story, right?

So there’s a nice paper where they show that the metabolites of cortisol are half in an anorexic patient. You say, “Okay, half the metabolites means half the production.” And then there’s a paper published the next year that evidently didn’t read that paper that looked at salivary cortisol, and the saliva was the opposite. The saliva was elevated for cortisol in anorexic patients, which was a problem for them, right?  But there’s a paper clear back the year I was born in like 77, that says that anorexic patients don’t clear their cortisol very well because they end up with a thyroid problem. So you end up with this really complex situation where you have high free cortisol. So now you’re going to struggle with things like depression because of high cortisol. But if you tell yourself anorexic patients make too much cortisol, you’re wrong. What’s going on is they have sluggish clearance of cortisol because of a concurrent, likely a concurrent thyroid issue because of the anorexia, and so they don’t get rid of their cortisol very well to the degree that their free cortisol is high.

So if you want to go in and fix that problem, the first thing is understanding it well. If all you’re thinking is, “I’m making too much cortisol,” you’re barking up the wrong tree in terms of solving that problem. It’s just more complex than that. And we see those types of cases all the time where it’s just there’s a complex thing. And you’ve got to get as much information as you can before you start shooting bullets at your problem. You want to define it really well because you really can run confidently in the wrong direction so easily when you’re just basing it off of a simple serum cortisol or even when it’s just salivary cortisol. There’s a broader story there, and that’s what we’re all about is digging into those complex stories and trying to figure out as much as we can about them so that you go to the right solution for those patients.

Dr. Weitz:            I know that treatment’s you’re not a treating doctor and that’s not one of your specialties, but still to just think through some of the potential treatments that might be effective for patients with cortisol abnormalities or adrenal dysfunction. So, and I have two thoughts. One is even though the brain may be what’s not telling the adrenal glands to produce enough cortisol in the case of hypocortisolemia, it still might be beneficial to nutritionally support the adrenal gland to make more cortisol even if the problem is not that… Even if the problem is that it’s not getting the signal from the brain, because that may be easier than fixing the brain. I don’t know if we know yet exactly how to fix the brain, except maybe to work on the gut. And that may validate some of the treatment approaches that functional medicine doctors have done where they support the adrenal glands.

Mark:                   Right. Well, I mean I think, look, if you have an overt nutrient deficiency, the odds of success are probably low. So I think if you’ve got basic nutrient deficiencies, those are definitely worth fixing. And there is some good research on some of the adaptogens that people use working in the brain. Pregnenolone is a really interesting one because pregnenolone is this neurosteroid, right? And if you take it for HPA axis dysfunction, people have had success. But some people have had success with that for let’s see, how would you say this? Mistaken, it’s sort of lucky that they got it right kind of a thing, because part of this thing that goes along with adrenal fatigue in terms of this nomenclature that we use, is there’s also this concept of progesterone steal and pregnenolone steal. And if you-

Dr. Weitz:            For those who are not really familiar when you look at the whole cascade of the production of male and female hormones, at the top of the chart is pregnenolone, and it’s often considered the mother of all hormones.

Mark:                   Yeah, let me just pull that steroid pathway up. And then that way, if people want to stare at it, they can. Oh, shoot, I didn’t advance my slides here. Because this has led to a lot of confusion in our industry.

Dr. Weitz:            Yeah.

Mark:                   Let’s see. Are you seeing that there?

Dr. Weitz:            Yeah. Yep, steroid biochemistry.

Mark:                   Okay. Okay, so if you look at this, you’ve got cholesterol and then pregnenolone. And then downstream, you have progesterone. And then you take a right hand turn and then another right hand turn and you get cortisol, right? So, people will assume that then if you’re stressed, the cortisol is made from the circulating hormones that sit above that. And this, I’ll show this, but I’ll describe it for those of you that are just listening. So ACTH is made in the brain, right? It circulates, and then it find its way into the adrenal gland, into the cells in a particular location in the adrenal gland.  Then ACTH knocks the StAR hormone into cholesterol within the cell. Now cholesterol can go into the mitochondria inside the adrenal cortex cell. The cholesterol right there then gets turned into pregnenolone. That pregnenolone is your substrate. That goes outside the mitochondria and into the endoplasmic reticulum, and it gets turned into progesterone. That progesterone is your substrate for making cortisol. So now if you pause right here, and say, “Okay, I’ve taken ACTH. I’ve taken cholesterol into my mitochondria. I’ve made both pregnenolone and progesterone.” At this point, if you start taking supplements: progesterone, or you start ovulating, or you get pregnant… And do pregnant people make more cortisol because they have all this progesterone? No, because it isn’t in the adrenal cell.

So the steroid cascade is really helpful for us, but it also has been misleading for people because they see it as this sort of, “If I just get the precursor.” So for example, if you give a woman DHEA. Yeah, she’ll make a little testosterone out of it. And a guy? Yeah, he’ll make a little testosterone out of it. You will never rival testicular production of testosterone by shoveling precursors at men, because it’s the same thing. Cholesterol because of LH gets pulled into those cells within the testes, right? And in that little cell, they have the machinery to make testosterone out of cholesterol. You will never rival that by giving supplements of upstream hormones.

The same thing with cortisol is progesterone. And just to finish this animation if you’re watching it. Progesterone then turns into deoxycortisol. It’s so complex. It then goes back into the mitochondria. Turns into cortisol. Now I have cortisol which can leave my adrenal gland, right? And then it’s going to go out and circulate. So the point is when you look at the steroid cascade, and you look at what’s upstream, and we think, “Oh, that’s what I make it out of.” So if I steal cortisol because I’m stressed, my woman will no longer make progesterone. Yes, there’s a relationship between stress and reproduction, right? When you’re getting invaded by the northern invaders, it’s not time to make a baby, right? So your body is smart in that when you’re stressed you might stop ovulating, you might become anovulatory, you might not reproduce when you otherwise would. But it’s not this simple biochemistry mechanism of thinking that there’s a cortisol drain that gets opened, and all your pregnenolone and other hormones just filter into it.

So here’s what happened in our industry is people looked at that steroid cascade and said, “You’re stressed. Oh, my gosh, you don’t have enough cortisol, I’m going to give you pregnenolone, and it will go where your body needs it.” And that is not true. But what pregnenolone was doing, was going into the brain and acting as a neurosteroid and actually helping the HPA axis from a neurohormone standpoint and helping people in their cortisol dysfunction. So that’s why I say people succeeded by accident.  But we can’t stay there. We have to move forward in understanding why these things are working, which is why doctors will use things like ashwagandha, rhodiola, like some of these adaptogens that people package into supplements and sell them. I’m not telling you which ones you should buy, but there is good research that shows that those things can actually help modulate that stress response at a brain level. And that’s where our further advancement is, is understanding that chemistry and what’s going on. And in order to do that, my point being that concept of adrenal fatigue, and that concept of cortisol steal, or if you want to call it pregnenolone steal, or progesterone steal, people call it different things. But the idea that making one hormone is at the expense of another does not work the way that story was sort of originally told.  Now, it pushed us in a good direction, right? Because people need to explore this, but we have to follow the literature and follow the science to where it’s going, which is to a more I think full understanding of that. And again, our whole thing is the more of that data you’re looking at, the more of that picture you have visibility on, then you understand what’s going on a little bit better, and then your solutions you’re going to pick are going to be more likely to be the right ones.

Dr. Weitz:            Another follow up question on potential treatment strategies is when it comes to say male hormones, if I have a male patient, and his testosterone’s a bit lower, and maybe has some issues with libido, and his sex hormone binding globulin is high. We know that’s tying up some of his testosterone.

Mark:                   For sure.

Dr. Weitz:            And so there’re certain strategies we’ll use, herbal and otherwise, to try to lower the sex hormone binding globulin. And I wonder if there’s strategies to manipulate the cortisol binding globulins to free up free cortisol?

Mark:                   Well, we know some things that induce them, like birth control, right? If you take birth control you end up with a lot more binding proteins, which is the same binding protein I believe that binds progesterone. But I could not speak intelligently to how that works because I think when you look at the birth control literature, your body for cortisol adjusts to that pretty well. But it’s possible that in a subset of patients, that it sort of overwhelms their ability to continue to make cortisol, but I couldn’t speak to specifically how that could be done. But I do know there are good strategies with SBG that do impact your sex hormones. And birth control is another good example. I mean, one of the reasons birth control is… One minor reason that it’s effective is because it increases sex hormone binding globulin, and now girls no longer have their testosterone and they’re really not interested in making babies. So to manipulate that can definitely be part of your practice.

Dr. Weitz:            And that’s because testosterone plays a significant role in women’s sex drive?

Mark:                   Right, exactly. Exactly.

Dr. Weitz:            Interesting. Interesting. So, talk a little more about cortisol and thyroid and how they’re related. You talked about having higher levels of thyroid, either taking too much thyroid or having hyperthyroid increases the clearance of cortisol, right?

Mark:                   Yeah, there’s a direct relationship between… I can show you the data here. I’ll just do it that way. So you can see on the X-axis on that left graph is thyroid, like three to four, right? And on the Y-axis is cortisol metabolites. And the reason that I show you that is just to show you how strong that relationship can be, that thyroid essentially helps you get rid of cortisol. So when you have a picture of someone not getting rid of their cortisol, that’s something to think about. I mean, I think if you’re going to be comprehensive in someone’s hormones, you’re definitely going to want to look at a thyroid panel. And thyroid and cortisol, the adrenals, they talk to each other at multiple levels. TSH and cortisol and T3. There’s a lot of crosstalk between those. And one of those is that the thyroid helps cortisol to clear the way that it’s supposed to.  So you definitely want to look at those things in concert, which is why for our testing, it isn’t everything, right? This urine-saliva combo that we do is a lot of information on reproductive and adrenal hormones, but serum testing is still really necessary to get some of those staples of thyroid panels and blood chemistries, and all of those things, as well as things like as SHBG. So I think those don’t necessarily compete with each other, but complement each other really well. But it also points out the fact that if you want to know how the relationship between those is working, you need to see not just…  This is that case I was showing you where if you’re looking at your screens, fix the thyroid problem. Now, boom, the free cortisol bounced back like crazy. And for me, it’s not about teaching about thyroid and adrenals, and all of that, that would be someone else could speak more clearly to that. My point is if you want to define what’s going on in the patient really well, that you need to see this three-dimensional picture. Free cortisol all up and down, that’s two-dimensions. And the metabolites is this third dimension. And if you work without one of those dimensions, you can get it right some of the time, but it’s significantly easier to get the story wrong.

Dr. Weitz:            Right. So that metabolites cortisol that you collect through urine is essentially a way to tell the total cortisol levels?

Mark:                    Glandular output, yeah. And again, when it tells the same story as the free cortisol, you just move along because it confirms your story. And when it’s really different, then you slow your thinking and go, “Okay.” This is the functional medicine thing, right? You start asking why questions, like why would this pattern be in this patient? And you think about those things that are related. Some of the chronic fatigue literature shows a story of getting rid of your cortisol very rapidly, meaning you have higher levels of metabolites that says, “You’re actually making cortisol here, but your free cortisol that hits the brain and does what cortisol’s supposed to do is relatively low.” So in some of those cases, seeing that full picture can be really helpful.


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Dr. Weitz:            How does cortisol interact with melatonin which is a hormone that tends to get produced when it gets dark and helps us get ready for bedtime? And then I wonder if the hypothalamic-pituitary-adrenal-thyroid axis should be expanded to include the pineal gland as well?

Mark:                    Right. Right. Because those cortisol and melatonin are going to oppose each other. So in an ideal world, as soon as the lights go out, you make melatonin and it helps you sleep. And we know your gut makes a lot of melatonin as well. And then when you wake up, if your melatonin hangs and stays up when you’re supposed to be awake, you’re going to have issues and that does correlate with issues. But ideally, it’s going to drop down as you reach your waking time, and then cortisol is going to rise up. So you get this up and down natural rhythm between the two.

And that’s why for us… So for us, for melatonin what we do is we take the… This is why we collect four samples throughout the day. One, we can see that cortisol pattern if you want to get it out of urine, but I don’t really want to know your 24-hour melatonin, I want to know what you make at night. And so they did this nice little study where they measured people’s serum melatonin while they slept. They added all those numbers up, and then they collected a urine sample right when they woke up. And adding all of those up or just looking at a waking urine measurement of the melatonin metabolite correlates really nicely.

And it’s good to note that it’s completely useless when you’re on melatonin therapy, because you just get big stupid numbers in urine when you take melatonin orally. But to get a baseline value on asking the question, do you make sufficient amounts of melatonin? That’s included in our DUTCH panels, so that you can look at the big cortisol picture, melatonin, and all the other things that are related there. Again, the name of the game for us is comprehensiveness when it comes to those hormones.

Dr. Weitz:            I wonder if you have some insight as to normally when we think about hormones, if you take an exogenous hormone, if you take testosterone or any other hormone, your natural production will tend to decrease? And it’s often said that that doesn’t happen with melatonin. Is that really true?

Mark:                    That is definitely true for testosterone. So we have on our… Our panel’s got this kind of fun marker. Fun if you’re a hormone nerd like me, called epitestosterone, which is that so your testes make testosterone, and its, let’s call it its impotent twin epitestosterone. So they’re both up here, and then but your testosterone level’s lower, so your gonads aren’t making testosterone anymore. And then you go, “Okay, I’m going to take some testosterone.” So let’s say you take an injection, so testosterone is going to bounce up. And then you say, “Well, how much is that for my testosterone that I took? And how much am I making?” You don’t really know, right?

Well, this other cousin of testosterone is also made by the gonads, so it will drop to zero if you take an injection. So it’s a marker of endogenous gonadol androgen production. And so we measure both of those so that you can see… So for example, if you take a 50 milligram gel, testosterone will go up a little, and the epitestosterone will only go down a little. But if you take 200 milligrams or you take an injection that’s really big, you’ll see that complete suppression of LH from the brain, and then the testicles stop making testosterone. And of course, long term your testes will shrink up because they’re not doing anything.

With melatonin, it’s a more complex thing than that, and I’m not entirely sure, I don’t know how you’d ask the question of whether you still make a little melatonin when you take it. The question of whether long term production of melatonin is suppressed by exogenous melatonin is a really good question. I couldn’t speak to what the literature says about that. I’ve always had a little bit of hesitancy with my kids of if we’re traveling or something, giving them some melatonin, great idea. But because that’s that same pathway that makes serotonin and all of that, I’ve always been a little hesitant to give it to them long term because I don’t understand how that pathway continues to function in the presence of exogenous melatonin. It’s a very good question, but I wish I had a better answer, but I don’t know what the literature has to say about that.

Dr. Weitz:            Do we know anything about potential negative effects of high levels of melatonin?

Mark:                    Gosh, there are people who’ve studied that at a higher level than I have. And some people take doses that make my jaw drop.

Dr. Weitz:            I know one doctor, and he takes 50 milligrams every night, and he takes it for longevity purposes. There was one study that seemed to show some benefits. He says he feels great from it.

Mark:                    Yeah, I mean, I think the safety profile for melatonin is good, but I couldn’t speak specifically to if you’re taking two milligrams versus five, versus 50, that’s a boat load of melatonin. And especially in this COVID world, it’s got that… It’s a powerful antioxidant. And when you get that inflammatory response from COVID, I think there’s probably some use for it there. But I wouldn’t want to give medical advice to the masses on that because that’s a specific area of expertise, and it’s not mine, so I wouldn’t say too much about that.

Dr. Weitz:            Interesting. I was just wondering if that’s-

Mark:                    Yeah, it is. It is.

Dr. Weitz:            Yeah, great. So I think that’s the questions I had prepared. Great discussion. A lot of interesting information. Tell us about how practitioners or patients can access the Precision Analytical DUTCH Testing.

Mark:                    So you can go to dutchtest.com to get some information from us. We do encourage patients to work through providers. This stuff is complex, the solutions. We love lifestyle, but oftentimes, there might be some sort of pharmaceutical hormone-type intervention that requires a doctor’s help. But we definitely encourage people to get a doctor’s help in terms of understanding it. We have a Find a Provider on our website, but you can get a test as a patient through our website at dutchtest.com.

As a provider, if you go to our website and just sign up to become a provider, it takes a little while to really integrate this into your practice. So we always offer new providers to us up to five kits at half price. So you can take advantage of that as a new provider. What I always encourage providers to do is just get a couple of those, try it out. And then we have a team of 12 doctors on staff that can help you understand this because there is a… This sort of intellectual bridge to get over in terms of understanding not just the hormones, but their metabolites and how they interplay between those.

So we have a team of really good clinicians that use the testing themselves in their own personal practices that can help sort of mentor you to figure out where this fits in your practice. For me, I think it’s the best all around HRT monitoring tool. And we have some videos on our website that can speak to different scenarios. But because all tests have their advantages and their limitations, and we try to be really upfront with where DUTCH really works well, and where you might need other tools. And serum testing isn’t going anywhere, you’re still going to need that in your practice, but this can be a pretty powerful tool, particularly in those complex cases. So, if you just go to dutchtest.com there’s lots of information there about the testing.

Dr. Weitz:            Great. Thank you so much, Mark.

Mark:                    I appreciate your time.



Dr. Weitz:            Thank you for making it all the way through this episode of the Rational Wellness Podcast. And if you enjoyed this podcast, please go to Apple Podcasts and give us a five star ratings and review, that way more people will be able to find this Rational Wellness Podcast when they’re searching for health podcasts. And I wanted to let everybody know that I do now have a few openings for new nutritional consultations for patients at my Santa Monica Weitz Sports Chiropractic and Nutrition Clinic. So if you’re interested, please call my office, 310-395-3111 and sign up for one of the few remaining slots for a comprehensive nutritional consultation with Dr. Ben Weitz. Thank you and see you next week.


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