Dr. Kara Fitzgerald Episode 32: The Cortisol Awakening Response with Mark Newman, MS

Check out this Podcast our founder and president, Mark Newman did with Dr. Kara Fitzgerald on the Cortisol Awakening Response.

In this podcast you’ll hear:

  • Why measuring metabolites matters
  • How the complex interplay between cortisol and thyroid hormone connects to overweight/obesity
  • About the importance of testing the Cortisol Awakening Response and the critical half-hour testing window just after waking
  • Why urine is better than saliva for sex hormone testing
  • When it’s important to do run urine and saliva tests at the same time.
  • How to test the Cortisol Awakening Response in patients who wake multiple times each night
  • Why DUTCH doesn’t add thyroid panels to its urine testing


Full Transcript


Dr. Kara Fitzgerald: Hey, everybody. Welcome to New Frontiers in Functional Medicine. I’m Doctor Dr. Kara Fitzgerald and we are jumping back into the pond with Mark Newman, the founder and developer of the DUTCH Test, the founder of Precision Analytical and his flagship test called DUTCH, which we are going to go over carefully and we’re going to talk about some of his new innovative stuff. But let me give you a background on Mark. He is a recognized expert and international speaker in the field of hormone testing. After over 10 years of developing several hundred novel tests at multiple labs, Mark began his own laboratory, Precision Analytical, where he continues to develop the latest innovations in hormone testing.

His flagship product is the DUTCH Test, a dried urine test for comprehensive hormones and his most recent advancement is the DUTCH Plus with Cortisol Awakening Response. We’re going to talk all about the CAR today. Mark is committed to helping providers find the answers they need in hormone testing and has educated thousands of physicians on different hormone tests available and best practices, especially in hormone replacement therapy and bioidentical hormone replacement therapy. Mark, welcome to New Frontiers in Functional Medicine.

Mark Newman: Thank you. Great to be here.

Dr. Kara Fitzgerald: It’s great to have you again. Folks, we’ll have links to Mark’s original podcast with me, which I think, Mark, we did in either early 2016 or late 2015.

Mark Newman: I have no idea. But I’m sure you’re close. I have no idea.

Dr. Kara Fitzgerald: We definitely went down the geek rabbit hole.

Mark Newman: Yeah. That’s for sure.

Dr. Kara Fitzgerald: We talked quite a bit about creatinine, urinary creatinine. I think we got off on a tangent on that. But it was a great, it was a really fun podcast and it just kind of highlighted some of your laboratory geekiness and just really the fact that you developed an awesome, very unique test in our space and it’s highly regarded, it’s highly respected by, I know my peers. I think Bethany Hayes and Sara Gottfried both were talking about DUTCH and that peaked my curiosity and I reached out to you, I think, to learn more about it and we ended up podcasting together. So, I just appreciate the effort you put into developing this and, I’m going say one other thing and then hush. When you say in your bio that you’re committed to providing clinicians the answers, you are actually one of the most available CEOs and analytical chemists out there and we appreciate it. So, thank you.

Mark Newman: Yeah, we appreciate finding clinicians that like to geek out with us on these topics.

Dr. Kara Fitzgerald: Yeah. Indeed. All right. So, let’s do, first of all, before we talk about some of the new analytes you’re working on and where the tests are going, just give me an overview of the DUTCH test and, you know, just some of the panels that you offer.

Mark Newman: Sure. Yeah. For us, most everything folds into this DUTCH model of testing, which is for me just a concept of liking urine analysis for hormones because of all the metabolites that you get and, for me, my history was running urine testing and seeing its pros and cons and then running saliva testing labs and looking at the pros and cons and trying to build a model that has the benefits of both. Because I want that up and down pattern of free cortisol throughout the day, but I want all of those metabolites. For me, I’m greedy for information in terms of trying to find just what’s going on with a particular patient. The more pieces to the puzzle we can add the better. So, we’re looking at the cortisol pattern throughout the day using those urine markers instead of saliva for the free cortisol, which is a good replacement for free cortisol in just that up and down pattern and then estrogen metabolites and androgen metabolites and the cortisol metabolites.

To each of those families of hormones, adding the metabolites in just gives you a fuller picture of what’s going on and it’s, for me, it’s a strong model when you’re trying to get a feel for what’s going on with somebody for their reproductive and their adrenal hormones.

Dr. Kara Fitzgerald: You’re looking at so, so, so much. So, you’re looking at DHEAs; you’re looking at testosterone; then you’re looking at the estrogens; then you’re looking at the estrogen metabolites. So 16-hydroxyestrone, 4-hydroxyestrone, 2-hydroxyestrone, 2-methoxyestrone, so you’re looking at catechol-O-methyltransferase activity in methylation. You’re also looking at 5-alpha reductase and 5-beta reductase activity. So that’s the production of the metabolites from testosterone and whether an individual is generating more potent androgens via 5-alpha or less potent androgens via 5-beta. And this is extremely useful if you’re analyzing, as we talked about on our first podcast, if you’re looking at PCOS in women, maybe if you’re looking at imbalances in men, you know, acne, male pattern baldness, et cetera, et cetera.

There’s all sort of reasons that it’s helpful to have those analytes and, of course, with regard to estrogen metabolites, we know that we want to correct balance or we increase risk for estrogen-sensitive cancers and all sorts of estrogen-dominant conditions. You also have the progesterone metabolites and, what else, you’ve got melatonin and then you have the cortisol.

Mark Newman: Yeah and then we just recently added 8-hydroxydeoxyguanosine so there’s an oxidative stress marker. So, yeah, we’re just trying to look as broadly as we can. I mean, if you look at someone with an estrogen problem, they could just be making too much estrogen. But often times, there’s also a phase one issue and/or a phase two issue with methylation, so just being able to look at how much of this hormone do you have and what is your body doing with it both phase one and phase two, you just understand what’s going on with the patient in terms of their particular flavor of dysfunction. More often you’re going get it right if you have more information.

Dr. Kara Fitzgerald: Absolutely. It’s extremely useful and it’s illuminating to the patient. Without exception, any patient that I’m walking through their laboratory data with is interested in it, and it’s motivating to see what we can tweak and how we’re going do it and why, and it’s easy to do a follow-up and just confirm we’ve achieved what we wanted to. So, the nice thing about doing the dried urine assessment is there’s just four specimens collected through the day, too.

Mark Newman: Yeah, it’s easy to do, so you can get that big look at your hormones without torturing your patient. So it’s really simple for them to do and then we’ve just been on a quest to figure out where are the holes in what we’re doing. So, if we’ve got this nice test for one day, that’s great. But then if you have a woman with irregular cycles, or she doesn’t happen to be bleeding because she had a partial hysterectomy or an ablation, or she’s got a fertility problem, then we’ve created the cycle mapping version of it where you can collect one of these little samples most days throughout the cycle and then we’d look at the length of the cycle and the samples and try to map out that pattern, so you can look at the ovulatory peak, you can look at the luteal peak with respect to estrogen and progesterone. Because for some people, one day is not enough. And so that led to the development of the cycle mapping version and then, as we discussed, to try to get an even bigger picture of what’s going on with cortisol in the adrenals, that’s why we’ve moved in the direction of what we call the DUTCH Plus.

Dr. Kara Fitzgerald: Yeah, so, you have the four-point salivary, excuse me, the four-point urine, which is akin to the four-point salivary. Clinicians, if you’re doing a four-point salivary, you can bang that out using the four-point urine plus you can get the sex hormones and the metabolites. It’s, you know, it’s really cool and just, I know we’re going to talk about the Cortisol Awakening Response in a second, but just, regarding the DUTCH comprehensive, what was the epiphany that prompted you to create this? It’s unique in our space.

Mark Newman: It honestly was obesity. So looking at literally over a million data points from saliva and, at this point, my understanding of the relationship between cortisol and weight gain in some of this was more the simple understanding you get when you drive down the road and listen to the radio and hear people with commercials saying, “Hey, cortisol makes you fat. Takes this anti-cortisol product.”, or whatever. And we had clients that were testing tons of people with the understanding that when you have high cortisol you’re gaining weight and when you’re gaining weight you have high cortisol, but when you look at the data, and then as you dig through the literature, it’s not true of free cortisol. The free cortisol correlation that I looked at with these millions of data points was actually a very slightly negative correlation, meaning the higher someone’s BMI is going, it was just slightly negative.

Look in the literature, it’s more or less there’s none, right? As you get heavier and heavier, more adipose tissue, the free cortisol has no relationship and so I’m scratching my head at that and thinking that doesn’t make any sense. And then as you dig through the literature further, what you find is yes, the production of cortisol increases as patients get heavier but it’s all seen in the metabolites. So, if you look at the metabolites of cortisol, which at that point I’m blind because I’m looking at saliva, and you cannot measure these terminal metabolites of cortisol any other way but a urine test, that’s really what drove me to develop it.

Then we started looking at, hey, the parallel pattern of free cortisol in urine is very similar, urine and saliva, so then can we develop this model where we can look at both and then when we started doing that, and now that we’ve done literally tens of thousands of patients, we’ve started to see these really interesting patterns where there’s this connection between firstly, BMI, like the metabolites are going way up because you’re making all this cortisol, and if you’re free cortisol happens to be a little bit low and you’re making tons of cortisol, does it still make sense to ramp up someone’s cortisol production. We’ve started approaching that, I think, as an industry a little bit different and then you start to tie in thyroid and how many of your patients have concurrent thyroid problems. It’s so common. Well, there’s a direct relationship between your body’s ability to clear cortisol and your thyroid status. Right?

So, if you look at free cortisol and you look at the metabolites of cortisol, then you have this window into the clearance rate of cortisol and, very early on in the process, I tested a friend who was really low free cortisol and really high for the metabolites. And I’m going, “Well that’s weird because I see that in obesity but you’re skinny as can be.” Well, it turned out her doctor had given her Thyroid (medication) and she misunderstood the instructions and was taking it twice a day instead of once a day, so she had induced hyperthyroidism and looking at the test actually prompted this evaluation of, oh, we’ve induced hyperthyroidism accidentally and you could see this connection. And that’s something we see often is this connection between your thyroid status and the cortisol picture. And then you throw obesity into it and it just gets more and more complex. But that’s why we want more data because there are so many different scenarios where having extra information really gives you a clearer understanding of just how to characterize that patient with respect to cortisol. So, that was the main driver behind that was just trying to get a bigger picture for what’s going on with cortisol in patients.

Dr. Kara Fitzgerald: That’s so interesting. So you have the kit and caboodle, direct cortisol, as well as the metabolites. It is really useful and it just so happens that the test is easy to do because there’s just four points. You don’t have to collect your urine all day and drag that jug around.

Mark Newman: Right.

Dr. Kara Fitzgerald: And so it’s an inverse relationship anyway, just to kind of color that in for people with regard to the, I mean, everybody knows we learn in medical school there’s an inner connection between thyroid and adrenals and you need to track both of them or, in fact, if you over treat thyroid and somebody has adrenal insufficiency, that could be a really dangerous problem. But in the subclinical issues, thyroid is promoting cortisol metabolism, so you can see an accumulation in hypo, and in hyper you can see an insufficiency in cortisol and then increase in metabolized cortisol. Is that correct?

Mark Newman: Right. So, yeah, and it’s complex because that’s just one layer of the connection because there’s also a connection between cortisol and TSH and your conversion from T4 to T3. So, they play off of each other in several places and so the look that we get of excessive cortisol clearance is the same look that we tend to get in obese patients and the opposite in a hypothyroid case. So, then what happens if they’re hypothyroid and obese? So, you get all these complexities and that’s where, yeah, I just don’t feel very confident in understanding how I want to describe your cortisol state, if you will, or situation, unless I’ve got more information to go off of; the diurnal pattern, the free levels, and then also what is your total output of cortisol by way of those metabolites?

Dr. Kara Fitzgerald: That’s great. Thank you so much for that explanation. Let’s talk about where you guys are going with regard to assessing cortisol and the new release of Cortisol Awakening Response. Talk about just your decision around doing that and just what the test is, what it measures. Just give me the whole story on that.

Mark Newman: It really is just one more piece of the cortisol story, if you will, but it’s a really important piece and there’s a little bit of irony to it in that you’ll talk to some sort of cortisol experts, like Tom McWilliams, he’s a smart guy, works for Ortho, he digs through literature all the time and, for him, he’s come to the conclusion that the most single piece of information [crosstalk 00:15:02] on cortisol, is the Cortisol Awakening Response and then what I mean by the irony in that, is that nobody’s doing it. You have all these salivary labs doing salivary cortisol, we’re doing the same thing in the urine, the free cortisol picture of up and down, up and down, but that’s not a true CAR. The true CAR is I must have a sample at waking, meaning a saliva sample within the first five minutes, I’ve got to have that as a baseline.

Then I test 30 minutes later and that’s usually the first test. If that’s the second test, now I can look at this dynamic change between waking and 30 minutes later and then there’s some more collections throughout the day, but it’s really, that’s the heart of the issue, is looking at that gap between waking and 30 minutes later, because what we want to do above anything with cortisol is I would want to be able to test you at moment zero and then have a lion chase you or poke you in the eye or whatever acts as a stressor for you to say, “Hey, here’s a stressor and then I’m going to test your response to that”. That’s a really valuable piece of information to see how does your body respond to stress and, of course, that’s pretty hard to simulate in the middle of the day. But it just so happens that the act of waking up triggers the body like a stress does. So, your cortisol’s been climbing since about 2 a.m., this slow journey up, and then when the light hits the back of your eyes, it triggers all of this physiology and boom, your cortisol, it’s supposed to, go up about 50%, or a little bit more in those first 30 minutes and that’s a variable related to HPA axis function that you just can’t get any other way.

We want to see the diurnal pattern, we want to see the total production and all of that. But the Cortisol Awakening Response is a good piece of information and there have been some nice studies. I think I sent you one of the papers that we were looking at and discussing where they were looking at, “Hey, who’s going to get depressed? Who is going to get major depressive disorder.” And when they looked at cortisol, none of the individual points in these people when they tested before the study, none of the individual points correlated as strongly as the CAR, meaning that gap, that delta, that change between waking and 30 minutes later, meaning when your change over those first 30 minutes is exaggerated in this study, you had a significantly increased risk for going on to develop major depressive disorder because we all know there’s a connection between having too much cortisol and getting depressed and looking at this gap, even if your levels are within the normal range, if that bounce in the morning is excessive, then your HPA axis is in a bit of overdrive, whether that’s because of your life, like your stressed, you have way too much perceived stress, that’s one option.

Or, you don’t have too much stress, but your body responds in an exaggerated way to a stressor and in either case, you’re at risk for symptoms related to high cortisol and this is one more variable to define someone that way. So, certainly if your free cortisol’s high all day then yeah, you’ve got high cortisol but even if that’s not true, you could end up in that designation, that camp of overactive HPA axis if you’ve got this exaggerated response in the morning. And then you’ve got the opposite story, too. If you wake up and it’s flat, even if you’re in the normal range, if you don’t have a dynamic change at waking, then that says, “Hey, when you’re faced with a stressor at 1 p.m. or dinnertime or whatever, your body’s response to that has been blunted by whatever it is but that is a measure of dysfunction in the HPA axis and so, as we look at our test, we’ve got the most comprehensive look at cortisol but if I want that last really critical piece, I have to go back to the drawing board and say, “Okay, I’m not willing to give up the metabolites, because that’s still a really important measurement.

So, we’ve created a combination test where, and it’s pretty simple actually for patients to do, they wake up and we use these cotton swabs for collection, which makes it way easier. So, you pop that in your mouth right when you wake up and a minute or two later you’re done. You pop it back in, and then half an hour later, 60 minutes, and then dinner and bedtime you’ve got this cortisol story told by the saliva, but then we also capture the dried urine test so that we can still look at not just the cortisol metabolites, but we still want to tell that big story for estrogens and androgens and progesterone and so on. So, that’s where that came from is that if you want the best cortisol story, that’s how you get it. The DUTCH Complete, I think is an improvement on the story that you can get for cortisol relative to what people have been doing but this just expands it one step further but it’s a pretty valuable step.

Dr. Kara Fitzgerald: Yep. I think that it is. There’s a nice body of literature on Cortisol Awakening Response, folks. You can head over to PubMed and you’ll readily pull up hundreds of papers if you do a broad search on it and then you can type in specific areas. I have the papers that Mark just referenced and we will include those on his show notes page so you can see some of the things that Mark was thinking about in developing it. Listen, it’s just, I’m really glad that you decided to take it on. Because I know Tom has been arguing for the Cortisol Awakening Response and he’s had a really compelling argument and I just, I appreciate the fact that you guys took it as a call to action. I know you did your first, obviously, due diligence in determining whether or not it was something that was worth you putting your time in. Developing the new assays is no small feat. So, I appreciate you looking at it and then actually jumping in and doing it.

Mark Newman: Yeah and you know it’s funny the things that limit us as labs. If you ask yourself why it doesn’t exist, it really, in the market space much, it’s because of logistics. You have to get a saliva sample within five minutes and you have to get enough to test. So, what are the options to do that? It’s really difficult to do that if you don’t use these cotton swabs. But, if I’m a saliva lab, I’m testing my saliva for what? Cortisol but also progesterone. Well, guess what? Those stupid swabs absorb progesterone. So you cannot use them for collection for both the CAR and your sex hormones. So we’re, I mean, just sort of ironically, uniquely positioned to be able to grab the cortisol out of the saliva and ignore it for the reproductive hormones because I think urine’s a better way to test reproductive hormones anyway.

But that’s been this major hang-up to doing it because there was another lab that’s doing it and that’s good, but they’re asking you to collect two milliliters of saliva by just spitting in a tube right when you wake up, within five minutes, without rinsing your mouth, eating anything, or drinking anything and it’s like, you just, you can’t do it. If you take too long, it screws the whole thing up because your cortisol [crosstalk 00:22:12]. You know what I mean? So, yeah, it’s a funny reason why it was uniquely in a position for us to be able to do that.

Dr. Kara Fitzgerald: That’s really funny. That’s stressful in and of itself having to collect that much spit. So, yeah, you guys were. Listen, give me in 30 seconds, ’cause people are wondering why urine is better than saliva. 30 second rundown, for sex hormones. [crosstalk 00:22:37]

Mark Newman: Okay, so just talk about estrogen. So, it’s simple. There’s a thousand times more hormone in urine than in saliva. If you look at the, and this is with all due respect to saliva testing, if you look at the reference range for estradiol in good labs, there is a ton of overlap between pre and postmenopausal women because there’s not very much estrogen there, the technology we have can, let’s just say, barely get down to those levels, so I can point you to a very well respected lab where the postmenopausal range for estradiol and saliva is actually higher, very slightly, than the premenopausal range. Because when they test otherwise healthy people, they get about the same results in pre and postmenopausal women. When we do that in urine, we can use GC Tandem MS, really sensitive, really accurate methods and there’s a tenfold gap between the average premenopausal woman and the average postmenopausal woman.

So, what am I trying to do? I’m trying to define you. Are you the have, are you the have not, are you the excess? Which group are you in? And it’s just a better tool for doing that. I think serum would be about on par with that in terms of asking that question, then the benefit here is we add the phase one and the phase two metabolites and so you get a lot more information. But analytical accuracy is not a problem for cortisol in saliva. It’s not that bad for progesterone but when you get down to estradiol, I think I went over 30 seconds, but it’s just a really difficult measure. So, there you go.

Dr. Kara Fitzgerald: And the urine hormones correlate pretty nicely with serum, would you say?

Mark Newman: So, we’ve done full disclosure on urine, we’ve done a serum correlation with the progesterone metabolites that we have, we got a lot stronger correlation than when we did the salivary analysis. The same was true for estradiol. Statistically, there like was equivalence in terms of what we did, looking at postmenopausal women, follicular phase, luteal phase, ovulatory phase. I would say for testosterone, I would lean more heavily on, like I think serum is the gold standard for testosterone. A free and a total testosterone, there is some caveats to urine testing with testosterone. We have all these metabolites, which adds information and testosterone is okay. It’s good but I think it’s better in serum. So, yeah, so it depends on the hormone. I prefer urine for estrogen. I think it’s fairly equivalent for progesterone. For testosterone, I like our metabolites but if I’m me, meaning a male patient, I would still want a serum free and total testosterone so that’s kind of how I would break it down in terms of … So, yes. I think really good equivalence for estrogen and progesterone. It’s okay for testosterone but it’s not excellent like it is for the other more female-related reproductive hormones.

Dr. Kara Fitzgerald: Well, what about the testosterone metabolites? Is urine better than serum?

Mark Newman: You just don’t get them in serum for the most part.

Dr. Kara Fitzgerald: What about –

Mark Newman: Like I –

Dr. Kara Fitzgerald: Okay. Go ahead. No, yeah, go ahead.

Mark Newman: You can look at DHEA either way but you could look at those DHEA metabolites, the androstenedione metabolites, androsterone and etiocholanolone. Those are the most abundant end products of DHEA in androstenediones. So, I think if you just wanted to say, “Hey, how much of this stuff is my adrenal gland putting out?” I think urine’s a better place to get that and then one happens to be a 5-alpha metabolite, the other is a 5-beta metabolite. So you get a good picture of am I shoving towards DHT, the 5-alpha pathway, the more androgenic pathway, you know, PCOS, hair loss, whatever. And so, in that sense, I think you get a more complete picture in urine. You can measure androstenedione glucuronide in serum and that’s a pretty good marker for DHT. Nobody seems to do it much for whatever reason. So, there are some options.

Dr. Kara Fitzgerald: Okay.

Mark Newman: Than serum ,but you get a more complete picture in urine but when you’re talking about just testosterone in isolation, by itself, I’ve got an injection, I’m measuring testosterone, whatever, that kind of situation, I think the serum is a better number than you get in urine for testosterone.

Dr. Kara Fitzgerald: Got it. Got it. I actually didn’t articulate my question correctly. I was interested in 5-alpha activity and using serum versus urine, specifically for 5-alpha. And what you’re saying is urine is preferable?

Mark Newman: Yeah, what I like is I get those androgen metabolites but I can also see 5-alpha, 5-beta metabolism in progesterone, I can see it in cortisol. So, you get a nice look at, “Hey, does this person really prefer 5-alpha?”. The thing that’s weird about DHT, and this is maybe too long of a conversation, but it’s a paracrine hormone, which means it’s made in the cell, I made DHT in the cell, it acted in the cell, and then it’s deactivated in the cell. So, measuring DHT itself in serum is not, like DHT isn’t a good marker for itself. You want to look at in serum, it’s that terminal metabolite, androstenedione glucuronide that actually is a better marker for DHT than DHT itself. But in urine we get this big look at alpha versus beta in multiple, in four different places actually. I feel like I have a pretty good handle on whether someone’s shoving down the alpha pathway or not. And then we have so many androgens. The other question is how much just general androgen do I have? If I’m a 5-alpha metabolizer, but I have no androgens, like who cares? You’re not going to get hair loss if you have no hormone, even if you happen to push in that direction.

So, asking the question, “Do I have a lot of androgens?”,yes or no. And then, “Do I push it down that androgenic pathway?” I think urine’s a better way to do that but if you add in that one serum metabolite, I think you can get a decent look at it there as well.

Dr. Kara Fitzgerald: Good. Okay. Good. So, take home for testosterone and metabolites: consider doing both urine and serum and serum especially for testosterone.

Mark Newman: [crosstalk 00:28:33] Yeah.

Dr. Kara Fitzgerald: Got it. Okay. So, let’s circle back to Cortisol Awakening Response. For the patient with frequent wake-ups, what do you … Are you messing with the assessment? I mean, if somebody’s-

Mark Newman: You know, that’s … The question you have to ask yourself, is it worth the hassle, is it worth the extra, for us it’s 75 more bucks to do the CAR? If someone’s waking up all the time, it might not be worth it because if you wake up once in the middle of the night and go back to sleep and then you get up at waking time, it doesn’t screw up your CAR. But if you, like, if you’re severely sleep disturbed, you can probably pretty well guess that when you happen to get out of bed at 6:43 or whatever it is and then 30 minutes later, you know, it’s not going to be crazy that that’s not going to be a true CAR because you’ve been rolling around all night and up and down and what have you. So, in some of those cases, I might just do the DUTCH Complete and call it good because I’m just assuming that you have a problem in that area. So, yeah, I wouldn’t necessarily say it’s a slam dunk if that’s going to show you something profound in a patient like that.

Dr. Kara Fitzgerald: Well, it might be interesting actually to look at and see that it’s higher when it’s not supposed … Like, you know, an individual’s already moved into some degree of stress response when they’re supposed to just be not quite there yet. I know we start pumping cortisol out at night but it’s kind of a slow push and then there’s that CAR leap in that first half hour. But I would imagine in the insomniac, and you can tell me whether this is true or not, you’re seeing almost like that early response. They’re in a fight-or-flight already. They’re already high and then their 30 minute follow-up is basically the same. I mean, is that what you’re seeing or would you see two measurements that are really low? I mean, what you-

Mark Newman: You see different flavors of that. I mean, some people do look as you described, but it’s not always predictable. But it’s hard to know in some of those cases like when to actually do that true CAR if you’re severely sleep disturbed and in some of those cases, what we have with the DUTCH Complete, is you would wake up in the middle of the night and go to the bathroom and we’d measure that for cortisol. And then you’d wake up and get out of bed and there’d be another sample there and we’d measure that as an individual measurement. And we didn’t used to report both of those numbers as individual numbers and we just like a few months ago started doing that. So now you can see here’s my I-woke-up-in-the-middle-of-the-night, here’s my number-between-then-and-getting-out-of-bed, and then you have a sample two hours later. So, if that CAR, if that big push of cortisol has happened while you’re rolling around in bed, you can see it there. So in some of those cases, the urinary free cortisol is actually useful, too, cause you can sort of deduce whether the CAR happens while you’re hanging around in bed, or if it actually did happen in those first two hours of being up and awake and in light and those sorts of things.

I, honestly, the sleep disturbance is tough for me in terms of if it’s severe, which task is actually preferable, with the CAR or with the urinary picture. Because with the urine picture, one value that we get that’s unique to anyone doing cortisol testing, is we get a free cortisol number when you wake up and in urine, that’s a while you’re sleeping cortisol. That’s an interesting number when you start looking at cortisol and its relationship with melatonin. If I’ve got too much cortisol while I’m sleeping, then it’s going to suppress melatonin and if you don’t do any lab analysis until you’re out of bed, which is what you usually do, you just missed that whole window of time. So, that is one of the advantages of our original DUTCH Complete is it gives you that while-you-were-sleeping lab value on cortisol to see, and we’ll see sometimes someone who has low cortisol all day. And it’s doing absolutely crazy while they’re sleeping. What other lab test is going to give you that information? You have to wake up and go do lab testing. You have no other window into that world and that’s one of the advantages of that urine cortisol pattern.

Dr. Kara Fitzgerald: You guys are going to have just an ethical obligation to look at all these data over the next number of years and then publish because you have the combination of CAR plus you’ve got the four-point urinary measurements. It’s just really, really cool stuff. So, while you were talking, I was just looking at shift work and Cortisol Awakening Response and of course there’s a bunch of interesting findings there. And you’re going to be able to add to that conversation, what happens with the derangements of shift work and you’ve got melatonin, you’ve got the four-point cortisol, and now you have the CAR plus you have the sex hormones and you have 8-hydroxy, 2-deoxyguanosine, that really great, very well researched metabolite of oxidative stress of damage to the DNA. So, you’re going to have to get a postdoc, Mark, you know, you need to plow through this data and start publishing on the conversation. I’m going to hold you to it.

Mark Newman: Okay. Well, that’s the whole point. It’s like when you look at breast cancer and the literature, breast cancer’s got an estrogen component, a progesterone component, an estrogen metabolite component, melatonin’s too low, that’s correlated with breast cancer. If cortisol is high, that’s an issue and guess what? If cortisol is high, 8-hydroxy goes up and if melatonin is low, 8-hydroxy can go up. So, there’s like all these different touch points and that’s I think the beauty of functional medicine is it’s not this single variable mess and that’s what you’re spending so much time wrestling with, with all this genetic stuff, it’s not about one variable. It’s about looking at as much of that person’s collage as you can and say, “How do I reduce the risk for X?”. Well, it’s not a single thing and we want to look at as much of that as we can so that we can take the best course of action. Not only do you get people better but to prevent some of this stuff in the first place.

Dr. Kara Fitzgerald: Yes. Yep. Indeed. Yeah, I’m with you. You have to, we really need to cast a wide net. On that topic, we’re talking about a lot of stuff and a lot of markers and how to interpret them and there’s nuances based on clinical history, et cetera. So, it can be challenging, especially if you’re new to DUTCH. But you guys have some pretty nice resources over there. I know Carrie Jones leads up your medical team and she’s quite brilliant and handy and accessible to clinicians, again, also for the treatment side, for interven … So not just laboratory data interpretation, which they can go to you on, but to really think about how to address the patient in front of them, I think Carrie is really quite helpful in that.

Mark Newman: Yeah, for me it feels like a little bit of a new day in lab testing in that it’s not enough for a lab to give you a number and a range. This stuff is so, like there are so many inner relationships and complexities that we’ve taken it upon ourselves to say, “Look, we have to educate people.” You know, people come to us that are brilliant doctors that are educated in all this stuff but who has time to dig through the relationship between inflammation and androgen metabolism and the thyroid and cortisol clearance and all of this kind of stuff? So, we spend a lot of our effort really trying to educate the people that are using our tests, so that they’re able to quickly and easily draw appropriate conclusions from the testing, both from the standpoint of evolving our reporting. We have report tutorials embedded right in our reports. We have special circumstances where people have weird patterns that mean things that are kind of caveats to our testing.

And so we’ll put a little video link right on the front of the report that says, “Hey, you know what? This is a weird case. You need to be probably educated on this weird topic.” And then we spend, every doctor that tests with us for their first report, Carrie, as our Medical Director, sends them an overview, just a doctor-to-doctor conversation to say, “Hey, let’s work on A, what does this mean? And then B, what do we do about it? And then we’ve got three phone consults for all of our providers because it’s just a necessary part of doing complex lab analysis is that you need to dig in to how to best present it to people and then ultimately how to help them bridge those intellectual gaps and fill in some of the pieces of some of these concepts that are going to be new and some of the interconnectedness is, not only some of the interconnectedness is complex, but we’re still learning. So, as that education as an industry unfolds, I think it’s really on the laboratories to start presenting that in more intuitive ways for providers so that they can use it efficiently in their practice.

Dr. Kara Fitzgerald: Yeah, absolutely. Just kind of an aside, why not measure thyroid hormones alongside? Like urinary thyroid hormones or thyroid hormone metabolites? I mean, I’m sure that you’ve looked at that and obviously it’s not useful. So, just comment on it.

Mark Newman: Yeah, so, we get that question a lot. It’s a good question. Because if I can add thyroid, great. You know, to be honest with you, just practically speaking, if I had thyroid the way in which we would do it, it would increase the price. So then, I’m asking myself, okay, is it worth it? Well, what do I get? I get T3 and T4. But there’s a problem in that if I’m looking at T3 and T4 conceptually, I want to know how much T3 and how much T4 and the relationship there is interesting, too. But, there’s interconversion between the two in the renal system, which is annoying because now it makes it just one kind of gemish. So, I really only have like one kind of look at thyroid. And if I want to look at thyroid, I want TSH, I want the antibodies, I want T3, I want T4, looking at total T4 but then free T3 and then maybe sometimes reverse T3, and where do you have to go for all that stuff? You’ve got to go to blood. So, most of the people that test with us are getting blood chems, CBCs, all that stuff.

Why don’t we just add a thyroid panel? I mean, that’s really the best way to do it and tying that information in intellectually to what we’re doing makes a lot of sense but adding the thyroid from a urinary measurement, we just haven’t seen the value in that because you don’t get enough information and it’s not, you know, I think in urine those values would always be like, you know, B minus, C plus, like it’s just not a great assessment of thyroid and it’s only an assessment of the urinary excretion of T3, T4, this kind of weird combination. So, we just haven’t seen enough value in it for what it would do to the price of the analysis, to be honest with you. We’ll tell people, “Here’s your result, now go get a blood test so we really know what’s going on”. And that just doesn’t seem like it makes sense.

Dr. Kara Fitzgerald: Yeah. Got it. Nope. It makes no sense. Okay. Thanks. I’m sure that some people were wondering about that. Yeah, it makes no sense. It’s easy to get through any standard reference lab and it’s always covered by insurance. So, [crosstalk 00:40:06] so it’s just, yeah, it’s not a big deal. Okay. So now, fun. Let’s talk about the future of what you guys are doing. Let’s talk about some of the cool analytes you’re wanting to jump into.  [crosstalk 00:40:22]

Mark Newman: Kind of the frontier for us is, in a former life I was doing, and it’s funny because we have the sort of similar history of just digging into organic acids and my history with organic acids is I like the panel, I don’t love the panel because I think there are some of them to me feel like a little bit of a stretch in terms of, how much relevance is there to this? As far as some of the citric acid cycle intermediates and some of the markers are awesome and some of them are just kind of okay. But the bigger problem for me is they’ve always been in silos. You’ve got your organic acids over here and then you’ve got your hormones and there’s no interconnectedness between the two, but there is. There are so many touch points between what’s going on with your hormones and what’s going on in those sorts of panels.

So, what we’ve been trying to do is, we do a full-blown organic acid panel, like people already do that and that’s nice and Genova does a good job and Great Plains has got their really big panel and U.S. Biotech has some but what we want to do is say is there a way, and this is what we’ve been working on, is to keep it cost effective, meaning leaving our pricing where it is but to add like a critical central core of these that fold into what we’re already doing. So, for example, if I give you estrogen and estrogen pushes tryptophan, and I know you know this, but we’ll just repeat it all. Estrogen pushes tryptophan down the kynurenine pathway, away from serotonin. If you don’t have enough B6, you make xanthurenic acid, like that’s sort of a left-hand turn it makes, if you don’t have B6. And xanthurenic acid complexes with insulin and now you’ve got an insulin issue. Why? Because you took the estrogen and you’re concurrently B6 deficient. Xanthurenic acid, then we can measure in urine as a B6 marker and it’s nice, as just in isolation a B6 marker, but if you have a patient on estrogen, like that’s a very relevant finding.

It just so happens, as you know, that cortisol also pushes tryptophan down that kynurenine pathway and again there’s this relationship between getting diabetes because of this whole insulin issue and then it also ties into depression. How? Because if tryptophan pushes down the kynurenine pathway, where is it not pushing down? Serotonin and there’s a serotonin organic acid, metabolite 5, hydroxy and diacetic acid. Oddly, I was just at the doctor the other day and I did this weird brain map thing. I don’t even know how legitimate it is yet but, he said, I think you have low serotonin levels based on whatever he was looking at and I was like, “I feel fine”, but I went and we had just, I had just done my own serotonin metabolite and I was like, “Oh, crap, he’s right.” My serotonin levels are actually a little bit low because there’s this metabolite. So, there’s this connection between estrogen and cortisol and inflammation and tryptophan heading down this other pathway and away from serotonin and we could look at that. We could add that to the panel and then if the patient’s also B6 deficient, then you’ve got this increased risk for insulin issues as well as just the fact of just highlighting the fact that you have a B6 deficiency, which is not good for you.

And there are urine markers for, I mean, everyone knows methylmalonic acid. Why not have a B12 marker that’s going to relate to my folate status, which is going to relate to my ability to methylate what? Estrogens. So, there’s this interconnectedness between this core of organic acids that have been treated in isolation, I think, from the hormones and we’re trying to bring those together and say, look, again let’s expand the picture, put a few more pieces into the puzzle, and then when you’re dealing with these complex cases of somebody who has high cortisol and happens to be depressed and maybe has a vitamin deficiency that’s exacerbating some of these issues, our likelihood of success will go up if we can do that and present it in a way that is intuitive and useful and all of that and for me it’s just fun because it’s just so interesting how wonderfully complex this human body is and so the more information we can get, the more we can piece together what the best direction is for a particular patient.

Dr. Kara Fitzgerald: Nice. Nice. And you’re going to again have a ton of data. So, you know you’ll have a unique perspective looking at estrogen’s influence on tryptophan metabolism via the kynurenine pathway and the indolamine pathway. Okay, so you guys are looking at … Well, first of all, what are these organic acids hopping on the DUTCH panels?

Mark Newman: And we’re a little bit out in front of this, which is kind of my style because it’s like, who cares? But we’re not ready with that yet, probably winter. We’re shooting for like first of December to be able to add your neurotransmitter metabolites so, a serotonin metabolite, a dopamine metabolite, norepinephrine – epinephrine metabolite, to kind of round out that story.

Dr. Kara Fitzgerald: Well, and you’ll be looking at catechol-O-methyltransferase as well. So, you’ll have both of those, which is pretty sweet. Okay, so winter for those and then-

Mark Newman: And then along with that is, hopefully, supposed to be your B6 markers, [inaudible 00:45:56] your B12 marker, methylmalonate. And then the estrogen metabolism, one of the big holes in what we do conceptually, is let’s say you make lots of 4-hydroxy estrogens. Okay. No good. You [inaudible 00:46:12] methylate crap, even worse. Now, what is your parachute to escape? The biggest one left is glutathione. So, we have no marker for glutathione deficiency and pyroglutamate, pyroglutamic acid is a decent marker as far as I understand it from looking at the literature thus far, that’s your organic acid that gets elevated when you don’t have enough glutathione. So, then if you have high 4-hydroxy, you’re a poor methylater, like I am, because I have a COMT defect and your pyroglutamate is high, you better address that. That’s going to be like triple whammy breast cancer risk. And so that’s the last piece is that glutathione marker to add in to the puzzle.

Dr. Kara Fitzgerald: Nice.

Mark Newman: So, yeah. So, I’m super excited about that. We’ve been getting some really interesting data already on those. We’re in mid-stream on validation and then we’re going to present that to people and try to make it as palatable as it can be but it’s going to be, yes, I think really powerful data and information to add to what we’re already doing.

Dr. Kara Fitzgerald: I love pyroglutamate. I think it’s just an underappreciated and really, you know, fairly well-researched marker. Pyroglutamic aciduria is a phenomena. We see that in Tylenol toxicity, in a host of other issues and there’s cool data out on it. And you have 8-hydroxy, 2-deoxyguanosines, so you can see-

Mark Newman: Yep. That’s already there.

Dr. Kara Fitzgerald: Yeah, and you can kind of, you can look at that in conjunction with the pyroglutamates and so forth. There’s a lot you can connect. And the other thing, Mark, that you did not mention, is that you’ve got another indolamine metabolite, another serotonin pathway, not metabolite, excuse me, product. Pop quiz. Melatonin. You have melatonin, which is made from serotonin. So, not only do you have 5-HIAA from the serotonin pathway but you also have melatonin, which is really sweet. And I think that’s unique to you guys. Right? [crosstalk 00:48:13]

Mark Newman: Yeah, I mean there are a couple of people doing melatonin and most people have been doing it historically, I think in saliva more than anything.

Dr. Kara Fitzgerald: But not with 5-HIAA.

Mark Newman: Oh, no, to combine those together is beautiful. Yeah. Nobody’s doing that. So, that’s where we went ahead is to fill in that picture even more than what’s available now.

Dr. Kara Fitzgerald: We were looking at all the analytes you mentioned when I was at Metametrics but we were not looking at urine melatonin and that’s pretty sweet. So, you can see melatonin and serotonin insufficiency in inflammation when that kynurenine pathway is up and running. So, a high xanthurenate could be associated with-

Mark Newman: Right. Exactly.

Dr. Kara Fitzgerald: Low, in both of those. So, a depressed insomniac. And you’ll start having that data pool, which is pretty, it’s pretty sweet.

Mark Newman: Yeah.

Dr. Kara Fitzgerald: Okay. So, we’re pretty much wrapping up here. Anything you want to add? Oh, let me just confirm, you actually said the price point is not going to be increased, even though you’re adding these new analytes. Did I hear you right?

Mark Newman: That is the goal at this point. Yeah, I mean, one of our main objectives is to make laboratory testing as cost effective as we can and one of the things that I’m pretty good at is figuring out a way to build this mouse trap in a way that it’s efficient and so as we scale up and as we increase efficiencies, that’s how we’re investing back into this whole system, is to add information as we grow so that we can add to the picture. And yeah, that’s the plan at this point is to leave the DUTCH Complete and the DUTCH Plus at their price point and to add these markers into them to make it even better.

Dr. Kara Fitzgerald: Well, it’s going to be a lot of fun. I mean, it already is a great panel. So, it’ll be nice to see those new analytes and just have that bigger picture. I’m looking forward to it. All right. As always, Mark, it’s just really fun to get to hang out with you and pick your brain. So, thank you so much for joining me today on New Frontiers.

Mark Newman: Oh, you’re welcome and thanks for having me. I appreciate it.

Dr. Kara Fitzgerald: Absolutely.