DUTCH Test Founder Mark Newman Interview

In this episode of The Dr. Hedberg Show, I interview DUTCH test founder Mark Newman.  We covered a lot of detailed information about hormone testing and why the DUTCH test is superior in many ways to other forms of hormone testing.

Here is a transcript of my interview with Mark Newman on the DUTCH Test

Dr. Hedberg: Okay, well, welcome, everyone. This is Dr. Hedberg and welcome to “The Dr. Hedberg Show.” I’m excited today to have Mark Newman on the show, and Mark is the founder of Precision Analytical. This is a lab that I’ve been using, I think, pretty much since the beginning, but Mark is a recognized expert and international speaker in the field of hormone testing. He has assisted many labs in developing novel tests to create world-class laboratory testing. He’s also educated thousands of providers about hormone monitoring best practices. Welcome to the show, Mark, thanks for coming on.

Mark: Yeah, glad to be here. It’s good to chat with you.

Dr. Hedberg: Why don’t we start with you just filling everybody in on what you’ve been doing and what you’ve been working on with your testing?

Mark: Sure. The tests that we do and most people know it by its acronym, which is DUTCH, so it’s a Dried Urine Test for Comprehensive Hormones. It’s kind of a culmination of everything I’ve done career-wise vocationally in this world of hormone testing, starting off developing and working on 24-hour urine testing and kind of taking a good look at that in terms of the pros and cons. And then moving on to blood testing and saliva testing and governed over about a million of those tests over a five or six-year period. And what we’ve been doing the last five or six years is trying to piece together a little bit of a better model for people to get more information when it comes to reproductive and adrenal hormones.

You know, saliva testing has its advantages and blood testing has its advantages, and we’ve tried to combine all of that into one model that people can use to get a lot of information. So, we’ve got a uniquely comprehensive look at your adrenal hormones and your reproductive hormones and that’s what we did and launched in about 2000, early 2013. I think you were kind of one of the first to jump on with us, which we’ve, of course, appreciated. And since then, we’ve been looking at this puzzle and saying “Okay, what else can we add to this to add into the picture?” So, we added a melatonin marker, we added 8-Hydroxydeoxyguanosine for an oxidative stress marker.

And then we’ve recently added a handful of organic acids so that we can see B12 deficiency, B6 deficiency, glutathione deficiency, a window into the neurotransmitter world. Because those all have a lot of crossover with the hormones and our goal and my goal is really just to give people the best most cost-effective tool they can for when you’re dealing with functional medicine, integrative medicine and just some of these tough cases where you’ve got multiple things going on and we’re trying to figure out as much as we can about those patients so that we can treat them well.

Dr. Hedberg: Yeah, I was really looking forward to this interview so we can really delve deep into some of these areas. So, like you said, I think I was one of the first to start using the DUTCH Test and like a lot of practitioners out there, I started with saliva and blood. And then I had done some 24-hour urine, but that always was a little bit difficult to get the patient to do all 24 hours of collection. And then with that, we didn’t have the cortisol rhythm that we have with the DUTCH Test. So there were a few disadvantages there, but why don’t you give us a general breakdown of the advantages of urine compared to saliva and blood testing?

Mark: Sure. Yeah, I mean, I think historically, if you’re trying to use something for its biggest advantage, then you’re really better off, if saliva and blood are your options, you’re really better off going to saliva to look at cortisol. Because you want to look at not just free cortisol, which you’re not typically getting in blood, but you want to look at free cortisol at multiple points throughout the day, right? Blood cortisol is not a useless test, but it really tells you so very little, and we could go into the specifics of that, but it’s just well-documented that going to saliva to get free cortisol over time is better. But then when you look at the reproductive hormones, there are very significant advantages to testing the blood over saliva, and I would point mostly to the problems in testing estradiol.

And that is, you know, with no disrespect to the labs that are doing the test, there’s just so little hormone in saliva that your ability to differentiate between “sufficient” and “deficient” is really just not done well enough for us to make decisions. So just as an example, I can think of a very prominent lab that does a good job with lab testing, but if you look at their saliva assay, the estradiol range for postmenopausal women and premenopausal women is essentially the same. So what I’m saying is when we test otherwise healthy people who are estrogen-deficient and estrogen-sufficient, we get essentially the same values.

And when you look at those in blood, there’s a full tenfold difference between those two groups, so blood is a much more accurate way to test reproductive hormones, typically. So what you’re gonna do, you use both, you got to kinda pick and choose. And what we’ve shown is that our pattern of free cortisol in urine parallels saliva very well, and we just about got in print our correlation data for reproductive hormones, particularly the female ones, between our urine testing and blood testing.

And one of the other things about blood testing is, well, the numbers, I think, are better than what you’re gonna get in saliva, I was just reading a paper actually last week where they tracked a woman throughout a day, and her progesterone varied from 5, which is really on the lower end of, you know, in ovulatory number, all the way up to 35 throughout the day, so it’s bouncing all over the place throughout the day. With a urine test, you can average that out and get a truer picture of what their production is.

So, our goal is to give you a viable alternative for those reproductive hormones and the cortisol pattern and the reason that that was my angle when we started working on the DUTCH Test is because once you’ve established that, now you can open up your panel to everything else that you can do in urine, which includes your estrogen metabolites. So not just estradiol, but, you know, phase 1 metabolites, 2-hydroxy, 4-hydroxy, 16-hydroxy, then you can look at methylation, which is a part of phase 2. And the same story for the androgens, you can look at the hormones, but also the metabolites to see if they’re pushing down that highly androgenic 5-alpha pathway like you see in PCOS patients and other situations.

And this story continues to unfold for cortisol and other things. As looking at the metabolites, just adds a lot of value to try to figure out what, really, someone’s story is as it relates to that hormone and then when you continue on melatonin, 8-hydroxydeoxyguanosine, organic acids, you just got a really, a comprehensive look that just isn’t there with those other tests. Although, having said that, you know, if I’ve got a testosterone injection and my only goal is to get a good testosterone value on a guy, a blood test is a great way to do that. To get a total in a free testosterone, you know, that works well. If you just want to look at that free cortisol pattern, you know, saliva can do that quite effectively. But when you want to get comprehensive and really see what’s going on, that’s where, for me, urine brings a lot of value because you’re getting everything that you had in those other tests, but you just add, you know, so much more.

Dr. Hedberg: Yeah. I always felt the least comfortable with saliva, the most comfortable with blood and urine, blood especially with testosterone and then urine with the adrenal hormones. But like you said, for me, there was, all was…there just always seemed like there was a lot more to look at and then when the estrogen metabolism markers came out and that became an individual test that was available, I started getting interested more and more into that. And that’s something that the DUTCH does test for, so can you talk a little bit more about estrogen metabolism and if there’s any advantage to adding those metabolites?

Mark: Sure. Yeah, the metabolites, to me, have kind of two or three different angles. One is, and this is another benefit of urine testing, is if I’m gonna call you estrogen-deficient or estrogen-sufficient or whatever, it’s sure nice to have more than one marker, right? So, if I’m looking at, now we have 10 estrogen metabolites, right, when they’re all tanked in that postmenopausal range, like, I know who you are as it relates to estrogen. And if there are high, like, that’s clear, too, but when you get some of these weird cases where they’ve got some unique patterns, it’s sure nice to see a lot more to just confirm where that patient may be as it relates to just not enough or enough or too much.

But then there’s another story that we often see and that is what if your, the reason that you have too much estradiol is not because you’re making too much, but because you’re not getting rid of it properly. I’ve had a number of friends who, you know, have come to me and they’re just not feeling right and it sounds like estrogen dominance. “Okay, we could just put you on a treatment of, you know, calcium-D-glucarate and high fiber diet and try to get rid of inflammation and maybe some DIM and some of those things.” But then we test them and we see is, “Okay, your estradiol is high, but all of your phase 1 metabolites are low.”

So, here is a picture of a woman who is making just a decent amount of estrogen, but she just can’t get rid of it. So, in a case like that, you know, when you put a woman on say DIM, DIM will open up that channel of the primary phase 1 pathway, which is 2-hydroxylation, that’s CYP1A1 pathway, and sure enough, that estradiol and estrone and the 16-hydroxyestrone, which is your most potent metabolite other than estradiol, those will all come down as this drain is essentially opened up for the woman to more normally process for estrogen. So that, to me, is just a more intelligent way to address someone rather than just saying “Okay, your estradiol is high, let me grab every weapon I know that will lower your estrogen.” Well, you know, let’s take a deeper dive and see what’s going on, and then the other angle on that is, of course, just the whole issue of risk of cancer, particularly, we focus on breast. Most of the research is on that, but it’s also true of prostate cancer and other estrogen-related cancers. But if you’re really pushing down, particularly, the 4-hydroxy pathway, we know 4-hydroxy estrogens create this reactive quinones species and then that can damage your DNA.

And when we see that, then we want to address that and there are a couple ways you can get rid of that stuff, one is methylation, well, we can look at your methylation. So, if you make a lot of it and you’re not methylating well, now I’ve got double trouble, right? And then you can look further at that pathway and, you know, you can make some interventions that probably are gonna benefit the patient. You know, that last step before those nasty estrogen metabolites damage your DNA, glutathione is the last detox step. So, if a patient is looking poor in that pathway, doesn’t it make sense to probably support their glutathione pathway?

Which is why we added a pyroglutamic acid to the DUTCH panel because that’s a marker for glutathione deficiency, so you get the sort of layering effect of your estrogen’s phase 1 metabolism, then methylation, and then nutrient deficiency, so this whole picture starts to emerge for these patients instead of a very simplistic picture that just says “Hey, your estradiol is high,” right? So, we can take, I think, a more targeted approach to not only helping them feel better, but hopefully put them in a better place as it relates to their relative risk for things like breast cancer.

Dr. Hedberg: Right, right. That’s really well put together. A couple of things I would add would be, and most of our practitioners out there are doing this, but stool testing to identify issues there that would affect estrogen clearance, especially β-glucuronidase is something where we want to look at. But, yeah, if there is detox issues and clearance issues, gut issues and then I would also add either hypo or hyperthyroid are both going to have some profound impacts on estrogen metabolism. You really have to look at every single piece of the chain and see where the weak link is and that’s the great thing about this test, is you can see most of those links. So let’s talk a little bit about the menstrual cycle, what is the best time to test during the menstrual cycle?

Mark: So, if you split the menstrual cycle up into the follicular phase, which is that early part, and then you hit ovulation, so at ovulation you should get a massive surge of estrogen and then following that, you should get a surge of progesterone. So, if you test in the follicular phase, it really doesn’t tell you anything. A postmenopausal woman and a premenopausal woman as it relates to progesterone should be equivalent there, so testing there is more or less useless. If you test that ovulation now, I’ve got this highly volatile estrogen peak, so you’re shooting at a moving target, not a good idea, progesterone still has not climbed. So, now we move to, in a typical cycle, day 19, 20, 21, 22, that’s a really nice window because the estrogen comes back up on a, like, a little plateau and the progesterone should be at its peak.

So, if we want to ask, “Are you producing normal estrogen, normal progesterone to balance out estrogen,” that’s really the window that we wanna shoot for, and then if you have an odd cycle, then you probably wanna shift, right? So, if you’re a 26-day cycle, now just shift to the left two days. If you’re a 31-day cycle, you know, then we’d be more day 22 through, you know, 25 or 26. My rule of thumb is if you take a sample and you cycle within three days, you start your cycle within three days, it’s probably a little bit too close to accurately assess progesterone. And I’ve even had patients who say, “Look, I’m a little irregular,” say, “Well, you can do our cycle mapping test, or you can collect, let your samples dry, throw them in the freezer and then wait.” There is nothing more frustrating than a patient who calls and said, “I sent in my samples yesterday and I started my cycle today.”

Then, you know, if we wanna do right by you and you really care about progesterone, I mean, the rest of the panel is gonna be pretty valid. But, you know, you might need to do it again next month, so that’s…I’ve even had patients collect five days apart, let them dry, put both them in the freezer, and then once their cycle happens, then we say “Okay, well, this one actually is more in line with your luteal phase, send that one in.” So that’s what we wanna hit, the luteal phase when progesterone is peaking and estrogen’s on that little plateau.

Dr. Hedberg: Right, right, exactly. So, you’ve come out with a cycle mapping test, I think it was a few years ago, can you talk a little bit more about that way of testing?

Mark: Sure. You know, it’s just a matter of having patients where you say, “Do you know what, our test actually is not enough for you.” And that is if your cycle is highly irregular or if, let’s say a woman has had an ablation, right, she may come to you and say, “I have no idea where my luteal phase is because I don’t bleed anymore.” So, okay, “Well, I can test you and if your progesterone is low, what will I tell you? I will tell you either we miss the luteal phase, which is likely or you don’t make enough progesterone.” Well, that’s not good enough, right? So, in those cases and particularly in fertility cases, if your cycles are really irregular, or if you have symptoms where you say, “Hey, at certain parts of the cycle, I really am struggling with X, Y or Z,” okay, let’s do a cycle map, so what do they do there, they’re gonna get up, and most mornings of their cycle, so they’d start on day seven and they’d collect maybe day seven, nine, 11, 12, 13 and so on.

So just waking up collecting one of these little dried samples and they send us the samples, and then what I do is I lay them all out and I say, “Okay, how long was your cycle?” And once I know how long your cycle is, then I’m gonna pick the nine most relevant measurements to try to characterize the ovulatory peak and the luteal peak, so you’ll really get an idea of, you know, if those hormones are hitting the levels they’re supposed to, if they’re maintaining them. You know, if I’ve got an infertility or maybe even just PMS-type issues maybe my progesterone climbs, but maybe it dies early, you know, maybe it falls early. And if that’s the case, then that’s definitely something that’s worth addressing, now how would you ever know that if you only tested one day? Like, you just wouldn’t.

So, in some cases, it’s worth the extra money, it’s worth the extra hassle. Certainly, it’s a big hassle for us, so we don’t actually like doing that. People complain here when they come in because they’re a ton of work, but it’s beautiful data. Because then you have, you know, no question because sometimes you’ll see a patient who maybe she is not ovulating and her adrenal glands are making up with that, and so she has got high progesterone for someone who’s not cycling. Okay, then you have another person who cycles, ovulates, but has this little, tiny, cute ovulatory or luteal peak of progesterone that’s really small. If you test just one day, those two patients can look the same, right?

Because you say, “Well, either you’re not ovulate and your adrenal glands are kicking out a little extra progesterone and try to make up for that, or you’re ovulating and you’re just not making very much progesterone.” You know, if you’re dealing with a fertility issue or something like that, you know, differentiating between those can be really powerful. And when you have those nine measurements mapped out over a whole period of time, you know, it’s a lot more clear what’s going on with that particular female.

Dr. Hedberg: Right. So that’s a test that, it’s been around for a while, at least it was available in saliva, but obviously, we get a lot more data with a DUTCH Test in that regard. So, shifting into testosterone and androgens, so with the DUTCH Test, we get testosterone and epitestosterone and a number of androgen metabolites. How do we really interpret those and do we ever need a blood test to go along with that?

Mark: Yeah. I mean, there are a few layers to that. I mean, there are some caveats to your urine testing as it relates to testosterone, and maybe I’ll get into those in just a second. But just very generally, I’m measuring testosterone and I’m measuring three of its metabolites. So DHT, which we all know, that’s that really androgenic one, and then DHT becomes 5-alpha-androstenediol, so we test that. And then if it goes down the non-androgenic pathway, that’s 5-beta, so that’s the non-androgenic cousin of the DHT metabolites. So we’ve got 5-alpha and 5-beta-androstenediol, so three metabolites of testosterone. So, for me, I typically don’t put as much weight in those as I do testosterone itself, but it’s helpful, right? I had a woman yesterday whose results I was looking at, her testosterone was high, it was quite high.

She was taking testosterone and all three of those metabolites were actually low. Now, if all three of those were high, this is slam-dunk, like, “Hey, quit giving her so much testosterone, right?” And that I singled out females and testosterone is your patient is going to tell you if you’re giving them too much because they are gonna symptoms they do not want. But as I’m looking at that, I’m thinking, “Okay, you either have this little flare of testosterone that may be a short-lived or maybe the metabolisms a little bit funny or something, but it’s not the slam-dunk highly androgenic, too much testosterone sort of a case.” Because of those metabolites, while they have less value than testosterone, they help to confirm just how much hormone is pushing through that channel, and so I do look at those for that purpose.

The other thing that I want to look at is that 5-alpha, 5-beta metabolisms. So, you know, if a testosterone, let’s say a PCOS case. So I’ve got a PCOS case, I’m gonna ask three questions, one, “Do you make too much DHEA?” because that’s common. Right, so I’m gonna look at the total of all those DHEA metabolites, we add those up and present that as a separate calculation, and you can look at that, yes or no. Then I’m gonna look and say, “Well, do you make too much testosterone?” So I’m looking at testosterone, maybe I’m glancing at the metabolites that kind of confirm that story, “Okay, do I have too much DHEA? Do I have too much testosterone?” But then the other issue that the insulin creates in PCOS is it up-regulates 5-alpha reductase. So testosterone and all the androgens can either go down the alpha pathway, which is more androgenic, or they can go down the beta pathway, which is going to reduce the androgenic nature.

So, like me, every single time I test myself, I push down that beta pathway, right, now that’s may not be that highly, you know, relevant for me, I’m probably less androgenic than I would otherwise be. Maybe, my hair, which is thinning now at 40 would be doing so more quickly if I was an alpha metabolizer because DHT creates, you know, hair loss issues, men and women. And so that’s a separate question of, “Am I pushing down that pathway?” So, if I have a normal DHEA, a normal testosterone, but I’m shoving all those androgens down the alpha pathway, I’m likely to have some symptoms of high testosterone even though my testosterone is not high and I’m speaking more from the female perspective when I’m talking about that.

And there are things you can do about that, right? There are things you can intervene to lower someone’s predisposition to produce DHEA, same thing with testosterone. And there are different solutions for 5-alpha reductase, right, you can use things like saw palmetto and I’ve tested female patients’ PCOS, pushing down the alpha pathway, provider sees that, puts them on saw palmetto and that alpha metabolite ratchets down because saw palmetto, you know, we use it for prostate health in men and, as well, it’s a good tool. But you can also use it to intervene there, but you don’t want to do that needlessly, right? So that’s why we want to see those metabolites and that’s, again, one of those patterns you can only pick up in urine because those 5-alpha, 5-beta metabolites, you can’t really look at in any other test.

So that’s the, I guess, the basic level, like, “What do we do with testosterone?” We’re looking at androgens, we’re looking at metabolism, then there’s this fairly significant caveat with urine testing and that is I don’t suggest doing a urine test for testosterone without a concurrent serum measurement at some point if you’re looking at people of Asian descent. Which sounds really weird if you’re not familiar with this issue, but in urine, I’m not looking at testosterone, right? I’m looking at the phase 2 conjugates, which is a good reflection of bioavailable testosterone, but it presupposes that the patient is, in a normal fashion, making those phase 2 conjugates. So, we’re talking about testosterone glucuronide, that’s the water-soluble form that your body makes to get it into urine so that we can measure it and say, “Aha, here’s how much testosterone you’re producing.”

Problem is there’s a genetic defect in the enzyme that’s responsible for that, and it’s really prevalent in the Asian population. And so what you have is you have… There’s a study that they did where they looked at a large group of men from Korea, and a large group of men from, I forget, some European country. And the blood levels of testosterone, on average, were the same, but the urine levels were almost 10 times lower in the Korean men because it was really common for some of those men to have this genetic defect. There is no clinical downside to this, they’re not having problems, but just the testosterone has to find a different path to find its way out of the body, which is unusual, and so you’ve got to be careful with that.

So what we do is there’s a sort of a cousin to testosterone called epitestosterone, so it’s not androgenic, it doesn’t really serve much of a purpose except it helps us on almost, like, a QC level, and that is the average guy has got the same level. So, if my testosterone is around 50, my epitestosterone tends to be around 50. Well, it just so happens that the enzyme that’s responsible for getting epitestosterone in that form where it can go into the urine is a different enzyme. So, when someone has this genetic defect, what we see is we see normal levels of epitestosterone and these super-low levels of testosterone and then we would alert the provider and say, “Look, based on this pattern, there’s too much uncertainty here, you really need to go do a blood test.” It’s only, like, something like 1% of Caucasians have that, so when we see it, we flag it because we wanna make sure you’re not treating based on that, but in the Asian population, it’s, like, over half.

So you’ve got to be really conscious of that and that’s one thing that we really pride ourselves on is finding all of the caveats in the cracks in a urine-based model and educating our providers, and doing what we can to sort of fill in those cracks, as we’ve done in this case, by measuring other metabolites, looking at which ones are problematic when this situation arises, and then being able to let people know about that. So, there’s a lot to the androgens when it comes to that whole issue, but, you know, that’s only a problem in a fraction of people. But when we see it, we alert people and then, you know, like I say, just, “Go get a blood test done.”

Dr. Hedberg: So one of the things that I was just thinking about while you were talking about that is the ketogenic diet. So, I just wanted to ask you, have you seen, are there any particular changes you’ve seen in androgen metabolism with patients on a ketogenic diet? I’m just asking that because with the patients I see with PCOS, the ketogenic diet is extremely effective for that. Do you have anything to add there?

Mark: You know, that is a good question and it’s not a question that I would consider myself competent to answer. It’s not something that we have on a requisition form, so I don’t know when people are doing that. So I couldn’t speak super-confidently to that. Probably our providers that sit on the phone with doctors all day would have a better idea. I’ll have to ask them because, I’ll have to get back to you because that’s a really good question, but I don’t have…I just haven’t looked through that lens at our patients.

Dr. Hedberg: Yeah, yeah. I think it’s an interesting question to look at, especially with the increasing popularity of that type of diet. So, shifting into adrenals, so the DUTCH Test, we get metabolized cortisol, cortisone, and a number of metabolites there. So can you give us a kind of a general breakdown of how we interpret those highs and lows?

Mark: Sure. You know, if you’re gonna break it down into sort of its individual parts, you know, we wanna look, I think, firstly at that up-and-down pattern. So I’m looking at free cortisol, you know, “What are my levels while I’m sleeping, what are my levels in the early morning,” hopefully they’re going up, and then, “Are they coming back down appropriately in the afternoon,” and then, “Are they nice and quiet and low at that bedtime sampling?” So, we’re looking for that up-and-down pattern of free cortisol, and then the metabolites really give us a better picture of overall production. So free cortisol is the most important thing for us to look at, but it only represents about 1% of the total production of cortisol.

So, the metabolites represents something like 70-some percent of the production of cortisol, so that’s really just the bucket at the end of the day that’s catching all of that cortisol. Most of it ends up as a metabolite in your urine and that’s what we measure, right? So that’s really, you know, when you go to ask the question, “How much is my adrenal gland pumping out?” we wanna look at that. Now, why does that matter? Well, if it tells the same story as the free cortisol, it really doesn’t matter, right? If I’ve got a person…I mean, let’s go to an extreme example. If somebody is on some sort of medication that is suppressing their adrenal production, so I’m on prednisone or I’m on some inhaler or something that just happens to be shutting down my HPA access. So, I’m on opioid, whatever, a lot of things can do it, right?

So if you do that, your free cortisol is gonna be dramatically low, like, it’s not coming up near or into our reference range at all. And what happens when you get to the metabolites? Same thing, right, the reference ranges, let’s say, I don’t even know off the top of my head, but 2,000 to 5,000 and you’ve got 500, right? So you’ve got hardly any of those metabolites. So in that case, what has it done? It simply confirmed the story that you already know. The same point, I tested a buddy of mine a few months back that was really struggling with something, I don’t know, inflammation or whatever, but all four of those free cortisol points were off the charts. We looked at his saliva, same thing, just on fire, right? Now, we look at the metabolites, what do we see? Well, they’re high, right, so in that case, what have they done? Nothing, they’ve just confirmed the story that we know. It’s the situations where you have abnormal cortisol clearance that’s part of the picture that where it really is helpful, and this is actually the single issue that pushed me to develop the DUTCH Test.

Because I went back and looked at a million results, literally, in saliva, and I said, “Okay, what happens when people get heavier?” And as people’s BMIs go up, I’m thinking, “Well, hey, we all know cortisol is related to weight gain,” right, so as weight gain goes up, you’re gonna get more salivary free cortisol and it’s not true. On average, there is actually a very. very slight negative correlation there. It’s essentially nothing, it’s essentially a flat line between BMI and free cortisol, and you’re going, “Wait a minute, we know this to be true,” right, well, people have Cushing’s disease, they get, you know, this fat gain and there’s a lot of cortisol and all of that. But, with obesity, what happens is you’ve got this fat trap sitting around your belly and elsewhere and it sequesters the cortisol, it gets metabolized, it gets excreted. The adrenal gland goes, “Oh, thanks a lot, now I’ll make some more,” right, but the circulating cortisol is pretty much the same on average. People can be high, people can be low, but it’s not really related to the fat, right?

But the metabolites show it, there’s this hugely strong relationship where you get excessive cortisol clearance with obesity. We see the opposite, although it’s a little more subtle with hypothyroidism, right? So with thyroid, if your thyroid slows down, and this makes intuitive sense, what happens to your ability to clear cortisol? It also slows. So, we see this cortisol over cortisone preference, so you’re not deactivating it to that deactive form of cortisone as much, and then your ability to push it to these metabolites is also reduced. So, oftentimes, you’ll see a normal or maybe even an elevated free cortisol and you say, “Aha, you know, high cortisol production,” right, and then you look at the metabolites, wrong. Maybe those are low and so you say, “Okay, this is this picture of high free cortisol. low metabolites, so that’s a picture of sluggish or slowed cortisol clearance,” which, again, you’ll see in a hypothyroid case. So, when you have, and how often do we have, concurrent thyroid issues going on with adrenal issues, it’s really nice to see both the metabolites and the free cortisol.

I had a friend, this was a long time ago, but she tested and she had a low free cortisol and high metabolites. She says, “When do you see that?” I say, “Well, we see it in obesity,” she is super-skinny, like, “Oh, that’s not it.” And I say, “I see it in hyperthyroidism.” And she says, “Well, that doesn’t make any sense then because I’m hypothyroid.” And then she calls me back that night and says, “Aha, I looked back in at what my doctor’s notes were, and he had given me thyroid meds and told me to take it once a day, and I was taking it twice a day.” And so she had this induced hyperthyroidism because she was taking too much thyroid medication and what happens, she is ramping up her cortisol clearance, and yes, she’s making a lot of cortisol, but it’s all in that metabolized form because there’s an imbalance there.

Now, if you took her and did a little saliva test on her and that’s it, and you said, “Well, you know, not only are you hypothyroid, my goodness, you must have adrenal fatigue because your free cortisol levels are low.” Now you’re barking up the wrong tree there, right, you’re fixing a problem that’s actually the result of a treatment that you’ve already done on some other system. And so, for me, I have a lot more confidence in just sort of knowing your story as it relates to cortisol when we’re looking at both free cortisol and the metabolites.

Dr. Hedberg: Right, so there’s a lot to think about there just, like, with the sex hormones. So, let’s talk a little bit more about cortisone, can you talk a little bit more about why you would test that as well as cortisol?

Mark: Yeah. The main reason we test cortisone is because we can. We use mass spec, so it comes along for the ride and, you know, I try not to oversell it because it’s not this massively critical thing, but it is a nice confirmation of what’s going on. And there are occasional cases, and it’s not that rare, where it will really help you out and bail you out in a situation where you’ve got a weird situation. So what is essentially is the cortisone pattern doesn’t actually go up and down that much within the body. But what happens is where do we measure cortisol? We measure in urine, which comes, of course, from the kidneys and we measure in saliva, which comes from the saliva gland. In both of those tissue, there is a very active enzyme deactivating cortisol to cortisone. So, if I’m cortisol, I’m cruising around the body and the second I step foot in the kidney or the saliva gland, I get jerked over to cortisone, and then I go out of the body and then I get converted back to cortisol. So, a high percentage of cortisol, when it’s in the urine, when it’s in the saliva is actually there as cortisone because there’s a local conversion. So because of that, I want to see that, too, so the way I say it cortisone is a shadow of the cortisol, it’s just sort of this second representation of what’s going on with cortisol.

So, if I see somebody with a normal cortisol and a high cortisone, I’m thinking, “Maybe normal, maybe it’s a little bit high.” If I see somebody with a normal cortisol and the cortisone is low, then, you know, I’m leaning a little bit more and in that direction. So it kind of pulls my thinking a little bit because it represents, you know, a good fraction of the cortisol. The place where it dramatically helps you is if, let’s say a patient, and we’ve had a patient two weeks ago and her free cortisol was sky-high, so how do you interpret that? “Oh, well, gee whiz, your HPA axis is going crazy.” Well, guess what? Her metabolites were not high and her cortisone was very normal, so I call her and say, “Okay, listen, here is the thing. I need to know if anyone in your family is using hydrocortisone,” hydrocortisone is cortisol, right? “Because if you’re putting that on and you’re contaminated your sample, then I’m gonna get this weird pattern and it’s not real.”

And she says, “Well, my husband uses it, he likes to get a little [inaudible 00:36:30].” She tells this kind of embarrassing story. We’re like, “Okay, well, at least we can understand the results.” But guess what, I have a fallback plan because I know that there’s decent research that shows that cortisone is a reasonable, it’s not as good, but it’s a reasonable representation of the circadian rhythm of cortisol. So in that case, I completely ignore the cortisol, I look at the cortisone, I look at the metabolites or I have a recollect. But if I don’t have that cortisone, I got to worry a little bit about, you know, “Does she have an adrenal tumor that’s doing some weird thing?” I don’t know. You have to consider that high cortisol as being potentially legitimate if you don’t have this backup mechanism to say, “Hold on, like, there’s a real issue here.”

So, you can have really weird metabolism where the cortisol is just, like, crazy deactivated or maybe it’s not, right, if someone’s cortisol is high and the cortisone is normal or low, then, you know, I’d be asking, “Do you have high blood pressure?” Because, you know, “Why is my kidney doing this?” Well, the kidney knows that the aldosterone receptor is there and aldosterone raises your blood pressure, well, guess what, cortisol hits that receptor at 100%. It works just like aldosterone. That’s why the kidney says, “No, no, go sit over here as cortisone, where you’re inactive.” And that’s part of the mechanism of keeping your blood pressure under control. So if somebody has got this really imbalanced cortisol-cortisone relationship, then that can have health impacts and be part of their story. And so it does fill in some of the story, but it’s of much lesser importance than cortisol itself.

Dr. Hedberg: So the DUTCH Plus, this is a part of your test that has…it’s called the cortisol awakening response. Can you talk a little bit more about that and why we would want to see that?

Mark: Yeah. This is really just a result of us following the research and following the literature. So if you back up to when I started working on this, which was, you know, almost 10 years ago, the literature told me, “I want to know what your up and down pattern of cortisol is,” and that’s what all the saliva labs are out there doing. But it also told me, “I want to know your metabolites look like,” so we did that. And there’s been a lot of research since then that says that, “Look, if you measure cortisol right when you wake up,” like, within five minutes, so what happens, your eyes open, the light is part of the mechanism, right, the light hits the whatever which goes to your brain to wherever. You know, there’s this thing that happens every day when you wake up and what it does is it creates almost instantaneously the cortisol just gets going, right, it’s gonna double within minutes.

Now, it takes about five minutes for that response to hit your saliva, right? So I’ve got this little five-minute window where I’ve got an ability to get a baseline test and then if I test again half an hour later, I’m looking at that, “How far am I leaping, what is the delta, what’s the change there in cortisol?” And what the research says is when you are stressed, your body does X, Y and Z. When you wake up, your body also does X, Y and Z. So, it can be a mini stress test to show us whether the HPA axis is overactive or not. And to do that, you need a true baseline at waking and 30 minutes later, so we test right at waking, 30 minutes later, 60 minutes later, and we’re looking at that dynamic change.

So, for us, the DUTCH Plus adds the saliva collection. So what we have patients do is do a swab, so they just wake up, pop the lid off this thing, throw it in their mouth, about 90 seconds later, it’s saturated and you’re done, right? The challenge with this test is there’s always good research that says, “Hey, if you do this, you get this extra bit of information that is important for cortisol.” But then in a very practical sense, what all the saliva labs are doing is saying, “Collect a saliva sample and you need, you know, 2 milliliters,” or whatever. You can’t do that in five minutes in the morning, it’s really challenging. And they can’t use these swabs because they absorb progesterone. Well, we’re not testing progesterone from saliva, we’re just testing cortisol. So we can make the collection a lot easier, so what we’re doing is five total salivas, so waking, 30 minutes later, 60 minutes later, dinnertime, and bedtime.

So, now I’m just replacing my urine free cortisol with this salivary free cortisol and it allows you to see the same thing, the up-and-down pattern of free cortisol, where you’re still looking at all the metabolites of cortisol and estrogens and all of that, but then it allows us to go in more precisely and look at a true cortisol awakening response. Which a lot of people have said, Well, why don’t you just do that with urine?” Well, if I wake up, that urine sample represents the entirety of the night, it doesn’t represent the waking time. There’s no way to do it except using saliva, so… It seems like a subtle difference, like, “Why would you go to all this hassle to develop this new test and all of this when you’ve already got something that’s close?”

Well, there are studies that are pretty impressive that say, “Look, when we look at people and then we ask the question, ‘Okay, who went on to develop major depressive disorder?'” and when they split them in groups of “yes” and “no,” and they look at the CAR when they started the study, guess what, every one of those individual cortisol points, none of them were statistically related to developing major depressive disorder. Not the waking sample, not the second sample, not the third sample, not dinnertime, not bedtime. But when they looked at the delta, at the change between the waking and the 30 minutes, that’s where they went, “Aha, this dynamic shift when you are stressed, when you wake.” And it makes sense, right, the more cortisol you’re making, you know, we know cortisol is related to depression, so the more responsive you are to a stress in making cortisol, then, you know, you’re gonna have some issues, and you can look at the flip side of the coin, too.

People might be normal at waking, normal 30 minutes later, but if that’s flat as opposed to huge, if it’s really flat and it’s not jumping much at all, and that’s gonna be really independently related to things like fatigue or now, things related to low cortisol. So, it’s just one more variable in the cortisol world that can speak to you having either an underactive or an overactive HPA axis. And so it just takes that adrenal test of ours that’s already uniquely comprehensive and it makes it even more comprehensive and gives you just a lot of information to work with.

Dr. Hedberg: Yeah. That’s definitely more data than we’ve ever had available before. So, the other aspect of the adrenals is, of course, DHEA and you can do a DHEA blood test or DHEA sulfate and the DUTCH Test, you get DHEA and metabolites, as well. So, can you talk a little bit about DHEA and urine testing?

Mark: Yeah. I think DHEA, it doesn’t have a…it has somewhat of a circadian rhythm, so testing multiple times throughout the day has a little bit of an advantage, but to be honest, DHEA in blood is a good test. I’ve no problem with that. It’s just in urine, we’re able to give, I think, a very reasonable representation of your DHEA, but it’s really does metabolites that I think have some added value. I’ll give you an example, if I have a person who has DHEA-S, so the sulfate that we measure, that is low, you would think to yourself, “Aha, low DHEA,” right? But DHEA goes to androstenedione and androstenedione has two very large metabolites, etiocholanolone and androsterone, right? So between the three, I’ve got three fairly massive metabolites of DHEA.

Now, if those two downstream guys are normal or high and DHEA-S is low, what do I make of that? Well, I know that if you have a sulfur deficiency, you’re not gonna be able to make DHEA-S, but it will push downstream to the other metabolites. And I also know that inflammation, so people who have, like, rheumatoid, for example, make less DHEA sulfate because inflammation itself blocks the sulfation process. So, if I have DHEA and its metabolites, it’s, again, just in some cases you have a little “aha” moment where you say, “Okay, I’m gonna describe you in my own mind differently because I know this information.” So that low DHEA-S, if those metabolites are also low, then you’re just not making very much, right? But if you get this type of a pattern where it is low and the metabolites are not, you know, maybe there’s something else going on there, and maybe the adrenal gland actually is making pretty decent levels of DHEA, it’s just preferentially going away from DHEA-S and that’s pretty relevant. So, again, I have no issue with measuring DHEA in blood, it’s just, again, our goal of giving a little bit more comprehensive look at a hormone like that.

Dr. Hedberg: Right, right. Another advantage to the DUTCH Test is melatonin and this is something that hasn’t really been available across the board, you know, since the beginning of functional medicine. So why did you add this to the test, and what are these levels really mean that we see?

Mark: You know, our goal is to add things to our tests that sort of fold into the story that we’re already telling, right? So, if you’ve got a high cortisol while you’re sleeping, you’ve got all kinds of cortisol dysregulation, you know, your cortisol opposes melatonin. So, you’re gonna potentially have an issue there. It has some really good antioxidant properties we know, we’re looking at estrogen metabolites, right? Well, women with lower levels of the metabolite we’re measuring are more likely to get breast cancer, right? So, it’s part of the same story that we’re telling and how do you do it? Well, you can wake up at 2 a.m. and hope that 2 a.m. is your peak and do a really quick saliva test, that’s an option. And that works okay. You could, I don’t know, sleep in a hospital and have them draw your blood while you’re sleeping, but it’s not really a practical option, right?

So they actually did that in a study where they measured, they hooked the women up, right? Say, you know, nighty-night, and then they measured their blood, I wanna say, every hour while they were sleeping. They took those numbers, they added them up and they said, “This is your total.” They also had them wake up in the morning and urinate, and they measured the metabolites that we measure. And when they correlated that total from while they were sleeping, so the urine is this beautiful correlation. So the sum total of what you make at night is well expressed by looking at a urine 6-hydroxymelatonin sulfate. And so that’s what we do because it’s one more category, really, of hormonal wellness, whatever you wanna call it, that we can look at. The one downside to it is it’s completely useless when you’re on therapy. There really isn’t a very good way to test melatonin therapy and, obviously, there are all these other intellectual arguments about, you know, if there’s negative feedback and whether we should be giving melatonin or 5-HTP or whatever.

But from a monitoring standpoint, it’s sure nice to just know, you know, “What are your levels and is this something I need to address?” I will say if you use our test, our instructions will not tell people to get off of melatonin. Because we think your cortisol is more valuable information and if people get off of melatonin, they can’t sleep and it screws up their cortisol pattern, we’d rather be able to see that, which means they stay on their melatonin, the measurement we give you is completely useless because it’s just all this gut clearance of the melatonin they’re taking. It has nothing to do with circulating melatonin, it’s just a stupid, high number. And so it’s not useful for monitoring therapy, but it’s a nice little baseline test to look at whether someone might have a deficiency, not only of melatonin, but you’ve got to start asking yourself about serotonin, too, right? So, if melatonin is low and they’re depressed, you know, something to think about.

Dr. Hedberg: Right, right. So let’s talk a little bit about thyroid, one of my favorite topics. So I know we can learn a lot from estrogen metabolism and progesterone, testosterone, and all the adrenal hormones. So, can you kind of tie thyroid function into adrenal hormones and what we’re looking at?

Mark: Yeah. There are a number of places where thyroid and cortisol sort of talk to each other. And so it can be kind of tough to predict what someone’s gonna look like when they’ve got all of these issues, but the most fundamental thing that we see is that, and we talked about this a little bit before, is there is a correlation, and it’s pretty strong, between thyroid function and cortisol clearance. So, my free cortisol is the picture of free cortisol, my metabolites are the picture of what’s happens following cortisol clearance or cortisol metabolism. And so that is directly impacted by the thyroid function and, you know, the cortisol impacts thyroid’s ability to go from T4 to T3, and, I mean, they, and suppressing TSH and some of those things. So they talk to each other on a number of different levels. So it’s something that you need to work through carefully, but as you’re treating one and the other, you know, you definitely want to see them both as they sort of go through this dance, right?

Because if you have a hypothyroid patient and let’s say their free cortisol is high and their metabolites are low, well, if you just simply go in and address the thyroid, there is going to be an adrenal consequence, right? In this case, it might be a positive consequence that that cortisol is now freed up to metabolize more appropriately and maybe it comes down and it’s going to resettle, and so it’s good to be looking at adrenal hormones at the same time, you know, as thyroid when you’re testing both. And it’s kind of annoyingly complex. to be honest with you, because you’ve got, let’s say a person with low free cortisol and high metabolites. Well, when is the most common time we see that? Obesity. Okay, what’s the opposite picture, when do we see that? Hypothyroid. Well, what happens when you’ve got an obese person that’s hypothyroid? I mean, you know, you’ve got those patterns kind of pulling in opposite directions and so it can get to be complex and that’s why we have, you know, six doctors on staff that are, all day, on the phone with people kind of walking through these things because sometimes it is this sort of decision-tree thinking sort of thing where, you know, you have to walk through that.

But, you know, for me, I would take a little bit of confusion over confident incompetence, if you know what I mean, you know, to see to one lab value and to push forward in a particular direction when the story is so much more complex for a particular patient, you know, it’s almost better to scratch your head a little bit and go, “Okay, slow down,” and let’s figure out what’s really going on with this patient. And maybe we’re going to treat them, you know, in a much slower manner in terms of not just jacking up their cortisol, you know, production, you know, just to give you an example, let’s say I take the obese patient and I only test them in saliva by just looking at free cortisol, and when you start pushing up their cortisol production because you think they’re hypocortisol when they’re really not, then what happens?

Well, the first place all that cortisol goes, and remember, you’re making a lot of it, is into the middle, the medulla of the adrenal gland, right? In the medulla, guess what cortisol is doing, it’s pushing norepinephrine to epinephrine, right? So, in these patients, they’re already making a lot of cortisol even though you don’t see it in the saliva, even though you don’t see it in the periphery, in the middle of that adrenal gland, there is a lot of cortisol going on. And if you ramp that up because you’re looking at only part of the story, then, you know, they’re, a lot of times, are gonna get anxious and wired and whatever because you just, like, really jump-started their epinephrine production and yet they’ve already got [inaudible 00:52:44], right?

So, some of these stories get a little bit complex, but, again, I think it’s better to look broadly at the picture and try to figure out what’s going on rather than looking at isolated variables of, “Oh, just a TSH,” or, “Just a cortisol,” and trying to extrapolate. Because ultimately, we’re always guessing, right, we take all the information that we have and sometimes, we’re making very, very good educated guesses. But we never have comprehensive information and we don’t know what’s going on with your receptor, right? We don’t know what’s going on with all these different variables, so, you know, I think we look at the most information we can, we make the best decisions that we can, and we move forward with as much confidence as is appropriate for a particular case. And sometimes they get, you know, a little tricky.

Dr. Hedberg: Exactly. So, we’ve done a pretty good overview of hormones, and one of my favorite tests is the organic acids tests, I’ve been running those for about 14 years. And I think one of the biggest issues with that is number one, the interpretation that practitioners are getting from the labs that do the tests and then number two is, of course, how the practitioner is interpreting them in relation to the patient’s clinical picture. So, you’ve added some organic acids markers, and I’m really interested to know why you chose the ones that you did, and why you may have omitted other organic acids markers?

Mark: Yeah. There are couple of different layers to that. One is we already do what we do, so our biggest target was the things that fold into our story. So, for example, the pyroglutamate, right? If you have a glutathione deficiency, we talked about that, right, that’s gonna impact your estrogen metabolism. So, gee, wouldn’t it be nice if we had a marker for that? Now if I’m trying to methylate and I have a gross deficiency in B12 or B6, I’m gonna have a hard time making enough folate to methylate, right? So, wouldn’t it be nice to have methylboronic acid for a B12 marker, xanthurenic acid for a B6 marker? So, those, I think, relate somewhat closely to what we’re doing, and then there’s an area where our hormones that we’re measuring actually impact the organic acids. Then the biggest place that happens is in this tryptophan metabolism pathway.

So, and I’m drawing this out as I’m talking to you, so I don’t misstep here. So tryptophans get two main pathways, right? It’s got the serotonin pathway, which we’re more generally familiar with, but that’s only about 5%, okay? And then it’s got the kynurenine pathway that we’re less familiar with, but that’s actually where most of it goes and where is it heading, it’s heading towards NAD. So, if you push excessively down the kynurenine pathway, you’re robbing the body’s availability of tryptophan in order to make serotonin and that could be a problem.

Now, what pushes tryptophan away from serotonin down that other pathway? Cortisol and estrogen. So we often talk about cortisol’s relationship with depression, right? This is actually a causal, like, core of how that happens, is the cortisol up-regulates this enzyme and tryptophan is going in the other direction, and now what’s left for the brain to make serotonin is lower. Now, in that pathway on its way to NAD, there is a left-hand turn that it can make and that is towards xanthurenic acid. So, xanthurenic acid is just hanging out there, you’re making a little bit of it, but the next step in the process needs B6, and it’s really sensitive to B6. So, when you are B6-deficient, the tryptophan will take a left-hand turn, it’ll make lots of xanthurenic acid. So, it gives us a kind of a picture of what’s going on here, but the thing with xanthurenic acid is it tells you you’re B6 deficient, so it’s a marker.

But it’s also toxic because xanthurenic acid complexes with insulin and creates insulin sensitivity. If you take a rat and you feed it xanthurenic acid, it will get diabetes. Like, it’s that, it’s potent in terms of its impact on insulin sensitivity, so now there is this connection between excess estrogen or excess cortisol, and a B6 deficiency and, potentially, insulin sensitivity and, potentially, a serotonin deficiency. So these things start to connect and what we’ve been doing as a lab industry is saying, “Here’s your silo over here called ‘organic acids,'” and, “Here’s your silo over here called ‘hormones,'” and the two don’t talk to each other. And that’s what we’re trying to do, is create a test that has the most relevant impactful markers, but also those for which there is the most proof, to say it bluntly. There is good research that says if you are B6-deficient, xanthurenic acid goes up. If you give that person B6, it comes back down. Like, that’s really nice.

If you have a B12 deficiency, methyl malonate goes up, there is good research on pyroglutamate and glutathione. So, we’re looking at those three, but you asked me which ones I don’t do. One, we’re trying to keep the test reasonably simple so people can understand it. We’ve also been working on an extension panel of other organic acids, you know, Orotate has got some nice applications, some of the fatty acid markers and some of those. But there are also some for which, for me, there just isn’t enough evidence that they matter, right?

So, an example I would give, and I would be open to a rebuttal, but, is hydroxymethylglutarate. So, hydroxymethylglutarate is…I think I counted it on a pretty detailed pathway. It is 14, I could be wrong with that number, 14 steps ahead of CoQ10, right? So, an organic acid lab will tell you if hydroxymethylglutarate is elevated, then you must have a problem creating CoQ10 from hydroxymethylglutarate and you need CoQ10, right? If it’s low, then our conclusion is, well, there must be something stopping it upstream, you also need CoQ10. But when you look through the literature, I mean, 14 metabolic steps, that’s a lot, right, like, you can get…I’m pretty sure you can get from cholesterol to estrogen or testosterone or cortisol or progesterone in 14 steps, right?

So, there’s not a direct line between the two, and the reason that particularly one is of interest is because that’s right where statins work, right? Statins stop hydroxymethylglutarate, they will jack up your hydroxymethylglutarate and you will have a CoQ10 deficiency. So, you can even put together some nice case studies, but in the absence of a statin, is this precursor that’s way upstream, elevated, and I don’t mean to get off on this for a long time, but, you know, is it really a marker of CoQ10 deficiency? I wouldn’t say that I’ve seen any evidence that in the absence of a statin, it’s a solid marker. So, I’m putting less evidence on that and, you know, what, would we add that in an extended panel? Maybe. Same thing with citric acid cycle intermediates, they’re interesting, but if you think about them, you know, up above them, feeding into them, you have food, right, the stuff that you consume goes into the citric acid cycle, which is different every day.

And then out the bottom end of it comes energy, and those things are pretty variable. So when I tested myself for 20 days in a row, I went, “Oh, wow,” like, “My numbers are all over the place, but that kind of makes sense because it’s not a static sort of thing.” But what you do within that is you say, “Okay, I make isocitrate, isocitrate moves to alpha ketoglutarate.” Okay, that enzyme needs magnesium, so what the logic of what some people do with this test is say, “Well, if I have high isocitrate, I must be magnesium-deficient, and if I’m going to push isocitrate more readily to alpha ketoglutarate, I need more magnesium.” And that, again, like the ones that would prove that magnesium is involved in what, like, hundreds of different enzymes, and an elevation at any one of those steps doesn’t necessarily mean anything about your magnesium.

So, I think we need to be careful about the points there that are extrapolations because there still could be some relevance. But it’s a completely different than xanthurenic acid, MMA, you know, formiminoglutamic acid is another good one, we don’t measure that one yet. We’re kind of working on it, it’s a great folate marker. And there’s good research that says, “Hey, when you’re folate-deficient, guess what? This thing goes up.” So, if it’s up, you might want to get some folate. There is a lot more substance to that, so we picked three nutrient markers, B12, B6, glutathione, and then the three neurotransmitter metabolites, the serotonin, dopamine, and epinephrine, norepinephrine metabolites.

Dr. Hedberg: Yeah. I’ve always used the organic acids for identifying insulin resistance, inflammation, branched chain amino acid metabolism. B12, like you mentioned, B6, glutathione, and the neurotransmitter metabolites. That’s mainly what I’ve used it for, also the ketone metabolites have been helpful, as well, but those tie in with insulin resistance. I’ve never used it like it’s promoted to identify things like CoQ10 deficiencies, carnitine and things like that.

Mark: Well, I’ll be honest with you. I was involved in organic acid testing, you know, previous life. And we’re giving people customized supplementation recommendations, which was essentially everywhere magnesium is used, if you have an elevation, we’ll just gonna add some more magnesium on, right? It was totally ridiculous, right, totally inappropriate use of that information. So yeah, I’m right there with you, you got to be careful about the conclusions you draw and drawing these sort of specialty, you know, supplementation protocols based on things that are just loose associations.

Dr. Hedberg: Right, right, that’s exactly right. So, just lastly, the neurotransmitter metabolites. So it’s kind of a controversial area, and I’m definitely one of the people that is extremely skeptical of urinary neurotransmitters and those are very prevalent in the functional medicine world. And the organic acids, though, is a different picture because we’re looking at different metabolites of those neurotransmitters, so do you have anything you wanna comment in regards to those markers?

Mark: Yeah. I mean, I have skepticism, as well, in terms of whether a neurotransmitter measured in your urine is a good picture of the other side of the blood-brain barrier. You start looking at studies for these things and you start seeing these studies on cerebral spinal fluid measurements of, and you think, “Well, gee, why would you go to the trouble to measure someone’s cerebral spinal fluid if you can just take a urine sample, right?” And the problem is that it’s not the same world, right, they are different worlds. And so I think there is limited utility, but they’re still interesting, so for, like DNA, for example, is the metabolite of norepinephrine and epinephrine. That’s interesting because most of your adrenaline, noradrenaline stuff is going on in your adrenal gland. And it’s this systemic picture and VMA is a picture of that and guess what, it’s higher in people with depression, right?

So, there is an interesting connection there, but is it a perfect picture of what’s going on in the brain, no. I think that one’s pretty good. HVA as a measure of dopamine, I’m still kind of looking at that one a little bit. That’s supposed to be more of a central, not peripheral, but more central, like, in the brain, look at kind of what’s going on with dopamine. And I’m still kind of digging through the literature on that one. It is interesting in that you’ll see it higher in certain cases where it seems like there is an issue on the dopamine side of things. 5-hydroxyindoleacetic acid, that’s the third one we do, that’s a serotonin metabolite. That’s one where, you know, I look at that one with a pretty big grain of salt because it is interesting. It is a good reflection of overall serotonin, but we have all this serotonin made in our gut, right?

So, if most of the serotonin is coming from your gut and then most of that goes to this metabolite and that’s what I’m measuring, does that tell me what’s going on in the brain? No, I mean, it doesn’t necessarily, but if there’s a deficiency systemically in serotonin coming from tryptophan, is it worth barking up that tree a little bit considering 5-HTP, like, absolutely. Do we see cases where there’s some intellectual connection there worth chasing down? Absolutely, but it is not an A-plus marker, to me, it’s, you know, I’d give it a B-minus probably, because of the difference between gut production and brain production. If I’ve got a patient who has a brain deficiency in serotonin, let’s say, and then the next day, they get a bunch of gut inflammation, and their gut, like, an irritable bowel, that kind of stuff, you get more serotonin made in the gut, right?

So let’s say there’s a flare-up of that and then there, you could theoretically mask this serotonin deficiency in the brain easily by all of the serotonin that’s being made in the gut, right? And what do we see, we see this sort of combination of all of it, but most of it’s coming from not the brain, right? So, like, it’s interesting and it’s definitely worth your consideration.

For us, we added all six of these organic acids without changing any of the prices of our panels. So I don’t at all have a problem saying, “Look, some of these are A-plus markers.” MMA, xanthurenic acid, I think, are great, pyroglutamate’s slightly behind that, VMA, I think, is very good, HVA, I’m still kind of trying to figure out a little bit, but I think it’s a decent marker. And then the 5-hydroxyindoleacetic acid is, like, this beautiful little thing in theory, but it’s just kind of okay. Like, it’s just a decent look at your overall serotonin production, but it does not give me a picture of what’s going on in your brain. And we need to be, I think, more realistic about that because, you know, we don’t want people following that as if it’s gospel truth and really hanging their hat on it when it does have some, you know, some caveats there.

Dr. Hedberg: Right, right. So, this has been really good, very comprehensive. I think our listeners are gonna have a lot to take home and think about. So, I’m going to make a transcript of this and post it on drhedberg.com for everyone, and I’m gonna link to any of the resources we talked about today. So, Mark, how would you like people to find you online, is there anywhere you’d like them to go?

Mark: Yeah. You could find all of our stuff at just dutchtest.com. So, D-U-T-C-H, and, again, that’s Dried Urine Test for Comprehensive Hormones for those of you who have missed kind of what in the world that name is. So it’s dutchtest.com, and we’ve got a whole suite of videos, a video library that you can look at to answer questions about, “How the heck am I supposed to monitor hormone replacement therapy when I take it this way, when I take it that way,” different things like that, and just general resources on hormone testing. We are pretty narrowly focused. So, I always tell people, “I’m an inch wide a mile deep,” so it’s just hormones, hormones, hormones, that’s, you know, and we’ve, of course, added some things that fold into that. But that is our main focus and we hope to be a resource for people on just, you know, how to do that well. Whether it’s using our test or others, you know, saliva and serum testing have appropriate applications and we want people to apply them appropriately. And when our test is the best option, then, you know, we are here to help them get that, but also help them make sense of all this stuff.

Dr. Hedberg: Well, I appreciate you coming on today, Mark. I appreciate your time and all the information that you’ve given to us.

Mark: Yeah. I’m glad to be here and happy to chat with you, so we’ll do it again someday.

Dr. Hedberg: Definitely, definitely. So for all the practitioners listening, I highly urge you to, if you’re not already using the DUTCH Test, I highly recommended that. I’ve been using it since it came out in 2012, so about six years now. And if you’re a patient listening, you definitely want to discuss the DUTCH Test with your practitioner. If they’re not doing it, try and get them to start running this test. Because the amount of information that you get is just so far beyond any other types of hormone testing that you’re gonna get out there on the market. All right, so thanks for tuning in, everyone. Go to drhedberg.com and I will post everything we talked about today. All right, take care, everyone, and I will see you at the next podcast. Take care.

You can learn more about the DUTCH test here:

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