Written by Christopher Kelly
Nov. 28, 2017
Christopher: Hello and welcome to the Nourish Balance Thrive Podcast. My name is Christopher Kelly and today I’m delighted to be joined once again by Mark Newman. Hi Mark!
Christopher: Mark is the founder of precision analytical who are one of the lab companies we’ve been using to do deep-dive investigations on the athletes we work with as part of our Elite Performance program. I’m super excited to have you back on again, Mark. Last time we spoke, you described your knowledge as being an inch-wide and a mile-deep on hormones. Would you say that that statement is still true?
Mark: Yeah, we’re trying to get up to 2 inches so we are exploring new things but they all intellectually fold in still to the hormone mill use. So no, I’m still digging deeper on the same basic subject matter so there’s a lot there.
Christopher: The main test that we’ve been using is your urinary hormone and metabolites test which has been fantastic for us. Can you talk about how you got into producing that test?
Mark: Interestingly, it’s sort of the combination of everywhere that I’ve been intellectually in my career in a sense of doing 24-hour urine testing and saying “Okay, what do we like here?”. I’ve got all these metabolites, that’s great. But nobody wants to do the test because it’s rather cumbersome and difficult. And I don’t have a picture of one really important thing and that is the pattern of cortisol throughout the day.
So, then I went on and directed someone doing saliva testing and then other sort of testing and then you’d get this wonderful looking saliva of the up and down pattern of cortisol throughout the day. My collection’s a lot easier but I’ve given up all those metabolites which I had come to depend on because I just make better decisions when I have 8 estrogens instead of 1, when I had the whole family of androgens instead of just the testosterone value.
So, what I did is develop a testing modality where you can kind of look at all that in one test. We’re drive urine collection so that’s why we call it the ‘Dutch Test’, the dried urine test for comprehensive hormones. And we collect 4 times throughout the day because the pattern of free cortisol is very similar in urine compared to saliva if you collect at the right times.
And so we do that, we get a nice free cortisol pattern and then we get to expand from there and look at all of the metabolites to go with this parent hormones, so it’s androgens and metabolites, estrogens and metabolites. And digging into that, we really started to see the value of the cortisol metabolites as a better marker that the free cortisol for simply asking the question: how much cortisol are you making? How much is your gland producing?
And so, that started to give us a much richer look at what’s going on with the cortisol, particularly in cases like thyroid cases and obesity where cortisol clearance gets messed up. Your cortisol clearance gets messed up. You need to look at free cortisol and the metabolites to get an idea of what’s going on with the patients’ cortisol.
So from there, we have kind of our basic model which was really great because it was easy to do, you get all this data. And then, we’ve just been adding on to the picture from there. And that’s one thing nice working with a urine sample. It’s that there are markers for a whole lot of different things in urine that you just can’t see in a saliva or even in a blood test. Obviously, there are a gazillion things you can test in blood, but when you get into the hormones, the urine has got a lot of nice things that you can measure.
So we added recently then, 8 hydroxy deoxy quintozene which is your oxidative stress marker. So, when you got DNA damage, that ties in with both the estrogens and the cortisol. And then we’re looking now to expand it even further. We’ve added… I don’t want to get to off on rabbit trails just yet although we’ll go there but one of the pieces that was missing from all of that is the cortisol awakening response which is a unique window into HPA access function.
And how do you do that? Well, you need a saliva sample right when you wake up. And 30 minutes later, and 1 and 30 minutes after that and then so on throughout the day. And so, we’ve added a combination for that with the urine metabolites to give an even bigger picture of what’s going on with cortisol. And now, we’re exploring some other markers as well that we want to add. That’s what we’re all about. It’s just how many pieces of the puzzle can we add in that connecting one another. And then there’s this big process of trying to distill that down in our reporting so that doctors can very easily go through our report and see what clinically important information there is there. So, we’ve been up to a lot but it’s been really fascinating learning about all the interconnectedness between some of these different systems.
Christopher: Let’s use the answers in outline to this podcast and then I’ll drag you back and let’s drill in a little bit deeper on some of the things that you said. The first thing you talked about which I think is very interesting and interestingly, we very rarely see, maybe any 1 or two cases per year, I would say. And that is how cortisol becomes dysregulated in obesity. Can you tell us about that?
Mark: Sure, yeah. With obesity, there’s this interesting very general connection that even laid people off and no, because you listened to commercials and they say “Hey, cortisol makes you fat”. There’s this connection between cortisol and obesity which comes from way back when of like you’re just looking at a disease which you’ve a tumor that makes all this cortisol and these people tend to gain weight. So, there’s this general connection between cortisol and weight gain. But when you look at the data, when people get heavier and heavier, they don’t actually have higher levels of free cortisol. They tend to stay about the same.
But what you do get is you get this increased cortisol production and if you think about it, you’ve got a lot of adipose tissue, fat is really good at sequestering hormones. So with cortisol, the way that ends up working is it ends up getting sequestered and then metabolized and the cleared. And so, your adrenal glands is like “Great, you just stole my cortisol, I guess I’ll make some more”.
And so, it ends up making all this cortisol but it ends up in the form of a metabolite in the toilet. So you’ve got this person cranking out all this cortisol yet their brain and everywhere in the periphery doesn’t have higher levels of cortisol that’s a sort of compensatory mechanism, but there are consequences to that to get a little bit complicated in terms of you’ve got some hyper-cortisol symptoms, but you don’t really have higher levels of free cortisol.
And so, what happens a lot of times in this people is the free cortisol might end up being low. And so you say oh gee, this person doesn’t ‘make much cortisol, yet they’re pumping out tons’. So then, you go in and treat them like they have ‘adrenal fatigue’ and you ramp up their cortisol production and then you’re not going to help the patient well because their problem is not defined so simply by just their free cortisol.
So that’s why we like to look at free cortisol and the metabolites because you get this very consistent picture of elevated cortisol production and the free cortisol can be low, it can be normal, it can be high. It’s not really changing based on the fact that you happened to be obese, does that make sense?
Christopher: It does. And so, that’s the genius of the Dutch Test. It’s that you need urine metabolites in order to make this diagnosis. If you did a saliva test or if you did a blood test, you wouldn’t be able to spot this pattern, correct?
Mark: Right. So in saliva, you get a really, really good look at free cortisol but it’s only 1% of the total. It’s the most important fraction for telling yourself “Hey, how much cortisol is in my brain? How much cortisol is getting into the tissue?” but when you want to ask how much cortisol am I producing, that’s a different question and you need a different tool for that. And those metabolites represent about 80 percent. I just always describe it as it’s the bucket that catches all the cortisol that you make. At the end of the day, where does it end up? In your bladder, as a cortisol metabolite and out it goes in your urine.
And so, if we measure that and free cortisol, then you can see disturbances in the diurnal pattern. You can see disturbances in the free cortisol. You can see disturbances in the overall production of cortisol and that is a better way to just make more confident decisions about what you need to do with somebody.
Christopher: And I can tell you that the patent that we normally see in the athletes that we test is the hypothyroid under-retained pattern where you see normal or even low total cortisol production. And then the sluggish is really, really clear. And so now, at least the free cortisol on the high or even above your optimal reference range. And then when we look how swear on the blood chemistry, we see weirdness on the thyroid panel. So in particular, it’s a very, very low PT3.
And so, what’s interesting about this is you look at thyroid panel, you saw this person and you think “Oh, this might be hypothyroid”, do you have any of the classic symptoms. But then, you can also look at the Dutch and say “Okay, well this is not what we’re expecting” so can you talk about how thyroid function affects cortisol clearance?
Mark: Yeah, there are a couple of touch points between cortisol and thyroid. And the one that’s not that well known and it’s getting to be better-known because we’re highlighting this is that there’s a direct relationship between your ability to clear cortisol which is a liver thing and your thyroid status. So there’s a nice paper, it’s actually pretty old where they look at thyroid levels and they look at excretion of cortisol metabolites and it’s an amazingly strong relationship.
So, as your thyroid gets ramped up, you’re going to have lots of metabolites and not that much free cortisol. I tested a girl once and I think her thyroid was 4,5 or 6 times the reference range. It’s like hyperthyroid. And if you just look at her free cortisol, you would think she had Addison’s disease. You look at her and she does not make any cortisol then you look at the metabolites and they were super high. So this whole think makes sense, right? You make cortisol and the second you make it because your metabolism is so up-regulated, it just zips it down to a metabolite and out it goes into the toilet and it’s gone.
So, you are effectively hypo cortisol but the issue resides in your thyroid. Now, that’s not that common of a problem. We see that in the occasional person who’s overdosing on thyroid medication but what is more common is that you’re describing is someone who’s got the opposite problem which is low thyroid, sub clinical… you know, this slightly sluggish thyroid sort of an issue. And what you get is you get this downregulating of your body’s clearing or cortisol.
So, the first thing you’d see is that cortisol metabolites go low. And then if it’s more pronounced, you can actually see in come cases the free cortisol be elevated. So the narrative there is that it’s elevated, not because you’re making too much but because your body lacks the ability to get rid of it, appropriately so.
There’s been this long time belief that comes from this same sort of thinking along the lines of adrenal fatigue and this hyper focus on adrenal says you fix the adrenals, and then you fix the thyroid. But in the case like that, it may make a lot more sense to say “look at the thyroid driving my cortisol pattern”. Perhaps, you deal with that and then you reassess the adrenals you may find. And there’s studies where they’d done this. They’ve taken people without thyroids and as they start to give them thyroid medication, you see this clearance of the cortisol pick up.
And so, knowing that information really helps, particularly if you’re dealing with people who have both HPA access and thyroid issues concurrently.
Christopher: Yeah. It fits into that overall picture. It helps you form its overall impression. I should tell you that if we’re hyper focus anywhere, it’s not specifically, really on the adrenal glands. It’s on Circadian Rhythm. And I feel like that’s where most of the benefit comes from; from doing this type of testing for us at least. And that’s to be able to see the overall pattern of cortisol and of course the melatonin, last thing at night.
And what we quite often see is this regulated pattern and maybe cortisol is maybe way, way higher in the evening and perhaps that’s because somebody has been training after work or they can’t put the laptop down or whatever it is. And so, that’s the nice thing about the Dutch. It continues to keep that pattern, right? You would lose that if you just did a 24-hour urine test and just go to the metabolites.
Mark: Right. And having a flat cortisol pattern is associated with a lot of negative outcomes.
Christopher: I think that’s a really good Segway then, into the cortisol awakening response. And we’ve been looking at the literature with interest. And I know it’s now a part of your testing panel. We’ve not been doing any of them yet. Can you talk about the cortisol awakening response?
Mark: Yeah. We were somewhat reluctantly getting onboard with this because it’s hard to do the collection, the way that people classically do saliva. So we came up with a solution of that but essentially, when you look at the regular Dutch, we would look at all this variables, right? I want to know how much free cortisol you have throughout the day. I want to know what it is at different times as you mention the Circadian Rhythm. I want to know the total of the metabolites and the balance of the metabolites. Do I have more cortisol, more cortisol than metabolites? That’s like 4 different variables if you will, all that play in this sort of question of what’s the shape of my HPA access. But the cortisol awakening response adds a really critical one.
And what it looks at is “What would you want to do with cortisol?” If I was in an ideal world, I would bring you into my office and I would test your cortisol and then I would stress you. Punch you in the nose, have a bear chase you around, whatever. And then I would test your cortisol again and I would see the change like how are you responding to stress? There is a way to do that and that’s what the CAR, the cortisol-awakening response does. It says “Look, when you wake up and that light hits your eye, is it simulates the stress. It is essentially a stress on the HPA access.
So, what happens is when you wake up, it takes about 5-10 minutes for the cortisol to leap up 50% or more and it takes about 5 minutes for that to find its way to the saliva gland. So then, if you wake up and immediately collect a saliva sample, and then collect another one 30 minutes later, what the research shows is even if those numbers are both within the reference range, the gap itself as an independent measurement is independently correlated to things like depression. So, there’s one study where they looked at that gap and then say “Okay, it’s your CAR” and then they said “Okay, who got depression?”. And it was predictive of who would go on to get major depressive and none of the individual points were correlated as well to your risk of getting depression which is a symptom of what? High cortisol, overacted HPA access that responds too much distress with cortisol being the causal factor, at least in part of depression.
So we said “Okay, we love to do this” but how do you collect the saliva sample in 5 minutes, that’s difficult. So what we did is we started using the cotton swab, that’s actually a synthetic cotton. But you just pop this thing in your mouth and in 90 seconds or 2 minutes, you’ve got ample sample. And so, by using that, we were able to create the cortisol awakening response test which wasn’t really available on the market.
So, what we did is we created it with the Dutch model is the cortisol awakening. So, you’re looking at the saliva, with these 5 points throughout the day, including waking at 30 minutes later. But then we’re also capturing the dried urine collection so that if you have high levels of cortisol metabolites, we’ll see that. And we can also look at estrogens and androgens and metabolites and all that to get this complete look at your hormones.
But essentially, it just adds in one more variable to the cortisol picture but it’s a really important variable and we’ve seen some really interesting patterns in people where everything’s kind of normal but when you zone in on that CAR, maybe it’s flat and their symptoms are fatigue and some of this low-cortisol symptom or it’s an exaggerated CAR. And again, if they’ve got symptoms of high cortisol, then you’ve got a little bit more to work with.
Christopher: Explain to me why I can’t see the cortisol awakening response in urine. So I have said that I can do this time for urine collection and see the pattern of cortisol, why can’t I see that cortisol-awakening response in urine?
Mark: Right. We get that question a lot. It’s a good question but if you think your way through it, in order to get a CAR, I need a baseline. What is the baseline? In saliva, the baseline is I wake up and I collect the sample. Fine, what does that represent? It represents that 2-5-minute period. If I collect a urine sample right when I wake up, that’s been gathering in your bladder for hours.
And so, it’s ‘while you were sleeping’ cortisol, not an awakening cortisol. So, that only way to do that would be able to wake up and urinate and then urinate again in 5 minutes. That would be the sample you want and that is not a practical sample obviously to capture. So, it has to be saliva. I mean, that’s why we really love the Dutch completely because it’s so simple, it’s just these dried urine samples but you have to have saliva in order to do the CAR.
And the ironic thing is it is this independent, really interesting and valuable information. But the saliva labs don’t actually do it for the most part because it’s challenging logistically because typically, it’s only logistical issues. They’re trying to get all these other hormones off that same sample so they need so much sample but you can’t collect it in 5 minutes. And if you use the cotton swabs, they absorb progesterone so it’s this kind of a funny limitation with saliva labs where they can’t do what is one of the more valuable things to do with saliva.
Christopher: Is that good agreement in the scientific literature on waking up or for being a real physiological stressor? I mean, it’s a bit of a head-scratch to me because it’s not something that happens every day. It’s completely normal. It’s not like exactly being chased by a tiger. And I’ve looked at some of our data and looked for correlations between morning cortisol both in blood and in urine. And glucose and insulin and C peptide. And the primary purpose of cortisol is to raise blood glucose and yet you don’t see it. There’s no linear correlation between any of those markets I’ve just talked about. So, it’s kind of a bit of a head-scratch for me. And cortisol is going up but blood glucose is the same. So, maybe there’s something else to the stress response of just cortisol. You see where I’m going with this? Do you think the waking up is really a stressor?
Mark: I think maybe there’s some semantics in there that it’s not exactly the same as being chased by a tiger. But what happens to the chemistry in your brain was very similar. But it’s a very unique event. If someone sat down who is a lot smarter than I am on that topic, like Tom Williams or someone who really digs into this stuff, they can talk for an hour on what happens when you wake up.
You got this super nucleus and you got ACTH and it’s actually quite remarkable thing where you’ve got ACTH starts to climb and you go “The cortisol’s climbing but not really as much as you think it should”, it holds it back. The body’s got this mechanism of putting the brakes on your cortisol until the light is actually like a causal agent in this whole thing of when the light hits the back of your eyes, all this chemistry starts happening. And boom! Your cortisol pops up.
And it’s a parallel to the stress in the sense that someone who would respond in an exaggerated way to a stress is going to typically respond in an exaggerated way with this cortisol awakening response. So, that’s kind of a parallel. I mean, it’s not entirely a parallel to an actual stress. But the other thing that you’ll see is if you have stress coming today. So if you have the anticipation of stress and anxiety, then that sort of thing will exaggerate your CAR.
So it can mean 2 things. If my CAR is exaggerated, it can mean 2 things. One, I got a lot of stress coming and you need to work on lifestyle. Right? You’ve got some stress. But the other interpretation is the stress is normal and you are responding in an exaggerated way to a normal stress. So then, what happens when you’re actually stressed is it’s going to be even worse. And that’s where you’re going to get excessive cortisol production and then you got the consequences of that of depression and maybe some blood sugar issues and all of those things.
So, the literature shows that it matters. The matter in which it parallels with stress is pretty complicated and I would not sit here and tell you that on the finer details of that that I’m an expert.
Christopher: I know you’re not a doctor but have you heard about how any clinicians are using this new data? So for cortisol rhythm, there’s tons of stuff I can do. So, a great night of sleep starts first thing in the morning. So the first thing I do when I wake up is I go outside and I expose my eyes to whatever light is available and maybe I’d go for a walk and I eat most of my calories earlier in the day, I do the opposite at night. I try and keep my work outs earlier in the day, I ate light at night. I’m trying not to use my laptop until the last minute. It’s what it means. So, there’s a lot of things I can work on in the lifestyle perspective and in training my Circadian Rhythm. But how does knowing the Cortisol Awakening Response change what I would do?
Mark: In the simplest form, as I look at it. It’s just another variable to ask the question “Is the HPA access overactive or underactive”. So in the sense, it hasn’t changed your treatment at all. It goes further like there’s more to explore than just that. But to boil it down to just gee, how do I use this pragmatically, when I see a low-flat cortisol throughout the day, I don’t care what your cortisol awakening response is, you’re low.
I had just tested a buddy of mine who’s going through some health stuff and some stress stuff. Every single thing that talks about cortisol is elevated. So I don’t care what is cortisol awakening response is, he’s on fire, right? But when you get into some of this more nuance cases where you say “Okay, I’ve got some depression”, whatever it is that’s related to cortisol, everything’s normal. Okay, now what?
Well, you can say the same thing of like “Why don’t I just look for a free cortisol?”. Well, if you don’t look at the metabolites in some cases, you’re going to miss something. Those variables each add to the story.
Christopher: I see.
Mark: So, if I was just trying to not confuse myself, that’s how I would look at it. But then, there’s also just this idea that if it’s a parallel to stress, and I test you on a day that’s relatively free of stress, then everything’s pretty normal. But that cortisol awakening response is somewhat exaggerated, then I might go with the narrative myself of saying “Well look, when you are exposed to stress, you’re going to over-react to his.” And if you have intermittent stress in your life or whatever and you’ve got some new-found depression or whatever it is that’s related to high cortisol, I think that’s a relevant finding.
And then on the other side too, if everything’s kind of sort of in the normal range, but that cortisol awakening response is pretty flat, are you really responding the way that you should be? And also, we have to keep in mind that this whole idea of screwing up your HPA access is a continuum. So if I got a high-stressed professional that is like me. I’m pushing 40 and trying to run a business and all of this.
So, if I’m seen a fairly normal pattern but an exaggerated part, I maybe wanting to work on that and say “Look, we need to work on so lifestyle things, but a prolonged life of how this looks may start leaving to some symptoms you don’t have today”. So, it just adds to the narrative of cortisol but I don’t think it takes and shifts your treatment in really a dramatic way. It just helps you to define whether that person is in a state of hyper or hypo as it relates to cortisol I think with a little bit more precision.
Christopher: It’s a good answer and you could take my argument to the next level. And say “Okay, why do the test at all?”. I mean, all the things that you just talked about, anyone can do that. Everyone probably should be doing that. So, why do a test in the first place? So yeah, I think that’s a really good answer.
Mark: Yeah. Well, I think that’s where you also understand that overlap of some of these things. I tested a friend not too long ago. She was like “Man, I think I’m hitting menopause”. She’s like 47 or 48 and she was sure that she was mentally wasn’t there. She had all these symptoms. And when we tested her, her estrogens were fine but her cortisol was problematic. And the opposite happens too, where you find someone who thinks they’re having mental issues and things in their cortisol maybe isn’t in that bad of a shape. But wow, they’ve got estrogen dominance and some of these other things.
And I’ve seen people a lot who are fatigued that have high cortisol. These are the people who just assumed “Hey, I read this thing on the internet. I have adrenal fatigue”. And for some of those people, it’s a little bit more complicated than that. They’ve got an exaggerated CAR. A stressful life and it’s burning them out. But you get surprised a lot of what’s going on with people when you test, for sure.
Christopher: Let’s talk about 8 hydroxy 2 deoxyguanosine. It’s my favorite, knowing the names of things, it’s not the same. So, my story with 8 hydroxy, 2 deoxyguanosine, it was one of those markers that I looked at in the very early days and it really annoyed me that I didn’t even know how to say it, let alone what it meant. And so, I spent a little bit of time trying to understand what it meant and I would encourage people listening actually, especially if you’ve tested this marker. Go and find out what the hell is 8 hydroxy, 2 deoxyguanosine. You couldn’t find out very easily by typing 8OhDG PubMed into the Google and you’ll find some very well-sited, very well written papers. I found 2 this morning that are being cited over 80 times which I think is quite a lot. Tell us about 8 hydroxy 2 deoxyguanosine. What persuaded you that it is a good idea to add it to the Dutch?
Mark: Well, it’s just another thing that I think in any patient, if that’s elevated, you want to know because it’s a marker of oxidative stress. So, when oxidative stress damages DNA, this is the result. The result is 8 hydroxy, 2 deoxyguanosine. So certainly, when people have active cancers and things like that, we tend to see elevated levels but people that we in search of people that actually have stress going on, they just don’t know it.
So, for them to search out causes of that and to deal with that just makes sense. But it touches the hormones. If you look at studies where they’d look at 8 hydroxy deoxyguanosine and cortisol, there’s a correlation. The higher your cortisol goes, the higher your 8 hydroxy goes. It’s not this linear relationship but it’s strong enough of a correlation that it’s worth tying the two together. The reverse is true with melatonin.
Melatonin’s got this wonderful antioxidant type of properties. And if your levels of Melatonin are low, your 8 hydroxy tends to be high. And obviously, Melatonin and cortisol have that inverse relationship. But there’s also the estrogen metabolite subject and that is if you’ve got a lot of 4 hydroxy estrogens, and it’s damaging DNA, this can be the result of that.
I haven’t actually seen a lot of studies where there’s a super strong correlation between those but there’s a conceptual connection. So, as we’re looking at estrogen metabolites and as we’re looking at cortisol and as we’re looking at Melatonin, it just makes sense to throw this in the mix as well. Because if it is elevated, it’s definitely worth addressing and if it’s super elevated, then you might have some more serious questions to maybe chase down a little bit.
Christopher: Yeah. It was a gateway biomarker like active protein for me and when you dig in to the literature, you realized this could be being caused by literally anything, right? It could be iron overload, it could be gut infection. It could be something that you’re not supposed to in your environment like some sort of toxin, you really don’t know.
And so in a way, it’s just the non-specific marker that tells you you’ve got some work to do. So let’s talk about some of the other. You know, when we saw this, the firs thing we thought is “Is Mark Newman going to do a full organic acids test?” and then just last week, you announced that you’ve added some other organic acids to the Dutch completely. Now, we’re really thinking “Oh, Mark’s going to do an organic acid’s test”, can you tell us about that?
Mark: Yeah. The idea here is just to continue doing what we’ve been doing which is to add conceptual pieces to this puzzle that adds to it. So, we’re not interested at this point in chasing down esoteric markers that have to do with completely different topics. But when you look at some of the connections between organic acids and hormones, there’s a lot of overlap there.
So as an example, looking at neuro transmitter metabolites. What does my adrenal gland do? Well, it makes cortisol. Well, that’s fine. Why is it called adrenal gland? Because it makes adrenalin, right? But we don’t have a window into adrenalin or epinephrine. Same thing.
So, epinephrine and nor epinephrine create what? DNA. The organic acid. And then the HVA is the dopamine marker and 5 hydroxy endoclitic acid is a serotonin marker. So, if you’re looking at the hormones and you also have a window into the neurotransmitter metabolites, and as I’ve studied it, I’ve been blown away by the number of really interesting connections between those. We’ve been talking lots and lots about cortisol and depression, right? Well, what’s the mechanism? How does cortisol create or cause if you will, how does it cause depression?
Well, one of the mechanisms by which it does this is it pushes tryptophan down the kynurenine. Well, what is that a problem? Well, because it pushes it away from availability for the serotonin pathway. So, if we can look at cortisol and we see an exaggerated car or we see a sky-high cortisol all day, and you see a concurrent, low serotonin metabolite, then that person, if they’re not depressed, then that’s something your probably can look into because it might be coming. And if they are depressed, then you’ve got 2 things you can look at.
One, is to deal with the high cortisol. But two, maybe you need to look at 5HTP or something to support that serotonin pathway because they’re deficient. And that mechanism right there is also influenced by inflammation. And it’s also influenced by estrogen. So, when you put someone on HRT and put them on estrogen, could you cause depression? Not in every patient but if you see the occasional patient where once you put them on estrogen, that serotonin metabolite dips, that’s something to think about, both in terms of dozing and supporting serotonin.
And then the story continues to expand in that when it pushes down that kynurenine, where is it going? It’s going to NAD. All that stuff is just going to get turned in to NAD. But it has to have vitamin B6 to do that. And if it doesn’t have enough vitamin B6, it takes a right-hand turn and it makes a zoantharian acid which is another marker that we’re adding. And this one is interesting in two respects.
One, it tells you that you need some vitamin B6. That’s easy. But the other thing is it in of itself is bad for you. The zoantharian acid conflicts the insulin and decreases insulin sensitivity. So now, I could conceptually give a woman estrogen to get rid of her hot flashes and decrease her insulin sensitivity because I don’t realize she’s B6 deficient. And decrease her serotonin availability.
So, if you’re doing a hormone test, me as a hormone guy who is greedy for information, I want to know those. So those are variables we’re adding to say “Look, we can look at your estrogen. We can look at your serotonin metabolite. We can also look at this is zoantharian to see if you have adequate B6 as well as methodologic acid to see if you’ve got B12. And those also tie into what the making of availability of folate. And if you don’t have enough folate, then you’re not going to be able to methylate your estrogen.
So, there’s all this tie-ins between estrogen levels, estrogen processing or metabolism. And then what happens to cortisol and serotonin availability. So, these connections continue and continue and so we feel like it’s our job to give you as many pieces of that puzzle as we can but then also work on creating sophisticated reporting so that we can distil it down in a way that’s really easy to figure out what the significance of all these findings are so that we can just help people.
Christopher: Yeah. So we’ve learned about the influence of inflammation on a kaurenoic pathway for quite a long time now. Did you see the Kelly Brogan posted some really interesting stuff that ended up in our highlight’s email series about how all the birth control can also push that kaurenoic pathway in unfavorable directions? I’m very excited to learn about that. Do you maintain some sorts of bibliography that people can go and look at?
Mark: I don’t think we have easy access to that now of putting together some of those things. So, that will be coming to these task, it’s about the literature support because we want to be heavy on the evidence-based side of all this. So for me, part of the limitation of the organic acid testing that’s done is some of those connections that they’re trying to exploit are really theoretical and has not much evidence. And I know we don’t need to get into this but hydroxy methyl glutamate is supposed to be a marker for deficiency. But I think I counted it once, 14 steps up from ten.
And so, we’re drawing this connection and this is elevated. This kokuten pathway must be blocked. And I’ve not seen a lot of evidence that says that actually matters. Certainly, when you give someone statins, it blocks it right there and it jacks up your HMG and you’re kokuten goes down, that’s fine. But in that this marker is elevated so this downstream metabolite is 14 steps away, must there for be deficient, there’s not much evidence for that. And I’m not those are all bad markers but there are some that are much evidence-based. And so, we’re trying to stick with those real meaty once where metomalonic acid, that’s elevated. You probably have a B12 deficiency. You know, and there’s really good literature that supports that, same with the zoantharian acid so we want to try to stick the real solid markers there. But also those for us that are conceptually tied in to what were already doing with the Dutch test.
Christopher: My concern there and I’m sure we’re contributing to this, it’s that some analytical chemist, some lab has an idea and they realized they’re able to add a marker to a panel and so it becomes. Clinicians, they start running the test and they agree with the recommendations and they make it and they see improvement. Maybe they’d do a retest and they see improvement.
And then the literature never finds out. So, if you’re new to the game, and you’re just going to do a pop-med search maybe you would never know this. So, the data and the knowledge is out there, it’s just not on pop-med.
Mark: Right. But then, there are also some where the connection is illegitimate. And I’m not saying this is a wide-spread problem but if something has not been proven out, then there needs to be hopefully overtime. We’re looking at these connections enough that it becomes evidence-based whether it’s in published literature or if it’s somewhat anecdotal, that has some value. But those are questions that we as an industry… and I think that pressure should be on us as laboratory providers, that if we’re espousing some particular theory that relates to that, then long term we’ve got to continue to dig in to the data and make sure that those connections are actually legitimate whether it’s some marker for just biopsies or nutrient deficiency or whatever. Some of those are well established in the literature and some of them are theoretical connections that are interesting but there’s still work to do on the front.
Christopher: What do you think about doing some experiments? So obviously, you have sat on an enormous pile of data and you are uniquely positioned to add some of these speculative organic acids to your panel. Could you not do some experiments and then contribute to that scientific literature?
Mark: Yeah, you know long-term, how we would like to contribute to the scientific community, we’ve been in a mode of trying to add a picture at a rate at which that hasn’t really been feasible for us just from our time and resources’ standpoint. So, in the meantime, what we’ve been doing is a lot of anecdotal things.
For example, you say okay, let’s take something like dim effects or metabolism. Well, we know that in the literature. But if we didn’t know that in the literature, we would still be fully confident of that here because we’ve taken dozens of people who have poor estrogen metabolism patterns, put them on dim and tested them afterwards and said “Okay, yeah. There’s a connection here. This is working”. But I’ll also give you an example from the other side and that is when we look at estrogen methylation. It’s a legitimate thing to monitor, but when you address that with methylation support, it often does not move the meter. Estrogens are difficult to methylate. Sometimes, people approaches to increasing methylation are unsuccessful.
I’m a perfect example. I’ve got e genetic defect which means I’m a really poor methylator. And some of the steps I’ve taken thus far have not improved that at all. You know, the connection between methylation and what the estrogen metabolites tell you is legitimate but the intervention sometimes that we’re running with, still needs to be better characterized in terms of what works when and that sort of thing.
Christopher: Yeah. I mean, I would love to join you on some projects to do some experiments. So, I’ve got one MD PhD, Tommy Wood. He’s finishing up in the University of Washington in the Spring of 2018 and then of course Megan who just had part of her Master’s thesis published in the journals of metabolism. Both those guys are keen to an hour of working with clients but they’re keen to continue doing science. So, if you have any experiments that you like to do, we’d love to be a part of that. Part of writing and getting it published.
Mark: Yeah, we’re always interested in collaborative works. I mean, it’s not that difficult to set a small experiment up where you’re looking it before and after, some sort of interventional treatment or what have you. But yeah, for researchers that are interested in doing that, we are definitely very supportive of that.
Christopher: Talk about other markers you might be testing in the future. I wonder whenever time you go to a conference, you get a whole bunch of doctors dry-humping your leg asking you to measure the next thing that they’ve just read about some brand-new piece of science. Is that the case?
Mark: Figuratively, yes. We do have those conversations with people. There are lots of things we’d like to measure. One thing you’ll notice about our test is as we’ve added markers, we haven’t adjusted the pricing. So, our goal has been to do things that are logistically feasible. We have some really, really talented chemists here who are able to set things up in a way where as we’ve got increased efficiencies as we’ve grown instead of growing our margins, what we’ve done is we reinvested back in to the task itself by adding first melatonin, then the 8 hydroxy and now the organic acids. And then we’ll continue to explore some of those.
But there are some whole other families of organic acids that I think could make sense. Then I don’t want to tick my hand too much but I’m not entirely sure. At this point, where we’re heading… and I’ve spent a lot of time getting feedback from people because I do want to know what people find valuable.
The feedback we’ve got from adding the 8 hydroxy has been overwhelmingly positive. And you can go do that in other labs and spend a hundred bucks just to get that value. And because the way we’ve set up our system, we are able to add that and just live the price alone. And so, that’s where our focus has been.
But there are a whole lot of other markers that you can look at. But the other thing too is some of the markers just creates noise. There are other cortisol metabolites we could add and somewhat esoteric, random androgen metabolite but you’re going to dig through and explain to your patient what it means. Sometimes, it doesn’t mean that much.
And so, our goal has been we want to add value, not noise. There are some things that we will explore and look at and say “You know what, there’s not enough value because we also don’t want it to take an hour and 15 minutes for you to go through the report before you even meet with the patient. So, we want to keep it relevant for sure.
Christopher: Yeah. And that would be my criticism of the great plains organic acids that we’ve been doing. It is rather noisy and yeah, it could be trimmed down. I don’t think that all the markers have much value as some of the ones that you’re talking about today. I’m really interested, one of the things I heard you say on a really good interview with Dr. Kara Fitzgerald, I’ll link to everything that Mark has been talking about. I’ll try and find as many of the studies that he’s mentioned as possible. I’ll link at all the show notes.
I listened to this interview this morning with Dr. Kara Fitzgerald. In that interview, you said that your interest was making lab testing as cost-effective as possible. My question to you is have you investigated any machine-learning techniques that maybe able to reduce the number of things you need to test with that aspect?
Mark: Well, I’m an SPEC guy so be careful where you’re threading there.
Christopher: I knew I was walking on thin ice here but I figured it might make a more interesting interview.
Mark: So, you have a couple of different ways to test things, right? Everything we test is relative to creatinine, right? Creatinine is not a hormone. It’s the easiest thing in the world to test. It’s just little color metric thing. Not very many things have a color metric test. So then, you’re left with that? You’re left with things like amino assays, lots of hormone testers have done that. And then there’s MASPEC.
So, if you go to the county fare and somebody’s there and can do a cholesterol test and can give you a result right then and there, those are amino assay type tests and those work for things that are simple and things where there’s a lot of it. So, it’s harder to do that for some of these more esoteric things. For example, if I’m going to build an amino assay test for estrogen, I might be able to get that sensitive enough to say “Hey, now I can test saliva or maybe I can do that right here and right now”. Maybe that’s fine but there aren’t antibodies for 4 hydroxy estrogen. There aren’t antibodies for cortisol metabolites but then you also get your sacrificing accuracy if you do that.
If I take a saliva test, and I’m not bashing out saliva, that’s an example. You’re using an amino assay. If you add a boatload of estriol to that sample, it will increase artificially the value for estradiol. I’ve seen a case where a woman put estriol facial cream. Her estriol went from say 20 to 25 hundred. Well that’s fine, you can just explain that way and say that’s because of her facial cream. But her estradiol went from like 2 to 12. And that was not real. That’s a cross reactivity because you’re not using MASPEC.
So, I’m a MASPEC guy. I think that increased accuracy is worth the money because you’ve just get the wrong answer because of something random like that, less often. And providers are not educated. I mean, they’re brilliant, yes. But not in analytical chemistry. So, when providers see that estradiol of 12 which is really high, they just think “Oh crap, I’m giving you too much estradiol”. And no, you just have a test that’s not accurate when there’s a truckload of estriol and that’s the case for this patient and you got a bad lab test.
For me with MASPEC, I don’t think you’d be able to compete with the accuracy with some of those more cost-effective test but there are some scenarios where you know, if I can go pay 4bucks sand get a cholesterol, there’s no reason to use MASPEC for that. But for hormones, in the current state of technology, there really isn’t a good way to do it if you want more than basic information. There’s nothing wrong with a blood estradiol, testosterone, progesterone by just a regular lab test. Like that’s fine. If you want to do that, fine. Save your extra bucks and do that.
But if you want something more comprehensive where we’re looking at this families of hormones and these esoteric markers, there’s just no other way to do it probably in this generation.
Christopher: That’s an excellent answer and thank you for that knowledge. But my intention was to walk on far thinner ice than that. So you know, me being a computer scientist, I’ve been playing around with some of this stuff. My assumption, I think it’s a pretty good guess that if you were to give me a thousand examples of your cortisol awakening response, along with the other cortisol and maybe some other metabolites from the Dutch test, I think I would be able to train and build a model using machine-learning techniques that would predict the cortisol awakening response.
Do you see what I’m saying? So you would steal those test, the cortisol in the usual way that you do with the Dutch. And you still give that additional information on the cortisol awakening response but rather than measuring it directly with the saliva swab, I build a model that has a known sensitivity that will make that prediction. And so, we’re doing the test in silicone rather that with MASPEC’s.
Mark: Yeah. All the best of luck to you. I mean, if you look at the one paper that I talked about with one major depressive disorder, they did that. They looked at the CAR and they looked at the other data points throughout the day, and they said “Okay, what correlates?” And even the individual points that make up the CAR didn’t correlate to the degree that the CAR did to the risk for going on the development of major depressive disorder.
So, when you say independent clinical value… but having said that, that’s for us why we’re into so much analysis, right? I want the whole family of estrogen. I want the organic acids. All this stuff because you start to be able to predict a few things like that, if you’ve got this particular combination. But yeah, I think there are ways that you can get better information out of the same data but there are also markers that say “If you want to predict that I’m not methylating my estrogens well, you can do that with a genetic test and you can guess and you’ll be right a lot of the times. You can look at some other markers of methylation and project it onto estrogen, then you’d be right a decent amount of the time but you have to have markers for something to look at this stuff and I think what we’ve tried to do is take each variable and see what’s the best way to look at it. You know, I want to look at my estrogen, fine. I want to look at phase 1 metabolism, you’ve got that. I want to look at methylation, that’s fine. But at the same point, there are variables that we don’t have and that’s where we continue to look and dig and try to add things in a cost-effective way so that you don’t have to go out and do a bunch of other tests because you know what, if I can give you cortisol awakening response and all that other stuff and it’s in the same ball park price-wise, then I think we’ve done a good service. And if you are able to create something that’s even more sophisticated than predictive, then hey, I’ll tip my hat to you.
Christopher: Yeah, I think it’s probably a far more sophisticated technique than you’re used to seeing in the literature. There’s not many linear correlations in my data. So, if you’re looking for a good linear correlation, you’re not going to find it. I’m talking about a model with many, many more parameters. I’m talking about convolutional and deep neuro networks. I’m talking about boosted decision trees, these non-linear learning techniques. And for holding out, what you can do is “Okay Chris, I’m going to send you a big chunk of data and then you could hold back 20% of it, not even send it to me. And then, I can send you my model and then you can validate on the held-out data and then we can be able to calculate the F1 score, and you would know how good it is. And then maybe, we could use that model.
And we can say to people “Okay, we didn’t really do the test. Here’s the sensitivity. Here’s the specificity. You have to decide on the value with this but we’re having that much more information with keeping the cost down.
Mark: Yeah, and it really just depends on… I mean, it’s really all about changing your level of confidence. Because even when I have a lab test that says you have high estrogen, you might not have high estrogen. But maybe you’ll have a flareup one day because of some weird thing. Or maybe, just one estrogen metabolite happens to be high. Well, that’s the only one you measure. Then, that’s all you’ve got to work with. That’s why we like as much data and it offers much time. Like the Dutch test, it’s essentially a 24-hour equivalent because those samples represent hours and hours of time at different points of your day.
And so, we’re just trying to increase your confidence. But you know, if I take a hundred of people and I measure their estrogen in urine and blood, those are both really good measurements. But you know what, when you look at that scatter plot, there are a few where they don’t correlate. Why? Well, they’ve got some weird chemistry. Or they’ve got some weird clearance or something weird going on with their blood. And even though there’s really terrific correlation and both are perfectly legitimate tests, ultimately, we’re always just trying to guess as best as we can when we’re taking about the types or conditions we’re talking about.
I mean, if you have a tumor, that marker for tumor is going to be definitive for that particular thing. But when you’re talking about HPA access dysfunction, what happens during that day impacts some of the results. And there are many things that can impact these things and that’s again, why I think the more markers you have and then put in a format where you can easily digest it gives you the best chance at making the right decision for those patients. But the end of the day, I don’t know what your receptors are doing. You might have perfectly normal cortisol and a down-regulated cortisol receptor. Well, I don’t have a window into that so we’re always dealing with partial information.
I always liken it to a house. If there’s some mystery going on inside the house and I only get to look through one window, I don’t really know what’s going on. But if I can give you access through 9 different windows into that house, you don’t ever get to go in the house but if we can give you much more confidence of what’s going on inside that person with their health, and advanced data analysis can just be one more tool. But no matter how advanced it is, you will always be better with more lab data. So, it’s a balance between cost and effort and how much information you’re looking for. And so, as those tools continue to evolve, our tools will continue to evolve. And as you merge those two concepts, then I think you can have something that’s even better.
Christopher: I like the analogy. You can consider it stolen, I think I’ll use that again in the future.
Mark: Use it as you will, that’s fine.
Christopher: Well, as I mentioned in the beginning of this interview, we do the Dutch test as part of our elite performance programs. It’s one tool in a very large box. And as markers are pointed out, we now have some overlap between our organic acids test and the Dutch test. We’re going to have to scratch our heads and maybe think about that a little bit more. But Mark, one of the questions that I get very often is “Oh, I listened to your podcast on the Dutch test. I’m really interested in doing just that one test. Can I order one from you, can you interpret it for me?” Unfortunately, we just can’t make a living doing that type of work where we’re exchanging our time in exchange for an hourly rate. It just doesn’t work for us. So, let’s say you are that person? You just want to know what the result means. How do you find someone that can help you interpret it?
Mark: One, we have tried to do as much as we can to provide information to help you understand it. So, as you get your Dutch report electronically, there are hyperlinks to educational videos to help you understand the report. Beyond that, you need a provider… I mean, unfortunately, it’s complicated stuff. So you’re always in better shape if you are talking to someone who has some experience with this.
And so, as you go to a traditional healthcare provider, it’s not just the Dutch test. You’re in metabolites, they’re not really familiar with it. So, our customer service team can offer up people who do that and there are people who do remote services like that for clients to be able to help them understand it. But then, if you need treatment, some sort of tele-medicine type of thing doesn’t always come with the option of OG. Some people need hormones. Well, if you need hormones, obviously you need a prescription. But our customer service team is always happy to help people and connect people with some really talented providers that use our testing. And they’re always happy to have referrals of patients and we’re happy to connect to.
Christopher: So, you could order the test from your website and then I could speak to one of your customer service team and they can give you a 15-minute overview and then directly to a good practitioner?
Mark: I mean, to be honest with you, no. We’ll break the law if we’re practicing medicine by getting on the phone with patient and starting to go through results and explaining results and things like that. So what we can do is the videos explain what it all means very generally. And here’s how to work your way through the data and so you can look at it and say “Gee, I got an estrogen problem. I don’t methylate very well.” You can get there on your own. But if you have HPA access dysfunction, yeah you need someone who knows that they’re doing.
And that’s where I think you can contact our staff and they can help you. There are other resources too, you know. Institute of functional medicine connects you with functional medicine providers. Other groups that are into this type of medicine. If you go to a doctor who’s never seen our test before but he’s done 24-hour urine from metabolites and salivary testing, they can help you. And we do a lot to help educate providers. So, if you go to a provider that’s never work with us before and you sign off on their ability to talk to our clinical staff, our clinical staff is happy to help those people understand what the stuff means.
Christopher: That’s awesome. That’s awesome. As a user, a patient or client, I still think there’s some value in doing the test without any help or get as far as you can. Maybe not do any treatment, don’t start taking supplements or go to your local primary care doctor and ask for a prescription based on it. But at least do the test and start to understand what you see because I think that’s very self-empowering. And one analogy, we’ve got a VW Euro van that breaks down every week. And every time I take it to the mechanic, he has this little handheld meter that he plugs into the dashboard. It reads the fault codes and it tells me what’s going on. I really want that box! I want to know what’s wrong with the van before I take it to the mechanic. Even though I can’t do any of the work myself, I still want to know what those fault codes mean
Mark: Yeah. The opposite can be true also. I mean, medicine can sometimes be a process of illumination, you know. When you’re tired, and your cortisol is perfectly normal, that’s probably not a tree worth barking of. So then, you look elsewhere and be like “Gee, my testosterone’s super low” which can also lead to fatigue. “Okay, then maybe I’d go to somebody who can help me further diagnose and to do something from a natural standpoint or from a prescription standpoint or whatever”, but sometimes it’s just helpful to know that there’s not a problem when the particular family of hormones or whatever as you’re on your search whatever it is the cause of what’s going on.
Christopher: Excellent. Well, this has been really, really helpful Mark. Is there anything else that you want people to know about?
Mark: No. If they’re looking for more information on our stuff, we’re at dutchtest.com. There’s a lot of information there and for healthcare providers, we’re always happy to help answer any questions and if people are interested in using the test, they know where to find us.
Christopher: Awesome, thank you so much!
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