As a clinician measuring urine, serum and salivary hormone levels in my patients routinely, I’ve always got questions around which testing method is the best. Thus, I was excited to chat with Mark Newman and pick his brain on all things hormone testing. As he says, “I’m an inch wide and a mile deep. I’ve spent pretty much my whole career in measuring reproductive and adrenal hormones.” It’s true. As you’ll hear, Mark is a fount of knowledge in this arena.
In this interview, Mark covers the various specimen type and their respective utility and limitations, we then dive into a discussion around the unique characteristics of the DUTCH test….In brief, DUTCH is an easy 4 specimen urine test, collected over the course of a day, covering the bases of sex and adrenal hormones, plus metabolites (including 2-Methoxyestrone) and melatonin. It’s reflective of 24-hour output, but diurnal variation is captured as well– thus great for cortisol. See what you think.
*All new DUTCH providers are allowed a one-time, introductory offer of up to 5 DUTCH Complete tests for 1/2 price (pre-paid). Just mention Dr. Kara*
What you’ll learn in Mark’s podcast:
- Review of the different specimen for hormone testing- limits and advantages to serum, urine and saliva.
- The “eureka” of developing the DUTCH test. Why 4-point urine measurement for hormones (reproductive and adrenal) is a good idea for:
- The obese patient
- The hyper or hypothyroid patient
- Estrogen metabolites
- Tracking diurnal cortisol output- advantages over salivary
- Assessment of hormone replacement therapy using urine, saliva and serum.
- Conditions when this test shouldn’t be considered
Podcast sponsored by Precision Analytical
Precision Analytical: Building a better hormone testing model: Physicians have three options for hormone testing – serum, urine, or saliva. When testing adrenal and sex hormones, each of these testing methods is a viable option, but has limitations, which can be improved upon. Precision Analytical’s testing model is a comprehensive overview of these hormones, and it is the easiest patient collection of all.
FxMed Podcast Series sponsored by Designs For Health
Dr. Fitzgerald: Hi Everybody. Welcome to New Frontiers in Functional Medicine. I am Dr. Kara Fitzgerald. Today I have with me Mark Newman, M.S. I’m so thrilled to be talking to Mark today. He’s an expert in measuring hormones, and he’s particularly good at educating us physicians. In fact, he’s made himself very available to me, time and again, over the last number of months as I drill him with questions. I just appreciate his willingness to dialogue with me on this important topic.
Mark has educated thousands of physicians on hormone testing best practices, directing the development of over 100 novel lab tests using blood, saliva, and urine testing methods has uniquely positioned Mark to build a hormone test model that better meets the needs of providers and patients alike. Precision Analytical’s DUTCH testing model, that’s dried urine test for comprehensive hormones testing model offers providers a uniquely comprehensive hormone profile, particularly for cortisol. It’s also specifically built to monitor HRT, as well.
Mark, I’m just really excited to have you here today. You’re a really, really solid analyatical chemist, and I appreciate your knowledge in the area, but really your attention to detail and your doggedness to get this right. Hormone testing, I think, is challenging, and you guys are doing a great job over there at Precision Analytical. Welcome to New Frontiers.
Mark Newman, MS: Thanks. Yeah, thanks. I’m happy to be here. I always tell people I’m an inch wide an a mile deep. I’ve spent pretty much my whole career in measuring really just reproductive and adrenal hormones. You get outside the scope of that and I know very little, but I’ve spent a lot of time in this particular little niche.
Dr. Fitzgerald: Yeah, I know, and I’m so psyched to pick your brain. I’ve appreciated being able to do that with you. You know, you’re really curious about it, too. I love sharing research with you. Anyway, you’ve measured in all different specimen, and we’re going to talk about that in a second. First of all, why did you develop DUTCH testing? Why did you develop this method?
Mark Newman, MS: Those two questions kind of go hand-in-hand as far as different methods of testing and what we do. For me and my career, I started out in a 24-hour urine environment and helped develop that sort of assay. You see the benefits of it, like, “Wow, look at all these great metabolites I can measure,” and then you say, “Well, okay, what am I missing?” One, my patients hate me because they don’t want to do a 24 hour urine.
Dr. Fitzgerald: Right, right.
Mark Newman, MS: Two, like my mother is a good example. Her cortisol’s low in the morning and it’s high at night. If you look at her on a 24 hour urine she’s normal. You say, “Aw, man, now I’ve got to go do a saliva test,” right. That was my career path, as well, and then I ended up developing tests and directing lab testing at SalivaLab, a really good one, and so got to dig in and develop tests there. Okay, what do I like about this? Well, I really like that cortisol pattern, but now I’ve given up all those metabolites. Over the years they just put together this nice research that shows … Not done by me, by a group that was looking at Chronic fatigue, and they showed really identical patterns of the free cortisol pattern when they looked in saliva and when they looked in urine.
What we pieced together, which came together better than I could have ever hoped, is the ability to use urine testing. We use dried urine just to make it easy, so you’re just saturating filter paper with urine at specific times. From those times we can grab your pattern of cortisol and just finish the study looking at saliva versus this, and the correlation is beautiful. Now I have your free cortisol pattern.
The way we do it we take, essentially, what I call a weighted average of those four samples, taking into account how hydrated you are for each core sample, and we make a composite sample, and the correlation to the 24 hour urine is really strong. Now I have kind of the best of both worlds. I’ve got all that rich metabolism information along with the cortisol pattern, and so it becomes uniquely comprehensive. You can look at melatonin, and estrogen metabolites, and all of this and, again, you preserve that cortisol pattern. The nice byproduct, which is why people tend to think we developed it, but it was just sort of the way it worked out, is that it’s super easy for the patient. Just urinate on this filter for dinnertime, bedtime, right when you wake up, two hours later and, boom, you’re done. It’s really easy but really rich information.
Dr. Fitzgerald: Yeah, yeah. Well, bravo. I mean, it’s really quite amazing what you guys have done, and I’m a big fan and I’m using it now. A couple of big reasons are clinicians who I greatly respect and admire and have had the opportunity to dialogue with, and friends with over the years, Bethany Hazen and Sarah Gottfried both have mentioned you, in particular, and the test. You know, Bethany being a little bit of a lab geek, like me, or at least, not lab geeks, but geeky and wanting to do the drill down and understanding the analytics. She’s mentioned you a number of times over the years to me. Finally, that’s really when I started to reach out to you and, “Who is this guy and what’s he doing?” Bravo. I really like the test and, indeed, my patients do too.
Given your background, your extensive background in other specimen for hormone testing, talk about the advantages, beyond what you’ve already stated, with regard to serum.
Mark Newman, MS: With serum testing, for me I’m pretty happy with a progesterone, with an estrogen, and a testosterone in serum, particularly for measuring and binding proteins, right, so I’ve got a total and a free testosterone, progesterone, estrogen. Those are great values. Our goal is to match that. Serum’s I think the gold standard for those. The benefit of urine is that it’s an average of more time so the ups and down throughout the day are averaged out. I don’t really think that’s a huge problem. I think you’re on faiarly equal footing there. What we’re going to add into the picture is the metabolites, of course. With the androgens I don’t just get DHEA or DHEAF, I’m getting the downstream metabolites. I don’t just get testosterone, I’m getting the alpha and the beta metabolites so I can conclude some things about DH2 production, which we also measure, from that.
I would consider that a significant benefit, but I think you can work fine in either medium for the reproductive hormones. Where there’s really the biggest benefit is the cortisol. I can take two women who have the same cortisol and if I put one of them on birth control her cortisol is going to go up in serum, but her binding proteins go up to, and her free cortisol and her cortisol for status, if you will, it’s the same, but the value doubles, right? That serum total cortisol … You know, the literature tells us we really want free cortisol, and that’s why everyone hopped over to saliva testing, and rightfully so, because it’s better. It’s multiple times throughout the day, which is important, and it’s free, not total, which is a two-fold benefit. We get to do that as well, which is really good. Then, what we get to add on top of that, which is probably the most important thing that we do that people don’t tend to know about until they know about it, if you will, are the metabolites of cortisol.
Dr. Fitzgerald: Right.
Mark Newman, MS: That kind of gets the contrast with saliva, maybe more so than serum. That’s the single factor that led me to this test. I started looking at saliva data and I started saying, Okay, everybody’s telling me, “Cortisol equals fat,” right? Fatter people, obese people, like people who struggle with weight gain there’s more cortisol. When you look in saliva what I found is the values are actually lower, not by a lot but by a little bit. They’re not higher at all. Then you start digging in the literature and you realize, “Oh, okay, hold on, free cortisol is only 1% of the picture,” and the literature is very clear. I guess it’s not very clear. It’s either the same or slightly lower. There’s not a positive correlation there.
When you look at the metabolites, which you can only measure in urine, they represent more like 70-80% of the total production, and they double and triple as you go from very skinny people to morbidly obese people. There’s a huge positive relationship there. What happens is the cortisol production gets driven up, but the cortisol clearance gets driven up as well, and you miss that entire story in serum. You miss that story in saliva. With this test you get that information.
As it relates to serum testing, you’re getting a little bit more information, which is helpful on the reproductive hormones, and you’re three or four steps really beyond that when it comes to the adrenals. I think those would be probably the biggest benefits as it relates to serum.
Dr. Fitzgerald: Yeah, and I like that pearl you threw out at the beginning of this dialogue. I think you’ve just mentioned a bunch of really important stuff. Just the fact that oral contraception is going to ramp it up considerably and you won’t be able to see that impact in serum that you need to see the free cortisol and the cortisol metabolites.
I know we were talking about a patient of mine, an obese patient of mine, who did have relatively flat-lined cortisol in saliva and didn’t respond well to hydrocortisone. She was too sensitive to it. It was too stimulating for her. I suspect she was actually … Her metabolites were high. She’s pending a DUTCH test because I want to just look at that a little bit more closely. You’ll see that in patients who are obese, sort of a flatline salivary cortisol and then just profoundly elevated turnover.
Mark Newman, MS: Not just salivary. We see the same thing, right, because we measure the free cortisol. If you focused on that … As an example, there are labs who are getting into this whole, “Like, hey, you can do cortisol in your urine,” and they’re looking at the free cortisol. If that’s all you look at … You’re going to see that in urine, too, and then you look at the metabolites. The way I describe it to people is it’s like the bucket at the end of the day, right. The free cortisol is still the most important measurement because it tells you what’s free, what’s bioavailable and all of that.
If you’re depressed your free cortisol will be higher. Your metabolites typically aren’t. In some cases the free cortisol is really the most important thing. We want that. When you’re obese what happens, and that’s a common issue that we deal with all the time, is you see the significance of that as it relates to cortisol only in the metabolites, and so you really need … It’s a three-dimensional picture, right, free cortisol over time plus the total production as measured by metabolites. That’s really so much more of a comprehensive cortisol story, and that was the main reason I developed this test, because I got so frustrated.
I walk into a doctor’s office and they’ll say, “Look, we tested their saliva and it’s low. Shoot, now we need to go do a urine test to see if they’re just peeing out all their cortisol.” Well, good grief it’s frustrating, it’s expensive, and all of that. That was the main driver behind this.
Dr. Fitzgerald: Right, right. In some individuals you see that flatlined free cortisol and you haven’t looked at met … You may want to treat with cortisol replacement, with hydroxycortisone. I think like in this patient it was compelling to me how sensitive she was. She’s pending a DUTCH test. She’s a relatively new patient. I expect to see those high, and that will give me some , I think, as to her sensitivity. I just need to go another route with this particular obese patient. I’m sure in some cases, however, hydroxycortisone is reasonable.
Mark Newman, MS: The contrast is the patient who has low free cortisol and then you look at the metabolites and they’re also so, and now you’ve confirmed it.
Dr. Fitzgerald: Exactly.
Mark Newman, MS: Now you know they don’t make much cortisol. The point is those two patients are so different from one another, but they look the same in saliva.
Dr. Fitzgerald: Yep.
Mark Newman, MS: They look the same in urine, if you’re only looking at free cortisol. That’s the main story with cortisol is you need to look at both ends of the spectrum before you … You cannot characterize them well with respect to cortisol if you’re not looking at both of those pieces.
Dr. Fitzgerald: Right. Yeah, I got it. Lesson learned. Point taken.
Yes, it completely changed the way that I will treat her and other patients when I have these data available to me. Obviously, my approach with that particular individual is more functional. We’re working on, obviously, weight loss and balancing her out metabolically in other ways, and some adjunct adrenal support is indicated with her, but there’s all sorts of gentle interventions, botanicals and so forth we can use to support her.
Okay, I think we’ve covered … We’ve talked about the utility of this particular method with regard to 24 hour urine collection and saliva testing. I think you’ve put forth a pretty compelling argument on many fronts, not just to the ease of collection. We’ve talked about obese patients and some differences we might see, or hormone replacement or oral contraception and some differences. What other clinical situations would we think about where you would prefer this test to some of the other tests we use or standard serum?
Mark Newman, MS: Yeah, I think a couple examples where I really find lots of testing useful, just in terms of the number of things that we test, is one would be if you’ve got a thyroid issue. I’ll lead with this because it fits into the cortisol picture, is that we all know that thyroid and cortisol they talk to each other, right, they affect each other.
Dr. Fitzgerald: Yeah, absolutely.
Mark Newman, MS: One of the ways that thyroid affects cortisol, which is sometimes not considered in that whole concept, is that thyroid has a pretty direct relationship on how you metabolize your cortisol.
Dr. Fitzgerald: Right.
Mark Newman, MS: The literature spells this out fairly well, that if you take a hypocortisol group and a hypercortisol group, the low thyroid group is going to have sluggish cortisol clearance and the hyperthyroid group is going to have excessive cortisol clearance. Hyperthyroid ends up looking the same as obese, right because you ramp up cortisol clearance. The free cortisol goes down because you’re getting rid of it so fast and the metabolites go up.
I had a friend of mine, for example, who was misunderstanding her doctor’s instructions and she was taking her thyroid medication twice a day instead of once a day. She had that same look. Well, she’s really skinny. I’m like this is kind of an obesity look but you’re skinny. Totally different picture, right? The reason for up-regulated cortisol clearance was, basically, self-induced hyperthyroidism that sped up her cortisol clearance. This is by no means diagnostic of hyperthyroidism, but for her it helped get to the bottom of that problem. As you’re dosing thyroid, it’s a really good just piece of information to know. The flip side is hypothyroid where you can have in an extreme case, just think of the cortisol backing up, right. I make cortisol and I can’t get rid of it. You can actually have … I’ve seen cases where the free cortisol is elevated.
What do we think, “Oh, my goodness, you’re making so much cortisol. Here’s your phosphatidylserine, or whatever you go to to lower cortisol, and then we look at the metabolites and we go, “Hold on. Slow this conversation down. Your metabolites are low. You’re making very little cortisol, yet your circulating free cortisol is high. Why? Ah, your Hashimoto’s, etc.”
Dr. Fitzgerald: Yes.
Mark Newman, MS: “You have all these thyroid issues,” and in those particular cases where it’s extreme the free cortisol elevation is likely largely to some degree due to the fact that you’re just not processing that cortisol appropriately. Knowing that, as you piece this whole thing together is so much better than just sort of guessing to say, “Well, hey, you have high cortisol. Gee, you must be stressed,” or “Gee, you must need something to calm down your HPA actives.” Well, in those cases it’s a more complex nuance situation, and that’s really helpful.
Dr. Fitzgerald: Yeah, that’s great.
Mark Newman, MS: PCOS is another one. I really like having all this information for my PCOS patients, because I get to look at the progesterone and the estrogen. That’s good and I can do that anywhere, right? I can do that in serum or whatever, but I also get to look at those androgens.
Dr. Fitzgerald: Yes.
Mark Newman, MS: Not just the androgens but the metabolites, right? So, am I making a lot of DHT? Well, let’s go look, right. You can see that alpha metabolism. PCOS is driven mostly by this insulin issue. Well, insulin can also drive alpha metabolism, which means my testosterone gets pushed towards DHT, which is three times potent, and now that’s why I’ve got hair on my chin as a women, or thinning scalp hair, or whatever. I can address that, right. Obviously, you’re going to address the insulin issue, but if my sole issue is I’m losing my scalp hair, that can be because of DHT. It can also be because of thyroid. If you rule out the DHT issue and you’re not pushing in that direction then don’t go give them saw palmetto, and nettles, and all these things that block alpha metabolism. Give that to the patient that actually shows that alpha preference in their metabolism.
That’s part of the benefit of just having so much information to wrestle with as you’re dealing with these patients. You can see, you know, the progesterone, and the estrogen, and the androgens, but also the metabolism for those patients. I think those would be two good examples.
Dr. Fitzgerald: That’s awesome. I just want to summarize a little bit, just kind of nutshell this. So, hypothyroidism there’s going to be slower metabolism of the cortisol metabolites and, therefore, you might look at somebody and see they’re just really pushing out tons of cortisol, so you would see that in saliva. But, if you’ve got the advantage of looking at metabolism you’ll actually see, “No, in fact, they’re not metabolizing their cortisol normally.” Treating thyroid is going to support that, because thyroid will stimulate the metabolism of cortisol.
Then, in hyper is the exact opposite. In hyper you look at somebody’s saliva cortisol measurements, they might look flatlined, they might look very low. Yet, if you’ve got the advantage of having the metabolites you’re going to see that they’re, in fact, wildly elevated and there’s this extremely rapid metabolism going on. Then you mention PCOS, another really great example, and looking at DHT, looking at not just the androgens themselves but the androgen metabolites to see what’s happening, and the influence of insulin on testosterone production and DHT and so forth. Thank you. I appreciate that.
Now, you guys are also able to pack in all of the estrogen metabolites that we know and love. Any comments around estrogen metabolism and looking at the details there?
Mark Newman, MS: Yeah, I would say cortisol is the biggest reason I love this test, and then a close second would be the estrogen. The first practical application of the metabolites is just confirmation, right? I’m a skeptic of every lab work, my own work, whatever. When I see an estradiol that’s high. My first thought is, “Really, like is it really high?”
Dr. Fitzgerald: Right.
Mark Newman, MS: When I have these other seven, eight metabolites in this same family of hormones they help me to confirm the story. Like, “Okay, yeah, look, you’re pumping out lots of estrogens, okay.” Secondly, there’s this just practical application of this issue, like with the cortisol, of, “Are you just metabolizing it well?” The main reason people look at the metabolites, especially the phase I metabolites, is this issue with cancer risk.
Dr. Fitzgerald: Right.
Mark Newman, MS: Setting that aside for a minute, there’s a very practical application of just say …
I had a friend recently, Tricia. Tricia’s got estrogen-dominant symptoms, but guess what, her progesterone is fine, but her estradiol is high. I could have seen that in blood, but I saw it in the urine, right. Then I can see why. The reason hers was elevated is because her 2-hydroxyestrogens were low. She has a sluggish clearance of estrogen, and I get to look really smart, right, because I said, “Hey, just take a little of this supplement called DIM, which she doesn’t know really what it is, and it will make you feel better. She took them and we re-tested her and, what do you know, it pushed the estrogens down that 2-hydroxy pathway, which, again, we tend to think about cancer risks. We can talk about that. Just s a practical application she was able to get rid of those estrogens. Her estradiol, and estrione, and estriol, and 16-hydroxy E1 all came down within range. Her 2-hydroxyestrogens went up and she felt a lot better, right?
There’s this practical application of just seeing, whether you’re a man or a woman, am I getting rid of my estogens the way that I’m supposed to, and if not that’s an avenue for me being able to assist. Whereas, if everything’s high, 2-hydroxy’s high, everything’s high, you know DIM or I3C might work a little bit, but, man, I got to see what’s driving all this estrogen, because there’s clearly too much production. Maybe it’s inflammation, whatever it might be. I can go look at that and now maybe I’m looking at things like calcium [inaudible 00:22:58] or things that help on other fronts to lower those estrogens. You get a more thorough picture.
Then there is the application of, you know, potential risk factors for breast cancer, prostate cancer, and all of those. If I’m making lots of 4-hydroxyestrogens and not making enough 2-hydroxyestrogens that’s something I want to pay attention to. It also turns my focus to the methylation, which is another piece of it, right? That’s part of phase II metabolism where we take these hydroxys and we turn them into methoxys, unless you’re like me and you don’t because I have genetic defect in my COMT and I suck at methylation. I can see that and I can start to address that. I’m kind in the middle right now of trying to figure out what actually will improve … I’ve tried SAME and trying these different things to see what.
If you’ve got MTH ABAR, If you’ve got COMT, this is a functional test to show whether you’re a good methylator or not. It just gives you this big rich picture for the estrogens of not only what world are you in, low, normal, or high, but also how are you processing these estrogens. If they’re problematic then let’s deal with that.
Dr. Fitzgerald: That’s right. It’s great. It’s comprehensive. As you said earlier, with your friend, which incidentally, since you were able to get a nice full snapshot, you were able to do some pinpoint intervention. The only thing you needed to do was DIM. You didn’t have to like kitchen sink her. You didn’t add in any progesterone. It was really straight forward. You could look at her cortisol and see what’s going on over there in relation to the sex hormones, and then all of her derivatives. It’s handy being an analyatical chemist, isn’t it? You can just go and test yourself and look at all these things and look at them on your friends. That’s pretty neat.
Mark Newman, MS: I know all of my wife’s friends more than I probably should in terms of some of those [inaudible 00:25:00].
Dr. Fitzgerald: That’s great.
Now, you and I were talking, interstingly. This is diverging slightly. We were talking about your COMT mutations and your difficulty with methylation, and some of your own trials and tribulations with atttempting to support methylation. If you have the COMT and you throw a bunch of methyl donors at yourself you get really anxious and then maybe you’re going to improve your 2-methyoxyestrone, but you’re also incredibly anxious and wired, and all that stuff, because you’re not metabolizing your catecholamines very well.
Actually, the other thing you said that was really important was that it’s hard to move 2-hydroxyesterone over to 2-methyoxyestrone. That’s not an actively moving pathway. It doesn’t necessarily respond to very high dose methyl donors, as you said. It just prompted me to think about the whole stress breast cancer, or stress cancer, or stress anything connection. If you have methylation lesions, what little COMT function that you have, your methyl donors are going to go towards metabolizing your catecholemines way before your estrogens. Like, on the hierarchy of what your body’s going to do first, it’s going to be moving out the catecholamnines, the adrenaline.
And so [crosstalk 00:26:38] Go ahead.
Mark Newman, MS: I’m not an expert so much in that area, but just very practically speaking, yeah, it seems to be difficult to move the meter when it comes to … we see a really good connection between the ratio between these metabolites and people who have genetic defects like me, but when you start intervening, it can be difficult to go from bad to good. Usually, if you’re lucky, you’ll go from bad to decent, that sort of thing. Yeah, the estrogens are harder to move than the other methylation targets.
Dr. Fitzgerald: Right, right, right.
I definitely think stress reduction is a component of that, but, it’s just really an interesting marker. The 2-hydroxy to the 2-methyoxy, and I think it will be one to just be cool to track over time. You have a great position. You’re speaking to clinicians all over the place working on this. It will be interesting to sort of observe if there’s any interventions you see working better than others.
Okay, so what are the limitations around DUTCH testing. Are there any circumstances under which you would not recommend using it?
Mark Newman, MS: Yeah, there are a few situations where I would definitely go in a different direction. I think just first and foremost, it’s a good test for men. It’s a great test for women. For men I like it, but if my sole focus is testosterone I personally would go to blood. I would take a total and free testosterone over a urinary testosterone. Now, when you’re talking about the totality of our test I really like it for men or women, but as it relates to just testosterone, if I’m trying to monitor a pellet or an injection, I love all the estrogen stuff we’re going to get, the testosterone metabolism, but when I’m hanging my hat on a testosterone value I would rank blood ahead of the urine, but that would be exceptionally more so true if they’re of Asian descent, which sounds kind of weird, but there’s a genetic defect in … When I say defect it sounds terrible. There’s no clinical consequence of this, but essentially testosterone gets turned into a phase II metabolite, testosterone glucuronide. That’s what ends up in urine. That’s what I measure. I don’t measure estradiol. I measure estradiol glucoronide, the water-soluble form of it, which is a good reflection of bioavailable hormone, yada, yada, yada.
There is a defect … My brother-in-law I’m pretty such actually has this, although he’s not of Asian descent, where your ability to turn testosterone into that water-soluble conjugate gets broken. You have normal testosterone but your urinary testosterone is very, very low, and it’s over half of people with Asian descent have this. When they test in urine they get a low testosterone and it’s not a good idea to go treat them. You need to go get a blood test to make sure that that’s actually the case.
That’s probably the biggest caveat with urine testing is there can be phase II issues for testosterone and, again, they’re pretty rare in Caucasians. They’re a little more common in people of African descent, but still fairly rare. They’re really common in people from like southeast Asia. There’s a series of three hormones that are affected by this, and then two closely related hormones that aren’t, like epitestosterone. We have an algorithm for basically notifying physicians that say, “Hey, look, you might want to go get a blood test because there’s some uncertainty here.” But, if I back the decision up and say I have an Asian man and I really care about his testosterone I would go right to blood. That would be one area where urine testing has a limitation, is with that particular scenario. Actually, before I move on, did that make sense?
Dr. Fitzgerald: Yeah, it actually did, and I think it’s pretty cool that you flag the clinician so they’ll go to blood. I would also say, though, that if you’re concerned about low testosterone looking at the estrogen production and metabolites, and looking at cortisol is, obviously, going to be extremely useful in painting the full picture. It might be a scenario where you want to look at both tests. Yeah, you absolutely made really clear sense and I understand they’re not engaging in glucaronidation …
Mark Newman, MS: Right.
Dr. Fitzgerald: … as efficiently and so you’re just not able to pick it up in urine. Yeah, all right, great. That’s another useful bit of information.
Mark Newman, MS: The other thing is, if you have a kidney issue then our test is basically dependent on your creatinine being proper, if you will. If you have some significant kidney issue then it can kind of monkey with our test, because it’ll essentially bloat. If you have too much creatinine in your urine it will bloat the values. Actually, that will decrease the value. If you don’t have enough creatinine in your urine then it would bloat the values on our test, because creatinine is the denominator. Again, it’s correct for hydration, right, and it works really well. It’s a robust model. If you have a kidney issue you either need to look at it a little bit with some caution, or go use a different test. That would be another one.
We don’t test thyroid. We don’t test pregnenalone. Some of those things I think have to be tested in blood if you want to do them well. Yeah would probably be the main things I would say just in terms of limitation. It’s important for people to know, every test has limitations. There’s nothing that’s going to work in every single situation. We’re trying to really get to the position where we beat you to the punch, to say, “Look, here’s the situation where you shouldn’t use it. Go in a different direction,” so that you have confidence that when you do use you’re getting good information.
Dr. Fitzgerald: Right. I see that you report creatinine for all of the specimens. Obviously, if they’re out of range, at either end if they’re too high or too low you’re going to kick it back to the clinician, right, and tell them to do something else?
Mark Newman, MS: Yes, if the creatinine is a little low it just means your urine’s dilute. If your creatinine is very, very, very low then the instructions would ask you to monitor your hydration so you’re not like crazy hydrated, right. If you drink like eight gallons of water then the relationship by which creatinine corrects for hydration, it falls apart at a certain point. Probably one out of a thousand people that test with us we’ll say, “Look, there’s a particular problem here. Let’s have you recollect,” because you’ve got to watch your hydration status. That’s a different issue, which, again, is not usually an issue, but every once in a while you see it. That’s a different issue than if your creatinine is actually not excreted like it’s supposed to be. That would be more of a kidney issue, and that would compromise the fact that this wouldn’t probably be the best test for somebody who’s got a really substantial kidney issue.
I’ve only seen it once, to be honest with you, where I’ve actually had a patient recollect and we actually did a creatinine clearance and I said, “Look, doctor, this person is excreting 30% less creatinine than they’re supposed to.” In that case we actually made like a little research report for her to say, “This is what it would look like if it was appropriate, but in that case like it’s not the best test for you, so you might want to go do something different if you know that there’s a significant kidney creatinine issue with a patient.
Dr. Fitzgerald: All of other urine tests that use creatinine have similar issues. We would see this at the lab with the organic acids when I was at Metametrix, if they had an extremely high creatinine, like if they were a mega, mega body builder and they had wild amounts of muscle mass it might influence the results, or if they were … sometimes people would want to try to get organic acids on infants, and they might have such an obviously extremely small body habitus and the creatinine would be too low. Would that come into play in this test at all? Did the weight lift … or no?
Mark Newman, MS: I mean, it gets to a little bit of the nerdy side of what we do, but I don’t like that bias of saying, “Oh, but I’m a body builder,” right. There’s a really nice paper that a Japanese group put out where they tortured these poor people into doing 24 hour urines, like over and over again, tons of people. They actually figured out the regression analysis between your creatinine, your age, your height, your sex, and your weight. If we 130 pound railey guy and a 250 pound linebacker, like the amount of creatinine that’s supposed to be in their urine is different, and the difference between those two introduces bias into every test that uses creatinine to correct for hydration, right.
We’ve actually used the relationship between age, height, sex, and weight and creatinine and we correct for that.
Dr. Fitzgerald: Oh, my gosh, wow.
Mark Newman, MS: Yeah, that whole issue of like with a big guy, Yeah your values in a guy who’s got tons of muscle mass … How would that work, he’d have extra, so your numbers would be artificially …
Dr. Fitzgerald: Low.
Mark Newman, MS: I think. The creatinine is, it’s not artificial but it’s higher than it would be in an average guy, right?
Dr. Fitzgerald: Yeah.
Mark Newman, MS: You’ve got to pull those numbers down.
Dr. Fitzgerald: Right.
Mark Newman, MS: For kids, this is a great model but creatinine changes with size of kid and so we would have to do extensive reference range studying. For organic acids you get a direct linear relationship between creatinine and the size of the kid. Height is actually the best predictor of creatinine. When I was working on organic acids at someplace else, we actually like came up with a way to correct for that with a regression analysis, because otherwise it’s pretty challenging. A 4-year-old kid and a 9-year-old kid may have the same amount of something, hormone, organic acid, whatever, but the creatinine is going to be different, and there’s going to be bias in that potentially, so that would be the last job to correct for that.
We have those relationships figured out in urine for kids, but we don’t have the reference ranges yet, so went don’t test kids yet.
Dr. Fitzgerald: Okay. Okay. All right. That was a really geeky [crosstalk 00:37:20]
Mark Newman, MS: That was probably more than you thought was coming. Sorry.
Dr. Fitzgerald: Well, it’s great. I think that the take-home here is that you guys have corrected for this, and the outrageous outlier you’re going to kick back to the clinician. There may be some people with a degree of kidney disease for whom this test isn’t appropriate for but, as you’ve said, that’s rare and for the most part you’ve been able to correct for all of these potential issues. I think that’s the take home.
Mark Newman, MS: The trade off is you have a 24 here urine, right? I’m dependent on the patient collecting it correctly. Someone did a study once and they said 40% of people screw it up. I don’t know if that’s true or not. Even if 20% that’s a lot. The patient has to measure it, right? The first laboratory measurement in a 24 hour urine is done by the patient, right? They havc to take that graduated urine jug, and hopefully they didn’t go over and get into two jugs or it’s a big mess, but they’ve got to measure that correctly. If they’re off by 15%, you’re just off. The uncertainty of that is significant. You can overcome it, but it’s significant.
The uncertainty for us surrounds creatinine and hydration and whatever. What I’ve found in running both tests is that this model is more robust, and it depends less on the competence of the patient, and I like that trade off. There is still like some issues that we have to wrestle through. Occasionally they snag you up and you got to re-collect, maybe one out of 10,000 patients didn’t actually get successful results because something weird was going on or whatever.
Dr. Fitzgerald: I got it. All right.
Well, let’s move away from this analytical back story, because I don’t know if everybody’s going to be that interested in it. I think that you’ve made your point, and I appreciate, again, the amount of effort you guys have put in behind the scenes to get it right. You designed this to be particularly useful for monitoring HRT. Do you want to talk a little bit about that.
Mark Newman, MS: Yeah, that’s been kind of a little project of mine is over the last 10 years it’s putting together information. Okay, if I move from a transdermal hormone, to a vaginal hormone, to an oral hormone, sublingual, like everyone of these routes of administration is a different set of questions as far as which tests work well. Some of them have pretty extreme limitations, and we’ve tried to address some of those in the way that we’ve developed our test.
I’ll give you an example. Oral progesterone, right. If you take oral progesterone, the kinetics of oral progesterone say that it should be gone from your blood or your saliva in about 4 or 5 or 6 hours. People take it at bedtime and when do they test? In the morning, right, like 10 hours later. It’s supposed to be gone. In addition to that, all the metabolites you make from the oral progesterone actually cross react with the test, the assays, and artificially increase the value. Now I have a value that’s not that accurate. It’s not even supposed to be elevated by the time I test. Blood and saliva worked fine for progesterone, but they were a really bad match for oral progesterone.
We said, “Okay, with the urine testing we can actually do something a little bit better. When you take oral progesterone it’s almost a prohormone. Progesterone doesn’t help you sleep when you take it at night. Allopregnenalonee helps you sleep.
Dr. Fitzgerald: Right.
Mark Newman, MS: The progesterone turns into that, right? It’s a metabolite. We said, “Okay, progesterone goes down two primary pathways, alpha and beta. Alpha’s more active. That’s where you get Allopregnenalone and that whole family of hormones. Beta is not. We look at those metabolites and we can actually help you assess whether patients are pushing down that pathway or not. We see patients all the time that are on higher doses. Well, how’d they get there? Well, they took 100 mg. It didn’t really work and then they took 400 mg and maybe it was too much, and then they are at 200, fine.
Then, we see patients who are like, “Oh, good grief, 100 mg knocked me out, right, so they scale back to 75 mg. What we see is the patients that it works really effective for it’s because generally they push down that Alpha pathway. We can help providers assess that by looking at those metabolites. If you don’t sleep well and you’re on oral progesterone and it’s because you push it down the other pathway, then maybe you want to take a little bit more.
Dr. Fitzgerald: Right.
Mark Newman, MS: If you do push it down that pathway and you’re still not sleeping, maybe you should go look at cortisol. Maybe you should look at melatonin. It just helps you better in that assessment. For oral progesterone I feel like we have a better answer. For patches, for pellets, for injections, I think anything works well. Those are pretty steady states. Everything should get elevated to an appropriate relative amount, and you can use just about anything you want. Vaginal hormones is another one where we came up with a special solution, right, because with vaginal hormones the up and down in blood is unpredictable. I can show you two women’s paths of testosterone taking vaginal testosterone. One of them peaks at eight hours. The other one peaked at two hours and is at baseline at eight hours. If you test them at eight hours you don’t really know what’s gone on, right. There’s a story there that you can miss. If you’re collecting urine you’re collecting over time. You say, “Oh, well that’s better, because I’m going to collect over a much longer time period for a urine test, and that’s better. However, what’s the problem? You just contaminated your sample because the hormone is going into the area from whence the sample comes, right, so you can contaminate the sample with hormone.
We look at that and say, “Well, hold on, we don’t test testosterone, right? We test testosterone glucuronide. We test testosterone sulfate. These are [inaudible 00:43:07]. The free hormone’s not supposed to be there so we set up our method to systemically remove free hormone, right. I don’t care what your free testosterone is in urine because it’s negligible. It’s 1%. If you’re on vaginal hormnone and now all of a sudden your testosterone is way high and it’s all free testosterone, that is hormone that is there by way of contamination and we remove it so now you get this really nice solution where it’s an average over time, which I think is beneficial relative to serum, or saliva, but it’s not contaminated, so we can actually use that as a really robust testing situation. I think it works really well for pretty much every situation except sublingual hormones don’t really work very well in terms of dosing monitoring, because you swallow some of it and the other part you don’t swallow. I don’t know which fraction you swallowed, and the urine is going to go way crazy high from the stuff you swallow, from first path metabolism, right? I’m going hormone in my mouth, hormone in my gut, hormone in my bladder and it’s never been in circulation as a free hormone, the stuff that’s first passed, right? It just gets kind of washed through your body.
The rest of it goes in sublingually, gets into your body, and some of it goes into urine. That’s what I want to see, but I see all that other stuff and it’s become ambiguous. Sublingual hormones is the one where you can look at the metabolites and that’s nice, but to say, “Oh, you need more of a sublingual hormone is really tricky to do with urine testing.
The last one is this big vortex of a conversation that you could have a whole separate call on, which is transdermal hormones, right? People do such different things on transdermal hormones, because it is confusing, right? You put transdermal hormones on, salivary levels go through the roof. They’re really variable from day-to-day, but they are really high a lot of times. The serum and the urine lag way behind. There’s all this confusion. I don’t want to get into it too much, because it is a really separate confusing conversation, but I’ve done a lot of work on that to try to best figure out how do we test with transdermal hormones, because they are so popular, and especially with progesterone where you get this huge dicotomy, right? The saliva’s really high. The urine and the serum lag way behind, and the clinical response seems to be kind of in between, you know. You sit there and go, “Do I really want to give you hormone until my urine and my serum are at this really elevated level,” at which point the dose is really high.
That’s a tricky one, but for everything else I think it’s a really good catchall. For any situation you get the metabolites, which is good, right? If I’m giving estrogen I want to know how you’re processing it.
Dr. Fitzgerald: Right.
Mark Newman, MS: I think as a general rule we’ve been very specific about trying to make it as applicable to as many situations as we can, so it’s a pretty good catchall for HRT, but those are top topics. I have a whole video library on dutchtest.com where you can go through a separate video for each route of administration that will walk you through, “Here’s what happens in serum, here’s what happens in saliva, here’s what happens in urine, and here’s what we do, and you can make, I think, better decisions if you’re well armed with information.
Dr. Fitzgerald: Perfect, okay, perfect. It seems like in some cases, transdermal or sublingual, you might need some serum testing, as well, or watch the videos?
Mark Newman, MS: No. For sublingual the serum results move so fast. If I give myself sublingual testosterone it goes up and down in two hours, three hours tops. There’s really no good time to test, either you’re shooting at a moving target, or you’ve already missed it, so that doesn’t work super well. The issue with … I would pick urine over serum for transdermal because while you don’t tend to see the increase like you do in saliva, which I don’t think is a better testing option, but it tells you that there’s tissue getting a lot of hormone, that we may not be seeing all of it. The serum and the urine tend to tell the same story. The difference is with the urine you get the downstream metabolites, which adds to the picture a little bit, so if testosterone is getting into your tissue you may see it as testosterone. You may see as a downstream metabolite in some people, and I think that’s better, but it still is a really complex subject in terms of, “Do I hang my hat on this number and change my dose until I’m in a certain range? I think the story really there is to lean more hesvily on the clincal picture when the labs aren’t perfect.
Dr. Fitzgerald: Okay, got it.
Mark Newman, MS: The labs are not perfect for sublingual. They’re not perfect for transdermal. They can be useful, but you’re going to want to lean more heavily on the clinical picture. You put a woman on a patch, I’m gonna give you a solid number. I think serum will give you a solid number. Of course, still lean on the clinical picture, but that lab has a lot of merit, right. Whereas, with sublingual and intradermal you just want to be more careful with the lab, that it’s not perfect.
Dr. Fitzgerald: Okay. Got it. Got it. Got it. That’s a pretty straight forward take home I think, Mark. You just really need to lean on the clinical picture, but it sounds like urine can still inform decision making, because you will get to see the metabolites and all of that. For those folks who want to do the drill down and get into Mark’s library, we will have all of Precision Analytical’s contact information. In fact, you’ll have email address. You can access Mark and the team there.
All right. We’re heading on the home stretch here. Has this just been a remarkably useful conversation, lots of pearls for us. I’ll try to collect those and list them on the page. Anything else you want to add about the test, including how providers can get started using DUTCH?
Mark Newman, MS: If people are interested in the test itself, I think it’s worth at least kicking the tires to know. For some people this is their go-to hormone test. For some people this is the only when it’s really complex kind of stuff. For some people it’s just their adrenal test.
If you really want to try it out, we try to make it easy for new providers. For example the DUTCH complete is 250 bucks, right, so it gives you everything, melatonin, estrogen, metabolites, cortisol, everything. We offer that to new providers at half price. If you want to prepay you can get up to five, right. You can get one test, you can get two, you can get five for 125 bucks you get all that. That’s a great way to get started. We embed, in our report, right on the front page there are a series of video hyperlinks you can watch. If you say, “Look, I understand all this but I don’t get the cortisol piece. There’s a video on the cortisol stuff that’s me walking you through the concepts. “You know, I get that but I don’t get the estrogen metabolism. There’s a video right there to help walk you through it. We have on-staff physicians that give a detailed, specific breakdown of your first test, just to help you walk through it, so we’re really trying to help people bridge the gap, because there are some concepts here that you’re not gonna have if you’re just doing serum testing, or you’re just doing saliva testing.
If you go to dutchtest.com and sign up to become a provider you’ll get that offer, up to five tests half price. That’s a good way to just kind of get a look at it. Otherwise we just stock people with kits and use them in your practice as you see fit. Insurance coverage is pretty decent on the urine test, because our price is low and there are lots tests so the charge per [inaudible 00:50:46] ends up being like 10 to 15 bucks. When we give people insurance receipts they tend to do really well that way. If you want to just go to the website, dutchtest.com, you can get information there.
We try to make ourselves really available, so even if you have questions on, “I don’t want to use your test, but I need to know, “Can I use serum testing when I’m taking hormones this way?” We want to be a resource for people on those questions, because it’s really tricky. Like I said, “I’m an inch wide and a mile deep, and that’s our space, and we want to help providers in that space that they look. The questions you don’t have time to dig into, like that’s a word here when it comes to reproductive hormones, and especially HRT and those sorts of topics.
Dr. Fitzgerald: Thank you so much. Clearly you’re a mild deep in this area. I know you’ve been working on it for years, and, yeah, you’ve been a great resource for me. I think clinicians will enjoy checking out the DUTCH test. Again, Mark, thanks so much for joining me today.
Mark Newman, MS: Thanks for having me. It was fun.
Bio: Mark Newman, MS. President, Precision Analytical: Mark is one of the foremost experts in the area of hormone testing, especially regarding monitoring HRT. Mark has educated thousands of physicians on hormone testing best practices. Directing the development of over 100 novel lab tests using blood, saliva and urine testing methods has uniquely position Mark to build a hormone testing model that better meets the needs of providers and patients alike. Precision Analytical’s DUTCH (Dried Urine Test for Comprehensive Hormones) testing model offers providers a uniquely comprehensive hormone profile, particularly for cortisol. It is also specifically built to monitor HRT.