Hormone Metabolism and Testing with Mark Newman, MS: Rational Wellness Podcast 341

Mark Newman discusses Hormone Metabolism and Testing with Dr. Ben Weitz.

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Podcast Highlights

1:48  Dried urine testing or DUTCH testing uses a dried sample for convenience, which is a big advantage over the other leading type of urine hormone testing, which is the 24 hour urine test that requires carrying around a jug of urine that you keep in the refrigerator all day.  This is very inconvenient and you lose the the changes in those hormones levels, esp. cortisol, that vary throughout the day using a 24 hour sample.  The dried urine test you collect samples throughout the day so you can look at the cortisol pattern, which correlates with what is seen on saliva in studies that have been published.  And the urine testing of hormones allows you to see the metabolites of estrogens and androgens that you can’t see on blood testing.  And there is a DUTCH complete test that includes markers in urine for melatonin and B12 and B6, etc. that allows us to see a fuller picture of the hormone story.  For example, this complete testing is helpful if you have a patient who has fatigue you can find out if it is related to testosterone or cortisol or B12.

4:57  On the other hand, dried urine testing does not allow you to measure SHBG, which can be measured through blood, such as when a woman is on birth control and this drives up her SHBG, which drives down her free hormones. Urine testing is also not a good way to measure thyroid hormones. Also, if your kidneys are not functioning well, then you are not excreting urine as well as you should and this can impact urine testing. Also, saliva has some advantages for the cortisol awakening response (CAR), so DUTCH plus includes saliva for the first two samples of cortisol, since for the CAR you need an instantaneous sample when you first wake up within the first five minutes.  DUTCH uses a cotton swab that soaks up saliva instead of having to spit into a tube like other labs use and fill it with 3 ml of saliva after waking up without rinsing your mouth and without drinking any water and for most people this takes 15-20 min, which negates the value of the CAR test.

8:50  Estrogen metabolism.  Urine testing allows for monitoring of estrogen metabolites that you can’t get with serum testing and this can give us some information about how the person processes their hormones and also provides some information about estrogen related cancer risk.  Mark explains that the first thing to consider is the woman estrogen deficient or do they have estrogen excess. And there are three doors of metabolism that estrogen can go through, including the 2 hydroxy, the 4 hydroxy, and the 16 hydroxy estrone pathways and the 16 got a lot of attention because the 16 hydroxy estrogen is more active proliferative estrogen if this pathway is used more it can exacerbate estrogen dominance.  In terms of breast cancer risk, there is more focus on the 4 hydroxy than the 16, since the 4 has the unique ability to make a reactive quinone.  The 2 pathway is clearly more favorable in terms of cancer risk.  If reactive quinones are produced, then need to be detoxed and methylation plays a role and glutathione and resveratrol can upregulate the quinones.  If the quinones are not detoxed, they can damage your DNA.


Mark Newman, MS is a recognized expert and international speaker in the field of hormone testing. Mark spent nearly 25 years developing and directing urine, blood, and saliva-based hormone testing along with other biomarkers like organic acids. His unique experience led him to pursue a revolutionary way to test hormones; so Mark began his own lab, Precision Analytical Inc., to create the latest innovation in hormone testing, the DUTCH Test® (a Dried Urine Test for Comprehensive Hormones). In pursuit of the most accurate, evidence-based testing and best practices, Mark has co-written multiple peer-reviewed research papers and abstracts, highlighting the accuracy and clinical utility of dried urine hormone testing. Mark’s primary educational goal is to find and communicate truths about HRT monitoring to help providers care for their patients. He understands that each form of testing has its own strengths and weaknesses, which is why he encourages clinicians to follow the evidence even when lab testing isn’t clinically helpful. For clinicians to learn more about the DUTCH test, go to DUTCHtest.com Patients can find a referral to a DUTCH Lab provider to order and interpret the testing for them.

Dr. Ben Weitz is available for Functional Nutrition consultations specializing in Functional Gastrointestinal Disorders like IBS/SIBO and Reflux and also Cardiometabolic Risk Factors like elevated lipids, high blood sugar, and high blood pressure.  Dr. Weitz has also successfully helped many patients with managing their weight and improving their athletic performance, as well as sports chiropractic work by calling his Santa Monica office 310-395-3111. Dr. Weitz is also available for video or phone consultations and he uses DUTCH testing regularly.



Podcast Transcript

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

                                Hello, Rational Wellness Podcasters. Today we’ll be having an interview with Mark Newman about hormone testing and metabolism. Mark Newman is a recognized expert and international speaker in the field of hormone testing. Mark spent nearly 25 years developing and directing urine, blood, and saliva-based hormone testing, along with other biomarkers like organic acids. His unique experience led him to pursue a revolutionary way to test hormones so Mark began his own lab, Precision Analytical, to create the latest innovation in hormone testing, a Dutch test, which is a dried urine test for comprehensive hormones. Mark has also co-written multiple peer-reviewed research papers and abstracts highlighting the accuracy and clinical utility of dried urine hormone testing. Mark’s primary educational goal is to find and communicate truths about hormone replacement therapy monitoring to help providers care for their patients. He understands that each form of testing has its own strengths and weaknesses, which is why he encourages clinicians to follow the evidence even when lab testing isn’t clinically helpful. Thank you so much for joining us, Mark.

Mark:                    Thanks for having me, Ben. Great to be here.

Dr. Weitz:            I’d like to just dive into the science of hormones and hormone testing, but I realize there’s probably some listening to this podcast who might not know what dried urine or Dutch testing is. So perhaps you can give us a short summary of what dried urine testing is and what are some of its advantages.

Mark:                    Sure. Yeah. The fact that we use a dried sample is simply for convenience. The main thing that we’re after honestly isn’t convenience, it’s information and data. I spent years doing urine testing where people would carry a jug of urine and you can get lots of interesting information.

Dr. Weitz:            That was a 24-hour urine test. Yeah.

Mark:                    Yeah. Lots of information, not lots of fun. And the main thing you lose though is those hormones, particularly cortisol that’s supposed to go up in the morning and down at night, if you get that pattern to say inverted, you lose that in a 24-hour collection. And so people often go to saliva for that. So after years of doing 24-hour urine and saliva, we wanted to find one easy way for people to get lots of information, and that’s what the dried urine test is is multiple samples throughout the day so we can look at that cortisol pattern, which we’ve published the data correlating that to the saliva pattern, and then we measure the aggregate of those samples to give essentially a 24-hour urine equivalent on all the things that you can measure in urine, like the metabolites of estrogens and androgens and all of those things. So it’s a really nice look at reproductive and adrenal hormones. It’s about as comprehensive as you can get on that front.

                                And then after we’ve built that base, then we just started adding things to it that speak to that story. Melatonin, B12 marker, B6 marker, and so on. Filling in the other pieces of that story so that we can tell as broad of a hormone story as we can because a lot of the symptoms that … If you have fatigue, maybe it’s testosterone, maybe it’s cortisol, maybe it’s B12. There could be a lot of different things related to that. So comprehensiveness is the name of the game for us, and that’s where the idea of the Dutch test came from. So that’s the shortest version I can give you of that I guess.

Dr. Weitz:            And hormones other than cortisol also vary throughout the day. So another reason for taking various samples throughout the day as opposed to serum where you’re just getting one sample is that the dried urine allows that as well.

Mark:                    Yeah. It depends on the hormone, but there’s a really old paper where they took some women and tortured them and measured their serum all day long. It was actually astounding to me how a woman’s progesterone would move during the luteal phase from five or six clear up to 30. It’s pulsatile so it bounces quite a lot. I don’t think they’re always quite that variable, but the data they had, it was remarkable and it speaks to the advantage of having something that collects over time. With our four samples, it’s 10 to 14 hours of your day represented. So those ups and downs get averaged out, and I think that that does have its advantages. And serum testing certainly is always going to be a tool that complements nicely I think what we do.

Dr. Weitz:            What are some of the disadvantages of dried urine as compared to other forms of testing like serum or saliva?

Mark:                   There are certain things you just can’t measure there. If a woman’s on something like birth control and her SHBG goes up, that’ll drive down her free hormones. We see that. So oh, you have less testosterone or estrogen than you otherwise would. But in that case, the root cause is a little bit more clear when you’ve got SHBG, which is blood. We always like to complement what we do with a thyroid panel and there are people trying to eke out thyroid in urine, but it really is just better measured in blood. It’s more comprehensive, it’s better researched. So in terms of information, what we do is a lot, but it is just one piece of what we do. If your kidneys aren’t functioning right, urine testing’s not a very good way to measure your hormones because everything we do is relative to creatinine, which you excrete as you should unless you have a kidney issue. And so in those cases, we would push someone elsewhere. And then about, oh, three, four years into this journey, the literature really started to speak to us that there’s a unique story that saliva tells about cortisol that urine can’t quite match, and that is the cortisol awakening response, and that’s why we developed the Dutch Plus.  So Dutch complete is four urines, but saliva’s story of cortisol has a little bit more unique value compared to urine. So we have the Dutch Plus where you do the same urine samples, but also saliva at waking, plus 30, plus 60, dinner time and bedtime. And what you really want to hone in on there is that waking within five minutes and 30 minutes later there’s a gap. And that gap has to be an instantaneous reading and an instantaneous reading, which you can only get out of saliva. And that gap acts as we call it like a mini stress test. So when you’re stressed, your body does this. When you wake, your body goes through that same biochemistry. And so measuring salivary cortisol right at waking and 30 minutes later gives you not only the diurnal pattern that we can see in our urine-only test, but it also gives you the cortisol awakening response or the CAR. And so that gets even more comprehensive, which again is why we have our Dutch Plus, which is just a little bit more information but it’s great for those people really wanting to focus on the cortisol story.

Dr. Weitz:            And one of the advantages, the tweaks that you’ve come up with for that test is that instead of having to fill up this tube with saliva, which by the way is a lot of stress for people, you just have to have these little cotton swabs that soak up the saliva.

Mark:                    Yeah. We weren’t really comfortable doing it any other way because the reality is when you’re doing these things, you get what other people are doing and check it out. And I grab one kit from a company that’s actually no longer in business so I don’t mind picking on them. But here’s your tube. Fill it up with three milliliters of saliva, waking up without rinsing your mouth without eating or drinking anything. Most people, it takes 15, 20 minutes, but that completely negates the value of the CAR because when you hit five minutes, now you’re in the middle of that ramp. So if it’s a 15-minute collection, then it just doesn’t work. And the reason they do that is practical, is that they’re getting the CAR. But they’re also going back into that same sample for progesterone, testosterone, and estrogen, which we think are … Especially estrogen and progesterone are better measured in the urine sample. And it just so happens that those little cotton swabs, which are great for cortisol, absorb progesterone, and so you cannot use them if you’re testing progesterone. So for us, it was a perfect combination of what actually works best but also fits in well what we’re doing with our other testing because you can collect those in 60 to 90 seconds, but that’s really key if you want to know what your cortisol is at a moment in time.

Dr. Weitz:            One of the more interesting aspects of dried urine testing for hormones has to do with the estrogen metabolites. Can you talk about the estrogen metabolites, phase one, phase two, and also where we are with the data in terms of what’s affecting our risk for breast and other estrogen-related cancers? I know that several years ago there was the two to 16 hydroxy estrogen ratio that seemed to be the big factor, and that’s fallen out. And I think it seems to be pretty clear that the two is the healthier one, but maybe there’s more focus on the four as being a risk factor. Perhaps you can talk about that whole issue.

Mark:                    Yeah. It’s a complex issue. When it comes to estrogen, question number one is what’s your status? Are you estrogen deficient? Are you estrogen sufficient? Are you estrogen excess? And for that, you can look at the whole family, but we hone in more on estradiol and to some extent estrone. And we found that the urine test is a really nice way to do that. And then as you mentioned, now we’re looking at the cascade of where does it go? And you’ve got those three doors of metabolism that the estrogen can go through. Two hydroxy, four hydroxy, and 16 hydroxy as you mentioned. 16 hydroxy got a lot of attention before the four hydroxy was really known in terms of what it was and what its mechanism of action was in terms of breast cancer risk. And the main reason for that is that the 16 hydroxy estrogen is just a more active proliferative estrogen.  So I guess you would say it’s more estradiol like your primary estrogen. It’s more effective that way than any of the other estrogen. So it actually hits the estrogen receptor more powerfully than the other metabolites. And in that sense, if you have a woman who’s high estrogen and she metabolizes it down that 16 hydroxy pathway, that’s going to give her a little extra punch, which is going to exacerbate estrogen dominance in terms of symptomatology and need for progesterone to counteract that and that sort of thing. So the 16 is by no means irrelevant but it’s actual play in terms of breast cancer risk, I don’t think is quite as significant as it was initially thought when there was this hyper-focus on just the two and the 16. Because you can move around the two and the 16 and people watch that for a long time. You can give people dim and you can tilt towards two. And when you’re doing that, you’re also impacting the relationships of those metabolites to the four hydroxy, which if you go way back in the literature when they started asking questions about that, we were a little bit later to the game in terms of the four hydroxy.  The four hydroxy has unique characteristics as well. So the 16 is unique because it’s strong as an estrogen. The four is unique in its ability to make a quinone. So that is the four hydroxy means your estradiol has a little hydroxy group on that phenyl ring, and then the four gives it two of them. And because there are two of them, they can create this little reactive group and that can create some problems in terms of damaging DNA.

                                So you’ve got this relationship between the two and the 16. The 16 is this strong estrogen, and then the two is more favorable in terms of its cancer risks. And then you’ve got the same dance going on between the two and the four, but for a different reason in that they both can create this reactive quinone and then that reactive quinone if it’s not detox … And that’s what we talk a lot about detox. Methylation, glutathione, resveratrol to upregulate quinone … There are a lot of different … Well, not a lot. There are a handful of ways to get rid of that reactive species, and if not, they grab onto your DNA. And it happens that the two will let go because it’s a weaker bonding, whereas the four grabs on pretty tight so it can rip a piece of your DNA off. And that’s where it’s thought that the carcinogenic potential comes from is that unique chemical characteristic of the four hydroxy.  So we want to know which of these pathways is favored. And there’s some good research showing that the two hydroxyl has a more favorable profile when it comes to risk of estrogen-related cancers like breast cancer, and that the four hydroxyl seems to be more of a bad actor in that whole equation. So that’s phase one metabolism. Which of these three doors are we preferring? And then there are things that you can talk about to manipulate that. And then once you make them, then one of the main pathways for getting rid of them is methylation. So hydroxylation is phase one and then one of the steps of phase two is methylation.

                                And so for me, when I test my estrogen metabolites on the Dutch test, I don’t methylate very well because I have a COMT genetic defects. I have a single nucleotide polymorphism that I’m homologous for, so I don’t methylate. So what I’ll find is that the ratio is usually two to one. You make the two hydroxy, it’s like 10, you’re going to get five of this. So 10 to five, 10 to five. Well, for me, if I’ve got 10 of this, I’m more down there at like two because I just don’t make that conversion very well. Even when I’m supporting methylation, it’s hard for me to make that conversion because my genes don’t do that very well. So what does that mean? It means those reactive species are not being protected very well by methylation. So it’s smart for a person like me to support things like glutathione because that’s another way that we can get rid of those things. But the first step is just figuring out what your profile looks like. Do I favor 16? Do I favor two? Do I favor four? And then do I methylate well?  And so we like to focus in on the two hydroxy, two methoxy for methylation because we found that’s the most reliable way to look at methylation is to see that conversion there. And we see some relationship there with things like genetic defects and if people aren’t supporting their methylation well enough, and that’s an important protective step. Not the only one, but it’s a protective step. One of the genetic studies show that when you have the genetics that favor four hydroxy and you have the genetics that disfavor methylation, and then there was one other … I think it was the SOD, which is one other detox. One, two, and three. Each of those as individuals wasn’t a big player in breast cancerous, but when you had all three, it was something like six or 12 times higher risk because it just opens up that channel for those metabolites to head in the direction where it’s believed that they cause problems instead of heading in the directions of safety through proper metabolism.

Dr. Weitz:            Do we know is there any relationship between estrogen metabolism and prostate cancer risk in men?

Mark:                   There is some research on that same mechanism for hydroxy estrogen. DHT of course plays a role so the androgen metabolism is important in that as well. Gosh, it’s been a while since I really dug into the research on the men’s side of it. If you go back to where those cells are coming from in terms of estrogen related cancers and things like prostate cancer, there are some parallels there. And so estrogen is not friendly towards prostate cancer. And then if you’re making the four hydroxy estrogens, all the more in terms of risk. But gosh, it’s been a while since I’ve read the studies specifically on that one. It does have value in men as well to have your metabolism heading in a more favorable way, which is why a lot of doctors will use things like diindolylmethane or indole-3-carbinol. Those supplements that really push down that two hydroxy pathway.

                                For me, I always give a little bit of caution for people on that as well in that when you look at the genetic data on the genetics that speed up to hydroxylation, you think to yourself, oh, that’s good. Speeding up two hydroxylation will be favorable, but it actually correlates with overall cancer risks that are higher in certain settings. And I think the reason for that is when you go two hydroxylation with estrogens, we think that’s good. But when you do the same thing with things like poly aromatic hydrocarbons, things that are environmental toxins, a lot of those can use that same enzyme. And when they get too hydroxylated, they become pro-carcinogens. Things that alter that metabolism I don’t think should be given out like Tic Tacs to every patient that comes into your office. We really want to know, does someone have a need for influencing their metabolism preferentially in a particular direction? And if not, then we want to use some caution there.

                                The other caution there is knowing that it’s not just moving. It’s like opening a little vacuum there. So if you have a person who’s on estrogen replacement therapy … We’re actually working on a publication right now showing that women who take dim, it changes their metabolism. Yes. But it also lowers those parent hormones. So if you’re thinking about a woman’s estrogen status, whether it’s endogenous or exogenous, you’re going to be lowering their estrogen status usually when you give dim, and that’s going to be a dose dependent thing. So again, we want to be aware of these things. They’re tools in our toolbox, but we also want to make sure that whatever profile a particular woman has that we’re catering to that in terms of her needs and not just needlessly treating everyone the same way because their individual biochemistry really matters.

Dr. Weitz:            That’s interesting. I’ve talked to practitioners who prescribe hormone replacement and automatically they think that they’re lowering the risk by every single woman that they put on hormones, they automatically give them dim, they automatically give iodine, they automatically give them one or two other things.

Mark:                    Yeah. And there’s some logic there. But I think if you have a woman who’s already a big two hydroxylator and you’re using conservative doses of estrogen, then that may not be in her best interest. Money matters too. So just buying supplements that a person’s body is already shoving in a particular direction may not be something that they need. And the truth of the matter is there aren’t a lot of studies on that particular intervention and what happens in terms of outcomes. There’s an extrapolation there in terms of saying, hey, this profile seems favorable, this thing leads to this profile, therefore this thing leads to these outcomes. Those dots have not been connected in a strong way. And so I think it’s good to just be thoughtful as we address those things. And again, to also know if I put a woman on a patch, then I put that same woman on a patch with dim, it’s a lower dose patch when most women effectively. Because again, you’re opening up that channel of detox. So more than anything, just to be aware of those relationships and to know what’s going on as you’re making intentional alterations to someone’s biochemistry is really important.

Dr. Weitz:            And also a very strong argument for why to test versus guessing, because I’ve also talked to practitioners who say, well, I don’t need to test. I can just tell by how the woman’s feeling.

Mark:                    Yeah. And you can guess and you’ll guess right a fair amount. But I’ll tell you, when you test, you get surprised by someone often. I might put someone on dim and I might test them and then realize, oh, they’re a really, really poor methylator. Well, when you think through this, when you create hydroxylated estrogens and then you don’t methylate well, and then you load that up even more, that may be counterproductive. And knowing that that woman needs more methylation support because of her unique profile is really important. And the thing that I always caution people when you’re talking about HRT … And it’s conventional wisdom, you go to NAMS, you run around with people that are a lot smarter than I am, and most of them say testing is a waste of time. But when we test different people and they end up absorbing at different levels, and you stop and ask yourself, now, hold on, what’s going on with these women? So I pause and I look and I say, okay, let’s stop and look at the placebo studies for HRT. And when you look at hot flash studies for HRT, half of the impact is from placebo.

                                So if I put a woman on nothing. I say, “Hey, here’s your estrogen cream and it’s nothing.” A lot of them will feel significantly better. And then you pause and ask yourself, how did the placebo arm work in bone mineral studies and bone density? You cannot fool the bone with placebo. And so if you have women and all you’re tracking is that they’re feeling better, it’s important. But a lot of times you go to this functional medicine doctor, they’re brilliant doctor, so they’re fixing the gut, they’re fixing all these things. If you give an insufficient dose of estrogen, most of those women are going to feel better doing really positive things in their lives. But if seven years later they have osteoporosis and 15 years after that they break their hip, that’s not a net win on that front. And so that’s where I think it’s really important knowing that from woman to woman on the same therapy, you can get significant difference in terms of what their therapy does in terms of absorption in their actual levels of estrogen. That’s what we’ve been pushing on that front a lot is I think the urine test is a really nice way to monitor not only someone’s baseline endogenous levels of estrogen and their metabolism, but also to give an idea of systemic absorption of estrogen to make sure that what you think you’re doing, you’re actually doing in terms of adequacy of the therapy.

Dr. Weitz:            Let’s continue with that. I want to footnote. I want to go back and ask you about the … Well, let me ask you real quick. The two, four, 16, it seems like a lot of the testing focuses on the hydroxyestrone or the E1. Does what goes for the E1 is the same thing, go for E2 estradiol, which is the hormone most of us are more focused on?

Mark:                    Yeah. The actual impact of, hey, what’s giving someone cancer? They both play into that and you can tease into the literature and see is there a stronger impact of one or the other. What we find is that the estrone is the easiest to measure really well to see what someone’s preference is. Those enzymes, those four-hydroxyestrone four-hydroxyestrodial are different up on this end of the molecule. And then down here you have the four-hydroxylation going on. You have the methylation going on. So they’re very, very similar molecules in terms of what’s going on with phase one and phase two. But it just so happens that the estrone metabolites are at significantly higher levels. So they’re easy to measure really well. In fact, for us, for the four methoxy … Oh gosh, we’ve designed tests for that six, seven, eight different ways and looking at the data, we just don’t feel like it’s strong enough data for us to lean on that in terms of just asking the question, how is my patient methylating I’ve seen a handful of labs over the years add some of those metabolites and then take some of them back when you start to realize the data’s not lining up as well as it should. So for us, we’ve really leaned into what’s most reliable and what seems to correlate best to the actual data that we’re looking at.

                                I’ve seen a number of cases where people have brought to me and said, hey, listen, I’ve got a patient who’s got four hydroxyestrin and four hydroxyestradiol and one of them been methylated really heavily and the other one’s not methylated at all. What do I do? And as an analytical guy, my response is, it’s not likely that that’s biochemistry. It’s most likely that both of those methylated products are very, very difficult to measure. And so you get a little bit of noise and you’re down in that noise for us at an analytical level. And so the reliability of those values and the difficulty in the lab of measuring them well is probably more at play than someone who has some biochemistry where the same enzyme sees these almost identical twin molecules and methylates the crap out of one of them and doesn’t touch the other one. That doesn’t make a lot of sense.

                                And so when we’ve looked at all the metabolites that can be measured, we measure four hydroxy E1, we measure four hydroxy E2. But when it comes to asking a question of what’s going on with this woman’s individual biochemistry, we lean into those that have been proven to be the most reliable. And that’s a complex topic because different labs measure things differently. And I’m not here to throw stones at someone else’s methodology because I don’t get to look behind the curtain at what they’re doing. I just know that I’ve seen people learn lessons over time with some of those things as they’ve measured them and then realized that they’re very, very difficult to measure well at those really low levels, even using the really sophisticated methodology that we all have available in 2023.

Dr. Weitz:            Okay. So let’s continue into dried urine testing to monitor hormone replacement therapy. And this might be a good time to tell us about the paper that you published in the Journal of Menopause, looking at the efficacy of dried urine testing for monitoring women who are taking either compounded transdermal estrogen versus those taking FDA approved gels and patches.

Mark:                    Yeah. When you come into our world and you get educated on this stuff, someone like me is going to have a microphone and oftentimes there’s a lot of speaking with a lot of confidence, but there’s not a ton of data that’s been published in this area, and there’s a lot of extrapolating going on. And that’s been really a passion of ours is to get … Well first to interrogate our own views on these things. And they’ve taken shape over time as the data informs it, but to really get into the peer-reviewed literature. What does this therapy look like on not just our tests, but I’m also interrogating and evaluating. Because I used to run saliva labs. Looking at what these different products look like in all the different tests. And then what I like to do with that data once there is then overlay the clinical data that’s available with those products so that we can see which lab tests are speaking most true to the picture of what’s going on. And the biggest challenge in all of that is the compounded products don’t have any outcome data that’s in the literature. And so the best we can do is to extrapolate a little bit with that data.

                                So what we’ve done, which is not just one publication … That menopause one is a crescendo of several years worth of work, which is taking the most common products that we look at for estrogen and isolating the transdermal products and then looking at the relatively low doses, the medium doses and the high doses, and seeing what those patterns look like in urine in real time in a real data set. And so we published that data then in a couple of different journals, and then this aggregation of the data in the menopause article, which we’re super excited about. The way I work through it is our graph shows patch data and then gel data and cream data. And I start with the patch data because they’re the best characterized. So patches are really nice because one, they’ve been tested against hot flashes, vaginal atrophy, bone loss, all with placebo so they’re really well characterized.

                                The other thing that people oftentimes don’t understand about those products is they’re named after the delivery dose. So when you take a patch, it might have four milligrams of estrogen, it might have 10 milligrams of estrogen depending on what it is and all of that. But the naming of it is how much gets in every day. So a .025 patch has a whole bunch of estrogen and it delivers .025. And then when you go to .05 it delivers twice as much and .1 twice as much as that. So they’re really well characterized. And so we start with that data. And what we see is that women on no therapy that are postmenopausal, of course, end up in that postmenopausal range, and then that low dose moves them up and out of the postmenopausal range. And as the dosing continues, it’s a nice linear trend in the urine and it overlays nicely with the patterns you see in serum.

                                So that’s how I start my frame of mind of the best known products. Then what I want to do with that is overlay, which we’ve done in this paper, the gels and the creams. And the reason that’s really important is because there’s less data on those, but there’s also this huge controversy in our industry because when you put a patch on and you do blood and you do urine and you do saliva, the results look pretty similar. Like, okay, well that makes sense. And then you move to a gel and the saliva values are exponentially higher than what you see in serum and urine. And there were many years when I would’ve told you that because saliva is free hormone, that that must be speaking for the tissue level and so you better lower that dose because there’s a lot of hormone in saliva, therefore there must be a lot everywhere else. And as I’ve interrogated those beliefs that I had, that I had been taught in the industry, what I found is, man, these values are not in alignment with the clinical data on these gel products because they’ve been tested against hot flashes, vaginal atrophy, and a little bit on bone loss.

                                And according to the saliva, we should be using doses that are clinically completely ineffective. And that’s why we really wanted to look at the urine. And when we started the lab, our message was we don’t know. We really weren’t sure what alignment there was between the urine and the clinical. And so this was part of this process years ago before we published this, when we really started digging into the data is what we found is that the lowest dose that’s clinically effective for gels. We know that. Those FDA studies are really nice. They show you what dose works and then they go low enough that you can see it start to fail. And at that point, the values that we see on those low dose products are around the same area as that low dose patch. So minimally clinically effective doses put you in the same range. And I look at that and I think, oh, that makes a lot of sense because when I look at those same products in saliva, the gel is way, way high. Out of the luteal range, really high, giving me the message that, man, I better scale back on that dose. But we know those doses are minimally clinically effective based on placebo controlled studies.

                                So in that, I get a really nice concurrence and affirmation between the lab values themselves and the clinical studies that are done. So we overlay the gel data in this paper and you can see that the data makes a lot of sense, and the patches, they scale up linearly, the gels, they start to tip over, which is exactly the same pattern that we see in serum because the gels are not named after how much do you get in? It’s just how much is on your hand while you’re slathering it all over yourself. And so the low dose is penetrated at a certain level and if you use more volume of that, you don’t get a linear increase. And all of this data makes a lot of sense.

                                So then I can go, okay, now I can look at the big black box, which is the compounded estrogen. We know from the limited studies that have been done that the compounded estrogen creams don’t seem to penetrate as well as the alcohol-based gels and so it takes about twice as much of the cream to drive in as much hormone. That’s what we thought going in. And then when we looked at that data, what you can see is that the creams scale up similarly to the gels, but just at a lower level. So it takes more of the hormone to actually drive in the same amount if the urine is telling us an accurate story. So that’s where my interrogation of that starts is with the patches where everything makes sense and the data is linear and the data makes sense, and then you add on the more confusing of the gels and ask the data, does this make sense based on the clinical studies? And it does. And then we add the cream data in there.

                                And so where it leaves me is thinking that this is a pretty good medium for comparing two women on the same product, whether it’s a patch or a gel or a patch and a gel, just to ask the question, what is our overall estrogen exposure here? And then what we’ve been asking the data is where do those levels correlate with bone mineral density increasing and then the symptomatology relief of hot flashes and vaginal atrophy compared to placebo? Really well-done studies.

                                And so what we’ve been telling people based on that data is if you push people with estrogen and they don’t get out of the post-menopausal range, they’re still down in that post-menopausal range, you’re probably not getting the clinical effect that you want. If you get just out of that range, you’re probably getting mild clinical impact. And as you start to approach the pre-menopausal luteal range, you don’t need to go much higher than the early part of that range. But as you get into that range, that’s where you’re going to see significant clinical impact. And so using the testing to ask the question, how is my estrogen exposure, whether you’re not on therapy or are on therapy, seems to be a pretty strong model for us. The saliva data gives you really, really high data that doesn’t jive with any of the clinical data and the serum data, if you measure a lot of it, it actually makes a lot of sense. But the problem is the up and down pattern is so fast, that’s where serum falls apart, is you’re going to get some low values and think, oh, I need more hormone, but you might’ve just missed the peak because it’s fast. And so the urine, I think is a really nice medium for asking questions related to estrogen therapy. And that’s what we were trying to show in this publication. So sorry, that was a little bit of a long-winded answer.

Dr. Weitz:            No, that’s good. I love this. I’ve got several questions, but the first one is there’s one more form of testing that you haven’t mentioned, which is the pinprick.

Mark:                    Blood spot.

Dr. Weitz:            Yeah. So that’s testing essentially your capillary blood, and there’s some claim that that’s better at picking up these creams.

Mark:                    Yeah. And it’s a very reasonable theory. It just completely falls apart if you actually look at the data. And to be honest, if the clinical data and the blood spot data jived, we would be doing it. Because it’s a beautiful story. It just doesn’t work. And the place that you … And this is really important if people want to interrogate this, well, one, I have reviewed every single study that’s been done on this topic on one particular part on our website. It’s not for those that just want to looky-loo it. It’s pretty deep dive. But here’s the thing. You go to testosterone. Testosterone has tons of data. The pattern is very pronounced, meaning when you put a man on … 25 milligrams is a pretty good place. If you put a man on 25 milligrams, saliva will go sky-high in pretty much every guy. Okay, that tells me something. The capillary blood spot also goes sky-high. Oh, that’s interesting. There’s a correlation there that’s general. If you test people at the same time, the data doesn’t correlate. I’ve done that. But there is this general correlation and this general message that holy crap, that’s a lot of hormone is the general message you get from saliva and blood spot.

                                Okay. What does the serum and the urine say? The serum and the urine are going up modestly. And as you use 50 milligrams, 100 milligrams, they continue to scale up linearly, but on a completely different scale. Remember, if someone’s not on therapy, saliva, blood spot, urine, serum can all correlate fairly well. And then this is the place I start people on this so they understand how little sense this makes. Is if you give those men an injection, the serum, the urine and the saliva all correlate. There’s a very similar pattern. They dance together. There’s one nice study where they did that, and you can see this very parallel pattern. All the people start low, you give them an injection. And in this case it was this long scale, 84 day cycle of an injection or whatever. But at the peak, the saliva was high, the blood was high, the urine is high, so they’re similar. Okay, now stop. Now give them all a gel. You give them all a 25 milligram gel. The saliva and the blood spot go crazy high and the serum and the urine go up moderately. And if you give them 50 milligrams, the serum and the urine will go up again and the saliva and the blood spot will go up again. But again, on a totally different scale.

                                You say, well, perfect. Because testosterone, we have studies at 25 and 50 milligrams, and where we’ve looked at all the things that change with testosterone. Erythrocytosis, muscle mass, LH suppression, sexual function. All this stuff. You can look at the men, then you can shift and you can look at the women. Look at women who use doses that saliva and blood spot say, are you crazy? You should never give a woman this dose. Whereas the blood and the urine are saying, yeah, that’s a reasonable female dose. So we can look at what happened. And then you also have a body of literature on trans men. Super helpful to interrogate this question. Because according to saliva and blood spot, five, 10 milligrams given to a biological female should be incredibly effective at creating the changes you would want to see if someone was transitioning from a female to a trans man. And all of that data dances with the serum and the urine and none of it, not a single study says, you know what? That serum is really underestimating what’s going on in these humans be they male, be they female, none of those studies.

                                Erythrocytosis is the easiest place to see it. I think that makes a lot of sense. If you give a man an injection of testosterone, his erythrocytosis will go up like 60, 70%. Not crazy injections, not I’m a weightlifter body builder, whatever type, just normal injections. Erythrocytosis goes up pretty heavily. Okay, good. Now, if you give a man 50 milligrams of a gel and you pause and you say, okay, let each camp make their prediction, what would you predict? Well, the saliva is saying you’re using 10 times too much hormone. You’re insane. Erythrocytosis is going to go crazy. Whereas the serum and the urine would say that dose of 50 milligrams is clinically effective, but it’s less of an impact than that injection you just gave those other men.

                                And then you look at the erythrocytosis and guess what? It’s significantly less of an increase than the injection. And you go, oh, okay. As it relates to erythrocytosis, serum and urine were telling the truth and for whatever reason, saliva and these blood spot values, which are super interesting intellectually academically fascinating … How is there hormone there that isn’t speaking to erythrocytosis? The problem is when you move to LH suppression, it dances with the serum and the urine. When you move to muscle mass … There’s a great study on muscle mass increase where they took men, they shut down their endogenous testosterone with drugs and then they gave them testosterone back. So they gave them gels. And then they said, okay, split them into two camps. This camp had higher serum than before. This camp had lower serum than before. Now remember, with these doses, everyone’s saliva is super sky-high. Which people had muscle mass increase? Only the men whose serum went up.

                                So you start interrogating these … And this is what I did. I’m working in a saliva lab, I’m doing this, I’m slathering testosterone on myself as a 30-year-old man to try to test this stuff to say, I got to figure out a model where I can start interrogating this, finding data to be consistent with the clinical data. And I just threw my hands up and gave up because you could never make sense of it. And then I did what I should have started off doing is digging into the literature. I’m like, hold on, let’s go see what the literature says about the doses that we use and what happens clinically. And I just walked away going, oh, I expected to find controversy in these studies of, well, these imply serum is right. These studies imply serum is an underestimation and gee, maybe saliva is right, maybe blood spot testing is telling a more true story. But I literally could not find a single study on either estradiol or testosterone where the data implied at all that there was some mysterious way that saliva was telling a true story. So my overall … I wouldn’t say theory. Model that I use, which probably doesn’t describe it exactly, is this. Saliva and capillary blood spot have special access for fat-soluble hormones if they’re applied to the skin. If I filter all of the data through that, it all makes sense to me.

                                Now, I don’t know how it gets from the skin on your foot or the skin on your arm into your saliva gland without getting into the bones and the brain and all of that, but it does. And so that’s where I’m left in that debate and I’m left with testosterone, serum being the gold standard, urine being a nice compliment. And with estrogen therapy because of the pharmacokinetics, I think urine is the best primary way to ask the question, how much did I absorb and then to ask how did I metabolize? So it’s a super complex topic. I’ve dug into it more than anyone I know, and I’ve completely done a 180 on it over about a 15-year period. It’s an interesting topic, and unfortunately there’s a huge section of our educators that really aren’t digging into the literature. They just plant their flag on their position and hold to it. And that’s something that I’m pretty passionate about making people aware of is that if you’re listening to that message, you want to do that and use that model, you can, but you got to know you got no safety net of peer-reviewed literature. It’s all stacked up against that saliva model, which incorporates also the blood spot. So it’s super fascinating. No idea how the blood distributes into those things without getting systemic, but all the data imply that that’s the case.

Dr. Weitz:            One critique I could see someone having of your paper is that you’re comparing a 100% E2 patch to a compounded cream that’s 80% E3 and only 20% E2. So wouldn’t you expect less E2 to show up?

Mark:                    No. We did not take any of the biased data. The paper that we did … So one of the reasons that the cream data is a little jagged and dirty is it’s a smaller subset because we only looked at people on only E2. That’s not bias data.

Dr. Weitz:            Oh, okay. I thought I read that-

Mark:                    There is a serum paper that I cite often because it’s the only … I don’t know how this is true in 2023. There is only one paper that shows compounded estradiol in serum, and that is a bias paper. It’s in a lot of my lectures, so you might be thinking of that one. But that one was … I think it was something like 80/20. And so they followed the estradiol pattern, but those women were also on E3 which no doubt changes things to some degree. We have a whole bunch of bias data too. The problem is it’s really, really dirty data because when women tell us what they’re taking and they tell us when it starts being 80/20, 70/30, 50/50, the confidence with which we know how much estradiol is in one woman’s prescription is just so low that we look at that data, but I don’t think we could ever publish it. So we honed in only on the women that said E2 only was their prescription. So that data is just estradiol.

Dr. Weitz:            I see. Maybe we could touch on one more topic. One of the advantages of doing the dred urine testing is for women whose periods are irregular and maybe they’re trying to figure out what’s going on … Maybe there’s some PCOS symptoms or they’re not sure if they’re in perimenopause or not, is the cycle testing. Being able to measure their hormones every day of the month.

Mark:                    Yeah. So we call it cycle mapping. We have women collect almost every day from day seven until the end, and then if they just don’t have it and it’s longer, they just keep collecting. So what we do is we take the nine most relevant measurements from all of those. So what we’re trying to do is characterize the ovulatory peak and characterize the luteal peak with nine measurements. So that’s what we use that for. It’s a really nice tool for, as you mentioned, people who have wildly irregular cycles or women who … If you’ve had an ablation, which means you don’t bleed anymore, but you still cycle, you have no idea where your luteal phase is. So in cases like that, partial hysterectomies where you don’t have a uterus, but you do have ovaries. Fertility cases where you don’t just want to know, did my progesterone peak, but you want to know, am I maintaining that progesterone. Cases like PMS where maybe you’re fine until the tail end of your cycle and then you feel terrible. So you can interrogate the question of, gee, did my progesterone drop off a cliff? Did my estrogen rise? Did both of those things happen? That type of thing that relates to the timing of the hormones is the purpose of that test.

Dr. Weitz:            Okay. Cool. One more quick question on the paper and then I think we’ll wrap up. Is what we should take from the data about the compounded transdermal estrogen, do we think it’s the way the compounded cream is made, what it’s mixed with why it’s not getting absorbed? Is it that we’re just not prescribing enough of it? Why isn’t compounded estrogen transdermal cream working as well as we thought it was? Do we know?

Mark:                    Well, in terms of absorption, I think you do get less, but this is a general statement made about many products. Some of these women are using a VersaBase, some are using a different base, some are putting it on their forearms, some are putting it on their thighs. It’s a big mix of data. But you can even move out of the compounded world and just go look at Evamist. Evamist is an FDA product. It’s terrible. I’m not saying it doesn’t work, but you have to use four or five, six milligrams to drive in very much. You’ve got just dobs of estrogen everywhere. So I would never suggest that people use that. Now that data is worse than what the compounded creams look like relative to the gel. But there’s a nice paper out of Australia where they looked at serum levels of compound … Not compounded.  There are very few FDA cream products. There is one FDA cream testosterone product in Australia. And so they did a study where they compared … It was probably AndroGel, but I don’t know if it was specifically that product. But a testosterone gel versus their cream product. And what they found is the serum pattern looked exactly the same if you use two X. And this is already a known thing that the alcohol in those gels drives in the hormone such that the absorption is at a higher rate. Now what does that mean? What it means is for the gel, maybe you’re getting 10% absorption and what the cream, maybe you’re getting 5%. Now what you do with that information … You could use it to critique the creams, but it’s not like the gels you’re driving in 50%. So it’s just a matter of what’s the purpose of using a compounded product? For me, those patches are really well standardized, if the pricing and the compliance and all of that is fine, work pretty well, whatever. But when someone needs a compounded product because you want Estriol in there or you want some-

Dr. Weitz:            Well, that’s one of the reasons why is a lot of doctors practitioners feel that you’re lowering breast cancer risk by giving the Estriol as part of it.

Mark:                    Yeah. And you’re talking to a chemist here so I am not an expert in that, but my team’s been researching that pretty heavily, our clinical team. And it may be true, but I don’t believe that’s a proven … That’s a theoretical concept that we’ve run with that I think our industry would be wise to put some effort into in terms of evidence, in terms of whether that actually plays out in real life or not.

Dr. Weitz:            I think that’s come from just a concept that Estriol is a weaker estrogen.

Mark:                    Right. Right. So then is it better to use a lower dose of Estriol and leave it alone or is it better to Estriol? I honestly do not know. But if your conviction is that you need some Estriol in there, absolutely use a compounded product. And you can know that from one compounder to the other for how your patient puts it on, where they put it on the absorption is going to be different. Now that doesn’t mean it’s a bad thing. What it means is it’s a little bit of a black box for you. And that’s where I think the testing comes in helpful. But where it just so happens because of this paradox with saliva testing that the tool that you grab to ask the question, how’s my estrogen dose profoundly changes your dosing?  I know so many people when I was in the saliva world that would use .05 and you think oh .05 cream. Hey, a .05 patch is pretty big. And guess what? When you use a .05 cream, you can get higher numbers in saliva than a .05 patch. But then you pause and you step back from that and go, wait a minute, the .05 patch has like five milligrams of estrogen in it, and I know I’m delivering .05. The .05 cream means on your skin is .05 and then how much gets absorbed? Well, the question to that depends on which test you use. If you use saliva, what it’s implying is it’s all absorbed. That this barrier called your skin allows all that hormone through. And maybe that was going to be true, but as the clinical data has come out … And we can look at all the studies, it’s not true. When you look at a gel of .25 and .5, it appears that maybe 10% of it gets through. And the truer lab value that is aligning with the clinical data on that, I think is the urine.

                                And so I think using a product that drives a urine level up into that range where either a .025 or a .05 patch sends the average woman is the place at which we can be, I think more assured that estrogen’s efficiency is being achieved. And so if you’re using a compounded product, I think that is the way to go in terms of asking yourself, how much did I actually deliver? Because again, the blood test is going to change too fast. The saliva test is going to give you a big number that so far as I can tell, has zero clinical relevancy. And I know that that will step on some toes, but you can’t point to a single study that leans in that direction. They all lean in the other direction. So if people want to go in that direction, they can. We are not going to be offering that testing for that very reason that we just can’t substantiate the worthiness of those values in those situations. And the urine seems to be doing well in terms of telling a story that’s in alignment with the clinical data.

Dr. Weitz:            I noticed when you mentioned the amount to achieve better bone health, you didn’t mention anything about cardiovascular health. Do we think that’s a similar amount or are we more confused about the cardiovascular picture these days? Do we still think that estrogen has serious cardiovascular risk reduction?

Mark:                   We as a pronoun, that involves many of us, including me, but I am not an authority on that topic at all. So I would have to defer to people like Dr. Doreen Saltiel, and people that are experts in both the cardiovascular and the HRT side of it.

Dr. Weitz:            I thought they went hand in hand.

Mark:                   I think it’s a little bit more less clear in the literature, and I believe there is some justification for moving up just a little bit higher. So in serum instead of that 40 to 60 to range to maybe more that 60 to 80 range. But I am by no means an expert in that except to say that there are cardiovascular benefits of HRT, but where those target values are specifically for cardiovascular disease, I would not want to speak to specifically because I wouldn’t consider myself an expert on that side of it, even mildly.

Dr. Weitz:            Sounds good. So how can viewers and listeners … Practitioners find out more about the Dutch test, and I guess patients, lay persons who are listening to this find a functional medicine practitioner who’s offering the Dutch test?

Mark:                   Yeah. I think for patients, if you go to dutchtest.com, you’ve got to find a provider function. We always try to push people in that direction because this is complex stuff. Trying to walk this path on your own without a really good healthcare provider I think is very, very difficult. For providers at dutchtest.com you can sign up to become a provider, and we’ve got all kinds of educational resources. We just launched a mastering functional hormones course, which can be a really good way to just dip your toe in a little bit at a time, but then emerge from it competent at this whole hormone game. It’s just like hormones 101 and Dutch 101. And that’s would be my encouragement to a provider, is to try the test as a provider, but also go through our education there is really helpful.

                                And our team is … We’ve got 10, 12 doctors on staff who use this in their practice and are ready to help people get over that bridge of comfortability with the test. Because the Dutch test offers a lot, and that’s a two-edged sword in that it takes a little bit of time to get up to speed with what do I do with cortisol metabolites? What do I do with the androgen metabolites? How do I tie it all together? What some of these organic acids that you’re including and how does it change my treatment protocol? So we are really focused on education and helping people really leverage the testing as much as it can be. And again, for patients, go find a provider that is really gifted at functional medicine that can help you with your own health journey. If patients want to order the test on our website, they can, but we really do encourage people to order through a provider and to go that direction because I think that’s a … You’re going to get better outcomes I think, when you have an expert to walk your path with you.

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

Mark:                   All right. Thanks Ben. Appreciate the time.



Dr. Weitz:            Thank you for making it all the way through this episode of the Rational Wellness Podcast. For those of you who enjoy listening to the Rational Wellness Podcast, I would certainly appreciate it if you could go to Apple Podcasts or Spotify and give us a five-star ratings and review that way more people will discover the Rational Wellness Podcast.  And I wanted to let everybody know that I do have some openings for new patients so I can see you for a functional medicine consultation for specific health issues like gut problems, autoimmune diseases, cardiometabolic conditions, or for an executive health screen, and to help you promote longevity and take a deeper dive into some of those factors that can lead to chronic diseases along the way. And that usually means we’re going to do some more detailed lab work, stool testing, sometimes urine testing, and we’re going to look at a lot more details to get a better picture of your overall health from a preventative functional medicine perspective. So if you’re interested, please call my Santa Monica Weitz Sports Chiropractic and Nutrition office at 310-395-3111, and we can set you up for a new consultation for functional medicine. I’ll talk to everybody next week.


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