Androgens – The Good, The Bad, and The Ugly

In this foundational lecture, Mark Newman will take a deep dive into interpreting androgen metabolites through the DUTCH test, openly discuss the pros and cons of all available androgen testing, and why certain ethnic groups may have unique challenges when using urine for monitoring testosterone and DHT levels.

In this webinar, Mark will explain the differences between measuring DHEA/DHEA-S in serum and what we find in urine. We’ll also explore why we consider DUTCH a complimentary test for testosterone replacement therapy and why we still consider serum the gold standard, and primary test, for TRT monitoring. However, DUTCH androgens have unique insight not available in serum. Urine is rich with metabolites, giving insight into testosterone and DHEA production. Unlike DUTCH estrogen metabolites, testosterone metabolites have significant caveats that must be considered.

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Please Note: The contents of this video are for educational and informational purposes only. The information is not to be interpreted as, or mistaken for, clinical advice. Please consult a medical professional or healthcare provider for medical advice, diagnoses, or treatment.

Disclaimer: Special offer of 50% OFF first five kits is invalid 60 days after new provider registration.

Full Transcript and Time Stamps

(1:00) Marketing Team Introduces Webinar Information

(5:12) Mark’s Introduction

(7:36) Mark begins lecture

(10:22) Serum Testosterone

(13:52) Clinical Studies

(18:42) Salivary Testosterone

(24:19) DUTCH Published Data

(26:32) Urine Clinical Utility

(28:20) Urine Androgens: What stories are we telling?

(33:34) Female and Male Case Studies

(38:24) Urine Androgens: Advantages and Problems

(45:46) Urine Metabolites Case Study

(52:37) Monitoring TRT

(1:00:51) Q&A

(1:10:59) Wrap-Up


(1:00) Marketing Team Introduces Webinar Info
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Good afternoon, and welcome to Webinar Wednesday. Today's webinar is on Androgens: The Good, The Bad, and the Ugly. My name is Tim Burke, and I'm a member of the DUTCH marketing team.

(1:12) I wanted to thank you all for taking the time to be with us today.

(1:16) I have a few housekeeping items before I introduce Mark Newman, who is our speaker today.

(1:22) We have a great opportunity for all new providers to try out a DUTCH test, or 50% off up to five test kits. This includes free clinical consults, video tutorials, and patient referrals.

(1:35) It's simple to sign-up, just click on the link that we will post in the chat and complete the Become A Provider form on our website. After you complete the form, someone from our team will set up a one-on-one appointment with you to answer all your questions and walk you through our onboarding process. For more information about DUTCH testing and our webinars, e-mail us at sales@dutchtest.com, or call (503) 687-2050.

(2:05) That will be also posted in the chat.

(2:08) I've added the slides, or we'll add the slides, to the handouts section at some point in the webinar today for you to access, and we will also be sending the slides out tomorrow for all who registered.

(2:20) We will answer as many questions as we can at the end of the webinar. You can submit your questions in the questions section on the side panel of your screen throughout the webinar, and I will choose a few for Mark to answer when he's done.

(2:35) Once again, we will send out the webinar, and a link to the presentation tomorrow once we have everything done.

(2:46) If you're not familiar with Precision Analytical and the DUTCH test, that's stands for dried urine testing for comprehensive hormones. Our validated 24-hour four spot dried urine tests provide a complete evaluation of sex adrenal hormones, including metabolites or baseline hormone testing and effective hormone replacement therapy and monitoring.

(3:10) We offer simple and convenient at-home collection for patients, and an easy drop-ship option for providers, and our advanced testing methods help providers answer the most complex clinical questions with the most reliable and trusted results. In addition, our customer service and in-house clinical consulting team are always available to answer your questions.

(3:31) At this time, I'd like to introduce to you Mark Newman, our presenter today. Mark Newman is the Founder and President of Precision Analytical, Creator of the DUTCH test, and is a recognized expert and international speaker in the field of hormone testing.

(3:48) Mark has spent nearly 20 years within specialty laboratories, developing and directing 24-hour hormone testing, organic acids testing, and salivary hormone testing gaining unique and thorough perspective on blood, urine, and salivary hormone testing.

(4:07) This unique experience led to a vision for a revolutionary way to test hormones. Mark began his own lab, Precision Analytical, and is the creator of the DUTCH test.

(4:19) The question of how best to test hormones is what drove the creative process that initiated this lab.

(4:26) Blood, urine, and saliva testing all have significant limitations.

(4:32) DUTCH has a unique testing method which bridges the gap between existing methods to create better tools for health care practitioners to address the needs of their patients. Mark is committed to advancing innovations in hormone testing and helping healthcare practitioners find solutions and treatment protocols. Mark has educated thousands of physicians on the different hormone tests available and best practices, especially in HRT and BHRT monitoring. So, without further ado, please join me in welcoming Mark Newman.

(5:09) It's all you, Mark.

(5:10) Thanks, Tim.

(5:12) Mark’s Introduction
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Happy to be here today, and thanks for everybody joining us.

(5:17) Tim mentioned that we have a clinical staff that's available to answer questions and today's webinar is about an area where we get a lot of questions because it's a complex topic, and that is androgen testing. And we're not just going to hone in on the DUTCH test. But we're going to look at the pros and cons, which is something we like to do often.

(5:38) And to try to help you as practitioners understand where are the strengths and the weaknesses of all blood testing, urine testing, and saliva testing so that we can leverage the right tests at the right time for your patients.

(5:52) And often times, you know, we do these types of seminars because it's great for education. It's good at growing our business.

(6:00) In this particular case, my concern is not that you're all using DUTCH testing more. My concern is, with this complex topic, is that you're reaching for the right tool, at the right time, that you understand the strengths and the limitations.

(6:17) You know, no one's in a better position to highlight the strength of what we do, than we are, and so we do that. But likewise, no one's in a position to really help you understand some of the caveats of using a urine-based test when it comes to something complex like the androgens.

(6:34) And so today we really want to go through the details of that, so that we understand. So, I didn't write out an objective slide. Oh, before I get started, let me just tell you kind of what we're going to do. We're going to go through serum saliva. You're like, what are the pros and cons? Why would we grab one of those tests at a particular time?

(6:55) And then we're going to talk about the validation, we'll show you some of the validation data for the urine testing, show you where it's strong, when it comes to this story of the androgens. And then also show you some of the unique challenges of measuring androgens, particularly in urine, so that you're well informed on that. Because there are some interesting idiosyncrasies to urine testing of androgens. And then we're going to dive in at the end a little bit to hormone replacement therapy monitoring and how some of those metabolites that we measure are helpful for that.

(7:32) Let me get my camera out of the way and we'll get started.

(7:36) Mark begins lecture
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So, just a reminder here of what we're looking at: three different tests, three different forms that we find it.

(7:44) So, let's just say in a female, the ovaries make some testosterone. Obviously, it's going to be from the testes in men. That hormone represented there by the little purple H is going to circulate, mostly bound to a binding protein, right? SHBG, sometimes, albumin. When we draw blood, that's what we're measuring, is total hormone. And when we say total, we mean the hormone that's free, which is not very much, and then the hormone that is bound to the binding protein.

(8:13) That's what we get in blood.

(8:15) Now, the free hormone is able to slide into saliva. So, when you measure testosterone in saliva, you're not seeing the protein bound hormone, you're just seeing the free hormone.

(8:26) Now, if we're talking about urine, that's also true as it relates to cortisol.

(8:32) So, when we measure cortisol in urine, we're measuring free cortisol, just like all the hormones that you would measure in saliva, but when you talk about a hormone like testosterone, can it get into your, no, it really can't, because it's not water soluble. And so, it can't get in until it hitches a ride to the liver, and gets a polar little moiety put on it. So now, it's not just testosterone, it’s testosterone glucuronide, or testosterone sulfate.

(9:00) You're not able to conjugate it like that unless it's bioavailable.

(9:04) So, it's a nice reflection of bioavailable hormone, but it is a different type of measurement. So, for each of these measurements, they're actually different. They should correlate generally, but it's never going to be apples to apples to apples.

(9:20) So we have to think our way through this when we look at the pros and cons of using those tests, whether it's for baseline testing or for hormone replacement.

(9:31) So with androgens, and again, this is sort of the heart of this talk, is it's complicated relative to other measurements.

(9:41) So in women, elevations in androgens seem more easily tied to clinical outcomes, but androgen deficiency, particularly in women, that's where I think you probably get the most complex picture of what's going on with the androgens, and what we're going to see is that a broad view of the androgens seems prudent and particularly for females.

(10:06) So looking at DHEA, looking at testosterone, but also the metabolites, and we're going to talk a little bit about the advantages of using both serum and urine in combination to get a complete picture when it's necessary.

(10:22) Serum Testosterone
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So first, let's talk about serum testosterone.

(10:26) So, it is, I would say, the most reliable way to monitor testosterone as a single test.

(10:31) Like, if I want to look at testosterone and that's all I want to look at.

(10:34) Serum is the most reliable way to do that. You're usually going to test it in the morning because there's an up and down pattern. It's going to be highest in the morning. You do lose that as you age. But usually, you're going to standardize it. That's the best way to do that is to do an early morning blood draw.

(10:52) To look at testosterone, you're going to want to include things like SHBG, albumen, so that you can calculate a free testosterone. Now, there's a whole conversation to be had about whether measuring free testosterone is better or calculating free testosterone, my experience in that is limited.

(11:12) But my understanding of free testosterone, not as a calculated value, but as an actual measurement, they're pretty sophisticated tests. They're difficult to do well. So for me personally, I would rather know what SHBG and albumin are doing, and then allow free testosterone to be calculated, you know, as your SHBG goes up.

(11:34) That's really relevant because the amount of free testosterone is going to go down.

(11:38) So, you're going to have other tests, as well.

(11:41) Sometimes sex specific, whether you want to look at estradiol, or LH, or FSH, or some of these other tests.

(11:47) But when we're just talking about measuring testosterone, the one thing that's really important, particularly in the female levels, is we really need to make sure we have an accurate test, and it makes a huge difference. So, let me show you the data where I would draw this from as an analytical guy, and then I'll show you the clinical data.

(12:03) So, you can see here, it's testosterone, what are we looking at here? What we're looking at here is on the X axis, is what we'd call our gold standard method. So that's your LC-MS.

(12:13) And then if you want a cheaper test, you can do just your standard assay, which pretty much any lab can do. And when you look up in that male range of, you know, 200-ish to a 1,000-ish, it doesn't really matter which test you use. So, save a few bucks and do it the cheaper way, that's fine.

(12:31) But when you zoom in on the female range, the cheaper assayer are basically moving away from CMS. I think, not advised. You do see the same thing with estradiol. You see all this data that looks nice.

(12:43) But when you zoom in on the post-menopausal range, where you're going to find post-menopausal women, men, children, the cheaper test basically falls apart.

(12:54) But, when you're looking at serum-free testosterone, it is meaningful, particularly in looking for elevation.

(13:00) So, this study, we don't need to read the specifics of this, but they found that free testosterone really did a nice job of differentiating PCOS patients from patients that don't have PCOS.

(13:13) So, as you have higher androgen production, higher testosterone, when you're looking at both total testosterone, but especially free testosterone, if it's measured well, you're getting a nice differentiation between PCOS and I'm using PCOS studies a lot here.

(13:29) Because PCOS matters, but in a way almost representatively of those that have elevated androgens in the female population, you can have high androgens and not be PCOS.

(13:41) But when you find people diagnosed with PCOS, it helps us understand whether a lab test does a nice job of differentiating between those with high androgens and those that don't.

(13:52) Clinical Studies
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Now, here's a study that's looking for low androgen issues and they concluded no single androgen level is predictive of low female sexual function.

(14:01) So, they're looking at stuff related to low androgens, and they're looking at androgens. And they're basically saying, well, we wouldn't really see anything here.

(14:09) What's weak about this test is one, they don't include metabolites, which we're going to show here are actually potentially as important, or even more so, in some cases, than testosterone itself. But the bigger issue with this particular test, for testosterone, is they're using one of those cheap assays and amino assay.

(14:28) And here's a paper that I've never really seen someone get quite this sarcastic in a peer reviewed article. But they actually named this, is this better than a guess?

(14:38) And then they actually wrote guessing, would be more accurate and additionally, could provide cheaper tests, because you've got to test. So, they're being a little bit tongue in cheek there. But what they did is, they looked at the amino assays for testosterone. So that's, again, just your standard cheek hospital test.

(14:53) Our lab tests for testosterone, that's not LC-MS.

(14:56) And when they really broke it down, they said, we literally aren't much better than just guessing, which obviously, is not where you want to be, as a provider.

(15:07) Here's another paper that just starts to give the message.

(15:12) This is pretty complex. Right, serum testosterone levels do not account for the testosterone synthesized in peripheral target tissues and the individual variability in the sensitivity of the androgen receptor. Furthermore, the clinical effects of androgens are tissue specific and not solely related to serum levels.

(15:28) They are affected by metabolism by aromatase, which turns it into estrogen, by five alpha reductase, which turns it into DHT, and influenced by other factors that can cause a regulation or down regulation. Moving over to the right, low androgen concentrations, and women do not reliably predict clinical findings, and serum testosterone levels are not independent predictors of sexual function in women.

(15:53) So, part of the difficulty, if you think about testosterone, is you make estradiol, right? And we measure estradiol, and it matters and its metabolites matter, but none of its metabolites are better at doing what estrogen does than estradiol itself, right? So, the metabolites help fill in the picture. Maybe they teach us something about breast cancer risk, and they give us a more complete picture.

(16:15) But estradiol is the one that matters the most. Right? When you go to progesterone, progesterone matters the most, although the metabolites are interesting. Allopregnanolone is interesting as it relates to oral progesterone and sedating effects.

(16:27) But progesterone is the main thing, right? With testosterone, you know, DHT is three times as potent as testosterone, so the hormone that we talk about, and that seems to matter the most, is actually significantly less potent than what it gets turned into, and that's why testosterone gets a little bit complex when we go to measure it.

(16:48) And here is an interesting study where they said the glucuronide androgen metabolites are stronger predictors of bone mineral density than testosterone or DHT themselves.

(17:03) And so we start to start to unpack that. This is pretty complex.

(17:09) Here again in the yellow, there intracrine androgen synthesis often not reflected by circulating androgens, but rather by androgen metabolites and conjugates.

(17:22) And I'm happy to share these papers if you'd like to see, this one shows sort of pictorially what's going on, so this is why it gets complex, is testosterone is circulating and, like, DHT is also circulating out here and circulation.

(17:40) And then, but what happens is, testosterone goes in the cell. In this cell, it gets turned into DHT and that's the DHT that really matters, right? And it does its thing. It hits the receptors stronger than testosterone, but within that cell, it gets turned into a DHT metabolite.

(17:58) Here, they're calling it the three alpha dial, that's actually one of the things that we measure on the DUTCH test. So, you have three different things and the androgen sort of pathway here.

(18:08) But what's going on is, within this cell we don't necessarily get a window into that cell, but you can see what they're saying here, of the title of the paper, is that implies what matters the most is happening in the tissue.

(18:25) And then this paper, which is just from 2019, says it's important to consider both androgen precursors and metabolites when assessing androgen action, while androgen precursors and active androgens can be measured in serum, it's often more convenient to measure their metabolites in urine.

(18:42) Salivary Testosterone
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So, serum testosterone is an important measurement.

(18:46) It's most reliable in serum when we're just talking about testosterone, but the picture is more complex than that, because the things downstream from testosterone are really, really important, too.

(18:59) Um, I'm not going to talk about serum measurements of androstanediol-glucuronide, but that's essentially what you end up with, is testosterone turns into DHT, which turns into androstanediol, which is then conjugated, and the paper that I just showed you implies that that measurement in serum is actually a better way to test DHT in serum, than to test DHT itself.

(19:26) So, it's complicated. Does serum testosterone matter, yes? Particularly for elevated women, PCOS, those types of things.

(19:36) It does a pretty good job of differentiating, but when you get down to ask them questions about deficiency, it gets a little bit murky.

(19:44) Now, what about saliva? Saliva has the potential to effectively monitor baseline testosterone. But the levels are very low.

(19:56) And typical methods, I think, are really not up for the challenge for what's usually used commercially. Now, LC-MS is best, but it's difficult to do as a laboratory, most labs don't use that, but here's the potential.

(20:13) This is salivary testosterone, and this is a blood sample measuring free testosterone.

(20:19) And that is, that's gorgeous, right? That shows some really nice potential.

(20:25) That's from an RIA, which is kind of an older type of technology, but it involves a lot of work of prepping the sample a particular way to make sure that the analysis is good. That is not a method that's available commercially, I would expect that that data would match up really well with LC-MS data, but not necessarily with commercially available, which tends to be EIA's, LIA's, sometimes, you want to say, Elisa, the typical tests that are available don't have great data associated with them. So, here's some of the published data, for salivary tests, that are actually commercially available.

(21:04) So, in this one, it's showing estradiol and testosterone and looking at blood levels.

(21:09) You can see the estradiol levels here, which is, this is actually the only serum correlation data of estradiol that I've seen for salivary estradiol that's shown with a commercially available assay. And it's just not a very good correlation, right? We're looking for a 1 for 1 correlation with our R value, at least at point seven or point eight. And with testosterone, it's a little bit better there. But it's not great at those low levels. The assays are not great.

(21:41) Now here's a comparison where they looked at, this is just saliva samples tested one way, gold standard, mass spec, and then three different assays that tend to be used more in commercial testing.

(21:54) And so, you're hoping to see things right along that orange line with the value there. That's a whole lot closer to one, so these are three different assays.

(22:03) What they're basically saying is, it's difficult, right? What we showed in blood is that when you use this type of technology, when you get down into the female range for blood, it kind of falls apart.

(22:14) And in saliva, even the male ranges down that low because there's less hormone in saliva. And so, you just don't get great data unless you're using pretty sophisticated methods.

(22:24) And that doesn't tend to be what people are using. So again, that on the left is a saliva sample measured one way and measured another way. On the right with a more sophisticated method, that's saliva versus blood.

(22:36) So, that's much more difficult to get to correlate because it's a different sample, right? And yet it's a lot stronger, why?

(22:43) Because the methods are more, maybe sophisticated is not the right word, accurate would be probably the better word, so saliva shows potential, but what's available is probably not the best option.

(22:58) This is not the place to get into this whole debate.

(23:01) But you do find people who believe that the unique message you get in saliva for creams and gels for testosterone are more clinically accurate.

(23:10) If you actually look at the clinical data that shows what happens with creams and gels clinically, and then you look at urine and serum, it aligns much more strongly with what happens clinically. So, I would definitely not use saliva for HRT monitoring.

(23:28) And so for us, you know, we can develop salivary testosterone if it has a unique message. We'd do it by LC-MS. We could do that if it was helpful. But we really feel like, with the current state of things, that saliva is just best used for cortisol.

(23:43) So, that has left people historically with this sort of combination of, you know, measuring sex hormones in serum, hopefully using LC-MS here and here.

(23:54) And then going to saliva to get the cortisol picture, because cortisol is not very good in saliva, and that's where DUTCH came in and said, look, if we can measure these hormones, and we can measure the metabolites and some of these other things, like, that's a nice way to go. It also gives you the cortisol pattern and that's our DUTCH complete. And then if you say, well, I really value, which I do, the cortisol awakening response, not just the up and down pattern of cortisol, then you're going to go to the DUTCH Plus.

(24:19) DUTCH Published Data
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Just for a second, before I get into the particulars of urine, I just wanna brag a little bit on our published data over the last couple of years. So, we've published our cortisol data showing that if you use dried urine collections, and you look at this up and down pattern of free cortisol in urine and saliva, get nice correlation between the two. That was a really important data for us to publish for both of our assays, serum correlation, 24-hour urine correlation, for estrogen and progesterone.

(24:51) So, that paper was published in 2019. You can look at that if you want, and I will just say, this was pretty exciting. I'm going to share this with you, even though it has nothing to do with androgens. The North American Menopause Society accepted three of our abstracts looking at our clinical data when on therapy. So, looking at, here's your post-menopausal range, pre-menopausal range. And this is our actual data from all of the testing we've done over the years, looking at estradiol patches and looking at different doses from lowest all the way up and seeing that that data scales nicely. We showed the same thing with gels.

(25:25) So, that was a separate publication for North American Menopause Society and then we also looked at creams.

(25:31) So, this is estradiol creams.

(25:33) And we did a little three-way comparison and that was also accepted for publication for North American Menopause Society. That shows that the lower dose is getting you outside the post-menopausal range and the highest dose into the pre-menopausal range.

(25:48) And there's some interesting stories to be told there, but pretty excited to be sharing that at the North American Menopause Society meeting here in the fall. But, lastly, androgen metabolites. So, that was published just this year in BMC chemistry.

(26:05) And so, what we looked at there is correlation of DUTCH. So, that's our four spot urine test here and a true 24-hour urine on the Y axis.

(26:14) That was an important dataset for us to publish. So, those are some androgens there. We published liquid versus dried. We also published some of our organic acids, which relate to this story. But we're not going to get into those today.

(26:29) But you can see that all in that publication itself.

(26:32) Urine Clinical Utility
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The DUTCH test is validated for the androgens equivalent to 24-hour urine precise, accurate, analytically. So, what does that mean?

(26:41) That puts us in a position where we are then simply dependent on urine. So, the pros and cons of measuring urine is something that we need to understand really well, to know the pros and cons of using the DUTCH test as it relates to DHEA and testosterone, like, how does it work in urine clinically?

(27:02) So, here's a publication where they looked at, it's a good question to start with.

(27:06) If I look at a bunch of women with PCOS, and I look at a bunch of women without, do I get nice differentiation? Because that ultimately is what lab testing is for.

(27:14) Do you have meaningful differentiation?

(27:17) And what you can see here, that I want to point out, is the strongest performer keeps coming back to this DHT metabolite, called androstanediol.

(27:27) So, in blood, again, testosterone gets turned into DHT in the cell. In the cell it gets turned into this guy and then that guy gets conjugated. So, now you have a 17 glucuronide and a three glucuronide, and one of those papers we showed you said, hey, those correlate really well to bone mineral density in men more so than testosterone itself.

(27:48) Both of those conjugates end up in urine and then in urine, it gets measured as a total. And when they measure those in women without PCOS you can see the range that they got there, look how well separated that is from the PCOS.

(28:03) So, all of these metabolites are much higher in the PCOS group. All of these androgens, but androstanediol, especially completely separates the high androgen group from the control group, that's pretty nice clinical utility for a urine test.

(28:20) Urine Androgens: What stories are we telling?
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So, what are we trying to do with urine, we're trying to tell basically three big stories here?

(28:24) One is, how much of these adrenal androgens are we making?

(28:29) So, that's DGA and androstanediol, and what we're doing with those three is just adding up the three metabolites of DHEA that are the biggest.

(28:37) So, if you look at these three, you can see that those are not only the biggest numbers, right? So, that it just basically says, if I put up a bucket out and catch all the androgens that are made at the end of the day, these are the three forms you find them in most. Right, is DHEA and androsterone and etiocholanolone, and look what happens when you look at the median in the controls, relative to the PCOS group. You get a lot more in that PCOS group, right? So this is, again, showing nice clinical differentiation between people, in a state of high androgens, and people that would be considered normal.

(29:15) So, the DUTCH story is going to include these.

(29:19) So, this is a new report format that we're still working on. We were hoping to release this a little bit ago, COVID kind of got us sidelined. But this is not that dissimilar from what you're used to.

(29:30) If you're looking at DUTCH testing, which is that our normal ranges like, here, within this. Now, we have embedded age dependent ranges.

(29:39) So, the younger folks are going to be here, the women over 60, this is, uh, actually, I'm not sure if this is male or female, but you can see, you can see the age dependent ranges right in there. So, what's this person's story? Holy cow, they're making a lot of DHEA, right?

(29:54) And you can see then the three things that make that up: DHEA-S, etiocholanolone, and androsterone. Those are the three primary metabolites of both DHEA and androstanediol, which reflect overall production of those, and those bottom two can only be measured in urine.

(30:13) Now, one of the other things we can see after we look at DHEA and androstanediol production is relative metabolism.

(30:22) So, let's just make a theoretical person that has the same exact total here, right?

(30:28) Same DHEA-S, but they're pushing more down that five alpha pathway.

(30:34) Right? So, in the periphery, in the active tissue, you get a lot of five alpha metabolism, five beta metabolism, and it's the other way. It is important to note this is not a tug of war going on in the same cell, typically the liver's mostly responsible for five beta, and within target tissue, and in the periphery you get a lot of this five alpha and five alpha metabolism is pretty important.

(30:58) And you can see here that this theoretical patient on the right is the story I would tell here, is that they're making the same amount of these adrenal androgens, but they've got this highly androgenic metabolism going on.

(31:11) Because when androgens go five alpha, they get stronger, when testosterone goes five alpha, it turns into DHT, and it's three times as potent. All androgens get more androgenic as they go down that alpha pathway. So, it's an important marker to look at five alpha, and we have actually, if you want to get into the nitty gritty in four places, you can see that.

(31:32) What I just showed you is androsterone and etiocholanolone, that's mostly what you're going to see in the literature.

(31:38) But you've got five alpha androstanediol, five beta androstanediol. Those are testosterone metabolites. You have cortisol metabolites of THF, that's Tetra Hydra Cortisol, and there's an alpha and beta pair.

(31:51) Pregnanediol, those are your progesterone metabolites, again, a 5 alpha 5 beta pair. So, you can look at those.

(31:58) If you're looking for confirmation of a story of somebody who's pushing in a particular direction, you can look at those. Here's some of our data.

(32:06) It just shows that it's not exactly if you're pushing five alpha, five beta for one of these pairs, like the androstanediol pairs. If you look at a different pair, they correlate pretty strongly, but they're not 1 for 1.

(32:21) Right? This is a paper looking at PCOS and not the amount of androgens, but the metabolism, do you see five alpha metabolism?

(32:29) And this is an overview paper. That said, when we look at androsterone and etiocholanolone, you can see that there's an overall preference for that ratio going up, meaning of a five alpha preference.

(32:41) And if you ask that same question, but instead of using the androgens, you use cortisol, we know that there's a preference there, too. Well, what's the heart of that story is, is usually insulin, right?

(32:54) Insulin turns up, five alpha reductive. So, when you start looking at people with diabetes, they make more five alpha THR, they make more androsterone, they make more DHT and that's how we assess this is to look at the ratio of those. So, the three big stories are the androgen production of adrenals, DHEA, and androstenedione.

(33:15) Five alpha metabolism, am I pushing more androstenedione or not, and then testosterone production men, of course, it's almost all coming from the gonads and pre-menopausal women, it's about a quarter from the adrenals, a quarter from ovarian. And then about half that gets converted peripherally within tissue, that sort of thing.

(33:34) Female and Male Case Studies
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So, if we look at a female case study here, we can actually see all of the androgens that we're looking at here.

(33:40) So, we can see testosterone is, you know, the range, is 2.3 to 14 there, and testosterone for this particular woman, is normal. DHEA production is a little low, if she's in that younger age range, or the age group, but reasonable DHEA. And then, what do we get to do? Then, we get to go look at metabolism patterns.

(34:04) And you can see, in this particular case, and I chose this one, of course, because it's kind of a slam dunk to show you what an obvious case looks like. Testosterone is getting pushed five alpha big time.

(34:19) Androstanediol, which is that really important marker, that tells me how much DHT is being made in the cell more so than DHT itself.

(34:27) So, this is a really important marker, the testosterone that's going down the non androgenic pathway.

(34:34) There's not very much of it there, right? Here. Same thing. Five alpha, it's five alpha heavy.

(34:40) Five beta light.

(34:43) So, if we want to look further as I mentioned, you can even look at progesterone metabolites, five alpha heavy and THF, that we don't want THF with a dial like this. I just made one. So, you can see what that would look like. The range ends at 370, and boom, she's at 400, so, lots of alpha. Whereas, beta THF is on the lower side. So, the point is, in some cases, it's very obvious that you have this huge five alpha preference. What's that going to mean? That means in the tissue, you're making lots of androgens. It means you probably have an insulin issue. And so, you want to go and explore that, in terms of how you're going to treat this patient.

(35:23) Now, if I look at a male patient, we can kind of look at that just briefly here. So, here's testosterone for this guy.

(35:33) And here's the total DHEA production.

(35:36) So, if this is a young guy, right, he's actually, you know, within the larger range, but he is normal, for a 60 year old. Not normal for a young healthy guy. So if he's younger, that's a little bit on the lower side.

(35:48) I think this is actually a report from an older gentleman.

(35:53) Now, the five alpha picture that you can see here, when you look down here, it's pretty similar, right. You've got kind of middle of the road.

(36:03) Middle of the road looks like a slight, maybe alpha preference, and then when you look at androstenedione, you get more of an obvious alpha preference for this particular guy.

(36:14) Now, keep in mind, this is not always a clear-cut thing, because you've got five alpha reductives type one and type two. You have different metabolism going on in different tissue that have different sensitivities. So, you know, we can't always know precisely what's going on.

(36:31) I always start with that story here because again, that's more, it's more in the literature.

(36:38) We know that those correlations bear out when they look at them in the literature but then we've got these other three pairs of five alpha phi beta metabolites that can help to confirm maybe how strong of a leaning um, a patient might have.

(36:55) Here's a second guy, who's kind of middle of the road for DHEA?

(37:01) But if I told you which it is, this is a younger guy, you know, he's a little bit on the low side for DHEA.

(37:08) The 5 alpha, 5 beta, if you look there.

(37:11) Pretty similar, right?

(37:13) There's no real leaning in that sense, and down here, pretty similar, right?

(37:19) What you see here for this guy, is the testosterone's super high. This is actually getting a little bit ahead of myself, but this is a gentleman who's actually taking testosterone.

(37:31) So, he's actually taking, this was either an injection or pellet. I think it was an injection, so, and that leads us into something that we'll get to, in just a minute, which is this other interesting androgen that we've been testing, which is epi-testosterone. Just epi-testosterone's kind of the cousin of testosterone. It's made in about the same concentrations, but it's not androgenic, so it's just, there's sort of a flag to say, hey, here's a second look at what your gonads and a guy might be making. And why in this case, is it so low?

(38:04) Because he's taken an injection, right?

(38:06) The injection tells the brain, we're done here, and stops your LH production, so, we can see here he's got a fairly high testosterone, almost all of which is coming from exogenous testosterone, and then we can look downstream to see how he might be metabolizing that testosterone.

(38:24) Urine Androgens: Advantages and Problems
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So, the advantages of urine 24-hour productions helpful, given that it's variable, if you measure at any moment in time, but there's also a diurnal pattern.

(38:33) It includes adrenal and gonadal androgens, it's LC-MS work, which is nice in terms of accuracy.

(38:41) There's not a ton of data in the literature on testosterone replacement, but from all the data, I've looked at injections, pellets, creams, and gels, it seems to be helpful, we'll get to that in a minute.

(38:52) But first I want to talk about this. Conceptually, if we limit this story, urine has a really nice story to tell. We can add that into the serum story, or we can use it independently, and you get a lot of interesting things to try to overlay the clinical picture with and to see what's going on with the patient.

(39:15) So, what’s the problem?

(39:18) It's an imperfect test when it comes to measuring androgens in urine, and I want to make sure that we talk about those, there are significant caveats to measuring androgens in urine DHEA production is best tested, this is what we already talked about, add the three big ones up for DHEA.

(39:36) Now, when we're talking about DHEA in urine, you don't really need to remember this, but just to be clear about what we're actually measuring, we're taking DHEA sulfate, DHEA glucuronide. It'll be the same for testosterone, testosterone sulfate, testosterone glucuronide.

(39:50) But when it comes to DHEA, it's almost all sulfate.

(39:53) So, we actually call it DHEA-S, even though it's the total of those two. There's just not very much of that glucuronide.

(40:00) But it seems to tell a little bit of a different story than serum DHEA-S, and the reason that I say that, is because there's not much of a diurnal pattern with DHEA-S in serum. But, there is in urine, and so, it seems to be telling a little bit of a different story. Androsterone and etiocholanolone are the most abundant, and so, again, what's the most helpful, there are DHEA and androstenedione production is to add those three up.

(40:26) And to measure those, which is a little different than what we're doing in blood, but the most significant caveat to measuring androgens is testosterone.

(40:35) Testosterone can be artificially low in urine due to phase two conjugation issues. If you've run a lot of DUTCH tests, you've run into this. You've probably jumped on the phone with somebody to talk about this.

(40:46) The UGT2B17 enzyme, that's what conjugates testosterone, turns it from testosterone to the glucuronide, it has a variant form that just basically doesn't work.

(40:57) So, this is probably, to me, the biggest caveat to using urine hormone testing, is trying to understand and wrestle around this issue. So, when we started we showed you this conjugated form, right? It presupposes urine testing, presupposes normal phase two metabolism.

(41:15) Usually, that’s almost always true.

(41:18) But the glucuronidation of testosterone doesn't always happen normally.

(41:22) So, the liver is putting on this little sugar moiety, right? So, that it can go into urine. So, that doesn't happen.

(41:30) Because you have a variant form of that enzyme, then what's in your urine is going to be artificially low.

(41:36) So, the glucuronidation, that's adding this to an OH group, doesn't always happen normally, and the easiest place you can see that is when you look at urine testosterone in people who happen to be white and people who happen to be Asian.

(41:52) And you can see that the level, most of the graph on the left, is represented here.

(41:59) Right. So, you say, well, they just have lower testosterone.

(42:03) No, when you look at free testosterone in blood, they're pretty similar.

(42:08) Right? But then, in urine, they're way lower. Why? Because they can't go that route, right? It has to find its way out through other metabolites because of the fact that phase two conjugation isn't happening. Right?

(42:22) So, it's more than 60% of people with Asian descent that have this variant form of the 2B17UGT enzyme. Right, it's less than 10% of other ethnicities. I think in Caucasians, it's one or 2%, something like that. It's caused by gene deletion.

(42:40) There really aren't a lot of physiological consequences for this, so this is not like, hey, something's wrong here, although I do want to say that there are papers that show that maybe it makes testosterone hang around a little bit longer.

(42:52) And in this particular study, they found that women who had this gene deletion, actually had better bone mineral density.

(42:58) Testosterone helps with bone mineral density, you make it hang around longer. So, there are some, maybe, clinical nuances.

(43:04) But, mostly, it's just a pain in the rear when you're trying to use urine testing when this comes up, because as you look at the flowchart, right.

(43:12) So, you're making from androstenedione in the gonads of men, you're making equal amounts about, of testosterone epitestosterone, but, then, this can't find its way into urine.

(43:23) Nor can DHT, nor can 5 beta androstanediol.

(43:29) So, what does it look like?

(43:31) Low, low, low, those three are all put into urine by the same enzyme.

(43:38) Epi-testosterone, different enzyme, five alpha that one, we really liked. And thankfully, this is true. It is not conjugated by the same enzyme.

(43:47) So, testosterone is falsely low.

(43:50) DHT and five beta androstanediol also falsely low, and epi-testosterone of five alpha are what they should be. That's the pattern that we look for, just saying, hey, there's some uncertainty here as to whether this testosterone value is actually speaking correctly for this particular patient.

(44:08) And that's one of the caveats of the biggest, I think, of using urine testing, because those three are conjugated by the same enzyme.

(44:18) So, pros and cons, it's a better average over time than serum and saliva. That’s nice.

(44:23) You get accurate numbers analytically, because you're using all mass spec, and it reflects bioavailable hormone, but only of phase two is appropriate, which again, is almost always true across the urine board. But it assumes that's true. And here that isn't always the case.

(44:40) So, what? So, what did we do about that?

(44:43) And this gets important to patients not on TRT.

(44:47) Urine is a useful secondary test for testosterone. Serum is going to be primary when you're looking at testosterone itself.

(44:55) It's not going to be reliable for patients of Asian descent.

(44:57) So, I would be really cautious about leaning on any of those three markers in someone who has south-east Asian descent, Chinese. That area of the globe tends to have a lot of that variant enzyme.

(45:14) When epi-testosterone is higher than testosterone, it's suspicious, especially if DHT and beta androstanediol is low, if you have that complete pattern, our reports, because we really dug into this. Right. We put a comment on the report that says, hey, be aware of this pattern, we'll probably need to confirm with serum before we draw any conclusions.

(45:33) So, confirm with serum before TRT, for sure, and five alpha androstanediol may emerge as having more clinical utility as we continue to dig into androgens.

(45:46) Urine Metabolites Case Study
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So, here's a gentlemen, just looking at a couple of case studies, say, OK, what do we do with all of this information that we have?

(45:52) Here's a guy who has relatively low DHEA. This is another young guy.

(45:59) So, it's relatively low for a young guy for all of these metabolites, and testosterone is pretty healthy, but there's a reason for that, this particular guy is on Clomid, right? So, he's taking Clomid, which makes your brain make LH, which, then, stimulates your testes to make testosterone, which is going to help you make testosterone. Epi-testosterone is in the same neck of the woods, is which what we typically see. It's a little bit lower here. And then, that's getting pushed pretty heavily, down that five alpha pathway. We want to consider all of that when we're looking at therapy, when we're looking at baseline testing.

(46:37) Here's a female patient. So, what are we going to do with this?

(46:39) This patient, she's got relatively high testosterone, right? And then we're going to look further to see how much she's pushing it, as real heavy push down the beta pathway here, where she's way outside the range.

(46:53) You can see that consistent here, where the androstenedione and metabolites are also pushing towards etiocholanolone.

(47:01) So, when you're a little bit out of range and you're not a five alpha metabolizer, a little bit less than the five alpha, that's where we really want to overlay the clinical symptoms here to see, you know, how is the patient feeling?

(47:16) So, imperfect with significant caveats, for urine androgens, but the most common place, and this is where I'm kind of weaving this whole story to, for urine to steer you wrong, potentially, is with low testosterone levels that may not reflect the clinical picture. Like, that's what we have to watch out for more than anything. We want to check the metabolites, especially five alpha.

(47:38) Check overall DHEA, especially if they're post-menopausal. Why? Because once the ovaries stop, right? The ovaries give up and quit making hormones. Where does your testosterone come from? It comes from the substrate of DHEA, androstenedione, so looking at that can really help to tell you the story of what their androgens are looking like.

(48:00) Check epi-testosterone, but, and this is where it gets a little bit complicated too, only in pre-menopausal women. This is actually a new data to me which is really interesting, is it's just a bunch of aggregate data for us and you can see the androgen levels are dipping over time, right?

(48:15) But epi-testosterone kind of falls off a cliff around menopause, which, I think, implies I have not found this in the literature, so I think this is again where the androgen story, when you're looking at these papers. They're pretty recent right?

(48:29) That where the story is still being told, in terms of what are the absolute best markers to look at and one of the things I don't think that's been really unpacked yet, is that it seems like the epi-testosterone must be coming more heavily from the ovaries, or that would be my interpretation of this data.

(48:45) So, when you're young, the epi-testosterone helps to parallel testosterone for women.

(48:52) But when you get into the older women, where it's all coming predominantly from the adrenals, then epi-testosterone is going to drop off more so than testosterone, so, it's not going to be as helpful. So, the other things we can do, of course, are to check our serum testosterone, and of course, to look heavily at how the clinical picture overlays with the patterns that we're seeing with the biomarkers that we're measuring.

(49:18) So, here's a woman who's 22: the doctor said she had a bunch of exposure to some pesticides or herbicides or something like that, that they were kind of investigating.

(49:28) You got a lot of estrogens, you can look a lot of these above, above, above, a lot of estrogen, and then when you get to the androgens, you see, again, young woman.

(49:40) So, here's her story. So, what would we do with this?

(49:46) DHEA and androstenedione, so, here, here and here, are pretty decent levels, right? So, she's making a decent amount of those adrenal androgens.

(49:58) We can see that she's got pretty heavy, five beta metabolism, right, the five alpha metabolite is not down here with it, it's quite a bit lower and then you notice what with testosterone, it's low, we actually tested her again 3 or 6 months later is 1.2. So, it's consistently low.

(50:17) She's got plenty of DHEA to feed into that, right? Her ovaries are obviously working to some degree because she's making a lot of estrogen.

(50:27) So, then this is where I have some pause to say, OK. Like, what do I do with that?

(50:33) And the first thing that I'm going to check is the five alpha androstanediol, which is also low. That's a big conclusion, because it confirms that she may not have a lot of testosterone. In this particular case, it gets a little bit more confusing because she's got a fairly decent amount of epi-testosterone.

(50:53) So, this is the type of case where we have to say that there remains some uncertainty.

(50:59) What does her clinical picture look like?

(51:03) Then, if we really want to focus in on the androgens in a case like this, we may need to also look at serum androgen markers to give a more complete picture of what's going on. It appears, again, with the low testosterone and the low five alpha androstanediol that she does actually have low testosterone.

(51:26) If the five alpha androstanediol was significantly higher, my level of uncertainty would go up even more because that is really a nice marker for overall, like androgenic exposure, right? That's a really nice marker to be looking at, which is why in our new format, which we'll be getting out to you next year. We're actually putting those five alpha, five beta markers on the flowchart for women.

(51:53) Because I think that's going to be helpful as you look at this full picture. But, this is the type of case where we get on the phone with people, and we have to really talk through it because there is some uncertainty left. Once you understand it completely. There still is some uncertainty to that, right? And that, again, is for all the wonders and amazing things that urine testing has to offer. This is the one area where there is a lack of idealism to what we have here because of some of the things that we've just talked about. So, we want to be careful when we're looking at cases like that to be really thorough in both what we're monitoring and what we're considering before we think about any particular type of treatment.

(52:37) Monitoring TRT
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Now, we're running a little bit longer than I thought. So, let me just skip through some of the TRT applications. This is honestly, so, this point is trying to get you to a position of understanding the pros and cons of this, some of the nuances of this, and so, we can stop right there and take some questions. But I want to just knock through this. This is kind of the fun part for me where you can see some of these unique urine markers are actually pretty interesting.

(53:02) Before I do that though, I want to make sure, and remind you of something that we avoid a particular mistake and that is, as we understand what happens physiologically, LH comes from the brain it's going to get into the testes.

(53:16) And if that's little star protein grabs cholesterol goes into the mitochondria.

(53:22) Here's where your pregnanolone comes from for testosterone right there.

(53:26) Then pregnanolone goes where, outside into the endoplasmic reticulum. That's where your DHEA comes from right there, and right there it gets turned into testosterone.

(53:38) So, that's within the cell and then it can, of course, go out and do what it does in general circulation.

(53:46) The reason I tell you that is just to remind you, you cannot rival testicular production of testosterone by giving DHEA to men.

(53:54) Right here in the cell, DHEA gets turned into testosterone.

(53:58) So, if you flood DHEA into their system, with supplementation, you're not going to get it in the middle of that chain of making testosterone. Which means you're more likely to make a truckload of estrogen, or at least, as likely. So, yes, you're going to give a little testosterone. But, in women, it'll trickle down to testosterone, you can't trickle down to levels that are going to rival testicular production. So, just don't think that's going to happen. That could be a mistake.

(52:24) So, for patients on TRT, urine is a useful secondary test. I love it, because we get so much information. But, I think, when you really want to hang your hat on testosterone, serum is primary.

(54:35) Again, not reliable if you have a person of Asian descent.

(54:39) Use Epi-T, this is an interesting one, as a surrogate for approximate testicular production.

(54:45) Five androstanediol is also going to be helpful.

(54:48) OK, so Epi-T is also made by the testes in men. It's not androgenic, so it's not really doing anything important that we know about, but it acts as an interesting marker, and it's just different at that one little position, but that makes it not androgenic.

(55:03) It's made in similar concentrations to testosterone and again, approximate testicular androgen production.

(55:11) So, let me show you this in practice.

(55:13) So, if a typical aging man looks like this, around maybe around 40 for both, um, with TRT, Epi will go down to the extent the LH and gonadal androgen production is suppressed. Let me show you this in some examples and then it will make a lot of sense. So, a typical aging male. Maybe you treat that person. Maybe you don't. That's not for me to say, but the person is below, the entire range, maybe you're going to treat? So, what happens? So, this is not an individual person. This is our aggregate data. This is me going into our data and say, what do all the people on 25 milligrams look like? They look like this. How about 100?

(55:53) How about 200?

(55:54) So, what happens here?

(55:55) When each dose increase, testosterone is going up, right. That's what we'd expect.

(56:01) Epi-testosterone probably hasn't been 25 milligrams, that's probably a baseline level.

(56:06) As we use 100, it starts to get suppressed. And somewhere between 100 and 200, we've sort of broken its back.

(56:12) If you're less than five, really even less than 10 in a guy, that tells you that your man is not making any testosterone themselves.

(56:22) Here's three days post injection, tons of testosterone, and full suppression. After five days, less testosterone, full suppression, after 10 days. So, this is where you're ready for your next injection right is probably sometime before this.

(56:39) But all along, full suppression of endogenous testosterone.

(56:44) How about a pellet?

(56:46) Now, keep in mind, our aggregate data is probably a lot of people that use really high doses of pellets. So, I'm not endorsing any particular thing here.

(56:53) I just want to show you that early on after pellets, we got a lot of testosterone full suppression.

(57:00) Then, it comes down full suppression and somewhere in there you're going to put in a new pellet, right?

(57:07) So, the point is, epi-testosterone gives you an idea of how you're suppressing endogenous production, OK, so it's a useful tool, helps identify those UGT variants, because, again, it should be at normal levels.

(57:22) When the testosterone is artificially low, it approximates gonadal androgen production, for the UGT people and for TRT.

(57:30) And just to remind you, we're dealing with lots of complex stuff here, right?

(57:34) You got to think about reproductive hormones, you got to think about adrenal hormones, you got to think about their immune system, so, you've got guys who've got stress, that are causing low T symptoms, and then you've got testosterone and estradiol in all of this. You know, these situations really can be complex and that's why we think comprehensive testing is really helpful to pick at those things and figure out you know, what's going on with the guy which is, or a woman as it relates to not just their androgens, but their overall hormone production.  Right?

(58:10) If you're looking at guys, and you're looking at prostate health, you're going to want to know about androgens you're going to want to know about androgen metabolism because DHT matters in that story.

(58:21) Estrogen metabolites also matter in that story, and when estrogen metabolites play a bad story when it comes to prostate, the smoking gun of that is thought to be the four hydroxy estrogens. Well, how do you get rid of four hydroxy estrogens?

(58:35) One of the ways is with glutathione, right? So, we've also got markers in there that are going to help you put the whole story together in terms of, you know, what's going on with this patient from production and metabolism. You know, certainly you're going to want to look at cortisol and what's going on there in those patients. So, looking at a comprehensive testing, we think is really, really helpful. But, again, the point of this talk was to understand some of the nuances of the androgens, to make sure that we're not over leveraging that information.

(59:09) And that we're understanding some of the situations where we need to take a pause, and maybe even do some additional testing to really give us enough detail that we have confidence before we're making, you know, interventions for a particular patient. So, that is all the information that I have. I know that was a lot, thank you for hanging with us. I'm really happy to answer questions. Now, after the fact, again, I realize this is a complex topic.

(59:41) We want to be having, you know, ongoing dialogs with all of you, about these types of things, where there is complexity, and just to continue to pursue truth wherever that takes us.  So, that you can understand the pros and cons of all of your testing options that you have.

(59:58) I do think for most providers, the DUTCH test is a great tool to have in a lot of situations. And if you haven't tried it, and you want to just sort of see how that works in your practice, I would encourage you to get some of our half price kits that we have for our new providers. But this particular lecture, if you are an existing provider, will also offer you to the DUTCH Plus kits at half off.

(1:00:22) Um, and we thank you for working with us, and please do take advantage. Especially with these complex topics, of our great team of clinical consultants. They can help talk you through the patterns that you see, what they mean, as you get into making decisions about potential intervention for your patients. So, with that, Tim, I don't know if you've collected some questions that we can answer, but I will open it up for that now.

(1:00:51) Q&A
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Yeah. Thank you so much, Mark, I do have some questions for you that came through. One of the first questions was: A4M teaches us that saliva is the best way to measure testosterone.

(1:01:05) What would be your comments on that?

(1:01:10) So, when people say it's the best for measuring testosterone, what they typically mean, is that saliva has a unique message when you take the most common form of TRT, which is creams and gels. So, when you take, I should have thrown a slide in here, I should have known this question would come up. I was trying to stay away from getting into that because that's, like, my favorite soap box. There have been educators that have taught that, the elevated values you see, so remember saliva and blood and urine, they agreed, generally, you know, in young guys and old guys, whatever, they had, agreed gently.

(1:01:41) When you take an injection, they agree.

(1:01:44) But there's this paradox that when you put on a cream or a gel, the saliva goes up way more than anything else, OK?

(1:01:53) So, then you have to ask yourself, well, which ones right? And that data is not ambiguous on this, right?

(1:01:58) The saliva value is outside a young healthy range with 5 or 10 milligrams. So, then saliva testers, the people that promote that would say, 5 or 10 milligrams is a lot of testosterone for a guy. A lot for a guy. So, I'll give you a quick test to show you that that's not right. I can show you eight studies, the eight studies I've found where they've given 5, 10, 15, and 20 milligrams of transdermal testosterone the same exact products to women.

(1:02:26) So, what happens if you take too much testosterone for a guy, or enough testosterone for a guy, and you give it to a woman?

(1:02:34) They have terrible outcomes, right?

(1:02:36) They're going to get hair and acne and all of these things, none of those studies reported negative outcomes for the women. Right?

(1:02:45) Because the unique elevation that you see in saliva following transdermal hormone is a concentration of lipophilic hormones that does not have anything to do with any tissue, There is not a single study.

(1:02:58) I've sat down for more than an hour with Pam Smith, with Doctor Zava, and said, what studies can you show?

(1:03:04) Because there's the two, and, and they're colleagues and they're friends. But I think on this topic, I don't think they disagree with me.

(1:03:11) I think they disagree with the scientific literature, the scientific literature is clear when you get clinical outcomes, is when the serum and urine move.

(1:03:20) So, you need 25, 50, 75 milligrams of testosterone to get bone mineral density, to get changes to sexual function, to get changes to muscle mass, to get LH suppression, all of the things that have been studied, all of them dance with the serum, erythrocytosis is probably the best example.

(1:03:38) When you give an injection, you get a lot of erythrocytosis inquiries.

(1:03:43) If you give a big injection and even more so, then you say, OK, well, what happens when I give a 50 milligram transdermal gel?

(1:03:51) Well, saliva says that that's 10 times too much testosterone, if you give 10 times too much testosterone, erythrocytosis will go crazy, and you are being unsafe, but it doesn't, as the serum implies, as the urine implies, the erythrocytosis, such as this increase is 20% of a typical injection, which tells you the clinical change parallels serum. When you look at the clinical data, it is not ambiguous. The jury is not out on this. It is very clear, is this, but this is an old medical myths that some people have a really dug their heels in on, and if you think about it critically, you look at the data. It does not agree with that. It says that when blood and urine move, you get clinical change. And the saliva parallels serum when you're not taking hormones and is completely useless, and will not lead to clinical success when you're taking hormone by way of brain or shell.

(1:04:47) So, maybe I should have put some of that in my lecture because I would add some pictures that would help. That makes sense. And we've got some blogs and things that that address that more specifically.

(1:04:57) So, next question.

(1:04:59) Yeah, in one of your prior, or one of the prior speakers at DUTCH, androgens mentioned that topical testosterone treatment should not be measured with serum testosterone levels.

(1:05:12) Do you agree with that?

(1:05:15) No. I don’t. I mean, it's a common belief in our industry, Again, when you look at, well, OK, first thing, when you use a testosterone cream, there are zero clinical studies on creams. So, we can't lean on those at all.

(1:05:28) But with the gels, what we know what the gels, is we know that andro-gel and all of those that every study that's ever been done says that as the serum moves, the clinical picture moves and we know that saliva tests go up again in an exaggerated form.

(1:05:49) And it is a widely held belief that those numbers should be used for therapy.

(1:05:54) And I have put it to people that are proponents of that to show studies. And honestly, all they ever give are anecdotes. You know, I know a guy who took test, but there are studies that have studied erythrocytosis, LH suppression, muscle mass increase, all of those things. The bone mineral density is an interesting one, bone mineral density at 25 milligrams. It barely worked 50 milligrams and worked a little bit more what happened at 12.5 milligrams. It failed.

(1:06:19) It didn't work even though saliva values are saying, whoa. That's too much hormone. It failed.

(1:06:25) Because if you're not getting the systemic increase, when you get systemic increase, you're going to see it in blood and urine. And what goes on in saliva is an exaggerated look from fat soluble hormones, and I don't think it's clinically relevant, and I've never been shown a single study with testosterone that implies that those values.

(1:06:48) So, if somebody said that in one of ours, you know, they might have a different opinion of that. I don't think that's anyone that's on our staff, but it is a widely held belief, but I think it's slow going to get people to see that from a different angle, but the evidence just the evidence is pretty clear.

(1:07:05) It’s great, Mark, thank you so much.

(1:07:08) Next question. Is there any evidence for testing androgen receptor levels?

(1:07:15) That would be fantastic to know what's going on at the receptor level of androgens, don't know what's going on. Is there a separate level for estrogens and cortisol? I mean, it's a big, black, box, right? So, you know, that's why, in medicine, we do a lot of guessing, right? You get all the information you can and the best doctors are doing the best guessing, because you never really know what's going on at the receptor level.

(1:07:38) If you have a receptor, that's, and I don't know a lot about receptor science. But just conceptually, if your receptor was 25% as active as somebody else's, you'd need more hormone. And I don't know how you'd ever, you'd ever figure that out, except to really listen to the symptomatology of what's going on in a patient. And to be very careful about the way that you treat them.

(1:08:01) But none of the lab tests speak to what's going on at the receptor level. So, that's a great question.

(1:08:11) We don't have a window into that.

(1:08:15) Thank you, Mark. Another question, would you recommend salivary cortisol over the urine cortisol.

(1:08:22) Someone has been using the DUTCH Complete, but would it be better to change the DUTCH Plus, or when would you recommend what test?

(1:08:30) So, I think the question is priorities. So, what we've shown is that the up and down pattern of cortisol is comparable, either way.

(1:08:40) But if you want to say, I want to lean on the literature, you know, we've published our urine data, but that doesn't go into a lot of clinical outcomes, right?

(1:08:47) If you go into PubMed, and you're looking for free cortisol patterns, you're going to see some 24-hour urine stuff, that's OK. You're going to see some blood stuff that's like, not very impressive. And then you'll see a bunch of saliva stuff.  It is better.

(1:09:01) Urine is a viable option for the diurnal pattern and in our DUTCH Complete, you get a good look at that and all that other stuff for a little bit cheaper price and an easier collection. For me personally, and particularly if I want to look at adrenal issues, I want saliva, primarily because it has the cortisol awakening response.

(1:09:23) Some people, and even some labs that do diurnal, cortisol, and urine, try to look at that difference between the first urine and the second urine and then sort of say, yeah, it's kind of like a CAR.

(1:09:33) It's not, important information it's useful information, but a waking urine sample tells me your cortisol while you're sleeping.

(1:09:41) That's very interesting. I like that value. It's good to know. But it's not the CAR needs a value, right, when you wake up.

(1:09:49) And right when you wake up, when you take a saliva sample, it says this is your baseline, and we know if you look at baseline and half an hour later, that's really great mini stress test, right, the biochemistry that goes on when you wake up parallels a stress event.

(1:10:03) And so, that the balance you get in those first 30 minutes has to be looked at in saliva, and it has unique and independent value when it comes to assessing the HPA axis. So, if you want to hone in on cortisol, I would use the DUTCH Plus.

(1:10:18) If you got an extra 75 bucks, I would use the DUTCH Plus. If you're looking at general wellness and you don't really suspect an adrenal issue, then the DUTCH Complete is a little easier. It's a little cheaper and it's going to give you a lot of information about cortisol. It's just going to be missing that cortisol awakening response, so most of the time I would lean in that in that direction.

(1:10:40) But either one can be useful and I would consider urine-free cortisol, a viable alternative to monitoring the diurnal pattern of free cortisol. That's probably the wording I would use and so, you need to use in a particular case, you know, whatever matches up best with what you're trying to do.

(1:10:59) Wrap-Up
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Mark, thank you so much. I know we're not able to get to all the questions we're about 10, 11 minutes over our hour here, but we just want to thank everybody for participating today for interacting with us with this webinar. All the great questions, although we weren't able to get to all of them, we're just very grateful for our customers, and the providers we work with, and our whole team here at Precision Analytical. Thank you, Mark, for doing a fantastic job, for more questions. You can e-mail us info@dutchtest.com, or you can call the lab and our customer service team would love to help you if you need help with anything, any of our tests, or if you want to know how you can sign up, or whatever you need. Just give us a call. So, thanks again, Mark, and that's our time for today, and we'll see you in a month.

(1:11:55) We'll have another great webinar coming up in the month of September.

(1:11:59) Sorry. Thanks, Tim. Thanks, everybody. You bet, thanks.