00:00:00:02 - 00:00:26:01 

Noah Reed 

Welcome back to the DUTCH podcast, where integrative medicine providers can expand their understanding of functional endocrinology and testing. And everyone, no matter who you are, can learn more about their body’s most complex communication system. I'm Noah Reed, vice president of sales and marketing for the DUTCH Test. And coming up on this week's episode, we're getting out of the shallow end of the endocrine essentials, and we're going deep into some controversial topics. 

 

00:00:26:01 - 00:00:51:10 

Noah Reed 

So, buckle up. Our Ask the Experts series is back this week with Tom Williams explaining the truth about adrenal fatigue and answering the question, does chronic stress really steel pregnenolone? To make cortisol? There's no better person to bust these common adrenal mess than Tom Williams, who has studied this topic in detail and has written several papers and books clearing up the controversy. 

 

00:00:52:09 - 00:01:19:06 

Noah Reed 

Tom Williams is a Ph.D. in molecular immunology, having earned his doctorate from the medical college in Milwaukee, Wisconsin. For the past two decades, he has spent his time investigating the mechanisms and actions of lifestyle and nutrient based therapies. And he is an expert in therapeutic uses of the dietary supplements. Tom serves as an adjunct assistant professor at University of Wisconsin School of Pharmacy and is the VP of Science for Ortho Molecular Products. 

 

00:01:19:12 - 00:01:43:01 

Noah Reed 

Since 2014, he has been writing a series of teaching manuals that outline and evaluate the principles and protocols that are fundamental to the functional and integrative medical community. Tom is also the founder and the director of the Point Institute, an independent research and publishing organization that facilitates the distribution of his many publications. So, let's jump right in. 

 

00:01:43:14 - 00:02:12:05 

Mark Newman 

Thanks, Noah, and thanks to Dr. Tom Williams for joining us today. If we ever have to worry about being the smartest one in the room today, we don't have to worry about that. So, we'll fight for second place. So, Tom is the expert in all things cortisol in my mind. And I, I know, Tom, you dabble in more than dabble in a lot of other topics and write books and all of that of categories that I don't actually play around with much in terms of my intellectual capacity. 

 

00:02:12:08 - 00:02:34:19 

Mark Newman 

So today we want to focus on the things that, you know, that are sort of near and dear to what we do. For me, you've been really influential in, I think, three big ways in terms of how we interact with this functional endocrinology, functional medicine market. And so, I want to pick your brain on those things and try to illuminate those things for people. 

 

00:02:34:19 - 00:02:38:05 

Mark Newman 

But first of all, thank you for joining us. It's great to have you and good to see you. 

 

00:02:38:21 - 00:02:48:02 

Tom Guilliams 

Yeah, thanks for visiting me here in my bar. And I guess you guys are relaxing on a couch there. So glad you could. Glad I can stop in. 

 

00:02:49:06 - 00:03:06:20 

Mark Newman 

Absolutely. So let me just start. Well, you know what? Before we get too far into this, what is your entry point into functional medicine? I actually don't even off the top of my head know what your Ph.D. is in. So, what are you on paper an expert in? And how did you find your way into the functional space. 

 

00:03:07:20 - 00:03:36:12 

Tom Guilliams 

So, I got my degree in, let's say, the mid-nineties. So, 95, actually, right in the nineties from a medical college, Wisconsin, in molecular biology, more specifically molecular immunology. And so, we're not going to get into recombination of immunoglobulin genes and, and some of the enzymes that that perform that that function, which is quite fascinating. And I've been able to leverage that in a lot of things. 

 

00:03:36:12 - 00:04:13:21 

Tom Guilliams 

Immunology related but because of my entrance, because of circumstances which we won't get into, I was actually hired by all the molecular products, a dietary supplement company in the physician channel, and this was early on in the days of that company and really early on and sort of in the physician channel and at that time in the late nineties, there was a obviously that was just when the Internet sort of when PubMed became available sort of at the end of the end of the nineties, right when there was a lot of people that didn't have access to information. 

 

00:04:14:20 - 00:04:39:23 

Tom Guilliams 

There weren't that many papers being published or at least access to papers being published. So, I started really digging into the literature related to dietary supplements and soon found out that sort of the group of people teaching clinicians on how to understand what was at that time, you know, the early functional medicine, integrative alternative medicine or just sort of different ways of thinking. 

 

00:04:40:06 - 00:05:00:10 

Tom Guilliams 

Some of the educators were actually some of the labs who were doing some of these tests, and they were trying to explain to doctors, you know, this is what the path of physiology is. And that's why we're measuring this analyzer, this biomarker. And and so I started, you know, learning some of the same things the doctor was learning, going to a lot of these meetings. 

 

00:05:00:21 - 00:05:20:06 

Tom Guilliams 

Then I was being asked to begin teaching mostly on the supplements side of things. But again, in order to teach the supplements and how a certain herbs or vitamins, minerals, et cetera, work, you really have to learn the path of physiology and sort of the chemistry and the biochemistry behind it. And so, to kind of merge together into all of this. 

 

00:05:20:12 - 00:05:47:03 

Tom Guilliams 

And because of that, I started interacting with some of the labs that were doing some of the early studies or publishing giving doctors salivary cortisol, sometimes serum, but mostly saliva, cortisol, and then trying to interpret them and giving various interpretations. And of course, at the same time, the some popular books came out talking about adrenal fatigue and sort of this is what's going on with stress. 

 

00:05:47:15 - 00:06:11:11 

Tom Guilliams 

And I started writing about this sort of summarizing some of these things, both the path of physiology of the access, cortisol production, DHEA production, all these kinds of things. And it wasn't until I started writing about it that I started really digging into these questions saying, OK, wait a minute, I know that they're saying this, but what is the literature? 

00:06:11:11 - 00:06:30:21 

Tom Guilliams 

What is the published literature say about that topic? And then that was in the late nineties. I think I wrote the first thing I ever wrote on this area. And at that time, I was I wasn't using the term adrenal fatigue, but I was using adrenal dysfunction. I was still kind of focusing on the adrenal gland because that's where everybody was focused on the adrenal gland. 

 

00:06:32:00 - 00:07:02:07 

Tom Guilliams 

And then over probably the next decade, I really started refining everything and it sort of came to a head when I wrote the first sort of road map, the book on Access Dysfunctions and that was 20, 15. So, you know, it's almost 15 years later and where I basically probably the five or six or seven years before that I was really trying to focus and saying, look, this idea of adrenal fatigue, the way it's being defined needs to be corrected. 

 

00:07:02:16 - 00:07:27:05 

Tom Guilliams 

A lot of even the way the laboratories were were reporting, some of the ways that they were reporting cortisol and interpreting the results were really sort of a creation of their own. It wasn't really mirroring what was happening in the published clinical literature and the research areas. And so, so basically you know, it's funny that you say I'm one of the experts in this area. 

 

00:07:27:05 - 00:07:52:00 

Tom Guilliams 

It wasn't really my intention. It was sort of like everyone just was repeating the same things over and over and over in our industry, sort of in the functional integrative medicine community. And somebody needed to come along me along with several others and just codify this and say, look, we need to change our nomenclature. We need to change the way we're thinking about this so that we can better leverage the solutions that are available to us. 

 

00:07:53:07 - 00:08:34:09 

Tom Guilliams 

And stop using sort of these oversimplified terms which are, you know, physiologically sort of incorrect. And so I sort of I became sort of an expert in this area by default because I just I just went and did some of the hard work, I guess, and just looking up, comparing asking questions, calling people, you know, verifying things, you know, getting, you know, debunking things that, you know, a lot of people hold near and dear, some still hold near and dear and so I haven't been completely successful in changing some of the nomenclature, but so that's how I got to this place of a kind of roundabout way of saying. 

 

00:08:34:14 - 00:09:00:19 

Mark Newman 

Well, that's that's interesting. You know, I think 2001 was the original publication version of probably the best-known book using the term adrenal fatigue. It's a conversation that we have a lot. It's changed over time. So why don't you put on your adrenal fatigue hat for a second and just explain in basic terms what the understanding is of that model. 

 

00:09:00:19 - 00:09:08:04 

Mark Newman 

I'll ask you to explain why it's incorrect afterwards. But what like what is that model of? Like you have adrenal fatigue, which means what? 

 

00:09:09:01 - 00:09:47:01 

Tom Guilliams 

Well, that's actually a very interesting question because that actually has morphed a little bit over time. Really, there's two areas where where the two terms adrenal fatigue come in the more generic idea is that you have fatigue, that, you know, either you're tired of the fatigue characteristics because your adrenal glands aren't functioning properly. But ultimately, what a lot of people have explained is if we just go back to some of the work by hand, same way by the original research, I don't know if you've covered this on any other podcast. 

 

00:09:47:01 - 00:10:32:04 

Tom Guilliams 

No, but he basically is the one that, you know, took animals, did various stressors on them and sort of followed this, what do you call it, a three-stage model where the animal goes through their cortisol goes up, their excitement stage. They kind of go through adaptation to that and eventually you can exhaust them. Right. And this this notion that you can eventually exhaust the animal or that you can eventually exhaust the adrenal glands ability to compensate for stress was sort of just taken, maybe not even consciously and sort of attached to the idea that if you have chronic stress, your adrenal glands become fatigued they become unable to produce the level of cortisol needed 

 

00:10:32:23 - 00:10:57:04 

Tom Guilliams 

to balance out the stress as a response. And you have these sort of chronic issues sort of in the way that we think the pancreas becomes exhausted. The beta cells in the pancreas producing insulin you know, constantly feed, you know, glucose and they have to produce insulin and eventually they just exhaust they can't produce enough insulin. And you get type two right. 

 

00:10:57:04 - 00:11:03:23 

Mark Newman 

So, there are models that you can look at for which that sort of makes sense as a parallel. It just happens to be not true. 

 

00:11:04:19 - 00:11:24:16 

Tom Guilliams 

Right? As it turns out, I mean, obviously we have adrenal insufficiency, which is, you know, primary adrenal insufficiency where the adrenal gland not producing enough cortisol is an autoimmune condition where you actually destroy essentially the cells producing cortisol. So that is the we have that it's. 

 

00:11:24:16 - 00:11:25:16 

Mark Newman 

Real but rare. 

 

00:11:25:20 - 00:11:52:06 

Tom Guilliams 

It's real yeah. Obviously, it's relatively rare. And we get Addison's disease essentially from that. And so, the notion that this is also happening at a slower level, let's say with chronic with a chronic fatigue or a chronic stress situation makes sense. I mean, it makes sense. That's what we should think about because as it turns out, in some of those cases, you have low cortisol levels. 

 

00:11:52:06 - 00:12:13:05 

Tom Guilliams 

So why not just blame the adrenal gland? Right. Because it turns out the adrenal gland doesn't produce cortisol on its own. It produces it as a signal from the brain. And so, what we've learned and why I think this is so important is that the majority of changes in in adrenal production are what's going on in the brain. 

 

00:12:13:05 - 00:12:41:06 

Tom Guilliams 

What does the brain see as stress and then what I think is really more important in this particular case, when we end up having a low cortisol level, is what is going on in the brain that's causing a compensation or an adaptation to stress that is reducing the signal to produce cortisol. And so that's why this is so important when we start thinking adrenal fatigue, then the knee jerk reaction is adrenal support. 

 

00:12:41:18 - 00:13:07:15 

Tom Guilliams 

And so, we've completely then focused on the adrenal gland as a tissue that well, if we give it enough vitamin C or if we give it enough, whatever, glandular or adaptogen, we will make the adrenal gland happy again and it'll produce cortisol. Where we should be thinking about is why did the brain recalibrate its stress response, what is going on in the brain? 

 

00:13:07:23 - 00:13:31:04 

Tom Guilliams 

And that if we're focusing on that area, gives us a much broader understanding of the access and will be focused on the right things. So, I think that's why it's really important. You know, we're blaming the wrong sort of we're blaming the wrong part of the body the part of the wrong part of the anatomy. And we're also then focusing on the wrong or leveraging the wrong solutions. 

 

00:13:31:09 - 00:13:55:01 

Mark Newman 

Where you sit in an interesting spot because I think you you have a group of people, particularly historically, who are describing the wrong problem. So then obviously it's hard to find the right solution if you have the wrong problem. And then, you know, on sort of the other side of the aisle, you have the allopathic community, a significant portion of which is saying that this model over here is nonsense. 

00:13:55:22 - 00:14:19:12 

Mark Newman 

And then in a sense, they're right because the description is not correct. And then you have this evidence based, maybe middle ground is not the right description, but where when you properly describe it, what the adrenal fatigue sort of movement seemed to illuminate is that long term stress leads to problems that are not Addison's disease and not Cushing's disease and worth our attention. 

 

00:14:20:11 - 00:14:46:09 

Mark Newman 

But we have to describe it. Right. And that's why I think it's been so important to get our language right. But it's also frustrating because it's way more interesting and it's a lot easier to get a layperson to Google adrenal fatigue as opposed to access dysfunction. So that's a mouthful. And so, so I have some sympathy for the fact that it's nice to have like a catchy little phrase that describes a very real problem. 

 

00:14:47:02 - 00:15:02:06 

Mark Newman 

But I definitely appreciate your pushing our industry towards describing the problem more technically. In a sound way, because again, if you're if you're solving the wrong problem, you're not very likely to come up with the right solution. 

 

00:15:03:10 - 00:15:24:05 

Tom Guilliams 

Right? Well, I think I mean, the simple the simpler language would have been to use the word stress rather than adrenal. So, if we would just use, you know, stress related dysfunction or, you know, chronic stress, I mean, so we know that that obviously when we when we started talking about it from a pathophysiology, we want to talk about HIPAA of course, the A is adrenal. 

 

00:15:24:05 - 00:15:45:06 

Tom Guilliams 

So, we are not skipping the adrenal gland. Right. Just emphasizing the hypothalamus and doing it in that process. But you're right. I think, you know, sometimes oversimplification makes it easy to market things. Right. And that sounds good at the beginning. But then it's sort of like you dig yourself a hole in this area, which I think we did I think we we kind of emphasized the wrong things. 

 

00:15:45:06 - 00:15:55:09 

Tom Guilliams 

And I think we're slowly changing it. But but it's taken a while. There's been a lot of books written and, you know, we have to kind of wait for those cycle out. 

 

00:15:55:20 - 00:16:28:10 

Mark Newman 

Right. Well, and that's why you don't work in marketing, because your new book called Stress Related Dysfunction is not going to sell as well as adrenal fatigue, I'm pretty sure, to laypeople. But but the the service that you've provided our industry in in helping us to understand that more correctly is really important. So, what are some of the what are some of the solutions that don't really work on the brain that have been targeted at like sort of incorrectly at the adrenal glands? 

 

00:16:29:12 - 00:17:01:08 

Tom Guilliams 

Well, let me let me just go back to one thing you said before we go on to that. And that is I think you're right, the the aloe has that community has sort of because maybe because of the term adrenal fatigue or maybe just for other reasons, endocrinologists have not really embraced the idea that either acute stressors I mean, PTSD, of course, they recognize but but acute stressors or chronic stress has demonstrable effects on measurable levels of the HPV axis. 

 

00:17:02:00 - 00:17:26:12 

Tom Guilliams 

And I think one of the things that, you know, you obviously have done a lot of with and myself pointing this out is you know, if you are testing cortisol correctly, which obviously cortisol is being produced in the adrenal glands, if you do it correctly, you can get a it can act as a surrogate biomarker. For dysfunction. And a lot of that can change over time as someone who has a chronic stressor. 

 

00:17:26:18 - 00:17:51:17 

Tom Guilliams 

So going back to my my first thing that I said about Hansell, yeah, we are seeing a little bit of that carryover of his work. If we understand how to interpret and test correctly, something that the allopathic community probably doesn't recognize until you actually get to a stage of sort of something more dramatic, they would just say, well, there's nothing I psychosomatic, it can be dealt with. 

 

00:17:51:19 - 00:18:23:12 

Tom Guilliams 

Right. And I think what what this what what the the purveyors of adrenal fatigue, let's call it, or at least the functional medicine community has done is they've shined the they've put a spotlight on the idea that psychosocial stress and other aspects of aspects of stress have can have a major effect on a person's pathophysiology, their metabolism, their risk for cardiovascular disease, metabolic diseases like diabetes, etc.. 

 

00:18:23:12 - 00:18:52:22 

Tom Guilliams 

So I think I think that area has has been something that has been good but I think we've we've lost some of that momentum because of the nomenclature we've we've used as far as where we've gotten off on some of these therapies, you know, that's a little bit more difficult to know because a lot of the things that people think, ironically, a lot of the things that people think are helping quote the adrenals are actually helping the brain more than they think. 

 

00:18:54:19 - 00:19:14:16 

Tom Guilliams 

And so a lot of a lot of things that, you know, a lot of, you know, vitamins and B vitamins and vitamin C and adaptogen and foster title searing and a lot of the licorice and some of these things that we have been using for years within the functional medicine, integrative medicine community thinking that I'm helping the adrenal gland. 

 

00:19:14:16 - 00:19:41:07 

Tom Guilliams 

Probably. 80% of that is actually affecting the brain and they just think it's affecting the adrenal gland. Where they've missed it, however, is in the way that I teach, the way that I teach, understanding the stressors is to really get at the four areas. And I think you've probably seen this before sort of things. What are making the brain think? 

 

00:19:41:07 - 00:19:57:00 

Tom Guilliams 

There's a stressor that needs to be responded to. And typically, those are going to be circadian disruption. Glycemic dysregulation, inflammatory signals, all of those are reactive, meaning the brain is reacting to something that's changing in the path of physical energy. 

 

00:19:57:05 - 00:19:57:11 

Mark Newman 

Right. 

 

00:19:59:00 - 00:20:25:09 

Tom Guilliams 

And then one is what is, let's say, you know, anticipatory, and that is the whole idea of perceived stress stress. Right. Which is a huge thing. And obviously perceive stress. The events around us are interpreted differently by different people based on their, you know, their history, you know, their how they were brought up. Also, this is being affected by neuro steroids and endocannabinoids and a bunch of other things. 

 

00:20:25:18 - 00:20:55:19 

Tom Guilliams 

So if you're a clinician and you're in your state and somebody standing in front of you and you say you have a major amount of stress, there's a lot of stress in your life, or in a measuring, you know, various changes in cortisol or DHEA, I would rather that the clinician be thinking about glycemic control circadian disruption, inflammatory signaling in perception of stress, because that is what's going on in the brain rather than saying, you know what, Herb, can I give you right now? 

00:20:55:19 - 00:21:19:07 

Tom Guilliams 

Or what? You know, because I'm thinking I'm trying to help your adrenal gland, right? Eventually, some of those things may be applicable and very helpful. And obviously I help develop products in that area before, but those are going to be helpful only in as much as you can change the incoming stressors. And if you sort of get your eye off the ball in things you always have to do is support an adrenal gland. 

 

00:21:19:07 - 00:21:42:08 

Tom Guilliams 

Everything will be fine. You're really missing all of these incoming stressors. So, to me, that's the biggest area of shifting in focus. If we're asking what is what is the hypothalamus, what's triggering the hypothalamus to make this a stressor that's a more important question. Then, you know, what might help the adrenal gland, which again I said is very limited. 

 

00:21:42:10 - 00:22:09:08 

Mark Newman 

Right? Which is why I think also people tend to succeed by working with a good functional medicine provider because we tend to focus so much on stress as that perceived stress is so important. Our lives are a mess for so many people right now, but it's one out of four categories. And I think that's that can be pretty illuminating for people that it's yes, lifestyle and stress, but there are those other major areas of your life that can also set the house on fire. 

 

00:22:09:12 - 00:22:49:12 

Mark Newman 

And to your point, if the source of the fire is still ignited, then turning on the hose of whatever's going to adapt, that is not really fighting a winning battle until you get to the source of it, which is why you know, functional medicine, I think is such a profound shift is like get to the root cause before you start just shoveling, you know, some some products towards towards somebody so your talk on the things that people succeed with accidentally in a sense, could that list include pregnenolone? 

 

00:22:51:15 - 00:23:04:13 

Tom Guilliams 

So interestingly, pregnant. So of course, we probably need to get into this question about the relationship between pregnenolone and cortisol. And Pregnenolone and DHEA as a precursor. But yeah. 

 

00:23:04:13 - 00:23:07:08 

Mark Newman 

I'm forcing you into a Segway. How do you like that, Tom? Yeah, it's. 

 

00:23:07:19 - 00:23:36:11 

Tom Guilliams 

But I mean, we can come back to that. But interestingly, you know, maybe we should cover that first because, you know, all pregnenolone is kind of a mystery. It's so it's kind of a very interesting ingredient that I think we thought was fixing one problem and may actually end up helping in a completely different area. So, so I think you're probably familiar with the term pregnenolone feel maybe over too familiar with it. 

 

00:23:37:18 - 00:24:06:18 

Tom Guilliams 

And this is this is the notion that you know, most clinicians have been taught, you know, the stereo genic pathway. And so, they get a chart in front of them, and they'll show cholesterol. It starts at the top typically. And then cholesterol is converted into pregnenolone in the mitochondria of austerity genic cells. So, this would be adrenal cells, but also any cell in the body the ovaries, the testes, the brain, skin, a bunch of other tissues as well can make steroids. 

 

00:24:06:18 - 00:24:44:06 

Tom Guilliams 

And so, the first thing you need to do to make steroids is produce pregnenolone. In the mitochondria of that cell. And then depending on what is available, what enzymes are available, that pregnenolone will be then converted into one or several different steroid compounds. And as functional medicine, integrative medicine clinicians have been taught this, you know, you watch these charts and you see, you know, typically on the left hand side, you see cortisol being produced through its various intermediates and then the androgens are produced and then you get, you know, the estrogens come off of there and you see all these different pathways. 

 

00:24:44:13 - 00:24:44:23 

Mark Newman 

Right. 

 

00:24:44:23 - 00:25:15:10 

Tom Guilliams 

And what we've been told is, well, you know, very stressed individual, the pregnant woman that's available is going to be pulled over here to cortisol and then there's not going to be enough pregnant women available to produce either DHEA or estrogens or testosterone. And so that is often called pregnenolone steel or, you know, because the the the adrenal gland is stealing away all of the pregnenolone precursor and leaving these other hormone systems to sort of fend for themselves. 

 

00:25:15:10 - 00:25:17:18 

Tom Guilliams 

And they're not able to produce enough of what. 

 

00:25:17:18 - 00:25:48:18 

Mark Newman 

Right. So pregnenolone is being stolen. And then I've also heard it from the other side calling it a cortisol steel, which would be the cortisol is doing the stealing. So, whether you call it the pregnenolone, steel I've even heard people say you mentioned progesterone because it's also an intermediate or cortisol still. Either way, you're talking about the same concept that is also one of those words we put in quotes because it needs not necessarily mildly corrected, but more discarded in terms of its usefulness. 

 

00:25:48:18 - 00:25:52:04 

Mark Newman 

So so, continue on explaining how that works or doesn't work. 

 

00:25:52:14 - 00:26:13:04 

Tom Guilliams 

Yeah. So that was that was a common explanation used by, you know, pretty much everybody it seemed like that was sort of the standard knee jerk. I don't even know who to attribute this originally to, to be honest with you. But it was it was taught, you know, you go on to YouTube, you can find, you know, dozens and dozens of clinicians explaining this. 

 

00:26:13:12 - 00:26:41:10 

Tom Guilliams 

I actually ran into an article just recently that was talking about, you know, HPV access issues and kind of written as a summary review article. And and the person who's pregnenolone still isn't explanation for this, surprisingly enough. And gave no references. I mean, there's no reference list there. They just say this. So, as I was getting into this research, I started asking I sat this thing down. 

 

00:26:41:10 - 00:27:22:02 

Tom Guilliams 

I said, wait a minute, I've never seen anybody reference this idea before as a published paper. So, I started actually called some of the world's experts in adrenal steroids. Genesis. I just said, let me call these people and say, you know, is this even possible? Is this even physiologically possible? And I think one of the problems when we teach these theory, Genesis Pathways is if you notice and maybe you can even throw one up here is as you know, as I'm talking, you can throw one up on your screen for the podcast, but nowhere in there does it show that all of these enzymes that produce all of these steroids are not available in all 

00:27:22:02 - 00:27:50:13 

Tom Guilliams 

the tissues. Right. There are three different types of cells that produce cortisol, aldosterone and DHEA androgens in the adrenal gland. They don't share. They don't share. They're pregnenolone. They produce. All three of these zones are able to produce their own you know, their own pregnenolone in their own mitochondria. And they don't share this as one big pool. 

 

 

00:27:50:13 - 00:28:11:00 

Mark Newman 

So, if you back out of that, like a simpler concept for me is that the testes make testosterone, and the adrenal gland makes cortisol. That's an easy concept that, OK, it's happening in the testes, the adrenal glands, those are not the same thing and they're making different hormones out of the same substrate being cholesterol getting pulled in there. 

 

00:28:11:05 - 00:28:44:05 

Mark Newman 

And I think what what you've illuminated for me, which is really helpful, is that even as you get into the adrenal gland, that there are different compartments within that that make the hormones that all start with cholesterol within that adrenal gland, that those if I'm hearing you correctly, those are even in different compartments within the adrenal gland. And while the testes and the adrenal gland don't share a common pregnenolone, pool, even the aldosterone, the DHEA, androstenedione, cortisol, even those have their own source of pregnenolone. 

 

00:28:44:20 - 00:28:51:00 

Mark Newman 

Which is from cholesterol in the mini compartment within the adrenal gland. That makes the specific hormone. Is that correct? 

 

00:28:51:13 - 00:29:19:12 

Tom Guilliams 

Yeah. So, let's just take that to the two tissue types that produce cortisol, and which is typical, the two that you see in comparison because you test those two. So, there's only particular produces cortisol. The zone over particular areas produces DHEA. So, they are they're two different tissues really. They come from two different stem cell sources, and they're produced over different amounts of time zone two ridiculous is produced. 

 

00:29:19:18 - 00:29:21:20 

Tom Guilliams 

That's why you don't produce DHEA until you're. 

 

00:29:21:20 - 00:29:22:19 

Mark Newman 

Adrenarche, right? 

 

00:29:22:19 - 00:29:49:01 

Tom Guilliams 

Nine or ten. So, it comes along later. And so, there's no sharing between the pregnenolone between the two. But even more, I mean, this it should have been even simpler to figure this out because if you you know, the calculation of cortisol, even cortisol at its highest peak doesn't even come close in orders of magnitude to all the amount of circulating DHEA and sulfate. 

 

00:29:49:08 - 00:30:22:14 

Tom Guilliams 

So even even if this concept were theoretically possible, the total amount of pregnenolone needed to produce cortisol even at its peak, would not really take much of a percentage of the overall amount of DHEA and sulfate produced. So mathematically, it's also not even relevant. So, but what what drove this was sort of a logic. So, what we see in a lot of individuals is over, especially over a long period of time of stress. 

 

00:30:22:14 - 00:30:53:01 

Tom Guilliams 

Their cortisol levels seem to go down, but before that, their DHEA levels seem to come down first. And so, there's sort of this idea that, well, during this whole time period that you're making lots of cortisol, you're under lots of stress, what some people call stress in wired versus stressed and tired. So, when you're in that early stage, which all again, I don't really like that terminology because it doesn't always explain things well, but high cortisol, all of a sudden, my DHEA production is going down. 

 

00:30:53:01 - 00:31:15:10 

Tom Guilliams 

Eventually I've lost my pregnenolone, so I can't do either one. And now I'm at the point where I where I've exhausted both my DHEA and my cortisol. And so, the explanation that was given, look, when you put them all on a chart, it seems to make sense. But when you actually ask the question, is this physiologically possible, the answer is no. 

 

00:31:15:14 - 00:32:03:00 

Tom Guilliams 

And why that's important is because it is likely that elevated stress causes DHEA production to go down, but it does so in other ways, other signaling ways probably in this on a particular as for which we need to figure out what that is and if we assume that it's pregnant and still will stop looking for the right answer, so I actually believe and actually another side project that I would love for to be involved with is discovering why this on a particular is the tissue that produces DHEA is so vulnerable because it is a tissue that is not formed when you're born. 

 

00:32:03:12 - 00:32:31:05 

Tom Guilliams 

It eventually comes on when you're in an adrenaline, when you're eight or nine years old, it obviously produces until you're about 30, and then it begins sort of to atrophy and goes away and you slowly produce less and less DHEA. And so, you know, again, if you remember back in the nineties when I first got into this business, everybody thought if we give DHEA as a supplement, we will tend to levels of a 30-year-old. 

 

00:32:31:05 - 00:32:59:22 

Tom Guilliams 

Everyone will be young again. Right. And we obviously realize now that that was didn't happen. But I do believe that because DHEA is a counter regulatory hormone to cortisol, that it's early depletion, the early depletion of DHEA, or maybe let's say the early degradation of the production of DHEA from this one in particular. This is an early aging is a sign of early aging. 

 

00:33:00:10 - 00:33:21:09 

Tom Guilliams 

And because it doesn't act as a counter and because let me say it this way, when you produce less DHEA, you have less of a counter regulatory hormone to cortisol, then cortisol becomes more dominant. We'll call it maybe cortisol dominance, sort of like we think of dominance. Right. And then the down regulation of the stress response is more potent. 

 

00:33:21:09 - 00:33:55:03 

Tom Guilliams 

And then it sort of creates this snowballing effect. So, I'm very interested in discovering what drives the degradation of these honorific areas. It's likely going to be things that we all know like reactive oxygen species and probably stress of various kinds of metabolic stressors, all of these sorts of things. But the reason it's very difficult to do the research is because rodents do not have a zone or articulators. 

 

00:33:55:04 - 00:34:25:02 

Tom Guilliams 

They produce DHEA in their gonads not in their adrenal glands. So, we don't have a lot of good animal models to really understand what's going on here. So that is something that I'm very interested in so going back to our original question, just to summarize, so pregnenolone seal, cortisol seal is not a real thing. It's physiologically impossible for one of the zones of particular to produce producing cortisol to steal the pregnenolone from his own are ridiculous. 

 

00:34:25:14 - 00:34:38:08 

Tom Guilliams 

So that's not a good explanation. But likely there is a fundamental reason why DHEA is suppressed during chronic stress and figuring out what that is I think is important. 

 

00:34:38:20 - 00:35:01:19 

Mark Newman 

And one of the things I would add to that that confuses people sometimes is, you know, when you're being invaded by the Huns, it's not time to reproduce. Right? And so, when you see people with acute stress, you might get more and all of you later cycles and you might get lower progesterone. And that's fed in also to this idea of staring at the steroid pathway and go, OK, progesterone is north of cortisol. 

00:35:01:22 - 00:35:25:00 

Mark Newman 

So, if I'm sucking all this cortisol down here, I can't make enough progesterone. And that also is, as I understand it, an incorrect model of yes, stress plays a role in reproduction and there are signaling pathways that play into that. But this simple model of cortisol sucking all your progesterone away so that you can't make a baby is not the model that actually describes it accurately. 

 

00:35:25:20 - 00:35:47:14 

Mark Newman 

And it's interesting to me to hear you speak confidently of what is incorrect, which is sort of step one is knowing what's wrong. And then and then describe for us that we don't actually know all the mechanisms of some of these patterns that we see that are real, that are reproducible at a population level, but we don't actually know all of the pieces to the puzzle yet. 

 

00:35:48:04 - 00:36:19:14 

Mark Newman 

And that's also what makes this industry kind of fun, is, you know, you get out ahead of things. And I think that for functional medicine to me is has been a great place for functional medicine, is to get out ahead of some of these topics. But that's why I think it's also important that you do it with a pretty hefty dose of humility, because oftentimes you have, as you're describing, these really like linear logical conclusions that stare right at you on a steroid pathway and they're there entirely wrong. 

 

00:36:19:14 - 00:37:02:22 

Mark Newman 

Sometimes when you you know, when you understand it further. And for me, that steroid pathway, I think is a two-edged sword because as I want to have a man understand that his testosterone can get converted to estrogen. And as DHEA supplementation can help support testosterone, and support estrogen and maybe like a postmenopausal woman, that's helpful. But then we have to properly understand that when when the gonads make hormones, when the adrenals make hormones, that peripheral conversion of whatever is right ahead of you in the head of a hormone in the steroid pathway, that mechanism is not that doesn't rival glandular production of whatever it is, cortisol, testosterone. 

 

00:37:02:22 - 00:37:27:00 

Mark Newman 

I mean, I've seen men take more and more DHEA thinking I'm going to rival testicular production of testosterone by giving the thing that's just ahead of testosterone until it works. And understanding the physiology is so important for our patients, but particularly for providers to know that if you don't understand that correctly, then your solutions to a very real problem are not going to get you anywhere. 

 

00:37:28:04 - 00:38:07:17 

Tom Guilliams 

Well, right. And I think the other thing is the assumption, going back to your the question that you started this this little section with is all pregnenolone, right? What am I doing? So the assumption that you have with all DHEA or all pregnenolone is if I take this orally, it will get to the tissue and it will get into the mitochondria, let's say, or at least into the enzymatic pathway, so that the the adrenal gland or the testes or the ovaries or whatever will then take this pregnenolone and begin putting it into the pathway of producing the hormone at one whole hormone that at once. 

 

00:38:08:00 - 00:38:38:08 

Tom Guilliams 

I don't know that there's any evidence that all intake of these meat precursor let's say our intermediate hormones gets into a gland and then converts into a end end product. What we probably have going on here is something that most clinicians are probably somewhat unaware of because it's really not talked about much, and that is neuroscience, right? Pregnenolone, pregnenolone sulfate, DHEA and DHEA sulfate. 

 

00:38:38:08 - 00:39:13:05 

Tom Guilliams 

And then there's another whole nother set of aloe, pregnenolone, and some others, they're produced in the brain and have capacity to bind receptors in the brain. As DHEA, as pregnenolone, or the self-aided versions of those. They don't have to be converted to anything. And likely these high doses relatively high dose, let's say pregnenolone that were being used, that were having an effect on somebody, let's say stress related outcomes had nothing to do with precursors to cortisol, precursor to pregnant at DHEA. 

 

00:39:13:10 - 00:39:41:11 

Tom Guilliams 

It probably had to do with the fact that pregnenolone can get through the blood brain barrier, it can be self-aided and then can function as a neural steroid. Which then can modulate the hypothalamus and pituitary signaling, which then modulates, potentially modulates and down regulates some of the stress signals. So, you know, in the end you say, well, it may have worked for some people, but it worked in a completely different way. 

 

00:39:41:15 - 00:39:56:08 

Tom Guilliams 

Right. And what what clinicians were thinking and high dose pregnenolone has been only really studied for schizophrenia. It really hasn't been studied for any of these more nuanced stress related outcomes. But at least that gives us a model of probably how it's how it was working. 

 

00:39:56:08 - 00:40:21:18 

Mark Newman 

When you're bridging together these two phrases that are incorrect that have led to too enough accidental success, that it's entrenched people in their thinking, which is stop progress because you take adrenal fatigue. So, if I go backwards you take adrenal fatigue, you take a saliva test, I'm going to have like a paint by numbers simplified model which says if my saliva is low, I have stage three adrenal fatigue right? 

 

00:40:21:18 - 00:40:40:02 

Mark Newman 

And then I know what that means. So, then I'm going to give you pregnenolone because it's my master hormone, which if you are a cortisol deficient person, certainly your body is going to make cortisol out of that, and then that will fix the problem. And then what you're describing is, for better or worse, you're actually succeeding clinically. 

 

00:40:40:06 - 00:41:02:12 

Mark Newman 

So, you have a patient, you have a simple story, you have a simple solution, and you're actually succeeding. And on a on an individual basis, good for that patient that they feel better. But as an industry, shame on us if we're not correcting that, because we're not going to take that any further. If our model is actually a broken model that's having some measure of success, sort of by accident. 

 

00:41:02:12 - 00:41:34:20 

Mark Newman 

And that's why I think what you've done in outlining what's actually going on has been super helpful. To sort of recalibrating that where some of the some of the solutions are similar or the same and some of them are different. But the path towards the future of understanding this better and having better solutions is a lot brighter if we get our terminology and if we get our understanding, you know, corrected on on those two phrases of adrenal fatigue and this this idea of the pregnant lot and still. 

 

00:41:34:20 - 00:41:35:21 

Mark Newman 

So, I think that's really important. 

00:41:36:13 - 00:42:21:00 

Tom Guilliams 

Yeah. And I think when you combine, you know, you know, I think a change in a more appropriate understanding of the pathophysiology, which then will affect our nomenclature, will affect our questions. Hopefully it'll begin affecting more fully what we do with patients. But when you combine that with what you guys are doing and others are doing with changing laboratory tests, looking for now more, looking for things that we weren't looking for before, you know, back in the day before I even before I wrote the first book trying to, you know, you know, I went to all the different labs that were doing testing at that time and looked at their the way that they would 

 

00:42:21:00 - 00:42:46:06 

Tom Guilliams 

do the instructions for cortisol. And as you remember talk and I talk with you on that since everyone was doing them differently to capture that that peak of the cortisol, the waking response, which I know you guys have talked about, the car, most of these labs weren't catching that in fact, the majority of them were probably testing the first sample in the morning, a half hour to an hour after that peak. 

 

00:42:46:21 - 00:43:06:03 

Tom Guilliams 

And is it any wonder that when you look at the reference ranges, those individuals were hypo cortisol had low cortisol levels because that if you miss that peak, those people are going to look like they have low cortisol, right. So, I think there was, again, another sort of because of the logic that people had and the tests, the tests all were coming back. 

 

00:43:06:03 - 00:43:28:07 

Tom Guilliams 

Well, everybody's low cortisol therefore, we're going to put everybody in, you know, stage three, unless they happen to have really high cortisol. Everybody started being lumped into this and sort of that. There was sort of this group think of this is what's happening with everybody. And if I solve it with this, I'm seeing some success. But a lot of times they would have difficult patients and then they would they wouldn't even know where to start. 

 

00:43:28:07 - 00:43:38:06 

Tom Guilliams 

Then they would kind of they were like, well, this work this is telling me your, you know, stage three or whatever. And why can't why aren't you responding like I thought you would? It's because there's something else going on there. 

 

00:43:38:10 - 00:44:00:05 

Mark Newman 

Yeah, it's funny. And then there are other wrinkles to that that are interesting from a laboratory perspective. I can think of one example where a lab had a different assay for the morning cortisol and the afternoon cortisol. So used to be the same assay one, two, three, four, and then the assay switched but only for those latter three points because it was a more sensitive assay. 

 

00:44:00:10 - 00:44:39:12 

Mark Newman 

But the calibration in adjusting from assay number one to assay number two wasn't really done very well. And so, there was a moment in time where 40% of the people that were testing were actually coming out low because the reference range and the numbers were shifted a little bit. And so you get you get this confluence of, you know, as this industry evolves of our thinking can be so far off based on the understanding and ideas that take off and, and the technology needed to catch up and to get sophisticated enough to where the answers are that we're testing the right thing and also that our technology is accurate enough to give us the picture 

 

00:44:39:12 - 00:44:53:18 

Mark Newman 

that we want. But so, it's a complicated thing. I'm curious for you, when you want to peer into that world or you are encouraging a doctor to peer into that world, what's at the top of the food chain for you in terms of analytical tools to give you the information that you want to see. 

 

00:44:55:20 - 00:45:27:04 

Tom Guilliams 

Well, I think when you I mean, I think we've talked about this. I obviously probably the majority of the work or HP access related stress response so whether it's perception of stress, whether it's the prior social stress test where you can do that experimentally, people that have looked at long term stress for, you know, mothers who have been taking care of their, you know, sick children, actually teachers that have been teaching all these most of that work's been done using saliva. 

 

00:45:27:12 - 00:45:27:18 

Mark Newman 

Right. 

 

00:45:28:08 - 00:46:08:06 

Tom Guilliams 

And typically, like we talked about, either the diurnal or that that Salisbury cortisol in the morning that the car and that change because we're dealing with both a dynamic, you know, the sort of the the plasticity of the HP axis as well as the anticipatory stress of that day. Right. I think that's I think what this industry did and of course, you know, the many labs that didn't celebrate tests recognize that unfortunately they didn't always go back to the literature that had been, you know, been published over the last 20 years. 

 

00:46:08:06 - 00:46:29:05 

Tom Guilliams 

And I think I think slowly that has changed partly because of my book and sort of confronting them with the data and then adding the course, all the waking response. So, I think I think that has helped a lot. But again, and you know as well as I do try to emphasize this to clinicians, you could only you're only testing what happened that day. 

 

00:46:29:21 - 00:46:54:18 

Tom Guilliams 

They're sitting in a tube or they're holding a swab in their mouth day. They can't tell you what happened a week ago, cannot tell you what's going to happen a week later. So, a clinician needs to understand what they're measuring for that day and then how to how to get that information in with everything else they're measuring, you know, other biomarkers that they're measuring with that patient, other like life inventory in life stress. 

 

00:46:55:06 - 00:47:12:05 

Tom Guilliams 

So it's really important that they you know, for instance, they ask questions about, you know, what happened the day that you tested those kind of things, because you're measuring you know, when you're when you're sitting in a tube, it's all going to tell you what what the cortisol is in the saliva when they spit and interpreting what that means. 

 

00:47:12:14 - 00:47:33:08 

Tom Guilliams 

When did they wake up? You know, did they exercise that day, these kind of things so that, you know, you don't want to just rely only on the test result. You need to understand how does that what's the context of that information? In the life of the patient. And I think the other things that, of course, you guys are doing is is asking more questions. 

 

00:47:33:13 - 00:48:07:02 

Tom Guilliams 

Obviously, is there's more going on than just free cortisol. Cortisol converts to cortisone and that is affected by obesity. And, you know, insulin sensitivity and expression of different enzymes and probably inflammatory conditions and all kinds of other things. You eat as. One of the emphasis that I make in my book is that knowing what what level of cortisol is there is not the same thing is the knowing how much signaling of cortisol is there because there are all kinds of other things that influence cortisol signaling. 

 

00:48:07:08 - 00:48:37:11 

Tom Guilliams 

I'm not going to get to all of them now, but understanding that free cortisol represents what the body wants to have available as a signal, but understanding some of the other things that you are teasing out with the metabolites in the urine metabolites, maybe even in the saliva eventually or other other places to actually ask questions about, you know, what is the body producing in cortisol, but then how is it managing that process in in allowing it to be a signal. 

 

00:48:38:18 - 00:48:42:17 

Tom Guilliams 

And I think I think we're just at the beginning stages of understanding that that aspect. 

 

00:48:42:18 - 00:49:18:12 

Mark Newman 

Yeah. Yeah, it's complicated. Our goal originally was we want the diagonal pattern, which you're saying is really important. We added the metabolites in and we got some really interesting, you know, information that in a fraction of cases sort of profoundly like illuminated you know, what was going on when someone's got a concurrent thyroid issue, that's that's adjusting their cortisol clearance or in cases of obesity and then your insistence, thankfully, on the importance of adding to that picture that the cortisol awakening response. 

 

00:49:18:12 - 00:49:52:05 

Mark Newman 

So looking at yes the up and down pattern throughout the day very important but that spike that happens in those first 30 minutes that you can only see in saliva you know you were influential really just just you as an individual in doing what you've done and putting it in front of the faces of labs and I, I can still remember hearing that and sort of resisting that in my mind because a lot of work and then one day I just, I woke up at 2 a.m. and rolled over to the wife and said cardiac I got to go to lab and like six weeks later we launched the DUTCH Plus because we just like got on 

 

00:49:52:05 - 00:50:19:14 

Mark Newman 

fire with like, yeah, you know what, we have to listen to the literature. Not so much Tom as the literature because he's, he's putting that on a platter for us to, to consider. And the argument is, is strong that that adds an independent variable and that's where our DUTCH Plus came from. Is like heavily influenced from your insistence that the literature was right, that the diurnal pattern is important you know, and then we can talk about the metabolites. 

00:50:19:14 - 00:50:42:20 

Mark Newman 

But on top of all that, looking at that mini stress test of those first 30 minutes and what's happening was important. And what we found also is that the cotton swabs were really important that we'd say here, patient, you have not had anything to drink, your mouth is dry, and I need two milliliters of saliva. Some labs are even asking for three milliliters, and they're done, and 20 minutes have passed. 

 

00:50:43:02 - 00:51:09:12 

Mark Newman 

So, if 20 minutes have passed, you're, you're already halfway up that curve and you don't have an accurate, accurate look at that. So, we found that to be a really, really important piece which was sort of stymieing the the saliva industry because and it's, it's nobody's fault but those silly swabs absorbed progesterone. So, if your model is to get all your sex hormones out of saliva and add a car, it's like impossible. 

 

00:51:09:17 - 00:51:32:01 

Mark Newman 

And so, for us, we were getting really accurate progesterone levels, you know, which we've published serum correlation with our progestin on metabolites and same with the estrogen. So, we love getting that out of urine. So, then it made it easy for us to add the the cortisol picture from saliva to look at the diurnal pattern, the cortisol awakening response and the metabolites in our, you know, in our DUTCH Plus. 

 

00:51:32:01 - 00:51:41:19 

Mark Newman 

And that's been a really fantastic like most advanced way, I think, of a sort of telling that story of someone's of someone's access. 

 

00:51:43:03 - 00:52:10:22 

Tom Guilliams 

Yeah. I think, you know, it's kind of funny. There's a lot of different stories that that came about. I remember when I was putting this together before the book came out or maybe just as the book came out I had had personal conversations with a lot of the different labs and was beside myself in some ways to say, look, the course all the way in response is the most used biomarker for salivary cortisol in stress research by a long shot. 

 

00:52:11:08 - 00:52:33:08 

Tom Guilliams 

I mean, it was, you know, it was becoming the standard go to biomarker and none of the labs offered it. None of labs even talked about it. And I went to them individually, as you remember, perhaps, and this is actually maybe just almost before you had set up your company. So, I don't know that we talked on that at that time. 

 

00:52:33:08 - 00:52:50:01 

Tom Guilliams 

You may have been with somebody else. I won't. I don't say who. But and and really their answer to me was, oh, that's interesting. But basically, we've been doing this the same way, you know, in their mind they're thinking, well, I don't want to go through new reference ranges. I don't want to do all these different things. That's nice. 

 

00:52:50:01 - 00:53:05:00 

Tom Guilliams 

But, you know, nobody's asking us for this. So, we're just going to leave it and then when I came out, when the book came, was published and we invited everyone in the same room. And I said that and literally and I think you remember there was like probably five or six of the lab companies there. 

 

00:53:06:00 - 00:53:06:06 

Mark Newman 

Right? 

 

00:53:06:21 - 00:53:25:11 

Tom Guilliams 

Then I was like, OK, well, now they all heard me say it. And now I'm glad to say, you and a few others have really taken it to heart and even pushed it beyond what I had recommended and said, look, we need to not do what we've done for the last 20 years because it's just the same thing. 

 

00:53:25:11 - 00:53:50:02 

Tom Guilliams 

We've done that for the last 20 years. We need to begin engaging literature, begin as you are publishing some of your own data asking new questions because you have access to data that really doesn't exist anywhere. Nobody's doing the thousands of different tests that you're running and asking different questions and able to compare some of the metabolites that you're looking at. 

 

00:53:50:12 - 00:54:14:17 

Tom Guilliams 

And so, I've encouraged you and others to say, look, dig into that look, get a statistician, start asking, you know, start interrogating your own data and anonymizing it and things like that and see, see what's going on. Because these clinicians really are struggling to try to figure this out. And you're sitting on a pot of data that could help us start unraveling this. 

 

00:54:14:17 - 00:54:39:20 

Mark Newman 

Yeah, we we hired an endocrinologist who was also a statistician, and it's been great to see what was able to be pulled out of that data because the very thing that pushed me towards our model was all of these people talking about the relationship between weight gain and cortisol and what they meant was free cortisol and I mean huge companies selling lots of saliva tests. 

 

00:54:39:20 - 00:54:57:11 

Mark Newman 

And I don't mean the lab, I mean the clients of the lab that have these whole like world set up of come here, lose weight. We're going to look at your cortisol and all of that, all with this underlying assumption that there's this strong relationship between free cortisol and weight gain and fat mass and that sort of thing. 

 

00:54:57:11 - 00:55:18:00 

Mark Newman 

And then you I actually looked at the data, you know, hundreds of thousands of points and the relationship between BMI and free cortisol was either nothing or very slightly negative. Not positive. Right. And like it, it kind of rocked my world of like there's this narrative that we're telling that's not it's not that it's not as true as we want it to be. 

 

00:55:18:09 - 00:55:46:02 

Mark Newman 

It's just wrong. And that's what got us into looking at the metabolites is as you look at the metabolite weights and you plot those, which is kind of next up on our list of things to publish, we have the manuscript almost ready to go is when you look at those, there's a dramatic increase in how in the cortisol metabolite output as you go from the skinniest to, you know, the most fat mass in terms of when you're looking at the population and just what we see in in the lab results. 

 

00:55:46:15 - 00:56:07:02 

Mark Newman 

So that was really interesting. I want to I want to put one piece of this to you to get your feedback on something because it's been something I've described, but not with as much confidence as I'd like, is that cortisol is made in the adrenal gland. Right. And then it's shoved through the adrenal medulla at really high concentrations compared to what's circulating. 

00:56:07:07 - 00:56:42:18 

Mark Newman 

Right? Like really high concentrations. And you can correct me if anything I say is wrong OK, so the total amount that you produce as a very obese person is a lot more than a skinny person, but there's not more in circulation. There's just more goes out. It gets my interpretation stored in the fat metabolize and it ends up in a toilet, but it's not circulating as free cortisol at higher levels so the adrenal glands making a lot, which means the adrenal medulla is a hyper cortisol state in that person, even if they don't have even if they're salivary cortisol is low, right? 

 

00:56:42:18 - 00:57:03:12 

Mark Newman 

They're making lots of cortisol. And then in the adrenal medulla, norepinephrine turns into epinephrine. And that relationship is pushed by cortisol. So, in these patients, these were the classic patients we were seeing early on. That was so profound to me, is I have low free cortisol, which people used to say, oh, you don't make very much cortisol. Aha. 

 

00:57:03:12 - 00:57:22:00 

Mark Newman 

But I have high levels of metabolites. So, since people were ignoring that information, they were taking those patients and saying, we got to get you making more cortisol. Well, they were already making a lot. You just didn't know it, right? So, then they would ramp up their cortisol production and now the adrenal medulla is full of even more cortisol pushing norepinephrine to epinephrine. 

 

00:57:22:01 - 00:57:44:03 

Mark Newman 

And we were and then in my mind, anecdotally, we're seeing this sort of wired but tired because you're making more, you know, adrenaline, but you still got you know, this issue. Does that is that description interesting to you? And does it seem like an appropriate description of why it might be important to look at both the free cortisol and the metabolites as we do in our testing? 

 

00:57:46:12 - 00:58:12:16 

Tom Guilliams 

The USDA, a whole bunch of questions there. And I think a lot of them are interesting. A lot of them are probably very experimentally extremely difficult to ask like for instance, how, you know, how the production of cortisol affects internally to the medulla conversion between, you know, anything like whether it's epinephrine, norepinephrine or anything else that's going on there. 

 

00:58:12:16 - 00:58:54:03 

Tom Guilliams 

So, the one thing that's interesting is on top of all the issues that you mentioned is tissues can dramatically change their sensitivity to cortisol on either a circadian rhythm or in a dynamic fashion. So, for instance, you can you can put cortisol on a tissue at one time of day and it will have one effect versus another time of day, and it'll have a completely different effect also, the adrenal gland has different effects and, you know, these kind of things. 

 

00:58:54:03 - 00:59:19:11 

Tom Guilliams 

So, so the idea that all of this is static is or that all tissues are the same, I think is another area that needs to be sort of corrected in the way that we think about this. So I would I would guess that it would seem like the medulla would have a way to compensate for that so that you wouldn't have the fight or flight process completely overtaken by cortisol. 

 

00:59:19:11 - 00:59:56:21 

Tom Guilliams 

Or, you know, just just, you know, the idea of a circadian rhythm, the super charismatic nucleus which controls our you know, our central clock in the brain has no receptors for cortisol, no glucocorticoid receptors. So there's other tissues that have different sorts of glucocorticoid receptors to manage this effect. So so so when I first got here, the idea was there were three, three, three parts on your your diet, stage one, stage two and stage three. 

 

00:59:57:02 - 01:00:21:02 

Tom Guilliams 

Right. And it was assumed that if I measured cortisol, free cortisol, let's say I can, I'll be able to and I'll be able to tell you what three areas you're in. I think what we're realizing is that maybe those three stages are are not there really perhaps, but certainly almost every cell has a dimmer switch or an intensifying switch. 

 

01:00:21:18 - 01:00:49:04 

Tom Guilliams 

So when you're talking about obese patients and adipocytes, where you have an accumulation of cortisol or cortisone, which then can convert back to cortisol in, you know, the adipocytes and be released. So as you know, the question about am I measuring the cortisol produced today or my measuring the cortisol produced and stored in the adipose tissue and released today? 

 

01:00:49:09 - 01:01:13:19 

Tom Guilliams 

Right. And so all of these questions are questions that we don't know the answer to. We don't we don't know and when you add what you're talking about is upregulation or down regulation of, you know, the enzymes that metabolize in the kidney, in the liver, and then what you're seeing in the urine, how much of that is free cortisol produced today? 

 

01:01:13:19 - 01:01:57:09 

Tom Guilliams 

How much is this pre cortisol that was released? How much was metabolized what's been upregulated, what's been down regulated? These are questions that I think that I'm hoping that, you know, you and I can start, you know, asking and teasing out and getting at because I think as we do, not only will we be able to fact what I was talking about the aspects of stressors but then if we can start getting at what causes cortisol signaling to change, how can we you know affect that and reduce some of the negative consequences of of cortisol triggering let's say metabolic dysfunction and you know adipose tissue synthesis and things like that. 

 

01:01:57:16 - 01:02:19:22 

Tom Guilliams 

Then I think we are really getting at sort of both ends of the spectrum when it comes to sort of stress responses. But but some of the experiments that you described, some of the questions that you describe, I'm not sure we have good experimental models to get at that. So those are going to those are probably going to be theoretical for a while. 

 

01:02:19:22 - 01:02:20:23 

Tom Guilliams 

My guess would be right. 

 

01:02:21:00 - 01:02:51:02 

Mark Newman 

Yeah, it's been difficult in the literature to find some of those like deep questions or maybe they're more they're more esoteric questions, but they're important. It's hard to find work on on some of those, you know, interestingly, the measuring of the metabolites was one of the final sort of clues to me that you were right about adrenal fatigue, because if you take a skinny person and you stress them, they make more cortisol, their adrenal gland makes more cortisol. 

 

01:02:51:07 - 01:03:29:18 

Mark Newman 

If you take a very heavy person and they're not stressed based on their metabolites, they make two to three times more cortisol than that skinny person every day. 24-7 for their whole life. So then if you think about that from the fact that the adrenal gland is every day making three times more cortisol than that skinny person, even if they're stressed out, you should have we should have seen a relationship between adrenal fatigue and body mass index that ran through the population because those people are literally cranking out gobs of cortisol every day, whether their stress response is functional or dysfunctional. 

 

01:03:29:18 - 01:03:40:07 

Mark Newman 

So that was that was a pretty good tell for me that like, yeah, the model that model is broken and needs needs adjusting so well. 

 

01:03:40:17 - 01:03:54:12 

Tom Guilliams 

And of course, you probably I don't know if you did the mathematic calculation of the three cortisol plus all the metabolites. My guess is those those obese individuals are producing more total cortisol because of that. 

 

01:03:54:22 - 01:04:04:17 

Mark Newman 

Yes, not well, they're free. They're free cortisol. And the semantics get complicated. But if by total cortisol you mean the total of the free cortisol, they don't make more of that. 

 

01:04:04:19 - 01:04:06:12 

Tom Guilliams 

If you mean of all cortisol. 

 

01:04:06:12 - 01:04:30:17 

Mark Newman 

Yeah, the total of all the metabolites is easy to approximate because you just need to measure the metabolites because they're so much bigger than the free cortisol that it's it's irrelevant in terms of the total because it's really only a couple percent of the total of those metabolites and the total the metabolites correlate nicely with BMI, which is again something that we have written up and we need to get out in the literature. 

 

01:04:30:23 - 01:04:49:18 

Tom Guilliams 

So and that's why I think if you look at the historical data that connected elevated cortisol with obesity, that was all done with the serum and probably that was serum total cortisol, not free cortisol so that's probably why, you know, people assumed that if you just went to free cortisol, you would see the same thing. And what you're telling is, no, you're not. 

 

01:04:49:18 - 01:05:10:19 

Tom Guilliams 

You're saying something different, which obviously is interesting because on the one hand and you and I have kind of bantered back and forth, you know, what do you what do you treat as a clinician? You treat the free cortisol, which is what the body is trying to control, or do you treat, you know, these other things? And I think the answer is you want to treat the patient. 

 

01:05:10:22 - 01:05:35:20 

Tom Guilliams 

So, I always these are biomarkers. You don't want to treat these as a disease or a condition. But it's interesting that the free cortisol I always tell people is this is what the body wants to control because it is the it is the most powerful signal. But I think what you're learning is some of the physiology behind that and and we need to understand that that can be maybe modulated as well. 

01:05:35:20 - 01:05:55:04 

Mark Newman 

Yeah. In the majority of cases, the free cortisol is the primary information that you want to focus on. It's the cases where, you know, the friend of mine who was accidentally overdosing on thyroid, who had low free cortisol and gobs of metabolites as a skinny woman was like, well, what in the world is causing that? Because you're hypothyroid? 

 

01:05:55:04 - 01:06:20:19 

Mark Newman 

That's the opposite of what makes sense. And then she figured out, oh, I'm dosing twice a day. My doctor told me once a day, oops, and so she had low free cortisol as a consequence of induced hypothyroidism. And in those types of cases where you're not necessarily treating one or the other, you're just understanding their story better so that you can you can get to the final solution when considering, you know, all of the variables that you're looking at. 

 

01:06:20:19 - 01:06:46:04 

Mark Newman 

And it's those types of cases where it profoundly, you know, illuminates what's going on with somebody where where we really like appreciate having that extra information. Right? So awesome information on these topics. So, you know, as I look at it, adrenal fatigue, pregnenolone, steel all cortisol awakening response like your influence has been huge. You're out ahead of the industry on that. 

 

01:06:46:11 - 01:07:05:06 

Mark Newman 

As you know, the super nerd that's in the literature more than the rest of us. So, what do you see out ahead of this industry that hasn't been adopted that needs to be considered more more strongly as it relates to cortisol, age access, those types of topics? Anything on the top of your mind? 

 

01:07:06:08 - 01:07:40:18 

Tom Guilliams 

Well, I think what I just said is I think one thing that's that I do lay out in the book, and that is understanding the cortisol signaling can be affected by so many different things. Cortisol binding globulin 11 HS the that converts cortisol that cortisol and these kinds of things. So I think that's an area that I think is often forgotten or probably the area that I have been spending the most time in recently is so if I said, hey, the HPI access is not at all all about adrenal, that's kind of one corrective that I'm trying to make, but now I'm kind of on to correct them saying the ATP axis is really not 

 

01:07:40:18 - 01:08:08:06 

Tom Guilliams 

all about stress. The ACA access is really a metabolic regulator. It is a surveillance for energy management for which stress hijacks, if you want to say it that way, or is obviously very good at correcting. If you don't live through today, you're not going to be, you know, it's not going to help to live through tomorrow. So, you know, the, the management of energy. 

 

01:08:08:18 - 01:08:38:11 

Tom Guilliams 

But there's there's a reason why the hypothalamus pituitary adrenal access is why glucocorticoid is a glucose regulating hormone, why it regulates energy, why it is highly involved in the state of fluctuation of metabolism. And so, what I'm trying to get clinicians to even understand more is the reason that chronic stress affects so many different things metabolically is because the ATP axis is the core metabolic regulator. 

 

01:08:38:21 - 01:09:05:03 

Tom Guilliams 

So when you when you take your normal system and you constantly say, hey, we need to borrow you because, you know, if I needed to borrow your help because a lion is chasing me, the classic way that we try to explain, right, is, you know, probably I'm going to either die or I'm going to have a solution that's going to need to be fixed for the next 12 hours. 

 

01:09:05:15 - 01:09:40:14 

Tom Guilliams 

But if I am constantly in a relationship or I have constant financial issues or I have my stomach dysregulation or I am working third shift or, you know, name all of the potential issues that we have, these chronic stressors that we impose upon ourselves oftentimes and we don't get out of them if we are constantly borrowing our normal circadian metabolic machinery to constantly fix this thing, eventually it's going to begin adapting to that chronic stressor. 

 

01:09:40:14 - 01:10:10:18 

Tom Guilliams 

And now our efficiency for running our metabolic machinery is going to be deficient. And so, what the reason we need to fix chronic stress so much is because it affects everything. It affects everything. And so, what I am what I am going to be teaching and sort of this topic I've been talking about it to understand not only how the HP access is integrated with circadian biology, but how it's being integrated with mitochondrial function. 

 

01:10:10:18 - 01:10:39:02 

Tom Guilliams 

I would say integrated with insulin resistance and gastrointestinal function and down the line. And when you start looking at things like CRH, we think, oh, it's just binds to the Sierra receptor. Well, it's in a family of something called Euro Courtney's and they bind or two different receptors and ATP, well, guess what? AC here is produced as this long peptide, which is divided up into all these other peptides, only one of which is a state. 

 

01:10:39:02 - 01:11:02:05 

Tom Guilliams 

And guess what? All of these other peptides bind to receptors that have effect on metabolism and immune function and down the line. So, as I, as I start as I start going back and we start thinking, well, the ATP axis, that's just CRH cortisol, right? And that's what we've learned. And as it turns out, it begins to mushroom. 

 

01:11:02:13 - 01:11:33:20 

Tom Guilliams 

And you realize that this is really a surveillance system that's designed to protect the whole body's metabolism. It affects the GI tract, the immune system, and the stress response becomes sort of like this, OK, everybody stop what you're doing. We got something to take care of over here. It's sort of like in your office, if you're if you're a flood in your office, everyone still has to you know, you hopefully all your your machines aren't going to shut down and everybody's samples aren't going to get lost. 

 

01:11:34:01 - 01:12:06:18 

Tom Guilliams 

But if you have a flood in your office, everybody has to stop what they're doing. Pump out the water, fix out, fix what's happening, dry everything out and then get back to work. Well, if there's a flood every day in your office, you're not going to get a whole lot of work done. And so, if you have have the constantly hijacked your own surveillance system, your own metabolic machinery, your own networking kind of system, for, say, sometimes false alarms and sometimes real alarms, you are going to have to compensate. 

 

01:12:06:18 - 01:12:31:16 

Tom Guilliams 

And I think that is the ultimate reason why chronic stress causes so much damage to so many different tissues and creates such a burden on chronic disease. And so so that's part of the other thing that I'm thinking about is if I can convince people that stress is not about the adrenals, I'd like to convince them that the H free access is not all about stress. 

 

01:12:32:09 - 01:12:40:15 

Tom Guilliams 

And and that, I think, will get us to the bigger picture of chronic disease management. Yeah. The brain is in control. 

 

01:12:41:07 - 01:13:03:10 

Mark Newman 

Well, if nothing else, you've convinced me that as I peel the layers of the onion, I'm still in that outer part that you don't even eat um, and I got a long ways to go, so which leaves more books for you to write and more things for us to discover about just. I mean, it's the amazing, like, complexity of of how we're made is just is like, a marvelous thing. 

 

01:13:03:10 - 01:13:20:03 

Mark Newman 

So I, I really appreciate your insights. I think it's super helpful. It's helpful. For us in the moment, but I mean, I mean, really, my hat's off to you in being in a position to just be honest with the information that's in front of us, in front of you in a way that really has shifted the course of things. 

 

01:13:20:03 - 01:13:35:06 

Mark Newman 

And it's exciting to think about where some of those things are headed, and it takes time. And so, it'll be fun to to continue asking those questions and trying to answer trying to answer some of the good questions that you're posing. So, so thanks for joining us today. 

 

01:13:36:01 - 01:13:42:02 

Tom Guilliams 

I appreciate it. And I'm glad you guys have the curiosity to want to know some of these things and keeps me asking questions. 

 

01:13:42:08 - 01:13:43:02 

Mark Newman 

All right. Thanks, Tom. 

 

01:13:43:15 - 01:13:43:22 

Tom Guilliams 

Yeah. 

01:13:44:07 - 01:14:04:09 

Noah Reed 

Well, it's been great having you on the show, Tom, and thanks for guiding us through these really complex and controversial topics. There is so much more that we could not get to. So please email any of your questions and comments to podcast at DUTCH Test dot com to continue the conversation. Thanks to everyone who joined us this week. 

 

01:14:04:09 - 01:14:28:00 

Noah Reed 

So, stay tuned for next week's episode. Where we have a very special guest, Doctor Deb Matthew. Mark Newman will be back in studio, and we'll get to learn together about the circadian rhythm which runs each and every one of our biological clocks. We really appreciate it. If you would take the time to rate and comment on your favorite streaming app, you can also share that you're listening to us on social media to help others find us. 

 

01:14:28:12 - 01:14:31:13 

Noah Reed 

I'm Noah Reed. Thanks for joining us today. Until next time.