An HRT Revolution is Underway. Are You Ready to Individualize Recommendations for Hormone Health?

For anyone who has been paying attention, you may already know that the takeaways related to hormone replacement therapy (HRT) from the original Women’s Health Initiative (WHI) study have been completely overhauled. It’s about time! As a result, it’s not an understatement to say that we are in the midst of a total transformation in hormone replacement therapy (HRT) and it’s essential that as providers we (1) get up to speed on the nuances of the new interpretations and (2) learn how to personalize the guidance we give.

Dr. Allison Smith, from Precision Analytical, is really a bright, guiding light in this new era of hormone care. She joins me in this episode of New Frontiers to start to unpack some of those important considerations and share resources for where practitioners can learn more. She explains why more detailed hormone metabolite testing can provide answers to hormonal symptoms when standard serum measures of testosterone and estrogen are “normal.” She also shines a light on the need for understanding how our patients are metabolizing hormones, especially if they are on HRT as well as to optimize their long-term cardiovascular, bone, skin, and brain health. This is indispensable listening and I’m sure you’ll enjoy this conversation as much as I did. – DrKF

Hormonal imbalances are at the root of many chronic conditions, but advanced testing can provide the key to unlocking personalized care for your patients. In this episode of New Frontiers, Dr. Allison Smith dives into how the DUTCH test offers a detailed view of hormone metabolism, revealing insights that go far beyond traditional hormone testing. From fatigue to weight gain, mood swings to sleep disturbances, Dr. Smith explains how understanding the full scope of a patient’s hormonal health can lead to more effective treatments. Learn how functional medicine practitioners are using the DUTCH test to uncover the root causes of complex symptoms and create tailored treatment plans that drive better patient outcomes.

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald: Hi everybody, welcome to New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine and of course today is no exception. I am thrilled to be talking to Dr. Allison Smith about all things hormones and hormone testing. Let me give you her background and an incredible promo from DUTCH, from Precision Analytical, and then we’re gonna dive into this cool podcast.

Dr. Kara Fitzgerald: Dr. Allison Smith completed her ND at National University of Natural Medicine in Portland, Oregon. She has worked in private practice focusing on primary care, women’s health, and dermatologic laser therapy. Over the last 10 years, she’s consulted with providers on thousands of cases in the context of hormone testing and brought awareness of testing to providers in clinical practice through consultations, webinars, case presentations, and articles. She now leads a large and esteemed group of clinical colleagues at Precision Analytical, home of the very famous DUTCH test. And if you haven’t done the DUTCH test or you’re a regular DUTCH user as we are in my practice, they have an amazing team to consult with. We use them routinely. So even though I’ve been doing the test for years, I just pinged you guys the other day in fact.

Dr. Kara Fitzgerald: But here’s some training that they’re offering. I just want to make you aware of it. Go to DUTCHtest.com and register to become a provider in order to access DUTCH Tests’ upcoming hormone replacement therapy course. This will be extraordinary, underline extraordinary a couple of times because they have such a strong clinical team. You don’t want to miss this opportunity to level up your knowledge and bring more clarity to your practice. Dr. Smith, welcome to New Frontiers.

Dr. Allison Smith: Thank you so much for having me on. I’m so excited to talk to you today about lab testing for hormones.

Dr. Kara Fitzgerald: Yeah. Well listen, I just want to say that you were involved in this training that’s going to be happening, I’m sure, because you’re a leader over there in the educational team. So I’m sure that you really had something to say about the design and everything. And like many things that you do, it’s probably just absolutely useful and top notch. Any words you want to say before we get into it?

Dr. Allison Smith: It’s about a year in the making. Yeah, we really wanted to distill down what has come from the next iteration of the takeaways from the Women’s Health Initiative. Which, if anybody has been paying attention, is totally different than the initial takeaways from the Women’s Health Initiative (WHI) when it came out and all of the sort of fear around hormones. It’s almost completely turned on its head now. We really felt it was important to dig into the research, to really give an in-depth training on all the different types of deliveries that people are using for hormones now based on some of the new recommendations, knowing that hormone replacement therapy is going to be ramping up probably quite a bit in the next few years. And we want people to know how to do it, know how to do it safely, know how to monitor what they’re looking for with bone health, so that everyone’s really prepared. Yeah.

Dr. Kara Fitzgerald: Bravo you, bravo you. You know, as I was preparing for this conversation, and we’ll actually start with a little bit of the WHI challenges and transformation that has happened, but it just made me reflect. We both went to the National University of Natural Medicine in Oregon, and Tori Hudson was my professor. Was she yours as well when you were in school?

Dr. Allison Smith: Yeah, she was. Yeah.

Dr. Kara Fitzgerald: And she was doing HRT back when I was in school. She’s such an extraordinary, brilliant, bright light in this space and was able to really kind of think through in a pretty sophisticated way the findings from WHI.

Dr. Allison Smith: Did she have you calculating the 80-20, the bi-est and tri-est? And she wanted all of us to graduate ready to walk out the door and convert a Premarin script to a bioidentical E3, E2 combo. Yeah.

Dr. Kara Fitzgerald: She’s just such a great teacher. Anyway, you know what? I definitely don’t remember doing that, but it’s been a while. It’s been a minute from when I was in school. But I would like to, I wanna invite her on the podcast. I just…

Dr. Allison Smith: Yeah. She’ll knock your socks off. Yeah.

Dr. Kara Fitzgerald: Yeah, well she has as my teacher, yeah, for sure. So let’s just talk a little bit. Our listening audience is primarily clinicians, so they’re probably aware of the Women’s Health Initiative and the fact that it’s really been roundly challenged. Do you want to just give me a basic overview? What are these findings that are turning the volume down on– I mean, it’s kind of extraordinary if you think about it. This just resulted in millions of women, I mean, uncalculable numbers of women, just being inadequately undertreated in the US and in the whole world because of the way the study was interpreted, was sensationalized, the study design, the use of synthetic non-bioidentical horse…

Dr. Allison Smith: Progestin.

Dr. Kara Fitzgerald: Anyway, it’s really extraordinary that we’ve come full circle on it, but go ahead and give me your thoughts and why you think everything’s going to transform here.

Dr. Allison Smith: Yeah. I think initially the takeaway was that the Premarin, which is the conjugated equine estrogens that were mostly being used then, along with a progestin to protect the endometrium from that overstimulation from estrogens, that combination was associated with cardiovascular risk increase, breast cancer risk increase, they were arms of the study that they had to stop, and I think that there was a general sentiment that this actually isn’t healthy for women, even if they have discomfort around the menopausal transition and there are benefits to bones.

Dr. Kara Fitzgerald: Discomfort.

Dr. Allison Smith: Discomfort, you know, just stick it out, it’s fine. But essentially, they sort of pinned some of these issues, really serious issues, on the estrogen side of the hormone replacement therapy incorrectly, right? It should have been more pointed towards the medroxyprogesterone acetate progestin, a progesterone-like compound that protects the endometrium similarly to progesterone, but in other parts of the body does not act like progesterone at all. In some parts of the body it acts like an androgen and it can increase our cardiovascular risk. So for many, many, many years, the baby was sort of thrown out with the bathwater and we thought of estrogen as increasing breast cancer risk incorrectly. And we thought of progesterone as increasing breast cancer risk even in some cohorts.

Dr. Allison Smith: So I think going back through that research and sort of teasing it out and separating it has really, really changed the way we see estrogen replacement in our perimenopausal and postmenopausal women. And really finding that it doesn’t increase breast cancer risk any more than a glass of wine in the evenings does. I think those types of conversations help us to understand what the risk actually is so that we can make those decisions with our patients when they are sitting in front of us with a family history of osteoporosis and you know hot flashes, night sweats, and sleep disturbances, and, you know, staring down the gun barrel of maybe having to quit their job or not being able to be there for their families.

Dr. Kara Fitzgerald: Accelerated aging. Like at every measure, I mean, that’s really fundamentally what it is. You know, it accelerates all the chronic diseases of aging, increases the risk for developing them. All of them really, as well as the aging phenomena itself. You know, this is the mother load for us as women when we go through the hormonal transition and to have that completely halted. God, it’s extraordinary. What’s amazing to me, too, is that when you actually tease the data out–-even using these poor-quality forms of the estrogen and the progesterone– there is, by and large, no increased risk with them, except in these isolated sub-cohorts: the older women, long duration of use and so forth. And I think the estrogen only, correct me if I’m wrong, the estrogen only group actually had a protective effect.

Dr. Allison Smith: Yeah, exactly, they had a lower risk.

Dr. Kara Fitzgerald: Right. And this is with equine estrogens.

Dr. Allison Smith: Yeah.

Dr. Kara Fitzgerald: So now we know, as you were just talking about the calculations that Tori made you guys do. That’s awesome, that’s so funny. But we’ve been using bioidentical hormones— certainly naturopathic medicine and in functional/integrative medicine more broadly, in the longevity space—-we’ve been using bioidentical hormones for many, many, many, many years. What are you able to extrapolate? What are the studies out there that really suggest bioidentical is the way to go?

Dr. Allison Smith: There’s the Million Women Study– There are actually some pretty big cohorts where they’re using estradiol and progesterone and finding fantastic outcomes. Nobody’s really questioning that it’s better to use as close to what the body makes as possible. And we do need more studies and there are new drugs out like the BiJuva with the oral estradiol and the oral progesterone and everything’s bioidentical. The patches are bioidentical. These are big pharma, lots of money behind them. They’re really well studied with big, big cohorts of folks. So, we look to some those studies with the big money behind them, they can afford to really power them with lots and lots of women and we can make those associations.

Dr. Allison Smith: A lot of us will be really detail oriented with our patients that don’t tolerate those bigger doses of hormones maybe that they’re using in the studies and we have lower doses compounded, very specialized and individualized formulas and—

Dr. Kara Fitzgerald: Delivery systems and routes.

Dr. Allison Smith: Yeah. I feel really confident about those and there are even compounding pharmacies that have been publishing for years and years, like observational studies based on their formulas and their patient base and looking at outcome studies. So I do think you can combine those types of studies and really feel confident moving forward with your patient base.

Dr. Kara Fitzgerald: I’m so excited about this. just want to plug the Hormone Replacement Therapy course again as you’re going to drill into this. People are going to really get to train in depth. So all the testing and the amazing work you’re doing over at DUTCH, but beyond that, just this, where the rubber meets the road, how to prescribe, what to prescribe, how to start working with our sensitive patients, different routes of delivery. The whole kit and kaboodle. That’s awesome. Well hats off to you and your team.

Dr. Allison Smith: Exactly. And there are more modules coming too. Yeah, it’s a work in progress. I think the initial modules are exhaustive on the FDA approved stuff. And then we have more coming out, a module on compounded hormones, testosterone in women, which is another area that’s kind of a ravine in research, unfortunately, for women. There’s plenty for men.

Dr. Kara Fitzgerald: It sure is, yeah. Right. Right, good. Well thanks for stepping up to the plate. This is again, you guys just go over to DUTCHtest.com to get details on this course. All right, well let’s jump in. We were chatting offline for a while and you have been in the laboratory space for many, many, many years now. So you just have a good background on how to do it, on what’s reliable. I guess you have two cool things. So you have the whole laboratory background, what we used to call when I was in the lab the people on the tile versus those of us in education on the carpet. So you have this strong tile background, but then also, as a provider, you’ve been using HRT in your clinic space. And you have the advantage of looking at, as I read in your bio, thousands and thousands and thousands and thousands of cases and consulting with doctors the world over.

Dr. Kara Fitzgerald: So you’ve got this exquisite vantage point from which to educate us. Talk to us about hormones– Maybe differentiate between using blood, the limitations of the blood, and then moving beyond to urine.

Dr. Allison Smith: Other body fluids? Why we even think about other body fluids more broadly?

Dr. Kara Fitzgerald: Yeah, just more broadly, other body fluids.

Dr. Allison Smith: Totally. I think about serum being the gold standard because that’s what we’re using in all of our clinical studies for clinical outcomes, I guess is what I’m saying. Obviously, we’re using serum for baselines, but the problem with serum inherently is that serum is kind of a water soluble body fluid and our hormones are lipids, lipophilic. And so they travel through the blood system attached to hormone carriers, called binding proteins. And estradiol and testosterone sort of famously bind to sex hormone binding globulin with high binding affinity.

Dr. Allison Smith: And that means that those hormones aren’t going to get taken up by tissues except under very special circumstances, possibly. But for the most part, free bioavailable fraction of our hormones is very, very low. Around 1- 5 % of all of what is made is going to be free and bioavailable. So there’s your first limitation with serum is that you have to kind of guess.

Dr. Allison Smith: Well, this is your total level that you’re producing, but we’re guessing as to how much is getting taken up by the tissues and creating that experience of hormones that brought you into the office today. And that means for somebody who’s coming in with acne, but their testosterone is normal, but what about their dihydrotestosterone? What about the way that they’re metabolizing these things can have an influence on your presentation when you come in.

Dr. Kara Fitzgerald: This says something to those almost useless reference ranges as well, because they’re just so ridiculously massive.

Dr. Allison Smith: Well, exactly. And they’re overlapping a lot of times too. So you have a postmenopausal range and a premenopausal luteal range and you’ll have some overlap. And if you’re in the overlap, you’re kind of wondering like, well, what does that mean? Are you normal or are you a postmenopausal female? And even some of the female and male ranges will overlap. It can be problematic with serum for a number of reasons. But I think from a functional medicine standpoint, we find it frustrating to have to do too much guessing. When you’re looking at a lab result, you want to be able to see what you’re looking for. And serum can give you a little bit of a 200 foot view, like a bird’s eye view of what’s going on. But often, it’ll be normal and we end up with all the patients who we’re told that they’re totally normal, but they don’t feel normal. And they’re in to see us to figure out what’s going on at a deeper level.

Dr. Allison Smith: So then we have to start thinking about other body fluids. How do we figure out what’s bioavailable to tissues? Saliva got really popular in the 90s. There were books written, a lot of excitement around compounded hormones and hormone replacement therapy. And in saliva, hormone levels go up just exponentially when you’re on transdermal hormones. And so they got really excited about saliva testing because you have only the bioavailable fraction in saliva. Only free hormones, so nothing that was bound to a sex hormone binding globulin or albumin or cortisol binding globulin is going to end up in the saliva. So we’re thinking, great, here we go. Now we’ve got some bioavailable hormones. We can see what the tissues are experiencing.

Dr. Allison Smith: But there’s problems with saliva too in that saliva levels of these hormones are really, really low. Like, picogram per mil amounts low— really tiny amounts. And they suffered from some of the same limitations as serum, where you have the ranges overlapping, like a postmenopausal range and a luteal range will overlap quite a bit, by 25 % sometimes, depending on the lab, or 50 % sometimes. So it really kind of begs that question— Is that helpful? Maybe not.

Dr. Allison Smith: And in the background, there’s always been urine, but urine wasn’t as convenient because you’re having to catch every bit of your urine over the course of a 24-hour period of time in these big jugs and do a science experiment and send an aliquot of your 24-hour jug urine to the lab for them to test it out. And people don’t want to do it. So getting buy-in to do the urine testing was tricky.

Dr. Kara Fitzgerald: Yeah. For sure.

Dr. Allison Smith: So yeah, right around 2013 or 2014, Mark and some other big brains in the industry kind of started thinking about dried urine.

Dr. Kara Fitzgerald: Who is Mark?

Dr. Allison Smith: Mark Newman, and you’ll find him published quite a bit in some of the bigger journals. He’s gotten some articles into Menopause and obviously some of the chemistry journals. We’re more and more getting into BMC, and Menopause, and some of the bigger clinical journals because with the dried urine test, he’s established serum correlations which really propels urine in the eyes of the clinician because you’re able to look at a urinary level of estradiol and say, okay, I know that I’m getting into the clinical range that’s protecting the bones, for instance.

Dr. Allison Smith: And I think this is kind of where lab testing is moving, just to try to find that perfect combination of things that gives you a deeper look for the people that we’re trying to be preventive down the road, to make sure we’re getting into the right ranges, and also provide the immediate support for hot flashes, night sweats, and lower urinary tract symptoms that often improve, interestingly, as a placebo effect with hormone replacement therapy, which is kind of another thing.

Dr. Kara Fitzgerald: Interesting. How has that been discerned?

Dr. Allison Smith: Well, they have done clinical trials where they gave people estrogen or placebo and were looking for hot flash frequency and severity and finding improvements even with placebo. So I think even if you pay attention to somebody’s symptoms and give them the impression that they’re gonna get some help, they often improve. So it’s kind of interesting. We do have to look at other deeper clinical markers. I mean, your bones probably aren’t going to increase in bone mineral density as a placebo effect. Probably not.

Dr. Kara Fitzgerald: Well, listen, I want to just ask you a question because I don’t want to forget it and you kind of threw out a little teaser that sort of–

Dr. Allison Smith: A nugget?

Dr. Kara Fitzgerald: Yeah, and that is where laboratory science is heading, providing reference ranges for targets. What do you see? This is where you need to be if you’re looking at bone density. This is where you need to be if you’re looking at brain health and dementia prevention and cardiovascular disease benefit, etc. You know, skin… Go ahead, yeah.

Dr. Allison Smith: Yeah. Well, that’s exactly, I think, where we are headed. We’re starting by publishing, or at least starting the conversation around osteoporosis and bone mineral density, because it’s a really easy stake in the sand. There have been quite a few studies that gathered together all of the serum laboratory evidence around estradiol levels and bone mineral density and you can extrapolate from that where somebody should be based on, you know…

Dr. Allison Smith: A study from the 90s was looking at premenopausal women and found that if their estradiol in serum was 60, then that meant that their bones were healthier than those who had estradiol levels under 60. So 60 was kind of the cutoff. But the methods have gotten a lot more sensitive since then. Now we’re using liquid chromatography, mass spec methods. They’re much more sensitive. And actually, you don’t necessarily have to have estrogen levels of 60. It may be more like 40 or even 20, depending on the method.

Dr. Kara Fitzgerald: Interesting.

Dr. Allison Smith: There may be a wheelhouse where people can live on their hormone replacement therapy that keeps them in that 20 to 60. That’s really where we tell people that they should probably be. Maybe towards the higher end of that range, if you’re going into menopause and you’re younger. Maybe you’ve had a hysterectomy and you don’t have your ovaries anymore and you’re 30, you should probably have estrogen levels that are higher, you know, towards the 60 versus the 20.

Dr. Allison Smith: But if you’re 65 or 70 maybe it’s okay to be 25 or 30 in serum for a total estradiol. Anyway, I think if we can be that precise with people that could make a huge difference. You think about what people end up struggling with end of life or the thing that takes away somebody’s mobility and puts them in the hospital and puts them on a trajectory towards end of life, it’s the hip fracture or the, you know…

Dr. Kara Fitzgerald: Yeah, that’s huge. Right. I like that. But you’re moving beyond, you’re starting with bone, putting your stake in the ground there with bone, and then you’ll move on and look at other associated issues. I appreciate the placebo comment. I have seen something that appears like that in practice where hormones are imbalanced and there’s huge symptoms associated with it. And just the awareness of that imbalance can cause a considerable drop—this is with elevated hormones— even though it’s going to take a little while for those to drop, I’ve seen on more than one occasion just the knowledge of, Oh, okay, I’m elevated… It’s almost like, okay, that’s what those symptoms were. You know, I’m not crazy. I’m not this—

Dr. Allison Smith: Yeah, that’s not nothing. Yeah.

Dr. Kara Fitzgerald: Yeah, okay. So I can almost just let it go. I’ve seen that multiple times. It’s really fascinating. But those symptoms were absolutely real before there was a conscious awareness around why they were happening, because there was a hormone imbalance.

Dr. Allison Smith: Absolutely right.

Dr. Kara Fitzgerald: As you peg reference ranges just really across the board for these imbalances that we see in our patients all the time, that’s gonna be awesome.

Dr. Allison Smith: Yeah, yeah, we just don’t want to be under-dosing people, just because their hot flashes went away, but their poor little bones aren’t getting what they need.

Dr. Kara Fitzgerald: Right, right, right. And thinking about all of the other myriad benefits. It’s like across the board, the system-wide benefit of sufficient hormones. Yeah, it’s incredibly important. The other piece about the WHI getting turned over was this idea that we can’t start women on hormones postmenopausal, that it’s not safe. That’s another welcome change to the conversation and empowering change to the conversation. I’m seeing Sara Gottfried, of course, you know who she is.

Dr. Allison Smith: Yeah. Yes.

Dr. Kara Fitzgerald: She’s a big influencer in this space, you know, talking about menopause 3.0, she’s terming it. But, I think there’s a revolution happening in women’s health. And the seed is this. The seed is the WHI and just really kicking it to the curb. I think it’s very empowering and a lot of us in this space just have an eye towards adequately supporting women and women’s health issues.

Dr. Allison Smith: People are still asking though, is it too late for me to put this person on estrogen? And even though they have all the symptoms in the book of low estrogen and they have bone loss and cardiovascular issues and I don’t know, you have to be willing and ready to individualize your approach, I think. And it gives us permission to do that now, which I think is really exciting. And I always remind people of that.

Dr. Kara Fitzgerald: It is. And now people need to learn how to do it if they don’t, and you will help them in that arena.

Dr. Allison Smith: We’re ready to help. Yeah.

Dr. Kara Fitzgerald: You mentioned something about, it was funny, you you first talked about collecting that 24-hour urine, which I’ve done. I can hold my jug up.

Dr. Allison Smith: Oh sure. Me too.

Dr. Kara Fitzgerald: Of course, of course you have. Yeah, what a pain, you know, just being at a laboratory myself where we did 24-hour urine measurements of various things and the lab team would all have to test the new assay and there’d just be urine jugs all over the place.

Dr. Allison Smith: Oh yeah, all the orange jugs, yep.

Dr. Kara Fitzgerald: For anybody not using the DUTCH test, it’s the dried urine specimen, it’s sort of the revolution, the aha moment for Mark Newman, the founder of Precision Analytical (DUTCH). Talk to me about what it is and why it’s way better than a giant orange jug.

Dr. Allison Smith: Yes, well the easy explanation is that there are four or five collections over the course of the day. Usually we have people start at dinner time. So before dinner, before bed, you’ll just pee on a strip. You can just stick it in the flow or you can pee in a vessel and dip it. Either way is totally fine and then you dry it. It’s dried urine, not a wet urine sample. So we don’t want the urine sample to stay wet when it’s in transit in the closed baggie because wet urine samples have hormones that degrade a lot faster and so it can cause weird results to happen. We always have people dry them really, really well. So before dinner, before bed, if you wake up in the middle of the night, you pee on that strip too.

Dr. Allison Smith: If you pee a lot in the middle of the night, we usually have people collect all that urine in a vessel and dip it in the morning. And then as soon as you wake up in the morning, you want to catch that first morning void, which is a really great way to look at cortisol levels during the night while you were asleep and melatonin levels while you were asleep. They’re all going to be evident in that first morning void. And then the last sample is two hours later, or your next urine that happens after your initial waking void. So it’s a pretty simple procedure. Dry all those samples, send them in, and then we use creatinine levels to kind of normalize for the dilution or concentration of the samples.

Dr. Allison Smith: And we also use a complex calculation that even includes height, weight, sex, and age of the patient, and that really hones even more the accuracy of the resulting. That’s how we generate our idea of what’s going on, and that really constitutes about 18 hours of the day. So it’s not a full 24-hour look, but it correlates very nicely with a 24-hour urine. We have published an article on that, validating that concept and the strong correlation between the analytes and the 24-hour urine samples. And we also have correlations between our DUTCH urine, four spot and serum.

Dr. Allison Smith: Yeah, if creatinine is too low. Yeah.

Dr. Kara Fitzgerald: Or they could just really restrict fluid for that day, right?

Dr. Allison Smith: Yeah, that’s true. Sometimes we can work around that, so as long as we can get our creatinine levels above the cutoffs, we can test the sample. And there are even creative ways we can, you know, if we’re missing a bedtime sample or an evening sample because it’s too dilute or the creatinine’s too low, even if we throw that one sample out and we have the other three, we’ve done all kinds of internal studies that show that doesn’t really change the final results very much because we’re sort of pulling and averaging. You wouldn’t get a free cortisol for that one time point, but the rest of the analytes would still give you, even if you didn’t have 18 hours of data, you had 14 hours of data, it doesn’t change all that much.

Dr. Allison Smith: However, if it’s a first morning void, we would reject the whole thing because that carries a large amount of hormone production. And so does the second morning void. So if it’s either one of those two, we’d probably have the patient recollect or talk to the provider to figure out if there’s a likelihood we’re going to get a better sample or maybe not.

Dr. Kara Fitzgerald: Okay, good. So you can just brainstorm if you confront these. And I have to say, just if anybody’s curious, it’s the exception. Maybe we’ve needed to do recollection in my practice a couple times over the many, many years. Mostly it’s completely solid and reliable.

Dr. Allison Smith: Yeah.

Dr. Kara Fitzgerald: All right, so we’ll put a sample report on the show notes. Anything else we’re dialoguing about here, a link to their hormone training, we’ll put on the show notes. We’re going to talk about the test and what’s on it. We’ll talk about some of the analytes, why this is embraced by our world, some of the benefits of seeing some of these analytes that aren’t available in our standard laboratories that we’re using. But anyway, pause this, go grab the sample report, and you can look at some of these with us. Why don’t you talk about just the report overall and what we’re getting and then some of those really cool metabolites that guide us in our treatment.

Dr. Allison Smith: Totally. Where urine really shines, I think, is it gives you an idea of the tissue experience of a given hormone. You can look at estradiol, progesterone, testosterone, and other body fluids, but you don’t always get the full picture of how it’s breaking down. Some of those breakdown products actually carry secondary actions at the tissue level that do something different. Progesterone is a really, really good example, right? It breaks down through 5-alpha reductase and into allopregnanolone and the 5-alpha metabolites bind GABA receptors in the brain and make us feel relaxed and help us sleep and give us our our idea of stress resilience. This comes from progesterone metabolites not progesterone itself.

Dr. Allison Smith: And I think that really underscores the importance of looking at these things. And estrogen is another example. Estradiol, yes, it binds its receptor, it has its actions at the tissue level that tend to be proliferative and predictable. But as it breaks down to become more water soluble so that it can leave the body, it becomes other things that still act like estrogens at the tissue level.

Dr. Allison Smith: So I think between those two things, we feel pretty confident that, you know, there are certain circumstances where urine is a little tricky or not very helpful at all. One is with urinary hormones where you’re looking at glucuronidated conjugated hormones. There’s a fairly common— when I say common, it’s probably like 5 or 10% of the population at large— but if you have like a large Asian or Southeast Asian population, it can be much higher, up to 80% in some populations have this gene deletion that is called UGT2B17. It causes you to not glucuronidate your testosterone, which means in the urine test, you have almost zero for testosterone. But it’s not really real. In circulation, you’ll find that testosterone is probably healthy and normal, but you just don’t pee your testosterone. That person will never pee their testosterone, so you wouldn’t want to mark in the chart, I think this person has a UGT deletion. We always try to identify that and comment very clearly on the reports when we see that because it is probably the biggest issue that urine has with not correlating with serum would be in that one area.

Dr. Kara Fitzgerald: Okay. And we’ve encountered that. We’ve discussed that issue in our clinical rounds when we saw them.

Dr. Allison Smith: Yeah, if you test with urine, you’re going to run into it. I’d be surprised if you didn’t. But if you just kind of dabble in urinary testing of hormones, you may never see it. It’s not super, super common. But yeah, don’t be surprised if you do.

Dr. Kara Fitzgerald: So obviously in that case, testosterone, we just want to do it in serum. Are there any other times we might be leaning in on serum instead of urine?

Dr. Allison Smith: Well, I would say if you have a patient population that has renal disease, kidney failure, any reason why what somebody is putting out of their body is not going to correlate with what they’re keeping in circulation. You know what I mean? That should go without saying, maybe. But sometimes we really want to stretch it because the patient can’t conjure up enough saliva for a saliva test or they are scared of needles, and you really want to use urine but they’re in kidney failure. Don’t do it.

Dr. Kara Fitzgerald: Yeah, not a good idea, don’t. It won’t be right, of course.

Dr. Allison Smith: No, it would give you the wrong impression, maybe, of some of the hormone levels. And then children is another area. Their creatinine clearance is different and DUTCH, at least, doesn’t have validated ranges for kids.

Dr. Kara Fitzgerald: Right. I did use it in one case as kind of an exploratory, but we all knew, mom and dad, as we were going into it, that we weren’t sure of the utility of it. It did end up helping. It provided some insight and some guidance, but we used it just really as an exploratory.

Dr. Kara Fitzgerald: So on this topic, the creatinine is muscle turnover, and if somebody has just a really low BMI or just poor muscle mass, would that potentially skew the concentration and would you reject the specimen in that case, in which case they need blood? Is that something that you would count?

Dr. Allison Smith: It can still bind to estrogen receptors, and some of them, like 16-hydroxyestrone, which is probably the most famous one. And it can be high in all kinds of things like lupus and rheumatoid arthritis and it is higher in those with higher risk of breast and endometrial cancer. Breast cancer in particular, but prostate cancer in men. So we we like to have eyes on that one because it binds estrogen receptors weakly. There’s a weak affinity, but once it’s on there it binds covalently and it never falls off until that receptor degrades. So its action on the DNA and that proliferative activity and the tissue is really intense with 16-hydroxy even though it’s technically a weaker estrogen.

Dr. Kara Fitzgerald: Wow.

Dr. Allison Smith: So, all kinds of interesting things you want to have eyes on when you’re looking at a urinary readout on hormones. You’re looking at so much more than just how much hormone was produced and is it in circulation to target tissues. You’re looking at what’s taken up, how it’s breaking down, how it’s interacting with those tissues on its way out. And that’s really what a hormone feels like in the body and why somebody’s in your office.

Dr. Kara Fitzgerald: So, prescribing estrogen, obviously it’s a no-brainer for a premenopausal woman, and it’s a no-brainer to want to look at those metabolites. I think that’s well established in our community and it’s very empowering because we can change the fate of how we’re metabolizing. We can get in there and manipulate it.

Dr. Allison Smith: Yes. Even with food. Yeah.

Dr. Kara Fitzgerald: Right. Yeah, that’s right. So just thinking– You brought men into the Prostate Cancer Foundation, and it just made me think of seeing, so somebody, man or woman, but you we could definitely see it in our testosterone replacement men converting some of it over to estrone and then down to the hydroxy-16. And so you would want to be tracking these estrogen metabolites really in anybody who’s on hormone replacement therapy.

Dr. Allison Smith: Definitely.

Dr. Kara Fitzgerald: So even testosterone alone, where some clinicians might not be thinking about the estrogen metabolites, we need to be thinking about the estrogen metabolites.

Dr. Allison Smith:  I sure think so. And I think one of the things that’s changed in the last 10 years in men’s health, I would say, is that we used to think about using aromatase inhibitors with testosterone replacement for most men, especially over the age of 50. Now we’re not using as much aromatase inhibitor in those guys because there have been a lot of studies actually that sort of show that erectile function suffers when there’s no estrogen around and bone mineral density and all these other sort of things that we weren’t really thinking about when we were trying to preserve all the testosterone at the tissue. So we do want more testosterone running into estrogen, but we do need to direct traffic down to the anti-proliferative metabolites that are supporting those tissues and not hurting them on the way out.

Dr. Kara Fitzgerald: It’s great, it’s super useful for so many reasons. So yeah, shutting down with a drug effect will often have some secondary fallout that’s not picked up immediately. I’m pretty curious about what’s in store for GLP-1, actually, with that idea in mind.

Dr. Allison Smith: Me too. Yep.

Dr. Kara Fitzgerald: Yeah, a different conversation. So there’s other estrogen metabolites, so why don’t you touch on those? Because there’s some that we really want. Go ahead.

Dr. Allison Smith: Yeah, yeah, exactly. So the way phase one metabolism works is estradiol and estrone go through the first step of hydroxylation and there are three different cytochrome enzymes that catch those estrogens and add a hydroxyl group to one of the carbons. Which enzyme is going to decide which carbon that hydroxyl group is attached to. And it’s amazing to me how much which carbon that hydroxyl group gets attached to influences the stability of that metabolite and totally changes its action at the tissue level— Just one little change. And so we have a 2-hydroxy, a 4-hydroxy, and a 16-hydroxy.

Dr. Allison Smith: The 16-hydroxys are bad because they influence our breast and prostate cancer risk. The 4-hydroxys are bad because they’re very unstable and they can damage the DNA and endometrial cancer. Fibroids and growth proliferation in the uterus are associated with those fours, in particular. And it’s a cytochrome system that’s upregulated by inflammation, which is epidemic, it seems. So, there are really some great things that we have in our arsenal to down-regulate some of those metabolites just by treating what we are finding. This is drawing people into the office.

Dr. Allison Smith: So, anti-inflammatory support because we want the 2-hydroxyestrogens. That leaves us with the 2-hydroxy E1 and E2, because they lead to the methylated 2-hydroxy, which converts into 2-methoxy E1 and E2, and those act as anti-proliferative and anti-tumor. They’re shrinking tumors. And there are even compounded to 2-methoxyestradiol formulas that people are starting to prescribe to patients as a way to leverage some of that anti-proliferation at the tissue level as well. So it’s interesting where we’re moving.

Dr. Kara Fitzgerald: Fascinating. Men and women.both stand to benefit from having sufficient methylated twos. Well, clarify this for me. I remember reading quite a while ago that 16- may be beneficial in post-menopausal women with otherwise very low estrogen. So it might help with bone density and help offset some—

Dr. Allison Smith: Yeah, totally. Because it’s such a strong estrogen, yeah.

Dr. Kara Fitzgerald: So do you think about it a little bit more nuanced? I mean, you also associated it with some hormone-sensitive cancers as well. How do you think about it in the post-menopausal woman?

Dr. Allison Smith: How do you juggle it a little bit?

Dr. Kara Fitzgerald: Yeah. I guess if somebody’s on HRT, then you don’t really need to keep any 16 around. You can just metabolize it because they’ve got estrogen.

Dr. Allison Smith: Yeah. But if you’re postmenopausal female and you’re not a candidate for hormone replacement therapy for any reason, and your 16-hydroxy is dominant, maybe that’s helping you. In fact, if your vitamin D levels are too low, it can cause your 16-hydroxyestrogens to also be low because D is a natural inducer of the enzyme that leads to 16-hydroxy formation. So there’s kind of this link in other ways, too, between low 16-hydroxy and low bone mineral density.

Dr. Kara Fitzgerald: Interesting. It’s all this balance. It’s balance.

Dr. Allison Smith: Yeah, the 16-hydroxy is kind of a twofer, especially when your estradiol is in the postmenopausal range. If your 16-hydroxy is also low, it’s kind of a one-two punch.

Dr. Kara Fitzgerald: Right, and you could be feeling pretty lousy. But in other cases, if you see some background 16, would you advise that clinician perhaps not to lower it? Because we may want to pull the trigger and lower it just reflexively, because we know 16 is associated with cancers. But in certain cases, you’re going to be more nuanced.

Dr. Allison Smith: Yeah. Well you’d weigh it out with the patients’ family history, what do their mammograms look like? You might be able to say, hey, let’s actually beef up your 16 a little bit, because maybe it’s a little bit too low, and you’re postmenopausal, and you’re not a candidate for E2, for whatever reason, let’s get you on the D and bone support. Let’s double down there.

Dr. Kara Fitzgerald: Yeah.

Dr. Allison Smith: There isn’t a lot of research on increasing 16-hydroxy in particular as a way to protect the bones. So I don’t necessarily think that that’s the right approach, although some of the supplements out there for bone support, I don’t know if you’ve noticed this, but they have St. John’s wort in there, which is an inducer of 16-hydroxy formation. So I think there’s some out there that are trying that direction.

Dr. Kara Fitzgerald: They’re playing around with it.

Dr. Allison Smith: Yeah.

Dr. Kara Fitzgerald: They’re playing around with it. That’s pretty interesting. No, I didn’t notice that. I’m not using any that have St. John’s wort in it, though isn’t that fascinating. Wow. Wow. Biochemists out there in our space.

Dr. Allison Smith: Totally. Like, what’s this gonna do? It can only help.

Dr. Kara Fitzgerald: The progesterone metabolites are incredibly important, you know, just making sure people are able to produce some of the juicy… They’re alpha-driven?

Dr. Allison Smith: They’re alpha driven. Usually 5-alpha reductase is problematic, right? Because it makes the androgens stronger, and it gives us acne, and it makes our hair fall out, and stuff like that. So usually we’re not thinking about increasing 5-alpha reductase activity across the board. But it is one thing that we want when we give somebody progesterone, usually as they’re in the perimenopausal transition or in menopause. Yeah, we want to protect the endometrium if we’re giving HRT always. But, we want to help them sleep a lot of times. It’s such a common complaint.

Dr. Kara Fitzgerald: It’s a potent anxiolytic. It’s incredibly potent. Yes.

Dr. Allison Smith: It really, really is. Yeah.

Dr. Kara Fitzgerald: And it’s brain protective and nourishing, I think in that same capacity. All right, so let’s talk a little bit about the testosterone metabolites, and then we can move on to cortisol. mean, the cortisol awakening response, you guys added it first. I think it is elsewhere, perhaps now, but yeah. So let’s tour the test.

Dr. Allison Smith: Do androgens? Yeah, I love it.

Dr. Kara Fitzgerald: Yeah, let’s just touch on androgens and then let’s move over to cortisol.

Dr. Allison Smith: I would say androgens are probably one of the top reasons people will order a DUTCH test. They want to understand the tissue experience of testosterone and DHEA. They’re interested in looking at dihydrotestosterone, but really even a longer term marker of DHT formation in the tissues is 5α-androstanediol. It’s the next one down metabolically. You can have a normal DHT but have an elevated 5α-andro, and that should tip us off that this person has an awful lot of DHT forming in the tissues, and it’s not necessarily testing what’s going on in the hair follicle or the skin, but you can get a pretty good idea of total body, what’s happening with testosterone utilization. And if you have a strong 5-alpha preference, even if your level of testosterone is normal in the serum and the testosterone is normal in the urine, if the 5-alpha is high or dominant, that really drives that person’s symptom experience when they are coming across their testosterone at the tissue level.

Dr. Kara Fitzgerald: Good, yeah, and I have seen that. I have seen what you’re describing. Yeah, go ahead.

Dr. Allison Smith: Yeah, and it helps you to understand what therapeutics are going to be high yield. So if you have somebody with hair loss and you do a DUTCH test and their testosterone is normal and they have a 5-beta preference, you know that if you put them on saw palmetto, it’s probably not going to do anything. So you’re not going to do that. You’re to look at other parts of the test and see, you know, Oh, they’re low in biotin or they’re a low methylator or they’re…

Dr. Kara Fitzgerald: Their cortisol pattern is high.

Dr. Allison Smith: Their cortisol patterns are high. There are other things that are going to take center stage and you’re gonna skip the 5-alpha blockers.

Dr. Kara Fitzgerald: Right.

Dr. Allison Smith: So I think that’s really where the DUTCH is helpful for androgens.

Dr. Kara Fitzgerald: Yeah, In PCOS. I mean, this is a whole…

Dr. Allison Smith: Ball of wax.

Dr. Kara Fitzgerald: Actually, we’ve talked about it on this podcast. We’ve had really good, juicy discussions on it and we’ll link them in the show notes. So all my previous podcasts with DUTCH, in fact, any content that we have available, we’ll just put it on the show note and maybe label, because it’s just exquisitely useful teasing out what’s happening in PCOS and offering some really clear guidance on treatment based on laboratory data.

Dr. Allison Smith: Yeah, we have so many case studies that are different types of PCOS, where some of them will be really, really low estrogen, but super high testosterone and epi-testosterone that’s just coming straight from the ovaries versus the high DHEA type, and it’s really easy to see the way it’s laid out on a DUTCH test.

Dr. Kara Fitzgerald: It is, it is. And we already have a discussion in place where we moved through a lot of those phenotypic presentations.

Dr. Allison Smith: Yeah.

Dr. Kara Fitzgerald: It’s so useful. All right, what else do we have? Let’s talk about cortisol a little bit and that amazing cortisol awakening response.

Dr. Allison Smith: Yeah, this is where saliva really, really shines, I think, is in the cortisol space.

Dr. Kara Fitzgerald: Actually, I was going to ask you that, when we might use saliva. If saliva is a viable specimen.

Dr. Allison Smith: Sure, and saliva, the way we do it is really easy, where you just put the little Salivette device in your mouth and let it fill up with saliva. You kind of chew on it a little bit and you can tell when it’s full. It usually takes me about six seconds to get that thing full and spit it back into the tube and you get that real time assessment of free cortisol levels. And I say that because there are so many different salivary testing labs that do it differently. You might drool into a big tube or you might— But the idea is that you’re doing this passive drooling. You’re not hawking spit, necessarily. You want the flow rate to be natural for those collections. But with those collections, it can be hard to get the precise data for a cortisol awakening response, for instance. So that’s why we have to use the Salivette devices.

Dr. Allison Smith: But they’re super easy, and with the cortisol awakening response, you’re really doing several sample collections over the course of an hour. So you wake up, you spit in the tube basically, and then a half an hour later you do it again, and a half an hour later you do it again. So it is a little bit front loaded, but when you do it that way, you’re able to get a sense of the HPA axis, the hypothalamus, pituitary, and the adrenal starting to talk to each other right when you open your eyes and come into consciousness for the day. There’s this relay that happens that involves the hippocampus of the brain.

Dr. Allison Smith: And it’s almost like it’s downloading whatever you did overnight into your adrenal function and informing your adrenals how to come online. It’s like turning on the photocopier in the morning at work so you don’t have to do it when you’re trying to make a copy later in the day. It gets everything ready. So your adrenal function sort of skyrockets upwards. And it’s very predictable. On a DUTCH test, it’s 50 to 160% rise you want to see in the first 30 minutes of waking. And then you want to see it come back down. You want to see it return. It should look like a triangle on the lab result.

Dr. Allison Smith: Any abnormalities there can speak to the health of the hippocampus and the HPA axis. And with chronic stress, you might not see a rise at all. Chronic, like PTSD, or people with chronic diseases, chronic pain tend to have no awakening response or even a negative one where they’re just moving downwards.

Dr. Kara Fitzgerald: Right.

Dr. Allison Smith: And then others like depression, you might see a really exaggerated one, or anxiety, you might see a prolonged awakening response.

Dr. Kara Fitzgerald: Profound stress.

Dr. Allison Smith: Yes, anticipatory stress.

Dr. Kara Fitzgerald: Right. Like Monday, morning stressful job I’m about to go to. Yeah.

Dr. Allison Smith: Yes, and for some people, maybe simply stressed about collecting their samples.

Dr. Kara Fitzgerald: It is really easy. You know, I want to just say something because you touched on samples and being consistent with collection. We’ve known for a long time that using saliva to measure cortisol is extremely helpful, but there was a very critical paper written because of the varied collection techniques. And I appreciate you bringing that forward and the inconsistent collection devices, the changing collection techniques. But I think there’s something incredibly important about just passively saturating the cotton. You’re not stressing out with the effort of spitting in a tube and your mouth is dry or whatever, and just really using that same type of collection for the full measurement, and repeat it like that’s the method that you guys use.

Dr. Kara Fitzgerald: This particular paper, it just struck me because we know there’s value in the cortisol awakening response and the four-point salivary cortisol. Extremely useful. They’re not invasive specimen. It could be very important if we got it together with regard to consistent appropriate collection. Yeah.

Dr. Allison Smith: Totally. And a lot of that research that was done that showed the utility and the application of cortisol awakening response in clinical, those are all laboratory studies where everything was collected so specifically and we’re not following people home and making sure they do it right so we try to set them up for success by giving them some equipment to use and it makes it really reproducible.

Dr. Kara Fitzgerald: Yeah, yeah, that’s right. It’s important. I think it’s important to continue to see research coming out using salivary cortisol because I know scientists will want to rely on blood cortisol, which is just crazy if you think about it. You know, going for the experience of the stick. But anyway.

Dr. Allison Smith: That’s right. Well, I think the other thing that DUTCH does right is we also test cortisone at all the same time points. So free cortisol and free cortisone, which I think is the bane of some people’s existence, because they’re like, it’s so hard. What do I do if one’s high and one’s low? It does force you to think an extra step sometimes in patients who are on certain medications. I remember working at another lab that didn’t do the free cortisone. They just did the free cortisol like everyone did in the early 2000s. And this provider I was talking to on the phone, he had put the patient onto lisinopril.

Dr. Allison Smith: And he was a very good historian so he had all of the labs from before the patient was on lisinopril and he put her on the lisinopril and then they retested and the free cortisol was flatlined. And he asked, does lisinopril lower cortisol production and I said I don’t know. So I Got on PubMed and I was searching around and there was one paper that said that lisinopril lowers free cortisol

Dr. Allison Smith: So I called him back and I said, yeah, it does. It lowers cortisol. And the takeaway was that there was some sort of HPA axis dysfunction. But that was incorrect. And I found out from being involved in looking at so many tests of patients who are using lisinopril and other ARBs like losartan, ACE inhibitors and ARBs act similarly, even spironolactone in the right dose actually increases cortisol clearance into cortisone. So it doesn’t lower your cortisol production, it just increases 11β HSD2 enzyme activity in the salivary gland and the kidney so that your saliva is going to have cortisone in it and not cortisol because that local conversion is happening right there.

Dr. Allison Smith: So that was a big aha moment for me that like, gosh, the metabolites really matter because sometimes that’s not an actionable thing. That’s what that medication is supposed to do and that’s part of how it keeps your blood pressure normal.

Dr. Kara Fitzgerald: Interesting. That’s really fascinating. Yeah, you have the opportunity of learning a lot because you do look at labs that we don’t see in real life that often.

Dr. Allison Smith: Right? I know. And then sometimes when you’re talking to somebody on the phone doing a clinical consult and they’ll say something like, Oh, but I know lisinopril lowers cortisol. You can say, well, it doesn’t really lower cortisol. Production.

Dr. Kara Fitzgerald: Yeah, and you really want to make that distinction. You do. It’s incredibly important. Yeah, it would not be a drug if it dropped cortisol.

Dr. Kara Fitzgerald: So we have covered a lot. I absolutely love your wealth of knowledge. It’s so fun. I could pick your brain all day, Allison, on the cases that you’ve seen, on all these pearls that you’ve learned, on other variables that are going to just influence the enzymatic activity and shift metabolism. One of the nice things about the report is that you capture all of that. That should be a publication. So you capture all of it. It’s available to us so we can do our drill down ourselves on why we’re seeing these results, that at a glance look a little bit crazy. So instead, don’t panic, read through the report. Reach out to the team. Yeah. But it would be an interesting publication because you look at way more natural interventions and you’re actually tracking them.

Dr. Allison Smith:  We do, and we publish on this stuff. That’s one thing that I really like about being a part of this lab is that we have a robust research team and we really spend a lot of money researching and publishing our findings because it’s important. We’ve published on DIMM and how it affects estrogen metabolism. We have all kinds of interesting tidbits out there on PubMed. A lot of it’s open access. Actually, all of it is open access, so you can read the studies in their entirety, and it’s fascinating. And we’re not done. We’re still going.

Dr. Kara Fitzgerald: No, you’re not. Whenever I see Mark, he’s talking to me about what you’re up to. OK, so we will we will corral together your publications. In fact, you know, maybe you can just we’ll we’ll reach out to you and so we can pull together kind of a curated suite of of publications and then we’ll pop those on our show notes as well. Dr. Smith, thank you for coming and joining me today. And I’m so glad we had a chance to connect. This was a really fun conversation.

Dr. Allison Smith: Me too, I loved it. Thanks for having me.

Dr. Allison Smith completed her N.D. at the National University of Natural Medicine in Portland, Oregon, and has worked in private practice focusing on primary care, women’s health and dermatologic laser therapy. Over the last 10 years, she has consulted with providers on thousands of cases in the context of hormone testing and brought awareness of testing to providers in clinical practice through consulting, webinars, case presentations, and articles. She now leads an esteemed lineup of clinical educators at Precision Analytical, home of the DUTCH test.

Dr. Allison Smith

Precision Analytical, Home of the DUTCH Test

DUTCH Test Female Sample Report and Male Sample Report

Women’s Health Initiative

Dr. Tori Hudson

Million Women Study

Mark Newman, M.S. founder & President of Precision Analytical, Inc.

DUTCH Trust – Featured research on DUTCH testing

Dr. Sara Gottfried

Study: Saliva collection method affects predictability of serum cortisol

Study: Evaluating urinary estrogen and progesterone metabolites using dried filter paper samples and gas chromatography with tandem mass spectrometry (GC–MS/MS)

JAMA Network

Comprehensive Cancer Information

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