Choosing the Right Progesterone Prescription: A Discussion on OMP & Vaginal Progesterone

These hormones are essential for women to be healthy, and only healthy women will have successful fertility and pregnancies without having all kinds of complications. Welcome to the Dutch podcast where we dive deep into the science of hormones, wellness, and personalized healthcare. I'm Dr. Jacqueline Svetin, Chief Medical Officer at Dutch. Join us every Tuesday as we bring you expert insights, cutting edge research, and practical tips to help you take control of your health from the inside out. Whether you're a healthcare professional or simply looking to optimize your own well-being, we've got you covered. The contents of this podcast are for educational and informational purposes only. This information is not to be interpreted or mistaken for medical advice. Consult your healthcare provider for medical advice, diagnosis, and treatment. Hi, and welcome to this week's episode of the Dutch podcast. Now, we're going to talk today about oral, micronized, progesterone, which has become the go-to progestogen for most of us who are practicing hormone therapy in menopause and for really good reason. The safety data over synthetic progestins is really solid. Press cancer risk, cardiovascular outcomes, venous thromboembolism, OMP just looks favorable across the board. But today we're exploring a question that's been coming up in clinical conversations. We've had a lot of you reach out to us with questions about this. And this is one that really doesn't have a clean answer yet. My friend and colleague, Dr. Philly Scourge, has been asking whether chronic, nightly OMP use, specifically what it does in the brain via its primary metabolite, alipregnanoleon, whether this is something our field has really fully examined. She's not making a definitive claim, and she's totally open that she's drawing on the combination of animal studies and basic science research, but she does point to some really interesting parallels with what we know about long-term benzodiazepine use, which has a similar mechanism of binding in the brain, and asks whether we have enough long-term human data to be confident that we've answered the question about oral, micronized progesterone. The spoiler here is we don't, not yet. So today's episode where I'm also joined by our founder, Mark Newman, isn't about telling you that something new is definitively true, or that something you've been doing is wrong. It's really about mapping what we know, being clear on what we don't know and where the gaps are, including some protocol considerations that you might want to think about when it comes to dosing OMP, maybe cyclically, or using vaginal progesterone, and it's really worth understanding all of these in context. If you don't have a lot of background information on this, I also wrote a blog which goes into some of the research that we're going to be talking about on the podcast today because I think it will really help you orient to this conversation. So that you can click to in the show notes if you want to have a read before you have a listen and just know that's a resource. If you are listening to the podcast and maybe need to slow it down and get some background information. But ultimately, I want you to think of this as less of a conclusion in more of a well-informed conversation about where the science is and where it still needs to go. And personally, I love these exploratory conversations. I found to be so exciting to be a part of because there's so many gaps in research that we're all excited to eventually cross. So let's go ahead and dive in. Dr. Feliz Gersh, medical doctor, is a globally recognized expert on women's hormones, gut microbiome, and circadian rhythm. She is one of the first dual board certified integrative gynecologist in the United States. And she's so passionate about helping patients on their journey to optimal health. She currently serves as an affiliate faculty member at the fellowship and integrative medicine through the University of Arizona School of Medicine. Dr. Gersh is really a born educator and she's been featured on so many guest podcasts, webinars, medical documentaries, and more. We're really lucky to have her back on the podcast today. Let's go ahead and get started. Well, Dr. Gersh, thank you so much for joining us on the touch podcast again this week. Thank you so much and Mark for joining us as well. It's always nice to have you jump into the conversations and today's going to be a great one. Well, I'm really excited to be joining you and the topic that we're going to talk about, we were talking Mark and I before, it's like really important. And so I'm really excited to have this opportunity to discuss this with you both. Fabulous. I mean, we're going to be talking today about progesterone and I'm really excited to dive into this because I've kind of heard through the great find from people who've heard you speak at conferences. And I want to dive into all of this new kind of new research that you've been sharing and your thoughts around progesterone use post-mediposally. But before we do, just in case there's anyone on the planet who doesn't know who you are, which I think is tough at this point. In our world at least, I do love hearing a little bit more about your background and I just find it so fascinating because you're trained in board certified in both OB-TIN as well as integrative medicine. And that's a fairly rare combination, I think. Can you share a little bit about like how you came to bridge those two worlds and when do you think that dual lens really offers to patients? Well, it's hard for me to even know why it just became sort of ingrained into me that there was more to offer to patients than I learned in my medical school and residency training. So early, early on in my practice and I started my own practice from scratch, I brought on board what I called my ancillary team. So I incorporated very early in my practice. So decades ago, a Chinese medicine practitioner massage therapist, biofeedback, psychologist, nutritionist, massage therapist. So I didn't even really think I was like really ahead of the curve. It just seemed like all of these things were necessary in addition to my conventional therapeutic approaches. Well, what happened was about 25 years ago, I started thinking, well, maybe I should have some training. Well, I didn't really get to it until I finally gave up doing obstetrics because I was busy delivering all those thousands of babies. And after I stopped doing obstetrics and now this is going back quite a few years ago, over 15 years ago, I felt this real void in my career like I didn't know what my purpose was. I did a lot of surgery. I taught how to do gynecological surgery, but I thought this is end stage disease. Can we be a little bit more proactive here? Do we have to wait and say, let's wait and watch. And then when it gets really, really bad, we'll cut organs out. It seemed like we needed to be more proactive, but I didn't really have the tools. I had my my ancillary practitioners, but I didn't have any of that training. So I went on a journey. I started going to conferences with naturopaths, with chiropractors, functional medicine doctors, but I was kind of doing a random sort of my own guide. And I didn't really have a real plan. And then at one conference, I was the only MD and I was in a room filled with other naturopaths. And I went up to Dr. Lowdog and I said to her, I'm really lost. I really feel like I don't have enough opportunities and knowledge to actually help my patients to optimize their health and to be proactive. And she said, well, why don't you come to the fellowship and integrative medicine? A new session is starting very soon. And I know you're qualified. So I went home that Friday, rather Sunday. And I filled out the application two weeks later. I was in Tucson. I did the two-year fellowship in integrative medicine at the University of Arizona School of Medicine. And I finished way back in 2012. And then it became a board certified program. It became board certification as an option, which is like just like if you're board certified in internal medicine or interventional radiologies, like a real official board. And I was, I think, I can't prove it at this moment. The first OB/GYN in the world who actually became dual board certified in both OB/GYN and in the new field of integrative medicine. And then I've never looked back. I just keep moving forward and taking more courses. And now I teach courses. So it's like that's the evolution. And so I love what I do. And that's why I love associating with other like-minded sort of people who question the status quo. And they're always looking for answers like you guys. We certainly love that. And you're a gem to have as a mentor in a field that's continually growing. I think it's really interesting that lately you're hearing more particularly OB/GYNs come out and say things like I only got 30 minutes of menopause training or one hour of menopause training or 30 minutes of nutrition in my whole med school program. And I think for people that have a natural curiosity about the why that underlies disease, hearing your trusted healthcare providers that are conventionally trained, share things like they only got an hour on menopause education. You know, it's it's remarkable and it could just go to show you have that continual education is just so critical. If you want to find a provider who's really knowledgeable to be able to help you in the way that you're looking for. Well, sometimes being around for a long time can be good. And I'm one of what is relatively a small percentage of practicing OB/GYNs who actually were around when the Women's Health Initiative was published back, you know, around 2002 and 2003 and when it was all coming out. So I was practicing medicine prior to that. So I actually did have education and I had a lot of experience prescribing hormones before and then ongoing after the Women's Health Initiative. I will say catastrophe. And so I do have that, I'll say earlier wisdom, an understanding of hormones and And now they're talking about at least 80% of current healthcare practitioners across all the prescribing areas of medicine. Over 80% of them were not practicing medicine back in the early 2000s. So once that happened, that Women's Health Initiative came out. That's when education and research came pretty close to a grinding halt. And even the studies that were done were based on the philosophy of the Women's Health Initiative which was hormones are risky, hormones are dangerous. If you use them at all, go with the smallest dose for the shortest period of time. And that way of thinking, that mantra, prevented even additional studies, the few ones that came out afterwards, which they even put into their studies. We actually use that philosophy. And so I talk over and over about whenever you're giving something, whatever it is, do you want the lowest, do you want the highest, or do you want the best? I say, I think we want best. So lowest only makes sense when you're dealing with something that's toxic. If I said to you, well, how much murky would you like in your diet today? I think you'd say, "Nuncleys, you know, so why would we want lowest? We want best." So that's where it comes in. Like, what is best? And that's been my journey in the arena of hormones is, I want best. And that's where it's been questionable. How what is best? Best in terms of dosing, best in terms of cycling, best in terms of how to give the hormones? Because I've always known that menopause is a huge metabolic hit to women's health, you know? So that always was clear to me. So it wasn't a discovery that menopause matters. It was, what do we do about it? And that's still the pervading question in my mind. It's like, okay, menopause is a condition of hormone insufficiency and then into deficiency. So what are we going to do about? And that's to me the overriding question. Well, I'm excited to spend some time talking today about this very thing. And particularly for post-menopausal females, we're talking so much about how we should be doing the best hormone prescribing for patients and marks something that you've been really passionate about as well. And I want to just frame up the conversation because we talk a lot about estrogen when it comes to menopausal hormone therapy. And then we talk about progesterone kind of as the necessary sister for women who have a uterus. This is kind of the conventional trope. However, there's rising knowledge around the importance of progesterone in cycling females and then even in peri-imposed menopausal females. So I want to start by just laying the groundwork for people who might be newer to hormone therapy, providers who might have been taught, you only need progesterone if a woman has a uterus and the only purpose is endometrial protection. Let's just start with that. What would you say to someone coming in that has that point of view? Because that's how they've been trained. That is the pervasive attitude. In fact, all the medical societies currently recommend no progesterone prescriptive use at all in women who don't have a uterus after a hysterectomy. They say don't prescribe progesterone. So I say that is misguided thinking, okay, pure and simple. There is no one thing in the body that does one thing in the body, okay? So every peptide, every enzyme, every neurotransmitter, every hormone has multiple effects in multiple organ systems. There's not a one-hit wonder that only works in one spot. And it's absurd to think that progesterone is only about endometrial protection in menopausal women. There are receptors in many, many organs throughout the body. And the ones that have had the most research are the neurological system, the bones, the immune system, skin, vascular system, the cardiovascular system. So we know that there are a multitude of effects that progesterone has throughout the body. Now one of the things I always emphasize is that these hormones that have traditionally been called sex hormones, estradiol and progesterone. We'll leave testosterone out of it for now. But estradiol and progesterone have classically been referred to as sex hormones. So I refuse to call them that, I stopped a long time ago and I call them life hormones because they are the givers of new life and they are also the providers of a healthy life. And that is so important to grasp that these hormones are essential for women to be healthy. And only healthy women will have successful fertility and pregnancies without having all kinds of complications. This became obvious to me early on in my career when I was delivering those thousands of babies that women who went into pregnancy, whether by luck or through artificial means and they got pregnant. If they were unhealthy, metabolically speaking, at the time they entered into pregnancy, they were high risk for having preeclampsia, gestational hypertension, gestational diabetes, preterm labor and so on. And so to that end, these life hormones, estradiol and progesterone have effects throughout the body to maintain health. Because without having total global health, a woman will not be successful with pregnancy. If you understand that the prime directive of life is the creation of new life and only humans, there are only species on planet earth that works to control our own reproductive destiny. There is no animal on planet earth that says, "Hey, this is not a good year to mate. It doesn't work that way." But it's and I'm all for, I'm like the ultimate feminist here. So I'm totally for women to have babies or not have babies when and if they want them. But if you don't understand the foundational evolution of the female body that it's designed for successful reproduction and to that end, you have to have optimal hormones from the ovary in order to optimize the health of every organ system. So I am a strong advocate for giving progesterone in a physiologic way to optimize the effects of progesterone on all the different organ systems that require it for optimal function. And that includes after a hysterectomy. In fact, that's what I'm doing now. I just wrote an article. I hope it will be published on why every woman who's had a hysterectomy needs to continue to use progesterone for cardiovascular optimization. But then I want to write one for bone, for brain, for skin and for, you know, and so on because that's how it works in conventional medicine. You have to pick an organ system to get into a journal that specializes in that organ system. But it's the total body unified approach to health that these hormones have receptors all over the body. People now understanding estradiol that it has receptors in all these different organ systems. So let's get on the ball. Progesterone is also about global health and functioning of multiple organ systems. Well, you are in good company with that belief system, I think, here. Before we get into those details, which I do want to get into, like, what do we know about progesterone for all these different systems of the body for post-motopausal women? Mark, I'm hoping that you can kind of lay the groundwork for us from the biochemistry perspective, particularly around progesterone metabolites, or just something that we measure at Dutch and we care a lot about it Dutch because progesterone metabolites actually have their own biological impact, which we are going to be talking about today in depth. So Mark, can you explain to us a little bit about the biochemistry behind progesterone? And then I also am hoping you can talk a bit about progestins versus progesterone because I think that's something from the WHOI where there were some risks associated with progestin use that would be really helpful to clear up from a risk data perspective. And why, what we're talking about today is something a little bit different. Yeah, maybe starting with that aspect of it is, I mean, just to keep it as simple as possible, different chemicals that have different impacts on the body. And I mean, we always talk about frustrating it is to read papers where they interchange them even to have the word progesterone in the title. And then as you get to page four, you're like, "Oh, I get into the methodology and you're not talking about progesterone, you're talking about a progestin." So, you know, the body makes progesterone and in a certain respect, it works also to use a synthetic version of that. And so in the WHOI study in many practices, they reach for that. And there are reasons for that that might get into politics and all of that, which I will not get into, just to say they're different compounds and different chemicals. And you know, the benefits of natural progesterone aren't completely mimicked by the synthetic progestins, although they do protect the uterus from too much proliferation when you also have estrogen on board. So a lot of confusion over that over the years. And we could get more into that. But as far as the metabolites go, that's a unique window that we have in a certain respect, the metabolites have a very simple role. And that is that progesterone itself doesn't really end up in urine in very significant concentrations because of the uniqueness of its structure that is uniquely different than testosterone and estradiol and some of the other compounds. And so. there's a fair amount of research that shows that these metabolites called pregnant dial track really well with serum progesterone, with whole body progesterone as progesterone moves, these metabolites move. There's one main pathway of the beta pregnant dial and there's decades of research on how that tracks pretty well with progesterone. What we did that was unique is knew that a decent fraction of progesterone also went down this other pathway, down this alpha pathway that also has a similar purpose in that it tracks with progesterone. So progesterone's in a sense going down two pathways and creating these two sort of cousins if you will of metabolites both of which track with serum progesterone, track with whole body progesterone when you're not in HRT land. And so we measure them both and they correlate and we've published that and that's great and so that's one use of metabolites is just a window into how much progesterone did Jacqueline make today or whomever it might be. And then you start to get into the progesterone's unique biochemistry of how it's broken down and then the metabolites take on a whole other purpose which admittedly has less value and less utility in just knowing how much progesterone you make but it also is interesting and in certain applications has some clinical value in and of itself in asking the question what is my body doing with progesterone. And so these alpha metabolites very much like when progesterone goes down its alpha pathway it makes its famous metabolite DHT which has a lot of interesting use and we don't need to get into that but progesterone in the same way when it goes down that alpha pathway those metabolites have some unique properties some of which is they're sedating and hit the GABA receptor and there's a whole story you know there with with that and that's I think a good leading I can just sort of maybe leave it right there in the sense that the big story being there are two uses of one it's indirect way of saying how much progesterone you make and then two we get to dabble a bit in understanding how your individual progesterone is metabolized and why that's interesting and then that gets a little more interesting when you start ingesting progesterone because those metabolism profiles and pictures are different from woman to woman but they're also very different depending on whether you're swallowing progesterone taking it intravaginally or you know by other routes of administration so it's a it's a multi-layered interesting topic. Yeah it certainly is interesting and I think you know this is an area that's so commonly confusing for even providers let alone for patients but when we look at like birth control pills most most of them are there synthetic hormones ethylene alessor dial plus some kind of progestin and there's a lot of different progestins available on the market there's norethendrone lever and nergestrol desogestrol just spironone and we could make madrupsy progesterone acetate like all of these ones that are utilized in cycling females and then you have the studies metriutilized with wh i which are using again a synthetic progestin I think most providers now that I've seen at least are using a bioidentical progesterone and estridial approach post metapositely although it's not off the table to use other synthetic progestins in certain cases but there's obviously a big difference between those and I think providers really get that you know not all progesterone or progestins are created equal and only the natural bioidentical progesterone can make these metabolites that can really have all these profound effects downstream right so um doctor urge can you talk through a little bit about let's focus in on the bioidentical progesterone now when we're looking at use of a progesterone product post metaposally the majority are using or a micronized progesterone but there are other forms that are available in the market as well can you just lay the groundwork on like what else is commonly prescribed well what's interesting about the micronization of progesterone if we just go back a little historically is that if someone swallowed progesterone that didn't go through this process called micronization the stomach acid would just break it down into amino acids so it would be of no value at all it'd be very poorly absorbed but through this process of micronization it can survive the stomach acid but then it ends up in the liver okay and the liver is the master org organ of we'll call it metabolic transformation it converts one thing through two and other things through these different pathways that exist in the liver as part of the sort of detoxification that's the function of the liver among many others and so when you swallow micronized progesterone it survives the stomach but it ends up heavily converted to metabolites they know that were touched on these metabolites that are produced in very large measure resulting in very very low levels of progesterone that actually get into the circulation and large amounts of these metabolites of you know over 30 different types and one of the dominant types of metabolites is called alopregnanolone and so alopregnanolone becomes produced in very large measure by the liver and gets into the circulation and alopregnanolone in the right amounts or is really a wonderful molecule it's not progesterone though it doesn't bind to the progesterone receptors but it does work in the brain when it gets into the brain as was mentioned so it can activate the GABA receptor and GABA is the inhibitory neurotransmitter which is very important for having tranquility and it reduces anxiety it's good for mood and it facilitates sleep and it balances other neurotransmitters like glutamate so it's like part of the whole balancing system but like anything too much of a good thing can be a bad thing so I did a deep dive into like what happens when you swallow all of this progesterone this micronized progesterone and it turns out that in different women like was said Mark was saying it can be variable but up to like 90% of the progesterone that swallowed is converted into metabolites largely alopregnanolone and it really over it can over activate the GABA receptor and they've done some level testing and when you take 100 milligrams every night which is so standard nowadays and we can talk about even forgetting the part about the alopregnanolone and the other metabolites while taking having progesterone every single day is not physically physiologically compatible with optimal health but just talking about the metabolites with the high levels of alopregnanolone it's like too much sedation can occur in the brain and there's a lot of rat data I know it's rat it's what we call preclinical data when you do studies in other animals that are not humans there's even a little bit of human data that it can impair memory formation also in rats if there's continuously higher levels of alopregnanolone it can alter the appetite regulation systems and actually promote weight gain and there's a number of studies in rats showing appetite dysregulation and weight gain when they were exposed to abnormal superficial logic amounts of alopregnanolone on a daily basis when someone swallows 100 milligrams approximately two and a half times the maximum amount of alopregnanolone in the blood that would ever be achieved during a normal menstrual cycle is occurring and 200 would get you approximately five times the maximum amount that a female would ever naturally have in her bloodstream and of course it goes everywhere in the body including in to the brain and there it gets even more complicated than that in that the liver has another enzyme that's much more prevalent in the liver than in the brain because the brain has the enzymes that can convert progesterone in the brain as needed into alopregnanolone because it does have these very important effects in the brain but when you have such a huge amount going into the liver directly there's another enzyme system that can actually produce more than you'd ever have in the brain of sort of like the cousin you might can call it a cousin it's like a different configuration in space which is called isopregnanolone instead of alopregnanolone and it acts as kind of a blocker of alopregnanolone so it's actually even more complicated and the liver is just not naturally supposed to get this bolus of oral progesterone and then have all these metabolites circulating in unnatural non-physiologic amounts so what other options are there? well there's just so many there's not that many but you can use compounded pharmacy products to use as vaginal suppositories you can actually use the same conventional progesterone little like sort of like a little pillow it's kind of a little bit soft and they come in white or orange I usually tell my patients that we could get the white ones if they don't want orange, okay? Because it does have that RNG dye and it's actually designed and there's plenty of studies, published studies, that you can use that same little oral use as vaginal use. So in the infertility world, vaginal progesterone is what is used. They can do shots, but no one in menopause is going to do shots. It's like not feasible to do a lot of progesterone shots. It's also extremely painful, even the fertility gops rarely use that. Yeah. So anyway, I'm a big advocate now for vaginal progesterone, whether it's a compounded product or the commercial product, which has plenty of supportive data, that when you use it vaginally, you get what's called the first pass through the uterine cavity, which actually causes the uterine lining to become completely transformed into a secretory state, like the perfect state for implantation of an embryo or the perfect period. Or, and as well, if you give enough, you're going to get good systemic levels. So you get the benefit to the uterine lining and you can get blood levels that are more compatible with the levels that a woman would have in a natural cycle, which you will not likely achieve with the oral. Now, every with those variations, but even when you do achieve good levels orally, which doesn't happen typically, you're going to get still a lot of those metabolites that we don't want so much, you know, once again, too much of a good thing becomes a bad thing. We'll be right back with more. If you're already running Dutch tests in your practice or thinking about it, there's never been a better time to become an official Dutch provider. Why? Because we go beyond lab testing. Our provider community gets exclusive access to clinical education, in-depth report interpretation, training, monthly case reviews, and one-on-one clinical support. Whether you're just getting started or looking to sharpen your functional hormone expertise, we give you the tools to grow. And thousands of providers already making a difference, visit DutchTest.com today. Welcome back to the Dutch podcast. So I mean, this is really getting to the heart and the meat of what I was hoping we could dive into today, because you're positioned on this, like you said, like it's, there's rat data. And this is how medicine progresses, right? You start with animal research. You see what you're observing. It moves on to clinical trials in humans. And then there are larger, you go to pilot study, then you go to a larger study, and then you're able to draw better clinical conclusions. And I mean, that process fundamentally takes a very long time. Like when we look at the research process, things making it into standard practice guidelines. But I know that there's also pushback around that point of view as well, due to like particularly the Keeps trial, which was a trial looking at the safety of oral micronized progesterone, and looking at the fact that it does appear to be safe for most women. But I think a lot of it maybe is around the nuances of some of the other effects that you're talking about at the brain, which were not the primary endpoints, you know, it did show no cognitive harm in the Keeps trial. But what do you say? I know you've read all this data. What are your thoughts when you look at all of that? Well, if we talk about the my concern, okay? Nothing happens very rapidly. Okay, so this is like the long haul we're talking about. In terms of progesterone, when you get too much aloe pregnaialin, I mentioned that there's some data in rats of weight gain and dysregulation of the appetite, in rats, they had significant occurrence of what you would call rat dementia, because you're suppressing the brain. You're suppressing memories. Like, if you think about what happens when you're falling asleep, you're not making great brilliant revelations about anything. You know, your brain is going into a very like suppressed state, and that's what has to happen in order to fall asleep. So now there is studies on this. If you look at what drugs work similarly, similar to aloe pregnaialin, the metabolite of progesterone, they're the benzodiazepines. So we're talking about drugs like valium, ambion, Xanax. So those drugs work on a different site on the GABA receptor, but the same mechanism, it is the same mechanism that increase GABA. Now those drugs are scheduled for control substances. They're considered potentially addicting and can impair judgment. The long-term use has been studied that it could increase cognitive decline. And that's what they found in the rats that they had this cognitive decline. But it doesn't happen rapidly, and I'm not going to say it's universal. I would say it's a yellow or red flag saying, like, is this okay? And if we have preclinical data that says it's not okay over the long haul, is this what we should be giving, plus when you look at some of the other negative things, like you're really not getting, in most cases, adequate progesterone. And once you recognize progesterone has many functions in the body to maintain optimal health, and you're not going to get actual good levels, that's another concern. So in the Keep Study, which is just a very few years, I don't think that's enough time to actually look plus. They did use it for only part of the time. It was in a cyclic way, not every single night. Like now has become the standard of care based not on anything physiologic based on convenience and ease of prescribing, and so on. So I don't think we have the data in humans. I'm the first one to be open about that. But when you have warning signs, like there are other studies that have been done for other pharmaceuticals, where there were warning signs in preclinical studies like using rat data. And so they put, you know, concerns about the drug. I think to do this without having concerns is not right. Now when, when aloe pregnenolone is a drug, you can get it. It's been used for postpartum depression. And when aloe pregnenolone is a pharmaceutical, which it is a pharmaceutical, it's a scheduled for controlled drug. I think that's really important when this came on the market as a pharmaceutical, it has the same controlled status as Valium and Zanix and Ambien. It's a controlled substance. And it has all the same warnings on the label. The other thing that has come out once again in preclinical studies, like using mice, where they found that when they gave the mice ongoing levels of aloe pregnenolone that were super physiologic, okay, that what it did was it down-regulated the receptors so that for progesterone. So it had an impact on how progesterone worked as well. When they used progesterone every single day, and so it could be from the aloe pregnenolone or from the progesterone, it's not like they broke it down. But when they did continuous use of progesterone every day, the receptors down-regulated. This is part of the way the body responds when you have something continuously given. It down-regulates. And then there was concern that when you stop the progesterone, that you don't have proper function of the progesterone receptors. And so that's a concern. So when I have patients who are on nightly progesterone for quite a few years, and then I take them off of it to try them on more physiologic cycling regimens, sometimes they really have trouble sleeping. They didn't have such trouble before. But maybe their GABA receptors now are completely-that's one of the concerns is that when you have constant GABA activation from constant aloe pregnenolone exposure, that you're down-regulating the GABA receptors and creating sort of a resistance state. And then it becomes very difficult for people to then sleep and have good mood when you take that away. It's almost like a sort of a dependency or almost like an addiction. The only-like you don't get a withdrawal effect, like a real addiction, but more like a dependence. So I have concerns of chronic aloe pregnenolone effects on the receptor, but also for chronic progesterone use on its receptors. So because when you have chronic use, you down-regulate receptors over time. Well, I'm really glad you're talking about this. And this is an area that is an exciting podcast to me because I think I view our job as bringing information forward to clinicians and listeners. And you feel you do the same as an educator, march as the same as an educator. And this is one where it's like the jury's not out. And I think one thing marks that's all the time, research is really good at telling you what's not true, but it's not so good at telling you what is true. You have to sift through everything it's not until you have some kind of final conclusion. And we're just in the process with that. And you have a history. You and I have had dinner a couple of times where I heard the stories from you of other areas of medicine where you've been, you've held the red flag up a little bit early. than many providers that you pay attention to that. So I really respect this that you're bringing this forward as a potential concern and issue. I do wanna go through just a couple of the studies that we have in this arena, because if people haven't, don't have awareness of it, we've talked about a couple of them already, but just like what they were, what they looked at, what we know. And that at Mark, I wanna get your weigh in on this as well, because this is the Metaposal Hormone Therapies and area that all of us spend a lot of time bringing the papers that come out. And you have a very thoughtful approach as well. So we talked a little bit about the Keeps trial. That one, I just pulled it up. That was a four year trial. It was sicklic oral micronized progesterone, 200 milligrams for 12 days and then off. So they cycled it like to mimic a menstrual cycle. There were no long term, there are no long term studies that I'm aware of, on continuous use of oral micronized progesterone and cognition. So Mark, maybe that's the first thing you can share is like what's the difference between continuous and sick? Like what do we mean there? And then the other piece is there has been from what we could find, no randomized control trial that looked at continuous use of estrogen and progesterone. - I know. - For more than 24 months. So the Keeps did cyclical. The Yoon trial was the one with continuous dosing, but that was only 24 months and only 37 participants. So very small studies and there's really not been long term. - And the elite, the elite was also cyclic. - Thank you. Yeah, the elite trial would be the other one. And that one looked at the vaginal gel as well. So we can talk about that as an alternative too. So Mark, tell us a little bit about kind of your unique perspective in this and any thoughts you have to add. - Yeah, I mean, my thoughts go into like all sorts of - I know, there's this. - The random little crevices of these topics because and it just goes to show like how much we have to learn about all of these topics. You know, and again, I don't want to chase down too many esoteric paths. But as we're measuring the metabolites, it's easy to think of it as when you say first pass and you swallow something and eventually it hits your liver as using that to represent the entirety of that process. And for me, I like to dig into those little details of there's a 95 paper where they went in and asked, asked like what's actually going on there and what they found is that the bacteria in the intestine actually get the first shot at it. And they send it mostly down the five beta pathway. And then the intestinal wall is the main one from that paper that sends it down the alpha pathway. And then when it hits the liver, the liver goes mostly five beta. And then also these esoteric metabolites that have a whole other story that are really interesting. I think it's the three alpha and the 20 alpha. There's an interesting breast cancer sort of nuance to that that's never really been unpacked by research. But if the alpha pathway is really interesting, like one of the things that I would like to unpack, but it probably is distracting to this conversation as how you guys are going so far is that the state of the woman's gut, if the state of the woman's gut and the bacteria send it down a pathway and then the intestinal wall is left to send it down the alpha pathway, which is the one you're talking about, that's a whole area of study that to my knowledge has never, that's a door that's never even been knocked on is to say, 'cause what we find in our anecdotes, one at a time times hundreds and thousands of them, is you get really different patterns from woman to woman, which I don't think is as much like what's going on in their liver as it is the gut. And what variables actually exist in a woman's gut to really change the metabolic state of what she's doing in terms of which of those metabolite hormones that are being made in a particular woman, is just, for me, it's a whole area that hasn't been studied that I want to talk about, but then it ends with a bunch of question marks, not with a bunch of assertions. And so I don't know how distracting that is to the conversation, but I think that's a really interesting area of study because the state of your gut matters. And then people talk about 100, 200 and 300 milligrams without making really big distinctions, but you're talking about doubling and tripling the dose of this super physiological, already super physiological progesterone, which has to do also with what dose of estrogen you use. So all this sort of triangulates into a very interesting, but also potentially confusing conversation with lots of different rocks to look under as we search for, again, best practices. And there's a lot of conjecture and a lot of questions that what you're raising just like is calling for a lot of research. And I wish you could pass forward 27 years to see what's unfolded with all of this so that our understanding can be accelerated. And it also is a call for a dose of humility with the things that we believe to be true today, because there is just so much more that needs to be studied. And at the same point while we're waiting, we don't want to ignore any of these, whether they're yellow flags or red flags or whatever, that might lead us in a direction to just treat women better as it relates to. So I don't know if I raise more questions, and I'm definitely not answering a lot of questions, but that's where my brain goes with that is just in that individuality of women as we're dealing with this and trying to understand that and unpack that more, because we do see individual patterns that are very strong in one way or the other. And I want to understand more about that. So I want to try to steer us one, I think the gut health aspect is so interesting and we could do a whole other part so it on that, because I think that that progesterone metabolism is a really critical piece to understand. And it's just one more layer as to where you have this connectivity between the gut, myom and hormonal health, because of course that's relevant not only for post-menopausal hormone therapy, but also for cycling females, right? It's going to be the same mechanism. While you're taking it orally, so potentially not the same depth of impact of the gut microbiome, but certainly an impact there. But to kind of keep us steered down the track, I want to talk about a couple of things, just kind of double click on the first, is this alopregnano-loan exposure from the use of continuous micronized progesterone therapy. And I know that there is really, when we look at the data, one, there is definitely that data showing that continuous alopregnano-loan elevation can impair our cognition through the GABA receptor, like you talked about. Interestingly, we haven't really touched upon the fact that some studies look at, when we look at cognitive impacts of menopausal hormone therapy, show that intermittent exposure is neuroprotective, and they're actually developing that as Alzheimer's is therapeutic right now. So can you talk a little bit about what is the difference for clinicians to understand about sick, like versus continuous when it comes to good. I think when we, this is very interesting, and it's very potentially you're raising a flag of something that comes with the earnings. And the next question is like, okay, well, what do we do about it? So it seems like we have a couple of options. Let's talk about timing progesterone first. - Yeah. Well, when you look at what happens in a normal menstrual cycle, we have a lot of data on that. So there's always like rationale for all this madness, what happens. When you have estradial, if you just like a quick review, the menstrual cycle has the follicular phase, if we talk about it from the ovarian perspective, and proliferative when you talk about it from the uterine perspective. So the first half, if you have a 28 day classic cycle, is the first half is only estradial. It starts with estradial being very, very low. The first day of the menstrual cycle is the first day of bleeding. And the estradial level at that point is very low. Then it starts to rise, but it's still not very high. Then it goes up much higher, and it has a peak that is very high, compared to the rest of the cycle. And then it goes down, and then there's a luteinizing elatious spike, and then a little FSH spike, follicle stimulating hormone spike, and that triggers ovulation. Well, when ovulation occurs, you then create what's called the corpus luteum, and they're the specialized thiccocells in it that make progesterone. In order for progesterone to be made, you need to have estradial in an adequate amount. It's a very complex interconnection. We call it the dance of the estradial and progesterone dance. And during the phase of the first half, which we'll call the follicular proliferative phase, the estradial as it's rising, is doing all kinds of things. It's setting the progesterone receptors. It's creating progesterone receptors. That's essential for progesterone to work. If you don't have proper functioning and develop receptors, the hormone won't work. It's also upregulating testosterone receptors, and its own estrogen receptors as well. So that's a critical time. And all of that will be negated if you are progesterone on the scene at the same time, because when you make progesterone in the second half, progesterone actually downregulates through more than one different method. It has an effect in a couple of different ways in terms of the production of the receptor and the function of the receptor of estrogen, particularly the alpha receptor, which is responsible for creating growth factors that grows the uterine lining, which is why they call the first half the proliferative or growing. Then after the progesterone is made along with very substantial amounts of estradiol. In fact, estradiol levels go up. So the average amount in the second half is higher than in the first half of estradiol. And it's to sort of work in this beautiful co-like project here between these two hormones. And progesterone is down regulating the creation and the function of estrogen receptors. And so predominantly the alpha so that you stop to having all that growth. And that's when the uterine lining, it like blossoms. And that's when we call it secretory. It's also down regulating the enzyme that creates dihydrotestastrone, five alpha reductase. And so it's actually sort of an anti-androgen. Women tend to have the lowest libido during the luteal phase. The second half of the menstrual cycle, which makes sense because they can't get pregnant. And remember, it's all about creation of new life. That's the prime directive of life. So nature doesn't care about women having a big sex drive after they can't get pregnant that cycle anymore. So why would we want to create that kind of a scenario by having progesterone on the scene all the time? Well, it's not just working in the uterus when you take progesterone. It's all the time every day. Even though the levels are very low, it's not zero. And it's going to affect estrogen receptors everywhere in the body, including in the brain. And when you have all of this progesterone, even though it's low levels, but it's constant, OK? Then it's going to accept how the brain is going to work. So you have small amounts of progesterone, but enough to suppress estrogen receptors, OK? So now it's like a double whammy to the brain, because estradiol is critical as creating neurons, maintaining neurons, creating growth factors, which both estradiol and progesterone can help create brain-derived neurotrophic factor, which is critical. Both of them help to create nitric oxide, which maintains proper vascular health. And you need to have good blood supply, good nutrients, good oxygen going to the brain. Progesterone in the brain is very anti-inflammatory. It keeps the embedded like immune cells, and microglia, the astrocytes, from going wild, it calms things down. It's very anti-inflammatory. And if you think about pregnancy, it's progesterone that helps to work in the interface of the placenta to help prevent the maternal immune system from attacking the embryo and the fetus that's developing through this immune modulation that progesterone does. And it does it in an anti-inflammatory way in the brain to reduce neuroinflammation, which estradiol also works. They worked in synergy. So you need optimal levels for optimal brain health and function. You need to have both the right amount and the right sequence of estradiol and progesterone. And once again, we don't want too much alopregnenalone. We need to have activation of GABA. GABA is the neurotransmitter that's predominantly activated by estradiol. It's the same neurotransmitter that's activated by infetimines that are used for people, sometimes, who have attention deficit disorder issues. They have to give them more focus, more attention, more memory. So there's this beautiful balance between these neurotransmitters. So you don't want to be too much playing with that in a bad way, so that you have too much inhibitory, not enough activating. You don't want too much of anything. It won't just right. And when you give hormones, like what is now the standard of care, little bitty bits of estradiol, too low to actually do enough good. And all this constant but low levels of progesterone and high levels of alopregnenalone, it seems like that's the perfect storm for not optimizing brain health. But yes, of course we need more studies. But we're working with science. And sometimes that's how expert opinions are created pending more human research. So we'll be talking about options for prescribers to be thinking about. Can you talk a little bit about the continuous versus cyclical dosing of OMP? Is that one good option? And then I know you talked about vaginal and we've got the elite trial that we haven't really dove into. But I want to briefly touch upon that as well as an alternative and just make sure people understand what do we know about that and what do we not know about the use of vaginal progesterone. Sure. So when you get back to a normal menstrual cycle, when you have an ending of progesterone, because progesterone would only be present during the luteal phase, which is about two weeks is a little variation, but typically it's 14 days. Well, when the progesterone drops off, that is the ticket to then having its own receptors rebooted and then having estradiol, then recreate and activate its own receptors without the progesterone being present. And so that's like the whole foundation of what you need to have happen in a normal menstrual cycle. You want to recognize what gives women optimal health and when they have optimal health, like say in their 20s, when they would have natural cycles. So we can't actually completely mimic that. It's much too complex, but we can get somewhere in the neighborhood. Something way more physiologically aligned with what is optimally going to give optimal health than what we're doing. So if we give estradiol to get levels that are somewhat similar to the levels that a woman would have in a normal menstrual cycle, and there's actually some interesting studies that have been done very small, where they gave a woman who had no estradiol on board, and they looked at what's called flow medialid dilation. They looked at the artery and it was constricted. Then they added one patch, 0.1 milligram, and the artery dilated. Then they gave the woman 200 milligrams of oral progesterone, and they did the flow medialid dilation study, and the artery constricted. And they actually measured levels. So the levels were in the 60 to 80 picograms per mil of estradiol with the 1.1 milligram patch. Then another study gave 2.1 milligram patches to try to be similar to the levels of the luteal phase, or the second half of the menstrual cycle. Then the artery dilated when they gave them the 2 patches. Then they added 300 milligrams of vaginal progesterone gel. Once again, they used the gel, and the artery stayed dilated. End of study. So what's the conclusion? Well, for me, it's due both. Give vaginal progesterone, whether it's a tablet, or a suppository, or gel, and give an adequate amount of estradiol similar to what happens in a normal menstrual cycle, where when progesterone comes on board, the estradiol production goes up above what it was in the earlier part of the follicular phase to have this balance between the estradiol and the progesterone so that you somewhat suppress the growth factors, but you don't want to suppress the production of nitric oxide in arteries to maintain vasodilitation. So there's this beautiful balance. So I think that it won't be too complicated to do studies and to do empirically based on studies that have already been published to give hormones that are somewhat aligned with what those studies showed, and they measured levels of estradiol during the-- both parts of the study and went with the two patches of 0.1, the levels of estradiol were in like the 120 to 150 picograms because we know luteal phase, progesterone, and estradiol are not at all like with the follicular, and that women in the second half, the luteal phase, their estradiol levels are typically well over 100, even into the 200 picograms. So we're like into that ballpark. And this is-- we already have data that shows vasodilitation will be banned or stopped if you don't have the right ratio or balance between these hormones. So I think that giving cyclic hormones and accepting-- I know that some people say it's unnatural. Yeah, but if you want natural, it's osteoporosis, fractures, hypertension, potential heart attacks, strokes, et cetera, all the degenerative diseases associated with aging, there's natural for you. So to continue to have a period that is created artificially through cyclic hormones is a small annoyance to be dealt with compared to using hormones in a way that is completely not aligned with physiologic data that we know that what the way the hormone receptors are not properly aligned and working when you have this continuous kind of adosing. You're also-- not getting adequate levels of estridial, typically, to create adequate growth factors, say in the brain, like brain drive neurotrophic growth factor, nerve growth factor. Another thing I didn't mention about progesterone in the brain is that it's really critical for maintaining and producing myelin, like insulation of nerves. It requires progesterone. So progesterone is neuroprotective. It actually helps prevent seizures. There are studies showing infusions after traumatic brain injury can help prevent the degree of damage that can occur without the progesterone. So, but nothing happens without the right rhythm and the right dose. Dose matters and rhythm matters. It's just how females were evolved. Yeah, though, the studies on traumatic brain injury, like progesterone post-medic injury are fascinating to go into. I want to just review just briefly with the vaginal progesterone options as well. The elite trial did look at 45 milligrams and 90 milligrams of cronon gel and then also vaginal capsules. But there's really not good long-term, randomized control, trial of data with systemic estrogen. So, I think that's something that we actually see a lot of providers use vaginal progesterone as an option compared to OMP. Oftentimes, because oral micro-nice progesterone isn't being tolerated by the patient as well. So, I think they're, it's nice. Like, from my point of view, looking at the data, there is enough data is to say that it's I mean, especially what we know about first pacifect in the uterus with progesterone, it's use of pregnancy. Like, I feel pretty comfortable with it, but it's not standard of. This published data showing safety for five years because, you know, they don't have long-term data on any of this. And there's actually some concern that oral micro-nice progesterone may not long-term be as protective as they think that there's actually been more occasions of endometrial had no carcinoma. So, you know, there's no, you're home free with any of these things. And it's so, but, when you have regular predictable bleeding, I can tell you as an OB/GYN that's not how endometrial had no carcinoma presents. It doesn't present with regular predictable bleeding. That's not how cancer is work. So, that is actually a signal of good function and health of your uterine lining. What percentage of women who are on continuous progesterone and daily estridile? What percentage of them have some unexpected unscheduled bleeding? It's really high. It's well over 40 percent. And in the first year, it's well over 60 percent. Yeah, I'm spree-cold. In the first six months, it's higher than that. So, it's not like, oh, if you use the daily routine, you're never going to bleed. Actually, there's a substantial amount of bleeding. And because that's unscheduled bleeding, it's always worrisome bleeding because you don't know what is that. Yeah. And I think sometimes women don't like that because they don't know when the bleeding will happen. But it comes to fitting into their life where a cyclical regimen, if they're getting it with for all bleed when they stop the progesterone, then it's a time that, you know, it's like, we're on the oral contraceptive, you could like take a placebo pill for an extra week to not bleed on a vacation. You kind of know when it's coming. Exactly. You can plan your life. There's a lot of line. There's no right or wrong way. This is where in a learning phase of menopausal hormone therapy, thankfully, we have some studies. What you're talking about, the physiologic dosing is more as a higher dose than is typically put into like standard practice guidelines. So, I want to be clear about that. So, if people want to learn more about that, they should talk with you and take some of your classes because it is a whole, another approach that you could consider. It is important for people to know that the standard of care for women who have early onset of menopause or what we call premature ovarian insufficiency or early, early menopause or early is from 40 up to 45 and premature is before the age of 40. The standard of care, not based on studies based on quote expert opinion, no studies is to give physiologic cyclic hormone therapy. What I am recommending is basically what is the recommendation for women who go into menopause early. All I'm saying is why would we not continue that the cause of standard recommendation is to stop it between 50 and 52, the sort of average age of menopause and then go to the daily routine of a little progesterone and estradiol every day. Up to that point, they were recommending physiologic cyclic hormones as the standard of care. So, what I'm saying is which is not the standard of care, why are we stopping it? That's all. You know, why don't we just continue it? The only, is that I don't recommend the oral progesterone, which I did for years, for years I recommended oral progesterone until I did a deep dive and I was like, what the heck, you know, what are we doing? And there is published data. There's a ton of data in the infertility world. Of course, in terms of menopause, there are studies published, never enough. And we definitely need more, but it's not like we're in a complete void of any data. There is data and we do know what kind of levels are achieved and what it does to the endometrium. And I just wanted to throw in there's actually published data. I know it sounds weird until you get over it, but there's actually published data on rectal insertion of progesterone tablets, which give you extremely good absorption and really good systemic levels. And so we do have published data on that. We don't have a lot of clinical studies. Of course, we don't, but we have clinical data on just what it does that it does get absorbed really well. And so if somebody say wants to have sex and they want to use an alternative, there is published data that it does work. I mean, we don't have the clinical studies looking out in the future, but it's not like we're doing something that's never been done, never published. We went into several different, as these conversations go into several different areas. And one of the things I think is conversationally hopping from continuous oral to cyclical vaginal. I was just wondering if you could state really clearly for this slow-minded guy, Dr. Gersh. When you stratify those in terms of like both of those moves, how would you weight those or grade those in terms of the value of reconsidering continuous and the value of reconsidering using vaginal, in terms of so route of administration and then continuous versus cyclical. Which of those do you see as being maybe more important for like reconsideration for women if that makes sense? I don't know that I can do that. I would say that if I had to pick which is the bigger deal, I would say cyclic is bigger than, but I don't feel good with that at all, so I won't do it. Actually, because I think you asked for a pick of favorite child. The fact that it's difficult though, is an answer. And the other thing is I think it seems to me we're very critical often of when medicine studies one variable in any particular thing. Like you get off down the wrong path and I think that is an example of that, where when you're studying the state of the endometrium only and that's the only thing you're thinking about, then you can build a case for continuous versus cyclical. And what I hear you saying, and again, my brain is not the clinical side. So I'm just trying to understand this as clearly as I can, is when you start thinking about all these other factors, that's where a case can be built for exposure and not exposure, having a cyclical approach to progesterone that does mimic more what the woman's been exposed to since they started cycling in their teens or 20s or whatever. So that's a helpful thing for me to just be thinking about more and watching for more of this research. And thankfully, we know that there's relative safety with what the majority is doing in terms of using bioidentical estrogen and probably giving it transdermally and then countering that with progesterone, either oral or progesterone. And we didn't even get into the topic of what the safety data says with transdermal and all of that. So it's fun. How many endless different roads this conversation can go down. And I really appreciate your perspective and input on it. So Mark, just one thing that I'm hoping you can cover before we close is around monitoring of progesterone because we take a pretty strong stance at Dutch on this. And I think it's an area of common confusion. So I'd like you to talk about that if you're open to that. Like when we're doing Dutch testing for postmanopausal females who are on menopausal hormone therapy, there's utility in understanding progesterone on a Dutch test, but it's not always what people think and when it comes to monitoring dosing. Mark about that for us. Yeah, I mean, it's another topic where like history has been very complicated. So Dr. Gersh said rightly that when you take oral progesterone, you don't get very big levels of progesterone in serum. But when you go back into the 80s, you use to because the testing was crappy. So you have these amino assays that track really well with progesterone, but as soon as you use it orally, they become inaccurate. And so there's this this interest well for a lab guy. It's an interesting history, probably not interesting for lots of details. But what it comes down to is the with progesterone and the main message of progesterone, the main thing that any of you doctors are trying to achieve with your patients, which is to make sure that the endometrium is protected. The lab testing isn't helpful. And I think that's where the lab industry can go wrong in trying to jam square pegs into round holes and saying that the lab testing has utility. And it really doesn't for asking that question of like did I get the dose right to protect the endometrium? We don't have answers for that in the labs. We have answers as you guys have rightly leaned into into the studies of which doses work for protection. We know that in the labs just they, I think they help with estradiol. I think they help with testosterone in terms of like did I get my dose right? But with progesterone, I don't think that the testing is helpful for either oral or vaginal progesterone, the two proven routes of administration. We are admittedly a little bit in the weeds in saying, hey, there might be some extra value in looking at that metabolism profile to say how your body's making that aloe pregnaial and what your body's doing with the progesterone, I think is interesting. In some cases, it's leverageable when we see very strong or not very strong analgesic effects from progesterone, the metabolites might offer some insight. But we oversell the lab testing as part of the MHT process when we try to ascribe too much value to monitoring progesterone because the primary job that it does just isn't spoken to by the lab. So we really want people leaning into the labs where they're useful. Getting your estrogen and your testosterone dose right? Absolutely. How your body's breaking down estrogen, breaking down testosterone, am I making DHT and I'm making those metabolites we don't want? Absolutely useful. And then also interesting how the body's breaking down progesterone, but forgetting the dose right, it's only a little bit helpful. And in some cases, not at all. So I think that's important to keep in mind, is to not over leverage the labs where they aren't helpful. And I think progesterone is kind of one of those areas where it has very good utility when you're not on HRT. And then mild and in some cases, no utility when you start adding progesterone specifically on board. So. Well, I'm really appreciative of both of you for making the time for their conversation. Today it's really important. And I can't wait to look back on this podcast in a couple of years and we have more and more data to draw a tighter conclusion over time. So let's keep researching. Let's keep getting some answers and see what we can do to help treat women better, which is what we're all here for. Dr. Gersh, what is the best way for our listeners to follow you or learn more about you? Well, I have an Instagram, like everybody. And I do Instagram lives and I have a YouTube channel. And I love for people to follow me. I try to post a lot of what I think is interesting and up to date kind of information. And I have three books, two on PCOS. Now we won't get into the name change on this one. But using the old name PCOS and one on menopause, menopause, 50 things you need to know, which I think is like the perfect little handbook for every woman who is pre or post menopause anywhere in the journey. And I have a medical practice. I'm very old fashioned. I actually have a brick and mortar medical practice where I see patients every day in person. I also do telemedicine is called the integrative medical group of Irvine. I'm in Southern California. And I see people. I see patients all the time. I'm a clinician. I'm not just a talker. I'm a clinician. I see patients. And that's my primary job and my primary passion. Well, we love that. And we love you. And thanks for joining us today. We'll make sure we put all the links to all the different places you can find Dr. Gerrish and her books and the show notes. So be sure to check that out. And thank you to all of you who are listening today. I hope you found this conversation as fantastic and in-depth. This is the kind of stuff we love to talk about in debates. This is a great conversation. Take a deep breath. Catch your walk. Catch some fun time. Clear your head before you go see your next patient. But really, thank you so much for joining us today for this fabulous conversation. If you want to learn more about hormones, you like this type of conversation, we do release a new podcast every Tuesday. So also be sure to click subscribe so you can follow the Dutch podcast. And you can follow us @DutchTest on all the socials. We'll see you next week. Thanks for joining us on the Dutch podcast. Join us every Tuesday for new conversations with leading functional health experts. If you like what you've heard, be sure to like, follow, and subscribe wherever you get your podcasts.