Practical Steps for Optimizing Your Protocol

Welcome to Everyday Wellness podcast. I'm your host, nurse practitioner, Cynthia Thurlow. This podcast is designed to educate, empower and inspire you to achieve your health and wellness goals. My goal and intent is to provide you with the best content and conversations from leaders in the health and wellness industry each week and impact over a million lives This is the start of a new Thursday series called The Midlife Minute that is really designed to address listeners' questions in a little bit longer length of time and or deeper dive into topics Ideally, we're going to keep these podcasts under twenty minutes. Occasionally we make over to thirty. but I'm trying to reinforce some key concepts and ensure that I'm addressing listeners' questions in a way that's really helpful. So the questions that I will be addressing, topics are gonna be items that I'm being asked over and over and over again. I hope you enjoy this series. Please share with your friends. And as you know, you can always send your questions to support at Cynthia Thurlo. com. I appreciate each and every listener a midlife Mute. This one is going to be prorogesterone centric. This is coming off of two podcasts that I did with Dr. Fhelise Gkurch that generated hundreds of questions. I'm specifically Weaving in questions from Amanda, Katherine, Alicia, Laura and Luciana from my free Facebook group, the Midlife Pause. and obviously all the other questions that we've received certainly went into the prep for this discussion I want to start with a question I've been sitting with since my conversation with Dr. Felse Gersh, which actually occurred in December. and I knew this was going to be one of these below your mind podcasts because Dr. Felse Gersh, who I trust implicitly and respect enormously, generating some really interesting conversations. A lot of her concerns about progesterone and we had a beautiful conversation that was divided into two podcasts She was speaking specifically to some of the neurocognitive effects for progesterone users And I want to be very clear, progesterone is not dangerous. Bioidentical progesterone is one of the most important and most misunderstood hormones in a woman's body But because of the way we are prescribing it, the doses we are using it at, and the assumptions we are making about how it works in the brain deserve far more scrutiny than we're currently getting. So I'm going to talk about progesterone versus progestin. I'm going to weave in all these questions that I've been asked And hopefully by the end of this discussion manyany of you will feel more comfortable with whatever decisions you're making about progesterone because remember, bioindividuality rules, what works for me may not work for someone else. And if you are still told by your practitioner that you don't have a uterus and you don't need progesterone You need to find someone else. Just remember, progestterone receptors are diffuse and throughout our body So foundationally, progesterone is very different than progestin. So progesterone is body identical, bioidentical. prorogestins are synthetic versions of progesterone And this is not negotiable. and you cannot talk your way out of convincing me that progesins are bioequivalent to progesterone We know that bioidentical progesterone is structurally identical to what our body makes Prootestines are synthetic analogs that behave differently in every tissue that they touch, much like In previous conversations, we've talked about estrdiol versus ethanol estrdol, very different formulations The Women's Health Initiative used Medroxy, progesterine acetate or NPA A synthetic progesterin and the fear that persisted for the past two decades is rooted in the data from the synthetic compound, not from body identical progesterone So millions of women were denied or avoided bioidentical progesterone based on risks specific to a compound that should have never been extrapolated to the natural hormone This is a clinical tragedy. I'm not the first person on this podcast that said it most recently Dr. Jordan Emond, one of the most important conversations I think I personally have had on the podcast to help dispel a lot of misinformation around hormones. He even talks about the tragedy of the WHI Today we're specifically talking about oral micronized progesterone available as Pometrium You can also get bioidentical progesterone in a compounded version as well. If you need the sustained release version, which is what I take, makes a big difference If you have a peanut allergy, you cannot take the oral micronized progesterone, you have to get something that's compounded The safety record for progesterone is real. There was an E three N cohort of over eighty thousand women, found no increased breast cancer risk with micronized progesterone plus estrogen. And the twenty twenty three JMA review treats continuous oral micronized progesterone as a mainstream guidelines supported option. What we are integrating today is not whether to use it, but how to use it well. That's the distinction. Allopregnantalin is what we're going to talk about next. It's a metabolite that changes the conversation around progesterone And when we take oral progesterone We get a first pass liver metabolism that converts a significant portion of progesterone into alopregnetalone It's a neuroactive steroid that acts directly on brain tissue. Again progesterone is broken down into allopregnetalone. And you can actually put the same progesterone that you take orally in the vagina or even rectally. and the first pass metabolism is largely bypassed That first pass metabolism occurs in the liver. If you put the And this is not medical advice, but if you are directed to use progesterone vaginally or rectally, You don't, it's not bypassed. It doesn't go through the limver Here, the drug will concentrate in either uterine tissue or rectal tissue and produces almost no allopregnant alone And this is basic pharmacology. Anyone that is healthca care knows that the rectum is incredibly vascular, which is why there are a lot of medications that we give there. Some women do better having P rectal progesterone, some people do better with having it placed vaginally In fact, when I was going through infertility treatments, when I was first pregnant I was required to use intravaginal progesterone for my first trimester and then moved on to not having to use it for my second. So it is a very bioidentical, bioavailable way to take it. So there's this Gaba A mechanism that I know that Dr. Sarah Zal, formerly Dr. Sarah Sarah Godfried, talks about in a really great recent sububstack article. If you don't follow her on sububstack, you should she has just a brilliant writer and medical expert Allopregnal is a potent positive allosteric modulator. This is a fancy way of saying It's a modulator of this GabBa A receptor the same receptors targeted by benzodiazepines, things like Aavan, valium Xanax, barbituates and alcohol The FDA actually approved brerexenolone, a synthetic form of allopregnantolone in twenty nineteen for postpartum depression based explicitly on this GABA A mechanism. This is mainstream neuroscience, not fringe pharmacology promoting an anti anxiety affects women experience on bedtime Oral progesterone are largely a byproduct of the allopregnantolone GABA A mechanism in action That is what helps me fall asleep It's a beautiful thing Lately, I've been falling asleep so quickly. My husband has found that I have a book on my lap or I end up having my iPad if I'm maybe like scrolling through reels. and I know I should be off electronics at bedtime but sometimes I need my brain to unwind before I go to bed Let's talk about what normal allopregnantolone levels look like across a woman's lifetime. So This is the context most clinical conversations are missing entirely and without it, the HRT numbers are largely impossible to evaluate or meaningless. So in the follicular phase when um, Estrogen predominates, the first half of our menstrual cycle, alope pregnal levels are low. tyypically in the range of zero point five to two Millie Osmoles per leaditer. In the luteal phase after ovulation, when progesterone rises alopregnantalone, rises with it, typically reaching four to six in a healthyle. Now I'm looking at paper because I don't have all these things these numbers committed to memory. This is the range in which the body has evolved to experience its neurological effects. In pregnancy, allopregnantalolone rises dramatically, not surprisingly, Reaching levels of fifty or higher in the third trimester. This is the highest the body ever naturally produces, and it corresponds to the profound sedation and mood changes many pregnant women experience Okay, after menopause, without any hormone therapy, alopregnanaline falls to approximately zero point five to one. Eesssentially follicular phase levels are lower because there's almost no progesterone being produced for conversion. Okay, this makes sense, right highest in pregnancy highest in the luteal phase with the exception of follicular phase and then the post menopause phase So where does oral HRT supplementation kind of fit into it here? So a standard one hundred milligram oral micronized progesterone dose produces a peak allopregnantalone level of approximately four to ten at roughly two hours after ingestion. So it rises quickly and falls, which overlaps with and modestly exceeds the upper end of the natural luteal phase range Something I hear constantly from women in our community and something I understand personally is this. Nothing about your effort has changed and yet our bodies are responding differently. Your midsection feels different. your blood sugar is much less stable and your cravings may have shifted. And let's be honest, your energy probably isn't what it used to be As a nurse practitioner with over twenty five years of experience, I want to be completely transparent with you about why Estrogen is one of the body's master regulators of metabolic health The influences how we store fat, how our tissues respond to blood sugar changes, and how efficiently our metabolism functions at the cellular level As estrogen shifts during perimenopause and menopause, the same lifestyle choices, diet, exercise, sleep genuinely do not produce the same results. This isn't a failure of effort. 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Again, that's timeline dot com and use code Cynthia for twenty percent off your order This is one of my foundational supplements that I never miss A twoor milligram oral dose, also commonly prescribed, produces peak levels of approximately ten to twenty, meaning fully above what a normal allial phase produces in most women And these peaks are transient, I want to make this really clear. They go up quickly, they come down quickly. Allopregnalone falls as the oral dose is metabolized, but a postmenopausal female taking t milligrams oral progesterone nightly is experiencing a nightly spike into a range her brain has not been exposed to since her reproductive years. And in some cases, into a range it is never experienced outside of pregnancy So again, very bioindividual This is clinically significant for two reasons. Number one, a menopausal brain, and I'm going to knock out the post. We'll assume if you're in menopause, you're in post menopause. A menopausal brain that has been operating at near zero allopregnenalone for years may be more sensitive GBA A receptor activation than a pre menopausal brain that has experienced regular luteal phase fluctuations The continuous nightly repetition of that spike removes the cyclic rhythm the body was designed to operate within. So let's back up. We're talking about the differences between fluctuations of hormones during a normal menstrual cycle, and I'll just say normal air quotes versus continuous oral use of progesterone in menopause And for a lot of women in perimenopause, so we'll include that as well I personally take My progesterone six nights out of the week and I take a break one night out of the week. I always make sure that the night I don't take progesterone is not a night where I have a super busy day Every once in a while, when I don't take progesterone, my sleep is a little bit fragmented or disrupted I can talk to you about what I do now to ensure that doesn't happen. That is what my provider and I have talked about. We have talked about the conversation that I had with Dr. Gersh I respect dor. Gersh enormously. Obviously, when I listened to that conversation, I was like, I understand why my community has so many questions Hence why I went down and did a deep dive. like this is several weeks worth of research pulling together this conversation. numberumber one to address listeners' questions, number two, to make sure that I'm giving you a lot of salient details that would probably be helpful in filling in conceptual gaps Okay the regulatory stealing the body builds in that oral progesterone bypasses. So this is an important like concept I want everyone to get In a normal menstrual cycle, your body has a built in regulatory ceiling on allopregnantalone production. As progesterone rises in the modial phase, enzyme five alpha reductase becomes saturated. So it's like soaking everything up like a sponge caausing the allopregnantolone to progestion ratio to drop roughly eightfold The body is specifically designed to prevent allopregnantin from climbing disproportionately. This is your body's brakes, okay When you take oral progesterone, the substrate goes through a through hepatic five alpha reductase, which is not subject to the same saturation kinetics. So again, there's not a sponge in the oral dosing that you're getting in perimenopause or menopause The result is a metabolite profile where allopregnantone climbs disproportionately in a way your own ovary was designed to prevent. So we have a sponge when we're in our reproductive years, and then in menopause, we do not that's kind of breaking this down This is not just the oral progesterone produces more allopregnant alone. It's that the bodies own biological safeguard for keeping the ratio in check bypassed. And the concern is not about any single dose. Let me be really, really clear. It's what the continuous daily repetition of that transient peak. does to G Gaba a receptors plasticity, so how well they effectively work over months and years in a brain that is starting from near zero baseline Now, that's a lot to absorb. I've had to like intellectualize this. I've had to have conversations with my prescriber, doctor Aaron Hartman. We've had some very vibrant discussions about this. And I think we have come to the conclusion that we don't know enough yet to make any changes to what I am currently doing. And this is not medical advice. I just encourage you If you are listening and you are one of a hundred different people who sent messages to the podcast, to understand, I'm trying to walk you through the physiology to understand what we're speaking to and then evoke questions for you to have with your own prescriber. okay. What does the human research actually show So obviously there's sedation and in certain people, some degree of memory impairment. There are multiple human studies documenting sedation and measurable memory impairment from oral progesterone in doses of one hundred to two hundred milligrams, which is considered to be You know, those are baseline doses. A double blind placebo controlled functional MRI study found that a single oral progesterone dose decreased recognition, accuracy and reduced amygdala and fusiform gyrus responses during memory encoding And critically, this effect was independent of sedation suggesting a direct GABA A effect on memory consolidation. Okay. Now there's this bimodal mood effect that most clinicians have probably not heard of. and I want to just say that this is less common to see. We know that Ala Pgental has a documented U shaped dose response for mood at certain concentrations, it paradoxically increases anxiety and irritability rather than reducing it I know from conversations I've had with multiple medical experts You know, this could be anywhere from ten to twenty percent of the population prevence, according to the research that I looked at, it's three to eight percent of women experience severe paradoxical effects Many of you have talked about this in your questions, anxiety, irritability, mood instability, and up to twenty five percent experience moderate symptoms. What you're experiencing is real, I'm not discounting that. I'm just saying that most people do not experience these things, but this is where bio individuality really plays a role One in four women on oral progester may experience a documented biological response that is being attributed to menopause, stress or anxiety rather than the medication itself And these numbers mirror PMDD. so peopleople had the worst manifestations of PMS prevence precisely the mechanism is the same. So interestingly enough if the allopregnenal and level context matters here too, the paradoxical negative mood effects tend to emerge most consistently in the four to six range, which is exactly where the standard one hundred milligram oral doses often land Mean women on lower doses of oral progesterone may paradoxically experience more mood disruption than women on higher doses or no progesterone at all, right? Mind blowing. o Tolerance and receptor adaptation. This is where a lot of questions came in. bothoth acute and chronic tolerance to allop pregnant and develop at the receptor levels. Remember I mentioned earlier During a normal menstrual cycle, there are mechanisms to blunt, so you get this oversaturation of receptors. We don't have that in menopause where when we're no longer producing as much progesterone And so this tolerance that can build up, it says women with PMS and PMDD are thought to develop this tolerance more rapidly. This makes sense. And the parallel to continuous oral progesterone is direct. If a woman's own naturally producing allopregnola across a single menstrual cycle can produce tolerance, what is happening in women taking oral progesterone continuously for months or years Research has also found that twenty four hours after progesterone withdrawal, the GABA the GABA potentiating effect of Lurzepam, which is a benzodiazepine falls drastically, in some cases disappearing completely, demonstrating that progesterone withdrawal meaningfully alters GABA A receptor sensitivity. Okay, so let's dor. Gersh Dr. Gersh believes in physiologic dosing for women in menopause. And she feels strongly that this is what makes sense to her and this is what she advocates for. I personally do not want to get a menstrual. I don't wantan to have a cycle of any kind in menopause. I prefer not bleeding. This is me personally, again, not medical advice. If you feel differently, then talk to your prescriber. Okay, so in our reproductive years During our menstrual cycles, progesterone is cyclical just like estrogen is. We have about fourteen days on with progesterone and fourteen days off. And that GABA A receptor is designed to experience allopregnantal in the same rhythm pereriods of modulation. followed by periods of downregulation. Dr. Gershch believes that cycling progesterone even a menopause honors this physiologic rhythm, giving these GABA receptors the periodic rest that continuous dosing removes and typically anywhere from twelve to fourteen days of oral progesterone per month alongide continuous estrogen The thought process is that when you're off of progester and the allopregnal levels go back to baseline And uterine protection is maintained with adequate duration and dose Some women on cyclical progesterone will experience a withdrawal bleed. This is expected and again, should be discussed if you are one of these individuals. Now, doctor Zal, like I mentioned, did an excellent recent progesterone substack article. and she is just like, I think of the same way with doctor Gerh, just a leading voice in women's health Bard certified UIN, And she confirms the metabolite ratio is non physiological, meaning that continuous dosing of progesterone eliminates the cyclical receptor recovery that the ovary has built in, remember the sponge. Just think about the ovary and the sponge. And a meaningful subpopulation of women are going to respond badly. Three quarters of the women that are listening that are on oral progesterone. You love it. It makes you feel good, you fall asleep Things are over Another twenty five or thirty percent of you feel very differently. And this is what Dr. Saul is speaking to Standard doses do not produce sustained superphysiologic allopregnantola. Remember I mentioned that you get a peak in one to two hours. The peak is transient The concerns about continuous daily repetition, not catastrophic individual dosing Her bottom line aligns with Dr. Gersch's clinical frame route, the route, the dose, the cycling pattern, and who you are as a patient matter more than any global answer. bio individuality rules and your conversation with your prescriber is going to help you make decisions. Okay Doctors All talks about how you can test this five alpha reductase testing tool. So One of the most useful advances in individualizing progesterone prescribing is a urine test for five alpha reductase activity. That's the enzyme that converts oral progesterone into allopregnantalone Women with high five alpha activity will convert more oral progesterone to alopregnantolone and are more likely to experience the GABA AFects, the sedation, the cognitive blunting, mood changes and most likely to generate peak levels at the upper end or above the luteal phase. So women with low activity, so on the other end of the spectrum under convert and producing allopregnmentaline levels well below the luteal phase range, it may respond better to vaginal progesterone or even rectal progesterone notot because these other routes are inherently superior, It's because the enzyme profile means oral is not being efficiently converted And this is very much precision medicine. This is bioindividual approaches This is why this is a very nuanced conversation. The other thing to consider is there is a gut connection. Allopregnoline story begins in the gut. That's the first pass effect, but gut health directly also affects first pass metabolism. You hear me talk about the gut microbiome ad nauseum, but the microbiome influences hepatic enzyme activity and the enterohepatic circulation that determines how efficiently oral progesterone is processed twowo women taking the same one hundred milligram progesteronese may produce allopregnanalone levels at opposite ends of the range. This is important. One landing in the very high four to six range, one clearing though very quickly, based on nothing more then the difference in their gut health and hepatic enzyme activity Gut restoration is not just a gut health intervention. 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Please support our show and tell them We sent you Okay So if you are having a lot of these symptoms, excessive sedation, or if you feel like you're not as sharp cognitively after taking oral progesterone, you might be one of these people If you have mood instability or anxiety particularly in women with significant histories of PMDD or bad PMS that may begin or worsen after starting oral progesterone especially at lower doses. The sense that initial benefits have diviminished over time without a dose change, I've had patients tell me that. like, o, I felt like I did really well on progesterone for a long time and then it stopped working. Or if you're waking up foggy, you feel like your mood is flat and you're struggling to wake up or you feel emotionally muted rather than rested. It might be a sign that there's something more at play. So Some practical options. Number one, you can think about different routes of administration, vaginal or rectal, cycling it twelve to fourteen days per month with a clinician who actually understands the uterine protection requirements, especially if you're on estrogen Dose optimization, sometimes you have to go higher in dosing, sometimes lower in dosing can make a big difference fiveive alpha reductase activity testing to guide the oral versus vaginal decision. Usually that's done with a Dutch test. Gut restoration, microbiome testing, stool testing, all can be very helpful I want to be really clear. This is not telling you to change anything. This is asking you to check in with yourself, How was your sleep? Do you feel like yourself If there's anything in this conversation that's setting off alarm bells in your head or you feel like your protocol's not working for you I want you to have a conversation with your prescriber and being very clear that the conversations that I had with Dr. Felise Gersch and I've had with Dr. Zal for many, many years, and they're different in very complelimentary ways. They represent the most clinically honest enngagement with the progesterone question, I've encountered in years of working in this space Dr. Gersch is asking us to take the allopregnellone mechanism seriously as a reason to rethink continuous oral prescribing. Dr. Zal is fact checking the most alarming claims while validating the core concern and giving us a precise biological tool in five alpha reductase testing that moves us from theoretical into individualized medicine. So there's very much a bio individual approach here. There's very much of how do you feel personally