Understanding Progesterone: Myths, Science, and Health Impacts
In this long‑form Menopause Mastery episode, Dr. Betty Murray demystifies progesterone for perimenopausal and menopausal women. She begins by explaining the natural hormonal cycle, emphasizing that progesterone declines steadily from the late 30s, preceding estrogen fluctuations. Dr. Murray distinguishes bioidentical micronized progesterone (the hormone the ovaries produce) from synthetic progestins used in birth‑control pills and older HRT formulations, noting that synthetic progestins raise clotting, stroke, dementia, and cancer risks, whereas bioidentical progesterone appears neutral or even protective. She reviews human clinical evidence: oral micronized progesterone at ~300 mg nightly improves vasomotor symptoms (hot flashes, night sweats) and markedly enhances deep‑sleep architecture without inducing depression. The KEEPS and KEEP trials show no cognitive harm and mood benefits, while a 2018 meta‑analysis finds overall neutral cognitive effects. Dr. Murray explains the pharmacokinetics – first‑pass liver metabolism creates the neuroactive metabolite allopregnanolone, which acts like GABA to promote sleep, but its effect follows an inverted‑U curve, causing paradoxical anxiety or mood worsening in some women, especially those with certain CYP2C19/C9 genotypes or a history of PMDD. Route matters: oral delivery yields higher allopregnanolone levels (good for sleep) but may trigger the U‑shaped response; vaginal delivery bypasses first‑pass metabolism, offering higher progesterone bioavailability with fewer neuroactive metabolites, useful for women who react poorly to oral dosing. Cardiovascular data are mixed – short‑term oral progesterone may improve endothelial function, yet a small study suggested it could blunt estradiol’s vascular benefits in young suppressed women, a finding not generalizable to menopausal women. Dr. Murray critiques the misuse of animal studies (mouse/rat data showing hippocampal shrinkage) for human conclusions, urging clinicians to prioritize human RCTs and meta‑analyses. She discusses dosing strategies: continuous low‑dose (e.g., 100 mg daily) versus cyclic higher‑dose regimens; continuous dosing is endorsed by FDA and societies for practicality and comparable safety, while cyclic dosing has older endometrial safety data but no clear superiority. Endometrial protection requires progesterone when a uterus is present; oral and vaginal routes are effective, topical forms lack robust data. Finally, she emphasizes personalized therapy—considering genetics, metabolism, symptom profile, and patient preference—and encourages women to seek clinicians knowledgeable about bioidentical progesterone and to question one‑size‑fits‑all protocols. The episode concludes with a call to action toward individualized, evidence‑based hormone care through Minerva.
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So there's a new controversy online, and it, you know, I would say maybe if you're watching and listening to menopause conversations, you might have heard it. It's the whole idea that progesterone is either completely safe and does very benign in the body, or that progesterone should be cycled, or we should be concerned about it for cognitive health. So today on Menopause Mastery, what I'm going to go into is the actual science around progesterone, what it does in the body, what the different forms of progesterone and synthetic forms do, and especially how you can use progesterone in perimenopause and menopause to support cognition, sleep, overall mood. And we're going to go into it deeply. So here's the first thing I want you to know. When we hear all those conversations, whether it's progesterone is completely benign and is great for sleep. They're right. Progesterone has been shown to affect memory in certain situations. It's also right. However, there's caveats, and so I want to go through both of those camps. So let's get into it. So let's start with the basics because I want to make sure that everybody has that. So most think— most people think of progesterone as a pregnancy hormone, and yes, it plays a massive role during pregnancy. By— and in a, particularly in a cycling woman, progesterone does a whole lot more. And especially when we look at the balance of estrogen. So when we are a cycling woman, our estrogen peaks and valleys throughout the month, and so does progesterone. And progesterone's major peak is in that second half of your cycle called the luteal phase. Here's the thing, progesterone supports bone density, It supports your thyroid. It supports your mood. It has a calming effect and it protects against cancer. So what happens when we get in perimenopause? So menopause, often long before you really get to the chaos zone of missed periods and those kinds of things, progesterone is already on the decline and it is the first hormone to decline. And estrogen, you know, fluctuates wildly. I like to call it the bungee cord. But progesterone has a relatively steady decline starting in our late 30s and early 40s. And this is why we see fertility issues. You know, I think one of the first things that I thought was crazy was, you know, I was sitting in class, and, you know, years ago, and one of the professors said that, you know, a 30-year-old pregnancy was considered a geriatric pregnancy. And at the time, I was, I was probably right in that range. I had just gone back for my first master's. And I was like, what? Because at the time, I couldn't even— I was, I was still like, I don't know if I want kids or not, but I don't really think I'm ready for kids yet. So, so the reality is, is progesterone can decline quite quickly, and it starts to drop really in those late 30s. So, so estrogen obviously fluctuates wildly later on. But here's the first thing I want to clear up. Not all progesterones, and particularly when you call them progestins, are the same. So progesterone is a bioidentical form of your hormone that your ovaries make in the second half of your cycle after the egg shoots out and goes on its little trip down to the uterus going through the fallopian tubes. Progesterone is, is actually made when the egg shoots out and the follicle compresses on itself. And then that actually is what makes progesterone. Now, progesterone can also be replaced synthetically, right? So we have, we have birth control pills and birth control that is a synthetic progestin or progestogen, and we have synthetic progestins that are also used in older forms of hormone replacement therapy for women.. And those types of hormones are very different than the micronized, biologically the same, bioidentical progesterone. And synthetic forms are very, very different. Now, this is the form— the synthetic form in Prempro is what was in concern in the 2002 Women's Health Initiative. The synthetic progestin is the, is the actual ingredient that increased clotting risk and stroke risk, especially in older women. It's also been associated with increased risk for dementia, cancer, and having negative effects on the brain. Bioidentical micronized progesterone does not, and it does not show those same risks. In fact, a study coming out of France— it was an 8— French— a study coming out of France for 8 years, it was a cohort study, looked at bioidentical progesterone and it was associated with lower breast cancer risk compared to the synthetic progestins, and possibly even lower than people who went on no treatment at all. So what's the take-home message? Synthetic progestins, not good for you. Bioidentical progesterone, good for you. Maybe cancer protective. It may be cancer protective compared to doing nothing at all. So when your doctor says something like, the research shows hormone therapy causes cancer, then the next thing you should ask is, which one are you looking at? Because progestins, synthetic forms, are associated with all negative connotation with hormone replacement, because the answer changes everything. So when we're talking about hormone replacement today, whether we're talking about what we're doing with Minerva in all 50 states, when we provide bioidentical hormone replacement for women, or whether we're looking at the clinic I've had for 20 years, we only use bioidentical forms because it is not the type of form that we would use a synthetic in. And specifically, oral micronized progesterone is what most of our patients use. And it's the route of administration that gets really important, which I'm gonna get to in just a second. So let's talk about what the research actually shows. So the research actually shows that bioidentical micronized progesterone is helpful even in hot flashes and night sweats. Now, many of you may have thought that estrogen was the only hormone that played a role in vasomotor symptoms. So that's the hot, you know, hot flashes, night sweats. But the evidence is actually pretty solid that oral progesterone in much higher doses than what we would normally think of at about 300 milligrams taken at bedtime reduces hot flashes and night sweats. One randomized controlled trial showed a 58.9% improvement in hot flashes and night sweats over 3 months compared to 23.5% in the placebo group. Another study showed 55% decrease overall, with even better results in women who had 50 or more moderate to severe hot flashes per week. Okay, that's— that is a game changer. So for a lot of women who may have been told that estrogen is their only choice if they have vasomotor symptoms, and maybe their doctors are gatekeeping hormones because we know 4.8% of women who are in the age range to get hormone replacement in the United States are actually receiving it. And so a lot of times doctors will gatekeep and they tell you you can't have your estrogen, you can't have your progesterone either. Well, the reality is, is even Even in a woman who might be experiencing sleep, those higher doses of 300 milligrams of progesterone may help with just the hot flashes and night sweats, you know, as a whole. Now, I want to be honest with you because you deserve that. A more recent Phase 3 trial in perimenopausal women found that the primary outcome vasomotor symptom score didn't technically reach what they call statistical significance. And here's what's interesting. Women in that study did report significant improvements in night sweats and sleep quality, but the study was what they call also underpowered, meaning it didn't have enough participants to detect a difference or a smaller effect. So the evidence is really actually strong here, and it's— but it's not perfect, right? So it's real talk here. And so what does that mean? I want to make sure that we— that you understand that, because what happens is especially somebody online, an influencer that's trying to gain traction, will pick up a study like this study about vasomotor symptoms and say progesterone didn't show statistical significance. And they don't clarify it by saying, hey, there wasn't actually enough participants for us to distinguish the difference between nothing at all and progesterone, which is essentially what that meant. And so the details matter. And that's why you listen to me, because I'm here to give you the actual scientific details. So, the take-home message on the first part, vasomotor symptoms are definitely better, probably at higher doses than your doctor may be prescribing if you're perimenopausal or menopausal. So, if you're still having hot flashes and night sweats and they have you on 100 or 200 milligrams, you may need to float up to that 300-milligram dose. Now, probably the most powerful, powerful indications for progesterone is sleep. This is where oral micronized progesterone really shines. So multiple randomized controlled trials confirm around 300 milligrams at bedtime improves deep sleep, not just falling asleep, but deep sleep, the quality of sleep architecture. Just because you pass out and your eyes are closed doesn't mean you actually got restorative sleep. And if you wear any of the little fun tools, you know, you might find out that your deep sleep is poor, right? And so, a lot of women have problems with sleep architecture. And, the other thing that was interesting in some of these randomized controlled trials is that it didn't cause depression either. You know, there was some indications at one point that it might cause some depression. But, so women were told prior to these studies that if you take progesterone in these higher doses, it might make you depressed. Well, we didn't find that in these randomized controlled trials. That's a, that's a conflation and a commingling of the synthetic progestins research and the progesterone research. So the take-home message here is higher doses, the 300 milligrams of progesterone micronized, can help with sleep architecture. And when it's taken orally, and here's the reason why, oral progesterone when it's micronized gets metabolized in the liver through what we call first-pass liver metabolism into a byproduct called allopregnenolone. Allopregnenolone has a natural calming effect in the brain. It works like your own GABA, which GABA is your brain's neurotransmitter that's kind of like your body's natural Xanax. And when you trigger GABA activation, it sort of switches the nervous system off. And so this is huge for women. There was a trial called the KEEPS trial, It was a 4-year randomized trial looking at 693 recently postmenopausal women, and it found that oral micronized progesterone showed no cognitive harm and actually produced more beneficial mood effects with improvements in depression and anxiety. And that's 4 years, 693 women. That's some real data. Now, one of the other areas that has a, a little more nuanced picture is Cardiovascular health. The cardiovascular picture, like I said, is a little more nuanced. And this is where we want to really pay attention because there's some genuinely sort of conflicting data here. Short-term studies show that oral micronized progesterone appears to be safe and helps cardiovascular function and may even improve endothelial function, which is the lining of your blood vessels. And that's the area that gets damaged, especially when estrogen declines. We see inflammatory processes like highly sensitive C-reactive protein. We see destruction of the glycocalyx, which— think of that as these little hair-like structures in your, in your arteries that swing back and forth when your heart beats, and they actually produce nitric oxide. So, when we start to go through perimenopause and menopause, we see huge vascular changes in women, and that's why women have the greatest risk of dying from stroke and heart attack. Now estrogen has clear indication here, particularly given early in the process, but progesterone seems to affect that. But there are some studies that show differently. So observational data like the one found in the E3N study cohort suggested that transdermal estradiol— so that would be your patches— with oral micronized progesterone does not increase venous thrombosis risk. What does that mean? So when we combine a topical estradiol with an oral micronized progesterone, we do not see increased risk for stroke and heart attack due to blood clots. We do see that with synthetic progestins, and that's a big, big deal. But in 2011, there was a study conducted by Miner and colleagues, and they found that oral micronized progesterone actually abolishes the beneficial effects of estradiol on blood vessel function in healthy young women. All right. So let me clarify some of this because this is really important. This was, number one, a short-term study in younger women who didn't really need progesterone to begin with. They were still cycling. And this is in women that had suppression of their hormones.. And it— so they had basically clinically suppressed hormones, then added these hormones back. Whole lot of things going on here. That is not the same as going through natural menopause and losing ovarian function. That does not apply to a perimenopausal woman who has natural reduction in progesterone, and it absolutely doesn't apply to a postmenopausal woman. So we have to recognize that you can't generalize that. Which generalization, when you're talking about a study, means can I take the context of this study and apply it to a larger group? It's not generalizable, right? So you can't take that. And but it is worth noting, it's like, okay, that's a signal that's interesting. We need to do more studies there. And interestingly, when you look at vaginal progesterone, which was studied instead of oral, that antagonistic effect disappeared. Which tells us the route of delivery matters. So what that means is, is maybe in a cycling woman who's way before menopause, adding a vaginal form of progesterone has zero effect. But, and, but maybe, you know, if they're especially on something suppressing ovarian function like a birth control or something like that, but that it's different in older women. Now, I'm going to come back to this oral versus vaginal because this is where a lot of this stuff comes up.. But I want to talk about the brain because this is where the real controversy lives. And lately I've seen a lot of really well-meaning practitioners. Some of them are luminaries in this space and then other influencers conflicting and conflating some of these studies. And I want to spend some real time here when we talk about the brain because this is where the confusion comes in. And it's really, really frustrating because it's an oversimplification. On both sides. So you're going to hear two versions of the story. Version 1: progesterone is neuroprotective, helps with working memory, calms the brain, protects against Alzheimer's. Version 2: progesterone impairs memory. It shrinks the hippocampus. Long-term studies show cognitive decline. How can both be true? And the answer is they're citing different types of studies., and mixing them up is doing a disservice to women and really, really, really is unethical. Okay, so what are the human studies? That's an important word, human, actually show. So let's start with human data because that's what matters most in clinical decisions. Yes, we use mice and rats in studies, particularly looking at efficacy and toxicity studies, because we don't want to start medication studies in humans We use animals. I'm not happy about that. I'm an animal person too, but we use animals to test for toxicity and safety before we try it on humans. Well, I hate to tell you, you're not a mouse and you're not a rat, and we don't metabolize things the same. There's some similarity because we're both mammals, but that's where it stops. All right, let's start here with the human data. A 2018 systematic and meta-analysis review So what that means is they systematically looked through all of the research and pulled it all together. And a meta-analysis said they, they like looked at all of it and then they threw out the studies that were underpowered or weren't really well done and kept the studies that were most, most valid. And they specifically looked at progesterone and human cognition. And it concluded— and I'm going to quote it here, so I got to look at it— the quality of the evidence is low, "But overall findings do not reveal consistent clinical important effects of progesterone on cognitive function in women." That's the honest summary. No dramatic harm, no dramatic benefit, largely neutral for women with some benefits in mood and sleep and cognitively related function, particularly around the sleep thing. So what's the take-home message? When we take the totality of all the studies out there, progesterone is benign, probably helps with sleep, probably helps with cognitive function. There's no major drama here. Now, one of the studies I mentioned before is the KEEP study. This is a 4-year follow-up study in women using oral micronized progesterone, and they did it cyclically, right? So instead of having a woman taking it continuously, they cycled it. They found no cognitive harm. None. Now, here's where it gets nuanced. There was a study in 2008 done by Kask and the colleagues, several people. This one I want you to pay attention to. It wasn't oral micronized progesterone. It wasn't even synthetic progestins. They gave intravenous allopregnenolone, right? So they gave the byproduct in an IV form to the women that your liver makes, which is dependent on your genetics and your detoxification pathways. Okay, which that is the main metabolite of progesterone. And then they tested their memory, right? What they found was episodic memory, your ability to remember specific events and experiences like right here, right now, what's happening, was impaired. However, working memory and semantic memory was completely unaffected, right? So the long-term memory and other things. Now, this is really important before you panic. This was an intravenous injection. Not how your body makes it. There's no brakes on how much hit your bloodstream. Right. Which creates a huge spike, huge spike, which is very different from when you take oral micronized progesterone. It goes through your digestive tract, goes to the liver, and gets metered out by the liver in the normal pathway of metabolism. So that is hugely variable when you're injecting it. And some women were barely affected, right? So others were more sensitive to it. Right now. That's why it's really important. So some women took the intravenous shot, didn't have any memory issues, felt great. Other women were really affected by it. And this is where it becomes important, because this is a signal that there may be differences between women and the metabolism of oral micronized progesterone, or their own progesterone. So here's the biological puzzle at the center of all this: allopregnenolone, the metabolite your body makes from progesterone, follows an inverted U-shape, right? We love to talk about this. So what it means at low levels, it can increase anxiety and irritability. At the middle range, specifically around where you get to kind of that second half of your cycle called the luteal cycle, at that middle range, that can cause a paradoxical negative effect in susceptible women. So let me help kind of clarify this for you. So some women feel awesome. Until they ovulate and they hit the second half of their cycle. And then they are moody as hell, right? That's where PMS comes from. Premenstrual syndrome is the variation of progesterone in the second half of your cycle. Then you have PMDD, premenstrual dysphoric disorder, which is even worse, right? This is that U-shaped curve. We're probably okay until we get to here. And then as it starts to come up, we get this paradoxical effect in some women. This is not a small quirk. Some women feel amazing on progesterone— calm, sleep better, less anxious— and some women feel like they're coming out of their skin. And that's not where the research is wrong. It's the individual metabolism, where I spent my research and my PhD, of how our body takes that stuff through the liver and processes it that is enormously impactful here. And this is what's the conversation that's missing from prescribing. Absolutely. And, and never talked about in the nuance of social media. So women who have a history of significant luteal phase disruption, PMDD, or a history of depression show changes in how they convert progesterone to allopregnenolone. They may have a much higher access point of the enzyme 5-alpha reductase which means they make more of that metabolite and it hits them, that metabolic range, that middle range that starts to hit that U-shaped curve. And that, if that's you, that's something you and your clinician need to talk about, right? And here's where it gets misleading and the animal studies come in. So this is where the animal studies can be very misleading, and there are several well-known clinicians talking about these studies, and they're mixing animal studies with human studies. And I want to be clear about this. This is where the alarming claims come through. So if you've heard alarming claims about progesterone and brain, they're all coming from animal studies. I don't know about you, but I don't have a long tail, and I don't hide in, in roofs, right? I'm not a rat. So there was a 2016 mouse study that showed that long-term continuous use elevation of allopregnenolone caused memory decline and caused hippocampus to shrink. That's part of your brain. It's very important to memory. That's a frightening finding. And it has been used to argue that long-term oral progesterone therapy is dangerous for brain health. But again, before we jump to conclusions, this is a mouse study. Mice metabolize hormones very differently than humans. Allopregnenolol was administered continuously, not at normal physiological levels, not at levels that happen in a mouse. It was given continuously, and that doesn't replicate how our body makes it, and it definitely doesn't replicate how it would be done with oral micronized progesterone. And crucially, we haven't been able to find that in humans in randomized controlled trial. The 4-year KEEP study didn't show it. Human observational studies haven't shown it. I'm not dismissing the animal data. What I'm saying is in science, animals help us generate the hypotheses. Could this be true or not? The warning signals, but they are not a substitute for human evidence, and they should be used only to identify those things. They should not be used to scare women, and they should definitely not be used to scare women just so I can get more likes on Instagram and cause more confusion for the 60% of women who are in perimenopause and menopause today that cannot get the answers they need because they are unclear about what's really happening with their body. So when we see a claim about hormone therapy and brain health, my first question is always, uh, is it a human study, a mouse study, or a rat study? Because if you're showing up with something else, the receipts are wrong. I only look at human studies when I'm trying to draw a human conclusion. So the, the honest answer right now, which is unsatisfying, and it's the one I've been harping on and why we're creating Minerva, it's why we're creating our technology, because we're going to fill the research gap. We need more long-term studies on women, particularly around progesterone and cognition. And we have reassuring short-term to medium-term data and long-term use and biological mechanisms that point towards neuroprotection, and especially for most women, and especially for women that take it and see a positive effect on sleep and anxiety and mood. Now, how you take it matters. All right, so I promised I would come back to this because we have the oral micronized progesterone. But what if you're one of the women that you, you get that weird U-shaped curve where you take it and you're anxious and you can't sleep? So this is when you take oral micronized progesterone orally, and you take it typically at bedtime, and it goes through your gut and your liver, and then it goes into the bloodstream as allopregnenolone and all those other metabolites, and then they cross into the blood-brain barrier and do their thing. This is called first-pass liver metabolism. And during that process, your body converts it to that very important metabolite. And this is why oral progesterone helps sleep. I'm going to tell you something. I forgot to take mine last night. I take a lot of stuff at sleep. I'm gonna be honest, I woke up at 2 and I was like, damn, because I knew I wouldn't get back to sleep. And, and so I went and took it in the middle of the night to help get me into sleep. It's that impactful for me. Just missing it once will affect my sleep. Progesterone and its metabolites also have a very short half-life. So progesterone in its micronized form is going to get absorbed and utilized rapidly in about 4 to 8 hours. The half-life is about 4 hours. We can also do compounded sustained release in somebody that might metabolize it more quickly because again, we're not all identical. We're genetically different. All right. So when you take progesterone like this, you're getting that GABA effect from the metabolites. And that's a feature, not a bug for most women. But for some women, particularly those again that had depression history, PMDD, or highly sensitive to those progesterone metabolites, oral delivery may be very problematic for them, and it's because they're in that middle zone. So we can use vaginal progesterone, which bypasses liver metabolism completely. You get higher bioavailability, about 10 to 40 times the bioavailability as taking it orally, and you produce far less metabolites systematically. So you're not going to see that high rise in allopregnenolone.. So you get more of a pure progesterone effect and less allopregnenolone. Now, this is really important because if you're a woman in perimenopause and menopause and you have a uterus, you got to use one of these two forms, right? We have to have progesterone in because one of the major things progesterone does is it suppresses the proliferation effect and the blood-bringing effect of estrogen into the uterine lining. If you have a uterus and you take estrogen without progesterone, you will get an increase in uterine lining growth that can become hyperplasia, that can increase estrogen-sensitive cancer risk in the uterine lining. It's not because estrogen's bad. It's not because progesterone's bad. It's because you're not doing what your body naturally does. So for the women who are really sensitive to the oral progesterone, We can use vaginal progesterone and it works great, but it has limited evidence for hot flash relief, right? So using it vaginally doesn't seem to affect the motor function and the vasomotor symptoms as much. However, if, if your symptoms are not hot flashes and night sweats, or if you're on estrogen, we often see an effect of that anyway. You can absolutely use vaginal protection to get that endometrial protection also. And you can use topical forms, creams or oils that you can rub on the skin. However, we don't have solid research showing that topical forms of progesterone have the protection for the uterine lining, which is extremely important. So I was speaking at the Women's Wealth Summit this weekend and it was great. It was International Women's Day. I'm super excited and I got a chance to answer a few questions. And one of the questions I got as I stepped off the stage was, 'You know, do I have to take progesterone?' I was like, 'Girl, girl, you want to take progesterone in one way or another.' But we want to make sure we're getting what it does, which is protect the uterine lining. And in those that don't have a negative side effect, the brain effects of progesterone. So the truth is, the topical forms don't have really strong evidence. And here's why. The topical form of progesterone— progesterone's a big-ass molecule, right? And so we micronize it to give it orally so you can actually absorb it and break it down and utilize it in topical forms. It doesn't, it doesn't make it through the skin very well. And so our preference is generally the oral form or the vaginal form. Now, we also use with Minerva, we also use a bioidentical form in jojoba oil for people that are sensitive to all forms, and it absorbs better. But generally, my recommendation based on the research, because again, I don't prescribe, I'm just here to tell you the science, is that an oral progesterone is always going to be your, your bioidentical oral micronized progesterone will always be the best choice. And then if that causes sleep issues with anxiety, mood, other things, use a vaginal form. Now, there's also a couple of genetic variations here that are important to point out. Your liver enzymes, the cytochrome P450 enzymes, or otherwise known as CYP enzymes, specifically CYP2C19 and CYP2C9, affect how you metabolize progesterone. Some women are what we call intermediate metabolizers and end up with higher blood levels of it than others. This may explain why two women can have exact same doses and a completely different effect.. And if you've listened to me, that's true of all hormones. We have to know how your genetics play into and how your liver metabolizes to actually get dosing correctly. And it's really important. And that's why we use such precision in Minerva, because no two women are alike. No two women's liver metabolism is alike, and we have to be precise. So if you have some mutations on that gene, you— those two genes, you may be a little more at kind of risk here for some changes. Now, the other argument I see online all the time is cyclical dosing relative to continuous dose. So I'm gonna talk about what the research says. All right. Now, here's the reality. Once you hit puberty all the way through menopause, your hormones are cycling. For most of us, they are altering every day throughout a 28 to 30 day cycle. Until you get to the chaos zone of menopause, and then all of a sudden they're going to get a little more chaotic, right? So we've encountered this a lot, and the argument goes like this: your body's designed to have cycling progesterone. It rises and falls. So taking it continuously might downregulate your receptors, making your cells less sensitive and rob you of the benefits. Therefore, you should only taking it— take it in a cycling manner. This is biologically interesting, and receptor downregulation is a true phenomenon of all hormones in certain tissues. And again, we don't have that precision to really make recommendations based on receptor activity. That's the holy grail of medicine. We can tell you if the hormone's in your bloodstream. We don't really know exactly how to tell you what the actual receptors are doing. We can do it in tissue studies where we take some tissues out and put it in a Petri dish., but we can't do it in humans. The clinical evidence does not support that this is a significant problem in the menopausal and postmenopausal woman. We have to look at the physiological context, which is completely different in menopause. You don't have fluctuating estrogen that drives a natural cycle in reproductive women. The regulatory environment has fundamentally changed. Now, there are people— T.S. Wiley being probably the most prevalent of this— that recommends that women cycle all the time. So even if you're 55, 60, that you mimic a cycling effect and that you also take varying levels of estrogen throughout your cycle and varying levels of progesterone and that you force a bleed. Now, I don't know about you. I am pretty damn excited that I don't have a period. And to be honest, we don't have strong, structured research that shows there's any value in that. Honestly. And so probably the strongest study we have here is the Replenish study. The Replenish study looked at continuous low-dose progesterone, so 100 milligrams daily alongside a counterbalance estradiol, and found sustained efficiency, high patient satisfaction, no evidence of diminished benefit over time. So the FDA and major clinical societies, you know, for looking at conventional medicine, looking at the evidence of the research, recognizes continuous regimens equally valid to cyclical ones, if not advantageous, because it's easy to remember. We're not inducing changes in hormones that are hard to manage. I don't know about you, but I don't want to have to try and figure out a dose every 2 or 3 days that's radically changing all the time. And cyclic, cyclic regimens do what I will say here, have longer-term safety data. Right. So if we look at the overall preponderance of the research, we do see the cycling regimens in older studies have better endometrial safety data saying that they help endometrial lining suppression of estrogen. But continuous regimens, we have fewer studies of randomized data. But that's not alarming. That's just because we haven't bothered. We only get 1% of all research dollars, ladies. The mechanism for endometrial protection is absolutely understood. You must have progesterone to protect estrogen's effect on the uterine lining. But the gap in the research is still there, right? We don't have tons of studies on it, and it's definitely worth watching. But the cyclical oral progesterone at 200 milligrams, at 200 milligrams per day may carry some risk when they put it together with Premarin. Right. So here's another study. So Premarin is horse mare urine. It's horse pee, and it's got 13 estrogens in it, all of which are oral, go to the liver, go through first-pass liver metabolism, all those genes I've talked about, and they make a ton of metabolites. It is associated with clotting risk and stroke risk in older women, not as strongly as synthetic progestins, but it is. There is a study that showed using 200mg of cycling oral progesterone with Premarin may carry some endometrial cancer risk. Now, is it because they were taking oral micronized progesterone continuously and then just cycling in progesterone at the time, pretending it's day 14 through 28 of the cycle? So the continuous lower dose appears actually to be safer than a cyclical dose if we take that study into measurement. So let me make sure I make that clear. In the Premarin study that kept Premarin at a static dose and they cycled 200mg of oral micronized progesterone, they saw a slight increased risk of endometrial cancer. Why? They were doing continuous dose horse, horse mare urine, and they were cycling progesterone, reducing its overall protective effect on the endometrial lining. So continuous use at lower doses and even those high doses of 300 milligrams in women that need it shows endometrial safety. And again, it's a nuanced area that's evolving. But here's the reality. We have a lot of signals here, and the cyclical versus continuous debate is mostly settled in favor of continuous use for practical reasons. Women prefer not to bleed. Again, I don't ever want to go through that again. The receptor downregulation concern, while intellectually interesting, hasn't played out in 4-year studies following a cohort, and it doesn't translate into, into clinical demonstrative harm. But if you're on a cycling dose and it works for you, cool, right? There's no reason to really switch. I just don't think there's a reason to implement it because of fear around studies that were inconclusive, or small studies at best. All right. So let me bring this all home to you. I've walked through a ton of science today, like usual. And I want to actually distill it down into what really matters. Number 1, bioidentical micronized progesterone is not the same as synthetic progestins like medroxyprogesterone, the progestins that are used in, um, IUDs, and it ain't like the ones that are used in birth control. Micronized progesterone has a fundamentally different safety profile and benefit, and the progestin studies like the Women's Health Initiative do not apply. Don't let those findings or those misuse of language mis— kind of misguide you, because the problem is, is a lot of times in the studies, especially when you start looking at meta-analysis and systemic, uh, analysis of studies is they start intermingling those words. They're not the same. And if you don't go in and look at the detailed data of the actual method and the actual conclusions and all those supplemental tables, you might miss that. And I know you guys aren't doing that. That's what I'm here for. All right, number 2: route of delivery matters for cognition, mood, and the cardiovascular system. Oral micronized progesterone is the one that's most protective for most women. It helps sleep, it helps reduce vasomotor symptoms, it helps reduce stress on the nervous system, anxiety, and depression. However, in some women, it'll cause a paradoxical effect. And so if you're one of those women and you take it and you're coming out of your skin, you may need a vaginal delivery instead. Know your options. And if your doctor doesn't know your options, fire them. They are not informed. Number 3, individual variability is real and it's not in your head. I can tell you, we've been doing hormone replacement for 21, almost 22 years, and one woman might need 400 milligrams of micronized progesterone to get the same effect for another woman at 100. We have some women that any dose of oral micronized progesterone makes them so sedated in the morning they can't handle it and they have to use vaginal. Just because your friend is on one does not mean it's the one for you. If you feel different on progesterone, that's important to know. If your sleep gets worse, you're more anxious, you get brain fog, that's an important signal, and your practitioner should be able to navigate that with you. And it warrants a conversation. And if they're dismissive, fire them. 4. Separate animal studies from human studies. The reality is, when you see alarming claims about hormones, causing brain shrinkage, hippocampal shrinkage, memory loss. Ask what the study population was. Mice and rats metabolize hormones differently. Human data at therapeutic doses do not replicate those studies at all. And number 5, demand a personalized conversation and protocol for you, not a protocol that they use for everybody. Your hormone therapy should be built around your symptoms, your history, your genetics, your metabolism, and your goal. It's not around what's easy to prescribe. It's not around what the FDA just approved, because hey, here's another thing: 30% of all medication use is off-label, meaning it has no FDA indication. The majority of men who are on testosterone therapy are using it off-label because testosterone is only approved by the FDA for hypogonadism, which means that their levels of testosterone have to be below the threshold level on the labs. I can tell you right now, that is not how men are getting prescribed. So don't fall for the measure that you can't have it because it's not FDA approved. Most of our medications are not FDA approved for the reason the doctor is prescribing it. So your hormone therapy should be built around you, not around the easiest thing. You know, and they should be asking about your mood history, your sleep history, your cardiovascular risk, your menstrual history, and not just assuming you're like everybody else. You deserve precision and you deserve so much more than what you're probably getting. So I want to thank you for taking your time today, or maybe over the last day or two, listening to me about progesterone. I know it's a lot and we covered so much. But I wanted you to understand and be informed, right? I think as women, we have too much going on in the world today where we're being subjugated and also we're being washed of the science, washed of the history. We can't even get studies performed because we can't use the word female or woman in the study data because they won't give us money to run studies. So here's what I want you to walk away with. Progesterone is not just a simple hormone. It's important, and the science is trending in a positive direction that micronized progesterone, particularly in comparison to all the other alternatives, is by far better. And there is no reason not to use it, particularly if sleep and cognition and anxiety is a big deal, even if you don't have a uterus, even if you're like, hey, I just don't think I want to do estrogen. We have Good clinical studies showing postmenopausal women can use progesterone levels. Most of the studies go up to about 400 milligrams for the sleep benefits alone, for hot flashes, night sweats, and better sleep architecture. It is safe, it is protective. And if you're a woman between the average age of 35 and 100 or more living somewhere in the US, you deserve the right to have somebody take your symptoms seriously. And I want you to know that we're here to help you at Minerva. And so we want to thank you for listening to Menopause Mastery. If you happen to be watching this on YouTube, thank you so much. And I'll be back with you next week.
