What's the Deal with Hormone Replacement Therapy?

Emily: [00:00:00] Hi, Perry.

Perry: [00:00:02] Hi, Emily.

Emily: [00:00:03] Are you excited to talk about hormone replacement therapy? I just want to tell the listeners that Perry was extremely reluctant to discuss hormone replacement therapy. Isn't that right that you preferred maybe hair loss, things about hair loss and no other man topics?

Perry: [00:00:18] It's not for the reason you thought when when you pitched hormone replacement therapy. I think I said something like, oh, brother. And and you assumed incorrectly, incorrectly, incorrectly that I was being a man. And I was like, ooh, lady stuff. And that's not true. I said, oh, brother, because it's really, really complicated. And I knew it was going to take a ton of research to get it right.

Emily: [00:00:45] I'm very excited. But also I wanted to mention, do you know about manopause?

Perry: [00:00:51] I have heard the term of manopause. And I think it's, um, I think it's really good that we're finally Recognizing, [00:01:00] um, men changes in men's life that are clearly just as severe and disruptive as anything that could possibly happen to a woman. And I say that as a man and as a father of a man.

Emily: [00:01:12] I think you may be in manopause.

Perry: [00:01:14] You'll have to actually tell me what menopause is. And then I'll tell.

Emily: [00:01:17] You, it's when you gradually decay between the ages of 40 and 50. Are you gradually decaying?

Perry: [00:01:23] I mean, more or less.

Emily: [00:01:24] I believe it begins with the rotator cuff. Rotator cuff. And then it's all downhill from there. I'm Emily Oster, I'm an economist and a data expert.

Perry: [00:01:35] And I'm Perry Wilson. I'm a medical doctor.

Emily: [00:01:38] It's Thursday, April 23rd, 2026. And this is Wellness, Actually.

Perry: [00:01:43] Because you're getting a staggering amount of health and wellness information nowadays from every source imaginable. And some of it is awesome.

Emily: [00:01:51] And some of it is, well, actually bullshit. Fortunately, we're both people who know how to read studies, how to parse the [00:02:00] data, and can tell you what's worth thinking about and what you can safely ignore.

Perry: [00:02:04] But before we dig in a note that this podcast is for educational purposes and should not be construed as medical advice. We don't know your unique situation, so talk to your doctor for personal health decisions.

Emily: [00:02:15] This week we're asking what's the deal with hormone replacement therapy? And this is a two parter. Next week we'll talk about testosterone. Perry and I will give the official smash or pass. And then we'll get to your question of the week. But first, let's do the health news roundup after the break. And now for the health news of the week. Perry, there is a new kind of diabetes. As if we didn't have enough with the first two kinds. It is called type five Diabetes. This has been recognized for many years, but it is now an [00:03:00] official diagnosis. So tell me, what is type five diabetes and what happened to three and four?

Perry: [00:03:09] Yeah. This is this is fascinating. The International Diabetes Federation has officially recognised type five diabetes after some period of time. I think people listening will know about type one diabetes, which is a childhood onset form, usually an autoimmune disorder, type two diabetes, which is the syndrome of insulin resistance that's associated with overweight and obesity that's so prevalent in the United States. Type three diabetes does exist. There's like various subsets, but one is caused by, um, damage to the pancreas, like like trauma to the pancreas or severe pancreatitis, for example. Um, type four is a very rare form of diabetes recognized as insulin resistance in lean older adults. So it's sort of an aging related form of diabetes. And then we [00:04:00] have type five, which is really interesting and very different. It's caused by severe malnutrition and actually protein malnutrition. We just did the protein episode. So um, this is quite common, but not in the developed world. So there are probably 10 to 20 million people in sub-Saharan Africa who are suffering from type five diabetes. Scientists are still trying to understand the exact causes and treatments of this, because it does seem like it is not purely due to issues with insulin sensitivity. Um, and it is driven by protein malnutrition. So these are people who are getting enough carbohydrate enough fat, but not those essential proteins. And it can affect the pancreas.

Emily: [00:04:43] That is extremely interesting. Okay. But this is rare. This is much rarer than either type one certainly than type two. But even then type one or type.

Perry: [00:04:51] Four it is it is certainly rare in the United States. But, you know, 25 million people around the world probably suffer from this. And so it's good that we're drawing [00:05:00] some attention to it and hopefully get some research in that area. Speaking of research, that might start to happen now. Npr and multiple news outlets have reported that some psychedelics, including psilocybin and ibogaine, may be reclassified by the Trump administration. Um, and make them eligible to get an expedited FDA review for mental health conditions. Um, Emily, you and I have talked about, I think it's on our show, our upcoming show list, actually talking about psychedelics. So what do you think about this news that it's going to be easier to study them?

Emily: [00:05:37] I mean, broadly, I would say I'm supportive of this. You know, there was a period of time in the 1960s when psychedelics were something that people thought were going to be so great, and then they started using them more recreationally. And it became, you know, something that we weren't thinking about as as medical treatments, but actually seems like in the last, you know, decade or [00:06:00] so, there's been a lot more evidence that used appropriately, psychedelics can actually be quite effective at treating some pretty refractory conditions like severe PTSD. There was actually a really interesting episode of the daily, which I realize is not research with the reporter sort of talking about his experience doing a sort of particular psychedelic in Mexico as a treatment for kind of long standing trauma issues. So, I mean, this feels to me like I always like more research. It does feel like an area that's probably under-researched for reasons that are, um, you know, understandable. But maybe we should try to get past. I will say, of course, for many people, they're going to read some of these articles. Trump made an announcement about this and Joe Rogan said he texted Trump about ibogaine, which is one of these psychedelics, and the president responded, sounds great. Do you want FDA approval? Let's do it. Which, of course, is not. It's going to cause some people to be [00:07:00] like, come on. But I actually think we should be researching these. Maybe we don't text FDA approval.

Perry: [00:07:06] Yeah. The categorization of dangerous substances you've heard like category one, category two, um, does have implications for research. It does make it much harder to run a placebo controlled trial, like in a university like mine. If you're testing something that's category one or category two. So moving these into category three does just kind of open that door. But you're right, it should follow the path. Like, let's find out if these things work. If they work, that's great. And we should learn how to give them safely.

Emily: [00:07:32] We'll see. Um. All right. Speaking of political questions, there is a new nominee for CDC director. This has proven to be an extremely difficult job to fill. People keep getting in and then getting fired. This new person, the quote I saw on CNN was we just need someone who is not crazy. So what do you think about the nominee?

Perry: [00:07:55] So this is Erica Schwartz, who is very [00:08:00] much a straight down the middle nominee for, um, for the director of the CDC. She is a physician. Um, she's a lawyer who has a master's degree in public health. This CDC position, as you mentioned, has been, um, it's like a defense against the dark arts in the Harry Potter universe. Like, it's just a tough one to keep.

Emily: [00:08:24] Every year different guy.

Perry: [00:08:25] Every year you need someone new or more, more often than that. Um, this is, I think, very much a reaction to some real pressure. The administration has been getting sort of pushback against the so-called Maha agenda. President Trump, I don't think is as on board with the full RFK Jr philosophy, then that group of people or the people who support those policies would like. And there's been, you know, particular pushback against the anti-vaccine rhetoric in the face of the rising number of measles cases [00:09:00] and whatnot. So here we have a CDC director who like could have been appointed by Biden, could have been appointed by Bush, like, you know, an appropriate down the middle CDC director. What is really going to be interesting if she gets confirmed is like, how does she work with RFK Jr? Because clearly they have some different policy beliefs.

Emily: [00:09:21] Absolutely. I mean, this feels like someone who can definitely get confirmed, unlike some of the people they've nominated. But the question of, you know, can can she work inside this administration? I guess we will find out.

Perry: [00:09:33] We'll find out. And that's it for the health news of the week after the break. What's the deal with hormone replacement therapy?

Emily: [00:09:46] Welcome back. Uh, so we're going to talk about hormone replacement therapy. And I want to start by saying upfront, this is not a full discussion of all of the potential benefits and whether you personally should be on hormone [00:10:00] replacement therapy. I think what we find in Perry, you can correct me if this isn't what you find interesting here, but I think what we have found interesting here is kind of how the discussion of this science has evolved. And so we'll talk a little bit about how we got to where we are now, where we were before, some of the data, and then some of the benefits that are potentially true here. But this is really something where whether one should be on this or not is very dependent on talking to your doctor about where you are.

Perry: [00:10:30] Yeah. This is complicated, folks. Um, you know, this isn't red light therapy where it's like, well, it's going to cost you some money, but it's probably not going to kill you. There are benefits. There are risks. We'll touch on some of these. There are subgroups of people that would benefit more. There are subgroups of people that have higher risk. This is like a real deal. Talk with your doctor, but it's also a completely fascinating area. Um, I do want to give one other disclaimer. There's like sort of an elephant in the room here, which is that I'm a man. [00:11:00] So we're talking about hormone replacement therapy for women. This could be like the worst case of recorded mansplaining in history. Um, so, Emily, I think we need, like a safe word or something. If I start saying something like boorish or dumb, you know, if I, if I'm like, oh, menopause, you know, is it's.

Emily: [00:11:24] Not that.

Perry: [00:11:24] Bad. Really beautiful transition or something like you just say, say rutabaga and, um, I'll, I'll back off.

Emily: [00:11:32] Safe word tampon. That's the safe word. And you shut your mouth. That's this actually can work. We can use this in all episodes. But yes, I take I, I think that is a reasonable point. And I will also say disclaimer on my side, although I am a woman of perimenopausal age who is presumably somewhere in perimenopause, the actual experience of a lot of the symptoms that people are using hormone replacement therapy to treat is very [00:12:00] different. And so I can say something about what it is like to be a 46 year old woman, but certainly cannot speak to the experience of all 46 year old women. So with that lengthy tampon disclaimer and so on, uh, let's go. And I think the place to start here is with the biology of what hormone are we replacing and why. So can you very briefly, from your doctor's standpoint, tell me what hormone are replacing and why.

Perry: [00:12:30] So can I say for, again, very briefly that hormones.

Emily: [00:12:35] Sorry.

Perry: [00:12:37] Sorry. I'll stop. I'm like, I'm just gonna, like, spin my chair around and sit in the corner. Okay. We're talking about steroid hormones, which include estrogen, progesterone, and we'll, we'll touch on testosterone at the end as well. And I do want to say something about the biology of what makes steroid hormones. And there are a few others as well, really special in the body. We have these cells in our body, which are like little factories, [00:13:00] right? They have a job to do. And most of the way that they sense the outside world or the world outside the cells is through these receptors on their surface. And the drugs we take, and a lot of the chemicals in our body bind these receptors on the surface of the cells, but they don't get into the cells. They just sort of bind the receptor. They say, hey, we're out here and it causes the cell to do something else, like produce more insulin. If it's a factory, produce more widgets or something. The steroid hormones receptors are not on the outside of the cell. They're in the nucleus of the cell, which is where the DNA lives. Steroid hormones have the ability to go right through the cellular membrane because they're lipid soluble and into the nucleus where they bind their receptors. And their effect is to change what DNA gets transcribed inside that cell.

Perry: [00:13:44] So to continue the factory analogy, it's like, you know, most drugs and substances kind of like send a telegram to the factory and are like, make more widgets and steroid hormones, go into the factory and can redesign the entire thing, which is why you can take [00:14:00] a hormone like testosterone. And all of a sudden, a cell that didn't grow hair now grows hair. That also explains why the effects of steroid hormones are so broad. Like they can do so many things, and we don't even fully understand why they do all the things they do. So they really are a special group of things. And that's my very basic biology of of what we're talking about here. When we speak about hormone replacement therapy in terms of women in general were, I mean, it is what it sounds like. We're talking about giving doses of the hormones that go down in perimenopause and postmenopause, which is estrogen and progesterone. Hrt is supposed to replace those levels, not to make them higher, but to get them back to where they were at baseline. In contrast, for women who are pre-menopausal, who might have used oral contraceptive pills or something, where the doses of those hormones are much, much higher because they're designed to actually [00:15:00] suppress the endogenous hormone levels. That wasn't very brief.

Emily: [00:15:05] It was not brief, but it was. I thought it was interesting. I think that's great. And I think the kind of big picture here you want to imagine is that during perimenopause and menopause, your estrogen in particular, although both estrogen and progesterone change, estrogen goes down a lot. Estrogen is part of what supports a lot of ways that we feel good. And so hormone replacement therapy is potentially a way to improve some of the symptomatic experiences. Perimenopause, we'll talk about this. But things like hot flashes or sleep disruptions, which are kind of characteristic of many people during perimenopause. Estrogen is a potential treatment. Vaginal dryness is another example of where just as your estrogen falls, this goes, this symptom gets more significant. And so we're kind of all of these reasons. There is a biology behind the idea that replacing some of that estrogen [00:16:00] would improve some of your symptoms.

Perry: [00:16:03] Absolutely.

Emily: [00:16:04] Make you have more, more of the hormone profile of a 35 year old than of a 51 year old.

Perry: [00:16:11] Exactly. And that made so much biological sense that for years and years and years, this was a very common practice. It was like we had access to these hormones. They were first discovered in the 1920s, I think. And it is true that estrogen to this day is still a lot of the estrogen that people receive comes from horse urine. Premarin is pregnant Mare urine. There are 750,000 horses around the world that are giving their urine to make some of these estrogens. Isn't that fascinating?

Emily: [00:16:43] So nice of them.

Perry: [00:16:44] But all of a sudden this study happened that essentially overnight tanked the use of hormone replacement therapy in the United States. That's the Women's Health Initiative study. And Emily, can you tell us the story of the Women's [00:17:00] Health Initiative? Because I think it's hard to understand any of this without talking about that.

Emily: [00:17:04] Yeah. So, so I actually before, before I tell you the story of this, I want to spend like, I remember how you nerded out on physics. I'm going to nerd out on statistical external validity just very briefly. And then I will talk about this. So when we talk about scientific studies, we often talk about randomized controlled trials as kind of the gold standard for generating causal effects. And that's because when you have a randomized trial, you you take some people, you divide them up randomly. So, you know, they're kind of the same at the beginning. You do something to one and not the other. And then you can be confident that for those people, if you see different outcomes, the different outcomes are a result of the treatment. That's like the idea. But that is going to tell you a causal effect for the people that you study. And if that effect is the same across all people in the entire population, then you have learned about the whole population. But [00:18:00] if you have a population where the effect might be different than like the rest of the world, then you haven't actually learned about everybody. So like to be simple, let's imagine that you have a study of a drug and you only include men, and then you want to be like, okay, this was effective for men. Now I'm going to give it to everyone. Well, it's very possible the effect for women could be different.

Perry: [00:18:24] I mean, we did this for 50 years, by the way. This was all of medicine.

Emily: [00:18:27] This is the main way science worked. And it turns out actually that doesn't port very well. There are a lot of things where women react differently than than men. So this is an idea called external validity. And we worry when we run randomized trials about this external validity. And this is a topic that I work on. So I feel very passionate about it. But I say that at the top. And then I'm going to tell you about the Women's Health Initiative, because I think in some ways that's some of the issues that came up with that trial. So the Women's Health Initiative is a study launched by the NIH in the early 1990s [00:19:00] and included about 30,020 7000 postmenopausal women. These women had an average age of 63. And they they randomized them to sort of two different treatments of sort of hormone replacement therapy and also a placebo. And when the follow up was published in, in 2002, they actually the, the people doing this study halted the study in 2002, or halted one arm of the study because of a concern that there was an increase in both breast cancer and cardiovascular events, which exceeded what they saw as the benefits of this. And it was a relatively small increase numerically. But percentage wise, it was quite sizable. So the relative increase of about 25% in invasive breast cancer and about 30% in cardiovascular events. It's actually also an increase in strokes. And [00:20:00] with that change, we pretty much saw a absolute tanking of any hormone replacement therapy prescriptions. So this was sort of the end, at least for some period of, of kind of widespread hormone replacement. And I would say that's the, the nadir. And then sort of over time, this has this has returned. But fundamentally, the thing to understand is there's a randomized trial of this, which showed some elevated risks.

Perry: [00:20:28] I want to double click on the relative risk versus the absolute risk, because that's another important concept that people need to sort of be aware of when they think about these studies. So let's take invasive breast cancer. When that arm of the Women's Health Initiative was was stopped, there was a 26% relative increase in invasive breast cancer. And so people interpret that as like my risk of breast cancer would go up by 26%. But if you look at the absolute numbers, there were 30 cases of breast cancer per 10,000 women per year [00:21:00] in the placebo group. So 30 per 10,000 per year in placebo, 38 per 10,000 per year in the hormone replacement therapy group. So we're talking eight extra cases per 10,000 women, right? And that doesn't sound as bad as a 25% increase, but people hear 25% and they're like, oh my gosh, that means I'm going to have a 25% chance of getting cancer or worse, or something like that. Really, the absolute risk is very small, not zero, but very small. And sometimes the way we help explain that to people is with a concept called number needed to harm, which is like, how many people would you need to treat for there to be one extra case of cancer? And in this case, if you do a little math, it would be 1250 women. If you treat 1250 women with hormone replacement therapy, you would get one extra case of invasive breast cancer per year. Not nothing. But again, Emily, and you're about to talk to us about this. That's [00:22:00] assuming that the women in the study are the same as the women that you're prescribing the hormone replacement therapy to. And is that the case?

Emily: [00:22:10] So first of all, let me just say I hate those number needed to harm things. I understand doctors like those as a way to describe risk size. And they. I don't think they make any sense to.

Perry: [00:22:18] It doesn't work for you.

Emily: [00:22:19] Oh. All right. It doesn't work for me.

Perry: [00:22:20] Listeners, tell us if you like number needed to harm.

Emily: [00:22:24] Yeah, I don't like it. Um, I, but I guess I'm not the only listener, but I'm the first listener and I don't like it. Okay. I will say that I think that there is this sort of difference between percent and percentage points, which is very important. People hear 25% increase and they immediately think, you know, that raises my risk from 0 to 25%, as opposed to it is a 25% increase.

Perry: [00:22:47] From an already low number.

Emily: [00:22:48] Relative to a very low number. So I think that's, that's like a, we can talk more at some point about how to talk about small numbers to people. Um, okay. So getting back to the, to the women's health [00:23:00] initiative in this, when this sort of first stuff came out in 2002, I think the, the prescription rates for HRT dropped by like 80%. I mean, it was a real tanking. And because it sort of fell to people like sort of sounded like, you know, hormone replacement therapy gives you breast cancer. That was kind of like the headline was like, you take this, you're going to get breast cancer. Yep. Um, but then sort of almost immediately, things got like quite more complicated. So there was a second arm of the trial that treated in a slightly different way. And that arm was halted in 2004 because of a concern about an increased risk of stroke. But actually in that group, the risk of invasive breast cancer had gone down. So now already there's like a little bit more of a complicated story which may relate to the overall small numbers could relate to, you know, some actual differences in impacts, but it was sort of made the story immediately more complicated. And then, you know, over the past, probably [00:24:00] over the ten years or 15 years following this initial publication, one of the things that became pretty clear was that the age group in this study seemed to matter a lot.

Emily: [00:24:13] So the primary group, the average age of people enrolled in this study was like 63. But when they cut the study, they. What's called stratified. Divided the study into people who were sort of closer to menopause. So people who were 50 to 59. So the kind of younger group within ten years of menopause, they actually looked like the treatment decreased their risk of cardiovascular disease and all cause mortality. So actually in that group, they seem to have an overall mortality benefit and a reduction in cardiovascular disease, which sort of was offset by these older individuals. So in some sense, what's really important about that is you kind of, again, getting back to this external validity [00:25:00] point, we put in a bunch of people, we drew some conclusions based on a much older cohort, and then we apply that conclusion to everybody, even though a it looked like the younger cohort, if anything, had some benefits. And B, actually treatment with HRT is somewhat more common in these younger cohorts. And that is where this symptomatic stuff shows up most significantly. And so you're sort of learning from a group that's like, not even the group you're really interested in treating. And I think that realization over time has kind of we've, we've started to return to the, to the use of HRT, but it's taken a very it's taken a very long time.

Perry: [00:25:38] Yeah. The Women's Health Initiative study was not designed to test whether HRT reduces the symptoms of menopause because, as you point out, 70% of the women in the study were more than ten years past menopause. Like they weren't symptomatic anymore. It was designed to test whether hormone replacement therapy is cardioprotective protects the heart. Because, you know, there's long been an observation that women [00:26:00] tend not to have heart attacks and stuff until after menopause. And it was thought that estrogen would be protective. That obviously didn't pan out in that older group of women. It may among younger women, but it was like this study wasn't designed to test the thing that we're using it for now.

Emily: [00:26:15] Yeah. And I think I mean, in some ways, many people would say, well, well, like, why, why not? And, you know, one answer is like, you know, the patriarchy or something, but you know, it really, it is a really important point because for many people, the reason to treat this is because of symptomatic, because of improvements in, in symptoms. This study just wasn't about that. It's not that it was. It evaluated symptom profile and showed that it didn't work or anything. It just like that wasn't one of the outcomes. And it wouldn't have made sense with this age cohort because again, the sort of symptomatic pieces of, of menopause are earlier. And so it really is an example of a place where I think a lot of people's lives were made substantially worse by this research, [00:27:00] which in principle was very well-meaning and from which perhaps we did learn something, but it caused a lot of people to not have symptom relief who could have. So we then find ourselves In the current moment where I think like overall, we are starting to see HRT. It's it's like it's having a moment. It's like having a comeback.

Perry: [00:27:24] Absolutely.

Emily: [00:27:25] People are into it.

Perry: [00:27:26] Yeah. I think the word has gotten out and it's making people very curious. And but part of this is word of mouth because unlike a lot of drugs we take and give ourselves like hormone replacement therapy really works for symptoms of menopause. And so if you are a woman or know a woman who has those symptoms, and then they start taking HRT, they'll tell you how much better it is. And that's, that's real. And so this percolates really quickly.

Emily: [00:27:53] But can I like sort of step back one step, which is, you know, looking at the Women's Health Initiative results, sort of what would you think we [00:28:00] should have taken away from that.

Perry: [00:28:02] From the initial results?

Emily: [00:28:03] Yeah. In 2002, what would you have had them do, sort of do or say differently?

Perry: [00:28:08] Uh, I to be honest, because the purpose of the study was to determine whether hormone replacement therapy reduced the risk of cardiovascular disease, and it didn't in the overall population. I think I would have said, okay, you should not give hormone replacement therapy to reduce the risk of cardiovascular disease.

Emily: [00:28:26] In postmenopausal women.

Perry: [00:28:27] In postmenopausal women. And I would probably still say that today, to be honest, although, you know, you could maybe convince me. Um, but the problem is when we extrapolate from one outcome to all outcomes and we'll get to some of those other outcomes. But I did want to give, I think, you know, women who are reading about this, it can be very confusing what is out there, right? I said estrogen and progesterone in terms of the biology, but there are so many different types and preparations. I think [00:29:00] it's worth just giving people a framework to sort of think through how to take these hormones. And so, so the framework that I have found useful is to remember that really the hormone that you want to get for hormone replacement therapy is estrogen.

Emily: [00:29:16] Yes, that's the best one. Estrogen is a great hormone.

Perry: [00:29:19] So it's a great hormone. We love we love estrogen. We love it. Estrogen is responsible for what makes women women, the secondary sexual characteristics and a lot of other other things. Progesterone is there to stop you from getting uterine cancer. I mean, that's that's really what it is. So estrogen clogs the lining of the uterus to grow and develop. That's one of its jobs during the menstrual cycle. If you don't allow the lining of the uterus to settle down and mature, which is what progesterone does, and it keeps getting hit by estrogen, the risk of uterine cancer really does increase. And so you want the estrogen, you need the progesterone. If [00:30:00] you have a uterus. And that other arm of the Women's Health Initiative study that you alluded to was an estrogen only arm, and you could only get in that arm if your uterus had already been removed for some reason. And I mentioned that because a lot of the outcomes for estrogen only hormone replacement therapy are actually a little bit better than estrogen plus progesterone therapy. It's just like not everyone is eligible for that. So particularly breast cancer, for example, the risk in the overall women's health initiative was elevated. But among those women who were on estrogen only because they didn't have a uterus, the risk was slightly reduced. So really interesting there and something to keep in mind.

Perry: [00:30:38] So ask about the uterus. The other thing is whether you're taking these as pills or not as pills, the pill forms have to get digested and pass through the liver before they get to your blood. And depending on the type of estrogen, the liver can break down, like straight up estrogen, like 17 beta estradiol, which is the norm. The estrogen [00:31:00] that women make in their own bodies. You can take that in pill form, and if you do, your liver will break down 95% of it before it gets to the rest of your blood. So you're actually taking pretty high doses to get like relatively normal blood levels, in contrast to a patch which goes right through the skin. You know, there's transvaginal or vaginal preparations as well, which can get right into the bloodstream. And the doses are much lower. That's worth mentioning, because some of the risk of clot seems to be driven by these oral preparations. And I don't think people are entirely sure why there's a higher risk there. But if you've got the liver breaking down 95% of stuff, you know, that's going to be variable woman to woman because everyone's liver's a little bit different. And I bet dosing is just trickier to get right in those situations. So I just wanted to that's the framework.

Emily: [00:31:46] I think partly that somewhat complicated framework illustrates sort of why this is a challenging thing to talk about in a podcast. And, you know, because everybody's needs. [00:32:00] Not for us, but for other people, you know, because everybody's needs here are going to be somewhat different. So there's an oral preparation. There's a patch, which I know is what a lot of people like.

Perry: [00:32:12] And there's a shortage of right now.

Emily: [00:32:14] And there's a shortage, uh, there are, you know, vaginal creams, which really are, are kind of intended to treat or are effective mostly at treating the specific issue of vaginal dryness. So people, you know, experience that symptom of vaginal estrogen based cream can be very effective, can also be usable even for people potentially who would not be wanting to take estrogen only therapies in other ways because of other risks. So it's sort of like all about, you know, what are the particular symptoms that I am experiencing? What are the other risk factors that I'm holding on to? And then what's the right way to address those symptoms? And getting back to the idea that a lot of what we're trying to do with this hormone replacement therapy, in [00:33:00] contrast to what the Women's Health Initiative was evaluating, a lot of what we're trying to do is dial down symptoms of perimenopause and menopause, which are very disruptive to people's lives.

Perry: [00:33:11] So let's talk about the symptoms.

Emily: [00:33:12] Let's talk about the symptoms.

Perry: [00:33:14] Does hormone replacement therapy work for hot flashes?

Emily: [00:33:18] It really, really, really does. So hot flashes, you know, vasomotor symptoms are very, very common, uh, experience of perimenopause. This is like the like joke on television shows where someone sticking their head in the refrigerator. That's, that's a hot flash. People get a lot of these at night and it's very disruptive at night because, you know, you sweat, you wake up, your bed is completely soaked, and then, you know, you can't just go back to sleep because you're like literally drenched. And it's very unpleasant having had this happen. It's very unpleasant. And, and hormone replacement therapy reduces the risk of hot flashes in these studies by something [00:34:00] like 70 to 80%. So it can be can be really, really effective at what is probably the most disruptive experience in perimenopause that people have.

Perry: [00:34:11] And perimenopause can go on for quite some time.

Emily: [00:34:15] It goes on. I mean, yes, it can go on for, for many years. So people maybe it's worth saying so menopause actually defined as 12 months, you sort of are in menopause when you are 12 months past your last period. So it's a thing that's sort of defined retroactively. So there's like a moment at which your last period was 12 months ago and now you are in menopause. Perimenopause is the sort of period leading up to that, when periods get less frequent or more frequent, like they kind of mess around. Your cycle isn't so regular. And that is where many of these symptoms start showing up.

Perry: [00:34:51] And I want to be clear that perimenopause has nothing to do with Perry Wilson. There's no relation.

Emily: [00:34:57] There's no relation. It's not even spelled the same, [00:35:00] you know.

Perry: [00:35:00] No, I was not named after.

Emily: [00:35:03] Even after you? I don't know.

Perry: [00:35:04] Perimenopause.

Emily: [00:35:05] Tampon. That's a tampon. Safe word. Perry.

Perry: [00:35:08] Um, I think, though. Hot flashes. Clearly works. You talked about the genital urinary symptoms, where the topical preparations are probably superior to oral preparations. Another reason to kind of discuss with your doctor about how exactly you're going to go about this, but it's the vaguer symptoms, I think, that are where a lot of women who I talk to are really have their questions like, yes, that's great. I don't want to have hot flashes. But also, what about my brain? What about sleep? What about, you know, memory? And you'll hear people online saying that like they started hormone replacement therapy and the scales fell from their eyes. And, you know, it was like they were granted a whole new lease on life, which to be honest, and maybe this is another safe word thing I'm always skeptical of naturally, just because [00:36:00] I never think there's any one thing that can be that transformative except the power of love.

Emily: [00:36:06] Oh my God. Um, so let me say sort of two things about that. So one is, you know, if you think about the, the sort of experience of the menstrual cycle, there's a period of the, of the menstrual is like before the menstrual cycle, when your estrogen is higher in the kind of preovulatory phase, and then the estrogen falls. And a lot of people do experience fairly substantial mood shifts with those cycles. So the idea that estrogen could affect.

Perry: [00:36:33] That's why whenever a woman's in a bad mood, my first question is like, where are you in your cycle?

Emily: [00:36:38] In your.

Perry: [00:36:38] Cycle? That's my.

Emily: [00:36:39] Question. Where that's where you want to start. Totally, totally. Is this. Yeah. I mean, that's where I, that's always, that actually is a great marriage tip. Um, that many people could use.

Perry: [00:36:48] We should, we could help so many people.

Emily: [00:36:50] We could help so many people. So I think it's not crazy to imagine that estrogen could affect your mood. I think a lot of that [00:37:00] experience the brain fog, the fatigue, whatever is in fact sleep. So if you think about there's a sort of evidence that that hormone replacement therapy improves people's sleep, that may be because of a reduction in vasomotor symptoms. There may be other, you know, like, no, you're not waking up in the middle of the night to change the bed, but it may also have sort of other other things that impact sleep. If you have slept better, you feel better. And so if the whole whole thing here was just improving sleep, that actually could explain a fair amount of just a general set of like, boy, do I feel a lot better. Yeah, the same way the first time your baby sleeps through the night, you're like, oh my God, I'm going to conquer the world. Because I haven't, you know, because I've slept right?

Perry: [00:37:42] Absolutely. And this is randomized trial level data. There's been a number of trials, but one called the Keeps trial. This was in sort of just recently, menopausal women showed a pretty significant improvement in global sleep quality scores in the group that got hormone replacement therapy compared to placebo. As you [00:38:00] mentioned, Emily, when they stratified that population by women who were having severe vasomotor symptoms, severe hot flashes, like that's where a lot of the benefit accrued. So it might just be that you'll see people online talking about progesterone actually, in particular, binding the Gaba receptor in the brain. That's the same receptor that alcohol and benzodiazepines bind to. One of my personal favorite receptors, but not much data beside the mechanistic, like petri dish stuff that would suggest that progesterone is a calming factor. But I think if you're certainly if you're waking up with hot flashes, like this can be really good.

Emily: [00:38:41] The other thing we should say is that there is some evidence of an improvement in fractures. So for people who are at risk of osteoporosis, that's another that's another place where we see some hormone replacement therapy benefits.

Perry: [00:38:54] Yeah. No, I mean, it's so important. Um, I looked also a little bit more into brain [00:39:00] stuff. The problem with brain fog is it's a bit of a Potter Stewart thing. You know, Potter Stewart, the Supreme Court justice.

Emily: [00:39:06] So like pornography, you know, and if you you know, when you see it.

Perry: [00:39:09] You know, when you see it, right.

Emily: [00:39:10] You know, when you see it, I use that in my class literally all the time. I'm constantly telling them it's like what the Supreme Court said about pornography. People are just like, okay.

Perry: [00:39:17] They're like, as they like load up Brown's, like report your professor page.

Emily: [00:39:22] I don't let them have devices in class just to avoid that kind of behavior.

Perry: [00:39:26] Um, so I think brain fog is, you know, we're all like, oh yeah, I know what that is. And then, but no one's studied, there's no randomized trials of like brain fog because that's. What do you mean? Like, how do you quantify that? And so what you do get is you get randomized trials of neurocognitive testing, which is across a variety of domains, you know, executive function, verbal memory, physical memory, like all these different tests that you can put people through. And the data is really not super compelling, that there are dramatic brain improvement effects, with the only exception [00:40:00] being verbal memory. There did seem to be an uptick in verbal memory. And, um, again, just, you know, get out your, um, your, your shock buzzer or whatever you're using for me here. But, um, I did feel like I was like, oh, that's kind of like a mom brain thing. Like you can't find the word for x, y, z. Right?

Emily: [00:40:18] Yes. That's called fatigue. I mean, I just, I feel like it's so hard to separate all this stuff from being tired, but all right, so let's, let's just leave the hormone replacement therapy at, you know, this is especially if you are someone who is experiencing symptoms of perimenopause, this is something you for sure would like to discuss with your doctor.

Perry: [00:40:42] Absolutely.

Emily: [00:40:43] All right. What about testosterone? So that feels like we're diving in a little more. We're gonna talk about testosterone for men separately, but testosterone for women feels like. Is it? I always think of this as like, this is how I could cheat in my sports [00:41:00] performance.

Perry: [00:41:00] Oh, but you will not be allowed to, because testosterone hormone replacement therapy is banned by almost every international sports authority and by the Wellness, Actually metric of: is it banned? Does it work then? It does work, yes.

Emily: [00:41:17] So why are people using this in menopause and. And are there reasons they should do it?

Perry: [00:41:23] Yeah. So women do have testosterone. Just just like men have some estrogen. It's just men have about ten times the testosterone and women have about ten times the estrogen. And viva la différence. Women's testosterone levels peak around age 20 and decline slowly thereafter. They do not suffer the same menopausal cliff as estrogen and progesterone. So they do sort of more the male thing, which we'll talk about next week, which is kind of like a slow, steady decline over time. Um, the interest in testosterone is really more recent than for women at [00:42:00] least is much more recent than the broader HRT, in part because this is a hormone that people associate with muscle growth and maintenance, uh, vigor to some extent. And to be honest, a lot of the research has been driven by sexual dysfunction. Um, so testosterone in women sort of first foray into organized research was to treat what's called hypoactive sexual desire disorder. You know, there's no, there's no viagra for, for women yet. And so testosterone, um, was sort of used for this purpose. Does it work?

Emily: [00:42:39] Yeah. Pretty. It does, it does work. I mean, it works for, for.

Perry: [00:42:44] For sexual stuff. It works. The largest meta analysis comes from The Lancet. Combining data from multiple studies, about 8500 women total randomized trial data. And there's a bunch of different ways to to [00:43:00] measure sexual satisfaction. But the women who are getting testosterone replacement therapy had approximately one additional satisfying sexual event per month. So a satisfying sexual event could be with a partner. It could be a loan. It doesn't necessarily mean there was an orgasm. It just has to be satisfying. Beyond that though, yeah, I don't have much for testosterone.

Emily: [00:43:24] I don't think it feels so like we know that testosterone is a part of why people no offense. Men like sex more than women on average. Uh, or at least on average. That's true. That's true in the data. Men. Men would like the optimal amount of sex that men want is more.

Perry: [00:43:40] I know, but I want to be offended by that.

Emily: [00:43:41] But you're not. Don't be offended. And so I don't think it's that surprising that if you gave people more of this, this hormone, they might be more excited about sex. But the sort of other benefit, which is like a real benefit. I mean, again, if you like, if you have a mismatched sexual desire with your partner or you miss [00:44:00] how much you used to like sex, this is a sort of interesting thing to, to think about. The other benefits don't really seem to be there. And of course, there are some symptomatic side effects of testosterone. The same kinds of things. You see if you use it to improve your sports performance, like hair growth and acne and other and other things. So certainly not something you should be purchasing, you know, along with your peptide stack from foreign countries on the internet or whatever.

Perry: [00:44:30] Yeah, yeah. And, um, testosterone is probably not as beneficial for heart health. If estrogen is beneficial for heart health, testosterone is not it is sort of the yang to the yin of estrogen. I'm not sure which one is the sort of more like violent one. But testosterone supplementation can increase cholesterol levels, potentially promote atherosclerosis. So it's like, it's I don't think we're all there yet. Um, but you're going to see more and more of it. And especially as we, [00:45:00] we just have to mention there's an entire industry that is out there that is selling hormone replacement therapy to women and men, you know, using telemedicine, um, this sort of direct to consumer prescription model. And I'm not weighing in on, you know, the ethics or legality of that. I'm just saying it is there. So people have access to these treatments in a way that they've never really had before. And so you're going to see more and more and more of this, and it makes it all that much more important to like, be really cognizant and talk with someone really knowledgeable before you start. So you know what you want to get and that you can make sure wherever you're getting it from Is legitimate.

Emily: [00:45:45] So, Perry, of course people can buy these hormones online. But the other thing I see a tremendous amount of is these tests like, you know, get this blood test, it's going to tell you where you are and your different thing and which kinds of things you need. Is that I, of course, have had all of these tests because I'm a [00:46:00] crazy person. Um, but is there a sort of actionable piece of that? Is that just selling people nonsense? Should I care about my T3 free number is not as good as I whoops as it should be, say.

Perry: [00:46:14] Honestly, no. When it comes to estrogen progesterone levels, yes, you can certainly buy tests online to measure your levels. But no, they don't really change the treatment paradigm, which is how we decide whether a test is valuable or not. So particularly in perimenopause, the levels can be all over the place. Estrogen can go up and then crash and kind of go up again. That's part of the difficulties of perimenopause. And so the indications for treatment with hormone replacement therapy is, are you at an age where it's reasonable that you're in perimenopause or menopause, and do you have symptoms of perimenopause or menopause? And that's it. So, you know, getting you to spend a subscription fee to continually measure these hormones over and over again, or even once, I think is a bit of a cash [00:47:00] grab.

Emily: [00:47:01] Okay. Fair enough. Thank you. Smash or pass. Perry. Hormone replacement therapy.

Perry: [00:47:08] Smash. Um, I'm going to go, uh, with a lot of the society guidelines, which say, you know, perimenopause first ten years of menopause, uh, you know, potentially 5 to 7 years of therapy is a clear smash. Probably needs some more data on how long you can extend this into menopause. Emily, smash or pass?

Emily: [00:47:30] I'm going to go with smash based on my friends who say that it's great. Uh, and when I feel like I need it, I'm going to be trying it.

Perry: [00:47:39] Let us know.

Emily: [00:47:40] All right. That's it for hormone replacement therapy. Your mailbag. Question of the week after the break.

Mailbag: [00:47:50] Hi, Emily and Perry. This is Mary from Toronto, and I have a question about Lyme disease. I've heard that dogs can get vaccinated for [00:48:00] it, but I can't. Does Lucy the Beagle know something I don't? Thanks so much.

Emily: [00:48:07] Okay, Perry. I love this question because it is asked in my household all the time. Like if there if and when there is a Lyme disease vaccine for humans, my husband will literally be the first person to get it. Like if there's a line he is standing, he's like, he's like the people who wanted to buy the first iPhone. That's my husband is going to be like that for Lyme disease. He had a vaccine. No, he hasn't had it. But he's like a he's like a tick lunatic. He's like afraid every night when he gets to tick season every night when we get into bed, he's like, okay, can you check me for ticks every single night?

Perry: [00:48:37] Oh, I find that kind of romantic, actually.

Emily: [00:48:40] It's a little romantic.

Perry: [00:48:41] It's like a grooming primate thing. Do you eat the ticks? If you find them.

Emily: [00:48:47] Uh, there's one summer I found, like, five ticks on my kid anyway, but we never got. We never got Lyme disease. Okay. So, uh, so there is a Lyme disease for dogs, but not for humans. And there used to be a Lyme disease vaccine [00:49:00] for humans.

Perry: [00:49:01] Yeah, yeah, yeah. It existed, um, uh, 19 late 90s, it came out and the, basically the only reason we don't have it anymore is it was a commercial failure. Um, there are a few reasons for that. One is the vaccine schedule wasn't great. I think it was zero. Like, so you got one and then you had a booster a month later and then another 112 months later. So it was like a series of three vaccines, which is a little bit annoying because Lyme disease is not transmitted human to human. The it sort of shifts the public health, uh, landscape of the vaccine. So the Lyme vaccine was never going to be part of the childhood vaccination schedule, which is really designed to protect all of society, right? Like Lyme disease, really only the vaccine is really only going to protect the person. The other thing about Lyme disease is it's a bacteria, not a virus. We have antibiotics that can treat it. So it's not, you know, the sort of risk isn't [00:50:00] there. But but I mean, we had it was FDA approved. You could have gotten it and then just stopped making it because they weren't making enough money.

Emily: [00:50:06] But exciting news is that there is actually a new Lyme vaccine that is in phase three trials. And they've just announced that basically, I think the phase three trials went well. This is like a very recent announcement. And so I do expect there to be a Lyme vaccine coming down the line. And although you're right, I think the commercial success was was somewhat limited. I actually think people have gotten more concerned about the sort of long term impacts of Lyme disease. And it is true that although if you notice the tick and you get treatment, basically you can avoid getting long term Lyme disease. Many people don't. And so this is, you know, can be a very significant. It can be incredibly debilitating if people don't have. My brother had Lyme disease once.

Perry: [00:50:52] My daughter had Lyme disease.

Emily: [00:50:54] Yeah. Because you live near Lyme, Connecticut. That's where my brother got it.

Perry: [00:50:57] My, my, my backyard is mostly [00:51:00] ticks.

Emily: [00:51:01] Yeah. That's where they live. Uh, and so yeah, I mean, it's like, you know, it's a, there's a telltale rash if your child has a tick watch for, for the rash. But I, I am excited about the Lyme vaccine.

Perry: [00:51:14] Yeah. Tick checks. You have 24 hours after the tick has bit to get it off before it can transmit the bacteria. So tick checks on a daily basis if your kids are outside.

Emily: [00:51:24] Yeah. My brother did not get my brother. He got treated and he did not have Lyme. He did not have any significant long term Lyme.

Perry: [00:51:31] Yeah. Um, you can save the tick if you want to show your doctor, they'll have fun with it. But a lot of the time, if the tick has been on, and certainly if there's that target lesion, you'll get empiric antibiotic treatment.

Emily: [00:51:42] Doxycycline for the win.

Perry: [00:51:47] All right. That's it for us today. Stick with us next week when we'll ask what's the deal with testosterone for men.

Emily: [00:51:54] Yay. Finally we're studying men. Woo! Well [00:52:00] this actually is produced in association with iHeartMedia. Our senior producer is Tamar Avishai. Our executive producer at iHeart is Jennifer Bassett. Our theme music is by Eric Deutsch, and our content is for educational purposes only.

Perry: [00:52:14] If you like the show, help other people find us. Leave a rating and review on Apple Podcasts or your podcatcher of choice and help us spread the word about the show. You can follow us on Instagram at actually Pod. And don't forget, we want to hear from you. Head over to wellness.fm and leave us a question for our mailbag or suggest a topic for a future show.

Emily: [00:52:36] We'll let the influencers have the last word.

Influencer: [00:52:38] Ladies, I want you to know these symptoms of perimenopause and menopause. These are 34 common symptoms. Acne. Allergies. Anxiety. Bloating. Constipation. Body odor. Breast soreness. Brittle nails. Cholesterol changes, depression, difficulty concentrating, dizzy spells, fatigue, gum problems, hair loss, headaches and or migraines, [00:53:00] heart palpitations, hot flashes, irregular periods, irritability or rage. Itchy skin joint and muscle pain. Libido changes, loss of breast fullness, memory lapses, mood swings, nausea, night sweats, osteopenia and osteoporosis, pain during sex, panic disorder, sleep issues, urinary incontinence, vaginal dryness and pain...