Perimenopause

24:30They went through menopause in their mid-50s, like 55. So I thought I was like 15 or 20 years away from this happening. It wasn't even on my list. So actually, while it was happening, I had no idea that that's what it was. And the doctors I went to did not help me figure that out. I went to OBJYNs. I went to endocrinologists. I went to an ENT because I was having vertigo and tinnitus. I went to like all these different kinds of doctors and it was like a strange time because it was during the pandemic for part of it. So I couldn't just like go in person. But that's part of why I feel like it's so important that people know about this in their 30s because it happens to people at a range of ages.

25:08The average age of the start of menopause in the United States is 51. And the average age of the start of perimenopause symptoms is 10 years earlier. So early 40s is when most women will start to have those symptoms. And I had no idea. I thought of it as this thing that was still 15 years away. But yeah, I did. I mean, it was really, really uncomfortable. It interrupted my sleep. It was kind of lucky for me that part of it was during the pandemic because it was easier to deal with on Zoom than if I had been in person. Yeah. So, I mean, there's a lot to say, but I just found it shocking that I had so little knowledge that that was going to happen.

25:43And then I got really interested in it because you guys know I'm a microbiome scientist. And so I started reading about how in Japan, people don't have hot flashes as much. And maybe it's because they eat more soy products that have estrogen-like molecules in them. And maybe it's because their vascular health is better. So when you were talking about the blood vessels constricting in your face, I mean, it turns out that in societies where people have better vascular health on average, the age of menopause is later and the symptoms associated with it are much smaller so there are entire swaths of the world where hot flashes are not really a thing wow so i was like man sign me up like yeah i think it's a little too late for me i couldn't just move to japan uh the damage is done but but man yeah i wish i had been born in japan well i think they do have some symptoms there too it's just less um and it's very individual that's true here too i have a friend who also went into menopause in her late 30s and it happened to her really fast and her doctors she went to a bunch of different specialists none of them could figure out what was happening and she literally thought she was dying because she's like I just keep feeling worse and worse and worse and nobody can tell me why and then finally she found the right doctor who's like you just went into menopause really early that's what it was and I think she was on birth control so she wasn't having periods anyway so she wasn't like realizing that her period wasn't coming And anyway, yes, we all should know a lot more about this.

27:08Yeah, actually, that was a big part of why I couldn't figure it out either because I had an IUD. So I didn't, once I had the IUD, my period became irregular. So that was like otherwise a really critical piece of information that was just missing. So that's actually kind of an important thing to tell someone in their 30s when they get an IUD that, you know, this is, it's just, it would have helped me to have that be on my radar. I wasn't, I just, you don't think of yourself as older than you are. You always think of your, like, you're kind of stuck in the last couple years in your head. I always feel like I'm not, like, always looking five years ahead.

27:40And it would have helped me to have a doctor do that for me. But, I mean, in my case, I figured it out by reading. Another benefit of rounding your age up, see. Oh, my gosh. Daniel welcomed me to the Round Up to 50 Club on my 45th birthday, which was not the favorite thing anybody said to me in my life. Let me just tell you. I see why you were given an award for patience, Katrina. Yes, exactly. Well earned. Well earned. I was wondering if we could dig in a little bit more into the biochemistry. We've been talking about estrogen and how it affects all these systems. And we use this phrase estrogen receptors and like, what's going on here?

28:16I'm the last person to ask for the chemistry details, but like you got one molecule bumping into another molecule. Can you tell us a little bit about what's happening there? Oh, come on, Daniel, a chemistry question. You've got to be kidding me. All right, I'll do my best. Okay. So there's something like four different kinds of estrogen receptors. And depending on what kind of receptor is bound, the cell will get a different kind of message for what it's supposed to do. So if a certain kind of receptor gets bound, certain genes inside the cell will be told to turn on and start making certain kinds of products.

28:51So essentially when the hormone binds to a receptor, the cell gets a message that it's time to do something in particular. And I think that's about as detailed as we need to get. You asked another question earlier about why you would ever stop this central system in your body. That doesn't happen to men. Testosterone keeps on kicking for men's whole lives. And I know there's lots of, especially recently, social media ideas about what you can do to increase your testosterone, like get yourself in the sun every day and stuff like that. So it's not like it's a total constant. There are some things you can do to impact your testosterone levels, which sometimes go hand in hand with other things we associate with health.

29:34But estrogen for all women is going to just stop at some point, which is a really different way to live. I mean, it's crazy, right? If that happened to men, think of all the research we would have done to try to help men have the end of their life make more sense. Or maybe it's a big part of why we treated women differently, because they lose this central feature of health earlier in their lives, which, you know, has big impact. And let's get into some of those reasons. Let's take a quick break. And when we come back, we'll talk about why we think menopause even happens at all.

30:18Hey, everyone, it's Cal Penn. I'm the host of Earsay, the Audible and iHeart Audiobook Club. This week on the podcast, I am sitting down with Ray Porter, the narrator of Andy Weir's audiobook Project Hail Mary, massive sci-fi adventure about survival and science and what happens when you wake up alone very far from Earth. I really had to make a decision because I caught myself getting that frog in my throat and starting to get teary as I'm narrating some of these sections. And it's like, okay, yo, yo, yo, is this indulgent? And I really thought about it. I was like, no, at this point, it would kind of be betraying the trust the author and the listener have in telling this story if I don't go through it.

31:01But there's places in this book that deeply emotionally affected me. And I left it on the mic. That's great. Because it served the story. People will say like, oh, my God, I cried at the end. It's like, yeah, dude, me too. Listen to Earsay, the Audible and iHeart Audiobook Club, on the iHeartRadio app or wherever you get your podcasts.

31:43There's one platform for all business. PayPal Open. Grow today at paypalopen.com. Loan subject to approval in available locations. Eczema is unpredictable, but you can flare less with EpGliss, a once-monthly treatment for moderate to severe eczema. After an initial four-month or longer dosing phase, about four in ten people taking EpGliss achieved itch relief and clear or almost clear skin at 16 weeks. And most of those people maintain skin that's still more clear at one year with monthly dosing. EBCLIS, Librikizumab, LBKZ, a 250 milligram per two milliliter injection is a prescription medicine used to treat adults and children 12 years of age and older who weigh at least 88 pounds or 40 kilograms with moderate to severe eczema.

32:22Also called atopic dermatitis that is not well controlled with prescription therapies used on the skin or topicals or who cannot use topical therapies. EBCLIS can be used with or without topical corticosteroids. Don't use if you're allergic to EBCLIS. Allergic reactions can occur that can be severe. Eye problems can occur. Tell your doctor if you have new or worsening eye problems. You should not receive a live vaccine when treated with EPCLIS. Before starting EPCLIS, tell your doctor if you have a parasitic infection. Ask your doctor about EPCLIS and visit ebclus.lily.com or call 1-800-LILY-RX or 1-800-545-5979.

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33:32Okay, we're back. Before the break, we were talking about how men don't have anything like menopause, But for women, something like a third of our lives on average will be spent in this postmenopausal period. And so why, from an evolutionary perspective, are we spending so much time not being able to have babies when you would suspect that evolution would like us to be able to keep having babies? So do you two want to share what hypotheses you've heard already? Because I feel like some of them are out in the ether and I collected some extra during my reading. Oh, cool. Well, I mean, I always like the grandmother hypothesis and how it actually helps to have the grandmother there to help with her daughter's or her children's children, which makes a lot of sense to me.

34:15I mean, who doesn't want a grandmother in their corner, you know? Heck yeah! Depends on the grandmother, I mean. Yeah, that's right. I'd like to have my step-grandma in my corner, but I don't know about my biological grandma. Throw in shade. Yeah, so the idea behind the grandmother hypothesis, I think it's a super interesting idea. But when I was reading about it, it kind of breaks down when you look at other animals who go through menopause. So the mammal that goes through menopause that has been the most well studied are orcas. And so they've looked at orcas and they've seen like, OK, do the grandmothers spend more time with their kids and grandkids trying to like help raise them?

34:54Do they find more food for them? Do they teach them how to hunt? And the answer is no. Orca grandmas. Are they just playing Mahjong? What are they doing? They do. So they are more likely to be like helping everybody navigate long distances and stuff. And so it looks like there's some evidence that having grandmas around is great because they have all of this like historical knowledge that they can use to help the entire pod. But are they specifically helping grandkids? No, they're not. So it's good to have them around, but not for the reasons we thought. And we recently got some evidence that chimpanzees might also be going through something like menopause.

35:33But the grandmother hypothesis breaks down with chimpanzees, too, because chimpanzees don't tend to stay in the same community as their daughters and granddaughters. They're not even around to be helping them out. And so maybe the grandmother hypothesis works for humans, but it doesn't look like it is a good way of understanding in general why menopause happens. And we think maybe it happens with like an elephant, maybe a giraffe. I think there's a beetle species that has something like menopause. Oh, well, the beetle is interesting because to me it's like a mammalian thing. Although then I started thinking about chickens and chickens must stop laying eggs at some point.

36:09So they must lose their hormones, too. Yeah. Is it widespread or is it pretty rare? I think we really don't know. That's crazy. I know, right? So, I mean, the number of animals that we've watched throughout their entire lifetime. And, you know, like if you've got them in a zoo, you might not necessarily be trying to breed them. So you might not be keeping notes on like chimpanzee bee has her period right now. Like, I don't know, do chimpanzees get periods? I think they do. And like mice, for example, mice and rats are obviously extremely well studied in labs. And we definitely see them going through menopause, although most studies don't go so long because it's expensive to keep the animals going.

36:50So a lot of animal studies end when the animals haven't entered menopause. But I've been working on Alzheimer's disease in mice for the last five years, and I've actually learned a lot about mouse menopause. And mice definitely go through menopause. Okay. Because our studies go long enough to see it. I think there's a lot more menopause happening in the mammalian world than I had realized. So we're not so alone. Well, that's interesting because if it's widespread, it seems like it must be something fundamental we all have in common, or maybe there's an advantage to it for some reason. I mean, it must be that after you've, you know, once you hit a certain point in your life, your health does start to change.

37:32And so just taking on the stress of pregnancy is not something you can do. That's like something you have to be very fit to pull off. So maybe it has to do with that. And we talked to Venki Ramakrishnan in our aging episode a bit about this. And so anyone who's interested in a little bit more information about why do we age and why do things change as we get older should pop back over to that episode and listen to it because Venki did a great job of explaining it. And I'm not going to do as well if I try to repeat it. All right. So we have this grandmother hypothesis that maybe it's good to have some female members of the community not having children so they can be grandmas, but that doesn't seem to actually pan out.

38:10What are the other hypotheses? So another one that I came across was that maybe eggs just have like an expiration date. Like 50 years is as long as you can expect eggs to be able to hold out. But there are elephants and whales that give birth into their 60s, and those are also mammals. So there are other mammals that are still giving birth way after human women have stopped giving birth, which suggests that there's not just like mammalian eggs just can't last 60 years. Ooh, naive biology question again. Do we understand why eggs are only made at the very beginning of life, like very early in the development of the female, whereas like sperm are constantly being regenerated?

38:46I don't think we do. We'll get back to you, Daniel. And then there was this other idea that I came across that maybe homo species, so not just us, but like, you know, our ancestors and us often didn't live to be 60 or older. And so we're just sort of optimized for a shorter lifespan. And so we just kind of run out of eggs because we were never really expected to live this long anyway. And I know there's a lot of folks who don't like this argument. I think some of them argue that, you know, we don't really know if women were living regularly past their 60s for these other species. We just don't have enough good evidence.

39:22And I think some people don't like it for, I guess, cultural reasons or like. Isn't this also based on a misunderstanding of the statistics? I mean, it's often said that, like, people only lived to the average age of 35 a long time ago. But I thought the reality was that lots of babies died and then lots of people lived what we would call normal lives. And the average of that was 35. Not that nobody lived past 35, which is very different. Yeah. So that is a great point. But I still think that doesn't change the fact that we aren't exactly sure how old like our homo ancestors lived. But yes, I think you're right.

39:59Humans in general have lived for a pretty long time when you look at like the average lifespan past five years old or something. Like if you survive the first five years, you can expect to have a much longer life. But also that wouldn't really be an explanation. Like if most people died when they were 60, that doesn't suggest your body should like shut down an important central function around 60. Like, OK, let's all get ready to die. You know, as Katrina was saying earlier, estrogen plays an important role in lots and lots of systems. Why would your body ever want to shut it down? Is there some danger to estrogen?

40:32Is there some downside to it? What is the benefit of menopause to the individual? I don't know that there is much of a benefit to menopause to the individual. But you're right. Like if we all could only expect to live to be 60, why are men still making sperm after 60? Like doesn't seem worth it. Well, it's just a smaller cost for guys to make sperm, though. So it might just be that the tradeoff of trying to keep pregnancy going as a woman is getting older becomes too costly. Yeah, that's a good point. Both for the baby and the mom, it's not easy to pull that off. Yeah. But it's hard to imagine a selection that would lead to that.

41:09I mean, we all know that evolution works through selection, through natural selection. And so it's hard to imagine how that would actually have been selected for. And it seems like there'd be selection pressure against it because women who lose this estrogen suffer all these things, which makes it harder for them to function normally. But those things all occur after the point of selection. Oh, I see. Yeah. But then why would they happen at all? I mean, that is a really interesting question. Yeah, I think it's a really interesting question. And to, I guess, bottom line this point, we really don't know.

41:41I think the grandmother hypothesis is the most popular idea right now, but it doesn't hold with other species. And that's kind of where we are at the moment. And so Daniel asked, is there any benefit to this happening? And I don't know if there's a benefit, but I do know that there's a lot of health risks when you enter menopause. So we've talked about osteoporosis. Estrogen also is important for things like how cholesterol is managed in your body. And so whereas women have better cardiovascular health on average than men before they hit menopause, after menopause, that benefit goes away and now our cardiovascular risk becomes even with men.

42:17And so this is one reason why people are interested in looking at menopause hormone therapy, which is also known as hormone therapy or hormone replacement therapy. It goes by lots of different names. Well, I'm really curious about why we can't just replace that estrogen, right? Like we know that women's bodies stop making it. why don't women just take that estrogen to replace it? Can we basically just out-engineer menopause? So let's dig into that after a break.

42:51Hey everyone, it's Cal Penn. I'm the host of Earsay, the Audible and iHeart audiobook club. This week on the podcast, I am sitting down with Ray Porter, the narrator of Andy Weir's audiobook Project Hail Mary, massive sci-fi adventure about survival and science and what happens when you wake up alone very far from Earth. I really had to make a decision because I caught myself getting that frog in my throat and starting to get teary as I'm narrating some of these sections. And it's like, OK, yo, yo, yo, is this indulgent? And I really thought about it. I was like, no, at this point, it would kind of be betraying the trust the author and the listener have in telling this story if I don't go through it.

43:35But there's places in this book that deeply emotionally affected me. And I left it on the mic. That's great. Because it served the story. People will say like, oh, my God, I cried at the end. It's like, yeah, dude, me too. Listen to Earsay, the Audible and iHeart Audiobook Club on the iHeartRadio app or wherever you get your podcasts. Every business has an ambition. PayPal Open is the platform designed to help you grow into yours. With access to business loans so you can expand and hundreds of millions of PayPal customers worldwide. Your customers can pay all the ways they want today. With PayPal, Venmo, Pay Later, and all major cards.

44:13So you can focus on the future. When you need a partner trusted by millions, there's one platform for all business. PayPal Open. Grow today at PayPalOpen.com. Loan subject to approval in available locations. Eczema is unpredictable, but you can flare less with Epglyss, a once-monthly treatment for moderate to severe eczema. After an initial four-month or longer dosing phase, about four in ten people taking Epglyss achieved itch relief and clear or almost-clear skin at 16 weeks. And most of those people maintain skin that's still more clear at one year with monthly dosing. Epglyss, LibriKizumab, LBKZ, a 250 mg per 2 ml injection, is a prescription medicine used to treat adults and children 12 years of age and older who weigh at least 88 pounds or 40 kilograms with moderate to severe eczema.

44:56Also called atopic dermatitis that is not well controlled with prescription therapies used on the skin or topicals or who cannot use topical therapies. EBCLIS can be used with or without topical corticosteroids. Don't use if you're allergic to EBCLIS. Allergic reactions can occur that can be severe. Eye problems can occur. Tell your doctor if you have new or worsening eye problems. You should not receive a live vaccine when treated with EBCLIS. Before starting EBCLIS, tell your doctor if you have a parasitic infection. Ask your doctor about EBCLIS and visit ebgliss.lily.com or call 1-800-LILY-RX or 1-800-545-5979.

45:25Apple Vacations, where your story starts. The Splash into Savings event from Apple Vacations is here. Now through June 25th, save up to$150 on vacation packages, plus instant savings at select resorts in Mexico, the Caribbean, Central America, and top U.S. destinations. Use promo code JUNE26 for these limited-time offers. Start planning today at AppleVacations.com or contact your travel advisor. Apple Vacations, where your story starts.

46:06And we're back. And I would like to reiterate a point I made at the very beginning of the show, which is that we are not providing medical advice. And if you are interested in hormone therapy, you should talk to your OBGYN. And there's lots of great books out there now that you can read about this to prepare for chatting with your OBGYN. Especially me. I'm definitely not providing medical advice. I know the least about this of anybody. That's right. Kelly says, that's right. Don't listen to Daniel. About almost anything, but this in particular. Fair, fair. No, no. All right. Unless it's about aliens, in which case, definitely, there's no one better to talk to than Daniel.

46:42But there are people out there doing research on this. This is not completely unstudied, right? So what does the research say about taking hormones to reduce the impact of menopause? Well, the research says lots of different things because most of the research can't be done as a randomized double-blind trial. So this is the golden standard of how science is done. So you essentially take a group that you're interested in studying and half of them get the actual treatment, half of them get the placebo, which is like, you know, a shot, but it doesn't actually do the thing. It's like a shot with just saline or something.

47:17And then you compare the outcomes for those two groups. But nobody knows what group they're in. That's the golden standard for doing this stuff. But for a lot of reasons, it's often not ethical to withhold a medication from someone who thinks they need it. But there was this one big study where we did do a randomized double-blind control, and this is called the Women's Health Initiative. And what they did here was they had planned on tracking women for up to 15 years, and they enrolled tens of thousands of women, and they ended up in one of two different kinds of treatments. So women who still had their uterus got estrogen plus progestin.

47:57And so progestin is another hormone that's usually associated with women. Progestin is a synthetic lab-made version of progesterone. And so half of women who had their uterus got estrogen plus progestin, and half of them got a placebo. But nobody knew what they were getting, including their doctors. And then the women who didn't have a uterus got only estrogen. And the reason that this happened is because if you have a uterus and you take just estrogen, you have an increased risk of endometrial cancer. So the endometrius is the lining of the uterus. So if you are someone who has had your uterus removed, you don't have to worry about the risk of that cancer.

48:37But if you are a woman who still has her uterus and you add progestin, that seems to completely eliminate the risk of getting this cancer. And I think that's because estrogen is telling the lining of your uterus to like divide, divide, divide, divide, divide at certain times of the month. and progesterone's job is to tell your body, stop dividing, stop dividing, stop dividing. And divide, divide, divide is the sort of thing that cancer does. And so progestin is sending the stop dividing message. And so that is why you are less likely to get cancer if your hormone replacement therapy treatment also includes progestin.

49:19Oh, I see. So they had these two different groups. The study was being done in the best way that science can be done. They were supposed to be followed for, you know, eight and a half to 15 years, depending on what group they were in. But in July of 2002, they shut down the study for the group that was getting estrogen and progestin. And they reported that they shut it down because they had noted an increased risk of breast cancer and cardiovascular issues for this group of women. They also noted a reduction in colon cancer and a reduction in osteoporosis-related fractures, but they got worried about the breast cancer and the cardiovascular risks, and they shut it down.

49:58But what they probably should have done is made the scientific paper with these results available to everybody immediately when they announced it was getting shut down. But instead what happened was there was a press conference and they announced we're shutting it down because there's a 25 percent increase in breast cancer risk. And that seems to be the only thing that the press heard. And so in a bunch of different press outlets, they were announcing, you know, estrogen increases, breast cancer risk by 25 percent. And the percent of women who were getting hormone therapy dropped overnight. Something like 15 million women had prescriptions for menopausal hormone therapy in the 1990s.

50:40And by 2009, 70 percent fewer insurance claims for hormone therapy were being made. So anyway, hormone therapy use dropped a lot. In the United States. In the United States and worldwide, actually. I think in Canada it dropped, too, when people heard the results of these things. But you're right. My numbers were from the United States. Then they announced that the group that was just getting estrogen also was going to be stopped early because of a slight increase in stroke. They didn't see an increase in breast cancer or heart disease, and they noted a lower fracture rate and lower colon cancer rates.

51:12But because of this cardiovascular issue, they shut it down. So there's a lot of problems with this study, and one problem was with the way the results were interpreted and released. So doctors who weren't part of the study didn't get access to the scientific manuscript for a week after. So they weren't able to answer any questions about why this study got shut down. But in principle, it's not wrong to shut down a study if you do see increased risks for the people in the study, right? That's okay. That's right. But let's talk about that risk. So for the placebo group, so the group who was not getting hormones, the risk of breast cancer was 4 out of 1 ,000 women.

51:53For the women who had estrogen and progestin, five out of a thousand women were getting breast cancer. Is that where the 25 % comes from? You go from four to five? Yes, that's where the 25 % comes from. And so that's what we call relative risk. But your absolute risk, your absolute risk of getting breast cancer has only gone up by 0.08%. This one study found this small increased risk, but the way it was reported made people feel like the risk was huge. But again, I'm not a doctor. I love how we're on one hand saying you should talk to your doctor about this. We are also saying, wow, doctors don't seem to know what they're doing or don't seem to be well-educated on this topic.

52:34That's a good point. So I read a book called The New Menopause by – you said her name earlier, Katrina. Mary Claire Haver. Yeah. And she noted that there is now training through some medical association where people can pass a test and show that they have been trained on the cutting edge of our knowledge of menopause. And so you can find these lists of OBGYNs who have this training online. From the Menopause Society. Yeah. Yes. Great. Thank you. And so you should search out one of these people because you're right. Exactly. Most doctors don't know, but there are experts. Thank you. That's a good question.

53:10Don't ask your dentist about menopause. Go find somebody who knows what they're talking about. But there was a really interesting article in the New York Times about two years ago about the history of hormone replacement therapy that actually cited the data from the study that you just talked about. So that was the first time I got to see that data. And my jaw dropped just from the numbers you were talking about that those tiny numbers influenced so many people. And my own doctor had been very convinced by that study and was unwilling to look when I showed her the numbers. This was not something that they were open to changing their mind about.

53:46Now they'd spent two decades telling thousands of people that hormone replacement therapy was dangerous because of increased breast cancer risk. And those ideas are very solidified in people's minds. But I actually have a visiting sabbatical researcher in my lab right now from Taiwan, an OBGYN. And I asked her how this study influenced medical practice in Taiwan. And she said that actually they did not take the data seriously. They saw those numbers and they did not change the recommendations about hormone replacement therapy in Taiwan. Wow. Which I thought was fascinating. So they had, honestly, a more scientific, rigorous look at the data.

54:26And I was really glad to see that there are societies where people look at the science and make decisions that are sometimes more rational. I think everyone was doing their best in this situation, but it had a lot of negative impact on people's lives. There was another problem with the study, I think, which is that the age group didn't reflect younger women who were just entering menopause. I think the average age of the women in that study was maybe 60. I don't remember the details, but that was another reason that the risks would be very different compared to what they would be for a younger woman.

54:59So from what I understand, the safest thing to do, not medical advice, but from what I understand, the safest thing to do is to replace the hormones as you're entering menopause so that you have a more seamless supply of the hormones. And the hormones are given at levels that are much, much lower than you would biologically have access to them. So it's still a trickle compared to what your ovaries would produce. but it's enough to be a little bit protective of joints and bones and so on. I think this also speaks to something else people struggle with understanding statistically, which is that inaction and caution is not always safety.

55:40Just because I understand these people don't want to give cancer to the people in their study, but stopping the treatment doesn't necessarily mean saving people's lives. It's just like we haven't studied the effect of Tylenol in pregnancy because you can't do studies on pregnant women, it's not ethical. That doesn't mean that if you're pregnant and you have a fever, you shouldn't take Tylenol, right? Like sometimes inaction is more dangerous than action. Yeah. Like taking Tylenol when you have a fever and you're pregnant is critical. That's way safer for your baby. Like having a fever while you're pregnant could be quite dangerous.

56:13So not medical advice, not medical advice. Yeah, definitely not medical advice. Talk to your doctor if you're pregnant and you have a fever. But to go back to Katrina's point about the age of the participants. So yeah, the average age was 63. They were almost certainly post-menopausal. Oh, wow. And now there's pretty good evidence that estrogen is good at preventing problems, but it's not a cure once the problems have kicked in. And so if you start estrogen therapy before you've completely entered menopause or pretty soon after, then it seems to actually help with a lot of things, particularly quality of life, but maybe even things like osteoporosis risk, cardiovascular health, stuff like that.

56:53But if you start the therapy 10 years after menopause has begun, then you suffer increased risks of a lot of things. And so it does seem like there's this critical window where you have to do it. And so this study sort of set itself up for finding failure by looking at women who were beyond the age. And I think at this point, we didn't know that there was an age where it was good to take it and an age beyond risk should seem to have more negative impacts. But it's important to keep that in mind when you're thinking about the results of this study that this is not the typical person who would even be considered for these therapies anymore.

57:27And these days we use a lot of different kinds of estrogens and progesterone. So for example, there's some risk that these hormone therapies can increase clotting. And clotting can be bad for a lot of reasons. If a clot gets stuck in your brain, you can have a stroke. But if you take the hormone therapy on a patch on your arm instead of on a pill, it looks like that reduces the clotting risk. So something about the hormones needing to go through your liver before they can make it into your blood to do their work increases the risk of clotting. But if you just put it on your arm, it goes right into your bloodstream, it bypasses the liver, and your risk of clotting goes way down.

58:05And so there's a lot of different kinds of hormones now, a lot of different ways that we administer it that makes this Women's Health Initiative study, you know, maybe not really relevant to what we have today and the groups of women that we would be thinking about giving this therapy to. And is there some plan for a new study to sort of complete the task that this earlier study was aiming for? Not as far as I know. So I read there's this book called Estrogen Matters, and it's an incredibly critical look at the Women's Health Initiative. And at the end, one of the points they make is that it's sort of unfortunate that we're in this position where this is the only big, random, double-blind control study that has been done on this.

58:44And for a variety of reasons, the study design wasn't great. And so we're sort of left without having really great data to make these decisions. And so people get observational data where they can. And, you know, we're coming closer to understanding the risks, but there's still a lot of question marks. And so when if you have a good doctor, this will be a discussion about the risks and the benefits and they won't be able to give you a solid answer. You're just going to have to weigh for yourself what risks you're willing to take relative to the benefits that you want to get. Yeah. And I think it's really hard to do these kind of studies.

59:17It's why we can't agree on whether eggs are healthy. I mean, there have been actually quite a few big association style studies. You mean eating chicken eggs? I mean, chicken eggs. Yeah, that's ironic for this conversation. It's been a while since we've had a cannibalism joke on the show. Thank you, Katrina. Wow, not where I was going. But yeah, I just mean these kind of studies where it's very individual, but the way that we need data to come from large studies can be really hard just because we're all so different. Like my personal favorite study designs for my microbiome studies are actually not randomized control where you have a placebo group and a treatment arm because people tend to be so different that it doesn't actually work very well to assume that your treatment arm and your placebo arm are at the same point in the start.

1:00:10So I actually prefer longitudinal studies where you use the starting point as the control and then you like watch what happens through time to each person as they go through the intervention. So just to clarify, instead of comparing one group with another group, you're comparing each person with their past. Exactly. Yeah. And sometimes household controls can be really valuable because people live in similar conditions in their households and their microbiomes tend to be very consistent within a household. That would be harder to do for a hormone replacement therapy study because it's not that often that you have women of the same age going through menopause in the same household.

1:00:47But maybe there would be ways to study that. I don't know. Yeah, but I think that, you know, we now have these options. And as Kelly said, you can talk to your doctor about the options and think about more than just this tiny risk of breast cancer that was revealed in a study that might not have had a good design. Because some of the other benefits, you know, can be quite substantial and unrelated to breast cancer. Well, speaking of cutting edge research, Katrina, can you tell us about your research, which involves lasers? Whoa. Okay. Yeah. I guess that was actually the real reason I was invited to this episode, isn't it?

1:01:28It sounds like science fiction, but believe it or not, I have a collaboration with scientists in the Beckman Laser Institute here at the University of California, Irvine, where the treatment to help with the genitourinary syndrome of menopause is to use a laser, which I haven't actually seen it with my... Tell us where you're putting the laser, Katrina. The laser is being used to treat the vaginal epithelia. And the purpose of this is to improve the vaginal wall thickness and circulation. So a really big symptom of menopause is vaginal dryness, urinary tract infections, and just general discomfort related to vaginal dryness.

1:02:22And so one measure of vaginal health is the thickness of the wall of the vaginal lining. And that can become thinner after you stop producing estrogen. And so in this study, the treatment is to use a laser, which, you know, is being used in a controlled manner to release a predetermined dose of lasery goodness. You're zapping it. But what does the lasery goodness do? Is it like the damage that thickens the wall? Or is it not Like, yeah, what's going on there? Damage sounds like destructive in a way that is maybe too extreme. But yes, it basically is almost like a swelling associated with wound healing, which brings liquid and circulation and healing to that area.

1:03:21And so what you find after the laser treatment is an increase in circulation and vaginal wall thickness and a decrease in vaginal dryness and an improvement in symptoms. And it's not just for research. Well, you know, lasers are physics. So I'm just going to chalk this up to the, you know, the famous physics biology. Yes, very important connection right there. It does sound like science fiction, and it's being done as part of a research study here at the University of California. In fact, we're still recruiting. So women both before and after menopause, paramenopause, postmenopause, premenopause are all invited to enroll in this study.

1:04:05And one of the benefits is that you might have the opportunity to learn about the composition of your vaginal microbiome, which is my contribution to the study. and this is not only done in an experimental way so in other parts of the world it's a normal treatment that's offered to menopausal women to use this laser treatment to improve vaginal dryness and the vaginal wall thickness the other standard treatment is estrogen cream so locally applied estrogen cream will also increase vaginal wall thickness and circulation so these are we actually are comparing those kinds of treatments in our study.

1:04:46Because when you add estrogen locally like that, it has really positive impact on vaginal health. But I can tell you from the vaginal microbiome perspective that when we got our first data set as part of the study back, normally we have to do really subtle statistics and it's sometimes hard to kind of tell the difference between the groups in our studies. But when you look at pre and post menopausal vaginal microbiomes, you see really clear differences. And in a healthy vaginal microbiome, you normally see domination by lactobacillus. There's a few different strains that can be the dominant ones.

1:05:24They're acid producing, so the vaginal microbiome thrives in a low pH, like high acid environment. And that's really happening in the premenopausal women in the study. But for the postmenopausal women, you can see that the lactobacillus become less abundant. And I don't mean to call it unhealthy because actually there's a huge swath of society that live perfectly healthy lives and don't have just one lactobacillus dominating their vaginal microbiome. So I always take issue when people try to define what health means because there's a lot of ways to be healthy. But to me anyway, it was just so striking that you could really see a signal in the vaginal microbiome postmenopausal.

1:06:04So the lasers bring back the lactobacillus? That's the question. So actually, I don't know the answer to that yet. We're still recruiting. So actually, I hope I that's that's kind of what I'm expecting. I'm very curious to see what happens. And I think we'll be able to see differences between what hormone replacement therapy does and what the lasers do. Or maybe they'll look similar. But yeah, that's the goal is to figure that out. So I'll probably need like two years to answer that question, if I'm honest. will bring you back on in two years. Well, I don't know if this reflects some sort of like genius experimental design, like understanding how photons interact with the biology, or if it's just like, well, let's just zap it with a laser and see what happens.

1:06:45Which is it? I think my colleagues would have a more reasoned response that was not just random zapping with lasers. You're being very patient again, Katrina. She's got to earn that medal. She has earned that medal. Okay, so I learned a lot from this conversation from Katrina. I learned a ton while researching this. There's a lot of books out there that you can read now if you want to learn more about perimenopause. And there's still a ton that we have left to learn. So I hope that we are investing more in women's health so more women don't end up going to the doctor and being told, we don't know what's wrong with you when it's menopause.

1:07:28And that should be one of the first things that people expect for women in their 30s, 40s and 50s. But one thing that really hit home while I was researching this and came across the list of all the symptoms is that middle-aged women are totally badass because we are accomplishing great things while dealing with all of this stuff on top of everything else. And, you know, jobs and sometimes kids. And anyway, way to go, fellow uterus havers or fellow women out there. I'm proud of us. I'm a big fan.

1:08:07Daniel and Kelly's Extraordinary Universe is produced by iHeartRadio. We would love to hear from you. We really would. We want to know what questions you have about this extraordinary universe. We want to know your thoughts on recent shows, suggestions for future shows. If you contact us, we will get back to you. We really mean it. We answer every message. Email us at questions at danielandkelly.org. Or you can find us on social media. We have accounts on X, Instagram, Blue Sky, and on all of those platforms, you can find us at D &K Universe. Don't be shy. Write to us. Running a business shouldn't feel like surviving a software group project.

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