Estrogen, Progesterone, and Testosterone: The Science of Hormones, Sexual Function, and Menopausee

Testosterone levels don't fall off a cliff in menopause. We need to be really honest about that. They actually start to decline in your 30s. They have a slow decline in your 40s. And the year before and the year after menopause, your body isn't like, oh, I suddenly don't have testosterone anymore. It's been low for a while. And so I don't think it's wrong ever to give testosterone, but I don't think we say, well, because now we're in menopause, we're not making testosterone. That's not actually physiologic. Yeah. You know, it's a therapy. The views and opinions expressed on on pause are those of the talent and guests alone and are provided for informational and entertainment purposes only. No part of this podcast or any related materials are intended to be a substitute for professional medical advice, diagnosis, or treatment. One of the most persistent problems in women's health care is that we've taken some of the most complex, intimate parts of women's lives, her hormones, sexuality, pleasure, pain, and identity, and either oversimplified them or avoided them all together. Today's guest is someone who has spent her career doing the exact opposite. Dr. Tammy Rowan is an obstetrician-gonecologist and leading gynecologic surgeon at the University of California, San Francisco, and an internationally recognized expert in sexual health. Her work sits at the intersection of hormones, anatomy, desire, pain, and autonomy. She doesn't just talk about sexual function. She studies it, teaches it, operates on it, and defends it in a medical system that has too often dismissed it. Dr. Rowan understands where so much of the confusion around women's hormones comes from. Conflating contraception with menopause hormone therapy, the fear around progestins, the lack of nuance in how we talk about testosterone, and the way sexual pain and loss of desire are still framed as psychological rather than physiological. Today, we're going to slow this down and get precise. We're going to talk about estrogen, progestin, progestins, and testosterone. What they actually do, where medicine went wrong, and how the confusion continues to harm women. We'll dig into sexual function in midlife, desire, orgasm, pelvic pain, GSM, and what is truly possible for women when care is evidence-based and not fear-based. This is a conversation for women who want clarity, not platitudes, for clinicians who want to do better, and for anyone who's ever been told that sexual health is optional or secondary. I'm Dr. Mary Claire Haber, a board-certified obstetrician and gynecologist and certified menopause practitioner. I'm also an adjunct professor of obstetric zygnacology at the University of Texas Medical Branch. Welcome to Unpaused, the podcast where we cut through the silence and talk about what it really takes for women to thrive in the second half of life. This episode is brought to you by Expedia and Visit Scotland. Start your story in Scotland. Experience the pull of wide, untamed landscapes and fresh cuisine that feels rooted in place. Discover castles steeped in legend and feel the genuine warmth from locals you meet in a place that will stay with you long after you leave. Start planning your own Scottish holiday today at Expedia.co.uk slash Visit Scotland. Instagram teen accounts have contact limits on by default, so teenagers get messages from people they know, not strangers, and default content settings. Plus, teenagers under 16 can't change these default settings without parental approval, so parents can help teenagers connect safely. Learn more at instagram.com slash teen accounts. Dr. Rowan, welcome to Unpaused. Thank you so much for having me. Yeah. Glad to have you here. Let's dig into hormones. Okay. You teach a course if I have this correctly called hormone therapy, estrogens and progestogens. And then you teach another one called Let's Talk Progestins. When I tell you on social media, I get so many questions about hormones, what kind. So formulation and delivery, when, how, where, whatever. And so I promised our audience we would take it slow. And I was going to bring on it expert and do a really deep dive. Are you down for this? I am down for this. This is my favorite thing to talk about. Let's give our listeners a clear hormone 101, explaining the difference. So the biggest questions for listeners is contraceptive estrogens and progestin. Let's start there. Okay. So that's where women are first exposed to hormones. Absolutely. So, you know, we're talking about right now the hormones that the ovary produces. So there's hormones made in all different parts of our bodies. You know, we think about thyroid, we think about the pituitary, but in the ovaries we make estrogen, progesterone, and testosterone. Estrogen is the hormone that will basically grow the lining of the uterus, get it ready for pregnancy. You talk about estrogen all the time. I'm not going to jump too far into it. But when we talk about estrogen in the context of contraceptives, we're talking about ethanol estradiol. And the thing to understand about estrogen is it is a class of molecules. And so those are just compounds that in the body target a receptor. And so I think about it as a lock and a key, right? The key is the hormone, the receptor is the lock. And there's going to be different keys that fit into it differently. So in the body, there are three natural progesterones made by girls to adults. And in terms of the estrogens, those are estradiol, estrone, and estriol. I know you know this, you talk about it. Well, birth control doesn't have any of those three. Right. And that's where the confusion starts. So what does it typically have? It has ethanol estradiol. Why? Because ethanol estradiol is a more potent form that works better for the goals of birth control. And this is the key, is that the purpose of birth control is to suppress ovulation, prevent an egg from being released so you can't get pregnant. Now, you can do that with natural estrogen, natural estradiol. The issue is that the number one side effect of birth control pills is bleeding. And it is bothersome and people stop taking them because of it. Ethanol estradiol actually is very good at stabilizing the lining of the uterus and helping to prevent bleeding while also feeding back on the pituitary. That's the part of the brain that tells the ovary to get an egg ready. Ethanol estradiol feeds back, tells it not to do that. It's not the primary way birth control works. It's the progestin we'll talk about. But it feeds back and then it also stabilizes the lining very well. And this surprised me because I graduated from my training program, blew the top off my boards. I was always taught, and this was probably a word of mouth. There's really no big difference between estradiol and ethanol estradiol. Because I've looked at thousands of packets of contraceptive pills that there is ethanol estradiol. And I just assumed the ethanol fell off and you were left with estradiol, which is not what happens at all. It binds to the receptor 300 times stronger than plain estradiol, which is why it works so well for contraception. Yes. So exactly, it's that lock in the key. So imagine that you now have this lock that has a key that will not get off. So it is incredibly attracted to the receptor. It stays on it, but it doesn't even just do that. When it's staying on it, you can imagine that there's lots of different bodily functions that respond when there's estrogen in the system. So the main one we think about is the liver. So when the liver sees estrogen, it starts pumping out different types of proteins, and it also pumps out clotting factors. And so the early birth control pills had about three to four times as much ethanol estradiol. And so that was when we started seeing all the blood clotting. And we started saying, well, all estrogen causes blood clots. No, ethanol estradiol is going to do that. And then we start talking about things like testosterone in our body. Because if your body sees estrogen, it's going to make a protein to bind some of it up. That protein is sex hormone binding globulin. Well, it's going to make more of it in response to ethanol estradiol, just because of how potent that molecule is. And when SHBG goes up, guess what? Testosterone gets bound up, and your testosterone goes down. So there's, and there's so many different things that ethanol estradiol does. It's not actually as good in the bones for promoting bone health as natural estradiol. So there is some evidence in younger women that if they're taking ethanol estradiol, birth control, compared to those that are just having normal cycles, their bone mineral density looks different by the time they get into their 20s. So I want to be clear. We are not saying that modern contraception is a bad thing. Modern birth control is a bad thing. I am so grateful it is here. I still use it. I still recommend it for certain patients in certain conditions. And I do menopause care because there is a pushback and a certain faction, especially on social media, that all contraception is bad. So stepping away at all from your natural cycle is not your best life. I really appreciate you saying that because it's actually something that I've addressed, I would say, on social media. And I think about as someone who's also board certified, subspecialty certified in complex family planning, I am someone who very much supports the use of birth control for many different things. It is incredibly valuable, including for preventing pregnancy. And if we're worried about blood clots and birth control, where there is nothing that's going to give you a blood clot more than a pregnancy. Right. Right. Yeah. And we're talking 100 acts in your first six weeks postpartum, or first two weeks postpartum. Pregnancy is the number one way. We have stasis and hyperquagulability. So yeah, all the side effects people talk about, they're like, it's going to affect my mood. It's going to affect my clotting. It's going to affect this. And all of those things are 100 times worse if you get pregnant. And these medications work to prevent that. And they have many other benefits. So I am not an anti-birth control person at all. But what I do think is important is distinguishing the two between natural estradiol and ethanol estradiol, because it gets confused, especially when we talk about menopause. Do you see a world where we would have an oral contraceptive or even transdormal agent that was effective with minimal side effects containing plain estradiol? So there actually is one. And so I- In Europe, correct? In Europe. And I wrote an article actually about it, because there was an article that was published comparing, it's a 17-beta estradiol, and it has a specific type of progestin. We'll talk about what that means in terms of the other component of it that they think was going to be better for sexual side effects. So they compared the sexual side effects of this pill to the worst offender when it came to sexual side effects of the traditional birth control pill. And I wrote an editorial about it, because that's apples to oranges to compare these two. But the reason that we don't have it here, one, is that the regulatory environment around birth control is a little bit different. There are different types of birth controls in Europe. But the big side effect of that medication is abnormal bleeding. And so, yes, we can do it. People ask me that all the time. They're like, why doesn't it have 17-beta estradiol? I'm like, this isn't a conspiracy. We're not trying to keep people from natural estrogen. We're trying to help them take their birth control. And if they bleed, they won't. What if we had a combination of estradiol and basaldoxamine in a dose high enough to suppress ovulation? Would you buy it? I would if it would suppress ovulation. If it suppresses ovulation. I'm not convinced it would. But if it did, that would be great. Yeah, because we're going in the weeds. But basaldoxamine is a serum and it protects the enemies from lining. It binds blocks and down regulates the estrogen receptor in the breast and uterus. So people don't bleed on it. So for my menopause hormone therapy patients who are having interactable bleeding with their traditional MHT, we are very quick to reach for the do-it-be. Yeah, I love that medication. And I love it. I'm using it actually all the time in patients who are at high risk of breast cancer. So the issue. We buy digress. Sorry. Yeah, the issue is the way that birth control works is mainly through the progesterone and progestins. It's the progestin specifically that feedback on the brain to tell the ovary not to ovulate. So the estrogen component is not the most important part of birth control. I did not know that is a fact. It is the progestin. I have been practicing OBGYN for 30 years. I did not know this. I honestly am so honored that I came to your podcast and actually taught you something you don't know. Okay, well, it makes sense because we have progesterone only contraception, but not estrogen only contraception. And you have to think about what is what is it doing? Your brain, you're trying to get the brain to tell the ovary not to release it. The only way it's going to do that is if it thinks it already did. What is the one hormone that is made in response to ovulation? Progesterone. So that's the receptor on the pituitary that if you sensitize that receptor, you're going to suppress ovulation. Damn it. Okay. Menopausal hormone therapy. How is that different? Menopausal hormone therapy has a different goal, right? The goal of it is not to suppress ovulation. It is ideal to suppress bleeding, but we do that in many different ways. And you're not going to see the kind of bleeding side effect profile with the dosages necessarily. So menopausal hormone therapy is comprised of two different types of estrogens now. That's what we typically use. So one is either going to be estradiol. These are the FDA approved ones. So that is bio identical. It looks identical to what the ovary makes. And then the other one is conjugated equine estrogen. And that was developed earlier. You've talked about it on the show before. It has over 50 different estrogens in it. It's actually proprietary. When I looked into the history of this, I actually gave a talk a few years ago on it. I was like, no one knows what's in this. And so random estrillin and things I can't pronounce. But as I said, you have an estrogen receptor where there's actually two, an alpha and a beta. There's two other minor ones, right? So it doesn't matter what the estrogen is as long as it targets that receptor. So conjugated equine estrogen targets the receptor, and it's actually a little bit stronger at the receptor. And that's why we use it at a little bit of a lower dose, but it is more potent than natural estradiol. Okay. Staying on the estrogen topic for menopause. I get a lot of questions in the last three to four years when so many of us got educated, scrambled, figured stuff out. Most of us in this wave are using pretty much estradiol based and then progesterone. Okay. But years before, there was a small group of practitioners who were trained, I'm not sure where or how, who were using a lot of compounding because that's what was available. We didn't have a lot of education around the FDA approved options. And they were using something called bi-est and tri-est. Explain what those are, what's FDA approved, what's not, and what your thoughts are on those. I appreciate that question. So bi-est is kind of short for bi-estrogen. And what it is, is it is a combination of estradiol and estradiol. So estradiol is another form of estrogen that is bioidentical. It is oftentimes touted as, quote, safer in certain ways. But again, the way to think about this is there is an estrogen receptor. And so there are estrogen receptors all over the body. Estriol is going to work only on that receptor. And the only difference is what is its affinity. And it actually has about a 30% strength compared to estradiol for that receptor. So the idea that it is somehow safer doesn't actually make a lot of physiologic sense. It's just weaker. And so some thought can be put into, well, is it different? Will it affect the alpha or the beta receptor? This is really detailed. And so people will say, well, it's better at the level of the breast. But we have good data showing that estradiol is not dangerous for the breast. So I don't think estradiol is necessarily better in that way. Both of these are going to be a wash. And then Triost is going to be the same as the estradiol, estradiol, and then you're going to throw in the estrone, which is the other form of natural estrogen that's made in menopause. Is estrone pro-inflammatory? I've read that, but I didn't see good data behind it. There's not good data for it. We know that there is some inflammatory properties of just estrogen in general. To say it's pro-inflammatory is tricky because, again, it's only acting on a receptor. And there are some tissues where the estrogen receptor is pro-inflammatory. Now, where is it made? Let's walk around. I think our audience deserves a little bit of an anatomy lesson. Yeah. So I know it becomes, most understand it becomes the dominant estrogen in postmenopause because where are these estrogens made? Review that one more time. And in what kind of levels at what ages? Let's go through after puberty. Yeah. So I said that the ovary is where these hormones are made, but they're made actually in lots of other tissue. I mean, there is estrogen that is made in the gut. There's in the brain. And then there's also estrogen that is made in adipose cells. So those are fat cells. And so that's where you're going to see the postmenopausal estrogens made. And that's where estrone is mainly going to be made. Estriol and estradiol are mainly made in the ovary in something called the granulosa cell, if you want to get into my science textbooks. What about body identical versus synthetic? Lots, lots of drama on the internet about that. Lots of drama on it. So again, we're talking about some sort of molecule that is affecting a receptor. I think that when we talk about body identical hormones, when it comes to estrogens, that there is evidence, I would argue, that estradiol in some ways is it's less potent. So you're going to see lower rates of increasing and clotting factors with it. We have data on conjugated equine estrogen. That's the other one that's FDA approved for things like dementia. If you give it an older age, that conjugated equine estrogen is probably not beneficial at an older age for dementia prevention. And so I think that it really is what people tolerate. And we are now really favoring the transdermal approaches, which I just tell people, we're just mimicking what your ovaries are doing. I get this every day. You probably get it too, where they're like, is this risky? And I'm like, I'm not giving you anything new. Your body has been exposed to this hormone for decades, and we're just replacing what your ovaries are no longer doing. Let's review for our listeners. We talked about contraceptive options. So premenopausal, generally used in premenopausal to prevent pregnancy. We have that's what is FDA approved for, what it was developed for. We use it off-label for lots of things, acne, cramps, heavy periods, premenopausal, dysphoric disorder, et cetera, to stabilize hormones. So some women do better that way. And then we have our premenopausal, postmenopausal treatment. And there is some overlap between the two. But then in general, postmenopausal hormone therapy is going to be estradiol for the estrogens. Yeah, because we're basically replacing what the ovaries are no longer making. So there's not really a reason to necessarily give somebody something that's synthetic. Certainly ethanol estradiol, unless our goal is to help prevent abnormal bleeding, or they need a contraceptive method. Then estrogens are easy. We're now going to get into, so the umbrella is progestogen. And then under that umbrella, we have the progestins, which are created or synthesized. And then we have progesterone, which actually has to be synthesized as well, but it is the natural occurring form. So they are often portrayed as the villain. We're seeing, and I do want to get into progesterone intolerance. There's so much more than I ever knew. But they are essential to keep you from getting into mutual cancer when you're using estrogens. And they're essential for contraception, which I'm still going to have to marinate on that for a little while. Talk to me about what the data shows about what are progestins. Give me your hormones 101. Yeah, so this is my favorite topic because progesterone is the- Everyone's asking, people are, all right, everyone pause, get out your pencils, hit record. Here you go. This is the world's expert, I promise. All right. So progesterone is just the most underappreciated hormone. We talk about estrogen and testosterone all the time, so you just seem to perk it out of my cold, dead hands. I know. Well, so progesterone is very interesting. So progesterone is one single hormone that is made. There are not multiple types of progesterones made by the human body. There is one. It is progesterone, and there is one progesterone receptor. It's actually in the pathway to the production of testosterone and estrogen. So what I think is so interesting about progesterone and people don't talk about is that this is a molecule that can actually be turned into multiple different really important hormones in our body, and it becomes really relevant when we talk about how the progestins, the synthetic progesterone, how they work, because natural progesterone has a very strong affinity only for the progesterone receptor, and there's one progesterone receptor, there's one progesterone molecule, and there are progesterone receptors all over the body, just like estrogen. Yes. Wow. So like where? So there's progesterone receptors in the brain. So we, I know that. We think about it in terms of, yeah, catamennial seizures, we hear about this where if you give people progesterone, it actually raises the seizure threshold, which means it makes them less likely to have a seizure. But there are progesterone receptors in the lung, so we know that people who take progesterone actually may have, it facilitates gas exchange. Now this is the opposite of estrogen. Estrogen in the lungs can sometimes inhibit it. Right. And we see this worse. Yes, asthma gets worse, but progesterone actually is beneficial in the lungs. There are progesterone receptors in the gut, and so it helps with gut, you know, I wouldn't say it helps with gut motility, it affects gut motility. Why do we get so constipated in pregnancy, a high progesterone state, right? It slows the gut down. I had a patient who came to me and she was, had really significant constipation, and her GI doc sent her to me, and you know, we see all these zebras where they're like, could it have anything to do with her hormone therapy? And I was like, let me think this through. Yes, you're taking natural progesterone. I bet that this is slowing your gut down and it's causing intractable constipation. There are progesterone receptors in the liver, there's progesterone receptors in the pancreas, there's progesterone receptors all over. So in the breast, obviously, sorry, I skipped that part because it was so obvious. What about muscle and bone? That's not a place that we see a lot of progesterone receptors, but in the breast, absolutely. So progesterone is what basically really helps with breast development. And in pregnancy, it's the progesterone that stimulates the mammary glands to get ready to release milk, but it actually prevents lactation until the pregnancy is over. And it's the drop in progesterone that induces lactation. Now, progestins, and how are they different than progesterone? So progestins are synthetic progesterone. Essentially, it is a molecule that has been created. Developed to prevent a pregnancy with lots of side effects. Exactly. So that was how they were originally developed. They were part of the combined hormonal contraceptives, and they were pretty high doses, just like the estrogen component. Very high doses. A lot of the early studies in side effects are from those high doses. But progestins, each of them has a little bit of a different formulation. And remember, they're designed to target the progesterone receptor. They target it better than natural progesterone, at least the progesterone that we take exogenously, which means we take a pill. So if we took natural progesterone, it would dissolve immediately in our body. So the way that we take natural progesterone is we micronize it. We turn it into this small molecule that will last longer so that we can get progesterone stimulation in our body. Progestins work better, to be honest, on the progesterone receptor in the uterus specifically. So they're better at preventing abnormal bleeding. They work better in the brain. It's incredibly hard to take enough natural progesterone to suppress ovulation. So that's why the progestins are much better at telling the pituitary, hey, I've got progesterone, I released an egg, don't release one. So the issue with the progestins, though, is remember how I told you that progesterone can be metabolized into the mineral corducoids and glucocorticoids? Well, progesterone naturally will not target anything but a progesterone receptor, but the progestins will. And so this is... Because we have like 25 on the market, different progestins. And they work differently. One's better for acne, one's better for sex. Because it's not just the mineral corducoids. Where are they binding? They're binding the androgen receptor as well, and they're affecting the androgen receptor. And the androgen receptor is what testosterone binds to. That's why you get different side effects, because they target the receptors differently. This is why this is the best topic. So drospirinone looks very different from most of the common ones. Remember, it is the one that is approved to prevent acne. Well, that's because it blocks the androgen receptor very, very well. And so that's a really specific type. And so if that's your goal, it's great. Well, as a sexual medicine expert, it has the worst sexual side effects. Because it blocks the androgen receptor. I heard anything good for your skin is bad for your sex life. The other ones we talk about a lot are norethindrone and norethindrone acetate. So the brand name is Agestin for norethindrone acetate. Norethindrone is actually the mini pill. When we talk about the very low dose progestin only birth control. Well, norethindrone metabolizes into ethanol estradiol. This is a little known fact. How? The molecules are actually very similar. Remember how I talked about how progesterone can be turned into estrogen? And so if progesterone can be metabolized into estradiol, well, then norethindrone can be metabolized into ethanol estradiol. How did I not know this? This is not common knowledge. But the key, so let's talk about it. Have you heard of adbac therapy? So if you gave Lupron and you give adbac therapy, what are the adbac therapies that you give? It's been a minute. Estradiol. Estradiol and or Agestin. So, okay. Okay, yeah. Why? Right, the question is why? So the goal of adbac therapy is to mitigate the side effects of something like Lupron that puts you into menopause, hot flashes, bone loss. For our listeners, we give Lupron in several situations, like for someone preparing for IVF, we want to kind of block everything to start fresh. But we used it for endometriosis. Exactly. When we could get it approved. Now it's almost impossible. But if you get it approved, then they go into menopause and we're trying to limit their bone loss and their hot flashes and all the side effects. So why would giving a progestin minimize? No one taught me to ask that question. And I wasn't smart enough to ask it on my own. It's a very reasonable thing. None of us were taught that, but it makes sense. Why would this progestin somehow magically be the only one because it converts into ethanol estradiol? And so it mitigates hot flashes. It can prevent bone loss. It also stabilizes the lining of the uterus partly through its progestin action, but partly through its ethanol estradiol action as well. Provera is another one we use. So that's medroxyprogesterone acetate. We're all very familiar. Yes. This one is the most potent at the level of the uterus. So it's probably the best, at least in the commercially available doses. North Indra and acetate is actually a little more potent, but we use higher doses of provera. So it works very well to control bleeding. That's why it was used for so long. Depomodoxyprogesterone acetate, that's depoprovera, is like a huge dose that we use for birth control. So provera works very well at suppressing ovulation, blocking the effect of estrogen in the uterus, but it is unique in that it stimulates the glucocorticoid receptor. And that's why people get so bloated on it. So when you see people that have different reactions to different progestins, that's why. And medroxyprogesterone acetate in some studies looks like it could stimulate breast cells in a way that makes you concerned that it could increase the risk of breast cancer. Now, I've talked about what the WHOI really showed in terms of breast cancer, but provera was what they used in that study. It's always been considered the villain when it comes to things like breast cancer risk. But all the progestins are going to affect breast cancer cells a little different. And natural progesterone seems to be the least likely to stimulate breast cancer cells. And the data we have, we only have five years worth of any natural progesterone. There's never been an increased risk with natural progesterone. Getting dressed shouldn't feel harder than it actually is, but for most women, it does. Closets are full, yet somehow nothing feels right. Too many options, not enough pieces that actually work together. And no one has time for the cycle of ordering, returning, and hoping the next thing fits better. That's where Daily Look comes in. Daily Look is the number one highest rated premium personal styling service for women. Each client is paired with a dedicated personal stylist who curates a box of clothes based on your body shape, preferences, and lifestyle, delivered right to your door. These are personal stylists, not an algorithm. You work with the same stylist every time, allowing the stylist to truly get to know your needs and your style preferences. You can receive up to 12 premium pieces per box, try everything on in the comfort of your home, and keep what you love, then return the rest. 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Women need access to clinicians who actually understand the science of female aging. That's the gap Midi was built to close. Midi is focused on health span, not just lifespan. That means looking at your metabolic health, bone density, cardiovascular risk, and cognitive function. It's the kind of proactive, evidence-based care I've always believed women deserve, and it's exactly what Midi delivers. And here's what matters most. Women in all 50 states can access this care, covered by insurance, with clinicians trained in the latest menopause and longevity science. Because your zip code should never determine your access to quality menopause care. Book your virtual visit today at joinmidi.com. That's joinmidi.com. So when I was utilizing oral hormone and contraception, so birth control pills, or the patch or the ring, for my patients, I, to be honest, knew some of the side effect profiles. But I kind of had an idea of where to start, but knowing no one ever sat us down and walked us through the endocrinology of it all and how it worked. And that would have just made prescribing and explaining to patients, I would basically say there's a lot of stuff we can try. Yeah. And we don't know what's going to happen to you. And you could have all these things, or you could get on it, and it's the greatest thing since sliced bread, and you're doing great. But it may take a lot of trial and error. I will say no one ever had this conversation or lecture with me, and I went to the top family planning program in the United States, the way I was taught, and this is not to throw shade on my wonderful, wonderful professors, but it was pick a pill, any pill, they all work the same. When I got into practice, I was like, they don't all work the same. And I started looking into this, and I started realizing that they target different receptors. Some of them metabolize into each other. So leave-in-adjusterol is one that we see all the time. It's used in IUD, it's used in birth control pills. Well, many of the other types of progestins just metabolize into leave-in-adjusterol. So if you're like, oh, I'm going to try a different one, well, it's just going to turn into leave-in-adjusterol in the body. And so knowing why would somebody do well with the next planon, knowing that the type of progestin in the next planon, that's the subdermal implant, is identical to the progestin that's used in the vaginal ring contraceptive. So if someone didn't do well on this method, I'm not going to give them the vaginal ring necessarily. And so getting really familiar with the progestins just opened up this whole world. So I love taking these histories and then figuring out, and I've had a really good success helping people find a progestin that works for them. I was a residence program director until 2018. So we're going on 10 years. This was not part of the curriculum. Is it part of the curriculum now? I've been away from academic. It's not. I will say that when I was taking my complex family planning board, so what's nice is when that became a subspecialty certification, for those of us that didn't do a fellowship, we could actually just take the exam and then get certified in it. This was something that came up and we were teaching each other about it and I was so excited because I already knew about it. And it started getting more discussed, but I am not sure even in our residency if we're getting this. But I talk about it when I give grand rounds and when I give my progestin lectures because I get really excited about this. It's important. I think it's so important. What advice would you give a woman who is struggling to find the right combination to work for her? Yeah, so this is really tricky. For using it for birth control purposes, it has to have a progestin. But if we're using it for menopausal hormone therapy, if you have a uterus, we have to do something to protect your uterus. So we can do trial and error of different ones. What I oftentimes find, I will say, is that because Dross-Spirinone has a very different molecular structure than the other progestins, it usually is kind of my go-to when everything else has failed. And it's been shown in PMDD, for example, premenstrual dysphoric disorder. It's the only FDA-approved medication for that because all the other birth controls don't work. It became my go-to. Yeah, because they act like progesterone in the brain. So instead of being like, I'm only going to have progesterone two weeks a month, now you've got it four weeks a month when you're taking a traditional birth control. And that's why Dross-Spirinone works better. If you could correct three myths about progestins, what are three things you would correct about? I would say the progestogens in general, one is that they're dangerous. I mean, I think that everything we do is a balance of risks and benefits. The fact that people think they all work the same, they don't. They work differently. And the idea that they're identical or interchangeable with progesterone, they're not. They're different. You said the magic word, testosterone. I know you've co-authored major reviews on testosterone in women, including the methodological challenges and studying it. For our listeners, what is the evidence support for testosterone today? So in women, the best evidence that we have shows that the only true indication that shows that if you give testosterone compared to a placebo, you're going to see an improvement in sexual desire and potentially satisfying sexual events in mainly post-menopausal women. And then I would argue also in perimenopausal women. That's where the best data lives. And we can talk about what the evidence is for a lot of the other reasons that people like to use testosterone. Let's go because the internet's exploding right now. It is very, very, very interesting. Let's go organ system by organ system. Brain. Start with cognition. There are multiple studies looking at testosterone and cognition. And the tricky thing about cognition is how you measure it. So there's lots of different ways. What Lisa Moscone taught me was forever the cognition studies were, does she have dementia or not? Not was she a high functioning attorney and now cannot remember her words, but she does not have dementia. It was like, does she have dementia or not? That was the scale. Not has she lost something so critical for her day-to-day activity, but she still doesn't have dementia. Well, it's the same thing as people saying dementia or brain fog. Right? And so it's like, if people say, well, if I take this, it's for a brain fog, that means it prevents dementia. No, those are two different things. If your hormone is keeping you from having brain fog, that's actually very evidence-based. So Lisa says, brain fog is, I can't find my keys. Yes. Dementia is, I don't know what my keys are for. That is a very good way of putting it. So when we study cognition, there's the shopping list memory test. There's the, how did you perform on this verbal recall test? There's lots of different tests. And what you're going to find is, in the testosterone studies, where people were given testosterone and then asked to perform various tasks, you're going to see a big variety in whether or not they got a benefit. So one study will say, okay, they had verbal memory recall was better, but the shopping list recall wasn't. If you gave them numbers, they remembered it, but then the shopping wasn't. And they get these really granular outcomes. If you look at all the cognition studies together, and you look at, was this quote statistically significant? That means, does it look like the, if there's a benefit, could it have not been due to chance? Almost all the studies show that any benefit could have also been due to chance when it comes to cognition. That's my takeaway from what the evidence shows, but I always talk about the difference between group data and individual data. Right? If a woman tells me, I started taking testosterone and I felt like I could remember my shopping list better and I could remember where I put my keys. And I, that brain fog went away. I'm not going to tell her that that's not true. Why not? Because there are people trying to control this narrative on testosterone who are telling women that's not true. I think you can say the studies of a hundred women, and this is where I know that the, you know, other people listening here who go based on all the studies are going to be like, how can you say this? Well, this is group data. If you take a hundred women, you give 50 of them a placebo and 50 of them the medication, there's going to be 20 women in that medication group that did get better. And maybe in the placebo group, there's a similar amount. That doesn't mean those 20 women didn't get better, you know? And so if you look at an individual, they may see an improvement, but across an entire group of people, you didn't see the signal that met significance. How do you counsel your patients then? That's what I tell them. I usually say, you know, there's group data versus individual data. I don't believe that the group data on testosterone shows that it improves cognition because it doesn't. That's really where the data is. But if someone is taking testosterone and they say, I feel good on this and my cognition is better, I'm not going to tell them that A, that's not true or B, we're going to take it away because I might have given it to them for libido. You know, and maybe their libido didn't get better, but something else did. Okay, let's go to mood. Stay in the brain, mood. Yeah. So if you look at, there's actually several studies looking at mood. And I just put together a talk because I'm giving a, you know, a long course at the International Society for the Study of Women's Sexual Health. Which you are the president of last president, Dr. Timmy Rowe. I'm so honored actually to have been elected into this role. I give all of the Sunday closing lectures, which is, you know, it's a lot to keep people there, but this is where I've given my protestant lectures and, you know, my PMDD lectures, but the testosterone lecture has been really the funnest one to put together because I know how much is out there in social media. So the mood data is actually really interesting. Almost all of the studies looking at mood and testosterone actually favor testosterone, but all of the quote, confidence intervals cross one, which means that they are not statistically significant. But it's different than like cognition, where you see it kind of all over the place. The mood ones actually consistently trend towards a benefit. But again, if you are looking at, could this be due to chance? Absolutely. And could it be due to the placebo effect? Absolutely. Things like mood are incredibly affected by the placebo effect. And if we talk about the story of libido and testosterone, I've got a great story about how the placebo effect is the entire reason that we don't have an FDA approved product for women. It's because of that placebo effect. Do you want to hear that story? Yes. Okay. So in the early 2000s, there was a lot of data coming out, looking at testosterone for low libido. There was a patch, a 300 microgram patch that was studied. It was brought to the FDA around 2007 for approval. And the FDA said we can see that it seems to improve libido, so sexual desire, as well as satisfying sexual events. But we are not comfortable with the safety data. We do not have enough safety data to prove that it doesn't cause breast cancer, for example. Now remember, this was in the aftermath of the WHI. Viagra had six months of safety data, just to whisper that there. We've covered that ad nauseam on this podcast. But say it again. I'll say it again. People died in the Viagra trials. But we did not. People have died from Viagra. They did, and they still got fast track approval in six months. There was such an unmet need of erections. I will say, as being married to a urologist who also focuses in sexual medicine, we have wonderfully robust debates when I talk about this, because he will definitely argue on behalf of men and their sexual function. And I have a lot of empathy for what it means for men after going to all these sexual medicine meetings. And I have even more for women, because we can't get a product approved, because we have to prove that it doesn't cause breast cancer. The amount of money that would be needed to do that, when in the patch studies, there was no increased risk of breast cancer. We have lots of data showing, actually, that it doesn't seem to increase the risk of breast cancer. Either way, what's so interesting is there was a company that then said, okay, we will do this. We will pay for the study that is required to show that there is not a signal for breast cancer, that it is safe. And it was a gel. It was a 1% gel. It was BioSanti was the company. The medication was called LibiGel. And the phase one and phase two trials were absolutely amazing. Well, in the phase three trials, these were the randomized control trials. They showed that those that took the testosterone gel had four more satisfying sexual events per month than before they took the gel. That is like Viagra level effect. That is more than any of the patch studies showed. It's better than any of the other studies. The problem was, so did the placebo group. Both groups had this huge increase in sexual desire and satisfying sexual events so that it was not statistically significant. The company went bankrupt. And this is why we do not have a product now. So that is the power of the placebo effect. Giving a woman permission to use a product. Turn the key for some of those women. Yeah. Okay. So we don't have an FDA approved product. How do we get it? So the way that we get it now is we can use FDA approved products that are approved for men. I borrow the men's version. Exactly. The benefit of the FDA approved product is you know what you're getting. Right? These are well regulated. You know exactly what's in them. The problem with the FDA approved products is that it's a pretty simple calculation to talk about the difference between how much testosterone a man has versus what a woman has. Now, the goal when we're treating with testosterone is to restore the level to what it was at our peak. And that would be in our mid 20s. So physiologic ranges. There's a lot of misunderstanding about this. So I want you to throw out numbers in the way they're traditionally measured in the US. Got it. So in the US we measure testosterone in nanograms per deciliter. And so the normal range will oftentimes see quoted between 15 and 70. But that's the 70 is kind of on the extreme I have to say. The best study that was done, it was published in the Journal of Sexual Medicine. The numbers looked more like between you know 15 and 45. But the truth is those were using old outdated ways of measuring testosterone. And this is why the level question gets so confusing. There are two different ways to measure hormones. And the one in almost all of the studies that we look at for even for menopausal hormone therapy used an older way of measuring that oftentimes overestimated. Because remember we talk about how estrogen, testosterone, progesterone, they're all related to each other. Well, their metabolites would all show a signal. And so they would get overestimated. And so the newer ways that we measure it are not included in most of the studies. So I just put that out there for the levels. But the natural physiologic level, if you look at my lab, it tells me at UCSF if the level is above 50 to 55, it's in the high range. That's outside normal. And if I test someone in their 20s, say I'm working them up for irregular periods, for example, I'll usually see levels around 30s to 40s for normal these patients don't have PCOS. So that's what I usually think of as like the physiologic level. So that's kind of my goal. I usually say my goal is 40 to 50 in a peri- or post-menopausal woman, nanograms per deciliter. That's physiologic. OK. All right. So formulations. So the formulations, if you're going to give the male product, men will usually use these products either a tube or a gel. They'll use one pump or one tube a day. Now you have to remember that the average male level, I just told you my goal is 40 to 50 nanograms per deciliter. Well, men have like 400 to 800 nanograms per deciliter of testosterone. So we're looking at 1 tenth to 1 twentieth. Right. That's our target. So you want to be using 1 tenth. We always say 1 tenth, but the truth is it's really 1 tenth to 1 twentieth. And so I typically will tell people to get a PPD syringe, like a, you know, small 1 cc, 1 milliliter syringe, draw up between 0.3 and 0.5 of a tube of gel and then rub that into their inner thigh someplace where you don't want children to touch. Right. These are women who oftentimes have small children or where they don't mind hair growing because you can actually get hair growth at the site of where you place it. If you're going to do the pump, so for the men, there are pumps. They use one to two pumps a day. Women can use those pumps, but then you're going to want to be doing like one to two pumps a week. And so what you're going to end up getting with that is these peaks in levels and then a valley. Right. If you use it on Monday, you're going to feel probably absolutely amazing because you have a very super physiologic level and then it's going to crash before you get the next one. And so it can be hard to dose. And we should talk about what super physiologic levels mean because this is something that I think we're seeing all the time when they come from other clinics through compounding and especially through pellets. So women have been prescribed testosterone for decades with no FDA approved option. And because we were never trained, I never touched testosterone ever in residency. And I didn't start using testosterone until about three and a half years ago. And thank God my ish wish friends taught me how to use it and sent me the guidelines. Depends on the clinician if she likes the packets or she likes the pump. You know, so I do want to just put a statement about the packets specifically. So packets are oftentimes if you order testosterone as a 1% gel, test stem, they'll give you packets. You do not want to use packets for women. Okay. This can and I've seen this actually like, you know, in some documentaries about testosterone use where we, you know, show the packet packets have alcohol in them, it will dissolve. So if the minute you open it, you take one dose out, it's done for. So you want to be very specific. You want the tubes. I did not know that you want the tubes, you do not want the packets. And so I put all over my prescription tubes, not packets. And the pharmacist will say the only thing we have are packets and I'll show them the generic tubes that are available where they can order them from and be like, no, you can find these. Okay. That is, I did not know this. It's very, yeah, it's a very misunderstood. I use the pump. Yeah. So it's, I mean, I prescribed the pump and I use it myself. Talk to me about, well, we can't say much about compounding other than it's out there. I don't think compounding is the devil the way a lot of people do. And I don't want to demonize appellate. It is simply a method of getting something inside someone's body. But let's talk about what's actually happening in real life. Exactly. So I think, you know, compounding pharmacies are not bad people. I do think that there is- No, I use them all the time. All the time, right? They are a drug delivery system, you know? And so people who can't get hormones a different way, it's a wonderful way to do it and testosterone doesn't have a lot of options for it. So going compounding, the problem with the compounding pharmacy, so these are pharmacies that will take the raw material and formulate it into a product. And so we're usually going to be using a testosterone cream in that sense. So we want a one, I usually will get a 1% cream and my goal is two to five milligrams a day. So I'll oftentimes start at two milligrams and work my way up. So remember when we talk about those tubes, right? If the FDA approved product, it's a 50 milligram tube, one-tenth of that is five, right? So we just do the kind of simple math. So that's our goal when we're doing the compound. That was when I started prescribing testosterone. I did compounded. I went to the guy down the street, had a long conversation with the pharmacist. We did the math together and we started with five. Exactly. It was just very reasonable. Before I became comfortable doing the FDA approved options. Yeah, it's very reasonable to start with five. Now, the other way that people do it is some people do subcutaneous injections. I'm familiar with people doing injections of testosterone because I take care of transgender people who do inject themselves and cis men inject themselves with testosterone at very high doses. And then pellets, physiologically, I'm not here to demonize them. I get why people like them. Someone doesn't want to use the medication every day. You say, okay, we're going to put an insert under your skin. The problem with the pellets is you have no idea how they're going to be absorbed. And so you will see people with incredibly high levels of testosterone coming in, losing their hair, covered in acne, and we have to then give them spironolactone and other medications to counteract the effect of the testosterone they were taking. So that's the problem with pellets. Some people will argue, well, you can get pellets in these really low doses. And I still say, again, you can't take it out once it's in. You don't know how you're going to respond. So I don't recommend pellets. I understand why people use them. I just don't recommend them. Most of the practitioners in our area are using a certain company. And in my clinic, when I'm seeing a patient, I'm always checking at testosterone level, especially if they've been prescribed. I want to see how they're absorbing and where they are before we restart the medication. And I've never seen a patient who wasn't super physiologically dose. But what does that mean? So super physiologic means that your level is above that target that we talked about earlier. So what is that kind of in a naturally physiologic state, you don't have a other condition like PCOS or an oberian tumor, adrenal tumor. What is a normal circulating state? So we already talked about really, I think of the goal as 40 to 15 nanograms per deciliter. I've seen people quote up to 70 is reasonable to say, if you look at the literature, I've heard people on other podcasts or big names say up to 80, which is not based on physiology. At that point, you're now super physiologic. I've heard as high as 100. Yeah, again, this is not over 100. Like, let me explain to our listeners, if we have a woman come to clinic and we're working her up for acne and hair and whatever, we check at testosterone level. If it's above 100 and she's not on any medication, we are obliged to check her for a tumor. Absolutely. 100%. Like, I just want people to understand the gravity of like, when in a normal healthy woman who's not on meds, if we see a testosterone over 100, it is malpractice. If we don't work her up for a tumor. 100%. So, you know, people are familiar with the condition of PCOS. Yeah, I had 90. But 90 was my specific level with PCOS. You don't see people with levels above 100 or PCOS. And I had global acne and hair growth everywhere I didn't want it. I'm sorry. That's okay. We managed it. What's so interesting about that though is, you know, I do see women who have testosterone levels above 100 and they don't have acne and they don't have all the hair growth all over their face. I'm Cajun. No. Well, but it goes to show that, you know, these people with super physiologic levels, I'm seeing them all the time. Now, oftentimes it's not me that's giving them that dose. I mean, it never really is, but sometimes I'll give somebody the normal dose and I'll check her level and they're super absorber. And so they have really high levels. And the truth is, some of them feel fabulous and they really are getting all these benefits without all of the side effects. And then it turns into a conversation. And I just want to be real about this. At that point, I'm not here to say it's bad. I've oftentimes hear people say it's dangerous. I take care of transgender men who have testosterone levels in the 500s and 600s. They, you know, have uteruses and ovaries and the data actually shows they have lower rates of breast cancer. There's some question about cardiovascular risk, question about diabetes. I'm not here to say it's not without risk. But what I want to be really honest about is at that point, this is not menopausal medicine. This is not physiologic replacement. This is a performance enhancing drug. And if you are taking it at those levels, that's what it is. And I'm not here to pass a judgment. I just think we should all be honest if we're at super physiologic levels, that that's what testosterone is. And that's oftentimes people who have some of the strongest side effects in terms of benefit. Right? Do you remember the New York Times article that recently came out? It's because they're on a performance enhancing level of testosterone. Okay. If you have a woman who feels absolutely fantastic is not having side effects, what do you do? Do you lever on it? To be honest, yes. And I know that that's against the guidelines. And I'm putting this out there for the world. But the truth is, I talk about, you know, where we have the data, where we don't have the data. I know the transgender literature very well. So, but remember, they also have levels, you know, which is basically the safety data. That's the safety data. That is the safety data is on the transgender population. And I want to include them in this conversation because we talk about testosterone for women, for sexual function, for, you know, in this idea of gender affirmation to feel more like themselves, to, you know, have all these benefits. And yet we're trying to take it away from our transgender people right now. And it feels like there's this, you know, like contradiction. And the data that we have is from the transgender people. And this patients are frustrated because it is FDA approved for the transgender patients, but not for them. That is a very fair point. And it should be, you know, it's not, well, I wouldn't say it's FDA approved for the transgender patients. It's covered by insurance. And so that is very, very, very different caveat. They're frustrated because they can't get their medication covered. And they should be by insurance. And it absolutely should be. Yeah. This episode of Unpaused is brought to you by Alloy Health. We talk a lot about hormones affecting mood and energy, but they also play a major role in your skin. Collagen, hydration, elasticity, and in midlife, when hormone levels start to shift, your skin changes too. I first heard about Alloy through a close friend who was a dermatologist. She shared how few products truly address hormonal skin changes. Once I understood that Alloy's approach is rooted in hormone science and physiology, I decided to try it myself. 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Primally, Pure's Blue Tansy products are designed to calm, stressed skin using real, biocompatible ingredients that work with your body, not against it. Blue Tansy is a calming blue antioxidant that helps soothe inflammation, redness, and irritation, which is especially beneficial for sensitive skin or for those people whose products tend to overwhelm rather than help their skin. Primally, Pure's Soothing Collection incorporates this ingredient across face and body, from their effective deodorant to the soothing serum and body oil, creating a cohesive and calming routine. They've become go-tos for our team with Simplicity Matters Most. Use code UNPAUSED to get 15% off your Primally Pure purchase, that's www.primalypure.com and use code UNPAUSED at checkout for 15% off your order. We had talked about the metabolites of estrogen and progestins. Can you cover the breakdown of testosterone and central and peripheral acting? Testosterone is metabolized in some tissue into estradiol. In the ovaries, you see it metabolized into estradiol in the bone and in the peripheral tissue. There's androgen receptors, but there's also estrogen receptors, so you're seeing it broken down there and where you're getting some of the benefits. It's also converted into another hormone called dihydrotestosterone. DHT is important because, exactly, you're pointing to your face because of acne. The thing to understand, you know I keep talking about receptors because I'm a nerd. There is no testosterone receptor, there is no DHT receptor, there is an androgen receptor. That is a lock that is then signaled by two keys, DHT and testosterone. Only testosterone and DHT bind to the androgen receptor. DHT binds with twice the affinity and five times a sticky. It doesn't want to come off. The DHT is where you're going to see the androgen receptors affect the skin and the hair. That's why it's the villain when it comes to male pattern baldness or excess testosterone hair loss that we see in women as well as acne. When we're trying to treat acne and hair loss, that's the minoxidil, these various things that are actually blocking the conversion to DHT. We're not going to affect testosterone levels, we're going to affect DHT levels. How does spironolactone work? Great question. Spironolactone works by blocking production of testosterone and blocking the androgen receptor. It will affect your testosterone. It's different. That's why you will sometimes see sexual side effects from spironolactone and you will also see menstrual cycle effects from spironolactone in some people because you are now affecting the metabolism of estrogen in the body because you can't make estrogen without making testosterone. Some people actually stop their menses when they take spironolactone. What about local activity of testosterone in the general urinary system? So we've learned over the years that the dogma, that the general urinary system, the vulva and the vagina are only sensitive to estrogen is actually untrue. So remember I talked about the receptors, there's estrogen receptors and androgen receptors all over the vulva and it actually is going to play a big role. Similarly to the way that the estrogens do in terms of blood flow, I actually get really nerded out on this, that it helps to produce glycogen. So that is a sugar. That sugar is fed upon by lactobacilli, right? Anybody who knows anything about the vagina knows lactobacilli. It's the good bacteria. It's the good bacteria. What does lactobacilli make? Lactic acid. What does lactic acid do? Decreases the pH of the vagina and keeps it healthy. When you lose your androgens and your estrogens, you see a cascading pathway that will lead to an increase in the pH lack of that lactobacilli and then a recolonization with unhelpful bacteria. Oh my god. So for recurrent BV, how are you treating this? So I want to restore the natural microbiome. So I will give people, I mean, especially in menopausal women, like the bottom line is we need to restore their estrogens and then I'll give them androgens as well in the form of prostarone. And even for premenopausal women, I'll do that. If the FDA approved regimens aren't working, I think about what's going on in this microbiome. Before we pivot, talk to me about the Dutch test, since you are the endocrine goddess. No. Okay. Why? So it's this idea of they're testing usually salivary hormones and salivary hormones have never been shown to be correlated to blood level hormones. And again, I'm going to go back to the receptor. The hormone in your saliva looks different than the hormone that's in your blood. And the hormone that's in your blood is the one that is directly acting on the receptors. Right. And you talked about the metabolites and how they can convert to one another. 100%. So what you're excreting doesn't represent what's in your blood, nor what's going on in your cells. This is why we could have two different patients. One has a, you know, estradiol level of 80. And so with, you know, estradiol, we're talking about pica grams per liter. So it's a little different. It's lower actually. But if you, we could have two patients with the exact same estradiol levels with totally different side effects because of how, what's happening at the level of the receptor. Same is going to be the true for testosterone. That's why when people say test my testosterone level, you know, prove to me that I have low sexual desire. I'll say I have two patients with the exact same testosterone level. A sexual desire is much more complicated than just testosterone. But that's why you see people feel good at different levels of hormones. Now I'm not somebody who treats to levels. I treat to symptoms for this reason. Do you ever check levels? I do actually. So with testosterone, I always want to get a baseline. I want to know where we're starting. I don't, you know, some people say if the testosterone level is in the kind of higher, normal-ish range, they may not get a benefit. I disagree with that. Again, how sensitive are the receptors? If I give them a little bit more, they might feel a little bit better, right? And then if I'm treating them continuously with testosterone, then I'll recheck it six weeks to see what the level is at, certainly depending on their symptoms. Estrogen, it'll be the same. If I give somebody menopausal hormone therapy for estradiol and they're not getting a benefit, I'll absolutely check and I'll see how much room do we have. And I have patients who really feel better at really high levels. And we have to have a conversation that this is higher than an average circulating estradiol in a premenopausal woman. But remember, in premenopausal women, our estradiol levels are in the multiple of hundreds, you know, around the time of ovulation. Talk to me about absorption. We use a lot of transdermal estrogen. I don't use much. I never use transdermal progestins anymore. You shouldn't. I always do oral micronized and we'll talk about progesterone insensitivity, is a whole topic. But, you know, I was thrilled to see the data come out of the clinic in the UK from Louise Newsom's clinic and her data talking about, hey, not everybody absorbs the same. Turns out a significant percentage of us are poor absorbers. Me. I had a patient. Oh my gosh, I loved this patient. She had terrible endometriosis. She was in her 30s and we did a hysterectomy and an uferectomy. She elected for an uferectomy because, you know, she really wanted to not have her ovaries and have control. There's a risk, obviously, of giving someone estradiol after an endometriosis surgery, but she wanted it. So I gave it to her and she felt absolutely nothing. And she said she took the entire box and put every single patch on her. And I just, I picture this woman covered and had to do it in patches. And I'll never forget this because I tested her levels and they were postmenopausal. And that was when I had this epistemic. She would not absorb. This woman would not absorb transdermally. And so I gave her oral estrogen and she did. We always talk about, oh, we have to do it one way or the other. No, you do it the way that works for the woman. And some people don't absorb through their skin and so give it to them orally. It's fine. You can also give it to them vaginally. The vagina is the most sensitive tissue for absorbing hormone. You know, it goes directly into the bloodstream through the vagina. Now I don't want to confuse patients to think, oh, my vaginal estrogen, my doctor prescribed me for GSM is going to treat my bones and brain and no. Thank you for the clarification. If you give a dose high enough, not any of the FDA approved products or how we do anything like this is very special or fem ring just to be specific. Exactly. There is one systemic vaginal estradiol ring that you can use 100%. Thank you for the clarification. When we are using vaginal estrogen, the goal is to treat the vagina. It will not go into the bloodstream. But if you want to get a blood level that's high in the system, you actually can put high doses in the vagina of all of the hormones, estrogen, testosterone and progesterone. Anybody who's been through fertility treatments is aware of this because they're putting a bunch of progesterone pills into their vagina. Why are they not taking it orally or why are they not injecting it? Because it works better to take it vaginally. Okay. They have better absorption rates. We do a lot of abnormal. It's just easier to check everybody rather than wait to see who's absorbing, not absorbing. So like for all our transform patients do a three month check. I think that's great. I mean, you could do it just, you know, again, I think it's a very reasonable approach. Sometimes if somebody, you know, is worried, you can check earlier just because the minute you give them a patch within a few days, you know, we hear their symptoms get better. What I do sometimes worry about is this idea if you get a level and they're like, oh, but that's not what my friend's level was or that's not the level I read about. It becomes a little bit tricky. And this has got the nuance. Some clinics are doing, everybody gets the same thing and it's a one size fits all and there's so much nuance to this. Now, what is progesterone intolerance? Okay. So progesterone intolerance is the fact that progesterone affects a lot of different receptors. And we already talked about that there's progesterone receptors in the brain, but some people are incredibly sensitive to progesterone. And we know that because think about premenstrual dysphoric disorder, that is progesterone intolerance. So that is when you get, you know, anxiety, depression, all kinds of symptoms that start at ovulation, peak mid cycle, and then go away when the period starts. Well, that is based on your progesterone levels. So we can already see that that when someone's going maybe be predisposed, if there's somebody that was sensitive to their own endogenous, their own natural menstrual cycle. So that should be a red flag. It's a red flag. Someone who had postpartum depression, that's somebody who was very sensitive to progesterone fluctuations. These are people who are going to be more likely oftentimes also to have worse perimenopausal symptoms and worse symptoms in menopause because progesterone levels fluctuate. They don't get high. They're actually lower as you are in the perimenopausal transition. But some people, when you give them progesterone, I mean, I had a patient who was suicidal from her progesterone. We've seen this and she had to be hospitalized. So that's the extreme and I don't want to scare anyone off. I don't want to scare anyone off, but it happens. And so that is, it's so people can get really significant mood changes. Some people just get too sleepy on it. Some people get horrible headaches. And I've seen the paradoxical effect for sleep. And so what do you do for those patients? Great question. And again, this is where there's so much nuance. And I love this conversation. And this is why menopausal medicine is so fun. And it's not algorithmic. So you can't just say, if this do that, it's like everybody's individual, you got to take a history, right? And think about what's going to work for them. So I do prefer to start with micronized progesterone if they have a uterus, phantom neutral protection. And then for some people who don't even need it, some people do get a benefit from it. But if I give them, you know, micronized progesterone and they start having these side effects, I will switch to a progestin. As I said, these are not the double, they work very well. And so typically the one I will give, I like North Indrone acetate, Agestin. I like that better than Provera. We've talked about, you know, we just don't use Provera outside of, you know, get your bleeding to stop, you know, in emergently, but it's not, it is not a medication to take long term. It's not just the concern about the breast. It's actually vasoconstrictive. If you look at the WHI, I know you spent a lot of time with this, but if you look at the cardiovascular outcomes, they were worse in the combined group. We always talk about the breast cancer group, worse in the combined group too, because Provera had is vasoconstrictive. And so cardiovascularly in the older women, they did worse with it. It's just not a good medication. So anyways, I go with North Indrone acetate, and then I'll also do a lot of Drasperinone these days. And so people tolerate it. North Indrone acetate looks a little bit more like progesterone. What about Combi patch? Combi patch is a combination of North Indrone and estradiol. It's a great method. I actually give a lot of patches. That's how I started. And you know, people again are like, oh, everything has to be bio identical. But I'm like, you need to just be able to take it, right? Like if people just want one thing, the Combi patch is great. It's hard to get covered by insurance. And it has it, but it's a North Indrone. Climera Pro is another combination patch that has leave an adjuster. We haven't talked about that as much, but that's another really good progestin. Both of them are designed to protect the uterus. If people can't tolerate those forms, slend is a great method. What is slend? Just spiranone only medication. You can also do a leave an adjuster IUD. So that's going to be an IUD that goes directly into the uterus. It's putting the progestin. It's the best way by far to protect the endometrium. It not only prevents uterine cancer, it cures it in about half of people who have an early stage cancer. It is the best for that purpose. And then if they can't tolerate any of them, then I will do duovee. Or if they don't want to take anything else but one pill, and if they're at high risk of breast cancer, we already know that conjugated equine estrogen prevents breast cancer on its own. That's what's in duovee. Then you add in a serum. Oh my God, you get even more bang for your buck. So patients that are really concerned, again, I've got a lot of opinions about the breast cancer risk. I know you've had even Blooming on here who debunked the myths around it. But there are people who are still concerned, but there are people with high risk biopsies. We use it because women who are survivors, pre-vivors, high risk have nowhere to go. They end up in our clutches. And so I use duovee probably a hundred times more than anyone else in Texas. I believe it. You know the other group that I love using duovee for two groups. One is the endometriosis patients. Because the estrogen is going to stimulate any endometriosis. So you've got now this serum that'll block. Now remember, 30% of endometriosis isn't sensitive to progesterone. And so those are endometrial cells. I did not know this. Yes. That's why they don't work for so many people. That's why you end up needing surgery and so many things. Otherwise it would be okay. No, endometriosis looks, the tissue in endometriosis looks very different than natural endometrial tissue. Very different receptor morphology. So I like duovee for those patients. And then the other patients I like duovee for is refractory PMDD. And you know, they don't respond to birth control pills because you're giving them another progestin. So their body's exposed to it. And that's premenstrual disorder. Thank you. Yeah. So that's the progesterone hypersensitivity. So what I do for those patients is I actually suppress their menstrual cycle entirely. We already talked about Lupron. So that will just shut off their menstrual cycle, but they need hormone. But I don't want to give them any progestin. I refuse to give unopposed estrogen. I just want to say that's my practice. I just refuse. Then I give them duovee and I have saved so many women by giving them Lupron plus duovee for refractory premenstrual disorder. Welcome back to another MIDI PAUSE. I'm Dr. Mary Claire Haver, host of UnpAUSEed. If your clothing has been fitting differently lately and you haven't changed a thing about how you eat or move, you're not imagining it. And it is not your fault. Today we're talking about changes in body composition. Hormone awake gain can be one of the most frustrating parts of the midlife journey. But with the right support from medication to lifestyle tweaks, you can feel like yourself again. That's why MIDI Health is dedicated to changing the way menopause is treated with a personalized approach to each woman's specific needs. Women come to MIDI Health to address the symptoms of menopause they see and feel every day. They partner with you to find a treatment, whether that's HRT or a non-hormonal solution, a weight loss medication, or simply a lifestyle change. Hormones play a major role in midlife weight gain. When estrogen levels begin to drop during perimenopause, our bodies can start to change, even if our diet and exercise routines have not. Instead of accumulating in the hips and thighs, it moves to the abdomen and that visceral fat. The kind wrapped around your organs raises your risk of heart disease, diabetes, and dementia. This isn't vanity. This is a health issue that deserves real solutions. The good news, this real fat responds to lifestyle changes. And here's where to start. Number one, prioritize protein, fiber, and reduce your sugar intake. Aim for at least 30 grams of protein per meal and 25 grams of fiber per day. Cut added sugar to under 25 grams daily. These three shifts alone can meaningfully reduce belly fat over time. Number two, lift weights. Resistance training is the single most effective tool for changing your body composition and menopause. Number three, protect your sleep and manage stress. Both poor sleep and chronic stress drive cortisol up. Cortisol feeds visceral fat. You cannot out-exercise a stress response. Number four, consider a conversation about hormone therapy. HRT can help address the hormonal root cause of this fat shift. Women who start estrogen therapy early in menopause often see a meaningful improvement in body composition. Ask your clinician. Progress starts with a personal plan. That's why the MIDI approach centers on a holistic combination of solutions from medications like weight loss medications to lifestyle changes in a care plan that works for your body and your needs. By doing so, MIDI health is setting a new standard for healthcare. As the nation's fastest growing women's telehealth company, MIDI provides accessible insurance covered services. Building on its leadership in perimenopause and menopause, MIDI fills the critical health gaps women face at every age and life stage. If you want a clinician in your corner who understands what your body and brain need right now, that's exactly what MIDI is built for. Go to joinmidi.com, joinmidi.com and connect with one of their clinicians today. I've got a few questions coming from my listeners and on social media. Can I, you ready? Always. Okay. What do you wish women in their 30s and 40s understood about choosing contraception for pregnancy prevention, cycle control, mood, and sexual function? So I think what I would, I wish they would understand is that birth control is not bad. It does so many good things. I just talked about the fact that if you are sensitive to your hormonal fluctuations and you want them to go away, you're going to get that only with birth control. I mean, there's nothing else that does that. The natural hormones don't. No supplements. No. Sorry. If you want to stabilize your hormones, you got to use birth control. And so what I would say is I take a really good history when I'm picking a pill to figure out what people's priorities are. So what are their worries and their priorities? If it's around bleeding, if it's around sexual dysfunction, if it's around acne. And so I am again, not a pick a pill, any pill person. And I will tailor which one I recommend based on their priorities. Hormonal contraception seems to be being blamed for ruining libido. So there is a biological explanation for how this does it in some women. Okay. And this is the key. We talked about group data versus individual data. If you look at the group data, you're going to find that there are many women who actually feel a benefit from birth control. Both, like I think not just the psychological freedom of it. I mean, birth control was the original sex med drug. All right. This allowed us to be honest about why people have sex. You take birth control so you can actually enjoy sex. Right? That's what it's for. We're not trying to destroy libido. But again, combined hormonal contraception will increase sex hormone binding, globulin and decreased testosterone levels. And everybody that takes it doesn't mean they're all going to have a sexual side effect. They just will have lower testosterone. Some of them are antiandrogenic like thrust spironone. Right? So that's your Yas, your Yasmin. Those also have a double hit then. Some of the birth controls don't do that. So the IUDs don't is really what it comes down to even the hormonal one. Leaving a gestural actually is a little proandrogenic. So that's why people get acne with the IUD. Right? And so that's the main thing. And then the there is also a subgroup of people who I just saw somebody yesterday who I cured. I'm sorry. I'm so, so happy when I see people who had sexual pain from long-term birth control use. There's a subset of women who do develop a vulvidinia. This doesn't happen to everybody. Again, don't stop your birth control for this reason. But if you over time develop sexual pain, it could be due to long-term use of birth control. And so if that's happening, see somebody who knows that and knows how to treat it. How did you fix her? I gave her back compounded estradiol and testosterone. The FDA approved. I'm not going to just give her estuary screen. She's got androgen and estrogen receptors. So I give her a little bit of a higher concentration than what you can get FDA approved estradiol and then a very low dose of testosterone. And then she don't want to get off that birth control. I always switch them to something that is equally as effective because you really can do that. She was questioning it and then her physical therapist, you know, because she's going to PT and pelvic floor PT. Yeah, pelvic floor PT. It's not doing anything because it's not a muscular issue. And a smart PT was like, you really should get off this particular birth control. And she did. And she's like, it was so satisfying as a sexual medicine provider to do an exam. And I'm like, you're a different person. And she's so happy. How would you help a woman navigate perimenopause? I think it depends on what their symptoms are. So the earliest symptoms of perimenopause, we know this, are not the ones that we always think about like the cycle irregularity or the hot flashes, it's sleep and mood. And so I honestly have found that in the early stages of perimenopause, you know, I always talk about how people have a progesterone sensitivity. That is one place I see people that do good if I give them solo progesterone therapy. How do you give it? So I give micronized progesterone. I usually will have them take it orally at night. Now, progesterone works twice as well absorbed if you take it with food. So we always tell people to take it at night, but it's not going to work as well if they're too far from their last meal. So I usually tell people to take it right after their last meal. It's going to work better. They may be tired within two to three hours. So it just depends on what their, you know, bedtime is. I heard take it with a scoop of peanut butter. That is a reasonable way to do it. It's an oil based molecule, it'll bind up to that peanut butter and then get absorbed. So that's probably why, why you do it with the peanut butter. So anyways, again, if the goal is sleep, then I have them take it orally. The sleepy side effect of progesterone is actually probably due to its metabolites. So what it's broken down into. So if people get too sleepy on it, but their mood is better, I have them place it vaginally because then it's not being broken down. The same little tablet. You can just take the little tablets, the mic, the promitriomiconized progesterone. It's a little tablet. Just put it in the vagina. Amazing. Why does my orgasm change in midlife? Oh, I wish it didn't. A couple different reasons. So orgasms are very complicated. You've had lots of good speakers talk about this, but in midlife, there is a change. First off, we're aging and we have to be real that not everything is hormones, but some of it is. And so if the tissue is getting more, we call it atrophic, we don't like that word. But if you're getting thinner tissue because of lack of hormone, you're going to have less blood flow. You will oftentimes, if you are someone who gets clitoral orgasms, you can see adhesions that form. The vagina also gets thinner. People also get a lot of stimulation from their vagina. So it can be hormonal. It also can be the nerves that are aging. And so that is something that is a little bit hard to, you can't treat that as easily as you can treat the hormonal changes. And then there's a musculoskeletal component. So orgasm has a lot to do with your muscles. And so if somebody, depending on if they have lax or muscles or overactive muscles, they may also notice a difference. Why don't I want to have sex anymore? I feel broken. Oh, I, you know, I'm giving you the easy ones. And those are so hard. So sexual desire lives in the brain. The brain is the biggest sex organ. And there are so many reasons that people don't want to have sex. I wish it were as simple as testosterone. I think we have to be really honest about what happens to testosterone levels. What percentage of people like, like walk me through the success of testosterone. What does that really look like? So if you look at the data, about 50% of people get better, I will say clinically, I don't see that number. I wish I did. I see less. But you're kind of a clinic of last return. You know, that is fair. That is, that is totally fair. I mean, other people are possibly getting, and it's not because I'm not giving them the way to do it, you know, appropriately, but I will say that, you know, if you look at the data, it's about 50%, which is the same for the other sexual medicine drugs. If you're keeping them physiologic, I will say when people come in with super physiologic levels, they may see the difference. Now, again, I'm not promoting super physiologic levels. Most of the data, again, all the studies we have on libido were at some of, again, if you look at the old assays they were using, some of them really were super physiologic, but that's in the weeds. So I would say it works probably for about half of people. But again, you know, testosterone levels don't fall off a cliff in menopause. We need to be really honest about that. They actually start to decline in your 30s. They stay, you know, they have a slow decline in your 40s. And the year before and the year after menopause, your body isn't like, oh, I suddenly don't have testosterone anymore. It's been low for a while. And so I don't think it's wrong ever to give testosterone, but I don't think we say, well, because now we're in menopause, we're not making testosterone. That's not actually physiologic. Yeah. You know, it's a therapy. It's not a replacement. It's a therapy for symptoms. Sexual desire and pharmacologic management. So there's too much that are FDA approved. Also, you want to just briefly cover them? Absolutely. So remember, I said the biggest sex organ is the brain. And the way to understand sexual desire is that it's neurotransmitters. It's the way that the brain cells talk to each other. So testosterone modulates those neurotransmitters. It's dopamine and norepinephrine. There are two medications that also affect those neurotransmitters. One is called flabansaurin. It's a mixed serotonergic drug. So it works on serotonin, which then modulates dopamine. It is a nightly medication, 100 milligrams at night. It works again in about 50% of people. You see similar results in the testosterone studies as in the flabansaurin studies, in about half of people. But those that it works in, it can work very well. So it helps people sleep. They're not too drowsy the next day. They've done next day driving studies where they did even better. It takes about two to three months to see an effect. Because it works on serotonin receptors, oftentimes people say, I just feel better. They actually will say the same thing. Well, wasn't it originally developed to treat depression or something? It was. Yeah. So because it's a serotonergic drug. So in the 90s, they were using it to treat depression. And it didn't meet clinical endpoints. But the people reported an increase in libido. Now, what does that sound like? Viagra. Viagra was originally developed as a blood pressure medication. Didn't work as for blood pressure medication, but the men wouldn't give it up. So it's very similar, but it is not the female Viagra. People oftentimes say that Viagra works on blood vessels. It vasodilates. It causes an erection. Flabansaurin works in the brain. So it's about two to three months. A lot of people just say they feel better on it. And then the other drug is Bremilanotide. And so that is an injection. It's a melanocortin receptor agonist. And so again, these are just functional molecules in the brain work the same way. Increase your dopamine, increase your norepinephrine, mainly dopamine. It's as needed. So it's different than these other medications like testosterone or flabansaurin that you have to take every day. The biggest side effect from Bremilanotide is nausea. And so the more you take it, the less likely you are to have nausea. The benefit of it is if it doesn't work, it's not going to work. So it's not like flabansaurin, which I use all the time. And I have results. You have three months to figure it out. With Bremilanotide, if you use it three or four times and you don't get a benefit, you'll know. And if you use it and you get a benefit, you'll know. This is the thing about sex met, I say all the time. There's no condition in medicine that everybody has a relationship to. We talk about the fact that everybody with ovaries is going to go through menopause, right? That's 100% of people with ovaries. But 100% of people have a relationship to sex. They may not have ever had a heart attack or diabetes or anything else. And our own relationship to sex, we project on to other people so much. And I think this is why it's been so hard for people to get care, because they'll say, well, nobody wants sex at this age, or I didn't want sex, right? Or sex is not spontaneous desire, is not good, or it is good, or receptive desire. Everybody's an individual. And our goal is to support those individuals and not project our stuff on to them. Excellent. Well, thank you so much for joining us on OnPause. And I think our listeners are going to benefit so much. Thank you so much for having me. It's been a total pleasure. You can find Dr. Rowan on Instagram and TikTok at Dr. Tammy Rowan. She is also the president elective Iswish, a major resource in sexual health for clinicians, researchers, advocates, and consumers, and can be reached at info at iswish.org. If you're a prospective patient, you can find her at www.ucsfhealth.org, where she is available for surgical and procedural consults, as well as complex sexual health menopause and survivorship consults. You could find full episodes of UnPause on YouTube at Dr. Mary Claire. I'd love to hear from you about this topic and anything else that's on your mind. You can find me on Instagram at Dr. Mary Claire, and get honest and accurate information on health, fitness, and navigating midlife at thepauselife.com. My new book, The New Perimenopause, is available now on Amazon. If you're loving this podcast, I have an important request. Please take a moment to follow UnPause on your favorite podcast app. Following and listening is what pushes this information to more women who need it. So if this podcast has helped you feel seen, understood, or supported, hit follow right now so you never miss an episode. Thank you for being here with me. Let's keep going, UnPause. UnPause is presented by Odyssey in conjunction with PodPeople. I'm your host, Dr. Mary Claire Haver. The views and opinions expressed on UnPause are those of the talent and guests alone, and are provided for informational and entertainment purposes only. 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