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

21:22Dr. Mary Claire Haver:Talk to me about what the data shows about what are progestins. Give me your hormones one on one. Yeah. So I this is my favorite topic. Because progesterone, everyone's asking people. 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 see me perk up. You will take 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.

22:01There 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.

22:37And there are progesterone receptors all over the body. Just like estrogen? Yes. Wow. So like where? So there's progesterone receptors in the brain. I know that. We think about it in terms of, yeah, catamenial 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.

23:10Right, asthma gets 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, 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 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.

23:42Yes, 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. Breast. 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.

24:14But it actually prevents lactation until the pregnancy is over. And it's the drop in progesterone that induces lactation.

24:23Dr. Mary Claire Haver:Now, progestins, and how are they different than progesterone? So progestins are synthetic progesterone. Essentially, it is a molecule that has been created 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 and 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.

24:57They target it better than natural progesterone, at least the progesterone that we take exogenously, which means we take a pill, right? 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.

25:36Yeah. 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, right? So the issue with the progestins, though, is remember how I told you that progesterone can be metabolized into the mineralocorticoids and glucocorticoids? Well, progesterone naturally will not target anything but a progesterone receptor, but the progestins will. And so this is -

26:00Dr. Mary Claire Haver:We have like 25 on the market, different progestins. Different progestins. And they work differently. One's better for acne, one's better for sex. Yeah, because it's not just the mineral corticoid receptors. 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. What does drospirinone do? 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.

26:33And 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 receptors. 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 Agustin for norethindrone acetate. Norethindrone is actually the mini pill when we talk about the, you know, very low dose progestin only birth control. Well, norethindrone metabolizes into ethanol estradiol. This is a little known fact.

27:06Dr. Mary Claire Haver:How? The molecules are actually very similar. Remember how I talked about how progesterone can be turned into estrogen, right? And so if, you know, 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 ad-back therapy? So if you gave Lupron and you give ad-back therapy, what are the ad-back therapies that you give? It's been a minute. Estradiol. Estradiol and or agestin. So why, right? The question is why? So the goal of ad-back therapy is to mitigate the side effects of something like Lupron that puts you into menopause, hot flashes, bone loss.

27:50Dr. Mary Claire Haver:So 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. Well, why would giving a progestin minimize? No one taught me to ask that question. And I wasn't smart enough to ask get on my own. It's a very reasonable thing. None of us were taught that, but it makes sense, right?

28:21Why 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 Endrone acetate is actually a little more potent, but we use higher doses of Provera.

28:55So it works very well to control bleeding. That's why it was used for so long. Depo-Medroxyprogesterone acetate, that's Depo-Provera, 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.

29:31Now, I've talked about what the WHI 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.

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31:22Dr. Mary Claire Haver:That's dailylook.com, code UNPAUSED. Hi, my name is Lloyd Lockridge, and I'm the host of a new podcast from Odyssey called Family Lore. In this podcast, I'm going to have people on to tell unusual and sometimes far-fetched stories about their families. I've heard my whole life that she invented the margarita. And then we're going to investigate those stories and find out how much of it is true. He gets a patent one month before the Wright Brothers. Oh, my God. Please follow and listen to Family Lore, an Odyssey podcast, available now on Apple Podcasts, Spotify, or wherever you get your shows. Many of you know I've spent my career pushing for better medical standards for women.

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33:28Dr. Mary Claire Haver:So when I was utilizing oral hormone and contraception, so birth control pills, or the patch or the ring, And, you know, 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, you know, 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 and 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.

34:08I 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, you know, 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 levonogestral 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 levonogestral.

34:42So if you're like, oh, I'm going to try a different one. Well, it's just going to turn into levonogestral in the body. And so knowing, you know, why would somebody do well with the Nexplanon, knowing that the type of progestin in the Nexplanon, that's the subdermal implant, is identical to the progestin that's used in the vaginal ring contraceptive, right? 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.

35:10And I've had a really good success helping people find a progestin that works for them.

35:15Dr. Mary Claire Haver:I was a residency program director until 2018. So it's, you know, 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, you know, 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.

35:44But 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.

35:55Dr. Mary Claire Haver: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. If we're 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 drospirinone has a very different molecular structure than the other progestins. It usually is kind of my go-to when everything else has failed.

36:26And 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, you know, 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 drospirinone works better.

36:48Dr. Mary Claire Haver:If you could correct three myths about progestins, what are three things you would like correct about? I would say the progestogens in general. One is that they're dangerous. I mean, I think that, you know, 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 in studying it.

37:22Dr. Mary Claire Haver: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 postmenopausal 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. around. Let's go because the internet's exploding right now.

37:57Dr. Mary Claire Haver:It is very, very, very interesting. All right. Let's go organ system by organ system. Brain. Okay. Start with cognition. Yeah. 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. You know, like 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.

38:34Well, it's the same thing as people saying, you know, 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. And if your hormone is keeping you from having brain fog, that's actually very evidence-based.

38:49Dr. Mary Claire Haver: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, you know, verbal memory recall was better, but the shopping list recall wasn't.

39:22If 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 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 that brain fog went away, I'm not going to tell her that that's not true.

40:03Dr. Mary Claire Haver: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 that the studies of 100 women, and this is where I know that the 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 100 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?

40:34And 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.

41:09Okay, 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.

41:20Dr. Mary Claire Haver:Of which you are the president-elect. Thank you. President, Dr. Tammy Rohn. 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 progestin lectures and 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.

41:56But 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. Right. 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.

42:34Okay. 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 nauseum on this podcast, but say it again.

43:15I'll say it again. People died in the Viagra trials, but we did not. We did not. People have died from Viagra.

43:22Dr. Mary Claire Haver: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.

43:57We 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, Biosante was the company. The medication was called Libby Gel. And the phase one and phase two trials were absolutely amazing. Well, on 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.

44:35That is like Viagra level effect, right? 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.

45:00Dr. Mary Claire Haver:Okay. Giving a woman permission to use a product. Yep. 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.

45:32Now, 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.

45:40Dr. Mary Claire Haver: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 U.S. Got it. So in the U.S., we measure testosterone in nanograms per deciliter. And so the normal range, you'll oftentimes see quoted between 15 and 70, but 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 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.

46:16There 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, right? 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.

46:52That'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 postmenopausal woman, nanograms per deciliter. That's physiologic.

47:16Dr. Mary Claire Haver:Okay. All right. So formulations. So the formulations, if you're going to give the male product, right, 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, right, 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 one-tenth to one-twentieth, right? That's our target. So you want to be using one-tenth. We always say one-tenth, but the truth is it's really one-tenth to one-twentieth. And so I typically will tell people to get a PPD syringe, like a small one CC, one 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?

48:08These 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.

48:43And 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

48:51Dr. Mary Claire Haver: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. 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, Testim, they'll give you packets.

49:32You do not want to use packets for women. And I've seen this actually in some documentaries about testosterone use where we show the packet. Packets have alcohol in them, it will dissolve. So 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 this. 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.

50:07Okay. That is, I did not know this. It's very, yeah, it's a very misunderstood aspect.

50:10Dr. Mary Claire Haver:I use the pump. Yeah. So it's, I mean, I prescribe the pump and I use it myself. So 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 a pellet. 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 was - 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.

50:41And 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.

51:13So that's our goal when we're doing the compound.

51:16Dr. Mary Claire Haver: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 or people who do inject themselves. And cis men inject themselves with testosterone at very high doses though.

51:47And 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 and 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.

52:22And 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.

52:32Dr. Mary Claire Haver: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 a 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 dosed. But what does that mean? So super physiologic means that your level is above that target that we talked about earlier, right? So what is the kind of in a naturally physiologic state, right? You don't have a other condition like PCOS, right? Or an ovarian tumor, adrenal tumor.

53:06What is a normal circulating state? So we already talked about really, I think of the goal is 40 to 50 nanograms per deciliter. I've seen people, you know, 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. Right. I mean, I've heard it's high of 100. Yeah. Again, this is not - But over 100, like,

53:27Dr. Mary Claire Haver: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 a 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 testosterone You don't see people with levels above 100 with PCOS.

54:02Dr. Mary Claire Haver:And I had horrible 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 a level and they're super absorber.

54:32And 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 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.

55:10This 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 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. wrong.

55:38Dr. Mary Claire Haver:If you have a woman who feels absolutely fantastic, is not having side effects, what do you do? Do you leave her 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. It's true. 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.

56:17And 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 the cis 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. I apologize. I apologize. But that is a very good point.

56:42Dr. Mary Claire Haver:They're frustrated because they can't get their medication covered. And they should be. By insurance. And it absolutely should be. Yeah.

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1:00:20Dr. Mary Claire Haver:We had talked about the metabolites of estrogen and progestins. Can you cover the breakdown of testosterone and central and peripheral acting? So testosterone is actually metabolized in some tissue into estradiol. And so 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. But it's also converted into another hormone called dihydrotestosterone. And so DHT is important because, exactly, you're pointing to your face because of acne.

1:00:57So 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. And so that is a lock that is then signaled by two keys, DHT and testosterone. So only testosterone and DHT bind to the androgen receptor. And so DHT binds with twice the affinity and five times as sticky, right? It doesn't want to come off. And the DHT is where you're going to see the androgen receptors affect the skin and the hair. And 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.

1:01:40So 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. So we're not going to affect testosterone levels. We're going to affect DHT levels.

1:01:53Dr. Mary Claire Haver:How does spironolactone work? Great question. So spironolactone works by blocking production of testosterone and blocking the androgen receptor. So it will affect your testosterone. And so it's different. And so 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. So some people actually stop their menses when they take spironolactone. Okay. What about local activity of testosterone in the general urinary system?

1:02:30So we've learned over the years that the dogma that the genitourinary 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.

1:03:04It'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 prasterone.

1:03:42And 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.

1:03:50Dr. Mary Claire Haver: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. And you talked about the metabolites and how they can convert to one another. So what you're excreting doesn't represent what's in your blood.

1:04:27Nor 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 picograms per liter. So it's a little different. It's lower, actually. But we could have two patients with the exact same estradiol levels with totally different side effects because of what's happening at the level of the receptor. Same is going to be 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.

1:04:59A 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?

1:05:30And 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 around the time of ovulation.

1:06:03Dr. Mary Claire Haver: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, which 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 oophorectomy.

1:06:45She elected for an oophorectomy 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 in head to toe in patches. And I'll never forget this because I tested her levels and they were postmenopausal. And that was when I had this epiphany. This woman would not absorb transdermally. And so I gave her oral estrogen and she did.

1:07:22We 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.

1:07:38Dr. Mary Claire Haver: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 femring, 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.

1:08:17Anybody 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.

1:08:28Dr. Mary Claire Haver:Okay, they have better absorption rates. We do a lot of transdermal. It's just easier to check everybody rather than wait to see who's absorbing, not absorbing. So like for all our transhermal 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.

1:09:00It becomes a little bit tricky. And this has got the nuance.

1:09:03Dr. Mary Claire Haver: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 anxiety, depression, all kinds of symptoms that start at ovulation, peak mid-cycle, and then go away when the period starts.

1:09:39Well, that is based on your progesterone levels. So we can already see that when someone's going to 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. situations. 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.

1:10:10But 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. 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.

1:10:40And this is why menopausal medicine is so... It's so fun. It's so fun, and it's not algorithmic. So you can't just say, if this, do that. It's like everybody's individual. You've 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 for endometrial 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.

1:11:08They work very well. And so typically the one I will give, I like North Endrone 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. emergently, but 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've 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 is vasoconstrictive.

1:11:40And so cardiovascularly in the older women, they did worse with it. It's just not a good medication. So anyways, I go with norethindrone acetate. And then I'll also do a lot of drospirinone these days. And so people tolerate it. Norethindrone acetate looks a little bit more like progesterone. What about combi patch? Combi patch is a combination of norethindrone 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 bioidentical. 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.

1:12:13It's hard to get covered by insurance and it has, but it's a norethindrone. Climera Pro is another combination patch that has levonogestral. 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, SLIND is a great method. What is SLIND? Jospironone only medication. You can also do a levonogestral 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.

1:12:51It is the best for that purpose. And then if they can't tolerate any of them, then I will do Duovie. 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 Duovie. Then you add in a CIRM, 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 Avram Blooming on here who debunked the myths around it. Yeah. But there are people who are still concerned, but there are people with, you know, high-risk biopsies.

1:13:24Dr. Mary Claire Haver:Yeah, we use it because women who are survivors, pre-vivors, high-risk, have nowhere to go. They end up in our clinics. Me too. And so I use DuoV probably a hundred times more than anyone else in Texas. I believe it. Who doesn't practice my kind of medicine. The other group that I love using DUAV for, two groups. One is the endometriosis patients. Oh, okay. Because the estrogen is going to stimulate any, you know, endometriosis. So you've got now this CIRM that'll block. Now remember, 30 % of endometriosis isn't sensitive to progesterone. And so those are endometrial cells. I did not know this.

1:13:57Yes. That's why they don't work for so many people. That's why you end up needing surgery in 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 DUO-V for those patients. And then the other patients I like DUO-V 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 dysphoric disorder. Thank you. Yeah. So that's the progesterone hypersensitivity.

1:14:27So 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 Duovie and I have saved so many women by giving them Lupron plus Duovie for refractory premenstrual disorder. Unbelievable.

1:14:54Dr. Mary Claire Haver:Welcome back to another MidiPause. I'm Dr. Mary Claire Haver, host of Unpaused. 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. Hormonal weight 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 MidiHealth is dedicated to changing the way menopause is treated with a personalized approach to each woman's specific needs.

1:15:30Dr. Mary Claire Haver:Women come to MidiHealth 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.

1:16:06Dr. Mary Claire Haver:This isn't vanity. This is a health issue that deserves real solutions. The good news? Visceral 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.

1:16:50Dr. Mary Claire Haver: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 MEDI approach centers on a holistic combination of solutions, from medications like weight loss medications to lifestyle changes. and a care plan that works for your body and your needs. By doing so, MidiHealth is setting a new standard for healthcare.

1:17:30Dr. Mary Claire Haver: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. Join midi.com and connect with one of their clinicians today.

1:18:05Dr. Mary Claire Haver: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, you know, 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.

1:18:36No 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.

1:19:09OK, 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 know, 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 decrease testosterone levels and everybody that takes it.

1:19:44Doesn't mean they're all going to have a sexual side effect. They just will have lower testosterone. Some of them are anti-androgenic, like drospirinone, right? So that's your Yaz, 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. Levenigestrel actually is a little pro-androgenic. So that's why people get acne with the IUD, right? And so that's the main thing. And then 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.

1:20:22There's a subset of women who do develop a vulvodynia. 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. It's 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.

1:20:55And then she don't want to get off that birth control. I always switch them to something that is, you know, 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, pelvic floor PT, it's not doing anything because it's not a muscular issue. Yeah. And a smart PT was like, you really should get off your, you know, this particular birth control. And she did. And she's like, it was, it was so satisfying as a sexual medicine provider to like do an exam. And I'm like, you're a different person.

1:21:20And 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.

1:21:52Now, 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 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 you would do it with the peanut butter.

1:22:20So anyway, so 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. The same little tablet. You can just take the little tablets, the Prometria Micronized Progesterone. It's a little tablet. Just put it in the vagina.

1:22:44Dr. Mary Claire Haver:Amazing. Why does my orgasm change in midlife? Oh, I wish it didn't. A couple of 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.

1:23:17The 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 laxer muscles or overactive muscles, they may also notice a difference.

1:23:40Dr. Mary Claire Haver:Why don't I want to have sex anymore? I feel broken. Oh, I, you know, I'm giving you the easy ones. 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, 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.

1:24:14Dr. Mary Claire Haver:But you're kind of a clinic of last return, you know? That is fair. That is totally fair. I mean, other people are possibly getting it. 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.

1:24:47So 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.

1:25:15Yeah. You know, it's a therapy. It's not a replacement. It's a therapy for symptoms.

1:25:20Dr. Mary Claire Haver:Sexual desire and pharmacologic management. So there's two meds 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 flabanserin. It's a mixed serotonergic drug. So it works on serotonin, which then modulates dopamine. mean. It is a nightly medication, 100 milligrams at night.

1:25:54It works, again, in about 50 percent of people. You see similar results in the testosterone studies as in the flabanserin 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 they feel about

1:26:19Dr. Mary Claire Haver: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 for a blood pressure medication, but the men wouldn't give it up, right? So it's very similar, but it is not the female Viagra. People oftentimes say that. Viagra works on blood vessels, right? It vasodilates. It causes an erection.

1:26:50Flabancerin 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 bremelanotide. And so that is an injection. It's a melanocortin receptor agonist.

1:27:02Dr. Mary Claire Haver: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 flabancerin that you have to take every day. The biggest side effect from breamalanitide 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 gonna work. So it's not like phlebancerin, which I use all the time. Then you have to have three months to figure it out. With breamalanitide, if you use it three or four times and you don't get a benefit, you'll know.

1:27:34And if you use it and you get a benefit, you'll know. This is the thing about sex med 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 onto 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.

1:28:06Right. You know, 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 onto them.

1:28:19Dr. Mary Claire Haver:Excellent. Well, thank you so much for joining us on Unpaused. 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-elect of ISHWISH, a major resource in sexual health for clinicians, researchers, advocates, and consumers, and can be reached at info at ishwish.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.

1:29:03Dr. Mary Claire Haver:You could find full episodes of Unpaused 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 thepawselife.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 Unpaused 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.

1:29:45Dr. Mary Claire Haver:Thank you for being here with me. Let's keep going Unpaused. Unpaused is presented by Odyssey in conjunction with Pod People. I'm your host, Dr. Mary Claire Haver. The views and opinions expressed on Unpaused 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. This episode was sponsored by MidiHealth, the first virtual clinic created for women by women for the treatment of menopause. Don't let anyone tell you menopause is something you have to suffer through alone.

1:30:26Dr. Mary Claire Haver:Midi can help. Visit joinmidi.com to learn more.