Menopause, What HRT Actually Does & What It Means for APOE4 Carriers

[0:00]I've actually had a Premarin tablet in my hand, and I cut it in half and sniffed it, and it smells Like horse pee The absolute risk increase was in a year.

[0:20]Estradiol levels need to be between and picograms per milliliter. The study that scarred a generation of women of hormones did not test the hormone you would be given today. It actually tested an estrogen made from the urine of pregnant horses. My guest today has held one of those tablets.

[0:44]Cut it in half and smelled it. And guess what? It smells exactly like what it is. So no serious doctor prescribes that anymore. But the fear it created, it's still influencing doctor's decision today. If you are in or past menopause one decade of your life is doing a lot of quiet work on you.

[1:06]Your estradiol falls. Before 50 Women have far fewer heart attacks than men, but by 60 it is even what is good for the heart is good for the brain. And if you carry APOE4 that is not a footnote. It's actually the whole point. And the sleep you are losing right now is the sleep your brain needs the most.

[1:28]I'm Doctor Kevin Tran I carry two copies of ApoE4, and I build the Phoenix community to help us APOE4 carriers, beat the odds and outsmart alzheimer's it is where carriers track what they are actually doing and compare it against each other. Every question here in this podcast came from a member.

[1:47]My guest today is Steve Goldring. He has been a licensed pharmacist for over 30 years. He spent years behind a compounding counter where the woman in front of him was usually in menopause, holding a prescription. She was too scared to fill. Now he teaches women directly and trains the doctors and nurse practitioners who prescribe these.

[2:10]The three things you are getting in the next hour or so. Number one, why that 26% breast cancer headline was really eight women in 10,000, and why the researchers never claimed it was solid. Two the whole menu of what is available to you, whether it's a pill, patch, gels, creams, vaginal pellets, what each is good at and what it actually costs you.

[2:38]There is no perfect one, and Steve will walk you through the pros and cons of each number three. We'll discuss why the pill form of estradiol lowers ApoB and lowers Lp(a), which is the particle you have been told cannot be moved, and stay until the end for the special number.

[2:56]There is an optimal Estradiol level, basically 60 to 100 picograms per milliliter. And Steve, explains why below 60, Your bones go unprotected even when you feel completely fine. Here we go. This is a very exciting talk. We split that into two parts. Make sure to check out part two as well.

[3:16]Alright, so most of our community is female. Most of you are somewhere in or past the menopause transition, and you carry at least an APOE4 gene. So those are not three separate facts, and they interact. They interact during one specific decade of your life. One thing before we start. So this is part of a monthly theme in the Phoenix community about female hormones and hormones in general.

[3:42]We have this Q&A where you can ask questions. And if you want to have your questions included in the next one, you can just push them inside the community in the topic that I have created every time. All right. So without further ado, Steve, welcome very, very excited to have you here.

[4:00]Thank you so much, Kevin. I do have to say that I saw multiple of the questions that were submitted on the the community platform and I found the questions fascinating. I'm excited to kind of dive into some of these details. And and your audience is very well educated and has some very insightful questions.

[4:19]And so it's great. I mean I'm excited about it. Yeah, awesome. I'm very excited about this talk as well All right, so Steve, you spent years behind a compounding counter, right? And most people coming to you were women in Menopause. What was the question you heard the most over and over and why did nobody have a good answer for it?

[4:37]So here's kind of the way I describe my experience in the compounding pharmacy and I had this happen over many years, and I never really realized it was happening. But I was working at a little mom and pop compounding pharmacy, a little tiny pharmacy in Wilsonville Oregon And I would have a woman come up to me in her mid-50s, and she was getting a prescription for maybe estradiol and progesterone, but she was wringing her hands and she was like, ohh, my doctor said I should take this, but I'm really worried and I don't know what to do.

[5:10]And I'm not really sure whether I should be taking it. And I'm scared about the risks. And I've heard about breast cancer and so I would I kind of be excited and I'd say, okay, here's what I need to talk to you about. And so I would go over the women's health initiative and I would talk a little bit about some of the overblown risks that these people have heard about, and also some of the The things that they should be looking forward to as far as symptom relief, but also relieving some long-term health risk issues.

[5:42]So, what would happen is this conversation that's supposed to last a few minutes in the pharmacy counter would actually maybe stretch out a 5, 10, 15 minutes. And that was, and what I would see is this light bulb would go off over this woman's head, and she's like, ohh thank you so much for telling me this is so great.

[6:01]At the time, I maybe wasn't as concise as I am now, but back then I would see these light bulbs go off on women's heads. And it was it was very rewarding to have that experience of being able to teach people and help them to gain some clarity and some confidence about taking hormones for their menopause situation.

[6:21]The only issue was that that woman left the pharmacy. There was another woman right behind her with the same questions, and then there are four or five more waiting in line and so I came to the realization at one point, this was about 10 years ago, that maybe I would like to take this this passion that I have for teaching women about hormones and menopause and giving them clarity and confidence. Maybe I could take it instead of one-on-one, do it on a one-to-many basis. And that's where simple hormones, that was the seed that started it about 10 years ago.

[6:57]And it's kind of grown since then. So that's kind of where I've been. But over the years I've really been drawn to learning about hormones, learning about menopause specifically. I have a a really good friend I have coffee with him every day or every Thursday. We had coffee this morning and he's always kind of making fun of me as the menopause man, but it I can't help it.

[7:22]It's just something that I'm just passionate about. it's a good nickname but it sticks, I think, the menopause man I like it. But I love the journey. It's it's very inspiring and it shows that education is like so important, right? So and to be able to and to be able to spread this information because and we'll talk about that study specifically, since I feel like it it did maybe a lot of damage.

[7:45]Almost every woman I feel like I've heard about that and the bad reputation is coming from from that study that started in 2002 the women health initiative. Can you describe it in a little bit more detail, what happened and what stayed true and what was debunked since then?

[8:03]So the Women's Health Initiative is actually one of the largest clinical trials ever conducted. and in the this the particular arm of the Women's Health Initiative, there were multiple, multiple studies that were all kind of bundled into one. And it was well over a billion dollars in cost, and it was a multi-center study all over the world.

[8:22]about 16,000 women roughly were given hormones. What they were given is a combination called conjugated equine estrogens. And that is a set of hormones, a set of estrogens that literally comes from horse urine. And the word premarin is the brand name premarin, which is a kind of a contraction of pregnant mare's urine.

[8:47]And I've actually had a Premarin tablet in my hand, and I cut it in half and sniffed it, and it smells Like horse pee, because that's what it is. And it's not really a purified form, it's just dried and put into a tablet. That's about it. And this drug would never be approved in 2026, but that was the gold standard at the time in 2002.

[9:14]Now, along with conjugated equine estrogen and was given a progestin, it was called medroxyprogesterone acetate And so that combination, we call it an estrogen and a progestin. And those two were given. The estrogen helps with menopausal symptoms, especially vasomotor symptoms or hot flashes. The medroxyprogesterone acetate was given to kind of counteract some of the negative effects of estrogen on especially the lining of the uterus or the endometrium, because estrogen naturally causes a buildup of the lining of the uterus.

[9:55]And if you allow estrogen to remain what's called unopposed, then that lining will just continue to get thicker and thicker and thicker. And eventually you can have endometriosis, or you can have a actually an endometrial cancer develop, which is basically an overgrowth of the endometrium. So they give this progestin to kind of block that effect.

[10:18]And so these two Drugs, these two hormones were given to women. there were a whole bunch of things that were a little bit like hmm, there were choices that were made in the study. here are a couple of examples. One example is the women in the study were on average about 10 or 12 years past the menopausal transition.

[10:38]so menopause is considered a day. It's the day, which is 365 days. after your last menstrual period. And so that's menopause. These women were 12 years roughly after that. That's a long time to go without hormones. And there were some ramifications for them going without hormones for so long.

[11:03]There were a number of other things, one other that I wanted to mention is the women in the study did not have menopause symptoms, especially not hot flashes. That was intentional They did that so that they could blind the patients. The patients wouldn't know whether they were taking a hormone or not because they're not having hot flashes and so they wouldn't notice their symptoms getting better.

[11:27]but it kind of makes you think, okay, well, we're giving a hormone primarily to help with hot flashes, but the study population, we don't want them to have hot flashes, which is a little bit of a disconnect. So there are a number of things like the age of the patients, which is quite old compared to menopause, and the fact that none of them really had the primary menopause symptom.

[11:54]And there are a number of of other things that kind of came along with that study. Very interesting because like this study I feel like since 2002 right? It created a lot of headlines, it created a lot of assumptions about HRT and so on. would you feel that a lot of these assumptions have changed?

[12:12]Which ones stay true and which ones are now kind of been debunked by the new, more recent studies that are are out? Yeah, so I would say there's there's a whole lot of information to unpack with the Women's Health Initiative. I like to think of the Women's Health Initiative as a vast, a deep data-packed study.

[12:35]there's a lot of data in the Women's Health Initiative that is useful. but there also are some interpretations of the data that might be a little questionable. Now the one that I tend to point out is actually the headline that is it was actually plastered around the world.

[12:54]At the time, it was in newspapers, but eventually it got to social media and websites because the internet wasn't that big of a thing in 2002. but the the headline was hormone replacement therapy causes a 26% increased risk of breast cancer. And that sounds terrifying. 26% more breast cancer oh my gosh, that is terrible. But what you have to recognize is that 26% is what's called there are two things about it.

[13:25]One is it's called a relative risk. And so what you have to look at is the absolute risk if that was published in the study, talks about 30 cases of breast cancer in 10,000 women. In one year is the norm. When they took hormone replacement, that number went from 30 to 38.

[13:51]so the actual what we call the the absolute risk increase was point zero eight percent, or eight women out of ten thousand in a year. So when you look at it in those terms, it's like, oh well, that doesn't seem All that high, even though technically, if you have 38 versus 30, that is a 26% increase It's a little bit of semantics, but what happens is the headlines really latched onto this 26% number and made it seem like it was absolutely horrifying.

[14:30]Now, the second thing to remember about the Women's Health Initiative, especially the very first report that was published of the Women's Health Initiative mentioned That the 26% increase in breast cancer was almost statistically significant, which is exactly the same as saying it was not statistically significant. It was almost statistically significant.

[14:58]And so this 26% risk of breast cancer increase is touted around the world as this terrifying thing. But if you look at the study, the researchers themselves said it's big, but it's not necessarily statistically significant. It could have happened by chance. And so those are two major things that have become basically law over the last 25 years that hormones cause breast cancer.

[15:28]But that's not what the study actually showed. And now there's a lot of other nuance beside that, but this is, I think a pretty major thing when the study itself talks about the results in that explicit of a way, we need to read the study very closely and not just take it for granted that this is a huge problem for women.

[15:52]and that's the thing, right? When you have like press that is more incentivized to have big headlines to actually sell papers, right? That's that's their goal. It's a very, very different interpretation and different way of framing everything compared to a discussion that you have with a healthcare professional. Talking about that breast cancer risk, a healthcare professional. Talking about that breast cancer risk, so from my understanding on the 10th of November in 2025, so not too long ago, the FDA actually removed those black box warnings from estrogen products. So the cardiovascular warning, the breast cancer warning and the probable dementia one.

[16:24]do you know what happened in between? Were there like additional studies that disprove those or what happened for them to really decide to remove those warnings on estrogen. Well, I think that's a more complicated answer. I think yes, there are additional studies. And the FDA has also maybe taken a second look at the Women's Health Initiative itself and one of the very interesting things that's in the original Women's Health Initiative study publication, it specifically says we shouldn't interpret this to mean that all hormone replacement therapy has these risks.

[17:02]It explicitly states that. And then a few years later, we get an FDA black box warning that says all hormone replacement therapy has these risks because of the Women's Health Initiative, which explicitly stated, don't do that. so this is a big problem in the FDA's interpretation of the study.

[17:26]It's not necessarily the Women's Health Initiative researchers fault that the FDA Took that information and blanket applied it to every type of hormone replacement therapy. Now, I will point this out because I mentioned conjugated equine estrogens from horse pee and medroxyprogesterone Part of the Women's Health Initiative was to have that combination together.

[17:51]There was also a second arm that was called an estrogen-only arm where patients got. Conjugated equine estrogens, but not the medroxyprogesterone And the reason they could do that is because they had had hysterectomies and they didn't have a uterus and they didn't necessarily need uterus protection. That group actually had a reduced rate of breast cancer.

[18:12]So this is an implication that of those two hormones, the medroxyprogesterone might be the one that is maybe more responsible. For increasing breast cancer risk. And that's a a major thing. And since 2002, people have really kind of pointed that out and started to realize that more openly.

[18:36]Now today we don't use conjugated equine estrogens and medroxyprogesterone At least no thinking provider will prescribe that. If they do prescribe it, they're not thinking very clearly. Now what we use is 17 beta estradiol and oral micronized progesterone. And those are two hormones that are identical. They're exactly the same as what the human ovary makes, where conjugated equine estrogen from horses is Totally a dirty drug. It's contaminated with a lot of horse estrogen.

[19:14]And then medroxyprogesterone is a synthetically altered form of progesterone that is totally different than the progesterone that comes from human ovaries. And so if we look at there are actual several studies that compare medroxyprogesterone with progesterone, and it's very clear that progesterone is much safer, especially for the breast.

[19:39]In fact, maybe breast protective. There's a study out of France called the E3N cohort study that was done somewhat after the Women's Health Initiative. But basically it was an observational study, but it showed a significant lower amount of breast cancer in patients taking progesterone as compared to medroxyprogesterone And there have been multiple studies that looked at various progestins that are progesterone like.

[20:08]And all of these studies essentially show that progesterone is the most protective and least dangerous to the breast. Okay. Fascinating. Yeah, it's important to know that everything that happened in those studies, the molecules they changed. and going back to to that specific study right? so what you mentioned to summarize it a little bit, the population selection was important and very different compared to maybe like real life population.

[20:34]and in the end like they were yeah, selecting like people who didn't have symptoms and and so on. So not really like overread in those even though the headlines might still stay here in the mind of people. We're looking at the questions from the the community, so looking deeper into the breast cancer one, Alex was asking kind of the opposite question on the breast cancer coming off the label because if a woman has had breast cancer in the past or if she's a high risk of getting breast cancer, it seems like hormone therapy is usually off the table.

[21:08]And the label change doesn't change that. So what is actually left for her? what do you do for a woman who can't have that? Well, I actually I have been really diving into this over the last couple of months with my really good friend Jill Chmielewski who's a nurse and she also has run a menopause forum and she's had some personal experience with family members who have gone through breast cancer, and her assessment of their treatment has been that it's quite horrifying.

[21:36]And it's my next door neighbor Has gone through breast cancer treatment and she has had some really difficult times. She was taking hormones before she had breast cancer. She has a estrogen receptor negative and progesterone receptor negative breast cancer, or triple negative it's actually called. and so it's not necessarily related to hormones, but they withdraw all of her hormones anyway.

[22:01]And I can totally understand that. But A lot of these patients find that their lives are totally destroyed in many, many cases, and not only by the treatment, but also by the withholding of hormones. and so there are a ton of questions, and I can't say that I have the answers.

[22:20]Now, one thing I will strongly recommend is I'm a fan of Dr. Avrum Bluming and his book, Estrogen Matters, and in chapter six of his book. Which is called Can Breast Cancer Survivors Take Estrogen? He goes through a number of clinical trials, probably fifteen clinical trials, some of which he was the primary investigator on, but multiple trials where women who have had breast cancer, gone through breast cancer treatment, chemotherapy, radiation, surgery, and then after five years, which is Generally, the accepted time period, those women were actually given hormones again.

[23:05]And Dr. Bluming makes a strong case that the recurrence rate, there is a recurrence rate, but it's no higher for women who take hormones than women who do not take hormones. and the the quality of life for the women who take hormones can be exponentially better than those who don't.

[23:25]Now, should women take hormones. After they've had breast cancer. I'm not gonna say yes or no to that question. It's absolutely between a patient and her providers, and there are gonna be multiple providers in this situation. But I would say the blanket statement that women should never take hormones after breast cancer, maybe we should question that to some extent.

[23:49]And Dr. Bluming is questioning it very loudly. Now, the other situation is a woman with maybe a higher risk for breast cancer. I think one of the major things to remember is there's this perception that hormones cause or increase breast cancer. And I just push back against that.

[24:11]I don't think that's actually true based on especially on the Women's Health Initiative, which we talked about the results were not statistically significant. They were relatively small increase if you look at the absolute risk. what we do find, I listened to a very well known OBGYN who wrote a textbook on on obstetrics and gynecology. And he he made a comment that said, hormones don't cause breast cancer, they influence breast cancer.

[24:46]And there are multiple factors obviously that go into cancers. But I think we have to recognize that human beings are designed to operate optimally with hormones. And whether we're men with testosterone and thyroid and Cortisol and insulin, or women with estradiol and progesterone and testosterone and cortisol. those are designed to work to help our bodies work optimally.

[25:14]And if we don't have those, there are going to be some consequences. I've actually just had a one of my YouTube videos and the title of it is whether you take hormones or not, you face risks either way and I think that's something that I really emphasize is you have to recognize the risks.

[25:34]If you do not have hormones, especially if you have extremely low levels after menopause, your level of estradiol and progesterone is not zero, but almost zero. There are some risks to that. Now, if you take hormones, there may also be some risks. So my encouragement is let's weigh the risks out.

[25:54]And see which ones are more important. Definitely. I like that it's a bit like a discussion I had with a a few friends about autonomous vehicles. People are rating based on the accidents of autonomous vehicles, but not rating based on the accidents that normal human drivers would have, right? So you have to compare like Apple to Apple, not versus like zero risk. And this is like the same case here.

[26:15]we had another question from from Elaine, who asked about the product that pairs an estrogen with a SERMs So a SERMs is a selective estrogen receptor modulator. instead of progesterone. Is that a real option for APOE4 carriers or is it like a niche one? Or is it even like available right now?

[26:34]I think it is available. It's called Duavee and it's Bazedoxifene and conjugated equine estrogens. That was the estrogen. And so here we are back to horse pee estrogens. And this to me seems like a little blatant way to sell more conjugated equine estrogens, but that's just my cynical self coming up, my cynical pharmacist self.

[26:59]It's a relatively low dose of the estrogens they have been used for preventing osteoporosis. There is really no evidence that Duavee or the Bazedoxifene can actually reduce fractures. it might increase bone density to some extent my impression of it is it's probably not as good as estradiol and progesterone at anything.

[27:26]it doesn't relieve hot flashes nearly as much as estradiol and progesterone, probably because it's a relatively low dose. and it also doesn't really add anything as far as the long-term risks that you have when you don't have enough estradiol and progesterone. So, for those reasons, I'm a little skeptical that it's all that helpful.

[27:47]It also hasn't really, as far as I know, it hasn't really a big seller. So apparently, Providers, especially hormone providers, are not all that convinced that it's working all that well. it has its place, but I don't know. I think the primary reason that Duavee has been available is because and this this is something that I've read several places.

[28:10]The primary reason is so that you don't have to take a progestin to protect yourself from The conjugated equine estrogen's effect on the uterus. Now that that's an idea, but I also believe that if the progestin that you take is progesterone instead of Medroxyprogesterone then you don't need to worry about it as much.

[28:36]Progesterone has some very well-established protective effects, especially on the breast, absolutely on the uterus. and so to try to avoid progesterone, that sounds to me like we're really trying to avoid Medroxyprogesterone from the Women's Health Initiative, and not necessarily progesterone, but that that's one of the things that is mentioned about Duavee or Bazedoxifene and conjugated equine estrogens, is it helps you avoid progestins.

[29:09]Okay, got it. So now since we're like diving a little bit into those, let's talk about the different options that are available, right? Let's say the menu that is available to technically like pick from. So walk me through all the different options, you know, whether it's like method of administration, like patch versus peel, the molecules or estradiol versus the older estrogen, progesterone versus progestin that you covered as well.

[29:31]where do you feel like people also get here wrong the majority of the time and where do they you think they'd make the biggest mistakes here? I'm going to stand up on my soapbox here because I have a lot of strong opinions about these very topics. So I was just thinking about this the other day.

[29:49]As a compounding pharmacist, dosage forms were my life. Compounding pharmacy is about doses and dosage forms. Our job is to create new dosage forms for drugs that are on the market in some other dosage form or different doses of drugs that are on the market in a certain dose.

[30:12]what I really believe strongly is there's no perfect dosage form, in spite of what people say. Now, if you talk to a hundred providers who are prescribing hormone replacement therapy for menopause, 90 of them will say the only way to give estradiol is in a transdermal patch or gel or cream.

[30:35]And any other way is not effective, it's not safe, it's going to cause blood clots, especially oral estradiol. And I would push back on that and say, especially oral estradiol. And I would push back on that and say, yes, there is a slight increase in the risk of deep venous thrombosis and pulmonary embolism, which are serious problems.

[30:56]There are a slightly higher number of those in patients taking oral estradiol. However, Oral estradiol has a lot more evidence behind it as far as making a difference in long-term cardiovascular risk. Oral estradiol has a much bigger impact. Actually, it has an entirely bigger impact than transdermal estradiol on lipids.

[31:24]In fact, oral estradiol has been shown to reduce APOB. It can actually reduce Lp(a) APOB is something that you can reduce with statins or with diet. But Lp(a) is a lipid that is hard to reduce. It's often considered kind of set for life, and you can't really change it. But oral estradiol is one thing that can reduce it and so this is all of these factors have to do with oral estradiol being.

[31:56]Probably more effective at reducing cardiovascular risk. And there are two studies. Well, the primary study is the elite study, the early versus late intervention trial with estradiol elite that study showed ... it used Carotid intimal thickness which is the carotid artery checking the the closing up of the artery as a surrogate for heart problems.

[32:21]It's a little less invasive than a cardiac scan. So they used this test, the Carotid intimal thickness to determine does hormone replacement make a difference? And it did, especially when women were taking it relatively early in menopause. But the type of estrogen they used was oral estrogen. Okay and so there's a lot of data around oral estrogen being used for cardiovascular risk.

[32:53]Now that doesn't mean that everybody should take oral estradiol. If a woman has Factor V Leiden which is a genetic risk factor for blood clots, if especially if that woman has a history of deep venous thrombosis or pulmonary embolism, those are cases where you should be careful, should be very careful about taking an oral form of estradiol.

[33:18]That's something that she would have to work out with her provider. And hopefully her provider would, you know, be knowledgeable enough to be able to assess where she is in that whole situation. But my wife, on my recommendation, takes oral estradiol because I believe that it's going to protect her the most from cardiovascular risk.

[33:40]and the data is a lot stronger for that. It's there's a little bit for transdermal estradiol, but not nearly as much. Especially with lipids. Essentially transdermal estradiol has almost no impact on lipids positively or negatively. All right. So like in in to summarize a little bit, there is no specific like one size fits all answer and there's no default choice, or would you say that if everything else is being equal, because that's a question that Amanda was asking the community, like among all the different options, right? If we summarize them, it would be like vaginal patch, you have gel, you have a cream, you have pills.

[34:16]what would be the default choice? Would you say it's a pill based on what you just answered? And second question linked to that. Is there any situation where you would combine different methods of administrations together? yes and yes or maybe I should say just yes. So I wouldn't necessarily say that there is a default.

[34:34]It should really be tailored to what the patient needs. And this is coming from a compounding pharmacist, and I'm all about customized doses, customized dosage forms for individual patients. I'm much less about off the shelf, everybody gets the same thing. And so that kind of principle is kind of ingrained in me and I never really thought about it until right now.

[34:56]so I really believe that every patient needs to be looked at on an individual basis as far as what dosage they're going to get, what dosage form they're gonna get. What I like to say is every dosage form has its pluses and its minuses, its advantages and disadvantages.

[35:11]So for example a lot of women complain about estradiol patches. They fall off, the they get allergic to the adhesive, they're inconvenient. okay. If they take a capsule, that's generally pretty easy. Most people can can take a capsule every day without much problem. pluses and minuses, right? Now, I have made a couple of videos about vaginal estradiol, and I personally believe, and many people do, that every postmenopausal woman should be at least offered.

[35:43]Vaginal estradiol for a couple of different reasons. One, vaginal estradiol is very is only allows a very small amount of estradiol to be absorbed systemically into the bloodstream. So the amount of estradiol that you get is negligible. There's a little bit, but it's not that much. It mostly is acting in the local vaginal area.

[36:06]The second thing is that vaginal menopause symptoms. get worse over time. Hot flashes generally disappear between seven and ten years after they come on at the beginning of menopause. Many other symptoms become less problematic. Vaginal symptoms can actually get worse and worse and worse over time. And they can lead to chronic urinary tract infections.

[36:32]They can lead to some serious vaginal atrophy issues. I actually have been very horrified. There are some women who have experienced uterine and vaginal prolapse. And if you're wanting to look that up on Google, I would recommend that you not, because it's absolutely terrible. And I wouldn't want any woman to experience that.

[36:59]And it's this is definitely not something that happens. Frequently. However, a lack of estrogen can be a very big factor in vaginal and uterine prolapse, which is essentially where the lady parts come out of the body. And it's just heartbreaking. now, obviously, this is an extreme version, but what what we need to look at is vaginal health is very important for women after menopause. Everyone complains about it.

[37:31]It's not going to get better. If we offer those women vaginal estrogen, that at least can make a big difference. And I can't tell you how many women have told me what a big difference it's made in their relationships, in their ability to not have urinary tract infections all the time just their general comfort, their quality of life, so many things now here's another soapbox about now that we're on the topic of dosage forms there are multiple dosage forms for progesterone.

[38:00]The most commonly used is called oral micronized progesterone. And that is the form that many people say, well, that gets that gets liver first pass metabolism, so that can't be good. However, when progesterone, first you take it orally, it goes to your stomach, then it goes to your liver.

[38:18]The liver does metabolize progesterone. And one of the things that comes out of the liver is something called allopregnanolone. And allopregnanolone is very effective at improving sleep architecture, which is extremely important for people with APOE4 who maybe struggle with sleep and really need to get adequate quantity and quality of sleep.

[38:47]I've had so many women tell me I sleep two or three hours every single night for months until my body can't just do it anymore. I'm a zombie all the time. And so oral micronized progesterone is literally the most effective treatment for menopausal insomnia. And it makes a huge difference for these women And it's because it goes through the liver first pass that that's why it's so effective.

[39:14]Wow, this is this is like fascinating because I feel like this is not very published or communicated, right? Like all these different options, the pros and cons and everything. I feel like having, you know, like a cheat sheet, like just a one pager with plus and pros and cons, how you mix them and everything would be like so so important.

[39:32]yeah, Elizabeth was asking a question about like brain health and delivery choice, mainly based on a steady level of hormone versus like a spike. So she was looking at patches, which will give a steady level, because it diffuses steadily versus a cream that is not as steady. Is there any reason to think that the steadiness level on a day to day basis matters to the brain?

[39:53]Or is it more the you know, overall amount of hormones that you get over a week that matters. You know, I'm sure there is some research about that. I'm not really familiar with that research. but again, I think what we're gonna have is every dosage form is gonna have its pluses and minuses, even when it comes to so for example, you use a patch, you let's say you put it on your arm, and maybe the most common patches are used twice a week.

[40:21]What I suspect I don't have the data, but I'm sure the data is out there. What I suspect though is that you probably get a relatively high amount for the first few days, and then it starts to taper off. And so let's say the day before you're gonna remove the patch, you may be at the tail end and you're getting a lower level.

[40:41]So right there is there is a difference in how much how much of a steady amount you're receiving. When you take an oral capsule, you get a peak. And then it gradually goes down over 24 hours, and then you take another one And so you have the same thing with a gel or a cream where you have a peak and then a trough ideally, your ovaries would be releasing estrogen continuously 24 hours a day, and maybe they'd have certain peaks at certain times of day when it was more needed, but we can't really replicate that very well.

[41:17]Here's another dosage form we could talk about. And I think someone in the community asked a question about pellets. Are pellets a reasonable way to experience hormone optimization? And I would say pellets, just like every other dosage form, have their pluses and their minuses. A big plus is you do get a big peak and it lasts quite a long time, maybe several months before it starts to drop off.

[41:44]and you don't even have to think about that, and it's just constantly releasing. And so that is a big advantage of a pellet. The disadvantage, there are multiple disadvantages. One is they tend to be the most expensive way to get hormones. The second is they require a medical procedure to insert them.

[42:02]And then if you have too high of a dose, to take them out and insert a lower one. there's also the potential for infection when you It's basically a surgical incision and they're putting it in underneath the skin. So there are multiple disadvantages. The the other disadvantage is that sometimes you can get supraphysiologic doses, and that could be a problem for patients. And then if your dose is too high, you've got to go through the procedure to get it taken out.

[42:29]and it you may be on that for a while before really recognizing that your dose is too high. And I think the patches do they do release relatively steadily with the caveat that towards the end they're gonna drop off, and they may actually physically. come off. And so that's a problem for patients.

[42:52]I've also noticed in, I think it was in the UK and in New Zealand and Australia and now in the US and Scotland have all had severe shortages of estradiol patches. And that's a common problem. This is something that we as compounding pharmacists dealt with all the time. We didn't necessarily make patches, but we made alternative dosage forms that would substitute for a patch.

[43:17]And so there are substitutes. I see a lot of women and providers who are kind of panicking that there's the patches are in short supply. However, there are alternatives and I like to emphasize that. No, that's that's really important then to to have like the proper information to make the decision, right? And I feel like it's very rare to have that fully explained to you as a patient.

[43:40]looking at patches, because I realize we have like exact questions that you mentioned slightly earlier about the peak and then how it slows the goes down. Even for patches, we have Jessica and Christy that were asking basically that, right? Jessica feels like her patch dumps everything in the first few Two days and then she crashes before it is time to change it.

[44:01]And the solution her provider gave her is to increase the dose, which basically will increase the peak. But then because you know it's like a half-life, it will go down like even like faster. she thinks it's the wrong fix. then we have Christy, who had the same problem.

[44:16]her levels is are basically like empty a day before the patch change. So the first question was are they imagining which is Probably not. And if they are not imagining it, like what is the solution? Is it a bigger dose to having a bigger peak and then going down? Or is there a different solution, like a different delivery method, a different yeah, between like dosage and form?

[44:39]How would you help them? So I find this so fascinating because the the conventional wisdom is that estradiol patches are the dosage form that we should be giving to women. But here we are with women who are struggling with this exact problem that they're not perfect. And so I think in the first situation where the dose seems to be dropping too soon, to me, it seems to be kind of an obvious solution to take those doses closer together. And so instead of taking them twice a week, maybe take them three times a week, which means it costs you more because you have to use three patches a week instead of two. But that would be the solution,

[45:22]the simplest solution if it seems like it's running out, rather than doubling the dose and then you start out with a higher peak. It seems like she hasn't mentioned that she thought her dose was too low. She mentioned that it got too low later on when the patch was on.

[45:37]And so to me that would be a A dosage interval problem And so giving it less often or giving it sooner would be the solution. I also think there are some different matrices that are used, some different delivery systems. Some use like a liquid reservoir and that comes through the skin, others use some type of Polymer matrix, and I'm not sure what all the technology is, but there can be some differences between different delivery methods, even between different brands of patches. And to be honest, I'm not as familiar with all of those, but I do know that there are differences, and there are multiple technologies that are used, and some may be better than others.

[46:25]And some be it may be more consistent and more longer-lasting than others some may dump a whole bunch. early on and then not have enough left at the end of the patch. but that's a matter of different manufacturers and different brands. Yeah. Looking at patches again, more in terms of optimization now.

[46:46]Trudy is basically going very often to the sauna which is a great thing for APOE4 carriers on the side. and a lot of our members are doing that. But then the patches they don't survive the heat and the sweat. so what should she do? Are there any patches that you know are able to survive that? And I'm adding in like swimming.

[47:04]and another type of, you know, like contact with water, or is there or should she like just change in terms of method of administration here? Yeah, that's this this is where we're bumping up against the limitations of patches. And no matter what, whether you're dealing with a nicotine patch or an estradiol patch or a testosterone patch, there are limitations of how those adhesives are going to be able to stick to your skin. When you think about it, an adhesive is stuck to the surface of the skin and sweat is coming underneath the adhesive, getting wet underneath. So It shouldn't be able to stick, stick very long. It just it doesn't from a physics perspective, I don't think it should work. Now,

[47:48]obviously there's different technologies as far as the adhesives go. and there there may be some that are sweat resistant, but I think we're we're basically bumping up against the limitations, especially if you do spend a lot of time outdoors. and obviously it's the kind of thing you don't necessarily want to just do it once or twice a week. You might want to do it every day and that limits the use of patches.

[48:11]I'm not sure what the solution is if you're still wanna use a patch, because that is a limitation. It's it's definitely a a conundrum. Yeah, I face the same issue with like CGM continuous like glucose monitoring like devices because I was like swimming a lot. One solution that I had was to use like this 3M transparent tape to stick on top so you have more adhesive in a better more surface and so on. It's working more or less.

[48:39]It might work here, I guess but yeah, otherwise like changing the method. If we look at creams, Like Anne was asking a question about when she's rubbing a gel or a cream on, how does she get the most out of it? Do you prep your skin? Where do you rub it on the body?

[48:56]Do you do exfoliating? Do you cover it afterwards? yeah, any advice here? I generally tell patients not to overthink that. what I recommend is a couple of different places. Most often, what you want to have is clean, dry skin, preferably like if you take a cream once a day, it would be right after you took a shower, but you've dried off thoroughly.

[49:19]And you'd want to apply it generally to an area that has plenty of veins and arteries underneath the surface of the skin, like maybe on your wrists where you can see those veins and relatively thin skin. Now your provider may have a specific recommendation for what they like to see And obviously if your provider recommends something, but there's no like cut and dried absolute best place on the body to place creams. Generally we don't recommend estradiol be applied to the breast area.

[49:51]It could probably cause breast tenderness, which would not be a good thing. I would say most commonly it's applied to the inner wrist or the upper or the the forearm, the inner part of your forearm, or sometimes to the inner thigh. I know testosterone is often applied to the labia, and it's essentially absorbed systemically through the labia.

[50:14]and it can also have some Some beneficial effects on the labia and the vaginal tissues. obviously, vaginal estradiol is most often applied vaginally, but also to the labia as well, because it has a a dramatic effect on improving blood flow to the labia and making the tissue a lot more healthy, which can be a very important aspect of using a vaginal cream.

[50:39]I have find it interesting, I hear this lots. Where women are taking a vaginal estradiol cream. But they also will take a little bit of it and they'll put it on their skin, on their, especially around their eyes and and the crow's feet in the corner of their eyes and the corner of their mouth.

[50:56]Because estradiol in a cream form has a dramatically positive effect on the elasticity of skin, on the the health of skin, on the just just the way skin works. one of the reasons why women lose elasticity in their skin is because they've lost systemic estradiol. And this is a way to kind of replenish some of that.

[51:21]It really does make a difference. That's just a side note. No extra charge for that. Different type of benefits we have more of a general question now from Kim. She has been on hormone therapy for years on estradiol, oral progesterone and vaginal testosterone, but she has no symptoms at all.

[51:40]However, her level sits below what the optimal charts say they should be. So what would be your advice here or thinking about that? Would she push the dose closer to the optimal number, even though like everything is working well, she has no symptoms, or should she leave that alone?

[52:00]And it doesn't really matter the level that the you know Yeah, that's a really good question. So I like to think of hormones from two different aspects. One aspect is menopausal symptoms. If we have our hormone levels optimized, or what I like to say, not too high and not too low, but just right, optimal hormone levels can do two things.

[52:21]Number one, they can either reduce or even eliminate menopause symptoms. So I'm talking about things like hot flashes. and vaginal dryness and painful intimacy and weight gain issues where you can't seem to lose weight when you want to, and insomnia and brain fog, and night sweats and mood swings and irritability.

[52:45]There's three dozen symptoms that can be dramatically improved. Now if you're not having those symptoms, what you also need to look at is the other side of the coin Optimal hormones not only reduce or eliminate symptoms, they also protect you from long-term health risks. And I like to think of four specific risks that hormones have an impact on.

[53:08]Number one is osteoporosis. I say that number one because that's the first one that's going to be a problem for most women. They lose a significant percentage within five years of going into menopause. and their risk for fracture continues to increase the further they get away from the actual menopause transition.

[53:28]So osteoporosis. The second is cardiovascular disease. Women have less heart attacks than men before age 50, significantly less. By age 60, they've gone without hormones for close to 10 years. They catch up with men and have an equal number as men of heart attacks. So cardiovascular disease, the single most prominent killer of women over 50, is hugely affected by your optimal hormone levels.

[54:00]Number three is metabolic disease. So we're talking about insulin resistance and type 2 diabetes, which have knock-on effects. When you have type 2 diabetes, you're much more likely to have heart disease. And there are all kinds of kidney problems that can come from that. So number one is osteoporosis.

[54:21]Number two was cardiovascular disease, number three is metabolic disease, and number four is cognitive decline, where it's not as cut and dried. The evidence is not as slam-dunk conclusive. But having optimal hormone levels can improve your odds of not developing cognitive decline as you get to your 70s, 80s, and 90s. So the the key though, and there are multiple studies that talk about this, especially for osteoporosis, estradiol levels need to be between 60 and 100, I think they're picograms per milliliter.

[55:02]If you're not at 60 to 100, I would really like to see you at 100. 100 is probably the best for cardiovascular risk, and it's definitely good for osteoporosis risk. If you're not at 60, though, you're putting yourself in danger of not having enough estradiol to protect your bones.

[55:21]There are several studies that show bone protection really kicks in at 50 to 60, and then higher levels make a big difference. and then the levels are not as maybe evidence based for metabolic disease and for cognitive decline, but the same principle generally applies that we want to have optimal levels, just right levels, and not down in the postmenopausal range of let's say 25 to 30.

[55:49]Those don't seem to be reasonable as far as protecting you from osteoporosis. Now, the same thing applies with testosterone. And progesterone, although the optimal level of estradiol, I think has a little bit more data behind it, and it seems to be a little bit more important in my mind.

[56:08]the progesterone is a little bit more difficult to measure, and there's some drawbacks to any type of measurement of progesterone, and so it's a little bit more fuzzy in my mind. But the estradiol has a lot of research on serum Estradiol levels especially. Got it. If we go back like very quickly on on doses and forms and so on, because I realize we have like great questions here from Alex.

[56:35]She has read that a lot of women, between ten and twenty percent of women, actually react badly to micronized progesterone. She's one of them. Estrogen suits her, testosterone suits her, but it's really the progesterone that doesn't really work for well for her. What are the options for women who cannot tolerate that progesterone?

[56:53]But she has a uterus and still needs, you know, that lining protection that you mentioned earlier in the video. anything about like root, dose, timing that could help? Or are we looking at something else entirely? Yeah this is a topic that I find incredibly fascinating. So a good friend of mine and my wife's, I started talking with her about hormones.

[57:15]she was just going into menopause and it was perfect timing for her. And she started taking estradiol and progesterone, and things were okay for a while, but then she realized that progesterone was causing some very major problems for her. Now, this is an interesting story. This woman When she was younger, in her 30s and 40s, when she was of childbearing age, she experienced pre-menstrual dysphoric disorder, which is an extreme form of PMS or premenstrual syndrome.

[57:51]It's where women have extreme insomnia, they get extreme anxiety, they get suicidal depression. This woman, this good friend of ours, she said she really felt terrible for her husband. Every month when she would go through these PMDD episodes, and it was like consistent every single month. The last six or ten days was extremely bad.

[58:18]And she would be in bed, she would not be able to function. there's the interesting thing was she had the same symptoms when she went into menopause, but only after she started taking progesterone. And there seems to be, I've done a little bit of research into it, there seems to be an interaction.

[58:36]I mentioned that progesterone, when it's given in an oral form, is metabolized by the liver. And one of the metabolites is allopregnanolone. Well, allopregnanolone, in the majority of women, probably 90% of women, it interacts with GABA-A receptors. And it acts as a help women sleep in a in a way that's actually similar to benzodiazepines so Xanax is probably the most commonly known benzodiazepine.

[59:10]and it it has activity on GABA-A receptors, and that's where allopregnanolone interacts. However, these women who have a history of PMDD have a paradoxical. Why am I not sleeping? Why if in instead of feeling relaxed, I'm feeling more anxious, more depressed. This is just a fascinating situation. tragic, but fascinating.

[59:38]Now, I've been talking to several providers. This provider is a nurse practitioner in Virginia. And I asked her specifically about this question, and she is convinced, and many others are convinced, that this is an underdosing problem, that patients actually need a higher dose of progesterone in order to saturate the GABA-A receptors and overcome this paradoxical.

[1:00:05]I call it progesterone intolerance. I've actually made a video that was, it's actually had quite a number of views, and it's I've had a ton of Comments from people who said, that's me. I've experienced that exact problem. and I'm gonna do some more content on it because it is it's not all that common, probably five to ten percent.

[1:00:23]But when women do have it, it can be very severe. Now, the question is, what can you do about it? So option number one is you can not take it at all. Now that has its drawbacks if you're taking estradiol, because you need to protect the uterus from the overgrowth that's caused by estradiol. So if you don't take oral progesterone, you can take it in a vaginal form.

[1:00:49]It's a bit inconvenient, a little messy, but it is effective. And there actually are several studies that show it's effective in protecting the uterus. What you do not get from a vaginal progesterone dosage form is any benefit or not much benefit from sleep because it doesn't go through liver first pass effect to a very significant extent. And so you don't get the side effects, but you also don't get the beneficial effects on improving your sleep architecture. And so that's if you're having trouble with insomnia and you don't take oral progesterone, that's a drawback.

[1:01:27]Now there are some providers Relatively rare, but some providers recommend a progesterone transdermal cream. And there are lots of studies that say progesterone in a transdermal cream is actually not very effective at protecting the uterus. That's not a hundred percent of the time. Now, I'm I've had some conversations with a guy named Dr. Daved Rosensweet and he's a very well-known menopause doctor.

[1:01:55]and he has actually a whole system called the menopause method. And he actually uses transdermal progesterone, but he does a transvaginal ultrasound to make sure that that transdermal progesterone is protecting the uterus, and he's had really good success with it. The success, though, is kind of spotty. Some people have good success and some people don't.

[1:02:19]I've actually talked with multiple hormone providers who have told me kind of they would classify them as horror stories where a patient comes to their office, wants to start with hormones for them, and they say, have you been taking hormones? Yes, I have. I've been taking this estradiol and then also progesterone in a cream.

[1:02:37]And they oh I'm not sure sure that's a good idea. So they test, they do a transvaginal ultrasound and they find out that patient has a quite increased thickness to their endometrium and they really need to have an intervention. Because the progesterone cream was not working. and this is a story that's happened multiple times for providers that I've talked with that the progesterone transdermal cream wasn't effective and it was causing a dangerous buildup of the endometrium. So we we do have options, but again, there's no perfect dosage form, right? That's kind of one of my soapboxes.

[1:03:17]And that that's why you're a compounding pharmacist. I think that's like really in your a last one before we we move on. Ellen had a question because she has actually quite a lot of symptoms. Basically, her hot flashes come back ~ about six hours after she takes her progesterone every single night.

[1:03:35]and they wreck her sleep, which is kind of what you also just mentioned. if you set her specific case aside and if you give me the general principle, when you have a symptom that comes back very often, on the clock, you know, like very regularly. What is it usually telling you?

[1:03:52]And is the fix you know, like estrogen is it on the estrogen side or is it more on the progesterone side? Yeah, so hot flashes I would say in general are related to estradiol levels. So I would have a couple of different questions for Ellen. One is what time are you taking the estradiol dose?

[1:04:10]She's taking it at night, which is what I would recommend because taking estradiol at night, in general hot flashes are the most upsetting and concerning if they wake you up in the middle of the night, especially if you have a APOE4 and you want to get quality sleep.

[1:04:26]And so if you have a hot flash during the day, it's inconvenient and embarrassing, but it's not as dramatic as it might be if you have a night sweat in the middle of the night. So taking estradiol as late as possible allows you to have the highest level throughout the night.

[1:04:43]And if you're taking it at another time of day, that would be the first suggestion is the timing. The second suggestion is the level. What level have you gotten on your your lab panel? and if your level is not Optimal between 60 and 100 picograms per milliliter, you might want to consider a higher dose.

[1:05:03]and then the third is you might want to just generally consider a higher dose in order to affect your hot flashes for a longer period of time if you're taking it at night. and so there are multiple things to think about the timing of the dose, the overall estradiol level, which I realize is usually taken During the day, like most people would take their estradiol level, they go to the lab at say 11 o'clock in the morning.

[1:05:28]That's what I do, and that's what my wife does, mainly because you're getting your lipids tested, you're fasting. You know, there's timing of a whole bunch of different things. In general, what you want to do with labs as an aside is you want to test them about five hours after your last dose.

[1:05:45]and sometimes that's a little tricky. So on estradiol, if you're normally taking it at night, you're gonna want to take it in the morning on the day when you get your lab test done, about five hours before the lab draws your blood, roughly and you wanna do the same thing for progesterone.

[1:06:01]Obviously, you're gonna have some compromises there. but this is a situation where you've kind of gotta figure it out for a day or so. but I would say those Three strategies. Look at your overall level, look at the timing of when you take the estradiol, and look at the dose. If you're having breakthrough hot flashes, the first thing you might think about is maybe you need more.

[1:06:24]because estradiol generally can eliminate hot flashes a very high percentage of the time. Yeah, got it. And if we look at the last hormone that's kind of getting a lot of hype like these days for both like men and women, looking at testosterone, where is the evidence now for mainly like female and also male?

[1:06:44]And do you feel like you know, marketing and all the hype is worth it? Testosterone replacement yeah, testosterone replacement. I'm a firm believer that testosterone replacement is a very good thing for both men and women so many women don't realize that you actually have much more testosterone in your body than you have estradiol.

[1:07:06]The level of testosterone is substantially higher than the level of estradiol in most women, or probably in all women who are Pre-menopausal. Testosterone has some major benefits as far as muscle strength, muscle stamina. libido issues are definitely improved with testosterone. bone density also can be impacted by testosterone.

[1:07:32]Sometimes it's a little hard to tell because testosterone is converted into estradiol, and so that may have a A two-pronged positive effect on bone density. But I know from personal experience in my family that sarcopenia and osteoporosis are absolutely huge problems in older adults. And testosterone is a major factor, especially in the sarcopenia part, but also in the osteoporosis part.

[1:08:05]Now My dad just passed away in January of this year. sorry to hear that. Yeah, thank you. Well, the the majority of his health problems were sarcopenia and osteoporosis related. He was very unstable. He fell, he broke a hip because he had severe osteoporosis. And within a year, this is extremely common, within a year he passed away.

[1:08:30]The statistics are that Older adults who fall and break a hip, 30% of them will die within a year. And that is a direct result of not having enough testosterone, also not having enough exercise. And my dad got I don't remember the last time my dad got more than you know, walking across the room.

[1:08:53]and so these are absolutely huge problems, and so testosterone is definitely at the top of the list. there's a very interesting study that showed testosterone. It's called the the Dayton study a woman named Rebecca Glaser, I believe, is the primary investigator. And she gave women a testosterone implantable pellet.

[1:09:15]We talked about pellets a little bit earlier but the result of the study was actually a significant reduction in breast cancer risk for those patients taking testosterone in a implantable pellet. So it was an interesting study. I did a video about that a couple of years ago. I found it fascinating.

[1:09:33]I'm not saying that testosterone is, you know, the thing That's gonna protect women against breast cancer, but it was a very interesting approach and an interesting study. Testosterone has definitely been looked at very closely for hypoactive sexual desire disorder or HSDD, and it's been shown to be extremely effective at relieving those issues in women.

[1:09:57]There's a there's a very serious problem in menopause, There's a there's a very serious problem in menopause, it's called gray divorce. And menopause directly leads to many divorces because of sexual dysfunction. Now, the sexual dysfunction can happen for both men and women, but menopause causes some major issues with sexual dysfunction, and it's it's quite heartbreaking for a lot of women.

[1:10:22]and testosterone isn't the panacea, it's not the miracle cure, but it is a tool. That can help make a difference. I like to tell people when we're talking about sexual desire and libido issues and marriage after menopause that there are relational issues that maybe you don't trust your husband, maybe you're not getting along, there's all that stuff, maybe there's communication issues.

[1:10:50]Testosterone is not going to fix any of those. But it can be a tool that can help increase sexual desire, libido and the physiological response that is necessary for that to be a satisfying aspect of people's lives. and I think it's this is an area that has been neglected.

[1:11:10]There are multiple FDA-approved drugs, including testosterone, available for men, but there's very little for women in that situation. And that's a tragedy, I think. And it's a tragedy that in the US there is no commercially available FDA approved testosterone product for women. All right. I hope you enjoyed that discussion as much as I did.

[1:11:34]It was really packed with information. One thing that I want you to walk away with this. You are not choosing between risk and zero risk. You are choosing which risks you carry. That is exactly Steve's line, and I believe it's a very transparent and honest one. His links and everything you need to learn about him are in the description below.

[1:11:54]Now, I suggest you head on to part two of this Q&A, where we talk about whether it is ever too late to start. How to get taken seriously by a doctor who has dismissed you. Everything is linked in the description below. And again, if you want your question answered in the next video, in the next Q&A, post that directly in the Phoenix community.

[1:12:16]See you.