Episode 6.12 Hormone Replacement Therapy Myths Part 1

In this episode we debunk the first of five myths about menopausal hormone replacement therapy.

00:00:02 Hormone Replacement Therapy For Smokers, HTN

Links Discussed

NAMS 2022 Statement

E + P and Breast Cancer Outcomes

Twenty Year Follow-up of WHI

Reduced Risk of Breast Cancer in Women Using HRT

Thomson vs Western States Medical Center

Compounded Bioidentical Hormones

Transcript

Howard 00:19

What are we thinking about on today’s episode?

Antonia 00:22

Well, we’re going to cover some myths about hormone replacement therapy for women, particularly in the menopausal transition and postmenopause. In the last episode, we talked about using vaginal estrogen cream in several different scenarios, as well as non-estrogen alternatives, but this time we’re going to focus more on systemic hormone replacement therapy, including estrogen, progesterone or other progestins, and even testosterone maybe. But first, what’s a thing we do for no reason?

Howard 00:53

Well, since we’re going to talk about hormone replacement therapy, how about avoiding the use of menopausal hormone replacement products or hormones in women who smoke or who have hypertension?

Antonia 01:05

Okay, yeah, sure. I think a lot of times clinicians will assume that because we avoid birth control pills or other combined hormonal contraception in certain populations, including smokers over 35 years old or in hypertensives, and because birth control and hormone replacement therapy has essentially the same ingredients, then they just think they can apply the same exclusions and the same rules. So if you can’t get birth control, you also can’t get hormone replacement therapy.

Howard 01:37

Yeah, I see this a lot. So primary care doctors in particular. They seem to be more afraid of hormones than objuanas, or at least. But we all know, hopefully, that we shouldn’t prescribe birth control pills to women over the age of 35 who smoke or to those who have uncontrolled hypertension. And hormone replacement therapy does look like the same thing if you just read the label superficially. But doses matter.

02:03

A lot of the myths that we’re going to talk about on this episode, I think they exist because partly because we forget that dosages matter or because we don’t think about the magnitude of effect of a particular finding.

02:15

So, as an example of what I mean by that, we’ll talk about this later but the original WHOI trial linked combined hormone replacement therapy to breast cancer, and again we’ll get into that. But this was with a magnitude of effect equal to that of women who report drinking one or two alcoholic beverages a day and their increased risk of breast cancer. So while many physicians are, as we’ll discuss later, perhaps inappropriately telling patients to stop their hormone replacement therapy because of this breast cancer risk, they aren’t telling them to be T totalers and avoid all alcohol, even though the magnitude of effect, at least for that one area for breast cancer is the same. So the magnitude of effect of a finding is important, and as well as to put into context how much risk we’re talking about. And of course you have to weigh that against potential benefits. But the dosages of different interventions will have different effects at different levels, and birth control pills and hormone replacement they’re not the same thing.

Antonia 03:14

Right. Even too little water or too much water will and you’ll die. So the idea of the dose effect can often get muddled in areas of alternative health or those who make simple associations without really understanding the relevance of the doses. So for as a maybe an unrelated example, many folks might be hesitant about vaccines because of trace amounts of aluminum which are used as an adjuvant, which actually helps to reduce the total needed dose of the vaccine. If you just add a little aluminum you can get, you’re able to get by with much less vaccine with the same effect. So that’s good.

03:56

But that trace amount of aluminum spooks people when they don’t realize that there’s more aluminum exposure in six months of breast milk than there are in all of the vaccinations that kids receive throughout their entire childhood. And that is a low amount. That’s not to say that kids get excessive aluminum from breastfeeding. They get less aluminum from that than from other sources. It’s a lot less aluminum than formula feeding, for example. But regardless of that, the amount of aluminum in the vaccines in breast milk or in formula have not been shown to be harmful and I can’t say I’ve been particularly challenged or questioned by anybody about aluminum in vaccines. And why am I recommending these vaccines with aluminum? I have patients declining vaccines, but they’ve never said it’s because of that, so I’m not sure if my patients care about the aluminum, but plenty of people.

Howard 04:52

Mind you, mind you.

Antonia 04:52

Yeah, there’s plenty of people on the internet, I’ve seen it. So just for that reason I figured I’d look up relative amounts just to put it in perspective. So anyone who ingests at least one milligram per kilo of their body weight per day is considered to be exposing themselves to a toxic amount of aluminum. And most adults will end up having less than 10 milligrams a day and through their food and water that they drink. They might get a little bit more if they eat a lot of citrus or take antacids, but still nowhere near one milligram per kilo. So for an average adult that would be like 70 milligrams or more. And also, in case anyone’s wondering, you don’t get aluminum poisoning or any extra exposure really from drinking a lot of soda cans or having food that’s wrapped up in tinfoil. Okay, so one milligram per kilo per day being toxic.

05:44

Infants will receive four milligrams total of aluminum in their whole first six months of life from vaccines, and that’s not just all in one vaccine, that’s in all the vaccines spread out over six months. And at the same time if they’re breastfeeding they’ll get seven milligrams total over those six months. So that’s much less than that one milligram per kilo toxicity. Formula-fed infants are going to get about five times that amount, so 38 milligrams over six months. And then infants who are on soy formula. I don’t know what it is about soy, but they’re going to get over 100 milligrams of aluminum over the first six months.

06:27

People know we’re near toxic levels, but for someone to be worried about the four milligrams when all these other things are more and it’s not anywhere close to tipping them over some toxic threshold, I think they just don’t realize the numbers. But it makes no sense to be worried about that. It’s literally a drop in the bucket. So that’s just to bring it back to this hormone therapy discussion, where people might be worried that the effect of a massive dose of hormones means that you can’t even give a small dose of hormones.

Howard 06:58

Yeah Right, doses matter and you actually can’t just read the ingredients list and determine whether or not something’s good or bad for you. As often say, medicine in general, human biology in general, it’s a complex system and you just can’t make these first order assumptions and many things will have a positive benefit while also having a negative benefit or effect at the same time, and you have to understand the magnitude of effect and the overall outcomes and what the balance is between pros and cons to appreciate whether you should use something. So the same hormone, estrogen, might increase your risk of thromboembolism slightly, but by a much greater magnitude it may decrease your risk of osteoporosis or death from osteoporotic fracture. So you can’t just look at one narrow outcome without appreciating the total impact of the intervention at the dose. That matters, at the dose being used, and you can’t draw corollaries necessarily from clinical situations where different dosages of the medications are being used.

07:58

I do think sometimes that even physicians maybe internal medicine, family medicine doctors, who don’t deal with hormones a lot they assume, if anything, that hormone replacement doses of these hormones are higher than we might use in birth control. But that’s simply not the case. So if you take a hormone replacement product that uses the same type of estrogen, so say FIMHRT or Genteli, which uses ethanol estradiol. The high dose of FIMHRT is five micrograms and that compares to low dose birth control pills that are typically on the market is 20 micrograms of ethanol estradiol, and many of the studies that have harm data associated with things like smoking and hypertension are based upon older pills where the dosages were 35 or 50. And a lot of patients are only taking 2.5 micrograms of ethanol estradiol for hormone replacement therapy. So literally we’re talking about seven to 10 to 15 times the dose in a birth control pill than what we’re often using for women in the menopause.

Antonia 09:02

Yeah, I think people can get confused with that, because different estrogen types have different equivalents so the numbers might look different, but the effective dose is still.

Howard 09:14

Or sometimes it’s in milligrams rather than micrograms right. But it’s estradiol is different than conjugated equine estrogens. It’s different than ethanol estradiol. So you can’t just make those back of the envelope assumptions.

Antonia 09:25

Yeah, okay. So we do agree, though, that giving those high doses of birth control to people who smoke or have hypertension increases their risk of DVT, probably more so than it benefits them. So how does this shake out, then, for postmenopausal hormone therapy?

Howard 09:45

Well, obviously we want to control hypertension and we want folks who smoke to quit smoking please do and that’ll make a big difference, obviously, in your total health outcomes. But if they’re suffering from vasomotor symptoms of menopause, then they should be allowed to take hormone replacement therapy unless they have another independent contraindication.

Antonia 10:01

Because the risks are lower and also because smoking has an anti-estrogenic effect. So, ironically, patients who smoke probably have even worse symptoms and higher need for hormone replacement therapy and will get less benefit from it.

Howard 10:18

So that’s another reason to have them quit smoking too Well, smoking’s bad for you in ways that we could spend the whole next season discussing, but that’s not our main focus.

Antonia 10:29

Okay. So the bottom line is the risks are not the same, so let your smoke. Or patients that are having hot flashes, take some HRD. Okay. Well, we’re going to get into some more myths. I don’t know if that even maybe that counts as a myth too, but before we get into those, I think it’s interesting to talk about why these myths are pervasive. To begin with, not just on TikTok or other social media, but among physicians of various specialties and other people who present themselves as experts, and, of course, among women that are patients and that are seeking care for these symptoms.

Howard 11:09

Yeah, I think a question like this is important and I think, well, we already gave a couple of reasons why people will get this sort of information confused. The magnitude of effect of these negative outcomes it sounds scary, but when you look at them in scale they’re very inconsequential compared to potential benefits. And then the dosages, obviously lumping all hormones together regardless of dose. But there are many more reasons, and so I think that we could quickly list a few of these reasons why these sorts of falsehoods that we’re gonna discuss exist for menopausal hormone therapy in particular. So I think the big first one is the Women’s Health Initiative trial was widely misunderstood and misrepresented.

11:49

People took and spun this in different ways depending on what their bias and interest was.

11:53

The media did a really horrible job with this back in the early 2000s and then physicians also were caught cross ways and not really understanding or having definitive answers, and influencers at the time.

12:06

Tiktok is new, but the big influencer for women and women’s health at the time the WHOI came out was Oprah Winfrey and she frankly did a lot of damage with many of her episodes related to hormone replacement therapy. And so we all had these opinions, formed, these narrative fallacies. And then, secondly, when women stopped using their hormones, back in around that time, back in 2002 and 2003, as a result of the WHOI misinformation backlash well, and then they became very symptomatic there was an alternative medicine industry that sprung up. That’s very huge, lots of money being made and a lot of people including a lot of compounding pharmacists and other people, putting themselves out there as gurus. They swept in with very bold claims and stole the market share of half the women that stopped their hormones and they made a lot of money, and that continues to this day, and so there’s a whole wellspring of false information from that aspect of this particular topic.

Antonia 13:05

Yeah, and we talked a lot about the Women’s Health Initiative trial, the WHOI way back in episode three of this podcast, so way in the beginning. So just to remind listeners, the trial was stopped at its midpoint because the review board did not see a decrease in cardiovascular events, which was the main purpose of the trial, and I think they even said they saw an increase in strokes. So they stopped it. But they allowed patients to choose to continue therapy on an open label basis if they wanted to, or to let them just drop out of the study. And, based on a press conference then that the WHOI researchers held, it ended up being reported that estrogen was causing breast cancer in women and that hormone replacement therapy was causing the heart disease, blood clots and strokes. So, as a consequence, almost half of the women in the US who were using hormone replacement at the time stopped using it quite abruptly.

Howard 14:14

Yeah, it was a wild time to be alive. Women were angry and the headlines of a lot of major American newspapers had that big font, like after Pearl Harbor, like this was O shaking. But the media typically does a pure job with science, reporting and drawing conclusions, and aren’t supported by the data or jumping some steps ahead, and then that’s what people remember and so a lot of confusion. And, of course, those women who stopped, they many of them had very bad menopausal symptoms. So the alternative health markets swept in with lots of products that they claimed would help. Suzanne Summers was on the Oprah show a lot back then talking about bio-identical hormones and this bio-identical hormone replacement industry came about and they claim that their products wouldn’t cause the problems that these pharmaceutical drugs, pharmaceutical synthetic, fake hormones were having and the side effects and the complications that were being reported at the time, and so that industry came about.

Antonia 15:12

Yeah, and we’ll try to talk about bio-identicals a little bit more today.

Howard 15:17

Well and for a long period of time, and even today there’s still a degree of uncertainty in the medical community and our own literature about what are the real risks and benefits.

15:26

Ask 10 people, you get 10 opinions, almost 11.

15:29

And back then there was also a lot of angry patients, as I said, so the FDA and other medical societies.

15:36

They were taking a back two about what to do and they took a very neutral and just cautionary approach, especially in face of so many potentially angry women. You thought you got cancer because of this, perhaps right. And so they took a cautionary approach to hormone replacement, which then led to now a whole generation of physicians being very hesitant and risk avoidant of hormone replacement therapy. I’ll also mention that the pharmaceutical industry itself created lots of alternative products, including non-estrogen therapies for some of these symptoms, but also different routes of administration of estrogen that were expensive and branded, at a time when estradiol was generic, and they made lots of bold claims to physicians who were not very confident about what was going on and what they should be doing, and they claimed if you use our newer products, particularly transdermally administered products, then patients won’t have many of these side effects like blood clots or things like that, that it was the oral route of administration that was a problem. So doctors were getting it every which way and patients were just as confused.

Antonia 16:39

We won’t go fully into the problems with the WHOI trial that led to all of this for time’s sake, but if listeners want a refresher, they can go back to episode three, where we talked about that some more.

16:52

So if you need to just pause here and go back and listen and then come on back, we’re gonna get going with a few myths about HRT and we’ll get a lot of our data on our discussion from the NAMS position statement the North American Menopause Society from 2022. And that has tons of good references in it and we’ll give other sources as necessary, but generally we’ll get our data from the NAMS position. So the first myth is that estrogen causes breast cancer. This is still everywhere. I think we already covered it before, but it’s still everywhere. It seems like almost all patients seem to believe this. As soon as I even have 19 year olds coming in for their first guide and visit, don’t wanna start birth control because they said it’s gonna cause breast cancer, and I think a lot of doctors and medical providers seem to believe it too, unfortunately, yeah, it is a big deal and it’s a myth.

Howard 17:47

Again. Episode three, therefore, that was about and we go into detail about a lot of this and more than we have time to do now, but it just simply isn’t true. But here are some key points and again, using that NAMS document, which is really good and very fairly written, they’re not pushing anything. They’re being very, almost reserved in trying to present both sides of everything and all the potentials, and so it’s actually quite good. But in the WHOI estrogen only arm, the women who received the Conjugated Acquain Estrogen or Primeran in that study had seven fewer cases of invasive breast cancer per 10,000 person years compared to the women who took placebo, and this remained true and was statistically significant at 20 years of follow up for those patients. So long-term use included. Also, the women who developed breast cancer while using estrogen had better outcomes. So if anything, you could argue it’s protective and to a statistically significant degree 20 years after women started therapy.

Antonia 18:51

Yeah, yeah, it was a big enough difference, like it was not a random finding, most likely. But of course people with maybe a halfway basic understanding of the theory of how breast cancer develops will easily assume that estrogen makes breasts grow. Some breast cancers are ER positive, so that must mean estrogen is causing them to become malignant when they were would have otherwise been normal, and estrogen does that. In the uterus You’ve unopposed estrogen. That’s a risk factor for endometrial cancer, but it doesn’t do that in the breasts. Now I don’t know the mechanism of how unopposed estrogen in the breasts would actually be preventative and protective, but clinically we have seen it in the WHI. But in the original trial there were additional breast cancer cases reported among the combined group, estrogen plus the MPA, the medroxyprogesterone acetate group. So then the question is does that mean? Is it the progesterone or the combination of estrogen, progesterone that causes breast cancer? Even though we do still need that progesterone? We need it to protect against uterine cancer.

Howard 20:09

Well, again we get into that in more detail in that old episode when we were just young kids figuring out how to do a podcast.

20:15

I think we’re better now, but based upon the timing of the breast cancer cases that developed, it seems to be that progesterone makes women’s breasts more sensitive and perhaps hormone replacement therapy makes tumors that were already there grow a little faster. And of course, that said, he had no progesterone, only arm. There wouldn’t be a reason for that. So when they talked about increased cancer risk with the combined group with both estrogen and progesterone, it was the estrogen that got blamed, because people were familiar with using tamoxifen to block estrogen receptors for women who had had cancer. But as long as women were getting regular screenings and timely care and evaluation of new masses and this probably was just a sign of earlier detection in most cases, rather than new cancers that wouldn’t have otherwise existed. So on a 20 year follow up there wasn’t any increase in breast cancer mortality in the estrogen plus progesterone group compared to placebo, just increased detection.

Antonia 21:17

Yeah. So the participants had to have a normal mammogram screening to enter into this study and their frequency of ongoing screenings during the study was also recorded and controlled for. So I think the study at least did a good job of assessing for their screening status well and perhaps even encouraged participants to make sure they were getting at least every two year mammograms. But out of the breast cancer cases that occurred in the patients on the combined hormone therapy group, those tumors were more likely to be of the easier treatable kind, so they were well differentiated estrogen progesterone receptor positive. In contrast the cancers that happened in the placebo arm, even though they were less frequent, they were more likely to be poorly differentiated cell types. So those are generally considered a worse prognosis and more aggressive. Even though overall the stages and how many had lymph node met’s at diagnosis were the same, it was those cell types that were different.

Howard 22:28

Right and we don’t have time to talk about the potential for overdiagnosis of tumors that would have been relatively harmless or just misdiagnosis, but it should suffice to say that a lot of mammographically detected breast cancers are overdiagnosed or misdiagnosed.

22:45

There’s a lot of false positives among breast cancer survivors, but that still can paint the picture of the progestogens encouraging existing tumor cells to grow. Of course there are progesterone sensitive cells as well, but selectively, somehow, only the good prognosis type of tumors. So it’s well known that most breast tumors actually take a decade or so to grow from the original mutation in the cell to something that’s clinically detectable. And there are no basic science or animal studies that demonstrate a link between progesterone and malignant transformation. Changing the half-life of the cell or the doubling time of the cell is one thing, but are you actually causing the mutation? So just the proliferation of the cell, not the transformation. So although on the whole we probably can’t claim a breast cancer benefit, in the combined group, at least based on WHI data, we can likely reassure patients that any increased risk is related to highly treatable cancers and there’s no increased risk of deadly breast cancers from HRT, and estrogen might even be protective, if that’s all you’re taking.

Antonia 23:45

Yeah, yeah, and I’m guessing those well differentiated cancers probably were also there in the placebo group but just tended to stay more dormant for longer in those patients because they weren’t getting stimulated to grow as fast.

24:02

They were still there, but essentially subclinical, you could say. The WHI is still really our only long-term study on HRT, especially regarding this outcome of breast cancer incidents and mortality. So just to break it down, the women on estrogen alone no progestin, because they didn’t need it if they didn’t have a uterus had a hazard ratio of 0.78 for getting diagnosed with breast cancer and 0.6 for dying from breast cancer compared to placebo. And obviously these were the women without a uterus, so their uterine cancer risk was essentially zero as well. So it almost makes me think I’m not sure if this is a strong enough effect to be actively recommending hysterectomy when someone needs treatment for a benign guy and disorder. But it’s kind of a nice effect, a nice downstream benefit to have both a lower uterine cancer risk and also later on in life have a lower breast cancer risk if you do HRT because you can skip the progesterone.

Howard 25:06

We should do an episode on the alternatives to hysterectomy movement.

Antonia 25:12

Yeah.

Howard 25:13

We’re now seeing rising uterine cancer rates, as we discussed in a previous episode among black women, and more fatal cancers and more advanced diagnoses, and, after a generation of, stop doing hysterectomies and do alternatives. It is not a simple conversation and a lot of that conversation has been driven by industry. We’re probably seeing too many myomectomies and too many endometrial ablations, but maybe we’ll do that next season. But, yeah, more things to weigh against a surgical risk of hysterectomy. And also, should we be maybe protecting the uterus with IUDs instead of systemic progesterones? Whole other conversation, but there’s something there to think about.

25:49

But yeah, so, yeah, you’re right, the WHOI is the only prospective randomized trial to look at mortality, but there are a lot of observational studies which show good benefits. The most recent one is from Finland and I know that makes you happy and they found that breast cancer mortality risk was reduced in all hormone therapy users who would use the products for at least five years, including in groups of women who used it for more than 10 years. And this was the most profound in menopausal aged women who were within 10 years of menopause when they started hormone. But it persisted in all age groups and this was better in the estrogen alone group, just like WHOI, than in their estrogen plus progesterone group, and the reduction of mortality across the board was around an average of 50%. Just like WHOI found a 40% reduction.

Antonia 26:35

Yeah, so finished medicine for the win. I guess this one was not that recent, it was from 2016. And of course it’s women in Finland, which is mainly Finnish women, it’s not the WHOI. So you could argue there’s possibly lots of different environmental and lifestyle and genetic factors in the background. But in their bottom line they said breast cancer was historically fatal in 10% of cases. But then for all of these HRT users, whether it was combined or not, but especially in the not combined estrogen only, it was only fatal in 5% of cases. So yeah, 50% mortality reduction.

27:19

The other little nuance to note is that they didn’t use the same type of estrogen as the WHOI did. Whoi was premmarin, the conjugated equine, and in this study they used estradiol, which I can’t see exactly why. That would be even more protective against breast cancer, but I guess you could argue that too until there’s further evidence. Either way, but as far as I can tell, the progesterone or the progestin effect was the same. So either way, this myth about estrogen causing breast cancer is very busted, and it’s an important one to bust because I think it seems to be the biggest deal breaker for a lot of patients who are considering starting this or not. So we’ll move on to the next myth, which is related, and it’s that women who have some high risk for breast cancer, like BRCA positive status or family history of breast cancer in close relatives, or even women who have undergone risk reducing ophorectomy or mastectomy for their positive status of BRCA, should not get to use hormones. So let’s bust this myth.

Howard 28:28

And I see this a lot from the surgeons. The rest surgeons told my patients don’t use hormones, never use hormones. We talked about this before in regards to birth control pills in younger women with such a family history or, of course, maybe their BRCA positive and women. These women are told they shouldn’t use birth control pills in their reproductive years to avoid these risks, but in fact they should use them to reduce the risk of ovarian cancer and when they do, that is not associated with an increased risk of breast cancer. In fact, one of the number one things you can do for a young BRCA positive woman who’s not doing risk reducing surgeries put it on birth control pills. But I think we can conclude this myth quickly by referencing again the NAMS position statement.

29:11

they cite evidence indicating that a family history of breast cancer or being BRCA positive status post ophorectomy, that those are just not reasons to avoid estrogen replacement and in fact, as I said, you’re probably harming those patients by withholding it.

Antonia 29:25

We don’t have to get too much into it today. But again, this idea that we use to moxifin or some other estrogen blocker type of medication in women who have had estrogen receptor positive breast cancer to decrease their risk of recurrence is another reason why people are so quick to make that estrogen link. It’s like get treated for breast cancer and then block the estrogen. Good, and estrogen must be bad right. So again, I’d refer folks to listen to episode three again. But I think you have a good analogy for how to contextualize how we should think about the estrogen receptor positive breast cancers.

Howard 30:06

I don’t know if it’s good or not, but people remember it. So, yeah, my analogy is that I’ve developed a technique to cure any cancer that a patient has, any cancer. Unfortunately, it also kills the patient and it causes the tumor to die from a lack of oxygen and nutrients. But in order to block oxygen to their tumor, I have to block oxygen to them, so it has the unfortunate side effect of killing the patient. But we do this in cancer treatments. We look for things that metabolites or things like that that stimulate continued or rapid growth of cells, and how can we block those?

30:42

But when a breast cancer mutation happens in a particular cell that happens to have estrogen receptors on it, we should be happy because then we can, we have an opportunity to block those estrogen receptors without causing much systemic harm, unlike if I block oxygen or glucose or something and then slow the growth of those cells in a very targeted way. Now we’re not preventing new cancers, but we’re slowing the growth of cancers that are left behind after whatever the primary treatment was. And by slowing down the doubling time of those cells we’ll likely prevent clinically detectable recurrence before the patient’s eventual natural death due to some other cause. And, of course we’re affecting other estrogen sensitive cells in the process, so we have to worry about the uterus, things like that, but we’re not killing the patient by generally blocking it. So estrogen doesn’t cause breast cancer any more than oxygen or glucose does. But there are therapeutic opportunities.

Antonia 31:36

Yeah, and just to be clear, we’re not advocating systemic estrogen for these specific patients that have ER positive personal history of ER positive cancer. But we talked about last time how they can still get vaginal estrogen and it won’t increase their risk. But this analogy is just to show that in certain patients estrogen is a target, but that doesn’t mean in all patients who don’t have breast cancer that if you give them estrogen it’ll cause cancer. So by that same token, the same train of thought, if you start taking estrogen in menopause and you happen to have an occult tumor, like one cancerous cell, that hasn’t shown up on mammogram yet and it happens to be estrogen receptor positive, well then you might speed up its growth and then eventually it would show up on a mammogram. But if you don’t give them estrogen, it’s still there and it’s still going to grow. It might grow a little more slowly, but they still have cancer either way.

Howard 32:37

And I think that’s why these studies are so hard to interpret and seem sometimes to be crosswise with each other, when you see higher rates of diagnosis of breast cancer in the first couple of years after a study starts. But that doesn’t mean that outcomes are worse. And hey, it might even mean that earlier detection, due to a faster growth of the cell, led to mammographic or clinical detection before metastasis.

Antonia 33:01

Yeah yeah. At least we know from WHI that it didn’t lead to increased death. It didn’t seem to decrease their death rates either, but definitely not increase. It’s earlier detection, earlier treatment. Maybe it just canceled each other out. Anyway, let’s move on to the next myth. This one also stems from the WHI, and that is that estrogen causes cardiovascular disease. So in the 90s, when this trial was started, the purpose of it was to prove that the difference between male and female rates of cardiac disease pre-menopausally because women have lower risk before menopause was due to the protective effects of estrogen in women and that after menopause, if women did not continue to take estrogen, then they would lose their protective effect and they would rise up to, I guess, the same risk as men in terms of heart disease. So the people creating this study wanted to prove that estrogen was cardioprotective, but by the time of that interim analysis, if anything, they were seeing more cardiac events, because until then they didn’t realize that the timing of therapy mattered greatly.

Howard 34:11

Yeah, this one has taken us a long time to understand and, of course, I don’t think we still completely understand it. But the main thing to know about the WHI is that the women in that study were, on average, more than 10 years post menopause. So in the clinical trial we have to divide women into those who started hormone replacement therapy around the time of menopause, within a few years of the transition, and those who were just arbitrarily started on it more than a decade after their menopausal transition. And that was what happened in the majority of women in the WHI.

Antonia 34:43

There was a 2015 Cochrane review of randomized controlled data that found that hormone therapy initiated within 10 years or less of menopause onset lowered the risk of cardiovascular disease by almost half compared to not initiating it, and there was nearly a 30% reduction in all cause mortality, with no increased risk of stroke but regardless still a slightly higher increased risk of DVT.

Howard 35:11

Yeah, and there’s another 2020 systematic review and meta-analysis of the previous 20 years worth of randomized trials done on hormones that showed basically no difference in women under the age of 60 in terms of all cause, mortality, stroke and venous thromboembolism.

Antonia 35:27

Yeah, so well. That shows how different one systematic review can be from the next, where one shows a significant benefit and the other one maybe shows no change at all. But different studies and reviews with different inclusion criteria and different methods can easily produce different results. But the important part is that none of these showed worsening heart disease or elevated risk of stroke in women who started therapy under age 60.

Howard 35:56

Yeah, and we’ll deal with DVT later. But yes, and the WHOI encompassed patients with a lot of different potential risk factors and it also didn’t assess the potential effects of different hormone routes or preparations. It was done by the company that made Primeran and Primpro and that’s what they wanted to sell. That was what they had. So a lot there to unpack and to look at through other studies. But it reveals that there’s likely a population of women who do benefit from hormone replacement therapy and those are probably younger women who start therapy right at the time of menopause, and the healthier women in that group who don’t have preexisting cardiovascular risk factors. Then, as women become more at risk with, say, age or obesity or hypertension or smoking or things like that, those benefits start to go away and you don’t see any protective effects. But it hopefully isn’t replaced by harm, as long as we’re talking about women under the age of 60.

Antonia 36:53

Yeah, and similarly to the breast cancer outcome, the subset of women who seemed to benefit in their heart disease risk so having less risk for heart disease and stroke was the estrogen only group, and the potentially protective effect went away when progesterone was added. It didn’t increase the risk, but it just leveled it out. Or when the women were over 60. And in the longer follow-ups, those women who were younger at initiation still 13 years later had a 40% reduction in their rate of heart attacks if they were using estrogen only. And then even at 18 years out, it was a slightly lower reduction by then, but it was still statistically significant.

Howard 37:35

And I will say and we’re going to talk about some of these things in the next episode but running is cardio protective, but if you run while eating a cheeseburger or something, it may cancel the protective effects out. So people are really going to be tempted to say progesterone causes breast cancer, but it may just reverse the protective effects. So don’t assume things, because that’s a way of your mind explains data. It doesn’t necessarily increase it, it just doesn’t allow you to be protected by estrogen. It could be a way of thinking about it.

38:03

But yeah. So now, in contrast to what we just said, in systematic reviews and in the WHOI alone, women over 60 or more than 10 years past menopause when they start therapy, if anything, seem to have slightly higher rates of stroke and thromboembolism. So it seems like the aggregate increased risk that you see, sometimes attributed to hormone replacement therapies related to stroke and even thromboembolism, is due to the subset of women who start the hormones after age 60 or more than 10 years after menopause, and that also seems to explain why you see some increased risk of cardiac events.

Antonia 38:38

Yeah, if the authors of the WHI had picked women who were 51 instead of in their 60s, we might not be making this podcast at all right now. And if that had been the majority of their population, it could be that they found a positive answer to their question, that they would have instead concluded that HRT prevents coronary artery disease. But in any event, the myth that it causes heart disease, at least in women who are starting it first menopause symptoms earlier in life, is busted, I would say. So let’s move on to the next one. I think we’re on myth number four, and that is that compounded bioidentical hormones are safer than prescribed to pharmaceutical preparations.

Howard 39:25

Yeah, okay.

39:27

So, largely in response to the first three myths that came into our public consciousness after the WHI, in which were promoted by folks like Oprah and others in the media, the bioidentical hormone market just took off.

39:42

And the other important thing that happened that year, in 2002, was that the Supreme Court case decided a case called Thompson, the Western States Medical Center, and this was in response to a 1997 amendment to the FDA control act, which the FDA was using to go after compounding pharmacies who were aggressively promoting various compounded drugs, with all sorts of claims that had not been FDA validated, evaluated or approved, and drug preparations that they had not deemed as safe or effective.

40:13

And the Supreme Court eventually ruled against the FDA and essentially said that the Freedom of Speech Clause allowed pharmaceuticals well compounding pharmacies who were making these compounded medications, to make whatever claims they wanted to about them and advertise them in whatever way they desired. They essentially said that these compounding pharmacies, as a result of having freedom of speech, could lie to patients. Now, the same is not allowed for drug reps, who do have to answer to some FDA rules, although they still obviously have their ways of stretching the truth, and you know how I feel about them. But this led to a perfect storm back in 2003 with the distrust of the pharmaceutical prescribed hormones caused by the WHI, and then an opportunity to make all sorts of money for compounding pharmacies and clinicians and docs who would get in bed with them. They were given full rights to claim, for example, that compounded hormones were safer than prescription drugs being used in the WHI, even though they had no scientific studies to validate that claim.

Antonia 41:20

Yeah, I’ll have to look into that decision and what their logic was for saying.

Howard 41:25

Freedom of speech baby.

Antonia 41:27

Yeah, but why not freedom of speech for the FDA and for regular pharmacies? Why can’t they lie?

Howard 41:33

Yeah.

Antonia 41:33

I’m glad they can’t, but it’s inconsistent, but anyway that’s the way it is. So every podcast on every other podcast.

Howard 41:42

Not this one.

Antonia 41:43

Not this one. Every other podcast on women’s health that is about bioidentical hormones and every other compounding pharmacy in the US runs ads all over the place claiming that this bioidentical HRT cures everything, it’s a fountain of youth, gives you your mojo back, makes you live longer, etc. And it’s just really disappointing to see how they’ve really run away with these claims and patients will ardently believe them and the compounders are just allowed to get away with it because of that Supreme Court ruling.

Howard 42:16

Well, and a lot of doctors participate in this, or nurse practitioners or PAs or whoever they participate in it as well, some willingly, some receiving kickbacks and some unwittingly, because sweet patients come to them and they have this pharmacist suggested prescription and all you have to do is sign here or renew that for me. Some doctors even participate in these schemes providing pellets in the office or other compounded things that they make a profit off of, and this has become the equivalent of like a multi-level marketing or franchising scheme, a money making pyramid for a lot of these folks doing this.

Antonia 42:52

There’s not even a clear definition of does bioidentical hormone therapy mean? People will use that term in a variety of different ways for a variety of different substances. It’s just like seeing the words all natural or organic on food labels or supplement labels, or like candy labels Like this is all, these are all natural gummies, so they’re safe for your kids. But these? It’s the same thing. These words are used freely, with no standards or oversight. There’s no requirement to fit certain checkboxes to be able to use that word. You can just put that word on whatever, and it’s used, of course, to invoke this image of it being wholesome and healthy, as opposed to being chemical or synthetic.

Howard 43:40

Yeah, buzzwords, yeah Well, originally, I think that bioidentical was supposed to mean that the hormones in the preparations were identical to the hormones made by the human body, so in other words, estradiol, perhaps, which is the key estrogen of the reproductive years, or just natural progesterone. The reality, though, is that when we take these bioidentical hormones from external sources, they’re processed by the liver, and the product will still end up in a different form as it’s metabolized by our human bodies, which are just biochemistry labs, essentially on legs. Progesterone supplements in particular, they get broken down so quickly that only a very small percentage of the ingested dose actually remains effective in the circulation. That’s why we tend to use synthetic progestogens for things like hormone replacement therapy or birth control or management of abnormal bleeding, so that we can actually see an effect from them. And, of course, it takes clinical trials to understand if the dosages are correct. But bioidenticals and synthetics essentially have the same ultimate effect on the receptors, but the synthetics require lower doses to achieve that.

44:44

But at some point, the term bioidentical hormone replacement therapy also came to imply that the hormones were being replaced to physiologic levels that your body needed to function optimally. Like we’re matching your levels it’s identical, so this also caused a fad of checking hormone levels and then following hormone levels to see what your levels were and if they were appropriate. And back in 2003, this all resonated because it was easy to say oh, that study was a horse piss. Estrogen, that was conjugated equine estrogen. That’s horrible, but this is the real thing and it doesn’t cause cancer like that stuff does.

Antonia 45:19

Yeah, I’ve had plenty of people say I don’t want the one that’s from horse pee. That seems to irk them too. And I have seen this happen where patients have been harmed because they had a provider that was changing up their hormone doses solely based on their serum estrogen or progesterone levels, not because there was any symptomatic issue. But then they’ll start having abnormal bleeding, for example after a significant dose increase after getting their labs checked. But we know that hormone levels can vary widely depending on all sorts of things, even the time of day. So those lab values are really useless for managing menopausal hormone therapy. There’s no evidence that following their estrogen levels and then chasing it with different doses results in any better symptom control or any lower risk of side effects. And there’s also no evidence that using these bio identical compounded hormones are any more effective or safer.

46:22

But since the WHI included the premarin, the conjugated equine estrogen and the progestin, the MPA, then after that Supreme Court ruling the compounding pharmacies were allowed to claim that basically any other preparation besides those was better and wouldn’t result in the more breast cancer diagnoses or cardiovascular events that we’ve already busted those myths anyway, not because it was true to make those claims but because they hadn’t been disproven yet. So they were allowed to say it wasn’t that hormone, so it must be better. So they specifically began to claim that if you took their versions of estradiol or estrogen or even estrial plus a natural progesterone that you have to take massive doses of because of how it breaks down in the body, then you wouldn’t have any bad outcomes. But, like I said, we’ve already established that the cancer and the cardiovascular risks were not related to the type of estrogen or the type of progesterone being used.

Howard 47:23

Well, the compounding act allowed pharmacists to make up different drugs that are needed for patients who can’t use a traditional regulated medication or produced medication in rare circumstances. So, for example, if you need a medicine that’s only available as a pill but you have a feeding tube, then maybe they can crush it and make it into a different form or, in some cases, make a transdermal cream or something like that so you can absorb it. But it was never meant for pharmacies to go large scale into the pharmaceutical production business and make medications in huge numbers for patients on a regular basis, as if they were a pharmaceutical manufacturer, because to do that they should be subjected to the same requirements of safety studies, efficacy studies and things like that for these preparations. But they use the compounding law and that serving court case to get around that and then avoid scrutiny from the federal drug administration. So, in general, pharmacists that are doing this in mass are violating the ethics of their own profession.

Antonia 48:21

Yeah, most people probably don’t realize that for compounding pharmacies there’s no quality control or standardization of what’s in their drug. There’s just no guarantees that a patient actually will get the dose or even the medication that they think they’re getting. So the bottom line for this myth is there’s no safety or efficacy data. There’s very limited pharmacokinetic data to tell us that bioidentical preparations are safe at all, let alone that they’re safer than the agents that we already have really strong evidence for.

Howard 48:55

And that would be important, for example, to know the absorption of progesterone to protect the uterus is key if you’re taking hormones and you have a uterus. It’s well known that Suzanne Summers, who was a large advocate for the bioidentical hormone industry, she herself developed endometrial hyperplasia a typical hyperplasia while on her own products and, of course, recently passed away from breast cancer after decades of use of her products. Now we don’t know if she absorbed the progesterone that she was using through her own product in an adequate way to protect the uterus against the estrogen that was perhaps unopposed. That would lead to a typical hyperplasia because there’s no safety studies on how protective it is or how the absorption through that route and that dose, if it’s effective or not.

Antonia 49:38

Yeah, we just have no data available to tell us about overdosing or underdosing or impurities or sterility or efficacy or safety. There’s no clear labeling about the side effects or the benefits based on any scientific studies for compounded drugs, and it’s being given to the patients by someone who is legally allowed to lie about the safety and benefit profile.

Howard 50:05

Yeah, there often also exists some financial relationships or kickbacks between prescribers and pharmacists and these products are expensive, often over 100 times the price of safe and effective prescription hormones. Estradiol is generic and is about four bucks a month, and some people are paying $400 a month for compounded versions of the same drug.

Antonia 50:25

Yeah, and in case anyone out there is wondering, especially anyone that’s in military medicine we know those kinds of relationships are not allowed in military medicine very strictly, but they’re also not allowed outside of the military either. They’re still punishable by big fines and other serious professional disciplinary actions. And even now that I’m a civilian doctor, I’m at an office that has regular lunches provided by drug reps. None of them ever even start to hint like hey, prescribe our drug, we’ll give you a cut, or anything like that. They’re still pretty cut and dry, just trying to sell the benefit and nothing else. And also, so far I’ve never had a compounding pharmacy rep come over and try to win my business for selling or sending patients to them. But I suppose it’s probably easy enough for shady people in medicine to make all kinds of under-the-table deals.

Howard 51:19

You probably won’t get any offers after this episode.

Antonia 51:21

sorry, Well, it’s fine. Yeah, I don’t want that, but anyway, we should bust that myth about bioidentical hormones being safer and maybe go a little bit further. We talked about tracking the hormone levels, so let’s make that a separate myth to address.

Howard 51:37

Okay, yeah, and you already summarized this one a bit, but there’s really two parts to this myth. The first one is that salivary or urine hormone testing or something like that is an accurate way or a surrogate for serum blood testing. And it’s not. But this kind of testing has become one of those franchise products where companies have made a lot of money selling these testing kits and services to either pharmacists or other non-physicians, especially various alternative medicine providers, who use it to tell patients that they’re deficient in particular hormone or to act like that the product they’re giving them is effective because of the results of a follow-up hormone check with a saliva test or something like that, but there’s no scientific evidence that this sort of testing is effective in terms of cross-walking well to serum levels. And then the second part of the myth is that there’s any value at all in knowing what your blood or serum levels of a particular hormone is, of these sex hormones, at least, when you’re dosing the hormones and providing these prescriptions to people.

Antonia 52:40

Yeah, and you can see how that would be easy to scam or sell patients on. Because of course, if you make them think that they don’t need a blood test, well, they already don’t need a blood test. But if they did, but you could do it by urine or cheek swab or something instead, then of course they would want to skip the needle poke. But regardless, any kind of testing of estrogen leads to the idea that patients would need just subtly different doses of hormones throughout, maybe throughout the course of their treatment, and need lots of adjustments and a follow-up testing of those levels. But it’s all just this made up scheme to keep them coming back and just keep taking their money. The scientific literature doesn’t support any specific lab value to aim for, or it doesn’t support frequent readjusting of their doses based on anything except symptom control or maybe new known medical risk factors, like if they have an active DVT all of a sudden. Then you would stop their therapy.

Howard 53:44

But I think the thing here is that people they’re treating sex hormone levels as if they were thyroid hormones. So you know, testing for thyroid hormones like TSH or T4 can help us guide the specific dose needed for your thyroxin replacement. And while making adjustments you want to follow those lab results every few weeks to make sure that your adjustments are appropriate. And there are a ton of different small variations in doses of the thyroxin products available, like levithoroxin or synthroid, because patients do need slightly different dosages to correct their insufficiency. But in the case of TSH, as an example, that serum level should be between 0.4 and 4, depending on which lab you use. Pretty much throughout your life, whether you’re male or female, whether you’re premenopausal or postmenopausal, whether you’re pregnant or not, whether you’re on your menstrual cycle or not, your TSH should be somewhere between those values.

Antonia 54:39

Yeah, and that’s not how sex hormones work. They instead have massive fluctuations throughout the lifespan and then also throughout the month, during the reproductive years especially, and then they also vary based on things like athletic activity, sexual activity, health status in general. Like there’s no standard for what lab value is healthy or appropriate for sex hormones.

Howard 55:05

Yeah, you only need to look at a chart of hormone levels during a woman’s cycle to understand how widely variant they are. In a reproductive age woman, for example, estradiol levels vary from 30 to 400 pikograms per milliliter, depending on the time of the month and other individual factors relative to her situation. Progesterone is really only around in significant amounts during the luteal phase, and so it varies from a low of 0.1 to 25 nanograms per milliliter during the menstrual cycle. That’s over a 250-fold change in the level of progesterone depending on where you’re at in your cycle. And in the same way, testosterone levels vary from 15 to 70 nanograms per deciliter, depending on a lot of different factors. And of course, I’m just talking about reproductive age women here, not postmenopausal women. We don’t have any data that says that optimizing a hormone level to a certain range in a certain age group is associated with better outcomes or is safer in some regard. Nor do we have any data that says that having them in some optimal or predefined range improves certain symptoms better than a different range might be.

Antonia 56:16

Yeah, the only scenario I can think of where it is appropriate is in the context of an active IVF treatment, where they might want to follow the estrogen levels to see how to dose the gonadotropin.

Howard 56:30

And in that case they have scientific studies that say you should aim for this target. So it starts with having scientific data.

Antonia 56:38

Yeah, but in the case of menopause, the incorrect assumption here is that there is some known ideal range for a postmenopausal woman to be at. But then the question is should they be at the same level as a premenopausal woman, or just three-fourths of that or half of that, or where should they be? And then not only that, but should they be at the level of the first half of the cycle, the proliferative phase, or should they be at the luteal phase? Or should they be at the level of a pregnant woman first, second or third trimester, or should they be at the postpartum level? So there’s no answer to that because the answer doesn’t exist.

57:20

If these levels are being checked in women who are premenopausal, then it’s going to matter greatly what cycle they’re on when they’re being checked. And if you’re checking progesterone in a postmenopausal woman, then why Do you think that she’s ovulating? It’s just kind of silly if you think about it, because it’s not like you’re checking progesterone levels in little girls before menarche. We’ll get to talking more a little bit about progesterone supplementation as well, but anyone who’s testing progesterone outside of the context of a basic infertility evaluation to see if it’s someone ovulating or not really doesn’t understand the role of progesterone in basic female physiology.

Howard 58:08

Well, they would claim to be experts on their podcast but yeah it’s just dumb if you understand basic reproductive physiology for a second.

58:16

In any event, there are just no scientific studies that say that the dosing of these hormones should be based upon a lab result, and there’s also not a reliable way to do that. Instead, we base the dosage of your hormone replacement on your symptoms and needs. If you’re having hot flashes or night sweats, we give you a dose of estradiol that we know from clinical studies is effective, and there are some choices there. We can increase or decrease the dose as needed, but our goal is to relieve your symptoms. And if you need progesterone to support your uterus and protect it from the potential harmful effects of that estrogen, then we give you a dosage of progesterone that we know from clinical trials is effective at preventing the cancer that that estrogen might cause. And if you do need some testosterone for low libido which we’ll talk about then we give you a dosage that we know provides some benefit from clinical trials without causing harms like melpattern, baldness or hair growth or clitoramagaly or deepening of your voice or things like that. We do it based on science.

Antonia 59:16

Yeah, and just to reiterate, the folks who prescribe bioidentical hormone therapy have no data to inform any of those decisions because they have no trials on the products that they’re prescribing. And they’ve talked more about this in the November 2023 Green Journal, where there’s a consensus document on bioidentical hormone replacement therapy, and this is well worth reading if you’re anyone that is a current or future board certified OBGYN or if you’re anybody else who ever prescribes hormone therapy. So this consensus was produced with ACOG in cooperation with ASRM, the American Society for Reproductive Medicine, and essentially they conclude that OBGYNs should not be participating in compounding, they should not be prescribing it unless there’s a specific need for a dosage or preparation that is simply not available through any FDA-approved products, and that should be an exceedingly rare circumstance.

Howard 01:00:19

Yeah, and they include a really great literature search. It’s different from the one that we’ve been using from NAMS about these topics in particular, and they review and they discuss the safety and efficacy of custom compounded hormone therapy and conclude that there are no quality data available about the safety or efficacy and that pellets, especially those containing testosterone, should never be used. They specifically say that hormone level testing should not be used and they include fairly strong language about educating patients that these products are not known to be safe or effective and that our job is to use FDA-approved products for treatment of postmenopausal symptoms. So this goes into a lot more detail than we’ve gone into with these last two myths, but it relates to those. But I do think this document can be useful in dealing with some of our colleagues who’ve kind of gone off and done some of these things, many of whom are receiving some financial incentives to do so.

Antonia 01:01:13

So I was unfamiliar with hormone pellets and really any kind of compounding prescriptions when I was a doctor in the military. I’ve encountered it more now in patients who are already on this stuff. But briefly, pellets are basically like little HRT nexplanons except that they fully dissolve over usually a few months and they’re maybe the sides of a tic-tac, I think, and they usually have estrogen, testosterone and sometimes progesterone mixed in together at some random dose. And the idea is that it is hard to get any kind of testosterone product approved for a patient. Their insurance will almost never cover almost any kind. I will talk about this more.

01:02:02

There are exceptions, but in general this seems to be one easy way for them to get their hands on it. They just have to pay a massive amount. But these pellets are slow release and they have their provider send in or sign the prescription. The patient goes to pick the pellet up, then they bring it back to the office and you pretty much insert it in their arm like an explanon. But because you have no idea what is their true dose, that they’re actually getting, what is the absorption, you can end up easily overshooting or undershooting the intended effect, but then you can’t remove it like you could with an explanon. So it’s going to continue to dissolve under the skin for months, regardless of what effect they’re having.

01:02:43

So you can see how this would cause problems if they’re starting to have virulization or other hyperandrogenic symptoms, and then you just have to leave it in there. So if the goal is to use hormone replacements that are identical to those made by the ovary, we can do that with FDA approved products. Obviously, the most common estrogen we use now is estradiol. That’s available orally, transdermally and vaginally, and we can use at least synthetic progestogens in a wide range of forms oral, vaginal, combination, hrt patches, also the IUD technically the next one on or depoprovera. Those maybe aren’t the most common choices in menopause.

Howard 01:03:32

And you can use natural progesterone now as an oral or vaginal agent. And there’s even a new drug from last year that is a natural progesterone with a natural estradiol bioidentical, if you want to use the term that has safety and efficacy studies, so that’s available if a patient wants it.

Antonia 01:03:48

So I think we’re getting to the end of our time, so we’ll save talks about DHEA and testosterone for our next episode. So this will be the three parter If you count what we talked about last time already as part one. But the point is, even if a patient desires bioidentical hormones, even after you’ve counseled them that they’re not superior, in most cases you can still get them on a regimen without using a compounding pharmacy.

Howard 01:04:16

Well, I do think we’re well out of time.

Antonia 01:04:18

So we’ll do maybe five more myths about HRT in the next episode, just to round it out for an even 10. And those will be really good ones too, including some ones that I have definitely fallen victim to believing. So stay tuned for that. The Thinking About OBGYN website will have links to studies we talked about. We’ll be back in a couple weeks.

Episode 6.12 Hormone Replacement Therapy Myths Part 1

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