Episode 6.13 Hormone Replacement Myths Part 2

In this episode, we discuss five more myths about hormone replacement therapy. Also, we discuss the utility of cervical exams at later pregnancy visits and the history of synthetic hormones.

00:00:02 Intro and Routine Cervical Exams
00:07:51 Myth #6: Lowest dose, shortest duration
00:17:27 Myth #7: Women without a uterus need progesterone
00:22:44Myth #8: Transdermal estrogen is safer than oral
00:36:25 Myth #9: All menopausal women should also be on Testosterone replacement
00:39:50 Myth #10: Ineffective alternative treatments
00:53:04 History of hormone products

Links Discussed

FDA issues advice to women taking HRT

The Mortality Toll of Estrogen Avoidance

Long-term effects of bilateral oophorectomy on brain aging: Unanswered questions from the Mayo Clinic Cohort Study of Oophorectomy and Aging – PMC (nih.gov)

Depressive symptoms in users and non-users of depot medroxyprogesterone acetate – PubMed (nih.gov)

Use of HRT and risk of thromboembolism

Comparative venous thromboembolic safety of oral and transdermal postmenopausal hormone therapies among women Veterans – PMC (nih.gov)

NAMS Testosterone Practice Pearl

2023 NAMS nonhormonal therapies


Howard 00:17


Antonia  00:18


Howard 00:19

What are we thinking about on today’s episode?

Antonia  00:21

Well, we’re going to continue our prior topic with five more myths about menopausal hormone replacement therapy that we had started on last episode. So if you haven’t heard the first five myths, then probably you should start there before you get too deep into this episode, because we’ll probably reference some of those. But first, what’s the thing we do for no reason?

Howard 00:43

Antonia. Well, how about doing routine cervical exams at some of the later OB visits?

Antonia  00:48

Howard, okay, yeah, so some doctors or midwives will routinely check the cervix at every visit, starting at even 35 or 36 weeks, and they might even be having their patients come back every week at that point and this practice was initially a little bit of a culture shock for me earlier this year.


It wasn’t part of the routine where I used to practice and part of that was because we didn’t really even do weekly visits until about 39 weeks and beyond anyway.


But I do see a lot more of this now and in fact a lot of patients have come to expect it at these visits and I’ll even see new medical assistants completely uninitiated into this whole specialty that’ll be taught by their more senior medical assistants and then within a week they’ll suddenly be having my patients get undressed at the 36-week visit without asking me or the patient, just because they were told the doctors wants to walk right in and check the cervix no questions asked, and I’m sure that those more senior medical assistants probably were taught that by more senior doctors or midwives maybe. But why don’t you tell us why this is a thing we do for no reason? I have noticed that even when the patients are not prompted to be undressed and get ready for a cervix check before I see them. I’ll walk in and then at least half of them will ask me can I get my cervix checked, even if they’re only 35, 36 weeks? Because they might be very eager to find out if they’re dilated or how much they’re dilated.

Howard 02:20

Right. The assumption, I think, for both the doctor or midwife and the patient, is that the amount of dilation indicates when she might go into labor, and the family wants to know. She wants to know. There’s a cultural aspect to this, but it doesn’t indicate that it just doesn’t mean anything. It doesn’t predict when she’ll deliver in any meaningful way and it likely just leads to an increased number of unnecessary inductions of labor, while causing women discomfort.


The exam itself is uncomfortable, perhaps embarrassing, and very frequently it’ll stir up some spotting or other symptoms which the patient may then confuse with the labor.


And this means that these unnecessary exams can lead to unnecessary triage visits. A woman with a closed cervix might go into labor the next day or might stay pregnant for three or four more weeks. In the same way, a woman who’s already three to four centimeters dilated might go into labor the next day, but she also might stay pregnant for a few more weeks. While it’s generally true that women who are more dilated will be less likely to need induction compared to women who are not dilated, at least the difference is so nonspecific that it can’t be used to reliably counsel a patient. In other words, what you’re dilated at 37 weeks gestation just doesn’t matter and won’t help the patient or the doctor plan for anything. The literature regarding cervical dilation in labor revolves around induction of labor. So if a patient has a higher bishops score, which of course measures five characteristics of the cervix for its favorability for labor or induction, well then she’ll have an easier and quicker induction of labor. But it doesn’t relate to when she might go into spontaneous labor. It doesn’t have a predictive value.

Antonia  03:56

Yeah. So in my current setting I’ve found that the value of an office cervix check is specifically for someone who has a planned induction that’s coming up soon, because when they show up for their scheduled induction the nurses are going to be the ones to start either the vaginal side attack or usually the Iveoxytocin not necessarily the provider right away. The provider might not even be in the whole facility for several more hours if this is, especially if this is a midnight admission. So knowing the cervix check from maybe a few days before really helps us plan the initial approach to the patient’s induction in those scenarios. But if you work somewhere else, like where I used to work, where there’s always a provider doing the exams from the beginning and making decisions on what agent to start them on from initial contact, then it doesn’t really matter what their cervix was a week earlier, because then everything will just be based on what’s their cervix when they showed up. So, regardless, we should, at 35, 30, at least 36 weeks, we should be checking to make sure the baby’s head down. But this is easily done by feeling the head through palpation, in most cases at least, and if we aren’t sure what we’re feeling, then an ultrasound would be necessary but that does not require a cervical exam.


But I think for a lot of patients, as I said earlier, they’ve come to expect this cervix check. They’re maybe eager to report to their friends or their family how much they’re dilated this time and sometimes it seems like maybe those last few prenatal visits, especially if they’re really frequent, don’t serve much of a purpose. So maybe the provider uses the cervical exam to make the visit feel more meaningful, like they’re getting some additional information that at least the patient wants to know. I guess you could compare these extra cervix checks like yearly PAPS, which I had not seen before when I was in the military. But that’s another thing that I have seen on the regular now, not by my physician colleagues, necessarily, but by definitely by local practitioners, and ironically that includes patients that had military insurance, and those specific patients, when I saw them, later told me that their yearly PAPS were getting denied by their military insurance.

Howard 06:24


Antonia  06:25

Yeah, because they’re not indicated.

Howard 06:28

And potentially harmful.

Antonia  06:29

Yeah, I guess a lot of commercial insurances pay for it, which is another anyway. Anyway, that insurance thing I don’t think applies to cervix checks in the third trimester. But the reason for these frequent third trimester visits really is to check the blood pressure and screen for gestational hypertension or preeclampsia. So it’s not to check their cervix, but that’s gotten added in.

Howard 06:53

Yeah, and like all tests and exams, cervical checks should be done with a specific intent. If you’re, as you said, planning on an induction, then performing a cervical exam can help inform the method and sensibility, perhaps, of proceeding with an elective induction, but that exam should be done just before that induction is planned, not weeks in advance. If a patient’s having regular uterine contraction something less than five minutes apart, then a cervical exam can help determine if she’s in labor. Or if a patient’s beyond 39 weeks and she’d like to have her membrane swept in an attempt to reduce the necessity of a potential induction, then go ahead, do it. So there should be a reason, though, and apart from having a specific reason like that, there’s really no point in a cervical exam. We should not do tests or exams that don’t change what we’re planning to do, and this is all the more true of something as invasive and uncomfortable as a pelvic examination.

Antonia  07:47

All right. So that’s the thing we do for no reason. So we’ll move on to five more myths about hormone replacement therapy, and that’ll finish up our little stint on menopause. So again, if you haven’t listened to our last episode, go ahead and do that first before listening to this one. So we’ll start with myth number six, and that is that hormones, and estrogen in particular, should be given for the shortest duration at the smallest dose possible.

Howard 08:16

Well, sort of a myth. I mean, this is the wording that the FDA uses in the labeling regarding hormones and hormone replacement therapy, and I think that this wording at least has created some confusion about what the intention of it is. So after the WHOI study that we talked a lot about before, the public was clamoring at the FDA for some oversight and some clarification about the safety and potential risks of those hormones that were FDA approved that they’d been taking all those years before. The WHOI study shocked them, particularly at a time when bio-dynical compounders were proclaiming that the hormones they had were safer and better in some way than the prescribed hormones. So they looked to the FDA for an answer.

Antonia  08:58

Yeah. So the implication that makes this a myth is that a smaller dose would be safer than a larger dose and that a shorter duration would be safer than a longer duration. I think that’s how most people interpret it. That’s how I always interpreted it when I was first taught this myself. But there’s no evidence of either of those things. It’s, in a way, it’s just the FDA covering themselves.

Howard 09:21

Yeah, absolutely. A lot of people have made it their duty to get women off of hormones, essentially, or to force them to a lower dose, or to take drug holidays to see if they still need it, or things like that, to see if they can comply with this maxim that they maybe don’t understand that well, but the FDA said this again in back in 2003 because they didn’t know at the time what to make. None of us did what to make of the results of the WHOI findings, and it’s not that they were overly worried about it when looking at the absolute numbers needed to harm in that study and weighing those against potential benefits. So they said well, if you have symptoms of menopause vasomotor symptoms in particular and you feel better using it, then take your hormones, but, as with all medications, use the smallest dose you need to treat your symptoms for the length of time or the duration that you have symptoms.

Antonia  10:19

Yeah. So in other words, they’re just saying don’t overtreat, but that should go without saying anyway. And of course if there’s some potential harm from the medications, and then you could also minimize your time that you’re exposed to the hormone. But that’s a lot of ifs. So if those don’t apply to you, then don’t worry about it. If you’re getting a benefit from the drug, then you should, and you don’t have an absolute contraindication, you probably should continue to take it.

Howard 10:48

Yeah, if you think about it, this is the advice we give about every single drug. So you take the minimum amount of blood pressure medication you need to control your blood pressure, not more, and you take it as long as you have hypertension. If you lose weight and don’t have hypertension anymore perhaps, then maybe you can stop taking that medication. So this is just general advice and labeling for every single medication that we use, because there’s always potential unknowns and potential harms and things that we haven’t clarified about various therapies, so we always seek to minimize exposures when those unknowns exist.

Antonia  11:21

Yeah, but I think this statement, in particular in the context of already all of this controversy about hormone therapy, made people scared of these hormones, as if higher doses or longer duration was definitely harmful. Not just that this was a general statement about use good prescribing habits for this, just as you would for any other medication. So I think it has led to the tendency that at every follow-up visit that someone has that’s on HRT the doctor might feel pressured to encourage their patients, like it might be time to start tapering down now or stopping it. But that’s not, yeah, that’s not what it should be.

Howard 12:00

Particularly among our internal medicine and primary care colleagues who have a shorter depth of knowledge about the hormones. That’s just sort of the takeaway that they formed from that, and the FDA in the mid-2010s actually apologized for the implication of this. They said we weren’t trying to imply that longer duration was known to be harmful or that higher doses were necessarily known to be harmful. We were just saying use good prescribing habits to treat people’s symptoms. I’ll put a link to the original 2003 statement that the FDA issued, but again, important to understand that this was made at a time this is 20 years ago made at a time of really great uncertainty and public unrest about hormones after the WHO publications, and they just meant to say if you need them, use them. If you don’t, and you’re not supposed to take these drugs or subscribe these drugs to all patients, that sort of thing. That was what had been happening up until then. Focus on symptoms and focus on symptom management.

Antonia  12:52

Yeah, yeah, that’s actually true. So this statement was made at a time that women, even without vasomotor symptoms or even genitourinary symptoms, were being prescribed these hormones to prevent heart disease or for other long-term health benefits, that those questions had led up to the WHO trial. And today we don’t do that, even though we actually know from the WHO that these hormones at least estrogen by itself do prevent serious illnesses like osteoporosis and seem to be protective against breast cancer, heart disease, if they’re started at a certain time. But we don’t prescribe it just for that reason.

Howard 13:32

But we certainly didn’t understand all of that in detail back then.


So, that being said, we don’t have to start out at the lowest possible dose half a milligram for a 51-year-old woman, for example, of estradiol then titrate our way up or force women to titrate down who are doing well on their dose.


In the same way, you might not take a hypertensive patient who comes in with their blood pressure normal and say well, let’s reduce your dose and see next month and see if it’s still normal. We don’t have any evidence that it’s been official to do that from trials, and it’s definitely the case that in younger women you’ll want a higher dose of estradiol, both to control their symptoms and to get some of those mitigating effects for osteoporosis and things like that. And it’s fine. An older patient may need less, though, but you’re not stamping out heart disease or something like that by putting every single person on a lower dose. You’re not preventing a bunch of blood clots or coronary artery disease by stopping or lowering doses, or nickel and diming them or that sort of thing. It’s just an area of uncertainty, and we don’t have science that says that that practice is beneficial.

Antonia  14:35

Yeah, and going along the lines of lowest dose, shortest duration possible. It became common to tell women upfront when starting them on HRT that they were on some finite timeline. So maybe expect to be on this for three years and taper off, or five years and taper off, and I think that was based on the idea that the average woman has vasomotor symptoms for about three to five years. So if you were going to try to reduce doses or stop the hormone, it would probably be after some number of years. That matches how long their symptoms would last. But again, there’s no data that says limiting therapy for three to five years or any other amount of time is going to save their lives or improve their quality of life. If anything, it’s just going to increase their rate of osteoporosis. And some women will have significant vasomotor symptoms for decades after menopause and will similarly feel better being on estrogen replacement for decades or for however long those symptoms last.

Howard 15:38

Well, in the WHOI data, in the estrogen only arm, this and lots of other benefits were seen for many years after menopause and this included a reduction in the rates of coronary heart disease, stroke, breast cancer, colorectal cancer, all cancers, all fractures, death from any cause and diabetes in the estrogen only group. Now, in the group of the women who also took progesterone, the only reductions were in colorectal cancer and all cancer mortality, along with fractures and death from any cause and diabetes. It’s still significant, but the progesterone seemed to cancel out some of the benefits on those first three things the heart disease, stroke, breast cancer reductions. But still the point is there’s no evidence that stopping the hormones earlier is needed or that it improves overall safety. And there was actually a paper published that I’ll put a link to in 2013,. This was part of the WHOI that looked at potential excess mortality that occurred due to women stopping their estrogen.


After that preliminary reaction to the WHOI study, this was a public health group that looked at the impact of how many women stopped their hormones. Now they looked at women again taking estrogen only. That’s the bigger benefiting group. So these women had had hysterectomies, but they concluded that between 18,600 and 91,600 premenopausal women a big gap there, because it’s a model and has inaccuracies and assumptions. But between 18,000 and 91,000 postmenopausal women, and just that first decade, had died prematurely because they were avoiding estrogen due to people not understanding that they could still take it. So there’s a real human toll, both in mortality and quality of life, when we misrepresent the risks and benefits of estrogen in particular.

Antonia  17:26

All right, let’s do the next. Myth Number seven is that women who don’t have a uterus still need to take progesterone. This one is fringe. I had never been taught this, nor have I seen it done, but we’re still going to mention it here because apparently it’s a thing, and I have seen it online.

Howard 17:45

I see patients almost weekly like this and it’s from the bio-identical folks, yeah.

Antonia  17:50

Well, at least from what I can gather, the people that promote this tend to cite some very shaky theories not even studies, but just theories about how progesterone benefits the patient’s mood and cognition. And maybe they’re thinking that if people that are still in their reproductive years develop PMDD during the latter part of their luteal phase, when the progesterone is dropping, or if they develop postpartum depression after delivery, also when their progesterone has dropped, that maybe giving patients progesterone would cause the opposite effect. But that’s a really shaky theory.

Howard 18:27

Yeah, and it’s been studied and found to not work specifically in those two conditions you mentioned.

Antonia  18:31

Right, and there is just as much, if not stronger, evidence suggesting that progesterone can also worsen the mood.


There was a Swedish study this was on the on my maintenance of certification this year that was on the incidence of depression in patients on hormonal contraception and the summary is combined hormonal contraception was not associated with depression and appeared to have less association than progesterone only contraceptive users. And there’s another study just on depopravera users versus non-users where the users were more likely to report depressive symptoms. And there’s also some basic neuroscience theories about how progesterone might affect mood, but nothing so far demonstrates any credible link for or against it in terms of having a good or bad effect on the brain. Definitely nothing causal. But certainly when you add progesterone into the hormone replacement therapy mix with estrogen, at least in the WHI, you do see higher rates of DVT, PE, coronary heart disease, stroke and breast cancer, and those last three are all reduced below average risk if you don’t have progesterone on board and you’re only giving estrogen. So if you don’t need the progesterone for uterine protection, then it seems that it’s really is the more harmful of the two, based on the WHI data.

Howard 20:01

And, more importantly, it’s the estrogen that makes the symptoms we’re treating improve the phase of motor symptoms. If you have phase of motor symptoms, progesterone’s not really going to help. There’s some evidence that very high doses might, but that’s through conversion and it’s estrogen that you need. But yeah, the bioidentical folks will check a woman’s progesterone level and tell her that it’s low, which describes every menopausal age woman ever and, frankly, describes reproductive age women for about two and a half weeks out of each month if you haven’t recently ovulated and you’re not pregnant, and then they’ll tell them, because it’s low or practically undetectable, that they need to take progesterone. So it is true that progesterone can have mild sedating effects, probably through a GABA agonist action, and so for that reason, you’re better off taking it at night if you do take it in terms of those symptoms. But honestly, that’s a side effect, not a benefit. And I say that because some people say, well, it helps to quiet your mood, it sedates you, maybe if it helps with anxiety because you’re asleep, but it’s a minor effect and it is a side effect, not a benefit, and studies, as you mentioned just, haven’t shown that it improves your mood and it doesn’t improve sleep duration or sleep efficiency, even though it has that sedative a bit benefit or effect, and there’s certainly no evidence, of course, that you’re going to be less anxious or depressed.


So, as I said, because of hormonal and steroid conversion pathways that some of these progesterones go through, a really high dose of progesterone sometimes can have a mitigating effect on vasomotor symptoms, but you’re doing that at a very high dose that comes with a lot of side effects and potential negatives, and you’re doing that at the cost of losing your protective benefits against breast cancer and osteoporosis and heart disease. And that’s not what these compounders are saying anyway and it’s not the doses they’re using. So that doesn’t. They didn’t even know that, probably. So the truth is progesterone causes most of the negative effects associated with hormone replacement therapy and side effects that people don’t like. And we really use it almost begrudgingly when we have to, because the woman has a uterus and we want to protect her against uterine cancer from the effects of the estrogen.

Antonia  22:08

Yeah, that’s really the only benefit. It’s an important benefit, but no uterus means you don’t need progesterone, so hopefully none of our listeners out there fallen for this one, or if they have, at least now they’re not going to anymore. So next myth number eight, I think, is a bit more tricky. So this is the myth that transdermal estrogens should be preferred because they’re safer than oral estrogens in terms of DVT risk, and this is a myth I’ve actively subscribed to for a long time. So it’s been my opening tip Dig into the background, because this comes up when I search for certain patients and it seems like it’s a very certain fact, but it’s not. So let’s get into why it’s not fact.

Howard 22:55

Yeah, well, it’s complicated and, in subject matter like this, really gets at the heart of what is good evidence and what kind of evidence do we need to make and draw conclusions like that.


But it’s definitely complicated because we don’t have essentially the right clinical trials to assess or answer this question.


It might be true, but you can’t claim it is without the appropriate evidence in trial and and that’s a trick we’re gonna talk later next year about Interpreting studies and things like that on an episode and we can get into this a little bit.


But you have to have the right trial to answer a question. So we need a specifically a randomized controlled trial that compares oral estradiol at some dose to an equivalent Transdermal dose of estradiol in a large patient population. That’s otherwise as similarly matched as possible, and then you could look at rates of thromboembolism. But instead what we do have are sort of published rates of thromboembolism in various populations exposed to various doses and types and routes of Hormones, and almost all of this is retrospective data. So it’s not scientifically fair to compare the rate of DVT published in one study about one dose of a transdermal estrogen to the rate of DVT Published in another study about a different dose of estrogen taken by a different route, in a completely unrelated study paradigm, with different patient populations who have not been randomized and, when you look at it, are often poorly matched, and that’s essentially what’s happened here.

Antonia  24:25

There are a lot of these studies that tend to indicate at least at first glance or if you’re just looking at the abstract that there there might be fewer thromboembolisms with transdermal compared to oral estrogen. We’ll link to an article from the British Medical Journal About four years ago. That just is typical of these sorts of studies. So this particular one is a large nested case control study, included patients not on HRT and also patients on conjugated equine estrogen as well as estradiol, and with or without hydroxyprogesterone acetate or other progestogens or even other methods of phasal motor symptom treatment, and it included different routes of administration. But it wasn’t randomized. So we don’t know necessarily why Different meds were selected for different patients, if they had, if it was just purely based on random preference or if it was based on an assessment of their risk factors, or or what it was based on. There were over 390,000 controls, which was women who did not have a DVT, including users and non users of HRT, and this was compared to over 80,000 women who did have a DVT diagnosis. Only about five percent of each group were on HRT and In the, the group that had DVTs, a slightly higher proportion of them had been on oral estrogen compared to the HRT patients in the no DVT side. So that was 85% of the HRT users that had a DVT were oral estrogen, compared to 78% of the HRT users that didn’t get a DVT were on oral. And, like I said, that Within the HRT makes there were a few patients on other treatments that included tibalone.


So this was in Britain Relaxing or just vaginal estrogen. But mainly the rest of the women that were not on oral HRT were on Transdermal. So if you do the math that leaves roughly 15% of the DVT patients on HRT were on estrogen patches, compared to 22% of the no DVT patients on HRT were on patches. So the authors of this study concluded that, firstly, that transdermal HRT was not associated with a DVT risk, but also that it was superior to oral estrogen in terms of the DVT risk, just based on really like a 7% absolute difference. The groups were matched by age, whether they were smokers or not, family history of DVT, bmi and a vague category of chronic medical illnesses that they probably didn’t get too detailed into. So although their claim and their conclusion was very Bold and certain and enticing, if you actually look at the numbers that they based their claim on, it’s really not impressive at all and not really convincing, I would say yeah, and again next season.

Howard 27:37

When we talk about Study designs and reading papers, we can go into more detail, but it’s the nature of this type of study that you can’t draw such conclusions.


It’s inappropriate to draw a conclusion from this sort of retrospective data and most conclusions of this nature drawn from retrospective data are invalidated in future randomized controlled trials. And so that’s the key this sort of retrospective data. It’s only as good as the information available in the database and in the controls. So it’s possible, for example, that someone who’s had prior thromboembolism has more data available in her record about comorbidities and risk factors because of the type of physician she saw or the attention that the thromboembolism was getting, and so maybe those patients look sicker in the chart, for example, compared to other patients. It’s also possible that Transdermal preparations were given to more affluent women who could afford them because they’re way more expensive, and those were overall healthier and had fewer risk factors for thromboembolism. There’s just a ton of stuff you don’t know from these sorts of retrospective data, and retrospective databases based upon cpt coding in particular, are horribly inaccurate. But, as you said, they, despite the nature of this method, they still drew a general conclusion right.

Antonia  28:57

They concluded that women on oral estrogen had a higher dbt risk with an adjusted odds ratio of 1.4, and that was estrogen only and that went up even higher to odds ratio of 1.58 when it was combined estrogen and progestin. And they also found that there was a lower risk If this was estradiol, compared to the conjugated equine estrogen with a hazard ratio of 0.85. They didn’t really speculate too much on the mechanism for that or a theory for that, but overall they found that the combination of prem pro had the highest risk with a 2.1 odds compared to no medication use at all, and the combination of estradiol with digesterone, which I think that might be unique.

Howard 29:46


Antonia  29:47

Unique to-.

Howard 29:48

The English.

Antonia  29:48

Yeah, had the comparative, comparatively the lowest risk among the HRT at least the world. Hrt users.

Howard 29:56

Okay, well, and just to summarize that in the studies of several transdermal products that came out in the mid 2000s, usually after WHI, they consistently reported no increased risk of thromboembolism, with estradiol only estradiol being one of the keys here transdermal preparations compared to the placebo arm. So I think the real question is what did the WHI find and how consistent are their findings with this sort of retrospective data that you just mentioned? And this is a hard question to answer, certainly harder than you might think it is to answer.

Antonia  30:30

Yeah. So the original paper did find roughly a twofold increase of thromboembolism with the Prem Pro preparation, and that’s consistent with what this retrospective British paper also found. The response to that has always been that it also has many benefits for the women and overall the benefits outweigh the risks. So you just proceed with caution.

Howard 30:51

Maybe, and one of the things we never think about too is that risk is compared to other postmenopausal women on nothing.


But how would he compare to a reproductive age woman’s risk of thromboembolism with her own endogenous levels of hormones? It’s probably lower. So risks are all relative and people can decide how much risk they wanna take. But yeah, it was a hazard ratio in the WHOI of 2.22 with a 95% confidence interval of 1.26 to 3.55 in the original data. But in that WHOI data most of this risk came within the first year of starting estrogen plus and these values declined over time so that there were actually no increased risks noted by year six and beyond, and that was statistically significant that there was no difference outside of that first couple of years. So the other question is does that mean that the risk is really only present in women with significant atherosclerotic disease or clotting defects that were particularly present in the older population of women who were on PrimPro, because they weren’t consciously excluding those patients back then, and today we do exclude those patients from therapy, but the authors of WHOI did not.

Antonia  32:04

And that could be what a decreasing DVT incidence over time might indicate over years of HRT use. Because if we found it on people firstly who shouldn’t have been on it to begin with by today’s exclusion criteria of atherosclerotic disease or thumb bophilia, then it’s like you’ve weeded out the ones that were gonna get a DVT anyway because they were inappropriately treated. Or maybe even these people are over time actually getting more stabilization of the plaques or some kind of cardiovascular benefit. So after that initial change then their risk actually goes away or levels out. Just theories. But even in that comparison we’re still looking at apples to oranges because we’re comparing what might be the worst therapy and the worst patients to give them to. So estrogen, progesterone, older patients with preexisting medical contraindications. We’re comparing that to estrogen only via any route or transdermal. And in the WHOI estrogen only group the final hazard ratio compared to placebo was not statistically significant. It was only 1.33.

Howard 33:19

Right and so and that’s really the question is estrogen to estrogen here, and that highlights the importance of not giving unneeded progesterone frankly to patients and assuming that risk for no reason. But again, highlight that last point it was conjugated equine estrogens in the WHOI study and that alone did not lead to a statistically significant risk of thromboembolism compared to placebo, and a lot of this data indicates, of course, that conjugated equine estrogen has a higher rate, potentially, than estradiol does, so we’re also comparing apples to oranges in terms of conjugated equine estrogens to estradiol. Now, in contrast to that British paper, there was a 2021 retrospective cohort study on female US military veterans sounds like you and they didn’t find any difference in the thromboembolism rates between oral conjugated estrogen estrogens, oral estradiol or transdermal estradiol, which again might get to the point about the age of enrollment and the comorbidities of patients today In that population. We’re not gonna give it to patients with atherosclerotic heart disease or starting fresh estrogen replacement therapy on older patients without vasomotor symptoms.

Antonia  34:33

Right. Well, I’ll admit this does seem like a hot take to me because we’ve all just been told for so many years that transdermal estrogen does not increase the risk of DVT, but oral estrogen does. But in the NAMS statement they essentially come to the same conclusion as I’d say that veteran paper. I’ll read it. They say, quote it is unknown whether non-oral routes of estrogen therapy or estrogen progestin therapy are associated with lower risk versus oral routes for VTE, breast cancer or cardiovascular events, because clinical trials have not been designed to examine those outcomes.

Howard 35:13

Right and that’s a fair statement. So most of our education about transdermal estrogen and DVT risk is probably rooted in the companies that sell these products, because estradiol is oral, estradiol is cheap and generic and these transdermal routes are still mostly branded and expensive. Ultimately that message will trickle through even to practice settings, whether you’ve been exposed to drug reps or not, like where you trained. You weren’t, but some of your attendings were and therefore we’ll assume that you might assume that you’re shielded from financial agendas and biases because you don’t interact with drug reps or whatever. But it infiltrates our whole community and culture. And it also comes from the other spectrum, the other end of the spectrum, from the bioidentical hormone crowd who very often use non-oral routes of administration. And then they claim that, by piggybacking on to the same arguments, that their stuff doesn’t cause heart and disease or blood clots or strokes or something because of the route of administration.

Antonia  36:14

Well, that was a good myth to bust, at least pending any prospective randomized trials that would tell us otherwise. So let’s move on to the next one, myth number nine, which is that all menopausal women should also be on testosterone replacement. This has come up more for me outside of the military. The bioidentical market has a huge incentive for people to believe this, and, moreover, they’ll promote dosing, usually via pellets or transdermal creams or gels based on blood hormone levels rather than symptoms, and both of those things we covered in the last episode.

Howard 36:49

Well, and we can do this myth quickly. Nams, in that statement we’ve been using, doesn’t discuss this in detail, but they do have a practice pearl from March of 2023, that we can put a link to. That talks about testosterone replacement for hypoactive sexual desire disorder, which is really the main reason why testosterone would be used in the normal course of hormone replacement therapy. But essentially, to summarize, testosterone has been shown to improve sexual desire and reduce sexually associated personal distress symptoms in both naturally and surgically menopausal women who have hypoactive sexual desire disorder. It also improves the frequency of satisfying sexual events, arousal, orgasm frequency, pleasure, responsiveness and self-image. So this can be done as a patch that releases 300 micrograms of testosterone a day, or with a cream that you have to get compounded that delivers five milligrams of testosterone in a 0.5 milliliter base. That’s that amount is used daily, and either of these will result in serum testosterone levels that are basically equivalent to what premenopausal age women have.

Antonia  38:00

Yeah, unfortunately, at least, I personally haven’t found a patch available to prescribe at that dose, at any normal pharmacy at least. And as far as the cream, the closest thing I’ve found to that is one that is delivered by a pump and it’s 10 milligrams testosterone per pump, so that might be feasible to instruct the patient to do one pump every other day, but I haven’t found a five milligram daily pump dose.

Howard 38:28

Yeah, I use the compounders to make it up.

Antonia  38:29

Yeah so, but this is a cream that is the very lowest dose option for testosterone therapy that is FDA approved and marketed for men for various indications, so of course it’s not without potential side effects. Even at that low of a dose of testosterone you can see increased acne and body hair growth. You wouldn’t expect to see much other androgenic effects like voice deepening or alopecia with those doses or even alterations in lipid profiles or other cardiometabolic markers, so these doses appear to be relatively safe. There is not a lot of data that says that it’s effective for libido and premenopausal women. It’s also important that all of the other potential causes of sexual dysfunction be addressed, because testosterone deficiency is not the most common cause, especially in premenopausal women.

Howard 39:28

All right, but the myth here is that, of course, all women should be put on testosterone replacement in menopause, and that simply is not true. It doesn’t have general benefits outside of the narrow area we’ve been discussing, at least not according to any scientific data, and it does have potential side effects that patients don’t like and should be counseled about. It’s not a panacea. It’s not the fountain of youth.

Antonia  39:51

All right, well, let’s do the tenth myth, and that’s related to some of the non-hormonal therapies that are often recommended for menopausal symptoms. This isn’t necessarily a myth, but we can summarize the findings of the NAMS 2023 position statement, which was about non-hormone treatments of menopause symptoms. We previously had already talked about non-hormonal treatments for genitourinary syndrome of menopause a couple episodes back, but here we’ll talk about the vasomotor symptom treatment and which non-hormonals lack evidence and which ones have been shown to be helpful or potentially helpful.

Howard 40:31

A big market for all these things, because so many women have symptoms and they look for treatments and they’re scared of the most effective therapy, which is what we’ve been discussing. So a lot of different things here. They note a couple of level setting ideas in the start of this that I thought was good, and the first is that, as I said, 80% of menopausal women will experience vasomotor symptoms like hot flashes and night sweats. They also note that these symptoms can be bothersome for seven to nine years or longer and that a third of women will have symptoms that persist longer than 10 years. So we talked earlier about how long women should potentially be on these hormones and that popular idea of just giving them three to five years or something like that doesn’t satisfy the majority of women with symptoms. But they also say that, since the WHO, young women who are usually good candidates for hormone therapy, are often not being offered it as often as is appropriate because of the myths we’ve been talking about.

Antonia  41:32

And that opens the door to all kinds of alternative treatments, including the nonhormonal agents that they discussed in this NAMS position, and also to the false claims made by bioidentical hormone therapy producers and peddlers. So let’s just quickly summarize the findings. They did a very exhaustive systematic literature search, which is worth keeping on hand for reference at least, and we’ll put a link on our website to this document as well.

Howard 42:00

You missed a pun opportunity. You said bioidentical peddlers. You could have said bioidentical pelleters. I know Well, it’s dad joke month for me, so okay. Well, they found very minimal evidence to support cooling techniques. Unfortunately, there are no good studies and that’s going to be the case for a lot of these things. This includes things like using breathable clothing or dressing in layers, or using those little portable fans or cold packs on your neck or back or cold packs under your pillows or mattress, or things like that. The only data really comes from small studies that are uncontrolled and usually from a company or someone selling the product being studied and usually have 20 or 30 patients enrolled. The better of the available studies has found no difference in randomized crossover trials.

Antonia  42:45

Yeah, and this was also similar to the practice of just avoiding triggers like spicy food or really hot food like temperature hot, and they found no replicated evidence that that was effective either. But again, there’s just no high quality trials. They also found that exercise or yoga was not beneficial in reducing hot flashes, but of course those things can be good for a variety of other health reasons. So I wouldn’t discourage people from doing that, but I wouldn’t tell them to just rely on only that either.

Howard 43:19

Yeah, and then they looked a lot at dietary modification and there that has some limited data. Like most nutritional studies, dietary studies are tough due to the methodologies used and things like that, but in general, women with more soy and less sugar in their diets tended to report fewer or vasomotor symptoms. In the same way, more vegetables and less carbs tended to show fewer vasomotor symptoms as well. I do think you have to wonder how much of that might be related to body weight or weight loss. So that would be the importance for randomized trials, which are lacking on the subject, because they also found small studies at least, which associated weight loss with decreased vasomotor symptoms, particularly if the woman was near the start of menopause, rather than for older patients.

Antonia  44:07

They have a long discussion about various dietary effects, and the short story there is they don’t recommend soy foods or soy extracts or other soy products with soy metabolites, due to a lack of evidence. They also don’t recommend a variety of over the counter supplements like polynextract lactobacillus, black cohosh, rhubarb, wild yam, dong kwae, evening primrose, maka, ginseng, chased berry, milk, thistle, omega-3s or vitamin E. All of those are out there and usually they’re proprietary blends of some combination of those things. So, given a lack of safety and efficacy data for those agents. And they also don’t recommend cannabinoids, again due to a lack of efficacy and safety data.

Howard 44:57

And they looked at the evidence for acupuncture and chiropractic interventions and also techniques that calibrate neural oscillations, and they found no evidence for any of those techniques either.

Antonia  45:10

Okay, what are things that calibrate neural oscillations?

Howard 45:13

Well, basically you wear a hat with some sensors on your scalp that detect the frequency of brain waves, and then those are translated into tones that are mirrored back into your ear, and you’re basically supposed to align your brain waves by getting biofeedback from the tones. Any event, it doesn’t do anything and it’s useless.

Antonia  45:33

Sounds trippy Well going. Maybe in that same train of thought, they also have a long discussion about cognitive behavioral therapy, which is a well-studied and well-established method for a lot of different issues, and the summary of that is that it may be helpful to alleviate bothersome symptoms, at least for survivors of breast cancer who may not be candidates for estrogen therapy, and also just for menopausal women in general. They did find there’s a lack of data that would allow for any recommendation for mindfulness based interventions to improve symptoms, but some of that’s just due to a lack of rigorous trials. The trials that did report any kind of benefit from those interventions didn’t have control arms.

Howard 46:18

I will say it’s tempting sometimes to say that absence of evidence is an evidence of absence and obviously a lot of this is a lack of control trials. At the same time, the onus or the burden on proof is the person making the claim. So if you’re going to recommend some of these things, do a randomized control trial that shows benefit. You can’t just use it and say, well, there’s no good trial, so I’m going to use it. It doesn’t work that way. They do report on a single small randomized trial that showed that clinical hypnosis led to fewer vasomotor symptoms, but these may be confounded by the impact of some antidepressants for alleviating vasomotor symptoms. In the subset of patients who suffer from depression. It does seem like things that help depression. Like you mentioned, cognitive behavioral therapy, or perhaps hypnosis or antidepressants. That seems to help at least the amount of symptoms that patients report and how they deal with their vasomotor symptoms. They looked at paced respirations or breath work and that wasn’t helpful, and they also found that relaxation techniques were not beneficial in reducing symptoms.

Antonia  47:18

I think that’s probably good news for a lot of people, and I guess if anyone out there likes breath work and relaxation, then keep doing that, because it’s probably helping you in other ways, but don’t rely on it for menopausal symptoms either. So yeah, as far as the antidepressants, these included paroxetine, satalapram, esatalapram, venlafaxine and desvenlafaxine, and these all have been shown to reduce symptoms in quality trials and the effect seems to be the most pronounced in those who are suffering from depression. And gabapentin has also shown to be effective but does have a more significant side effect profile, so that makes it less ideal as a, especially as a first line, and pregabalin is also not recommended for the same reason for the side effect profile.

Howard 48:09

Yeah, clonidine is sometimes used, but again due to its side effects and because there’s so many other more effective things out there, then they don’t recommend its use routinely. Oxibutinin has been shown to improve some vasomotor symptoms, but long-term use may be associated with cognitive decline, particularly in older patients. Again, limited utility for that. There’s a newer medication called suvarexant that is not recommended, and then there is a new medication called fiesolinitin, which is the oza that we’ve been seeing ads for.


I think their discussion about this is cautionary at best, because we don’t understand a lot of the long-term effects of using this novel neurokinin B antagonism pathway to treat vasomotor symptoms. It was better than placebo in their trial, which doesn’t mean much, but there are no head-to-head comparator trials against many of the other agents, whether estrogen or other SSRIs, et cetera, that we’ve been discussing. So we should probably discuss this medication in more detail later, especially as some of the evidence in the real world develops. But I will say that there are no head-to-head comparator trials, which is usually the minimum bar for adopting a new drug into your practice A very poor understanding, as the authors here point out, of its long-term consequences, of what happens when you disrupt this pathway, and it costs $651 a month instead of $4 a month for estrogen, or another alternative perhaps, like maybe Lexapro?

Antonia  49:34

Yeah, so that sounds like that would be prohibitive in the majority of cases. So there’s a lot of ground covered in that NAMS document but it’s just a summary so you can look at the link and kind of peruse that document for more details about any of those specific areas. The bottom line is that estrogen is the preferred and effective treatment for most women and avoiding estrogen should really only be done for known contraindications. So again, systemic estrogen. You avoid it for people if prior ER positive breast cancer. That’s one of the few really known contraindications where you avoid it in someone that’s starting therapy more than 10 years out or more than 65 years old, for example, and in that case some of these other therapies might be useful for those patients.


So that’s been 10 total myths about HRT. I want to do a bonus myth I don’t know if it’s really a myth, but just a nagging question about HRT. I know we’re short on time, but this is when I’ve seen claimed both ways about dementia. So I’ve seen both that HRT protects against dementia. Then I’ve also seen other articles saying that it increases the risks of dementia. So it’s confusing to know what to think and that’s definitely one side effect I would want to know.

Howard 50:52


Antonia  50:53

Which way Is it? Either one, or does it go one way or the other?

Howard 50:57

Well, in the WHO, alzheimer and dementia mortality were reduced in women using estrogen only with an odds ratio of 0.74. We also know that early ophorectomy is associated with an increased risk of cognitive dysfunction and dementia and women with primary ovarian insufficiency are at an increased risk of dementia. So they summarize in that previous NAMS paper four observational studies that support the idea that if you start hormone replacement therapy near the time of menopause then you may lower the risk of Alzheimer disease, but if you start it later it may be associated with an increased risk. This seems to be mainly for women in their 70s. There was a WHOI memory study that found that the risk with combination therapy was increased in women over the age of 65, whereas estrogen alone didn’t affect the risk. So many of the things I think we’ve discussed. It’s likely that estrogen alone is protective, or at least not harmful. But the later you start the hormones and the more you use progesterone, especially in older age, you might see increased risk.

Antonia  51:59

Okay. Well, that’s good because, again, we shouldn’t be starting HRT for the first time on a woman over 65, period and a lot of these estrogen-only benefits do make me wonder if we could keep some of those benefits Women and women who have a uterus, if we give them systemic estrogen and pair it with a progestin IUD instead of with systemic progestin.

Howard 52:24

The theory is there for sure, but again, good studies don’t exist. And you think about the size of studies needed WHOI size studies. We don’t know, for example, whether postmenopausal women may have higher risks with IED placement or perforation or other malpositioning issues, but I wouldn’t fault me when for doing this I’ve certainly done it a lot. There are some smaller IEDs in development in Europe and elsewhere that are specifically intended for this inometrial protection benefit. So it is, after all, a management option, of course, for inometrial hyperplasia and even early inometrial cancers and people who are poor operative candidates. So it does work and we know it can protect the uterus.

Antonia  53:03

All right. Well, that wraps up our little menopause series and actually our whole season six, so we’ll just preview a little bit about the next season before we stop talking today. We’re going to roll right into season seven without a break, but we want to just change up a few things and try a few new things out.

Howard 53:23

Yeah, and we’re planning for that now because there’s a new co-host on the way and we don’t know when he’s going to be here exactly.

Antonia  53:30

Yeah, okay. So I was referring to some new bits that we’ve talked about offline to talk about in the podcast, but yeah, but by our next episode we will have a new co-host.

Howard 53:41


Antonia  53:42

Yeah, so probably within two weeks or so after we record this. My IVF treatments worked, so there’s another baby boy on the way and I’ll probably have him nearby whenever I record the podcast, at least for the beginning of that season.

Howard 53:56

Back to crying. Yeah, yeah, loyal fans will remember the crying.

Antonia  54:00

Yeah, so maybe it’ll sound like a throwback. He’ll probably be wanting to feed sometimes and, I guess, snuggle and do newborn stuff. And our original co-host right now is just more interested in playing with Legos and singing ABCs, so he’s not quite as interested in thinking or discussing OBGYN these days. But what I was going to say about our next bits is that we’re going to have a monthly historical piece and we’re going to try to be regular about that. We have done them more sporadically in the past and those have always been really fun and, I think, well received. And since we’ve been talking about hormones today and the last couple episodes, why don’t you give us a little historical bit right now about how hormones were developed, if we’ve got time, and how they were first sold and how it got us to the point where, at least in the 90s, prem Pro and Prem Run were the top selling drugs in the US?

Howard 54:54

Back in 1930, in Canada, james Bertram or Bert Collop had been working on estrogen. And Bert Collop was a biochemist who had heroically taken Banting and Vests pancreatic extract and found a stable and usable form of insulin In 1922, he was really the chemist brains behind that hormone operation. The isolation and purification of insulin, of course, profoundly changed the world of medicine and has saved millions of lives, including mine. And then in the 1920s, the isolation of insulin led to an explosion of interest in isolating various other hormones from the body, and Collop himself had isolated parathyroid hormone in 1925 and used it to treat tetany. And, starting in 1928, he spent several years working on ovarian and gonadotrophic hormones with a fledgling Canadian company called Erist Laboratories.

Antonia  55:42

I think you’re a big fan of insulin, aren’t you?

Howard 55:45

Well, I am, because, well, Halle Berry and Adele are both type 1 diabetics. So we need insulin in the world. But it keeps me going so well. In 1930, erist released their first product, m&n, a conjugated estrogen product. That was in Canada only, it was. In 1933, it was released in the US and in 1936, the issue of the McGill Medical Journal.


They announced quote in a recent report by Salmon and Franks on a small series of cases suffering from disturbances of the menopause, montaneous and castrate. The efficacy of M&N was again confirmed. The subjective symptoms flushes, sweats, headaches, neurovascular symptoms, digestive disturbances showed improvement. So M&N was extracted from the urine of pregnant women and was therefore very expensive to manufacture with very limited production abilities. You could be contributing to this right now if they were still doing this. Save all of your pee. But this limited the availability, of course, of the drug to the wider market, and they next tried to extract estrogen from the urine of stallions to increase production, but this too was imaginably problematic. Finally, they settled on the urine of pregnant mayors and after its introduction in 1941, primarin, which stands for pregnant mare urine, went on to become the dominant product.

Antonia  57:00

It always sounds like you’re talking about M&M the rapper. Do you think he knows that he’s pretty much named after this hormone from pregnant women’s urine?

Howard 57:07

I’m sure he got that in the clubs in Detroit a lot on his way up, but it is spelled a little differently. Anyway, as I was saying, in the meantime a variety of hormones were coming to market. So while Collett worked in Canada and the US with Erst, the German drugmaker Schering also began to work on hormones in 1928. Schering worked with a Nazi biochemist, Eddolf Blutendant, on the development of hormones. Blutendant went on to win the Nobel Prize in 1939, right before the war, for his work. But in 1928, he had extracted estriol from a varian and placental extracts and later was able to obtain it from the urine of third trimester pregnant women, in the same way that Collett did in a product that Schering called progenon progynon in 1929, which was basically the same thing as M&M. Also in 1929, Blutendant, with help from his future wife Erika von Zigner, was able to extract estrone. Then, in 1934, he was the first to isolate progesterone from the ovary, Now facing the same production difficulties Erst did with M&M. Schering also switched to using estriol from the urine of pregnant mayors and called the new product progynon 2. And this inspired Erst to do the same when it introduced premarin in 1941.


The Germans had marketed progynon as a treatment for hot flashes and other menopausal symptoms.


From the beginning, Work was also underway for a synthetic estrogen, and in 1939, diethylstilbestrol, a synthetic nonsteroidal estrogen, was introduced, or DES.


This had first been synthesized at Oxford by Leon Goldberg in 1938, under the direction of Charlie Dodds. It was about 20 times as potent as M&M and significantly cheaper to manufacture, and since it was produced by funds provided by the UK Medical Research Council, it was not patented, and this allowed for it to be sold around the world by dozens of different manufacturers and promoted it, and it became very popular. It was originally used for treatment of menopausal symptoms as well as a growth stimulant in animals, but eventually, of course without evidence, physicians began to use it to try to prevent miscarriages. In fact, from 1940 to 71, DES was routinely given to pregnant women to prevent miscarriages, and this indication was widely promoted by Dr Carl John Karnacky in Houston, who boasted of giving it to thousands of women. For this reason, in the 1940s, despite being warned by the drugs co-creator, Sir Charlie Dodds, that it caused miscarriages and rabbits, Bristol-Meyer Scribb received FDA approval for that use during pregnancy way back in 1947.

Antonia  59:42

It’s crazy that it caused miscarriages, but it’s better than using it to prevent miscarriages.


I wonder if we would still have DES around, or at least have had it for longer, if it had only ever been limited to use for menopausal symptoms, and not for miscarriage prevention, but even for menopausal symptoms. At the time it was being used without having been properly vetted for safety or efficacy, and I bet back then they probably didn’t know about the risks of unopposed estrogen on the uterus. They didn’t, yeah, yeah. So probably instead of us seeing offspring from pregnant women developing vaginal cancers, uterine anomalies that then caused it to be ultimately pulled, maybe we would have seen DES pulled due to menopausal women getting uterine cancers from it.

Howard 01:00:30

Yeah, Lots of lessons of DES, and one we touched on is don’t use a product because you think it works. Use a product because you have replicated data that says that it’s effective and that it doesn’t cause side effects or harms in a controlled trial. Well anyway, in 1941, eris laboratories began selling primarin in the US and Canada, and then primarin was marketed to treat everything Hot flashes, other menopausal symptoms, cells exploded and soon primarin became the dominant estrogen on the market, especially since World War II prevented international cells of the German progynon. Primarin made Eris a success and in 1943, the company was purchased by American Home Products, who eventually merged with the company, with Weith and Weith Pharmaceuticals, and still sells those products.


Estrogenic compounds were being tried and marketed for a lot more than just hot flashes. Back then they would claim all sorts of things Infertility, depression, schizophrenia, eczema, arthritis, hypertension, heart disease, headaches that menopausal women might experience. It was used for dysmenorrhea, for abnormal bleeding and just about anything else you can imagine that you might want a hormone for. And drug manufacturers were keen to reframe menopause, not as a natural process that occasionally needed some symptom relief, but as a pathologic endocrinopathy, a hormone deficiency that needed to be treated with a long-term hormone replacement Sounds like bio-identical folks today and at this point there was no efficacy studies for primarin or other estrogens and the quality of safety studies was about as good as the quality of the safety studies that they did for DES, which obviously showed that it didn’t prevent miscarriage and went on to harm thousands of women whose mothers had taken it.


But women with menopausal symptoms who took DES or primarin did feel better subjectively, and intense marketing convinced women and their husbands to demand the medicine from physicians who might otherwise have been a little skeptical about it, and early primer and advertisements played on the tropes of the day and marketed really directly to the male physicians and the husbands of postmenopausal women.


One early ad showed a shagrined male bus driver, captioned he is suffering from estrogen deficiency, and on the opposing page was an over-emotional shouting woman. It was captioned. She is the reason why A 1948 ad entitled the Calm of Eventide promised that primarin could be quote, instrumental not only in alleviating the physical distress but also in restoring a more normal mental outlook. The tagline for the drug in those years was in parts a feeling of well-being, and an advertiser for the 1960s focused on the husband and declared quote the physician who puts a woman on primarin when she’s suffering the menopause usually makes her pleasant to live with. Once again, it’s no easy thing for a man to take the stings and barbs of business life than to come home to the turmoil of a woman going through the change of life. If she’s not on primarin, that is yeah they’re good.

Antonia  01:03:21

Yeah, they sound like a Saturday night live schedule. They’re just shameless. But yeah, you can do an image search of old primarin ads and see some of these yourself. Actually I did and then also found an old DES ad. It just popped up in that same search and that one had a smiling baby and it claimed 96% live birth rate when you use this for all pregnancies. So of course anyone that sees that is going to say give me the DES, I’m pregnant, which is quite frightening when you know what it really did. But I wonder how far have we really progressed when we still have the bioidentical hormone market and testosterone clinics for men, for example?

Howard 01:04:01

Yeah, human nature, I suppose. And yeah, and progesterone to prevent miscarriage, including products to test your urine progesterone level at home for fertility monitoring or miscarriage prevention, or whatever claims are made. But with primarin that menopause became a disease, not just a change of life, and modern science had conquered the hormone deficiency state, no longer ignoring unfortunate old women who bothered their husbands with mental instability.

Antonia  01:04:29

And I’m assuming that’s not what you believe currently. That’s just what they were claiming.

Howard 01:04:33

I was representing their claims.

Antonia  01:04:35

Yes, okay.

Howard 01:04:36

No hate mail, please. Okay, and that’s just yeah.

Antonia  01:04:39

Yeah, so that just is showing how industry drove medicine, and not the other way around.

Howard 01:04:46

Yeah, it was a whole cultural phenomenon and Wyeth also funded a book called Forever Feminine in the 1950s that they didn’t openly take credit for, but this was a best-selling book that we found out after the author’s death. He had been paid by Wyeth to write it and it claimed basically that primarin or primpro was the fountain of youth and it really changed the conversation about hormones in the United States. You can Google that as well, and that was a story of DES and hormone replacement. Eventually, after making wild claims about the benefits of hormones, we finally get to the 1990s where primarin and primpro are the number one drugs number one, number two drugs in America, and Wyeth Pharmaceuticals created and funded this most expensive study ever done, the WHOI study in order to try to prove that it really was the fountain of youth.

Antonia  01:05:33 And we see how that turned out. So there was a great historical segment that we’re going to start regularly doing next season, at least every month or so, so about every other episode. In addition, we’re also going to start a routine Q&A segment next year, again, at least once a month. So that’s for you listeners. So please send us any questions that you want us to answer. The spicier and more controversy the better,