Kendal Williams, MD (Host): Welcome everyone to the Penn Primary Care podcast. I'm your host, Dr. Kendal Williams. So one of the areas of great interest nowadays, both in primary care clinics, but also in obstetrician gynecology clinics, and in a variety of other settings, is menopause and how to better treat it. There's been a neglect over the decades with attention both scientifically, and also just in the public sphere about what women experience when they go through menopause.

And there's also a lot of energy and interest around the issue of hormone replacement therapy. And so for that reason, I invited two experts at Penn to come on the podcast and help educate us all about where are we at with both, sort of cutting-edge, modern, treatments, for menopausal symptoms and beyond.

And also, where are we at with hormone therapy, for menopause and for hormone replacement therapy, which we've now actually changed the name to hormone therapy. But with that, let me introduce our guests. With me today is Dr. Elizabeth Clement. Dr. Clement is an Obstetrician Gynecologist at Penn.

She is the Medical Director of the Helen O' Dickens Center for Women's Health. Elizabeth, thanks for coming.

Elizabeth Clement, MD: Thanks for having me.

Host: We also have here Dr. Arina Chesnokova. Dr.  Chesnokova is also an Obstetrician Gynecologist at Penn. And I also understand, Arina that you do research at Penn and, are part of the Leonard Davis Institute, right?

Arina Chesnokova, MD MPH MSHP MSCP: Correct. Yep. Thanks for having me. And a lot of my research focuses on how to deliver care better to a menopausal patient.

Host: So this is great, and I think we have all been hearing more and more about this issue. I think it's a very good thing. And advocates for hormone therapy, hormone replacement therapy have been present on some of the major, medical podcasts and at the ACP meetings and so forth.

And so everybody, as I think, out there in the primary care community is trying to get our arms around exactly where we're at with this. And so actually, let me just start with a question of why do you think that there is more discussion about hormone therapy more specifically for menopausal symptoms?

Has there been a change in the evidence or is it just a changing recognition of how things have unfolded?

Elizabeth Clement, MD: That's a great question. I think there has been a large push from people going through the menopausal transition, feeling miserable, wanting help and support. And I think in the era of social media, and, sort of this discussion that's happening from private individuals in the public sphere, there's been crowdsourcing of, we feel terrible. There has to be something to help us. And I think that that has really pushed the medical community to push this topic into the light, in a really, I think largely productive way, to recognize that this is a big issue for patients' quality of life. It's not that I'm feeling sweaty and that's a problem, and I need to just wear different clothes.

It's that I can't sleep at night and then I can't sleep at night and then I can't go to work the next day. So I think patients in addition to evolving evidence, but I really think the patients, who are going through this have been the big impetus to this being such an area that's been so discussed lately.

Arina Chesnokova, MD MPH MSHP MSCP: Yeah, I mean I think we can point to a couple of major events in the last few years. I certainly agree with what Elizabeth said. One was that New York Times article that made really large ripples in our both medical community, but for patients as well. I think the title was something along the lines of women have been lied to about hormone therapy.

And I think that created the first really big wave of the menopause moment. And yeah, sort of celebrities that have crossed the transition or have transitioned and sort of came across a healthcare system that wasn't able to respond to their needs echoed large swaths of what now is a highly economically productive, sort of sector of the population.

Women who are entering their late forties and early fifties, tend to enter the peaks of their professional lives and are economically very productive. And it is not a convenient time to be experiencing this hormonal transition. And so I think there's sort of a precipice of folks actually having a really large voice to kind of hop onto that wagon that I think a few isolated voices in that article kind of coalesced around.

Host: So in this discussion we're going to focus on menopause. But menopause is a period of time specifically. But also I think there's a larger issue of hormone therapy for women after menopause, which Arina, you have educated me is not called hormone replacement therapy anymore, but actually now is called hormone therapy when you give it to a woman who has gone through menopause.

But I, and I'm going to try to stick with that.

Arina Chesnokova, MD MPH MSHP MSCP: It is more of, it's just a more accurate representation of what we're trying to do here, right? We're not trying to replace physiologically replace hormones to the levels that folks have when they're of reproductive age. That's more of a goal in women who are less than 45 or who experience early ovarian insufficiency.

In those women, we do try to replace hormones physiologically, and then women who are undergo the menopausal transition we are more, trying to use menopausal hormone therapy at the doses that are much less than physiologic to treat symptoms

Host: So let's start with some history. So, in my reading, which it was very interesting to learn this history, which I didn't know previously. Estrogen was recognized, if you will discovered, in the 20th century, early 19 hundreds. It wasn't long after that then they were able to purify estrogen from pregnant mare urine, which is apparently how you got the name Premarin, which is very interesting. I didn't know that either. And so

Arina Chesnokova, MD MPH MSHP MSCP: was a thing.

Host: Yeah, exactly. So women in the 1920s started to use estrogen replacement therapy with what is now known as equine estrogen, right. Conjugated, equine estrogen, which is still, as you said, still around. Now, I understand that we really started to learn in the 1970s that doing that without progesterone, unopposed estrogen therapy led to increased endometrial cancer. And so there was an adjustment made there to add progesterone into the therapeutic regimens.

And, when I trained, I graduated from Penn Med in 1995. I trained afterwards and finished my chief residency, I think in 2000. And at that point, with intention to go into primary care and general internal medicine, we were being taught, that we really should be encouraging women to take hormone therapy at menopause.

And the reasoning was that though it was felt that there may be an increased breast cancer risk, there was a reduced risk of MI and stroke. And because more women died of cardiovascular disease than died of breast cancer, that we should actually be giving it to women based on some cohort studies prior to that because there was a lower risk of cardiovascular disease if you did it.

So then, of course the Women's Health Initiative was a large randomized controlled trial. Huge funded, tens of millions of dollars, if not hundreds of millions to do this extremely large study, that was then stopped early and it was intended to do, to look at this cardiovascular risk issue.

But then it was stopped early in 2002 with some fanfare because of an increased risk of breast cancer. And so all of us who were living at that time and sort of trying to follow evidence-based medicine turned on a dime and went from encouraging women to take hormone therapy to discouraging them. And then that was what brings us in sort of in the last 20 years, I think we've been living off the data in the Women's Health Initiative. Is that a fair summary of, things at least up until that point?

Arina Chesnokova, MD MPH MSHP MSCP: Yeah, pretty fair. I think it's worth spending a few minutes on the WHI though, and the specifics of it. I think you pointed out very correctly that the point of that trial, the question, the primary question in that trial was, does hormone therapy serve as primary prevention of cardiovascular disease?

And how does that balance against what we think is an increase in breast cancer? So what folks thought would be the outcome of the trial is decrease risk in cardiovascular disease. And the primary co-primary outcomes in that trial where coronary heart disease and breast cancer. And then the secondary outcomes were all-cause cardiovascular disease including BTEPE, stroke, MI , osteoporosis, colorectal cancer, dementia.

No, that was secondary outcomes. That was like, that wasn't part of the secondary outcomes delineated in the WHI. And then there were two arms, right? There's women who had had a hysterectomy who were in the estrogen alone arm, and women who had not had a hysterectomy who were on combined estrogen progestogen.

And given that the primary outcome of that trial was coronary heart disease, to power that trial, even though it was a very large trial, 16,000 women per arm, they still had to enroll women at all age groups, right? Fifties, sixties, seventies. As a result of that, they heavily as a result of wanting to power that trial to coronary heart disease, they heavily weighed the age groups towards women in their sixties and seventies.

Only 10% of women were in their fifties. Another important caveat on that trial is that they excluded women who were symptomatic. Reasonably so. So like if you came to the WHI enrollment office and you said, Hey, I am already on hormone therapy, or No, actually I'm not interested in going off of them because I was quite miserable before I went them.

And no, I'm not interested in the possibility of being randomized to placebo, so no thank you. And then women who were really symptomatic and looking for relief we're like, I don't, again, I'm not interested in being on the placebo arm for X number of years because I feel freaking terrible. So there were very, very few symptomatic women in that trial.

So essentially folks that we right now treat or target for treatment, for symptoms were not included in that trial at all, or very few of them were. And again, the primary question of that trial was not, are hormones helpful to symptoms or are hormones helpful for primary prevention, even in symptomatic women close to the onset of menopause?

No, the question was. Do, does hormone therapy prevent cardiovascular disease in all comers largely asymptomatic and largely in the sixties and seventies? And the answer is no. Great. Very helpful answer, but has nothing to do with sort of women who are looking to be on hormone therapy.

Host: So there were two aspects, it basically excluded women who were having active menopausal symptoms. And then you have the fact that it was an older population of women, generally over 60. So you're missing this whole 50 to 60 range when a lot of women are actually, this is when people are, women are most interested in it.

One other aspect I understand in my reading is that it was conjugated equine interest, estrogen and medroxyprogesterone acetate. And those are a little different from some of the modern stuff that's available now. Elizabeth, I see you shaking your head about that. Yeah.

Elizabeth Clement, MD: Yeah, I was going to agree. I think that was the other thing that I was going to chime in, which is the, hormone therapy that we prescribe now, those medications still exist and for various reasons, sometimes we have patients on those various components for various reasons. But in general, they're not what most of us are starting patients on as our first-line, our first go-to.

And for a number of reasons. So I think going back to not only the population and the study aims are different, the medications that they're actually using are different.

Host: Actually let's go back to sort of normal physiology. And with that, I actually want to pull us back later to the actual type of estrogen that exists in the human body and what we're replacing or giving back. And so, Elizabeth, I mean, let's just do basic reproductive endocrinology physiology here.

What is happening to women, hormonally with estrogen and progesterone, up till menopause? And then what changes at menopause?

Elizabeth Clement, MD: Yeah. So, for for a woman in their reproductive years who's ovulating and having hormonal menstrual cycles, they do have fluctuations in their hormones each month, but they're certainly in this like premenopausal range. So while there's, ebbs and flows, they're sort of in, higher range than in someone who is postmenopausal. As someone approaches perimenopause or is perimenopausal, the way I often describe it to patients, the hormonal rollercoaster that you take in puberty, it's the hormonal rollercoaster on the opposite direction where, sometimes if you were to check lab tests, which would maybe be a topic of conversation here, which labs, are not that helpful because of the variation.

One day I could check labs, they could be in the quote unquote post-menopausal range or the next two weeks later, quote unquote in the premenopausal range. I don't need a lab test to tell me that you're having hot flashes and your periods have become less frequent. I can tell your perimenopausal because you're 47 and you're having these symptoms and your periods are less frequent.

And so, essentially we have less coordination of that ovulatory cycles, some fluctuations in hormone levels. And then essentially, when you enter that menopause where you're no longer having periods, your estrogen, progesterone levels are low compared to your reproductive years.

And many symptoms such as hot flashes and sleep disturbances, genitourinary syndrome, and menopause. And so on.

Host: So when you go through menopause and you have a reduction of estrogen, there are significant effects on the body in terms of issues of vaginal dryness and changes with as you notice, the menopausal symptoms. We all the hot flashes and so forth. But there's also, that really starts a cascade of bone loss.

I know women will lose bone density, probably from their thirties. I think we all do, as with muscle mass and bone density loss. But it accelerates at menopause, right?

Arina Chesnokova, MD MPH MSHP MSCP: In perimenopause actually, a significant sort of steep decline acceleration in bone loss happens in perimenopause.

Host: And we don't know specifically if the loss of estrogen has cardiovascular effects. Specifically, do they, I mean, although, it's unusual for women who are prior to menopausal age to have coronary artery disease, for instance to have events. So there must be something going on there that's accelerating that. Right?

Arina Chesnokova, MD MPH MSHP MSCP: So there's several, kind of competing mechanism, maybe not competing, but parallel mechanisms happening here when it comes to cardiovascular health. Certainly loss of estrogen on its own has negative cardio-metabolic effects. And those cardiometabolic effects are further exacerbated by whether folks are symptomatic or not, particularly with vasomotor symptoms.

And there's the directionality of that association is somewhat questionable. However, we certainly see a very strong relationship between how symptomatic folks are in terms of the severity, the number, the onset of vasomotor symptoms, so hot flashes and night sweats, and worse cardiovascular outcomes.

And there's a dose response relationship between sort of how symptomatic people are and how bad their cardiovascular health ends up being. And we certainly see an estrogen related effect, in early menopausal women, meaning women with premature ovarian insufficiency. And there's certainly a dose response relationship between the age at which menopause happens, when it happens early, and the degree to poor cardiovascular outcomes.

There's a very direct kind of, there's a 3% per year increase in cardiovascular risk, depending the age of which you go into menopause. So there certainly are effects of both estrogen loss and symptomatology when it comes to cardiovascular outcomes. Now, the degree to which supplementing estrogen, replacing estrogen, using hormone therapy, mediates those outcomes, now that's a big question. We certainly see some of that mediation in very young women, and that's why we recommend that women prior to the age of 45, use hormone therapy, hormone replacement therapy with physiologic doses. For them, it is for primary prevention. Now, the degree to which hormone therapy in perimenopause, late perimenopause, early menopause for very symptomatic women has an impact on cardiovascular health; that's still, I think, somewhat of an outstanding question. We have some conflicting studies in that space, but it's very possible.

Host: But the logic of the thinking before the Women's Health Initiative data came out, that it actually would have positive impact on cardiovascular outcomes was reasonable. Right. Based on what we know.

Arina Chesnokova, MD MPH MSHP MSCP: Yeah. But, and what we found out from that trial is that the answer is no for women who are remote from the onset of menopause and are asymptomatic. So we know that it's not harmful for women within about 10 years of on the onset of menopause. If they're asymptomatic, it's not helpful, but it's not harmful and it can be harmful if it's given significantly after the onset of menopause.

So we generally draw the line that about 10 years, 10 years from the onset of menopause is when we say there's a increased risk or risk of harm from starting hormone therapy for cardiovascular disease specifically. And that's like, that is what we learned from the Women's Health Initiative.

Host: Does it matter? I mean, we addressed a little bit this issue of the type of estrogen that was used in the women's health initiative versus the types we're using now. And just to go into this, they were using Premarin, right? So they were using equine estrogen, and now we're using more estradiol synthesized estrogen, which is technically different. And I think there are some differences in amino. I was reading about it, you can tell reading, I've been in the rabbit hole on this. so there's some differences in the amino acids and some of these may actually because it's not actually, the most natural form and that that may have some prothrombotic effects. Is there anything to that?

Arina Chesnokova, MD MPH MSHP MSCP: So conjugated equine estrogen is essentially is a conglomerate of a whole bunch of different estrogens, and it does contain 17 beta estradiol, which is the predominant sort of natural estrogen or estrogen that our ovaries for the most part produce, is E2, or again, 17 beta estradiol. There are other natural, quote unquote natural estrogens or estrogens that are present in the female bodies produced by the ovary. Some of those other ones is estriol, that's E3. Estatrol is E4, and again, 17 beta estatrol, which is predominantly what we use in hormone therapy these days is 17 beta estradiol, E 2. Conjugated equine estrogen, again, has some of those components in addition to a whole bunch of other estrogens, and there's both positive and negative outcomes potentially in using conjugated equine estrogen. It's not all bad. I mean, the way that it's produced is kind of gross. Um, I don't know how else to put that, but it's possible that some of the components of that conjugated equine estrogen actually may have a positive breast effect, or at least a neutral breast effect.

So, coming back to the WHI, another interesting thing that we learned is that women in the estrogen only arm did not see an increase in breast cancer. And in fact, conjugated equine estrogen was protective against breast cancer. What we saw in the combination arm is a slight increase in breast cancer, but no breast cancer mortality. And the relative risk of combination conjugated equine estrogen, medroxyprogesterone in terms of breast cancer risk was 1.3.

I mean, comparing that to really dense breasts, the relative risk of dense breast to breast cancer is five. So it's a very big difference. Yes, it was there, but it's very, it was very minor. And clearly we see that, at least in the WHI the breast cancer risk is attributable to the progestogen component. Estrogen alone with conjugated equine estrogen, we actually saw protective effect against breast cancer. And we might not, that might not be true for 17 beta estradiol. We don't know some of the European studies that we have, one of the bigger ones is called DOPs or Danish Osteoporosis Prevention Study that ran concurrently, somewhat concurrently to the WHI was actually sort of stopped, when the WHI results came out unnecessarily.

I think, they used for the most part 17 beta estradiol. And we don't see any increase in breast cancer in that trial either, but we don't see a protective effect. But it's unclear whether that positive effect that we see with conjugated equine estrogen can be seen with 17 beta estrodiol. And it's not only the sort of the type of estrogen that we use, right?

It's also the mode of delivery of that estrogen. So the question is like, are we swallowing it? Is undergoing liver metabolism first pass metabolism or are we bypassing it by not administering the estrogen orally? And it's the oral administration that likely produces some hypercoagulability as opposed to necessarily the type of estrogen. We see an increase in VTEPE with oral estrace, which is 17 beta estradiol.

So it's more about the oral administration necessarily than the type of estrogen. It's both.

Elizabeth Clement, MD: I guess I'll just add to that in terms of the transdermal estradiol, which is I think what many of us use as our first-line estrogen, for hormone therapy versus oral. You know, there's that first pass metabolism And that changes just to sort of say it out loud, that changes the circulating estrogen metabolites.

When you have transdermal estradiol, E2 is your predominant circulating estrogen, and that's not the case when you take it orally. That first pass metabolism, changes that. So I think that, even though you're giving estradiol what's actually circulating in the patients body is different and I felt like that was helpful for me to understand.

Because I was sort of like, well, yeah, it all seems somewhat abstract and you're not doing it all the time.

Host: So if I want to summarize some of the potentially negative effects, positive and negative effects, let's just, talk about the cardiovascular and hypercoagulable aspect. It seems like, first of all, just to dovetail on the point we're making now, that hypercoagulability concern is largely taken away if we don't give it orally, that seems to be, promoted in the literature that I read that, we feel that we are okay from venous side hypercoagulability, that's separate from the issue of increased cardiovascular disease, specifically atherosclerotic cardiovascular disease, which is as we know by a different mechanism, but they're not completely unrelated.

And Arina, if I'm going to summarize there, the equine estrogen did increase risk in women who were in the Women's Health Initiative, which is largely 60 and older women. And we feel confident that that's true. But these were women mostly who had actually gone through menopause over 10 years earlier.

And then were started on this sort of de novo as opposed to women who were in the 50 decade, who were presumably at much less risk for atherosclerotic cardiovascular disease, anyway, and can remain at much less risk. And so even if we do see an increase over 60, it probably doesn't apply to the 50 to 60 range.

And we don't quite know whether or not the equine estrogen or the estradiol makes a difference there. Is that a good summary?

Arina Chesnokova, MD MPH MSHP MSCP: It's pretty good.A couple of asterisks to that. One is sort of the mechanism by which we think the effect of estrogen differs by age group is sort of this timing hypothesis and the time in which atherosclerotic plaque forms. And so if you hang out in menopause for 10 plus years, that's enough time for you to accumulate some plaque.

Obviously, if you're higher risk of cardiovascular disease, that plaque accumulates a lot faster. And if you then start estrogen after enough time of that plaque accumulation, you risk dislodging that plaque. So plaque accumulates, receptors remodel. Your response to estrogen changes with time. And so if you reintroduce estrogen after quite a bit of time has passed, you're going to dislodge that plaque.

Elizabeth Clement, MD: Which I think is an important thing to think about, or as you're seeing patients in your primary care practice who are also seeing a gynecologist who's prescribing it, will often if someone hasn't developed new risk factors, continue hormone therapy if a patient desires when they've initiated it at the standard time.

They may be 62 and be on it, but they started it when they were 54 and they haven't developed new risk factors and they say, I want to stay on this, which is very different than starting somebody newly at age 62, which I think is an important distinction.

Arina Chesnokova, MD MPH MSHP MSCP: Yeah, and we think that sort of women who start at the appropriate age don't remodel in the same way, don't remodel their response to estrogen the same way, don't accumulate plaque at the same rate. And that is supported by some evidence. So in addition to the WHI, two trials that have specifically looked at cardiovascular outcomes as their primary outcomes were Keeps and Elite.

So the Keeps trial, sort of the critical differences between the two of them without going into too much detail, was the duration of time for which women used hormone therapy Keeps, was shorter, it was four years. The type of hormone therapy that folks used and also the amount of hormone therapy that folks used and sort of Elites showed a positive effect for women who started hormone therapy early to the onset of menopause within six years in terms of carotid intimal media thickness, did not, it was shorter duration loss, hormone therapy, different hormone therapy.

So there's clearly some potential for benefit, but it is very dependent on the type of hormone therapy use, the amount used, the duration, and likely the degree to which women are symptomatic and how close to the onset of menopause that hormone therapy is started. And all of that has to be teased out some more.

The important thing is, I have a lot of patients coming to me these days being like, oh my God, I saw these FDA people who run the FDA now remove the black box warning. And they say that hormone therapy has the same effect as the statin does. So I'm going to go off of my statin and you're going to write me a prescription for hormone therapy. because that sounds just more lovely than being on a statin. And that's just insane. That's insane. I don't know where they got that from. Well, they got that from some of those like really, really early cohort studies where case control studies of hormone therapy users that are exceptionally biased.

Yes, it's possible that hormone therapy has a beneficial effects for cardiovascular health. Again, like if and if and if, and if like if you're super symptomatic, if you're starting a really close to the onset of menopause, if you're using 17 beta estradiol in quite high doses like. If all the, maybe, but that's a trial that we have to run.

Maybe it has a beneficial effect, but it certainly has no, there's nothing in the literature that suggests that its effect is similar to the benefit of the statin.

Host: Just to throw in another caveat here, and this came up today when I was seeing a 63-year-old woman who had premature ovarian insufficiency, was placed on hormone replacement therapy, and then, at age 62 was taken off of it. Her gynecologist said, you've been on too long. You have to come off of it.

She then, I guess maybe I'm getting exact dates right, wrong, but, she had an acceleration of bone loss now was put on Fosamax, and was coming in saying, I'm having all these terrible symptoms from Fosamax. What do I do? When I looked at her, her profile, I'm like, you know, I just did a coronary calcium score on this lady last year.

It was zero. She has no plaque that no discernible plaque.

She's at very low risk. So for me, I was thinking as a primary care doc, her cardiovascular risk is very low. So I don't much concern about putting her on it from that perspective. But what I did wonder about was the breast cancer. And so I want to circle back on that point because Arina, you had gone over the WHI, I mean that's why the WHI was stopped, right? Was the increased breast cancer.

Arina Chesnokova, MD MPH MSHP MSCP: The combined arm, yes.

Host: The combined arm. Right. Right. So the folks that do not have a uterus, right. Women who do not have a uterus and who are on estrogen therapy alone, actually at a reduced risk of breast cancer. Right. And with the equine estrogen, as you said. But let's hover on the breast cancer risk. I mean, we know, pathophysiologically that breast cancers are responsive to estrogen. You know, that's a well-known thing and we take advantage of it in our therapies to prevent progression of breast cancer.

So we know that you could feed the flames, if you will. Right. If you're not careful. Or theoretically you could. And so there was some logic to an increased breast cancer risk that came out of the WHI. Now, you had contextualized that and you said it was like what the relative risk was 1.3, which is actually not that high. I've heard also comparisons to its roughly equivalent to the effect of alcohol?

Arina Chesnokova, MD MPH MSHP MSCP: Alcohol, obesity. Yep. Like having two drinks a day versus none is a relative risk of about 1.3. Smoking particularly early in your life. Like being, being sedentary. Yeah. All of those confer the same kind of relative risk as the progestogen component did in the WHI. Again, that risk, actually, we didn't see that risk increase in the WHI until about three to five years.

That's when the Kaplan-Meier curve starts to diverge a little bit. So that risk is not immediate. Again, it's pretty small and we didn't see any increase in breast cancer related mortality. We actually saw a reduction in an all-cause mortality in women who were on hormone therapy in the WHI in both arms.

Host: So we believe that estrogen and progesterone therapy combination therapy does increase the risk of breast cancer, but we should be rational about how much of an increase. It's not a wild increase, right?

Arina Chesnokova, MD MPH MSHP MSCP: Yeah. That statement applies to the general population, right? The degree to which this applies to women with extremely dense breasts. Women who are at higher risk because of family history, whatever. We do have some limited studies in women with a BRCA mutation. Again, lots and lots of nuance there. Generally we see similar trends that women who start hormone therapy with estrogen alone do not see an increase, women on a combined therapy do see some increased risk. But that's sort of, again, that statement applies to the general population average risk.

Elizabeth Clement, MD: It's not as commonly prescribed, but I think, we were talking about progestogen or progesterone, but there is a serum bezodoxaphine which can be used instead of the progesterone component which is breast neutral on the progess, like in terms of, its activity on breast receptors, while still providing endometrial protection, from endometrial proliferation in the United States.

It's only available in a combined formulation with conjugated equine estrogen. And, bezodoxephine is like a combined pill and it's, that limits one, being able to use transdermal estradiol. And it also limits, dose adjustment based on symptoms. But I think just to sort of say there is an option for a patient who either, you're having this debate with them about, their personal breast cancer risk, their significance of symptoms, trying to find something, that could be an option for them. Just to mention that does exist.

Host: Do we make any differences between the types of progesterone, Elizabeth, that you're getting at this, that were used in WHI versus what is used now, vis-a-vis breast cancer risk or anything else? Is there anything there yet? Do we know much or is it.

Arina Chesnokova, MD MPH MSHP MSCP: Yeah, I mean there's some early evidence that suggests that synthetic progestogins or progestin, so progestogen is like an umbrella term that on encompasses all kinds of progestins and progesterones. So progestogens again include synthetic progestins. And that's medroxyprogesterone that was studied in WHI, Essin nor syndrome, nor acetate.

Those are some of the common synthetic progestins that we use. And we also use progesterone or micronized progesterone or prometrium that's a bioidentical or body similar, however you want to call it, progesterone. That seems to, there's some early signal that it may confer less risk, particularly when it comes to breast cancer.

Some hypercoagulability when it, as compared to synthetic progestins. That data's pretty early. The most convincing comes from Europe because they have these delicious all population data sets, that we don't have.

And it looks like in those delicious all encompassing data sets, it seems like progesterone doesn't seem to pose the same risk to breast cancer as synthetic progestins. Again, that doesn't include the IUD. We don't know whether an IUD what an effect an IUD has because it wasn't studied in these cohorts. But progesterone, like oral progesterone compared to synthetic progestins, again, doesn't seem to pose the same level of risk. That's sort of replicated in smaller studies, again, mostly from Europe and compared against some compounds that we don't use in the United States.

But generally what all roads lead to is kind of the most common thing that we use as a result as a first-line regimen when it comes to prescribing hormone therapy is like transdermal, 17 beta estradiol bypasses the liver. We don't have transdermal formulations of any other kind of estrogen right now. It's just 17 beta estrodiol, but it's body similar or bioidentical to the predominant estrogens that we produce together with an oral progesterone, because of that early signal around breast cancer risk and, less hypercoagulability, et cetera.

Elizabeth Clement, MD: I want to add that the regimen, that Arina just went over, each of them are quote unquote bioidentical, right? And I think patient's sometimes come to the office saying, I want bioidentical hormones, and or I've read about bioidentical hormones. And I think sometimes as a clinician, that sort of mentally translates to like compounded or like something, I don't know, off book or elsewhere.

And, essentially there are FDA-approved bio identical hormone therapy formulations, which are first-line, essentially. And so () I think, I find often when I talk patient's through that, they're like, oh, I didn't even realize that. I didn't know really what I was asking for. I was told to ask for bioidentical.

And I think, for reasons that we've explained, there's something to it. But I think sometimes that gets conflated with compounding, which is a different scenario that is not regulated. And it is very hard to know what doses are in that situation, which we encourage patient's to not go and seek compounded hormone therapy where doses cannot be regulated or known.

Host: I want to come back to this point because I'm going to get you guys very specific. I am an idiot, when it comes to this, and I want you to take me through exactly how to prescribe for a few different categories in a minute. So, we're going to come back to this point, but I just want to hover on a couple, last, sort of endpoints, if you will, of, WHI and other studies, so osteoporosis.

I'm assuming we universally feel that this is a good thing, for women who are at high-risk for osteoporosis, but even, going into the advanced stages of life that being on hormone therapy helps maintain bone density for longer periods. And then I just want to hover on a couple other things that came outta WHI.

There seems to be a reduced colon cancer risk. Nobody really has any idea why that's the case, I believe. And then the last thing is just the cognitive effects. Those are sort of the three other areas that I think would come up in our practices. And maybe can I ask you to address those three areas? Osteoporosis first, Elizabeth, are we agreeing that for bones, it's universally a good thing?

Elizabeth Clement, MD: Yeah, I mean, I think, hormone therapy, improves bone density certainly while you are on it. I think that certainly it doesn't replace the other important factors that need to be managed when it comes to bone density. And this is, I think, a big part of my counseling of these patients.

They should be on vitamin D, they should get enough dietary calcium, they should be doing weight bearing exercise. We should be talking about this in the reproductive years because that bone attrition has already started. And so I think that, that, if there's any sort of bone endocrine folks listening to this podcast, I feel like sometimes osteoporosis comes as like, it feels like a little less jazzy and exciting sometimes when it comes to what patients are coming for, unless they have a personal connection to someone who's had an osteoporotic fracture.

But certainly folks are coming in saying, I'm concerned about my risk. I want to be on hormone therapy. Technically or not technically, when you think of prescribing hormone therapy, it's not indicated as a primary indication for prescribing hormone therapy to, for the prevention of osteoporosis, but we know that it does have some improvement. And I do think there have been some exciting studies, in terms of prevention outside of the hormone therapy, world in terms of just IV alendronate in the early menopausal timeframe in reducing osteoporosis risk.

So I've been very excited by some of the work there. I, in my mind, I think osteoporosis is going to be a multi-pronged approach. And I don't think hormone therapy is the panacea there, but certainly, it's beneficial for your bones.

Host: How about colon cancer and cognitive function Arina?

Arina Chesnokova, MD MPH MSHP MSCP: Like you said, colon cancer, you know, I don't think anybody really harps on that as a, certainly not a reason to put somebody on hormone therapy A. Do we even talk about that as a perk, as a positive side effect to starting hormone therapy? Not really. It's not certainly something that I have time for in my clinical practice to address again because I don't really know what to do with that. Yes, we certainly saw it in the WHI, again, it's one of those questions of like, is that specific to conjugated equine estrogen? Did it act as some kind of, is there some compound within all of those estrogens that are mixed into conjugated equine estrogen that had some effect there that we won't necessarily see in 17 beta estradiol formulations.

Who knows? In terms of cognitive benefit, I think this is really important, and again, something that the FDA decided to bring up as one of the primary arguments in their reasons to remove the black box warning recently was the reduction in Alzheimer's and dementia in hormone therapy users.

 Yes, it is true for women who suffer from premature ovarian insufficiency, whether it's surgical, chemical, natural, iatrogenic or natural. But if women undergo early menopause prior to the age of 40, certainly in their thirties, maybe in their early forties, will derive benefit in terms of prevention of early onset Alzheimer's and dementia.

That is not true for women who are naturally menopausal in their early fifties. It's not harmful, but it's not helpful specifically when we talk about the outcome of, early onset Alzheimer's and dementia prevention. And it actually increases the risk of onset of early Alzheimer's and dementia if it has started late.

So in people's sixties and seventies, particularly with conjugated equine estrogen, that's another thing that we learned from the WHI is when you give women estrogen in their later years, it actually worsens their Alzheimer's risk. In terms of this like resolution of this very specific like word finding difficulty, this like fogginess, it's visual. It's like short term memory, it's word finding difficulty that's very specific to the menopausal transition. Again, the remaining question is whether starting hormone therapy for symptomatic women with severe hot flashes and night sweats, or moderate to severe hot flashes and night sweats, very close to the start of menopause or in late perimenopause, we don't have that study that says yes or no whether it's beneficial. Clinically, both Elizabeth and I certainly see an improvement in women who are symptomatic and, also happen to complain of, brain fog word finding difficulty all those things in terms of starting hormone therapy and in those aspects of their symptomatology significantly improving.

But then the question is, did you fix their night sweats? And so they're sleeping and now they can think during the day, was there some independent estrogen effect?

Elizabeth Clement, MD: And I'll just add that, like that what we're titrating medication to when I'm adjusting hormone therapy dosing is vasomotor symptom severity, right? I think that it is hard to titrate to some of the more amorphous symptoms of menopause. And I think focusing on, if you're adjusting medication on like how are your night sweats?

That's the place to be adjusting dosing, for the sort of physiologic menopause transition patients.

Host: Okay, so I want to actually dig into that and I want to be very specific. I'm going to ask you about three patient populations. I'm going ask you about managing the woman who is in perimenopause, who comes in with vasomotor symptoms and is miserable needs to get started. And we're going to get very specific about exactly what prescriptions you write and so forth and how you write them.

Elizabeth, you started alluding to that. I'm going to ask you about the woman who goes through that period feels better, and then you're a couple years out and do you start thinking about transitioning them off of it? So, I'm going to ask about the woman that really wants to stay on it until she's 60-year-old.

And then I'm going to ask you about the woman. So those are two populations, sort of the acute management of menopausal symptoms, in which you may consider transitioning somebody off after a few years versus the person that you're keeping on for a decade or more up until, and then there's this period in which you're in an early sixties where you have to decide whether to continue it.

That's the third population I want to talk about. And that's basically the woman I saw today. Who now she's not tolerating Fosemax. She's like, well, can't I just go back on the hormone therapy I was on? And sort of that. So three patient populations. The immediately perimenopausal woman, the perimenopausal woman who you'll carry through to maybe 60, some early sixties, and then the woman over sixties.

So let's talk about the immediately perimenopausal woman who comes in and says, I'm miserable. I'm having all these hot flashes, insomnia, my anxiety, I'm snapping at my husband and my children. I'm just miserable. I'm not getting good sleep. And so, Elizabeth, you had started to talk about the very specifics about how you treat that woman? So how do you treat that woman?

Elizabeth Clement, MD: Yeah. So, if it's okay, I'm going to start with the patient who is menopausal. Because I think it's the most straightforward. So it's just this patient's been, 12 months without their period. They are in menopause. They feel miserable, they are not bleeding. And I think that is the most straightforward scenario, where I generally do a 0.05, estradiol patch, and a hundred milligrams of oral pro micronized progesterone, nightly continuously every day. And the patch is usually a twice weekly patch. There are some formulations of the patch that are weekly. It depends on the brand. There are some national shortages of patches now, which hopefully means we're prescribing them more and they can start making more of them. so we sometimes have to contend with that.

But that's generally where I start. Point zero five is like the middle of the road. They come 0.02, .0375, .05. 075 and 0.1. And that's generally the range. And so 0.05 is like smack dab in the middle. You can go down, you can go up. It gives you a good starting pace. If you, if I have a patient who's particularly hesitant, I'll start at a 0.025, but sort of depends on how they're feeling.

But boilerplate off the bat, 0.05, estradiol patch and a hundred milligrams of micronized progesterone nightly. The perimenopausal patient, I think poses an additional challenge, which is that that patient might still be cycling, irregularly or regularly frankly. Because the perimenopausal symptoms start earlier than I think we've given respect for in the medical literature and the discussion of this.

I think many patient's in their mid forties are coming and complaining of these symptoms and we say, oh, you're not in menopause yet. And these patient's often have contraceptive needs, so are trying to avoid a pregnancy. And so that becomes a challenge because hormone therapy is not dosed to prevent pregnancy. While it's not approved by the US FDA for the progesterone component, a progestin IUD is a commonly used strategy to give both endometrial protection for progesterone, a local progestin, endometrial protection. And then a transdermal estrodiol patch, I think is a common suggestion I () make to folks.

There's other sort of strategies in this zone, but I think that's one that I often employ. But I think it's important to assess that when you're taking care of somebody who's still having menstrual cycles.

Host: So the progestin IUD prevents pregnancy during that period, manages periods, patients become, they have no periods during that time, right. While you may have some breakthrough, right. But for the most part, and it acts as a contraceptive as it would before perimenopausal period.

But then you're adding the estrogen in to help them deal with the symptoms that they're beginning to experience, even though they haven't yet stopped having full periods. Right?

Elizabeth Clement, MD: Yeah. Exactly.

Host: So yeah, let me ask you this question. In the patient that you put on and, you've put her on 0.05 of Estradiol patch, you've put her on nightly progesterone, she will not, she has stopped bleeding. Stopped having menstrual periods. So you're not worried about having the withdrawal bleeds right, for progesterone and you're just going to continue it daily. And then how long do you continue that regimen?

Elizabeth Clement, MD: Yeah, I mean, I think there should be touch points, where you check in, about their symptom management. Do you need to adjust the dosing and also do they want to continue it? I think that there are, I've seen sort of a couple different trajectories. Some folks like kind of get tired of taking a medicine as they do with many medications, and I'm sort of like, do I still need to be on this?

And we can trial coming off. Some folks who are afraid to come off and we sort of once again, go back through their risk calculation, recalculate their sort of cardiovascular risks and their, you know, sort of check in about their overall risks and to see if they've changed. And then there are some folks who are, can't pry the estrogen out of my cold dead hands.

I'm going to the grave with this. Never take it away from me. And I think, going back to the timing hypothesis, if someone doesn't develop new risk, I both continue to counsel and document on sort of the either are some risks of this. We don't have a ton of data, sort of the long-term continuation, but we think it's reasonable if you haven't developed new risk factors.

And I don't feel strongly to stop this. But I do think it's important to candidly address new risk factors. And there are times where I do recommend coming off of it because the patients risk factors have changed. And I say that this is no longer a treatment regimen that makes sense for you.

Host: Do you feel a need to talk to women about the breast cancer risk if you're just managing the perimenopausal symptoms? Or is that a discussion for a couple years down the line when maybe their symptomatic period is over and then you're just dealing with

Elizabeth Clement, MD: I think you have to discuss the breast cancer risk if you're prescribing it. I mean, I think it's such a heated area of conversation that I think you have to mention it. I will say in my patients with premature ovarian insufficiency, those who go through menopause early for a variety of reasons, I counsel them very differently where I say, this data really does not apply to you.

And we are, I think like these are what the studies show and people who are physiologically menopausal, but that is not you. And we are getting you back up to where your estrogen should be. And I don't actually have great studies to say what this impact would be, but I know here are the harms of not having estrogen.

So I'll say for those patients, my conversation's very different about the risks. I think someone who's perimenopausal, I think it's worth mentioning, but I, yeah.

Host: Yeah.

Arina Chesnokova, MD MPH MSHP MSCP: And the median duration of symptoms is seven years. The median duration of vasomotor symptoms is seven years. So it's not like people hang out on this for a couple years and then they're able to go off. That's not true for the vast majority of folks who have moderate to severe hot flashes and night sweats.

And again, sort of the breast cancer risk doesn't kick in until about three to five years of being on hormone therapy, and I think that that is the only risk that's worth revisiting in somebody who hasn't developed a contra otherwise hasn't developed a contraindication in terms of the timing of discontinuation on people on combined hormone therapy who are otherwise average risk for breast cancer.

So if somebody comes to me and their average risk for breast cancer and they start hormone therapy, combination hormone therapy with estrogen and progestogen, the only sort of reason to continue rediscussing or discontinuing is if, they have some trepidation about their breast cancer risk.

Elizabeth Clement, MD: But what if they develop a new, like they have a cardiac event? I mean, there's there

Arina Chesnokova, MD MPH MSHP MSCP: Well, sure. If they develop a co, if they develop a contraindication sure. If they develop, if they otherwise develop a contraindication. Yeah. I mean that's a reason to stop. I mean, you through an MI yeah. You shouldn't be on estrogen, but like if you develop breast cancer, yeah, you shouldn't be on estrogen. You have a clot.

We should figure out why you had a clot. No, in the absence of development of a contraindication, the only reason to sort of reevaluate again, is somebody on a combined therapy reevaluate their concern about their breast cancers. Monotherapy for women who are on estrogen alone, who don't develop a contraindication, who start at the appropriate time. I mean, I think until death do you part.

Host: The scenario that often happens, I think is that women have a neighbor or maybe another family member, which actually would impact their risk, but not so much the neighbor who has breast cancer and now they're starting to think about it and they come in and say, you know, am I really so Arina that's very helpful to say that a woman can expect vasomotor symptoms to persist for seven years. So what I take from that is that if I start a woman at 50, say just as a round number, it's probably till 57 that I have to worry about vasomotor symptoms were I to stop that right? Beyond that and that was the median, right?

So, it can be out farther out until 60, that women will experience withdrawal vasomotor symptoms essentially if you stop the hormone therapy.

Arina Chesnokova, MD MPH MSHP MSCP: Yeah. And I mean, we have some signs of who's going to be on what trajectory. I mean, people do all kinds of things in terms of, t here are certainly folks who kind of peak in early menopause hang out for a couple of years and they, and then symptoms level off. There certainly are those kinds, about 20%.

There are people who start really early way before, like Elizabeth said, way before they stopped having periods and it just keeps going and it never stops. And they have patients who are flashing into their seventies. There's some folks who like, kind of start early and they taper off, but much slower.

Those are closer to that kind of seven to 10 years trajectory. I mean, people do all kinds of stuff, but that seven years number is more to the point of like there's no point if somebody's severely symptomatic trying to wean at like a year or two. There's hardly ever a population for which that's going to be very successful. And there's also no need to do so.

Host: Okay, so let's go back to my 63-year-old woman who was taken off at a year or two prior, because she'd been on it for, now she had premature ovarian insufficiency. I don't know exactly when. But let's say she's been on it for maybe 15 years. But even if she weren't even, she went through menopause, was placed on it and at this point, it really comes down to your assessment of cardiovascular risk at that stage as to whether or not you continue and just leave people on it, as you said, till death do your part Arina, or have a discussion about coming off of it at that point.

Arina Chesnokova, MD MPH MSHP MSCP: I mean, again, like her cardiovascular risk was largely abated by her being on estrogen therapy. Your atherosclerotic plaque formation rate, at least in the studies that we see is lower, the rate of formation is lower in women who are on estrogen therapy and certainly quite good on women who are both on estrogen and, statin therapy.

But her, cumulative risk or her trajectory differs significantly from somebody in her situation who was not on estrogen therapy. So we don't think of her in the same way as somebody who would start at her age, who was estrogen naive for 15 years. And so for some, I mean for some reason in the last couple of years, she picked up smoking and became way more sedentary and is now diabetic.

Like, I mean, that's a bit of a different story, but, as long as nothing in her lifestyle changed super significantly, like you said, her coronary artery calcium score is zero. Amazing. The concern about sort of dislodging a plaque with starting estrogen is quite low.

Elizabeth Clement, MD: I'd back the thought that, estrogen is not, labeled as like a primary treatment for osteoporosis. So this patient was recommended to be on Fosamax, and to be treated for osteoporosis or other. I think sometimes we end up in this estrogen or hormone therapy is a panacea for all of the issues that I'm having. And so sometimes we say, okay, great. I'm going back on my hormone therapy. I'm not doing any of this other stuff. And then I think that can also sometimes do a disservice to our patients. But

Arina Chesnokova, MD MPH MSHP MSCP: Yeah. Agree. It is not a treatment for osteoporosis. It has been approved for prevention of osteoporosis, but it is not technically approved for the treatment of osteoporosis. Like is it going to be helpful to her osteoporosis journey? Yes, as long as she's on it and it weans immediately, or like quite rapidly once people go off of estrogen therapy.

So that's why you have to have a ramp off plan for folks who are in estrogen therapy for long-term and have some osteopenia or are in their sixties and they're suddenly coming off of estrogen. You probably have to have some plan to get them something else.

Kendal Williams, MD (Host): I'm hearing from you that you are generally favorable to the idea of starting women who, particularly those that are very symptomatic, who are perimenopausal on estrogen therapy, estrogen and progestin. Let's assume they have a uterus. She has a uterus, And then continuing it until something changes in her overall risk profile that you have to weigh the factors that we've discussed today, but you're continuing it. There's no necessarily specific end date.

Arina Chesnokova, MD MPH MSHP MSCP: There's no guidance, there's no sort of statement that says that one should discontinue hormone therapy. That comes from kind of, an old beers criteria that applied to Medicare. And lots of folks on Medicare were getting taken off of hormone therapy because of that Beers criteria, that five years after hormone therapy that you should discontinue.

But it's not based on any data and should be an individualized approach. Right? Like when were you symptomatic? Why did we start it in the first place? What is your breast cancer risk like? What is your osteoporosis risk again? Are you on both estrogen and progestogen? What, formulation are you on?

Like lots of people come to me and again, out of my cold dead hands, my Premarin, but I'm like, maybe we can just get rid of the Premarin bit, like, and try something a little bit more, or Prempro, try something a little bit more suitable for your risk profile.

Elizabeth Clement, MD: I mean, it's important to get at why they were on it. I think the person who was like, I only, I heard the risks that you mentioned to me. I didn't like them, but I was, so miserable that I wanted to be on it for a short period of time.

That person might be motivated to come off. Right. I think that there's, definitely individualization in this, area. There's not a one-size-fits-all approach, but I think the era, you know, when I trained, I felt like initially I was taught, you know, every visit you should talk, try to talk to them about coming off of it, I think that that was sort of like the, shortest amount of time, which I see is Arina's horrified that this is, I feel like what I was taught, but it was shortest amount of time for the duration of symptoms that somebody was having and, try to come off of it ASAP.

And some folks want to do that and some folks don't, and it is reasonable to continue it. And I think, to Arina's point, some people are like made to feel like they should come off of it when they're still symptomatic and would still benefit from continuation.

Host: So my understanding of how this has flowed over the last couple of decades is that WHI came out, we said, oh boy, this is terrible. Everybody comes off. And then there went to be this point where we said, okay, well you can do it for a while to handle perimenopausal symptoms, but not too long.

And then folks became more comfortable to going up to their sixties. And then it seemed like, women were being advised in their early sixties to come off of it. And now what's changed is that we're balancing all these risks and benefits in the individualized patient. And there is a reasonable argument for women who ha are comfortable on it, you know, have preserved bone, are maybe at-risk, and for osteoporosis and other issues, that they should just stay on it. Right? And that is different. That has changed.

Arina Chesnokova, MD MPH MSHP MSCP: Yeah, I mean the pendulum is swinging in all kinds of ways. Like Elizabeth said in the beginning, and the WHI certainly did a huge disservice to generations of women when it comes to just the level of publicity and honestly misinformation that surrounded the results of that trial and the mass panic that it caused.

But unfortunately, the pendulum swing is swinging in the totally opposite direction. That's also inappropriate now. And yes, while some women, it's very reasonable to stay on it, some women, their risk benefit doesn't necessarily pan out in that direction, both Elizabeth and I see lots of women who are at higher risk for breast cancer who probably should be on some primary prevention of, for that breast cancer, but choose to go on hormone therapy initially just because of how symptomatic they are.

And for those people, yes, we do drum, beat the drum and say lowest amount for the shortest duration if your breast cancer risk is in the thirties. Please, let's think about the primary prevention. So it's individualized, but so many women these days feel like they're missing out.

There's so much stuff out there about just how amazing hormones are and how amazing hormone therapy is and how amazing people feel on it, and all the things that it improves. And particularly for primary prevention, just so many people feel like they've been wronged or are being wronged by not being put on it, or again, are not deriving all the benefits for their hearts and their bones in their brains that they should be.

And it's just, it's, misinformation. There's no data to support any of this, and so many people are kind of benefiting from it eco economically, and it's really kind of annoying.

Elizabeth Clement, MD: Yeah, and I'll just add, especially with a lot of like direct to consumer, both prescriptions for hormone therapy as well as I think sort of just in my mind, what I feel like is predatory marketing towards menopausal patients because they are a group of people who are looking for solutions, have been suffering and there's a big market there for various treatments. I think that patient's will seek help outside of the traditional healthcare setting to feel relief. And I think that while hormone therapy can seem intimidating, I think, the service you can do to your patient by, assessing their risk, prescribing reasonable hormone therapy to a reasonable candidate, can save them the harm of being prescribed a non recommended regimen and can really be beneficial. And then escalating to sort of a menopause specialist or someone who's particularly comfortable if someone is a little bit more complicated and probably needs a little bit more of a nuanced risk benefit discussion.

Host: And if I wanted to sort through that, I could send a patient to one of the two of you. Right?

Elizabeth Clement, MD: Absolutely. be happy to see them.

Kendal Williams, MD (Host): To have those discussions. Yeah.

Arina Chesnokova, MD MPH MSHP MSCP: Yeah, And we have a whole cohort of clinicians who specialize in menopause, not just me and Elizabeth. There's also Danny Berkland and Carol Williams, and Ryan Offer, and Shauna Macintosh and Abigail Wolf over at Penn. I mean, we have a whole cohort that we're sort of trying to grow, kind of a center of excellence for menopause for folks to be able to escalate.

But yeah, it's certainly more than reasonable and also just so gratifying to start hormone therapy for patients who are really miserable. I mean, that's one of the major reasons for why I do a lot of it is just really. It was just the short term reward.

People think that you, changed their life by sprinkling a little estrogen around and it's just so great.

Host: Yeah. I used to joke when I treated a lot of congestive heart failure in the hospital that it made me feel like a surgeon because I could make people feel better very quickly, which is not an experience you often have as an internist. Most of focused on prevention and long-term, and things take a long time to get better and so forth, but this is something that will make people feel better quickly.

Arina Chesnokova, MD MPH MSHP MSCP: Yeah. Two weeks people feel better within two weeks.

Elizabeth Clement, MD: I'll also add on the like low hanging fruit of making people feel better, vaginal estrogen for genitourinary syndrome, menopause, systemic hormone therapy, not enough to essentially provide relief for genitourinary syndrome of menopause. And, there's minimal systemic absorption of vaginal estrogen.

There have been more recent studies that show there's not an increased risk of people with history of estrogen or, and progesterone receptor breast cancer, positive breast cancer with vaginal estrogen. And so I say that to be very reassuring to patients. The black box warnings have been removed in terms of that risk for vaginal estrogen.

And so, I joke to my patients, vaginal estrogen should come in like the welcome basket to menopause. We should just like give it to you.

Host: So that one we can prescribe to anyone. Alright, Elizabeth, I'm going to have you dig down and tell me exactly I'm an idiot, remember? So what do I write when I write vaginal estrogen? And what do I tell the woman to do?

Elizabeth Clement, MD: Yeah. So vaginal, estradiol, it comes with a like applicator plunger when you prescribe it, and one gram nightly for 14 nights and then twice weekly indefinitely. And that's it. At night, just because it's messy. There is, there are other options aside from the cream.

So if a patient says, Ew, it's messy. Yuck. I want something different. There are tablets and, rings and other formulations, I usually start with estrogen cream because it's usually inexpensive and covered by insurance. I usually say, we'll start here and let me know how it goes.

Host: Well, listen, we've run long, but this has been a great discussion and there's, a lot out there and it's a complicated area, especially when we're trying to think through all of these specific outcomes related to hormone therapy. And so, thank you for really digging down on this with us tonight and going through all of this specifically, And then leaving us with some very practical advice on how to start it and, whether to continue it and how long to continue it. So I really appreciate it. Thank you both being on the podcast.

Arina Chesnokova, MD MPH MSHP MSCP: Our pleasure short plug. There's going to be an agile MD pathway coming shortly to primary care folks to be able to use and to kind of go through some of the inclusion, exclusion criteria and end up with that sort of very simple script for twice weekly patch 0.05, Prometrium 100 at nighttime.

And then be able to escalate from there. If folks want to refer or some tips on how to troubleshoot and continue to manage that patient, if they would like to.

Host: Terrific. That's absolutely terrific. So thank you both for coming on the Penn Primary Care podcast and thank the audience for joining us as well. Please come again next time.