#253 ‒ Hormone replacement therapy and the Women's Health Initiative: re-examining the results, the link to breast cancer, and weighing the risk vs reward of HRT | JoAnn Manson, M.D.

Hey everyone.

Welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in depth content. If you want to take your knowledge of this space to the next level, at the end of this episode I'll explain what those benefits are. Or if you want to learn more now, head over to peterattiamd.com subscribe Now without further delay. Here's today's episode.

My guest this week is Dr. Joanne Manson.

Joanne is a Professor of Medicine and the Michael and Lee Bell professor of Women's Health at Harvard Medical School, professor.

In the Department of Epidemiology, along with.

Chief of the Division of Prevention Medicine at Brigham and Women's Hospital. She is also a physician, epidemiologist, endocrinologist, and the principal investigator or CO PI of several research studies including the Women's Health Initiative, which we of course discuss here in length, along with other studies.

Such as the cardiovascular components of the.

Nurses Health Study, the vitamin D and omega 3 trials known as VITAL.

Her primary research interests include randomized clinical.

Prevention trials of nutrition and lifestyle factors.

Related to heart disease, diabetes, cancer, and.

The role of endogenous and exogenous estrogens as determinants of chronic disease in women. Joanne has received numerous honors including the American Heart Association's Population Research Prize, the American Heart Association's Distinguished Science Award, the Research Achievement Award, election to the Institute of Medical of the National Academies and.

The National Academy of Medicine, membership in the association of American Physicians, Fellowship in the aaas, and so many other awards.

That I could spend the rest of the introduction of this podcast going over them. She has published more than 1200 peer reviewed articles in the medical literature and is the author or editor of several books and textbooks. She serves as the Editor in Chief.

Of Contemporary Clinical Trials and is the.

Past President of the North American Menopause Society. She is one of the most highly cited researchers in the history of published research and one of the physicians who is featured in the National Library of Medicine's exhibition History of American Women Physicians. In this episode with Joanne, we spend the entire conversation focusing on one of her main projects, the study that she was involved in called the Women's Health Initiative, of which she was one of the principal investigators in this discussion, we speak about the reasons for the study, the questions being examined, the study design, inclusion, exclusion criteria.

We then go into the nuances of.

The study, including why it was prematurely stopped and how it was interpreted.

Of course, the most important part of.

This discussion is what the implications are for someone today listening to this. Hormone replacement therapy is potentially one of the most controversial bits of medicine today. And I would argue, and I make this point to Joanne, that the misinterpretation of the Women's health initiative some 20.

Years ago May be one of the greatest missteps of medicine and by extension.

The medical press in the past several decades. I make no bones about my bias here in this podcast, which is that.

I think the fears of hormone replacement therapy are completely overblown and are generally being propagated by people who are not.

Familiar with the literature, which is why I wanted to sit down with Joanne today. I could think of no better person to sit down with and go through the details of this study than the person who is more familiar with them than anyone else. So without further delay, please enjoy my conversation with Dr. Joanne Manson.

Joanne, it is great to finally be sitting down with you. This is a topic that is arguably as important as any topic that we'll cover in this podcast. And there's probably no better person to speak with about HRT than you. So maybe just by way of background. Well, maybe I'll introduce you with one interesting statistic. Do you know how to actually calculate the H index?

Yes.

Okay, so tell folks what the H index is, how it's calculated. I'll embarrass you by telling people how high you rank on that.

Okay, this is very embarrassing, Peter, but let me start by saying it's great to have a chance to talk with you, and I'm so glad that you're interested in this subject and providing more information to your audience on this subject. The H index is calculated from the number of publications you have that are highly cited. If, for example, you have an h index of 100, that would mean that you have at least. We have 100 publications that have 100 or more citations each. An H index of 200 would be 200. Publications that each have at least 200 citations are referenced in other publications.

You know, we throw those numbers out, like 100 and 200. Those are epic H indexes. I mean, a person with an H index of a hundred has done ten people's, you know, lifetime's work in their lifetime. Your H index, Joanne, last I checked, is 305. Is that correct?

It may have crept up even higher.

Yeah. Well, I would say that you are generally in the top 3H index rankings in the history of biomedical science. And I know this because I've checked this. I've never interviewed anybody with a higher H index than you, and I've certainly interviewed a lot of people with a very high H index. So with that as a little bit of background, let's go into a slightly more.

It means I have wonderful colleagues and collaborations going on throughout the world.

Yeah, it certainly does. But let's talk more specifically about this discussion. So there is a study that many people, people have heard me talk about. It's called the Women's Health Initiative. It's a study that you were one of the principal investigators on. And it's also a study that has produced results that I think we would look back today, 20 years later, and say maybe weren't interpreted in the best way. And the implications of that are obviously significant from a public health perspective. But let's go back in time to the beginning of the planning of this study, which I assume would have been in the early 90s is about when you and your peers decided we needed a randomized experiment to test what was being found in the Nurses Health Study and other epidemiologic studies.

Exactly. It was the very early 1990s.

Talk a little bit about what was observed through the observational studies, the epidemiologic studies, and how that shaped the design of the WHI.

Yes. So back in the 1980s and 1990s, there were several observational studies. These are not randomized clinical trials, but large observational studies looking at women who chose to be on hormone therapy or whom doctors were prescribing hormone therapy for. And they did tend to have lower rates of heart disease in those studies compared to women not using hormone therapy. They also seem to have more favorable outcomes, such as less cognitive decline, lower all cause mortality rates. They were generally doing better. But we often say that observational studies of this nature cannot prove a cause and effect relationship, but they can generate hypotheses to be tested in randomized clinical trials. But before the randomized clinical trials were even launched in the early 1990s, there was already an increasing practice in clinical medicine to prescribe hormone therapy for the express purpose of trying to prevent heart disease, cognitive decline, and other chronic diseases. So this was a trend that was occurring not only in recently menopausal women, not only when women had hot flashes and night sweats and were in early menopause, but many clinicians were starting to prescribe these hormones for women who were well over a decade, 10, 20, 30 years after the onset of menopause. So it's very important to understand whether this practice of prescribing menopausal estrogen therapy or estrogen plus progestin therapy was advisable when used for prevention of chronic diseases. This was a very different question compared to asking, does hormone therapy reduce hot flashes, night sweats? And should women in their 40s, early 50s, who are just starting to go through menopause and have these symptoms, should they take hormone therapy to treat those symptoms? It was accepted that hormone therapy is effective for treating hot flashes and night sweats. It's actually FDA approved for that purpose. It has an indication for treatment to reduce hot flashes and night sweats. But the question of its use for prevention of heart disease, stroke, cognitive decline, other chronic diseases had never been tested in a randomized clinical trial. And that was the goal of the Women's Health Initiative, despite the fact that.

The epidemiology suggested benefits in all of those arenas. People who listen to this podcast are no strangers to the different types of biases that can creep in. And perhaps there's no greater bias that creeps into something like this than the healthy user bias. It could easily be the case that the women who had access to physicians or who had access to the type of physicians who maybe felt more knowledgeable or provided better care, and part of that could have been the provision of hormones. It could be that they were coming down with fewer cases of chronic diseases, not because of the hormone replacement therapy, but because of other factors that were a part of a healthy lifestyle or of which hormones might have been a part of it. So there's no doubt that an RCT is going to be essential to carry out the elucidation of causality here. Let's also talk a little bit about the formulations. I guess if we go back into, probably, gosh, the 1960s, when the idea first came along to physicians to replace estrogen in a menopausal woman, I think they were just probably using estrogen alone. Correct. And they didn't understand the role of progesterone as opposition to that to prevent endometrial hyperplasia. But where were we in the early 90s? Clearly, that had been figured out. What were the formulations that were most common?

Well, that's a very important question, Peter. And the most common formulations were conjugated estrogen with and without medroxyprogesterone acetate. And so women who had A hysterectomy could use estrogen alone, but women with an intact uterus needed to take a, what we call a progestogen, which counteracts the effect of estrogen on increasing the thickness of the uterine lining, the endometrium. And so if women who have an intact uterus take estrogen alone, they have a very high risk of developing endometrial cancer. And early on, they will just have proliferation of the lining of the uterus and increased vaginal bleeding related to taking estrogen without the progestogen. So those were the two formulations that were very commonly used. And also importantly, those were the two formulations that had been extensively studied in the observational studies where the results had looked very promising for lower risk of heart disease and cognitive decline all cause mortality. So it was felt to be important to test the formulations that had contributed so much to the observational study findings. As you say, the women who were taking hormone therapy in the observational studies tended to be a higher socioeconomic status, more highly educated, and more health conscious. And these were all potential confounding factors that may have contributed to their lower risk of chronic diseases. However, it's also important to note that in observational studies, the women who were being prescribed hormone therapy were still largely women in early menopause. They were at least being started in early menopause, even if they continued into mid and later menopause. So that's another important, perhaps biological difference between the women in the observational studies and women in randomized trials, where in the Women's Health Initiative the average age was 63 or more than a decade past onset of menopause, when the hormone therapy was being started.

I know you're not a gynecologist, so you may not know the answer to this, but do we know if the age of menopause is moving over time? I mean, we certainly know that girls are getting their periods earlier and earlier, even over just two decades. Do we know if menopause is also a moving target?

I don't know that that's been studied really rigorously and systematically. The average age of menopause is 51. Believe that stayed relatively constant for quite a while, although, as you say, the age of puberty and menarche start of menstrual periods has become younger over time. So there are those changes, but I don't know that there have been really clear differences in the age at menopause.

Do you have a sense of why the conjugated equine estrogen and the mpa, a synthetic progesterone, were the dominant forms of these hormones used in the 80s and in the 90s, which of course then became the precursor for the epidemiology. For example, the. Do we know why there was not just a bioidentical estradiol and progesterone, which of course is. We'll talk about those things later in our discussion, because, of course, those are the most dominant forms used today. But do you have a sense of just historically, why that was not the case even at the outset?

There are some theories about that, Peter. You know, one theory is that a pharmaceutical company developed the conjugated estrogens. As you know, they were originally and even many of the forms today derived from the pregnant mare's urine. And this pharmaceutical company really became the dominant force in terms of hormone therapy and the synthesis of estradiol, you know, from plants. And it's a more complicated process that really did not get going on a very large scale until more recent decades. But for quite a long time, many, many decades, more than 50 years, there was, you know, the conjugated estrogen available.

So the investigators, of which you're. How many of you were actually sort of the lead PIs, Were there three.

Of you in the overall Women's Health Initiative? There were initially 16 clinical centers and then expanded to 40 clinical centers for most of the duration of the WHI. So there were actually 40 principal investigators throughout the country.

Let's go over sort of study design and participant criteria, inclusion and exclusion criteria. So you've already alluded to several of these, and this is a very important distinction, and it's something I think you and I even discussed many, many years ago, not on a podcast, but just over the phone one day, which was women who were having vasomotor symptoms were excluded, correct? No, were not excluded.

This actually is a common misconception that women could not have hot flashes to participate in the whi. Women who had very severe hot flashes self selected out of the study because they wanted generally they wanted to be on hormone therap. At that time, the assumption was that hormone therapy would have very favorable effects. And they were already taking hormone therapy very often for their severe hot flashes. So they did not want to be in the study. But we didn't exclude any woman on the basis of the severity of her symptoms or presence or absence of hot flashes, night sweats. In fact, the majority of the women in, in the study, especially those in the earlier younger menopausal ages, did have at least mild or moderate hot Flashes.

I see.

I misunderstood. Yeah. I thought the thinking was by minimizing the number of women who had vasomotor symptoms, you would have less dropouts in the placebo group. Because, of course, women who are getting a placebo would presumably not be relieved of those symptoms which are obviously the most responsive to the HRT. You said the average age was 63. What were the exclusion criteria?

So women could not have a prior history of breast cancer, endometrial cancer, or any other estrogen sensitive cancers. And overall, if they had cancer, it had to be. Could not be estrogen sensitive cancer, and it had to be more than 10 years previously. Women could not have a recent heart attack or stroke or any of those major clinical cardiovascular events. Although a very small percentage of the women did have a more remote history of heart attack, stroke, bypass surgery, that type of clinical history. For the most part, the women were healthy in terms of past history of cardiovascular disease, cancer, other conditions. They were certainly allowed to have diabetes, hypertension, high cholesterol, and many of the more common health conditions that women will have and men will have in midlife.

Smoking not an issue.

They were not excluded for smoking, though we had a small percentage, less than 10% osteopenia.

Osteoporosis was not an exclusion.

No, it was not an exclusion. They were not selected on being required to have osteoporosis or osteopenia. But it's a broad range of bone health, similar to what you would expect in the usual population for women age 50 to 79.

And what about family history for breast cancer or uterine cancer?

Women were allowed to participate. It was really up to them whether they thought that their family history was so strong that they did not want to take any chance of being randomized to active hormone therapy. Many women did self select out of the study for that reason, but they were not excluded by these study investigators on the basis of their family history.

And was there a limit as to how long they could be out of menopause before enrollment?

No, it was on.

Sorry, into menopause. Yeah.

The criteria were based on age. So the women were 50 to 79, with a mean age of 63. Some of them had gone through menopause in their early to mid-40s. Some of them had even had hysterectomy with ovaries removed in their 40s or much earlier in life. So there was no exclusion on the basis of, for example, being more than 20 or 30 years past. Menopause was on the basis of age 50 to 79.

Wow. Amazing. Diversity of age there.

Right?

I mean, you think about basically three decades worth. What about prior hormone use? What. What fraction of the women had previously been on the exact same drugs that they were going to be potentially randomized to? And was there a required period of washout?

Okay, very good question. About 25% of the women in the estrogen plus progestin trial had prior use of hormone therapy. And close to 50% of the women with hysterectomy and in the estrogen alone trial had some prior use of estrogen therapy. So women were not excluded for having a past history of using hormone therapy. But especially in the estrogen plus progestin trial, the large majority did not have prior use. It was only about 25% who had prior use. And overall, just looking more specifically at the percentage of women in the trial who had hot flashes, night sweats at the time of enrollment, it was overall about 45%. 45 to 50% who had some symptoms, mostly mild or moderate hot flashes or night sweats, and a little over 50% did not have any hot flashes or night sweats at the start of the trial.

How many women are enrolled in this trial? About just under 30,000. Am I remembering that correctly?

Yes. So 27,000. A little over 27,000 in the two trials combined. In the estrogen plus progestin trial, close to 17,000. In the estrogen alone trial, close to 10,000.

And again, we've stated this, but I think it's very important that people, again, understand why there are two trials. If a woman has a uterus, she must be receiving progestin along with the estrogen. So that's the E P trial that we'll talk about. If a woman has had a hysterectomy, then estrogen alone is sufficient. There's no risk of endometrial hyperplasia because there is no endometrium. And there's an E alone trial. Each group has its own placebo.

Yes, Separate placebo for each group.

Great. So roughly, we're talking about four groups. The E only is roughly 5,000 plus 5,000. Where they randomized one to one.

Exactly.

And then the E P would have been, you know, roughly 8,500 in E plus P and then 8,500 placebo for that group.

Correct.

Okay. Primary outcome. Was there a single primary outcome, and was it ascvd? Was that the main outcome?

The primary outcome for both trials was coronary heart disease, with the primary safety outcome, because of concern even before the study was designed, was breast cancer. So the two really Key outcomes of the trial were coronary heart disease and breast cancer.

And obviously this is incidence of breast cancer, not mortality of breast cancer.

Correct.

Incidence. A diagnosis of breast cancer that's confirmed.

By medical record review and coronary artery disease would be what we would think of today as MACE. So major adverse cardiac event, MI, stroke, death as a result of anything, or was it more complicated?

The primary outcome was actually the coronary events. So it was heart attacks. It was either non fatal heart attack or fatal coronary disease, which is most commonly a fatal heart attack.

What was the study powered to detect on either of these? Obviously those numbers, the study subjects is something that I'm sure the investigators thought long and hard about. What was the power analysis suggesting? A difference that was anticipated.

Remember that the prior hypothesis was that there would be benefit for heart disease and that there would be overall many favorable effects of these hormones on chronic disease outcomes. It was powered to detect an important clinical reduction, such as a 20% reduction in heart disease.

Do you recall at the time what fraction of the women were taking lipid lowering therapies? How common would that have been in the early to mid-90s? You know, I think one of the interesting aspects of the WHI is that as you pointed out, hormones were being used as a preventive treatment for ascvd. You know, I think today very few physicians would really consider that. I think given the complete explosion we've had in both the availability, variety and efficacy of lipid lowering agents, a person who's deemed at risk is going to be managed much more critically with respect to blood pressure and lipids. Again, I don't know that I've ever come across that stat. That may not be something that you know, but I'm just curious as to how prevalent that was.

Yes, I do know it. It's right in the paper that we published in Jama in 2013 and we've published repeatedly on the subject of the use of many of these medications for chronic health conditions. So 7% of the study population was taking statins at the start of the study. By later in the trial, during the intervention phase, it was over 25%. There was a very large increase in statin use even during the trial itself. And with longer follow up, obviously these percentages are even higher, getting to 40, 50%, very high percentage.

What was known about oral estrogen at the time, again, going back to the early to mid-90s, as far as its impact on coagulability, for example, blood viscosity. Today, oral estrogen is not used very often as a Result of that. But at the time was it what was known?

It was understood that oral medications and as oral estrogen goes directly through the portal circulation to the liver and has a direct effect effect on the liver in increasing the synthesis of clotting proteins. That was understood at that time because similar to oral contraceptives, it had been seen in observational studies that both oral contraceptives and postmenopausal hormone therapy were associated with an increased risk of deep vein thrombosis and even pulmonary embolism. That had been suggested, but it was believed to be relatively rare and that the benefits for heart disease and for other chronic diseases would outweigh those risks of thrombosis.

What was your personal hypothesis going in? I mean, there's obviously the hypothesis that is driving this study. But do you remember back, you know, gosh, it's probably 30 years now since you were in the planning phase of this. What did you think was happening mechanistically to explain the observational data? Did you believe the observational data? Did you think that. That they were being confounded heavily? Do you have a recollection of that?

I believe that it was likely that there was at least a small amount of confounding because it was clear that women taking hormone therapy tended to have a higher socioeconomic status, tended to have better access to medical care, and to have somewhat more favorable lifestyle behaviors, be more health conscious. Many of these factors were considered in the data analyses. It's not. The observational studies were just looking very crudely at associations. There was adjustment for many of these lifestyle factors and socioeconomic status in some of the studies. But a benefit, a risk reduction for heart disease did tend to persist even after those adjustments. My thought was that women in early menopause who are transitioning from having their natural premenopausal estrogen exposure, which many studies suggested was protective, cardio protective, favorable in terms of risk factor status, in terms of dilating the blood vessels to the heart and increasing blood flow to the heart. There were many studies already suggesting that a woman's own natural estrogen during premenopausal years was one of the reasons why women started to have heart disease later, 10 years or more later than men. My thoughts were that it is likely that starting estrogen in early menopause would translate into at least a slightly lower risk of heart disease. But I was skeptical from the very start that the magnitude of risk reductions seen in the observational studies, you know, the 40%, 50% lower risk of heart disease would stand up to a randomized clinical trial assessment of this question. So I thought it was likely to be a small reduction. Wasn't sure whether that benefit might be offset by other risks that would be identified. But overall, you know, I thought there's likely to be some confounding going on in the observational studies.

When you think back to, again, that same period of time, what was your thinking with respect to the relationship between estrogen and breast cancer? You know, obviously the classical teaching, I mean, I was in medical school in the mid-90s, and you were taught chapter and verse that estrogen causes breast cancer. But on the surface, some of the assumptions are a little hard to understand in the same way that there has historically been the assumption that testosterone causes prostate cancer, except for the observation that men with the highest levels of testosterone, I. E. Men when they're, you know, younger, have lower rates of prostate cancer than men when they're older. And similarly, I mean, this was demonstrated as long as 15 years ago that the lowest levels of testosterone were associated with the most aggressive forms of prostate cancer. I don't know how similar the data are for estrogen and breast cancer, but given that most women get breast cancer in menopause and not prior to menopause, they're getting breast cancer, even estrogen sensitive breast cancer, at a time when they have their lowest levels of estrogen. So what was the understanding of the pathophysiology of the relationship between estradiol or estriol even, and, or maybe it's estrone that was deemed to be even more problematic? What was the understood relationship for why that relationship existed?

There was an expectation that there would be at least a modest increase in risk of breast cancer with giving either estrogen plus progestin or estrogen alone. In fact, the most surprising finding in terms of breast cancer was that no increased risk of breast cancer was seen with estrogen alone, even though the observational studies had suggested that both estrogen plus progestin and estrogen alone would be associated with increased risk of breast cancer. But there were many, many observational studies suggesting that hormone therapies associated with increased risk of breast cancer. But the thinking tended to be these are estrogen receptor positive breast cancers, they tend to be more favorable outcome types of breast cancer and that breast cancer mortality would not be appreciably increased. So that was the thought going into it. And also in the observational studies, there was always that concern that differences in mammographic screening patterns could be contributing to greater detection of breast cancer among women taking hormone therapy, because most doctors would not continue to prescribe the hormone unless the woman was having regular mammography and showed a normal mammogram without concern about a lesion there. So mammography also could have been contributing. More frequent mammography in women on hormones versus women not taking hormone therapy could have contributed somewhat to the increased risk in the observational studies, which was why it was important to look at this question in a randomized clinical trial with uniform surveillance for breast cancer with a mammogram being required every year. So there was an increased risk of breast cancer with estrogen plus progestin. Also, there were denser breasts developing over time. So breast density was looked at in a study of mammograms, several hundred women whose mammograms were examined, and there was a change in increased breast density, which is known to be a risk factor for breast cancer. The increase in breast density was greater with estrogen plus progestin than with estrogen alone. Now, what was really surprising, as I mentioned, although there was this increase, 25, 30% increase in risk of breast cancer seen with estrogen plus progestin, there, there was no increase in breast cancer seen with estrogen alone. And with longer follow up, there was the emergence of a reduction in breast cancer, close to a 20% reduction seen with the conjugated estrogen. And the view was that this may be something specific to conjugated estrogen, which is a relatively weak estrogen and may have certain properties similar to tamoxifen, where it may be both serving as an estrogen and an anti estrogen. But we cannot assume, importantly, we cannot assume that this finding with conjugated estrogen will necessarily apply to all formulations of estrogen alone and certainly will not apply to the combination of estrogen plus progesterone it.

So that's interesting. Joanne, I wouldn't come to that as my first kind of Occam's razor conclusion, because the same conjugated equine estrogen was used with the MPA that found a clinically irrelevant but statistically significant increase in the incidence of breast cancer. In other words, I wouldn't conclude from the differences in those two arms that it was the conjugated equine estrogen that was unusually beneficial.

No, I'm not. I'm not concluding.

Wouldn't it be that the MPA was the difference?

Yes, it's the mpa. But the only way to look at the role of the estrogen is in the estrogen alone trial, because in the estrogen plus progestin trial you can't disentangle. It was given a combined pill. Every woman in the trial was taking the combination. So I completely agree with you, Peter. The increased risk of breast cancer seen with estrogen plus progestin was mostly attributable, if not entirely attributable to the progestin to the medroxyprogesterone acetate. And of course, the question has been raised, would other types of progestogens, such as the bioidentical micronized progesterone, would that also lead to an increased risk of breast cancer? There are some observational studies that suggest less, less increase in breast cancer with that particular formulation of a progestogen. However, we have no large scale randomized clinical trials that have done head to head comparisons or even really tested long term the effects of other formulations of progestogen on breast cancer risk. So probably the most prudent and cautious approach is to assume that at least with longer duration of treatment, treatment with estrogen plus progestin, there will be an increased risk of breast cancer.

Let's go back and talk about the study being stopped. So the E P arm, so the CEE Plus MPA arm was stopped early. Correct. A little over five years.

It was stopped after 5.6 years and it was stopped 3.3 years early.

And this was stopped presumably on the basis of the finding for, for the increased incidence of breast cancer. Correct.

It was stopped on the basis of the increased risk of breast cancer, together with no reduction in heart disease, which was the primary endpoint, and an overall unfavorable risk benefit ratio as shown through the global index, which looked at all of these chronic conditions.

Now, one of the things that I didn't realize until somewhat recently was that the dropout rate was a little bit unusual in that in the placebo arm of the E P group in the first, second, third year relative to the final year. Do you recall what those numbers were?

The dropout rate is actually substantial in all hormone therapy trials. It's a combination of. People do drop out of all trials because it requires. There's a lot of effort to take a medication that's not being prescribed for your health. It's just part of a study. You don't know exactly whether it's active or placebo. So all trials have some dropout over time in terms of compliance, adherence with study medications. Also, there are some side effects of hormone therapy. The women who had an intact uterus and were taking estrogen plus progestin, some of them continued to have some vaginal bleeding. And some of them did not want to continue to have those symptoms. They may have had some breast tenderness or other symptoms and dropped out. And women dropped out of the placebo arm as well. Some of that is just taking a medication day in and day out, taking a study pill. Fatigue will set in in any randomized trial. Our participants were extraordinarily dedicated. I cannot imagine any group being more committed to women's health and to getting answers for women on these very pressing issues in menopausal women's health. But there's going to be some dropout in any trial.

Do you think the answer might have been different if the trial had gone to. It was originally for over eight years. About close to nine years.

Over eight years.

I mean, I guess we'll never know what it would have shown had it gone longer. So at the time that the study was halted, really, the big headline of the study was estrogen causes breast cancer. I use this as a great teaching example when I talk about the difference between relative risk and absolute risk. The relative risk difference in the group that was CEE plus MPA relative to placebo or versus placebo was 24, 25%, correct?

Yes, I think it was a little higher.

On the surface. That sounds incredibly startling, Right? So women who are getting CEE plus MPA have a 25% higher risk of breast cancer during this 5.2 years, year period. The absolute risk increase was 0.1%. It was a difference of one case per thousand.

Exactly.

Remember, if there's something correctly, the women in the placebo group were getting breast cancer at an incidence of four cases per thousand women. The women in the CEE plus MPA group were getting it at an incidence of five cases per thousand. The absolute difference of that being one case per thousand. It was about the opposite. That was seen in the CEE versus placebo alone. Although I don't think it reached statistical significance at 5.2 years, did it?

No, it didn't.

Yeah, it had a P value of longer follow up.

To see that reduction.

Yes, to see that there was indeed a reduction. In many ways, it seems that that was the headline that dominated the world. I don't have any recollection of it at the time, Joanne, because I was in my surgical residency when the study was first published, and I must admit I wasn't paying attention to this literature. I'm embarrassed to admit I don't even recall this patient paper coming out. What is your recollection of that time? How much it sort of captured the imagination and fear of the world.

Well, the medical community was shell shocked. There was a sea change in clinical practice, a seismic shift in clinical practice. But let's think about what the shift was. Two major things changed. There was a dramatic reduction in use of hormone therapy, 70 to 80% reduction in use of hormone therapy. So women who were being prescribed hormone therapy in the past for prevention of chronic diseases, prevention of heart disease, stroke, cognitive decline, those women were no longer being prescribed hormone therapy. And that was a positive thing. That was a positive change in clinical practice because the WHI showed that that when hormone therapy is used for prevention of chronic disease purposes in women who have average age of 63 and women in mid to later menopause, on average, the risks outweigh the benefits. So it was a favorable change. But the unfavorable change in clinical practice was that the results were extrapolated to women in their 40s and 50s who were taking hormone therapy for treatment of bothersome, even distressing hot flashes, night sweats and were in generally good health. And they were being denied hormone therapy to relieve these symptoms. And that was an inappropriate extrapolation of the findings. That was a negative outcome. Women never should have been denied hormone therapy for the treatment of, of bothersome, distressing hot flashes, night sweats to improve their quality of life, especially generally healthy women in early menopause who have such low absolute rates of adverse events. Now, as you say in the whi, even in the overall cohort with an average age of 63, most of the adverse events were relatively rare, such as one extra case of breast cancer or heart attack or blood clot per 1,000 women per year. I mean, it's still important and it can add up with longer term use. However, it's a low absolute risk and I think that the results were perhaps blown out of proportion, especially in terms of the use of hormone therapy for clear indication, an FDA approved indication of treatment of hot flashes and night sweats among women in early menopause who had even lower absolute risks than one extra case per thousand women per year. And that type of extrapolation really should not have happened. So there were some positive outcomes that hormone therapy was being used less for inappropriate purposes, such as prevention of heart disease, stroke, cognitive decline, but also this unfavorable change that it was being used less commonly for treatment of bothersome hot flashes and night sweats in early menopause.

I guess what I find most troubling is that when I speak with most physicians today, unless they're really, really steeped in this world, and most aren't they can't reiterate what you just said said the only thing that they seem to understand, and by extension the only thing that their patients seem to be led to believe, really the enduring legacy of the WHI from an insight perspective, is that hormones, in particular estrogen, cause breast cancer and that HRT is synonymous with breast cancer. And there are really two enormous, enormous inaccuracies in that that are so inaccurate that they're almost a parody. Right. And when we've discussed them both. But I think it's always worth bringing it back for the listener so that they aren't lost in the details. The first is that nothing about this study suggested that estrogen is causing breast cancer. If anything, this study suggested MPA is causing breast cancer based on the fact the group that was only receiving estrogen had a reduction in the incidence of breast cancer cancer, while the group that received estrogen plus MPA is the group that saw this small, potentially statistically significant, but potentially clinically insignificant increase. The second thing that seems to get lost from this, and again, it's sad that most doctors and patients who are contemplating HRT don't recognize this, is that the study only found an increase in the incidence of breast cancer to the tune of one case per thousand, but no difference in mortality. One has to wonder what the cost of that was. Let's talk about some of the other outcomes here. First of all, would you agree with that, by the way, that that would be perhaps a more charitable interpretation of the whi?

Two caveats. One, I think we cannot assume what was found with conjugated estrogen will apply to all other formulations of estrogen. And I think there is very strong evidence from several lines of biology that estrogen plays a role in breast cancer, including the fact that when women have their ovaries removed, it lowers their risk of recurrence, lowers the risk of development of breast cancer, lowers the risk of recurrence. And I think there is quite a bit of evidence that estrogen does play a role. The higher estrogen, estrone would be specifically the type of estrogen that, for example, is associated with, with increased adiposity in postmenopausal women is linked to a higher risk of breast cancer. So I think there are several lines of evidence that estrogen is a factor in breast cancer. And this was actually also known even before the whi, that many of the observational studies had linked hormone therapy to an increased risk of breast cancer. But I agree with you that it seems to be, when you're talking about Conjugated estrogen. It's the combination of estrogen plus the medroxyprogesterone acetate. It may be specific to that particular progestin. We don't know. We have very limited research in terms of randomized clinical trials, large scale studies of other formulations of progestin in terms of breast cancer mortality. The results in the WHI are very close to a statistically significant increase in breast cancer mortality with estrogen plus progestin. It doesn't quite make statistical significance, but it is getting toward a significant increase in risk. On the other hand, the conjugated estrogen alone was associated with a significant, a statistically significant reduction in breast cancer mortality. Really diametrically opposite effects of the combination with the medroxyprogesterone acetate of the estrogen with the medroxyprogesterone acetate versus the conjugated estrogen alone. I think that the absolute risks are still low. And that is a very important point to emphasize that we are talking about one extra case per thousand women per year. For a woman who starts out with a high baseline risk because of a strong family history or other risk factors, this would certainly be something she would want to avoid. But for a woman in early menopause at usual risk of breast cancer, who would derive the benefits of symptom relief, and she's suffering from disrupted sleep, very bothersome hot flashes and night sweats that interfere with her day to day activities, this would be a risk that you would probably be willing to accept with an understanding that all medications have some risk and that she could be monitored closely with mammography and breast exams. And, you know, usually there would not be a fatal form of cancer diagnosed. Overall, we did not see any significant increase in total cancer, total invasive cancer cancers with either estrogen plus progestin or estrogen alone. And interestingly, with the combination estrogen plus progestin, we saw a significant reduction in the endometrial cancer, the uterine cancer developing over time. And colorectal cancer also seemed to be at least borderline reduced. So I think the clinical message and the message for the public is the, that hormone therapy has very complex effects. It has a complex matrix of benefits and risks that vary according to a woman's age, her time since menopause. Her underlying health status and decision making about hormone therapy really has to be individualized, personalized. And women themselves play such an important role in the shared decision making. Because many women will say, I do not want to take hormones no matter what. And even if a woman's at low risk and the doctor, clinician may think that they really should consider hormone therapy. That's the woman's decision and you respect it. However, other women, let's say, will say that they want to take hormone therapy even though they know that there may be X, Y or Z increased risk because their symptoms are so bothersome, they're so distressing, they're being disrupted, their sleep is being disrupted, they are not being able to have work productivity, their day to day activities are affected, their quality of life is really impaired. And, and it is very important that women be able to help make that decision together with their clinician that they share in that decision making.

I don't disagree with any of that. I guess the only issue I would potentially highlight is that in the scenario you described where the physician thinks that it's the right thing to do, the patient is experiencing vasomotor symptoms, the patient already has osteopenia and their bone mineral density is only going to decline with time and they're not at unusually high risk for breast cancer. That scenario where the patient is in, you know, almost a fear mode of saying, oh my God, no way. I want, you know, hrt, it's going to cause breast cancer. I guess what I'm arguing is that's a very ill informed decision. So yes, it's their decision and yes, they should be able to make whatever decision they want. But that doesn't mean it's a good decision and that doesn't mean it's a decision based on good data, because in reality it's not based on data. That's my fear, is that this is no longer about the data. Because I think the data, what you and I are discussing today is the data and the data really don't make a very strong case for avoiding HRT outside of select circumstances. And yet I worry that the last 20 years of women entering menopause have been put into two categories, right? Either there are women who really want HRT but they can't find physicians who will get give it, or there may be a physician who understands the data at the level you and I are discussing it, but the patients themselves have been so frightened off it by misinterpretations of the data.

I think the conversation has to take place and you know, it is important for the clinicians to be informed themselves about benefits and risks and be able to discuss the benefits and risks in a very knowledgeable way with the patient. But my view is that if a patient feels strongly that she doesn't want to take hormone therapy. Maybe, you know, her mother developed breast cancer while she was on the hormones, whether or not it was directly due to the hormones. So she is going to have a lot of fear and anxiety surrounding use of hormone therapy and that will affect her overall well being. That's a factor in the benefit risk equation. So I would generally say don't push someone by just showing that the absolute risks in terms of number of cases caused versus prevented might be favorable for them because their emotional well being is a very important part of the equation. However, I do agree that we need to emphasize absolute risk, that absolute risks are low and that there are better candidates and there are worse candidates. It's amazing how the pendulum has swung. So in the 1980s, 1990s, the perception was that hormone therapy was good for all women. Women were being routinely started on hormone therapy. Then after the WHI in the early 2000s, the pendulum was in the opposite direction, that hormone therapy is bad for all women. And now I think it is coming, the pendulum is coming to rest in a more appropriate place. That hormone therapy is good for some but not all women. And the best candidates are women in early menopause who have, have moderate to severe or bothersome hot flashes and night sweats and are in generally good health. Those are women who will derive quality of life benefits and have very minimal absolute risk from hormone therapy.

One of the things I've thought a lot about is how many women, if you go back to 2002 and the data are published, but the media has a different take on it. The media has the take on it, which is kind of how we're discussing it now, not very exciting. So maybe that's why that's not the take the media had. But I play the what if game, which is how do things shake out. So instead of the pendulum going so far to the other side of women can't and shouldn't under any circumstance have HRT because they're going to get breast cancer. It turns into, no, there will be additional cases of breast cancer. You know, I've done sort of a back of the envelope calculation based on, on the assumption that somewhere between 4 and 5 million women probably missed out on HRT in the last 23 years, 22, 23 years as a result of the study, which saved, I mean, it reduced about 4,500 cases of breast cancer. There's benefit to that, didn't really reduce mortality from breast cancer. But here's what's interesting. Even though it's not a primary outcome, HRT reduced the incidence of hip fracture fracture by about 1 1/2% in absolute terms. That's remarkable.

Yes, there was the benefit for hip fracture and there were benefits for in.

Other cancers as well.

Yes, there were benefits for endometrial cancer with estrogen plus progestin. But here's the problem with the whole argument for using it for bone health. Women in their 40s and 50s have a low risk of osteoporotic hip fracture. They may have a hip fracture from a traumatic incident, but it's not likely to be related to osteoporosis. So it's when they get into their late 60s, 70s, 80s, that they're more likely to have the osteoporotic fractures. And if we were to treat women from early menopause into their 70s, 80s, that would be very long duration of hormone therapy use, which would lead, especially combination hormone therapy would lead to an increased risk of breast cancer. And once women go off of hormone therapy, bone loss is very rapid. All of the benefits to the bones in terms of preserving bone mineral density that dissipates very quickly within a matter of a few years after stopping hormone therapy. So that if a woman is taking hormones in her 40s and 50s, and then she stops, let's say at age 60, then by the time she gets to the age where her risk of hip fracture is very substantial, in her 70s and 80s, she's really not going to have a persistent sustained benefit from the hormone therapy. And we looked within the group at high risk of osteoporotic fracture, whether they had a favorable overall favorable outcome in terms of the global index combination of all of these outcomes with hormone therapy. And overall, there really was no group of women, irrespective of their risk of osteoporotic fracture, who had a clear electricity beneficial ratio from benefit risk ratio from estrogen combined with progestin when used for chronic disease prevention. Again, this does not mean that it isn't a very effective treatment for hot flashes and night sweats and that women in early menopause would have a favorable benefit risk profile taking into account the quality of life benefits. We haven't talked about age differences. I think that that overall it's so important for women to understand that the absolute risks of these hormones are much lower in early menopause than in later menopause. And in many ways, timing is everything when it comes to hormone therapy, because not only are the absolute risks, the risk of having adverse events on hormone therapy, lower in the younger women, women in early menopause, but also so we saw some signals that especially with estrogen alone, the women in their 50s, the youngest women in the study were 50 to 59. Those women tended to do quite well in terms of heart disease and heart attack rate compared to the women on placebo. There was a signal there for benefit, also a signal there for favorable outcomes in terms of all cause mortality. So overall there was were favorable signals with estrogen alone in the younger women and also lower risks of adverse events, suggesting that certainly for estrogen alone in a woman who's had a hysterectomy, if she is symptomatic with hot flashes, night sweats, the benefits of treatment are likely to outweigh the risk. And even for combination estrogen plus progestin, despite what may be a small increase in risk of breast cancer, the benefits are likely to outweigh the risk. Even combination therapy, when used for the purpose of treating bothersome, disturbing hot flashes, night sweats, disrupted sleep and impaired quality of life. And women should not shy away from the use of hormone therapy and should discuss the option, weigh the benefits and risks carefully with their healthcare provider, with their clinician, and see if it's the right decision for them. And if they have trouble finding a clinician, they can go to the North American Menopause Society has a website, menopause.org and they can find the tab for find a healthcare professional, a certified healthcare professional with training in menopause. And they can put in their zip code and find the clinicians in their area who have this expert training. I'm an endocrinologist and I know that many endocrinologists have the training to talk about hormone therapy and discussion, discuss hormone therapy with patients. But many clinicians have had limited training in, you know, use of hormone therapy. And it may be helpful for women to seek out a clinician who has had some additional training in menopause management and hormone therapy. Pros and cons. And for women who are not good candidates, the good news is that there are non hormonal options as well. They're not quite as effective as the menopausal hormone therapy for treating hot flashes and night sweats. But some of the antidepressant medications, SSRIs, SNRIs, some of the gabapentinoid medications, these medications have been found to be quite effective. 40, 50% reduction in hot flashes and night sweats with these medications. And there's a new medication that may be approved by the FDA a fairly soon. It works entirely in the brain in terms of making women less sensitive to the changes in temperature and has a very beneficial effect in terms of preventing hot flashes and night sweats.

I guess I still kind of come back to something that the math doesn't quite add up, right, which is if a woman stays on estradiol for the duration of her her life, say from age 50 to 80, we accept that there's going to be an increase in the incidence of breast cancer, though it doesn't seem to translate to a difference in lifespan. But on the flip side, we are reducing her risk of fracture during a very dangerous window. So the incidence of fracture saved is about one and a half percent and the mortality of that once she reaches 65, the one year mortality depending on the series is 15 to 30% percent. So even if we just want to do this on the basis of mortality, apples to apples, it doesn't even appear close, does it?

Well, let's look at the actual data because we published in JAMA 2017 the mortality results, the all cause mortality results by age and time since menopause. And we did see that the younger women, the women who were in their 50s, 50s, taking either estrogen alone or estrogen plus progestin, had signals for about 30% lower mortality, though it was not statistically significant in either trial individually. Yet the women who were older, in their 70s, 70 to 79, randomized to estrogen alone had a hazard rate 22% higher risk. Risk of all cause mortality was not quite statistically significant. So it was right at the border of being statistically significant. And with estrogen plus progestin it was actually quite neutral, almost completely null. So there were estrogen alone seemed to be just a tad worse in the women 70 to 79, though it was a tad better among the women 50 to 59. So again, again, timing is everything when it comes to the all cause mortality results. There are favorable signals for the hormone therapy. The women earlier in menopause age 50 to 59 in the study, quite neutral results in age 60 to 69. But in age 70 to 79 there's a bit of a signal that estrogen alone may be linked to a small increase in risk of mortality.

That is a little different than what I was asking. I don't think this study can answer the question I was asking, which is really more of conjecture, that if a woman is started at the appropriate time, which I think we all agree is during the transition from perimenopause to menopause, and I'm really asking this question through the lens primarily of hip fracture, which I think is just such an underappreciated cause of mortality in both men and women over the age of 65. But estrogen is hands down the most important hormone as it pertains to signal transduction from the strain gauge within the muscle to the osteoblast and osteoclasts. And so what I'm really asking is it's more of a thought experiment. If we put women on HRT at 50 and they stay on HRT for 30 years, by my calculation it's a 15x reduction in mortality because even if you accept a slightly higher insulin incidence of breast cancer, it's being more than dwarfed by the reduction in the hip fractures that they will be sustaining 15 years after beginning again. We don't know the answer, and we'll never know the answer because I don't think anyone's going to do that study. But the magnitude of that difference is so great. And that's where I just think the discussion is very confusing for people because they only see one thing, which is breast cancer, and they don't see it through the nuanced lens that we're talking about it. Which is why I'm glad we're talking about it. I think this is the discussion people need to understand, understand.

I agree that there may be an excessive focus on one isolated outcome such as breast cancer, when it's really the overall health of the woman. And of course, all cause mortality is an integration of all of these life threatening health conditions. And it was quite neutral with hormone therapy. Overall, the results were what we call null for all cause mortality. There was no increase, increase in risk or decrease in risk in the overall study population. And in the younger women there was a signal for some reduction in risk. But a randomized trial has never been done that would look at 30 years of hormone therapy treatment starting in early menopause and continuing into mid to later menopause. And, and the reality is we don't know whether the benefits would outweigh the risks. I know that some women will make the choice to continue to take hormone therapy into middle to later menopause because they started in early menopause, they did well on the hormones, their quality of life is very good. When they try to stop or reduce the dose, they feel hot flashes coming back and they end up taking these hormones well into the their 60s, 70s, even longer. And in the observational studies, this looks like it has a relatively favorable benefit risk ratio. However, keep in mind this is a very select group of women who are choosing to stay on hormone therapy long term because they're doing extremely well with it and they've tolerated it well and they haven't developed any of these interim events such as a heart attack, a stroke, a blood clot in the legs or lungs, lungs or breast cancer or other estrogen sensitive cancers.

So that's right. So we're selecting for healthier women, selective group of women.

And I think that overall we just don't know what a randomized trial would show with long term hormone therapy. But I think there would be concern that the risk would outweigh the benefits. Because keep in mind, the WHI showed an increased risk of stroke with both estrogen alone and estrogen plus progesterone. And there was cognitive decline and increased risk of cognitive decline among the women 65 and older, although that was not the case in the younger women. But we just don't know how the pattern of benefits and risks would change with longer duration. Once you get into 15, 20, 25 years of treatment, it's pretty clear to.

Me we'll never get another bite at the apple as far as far as going for that duration. But do you think we'll ever get another bite at the apple to use kind of better practices? I mean, CEE and MPA have largely fallen out of favor. Very few women. I've never actually seen a woman take those. I'm sure some do, but most women these days are using, you know, the Vivelle dot or one of the topical FDA patches, which is just pure estradiol. As you alluded to earlier, most women these days are taking micronized progesterone, which is a bioidentical progesterone, or foregoing oral progesterone altogether, and using a progesterone coated IUD which seems to offer the same degree of local endometrial protection without any of the systemic effects for some women who can't tolerate that. So in some ways the entire cluster of insights from the WHI are less relevant today. Given that the drugs that were tested aren't the drugs that are in mass adoption, do you think it's likely we will see see another short term study, and I call short term like kind of a five year study that tests the same question using the current formulations and potentially does so in a manner that is in line with more current use cases of the drug, or do you think that that's too much of an undertaking and something that we'll never really get another RCT to address?

I think that it is a good trend to move towards the transdermal estradiol and the micronized progesterone, these FDA approved bioidentical formulations of hormone therapy as opposed to the oral conjugated estrogen medroxyprogesterone acetate. I think that that is a good trend. We have to keep in mind that we really don't know the long term benefits and risks, but based on other, other, you know, in terms of clinical outcomes such as heart attacks, strokes, different forms of cancer and all cause mortality. But I think it makes sense based on how these different formulations affect clotting, affect biomarkers for clotting and cardiometabolic health, blood pressure, all of those parameters. I think that there's reason to use the transdermal and the micronized progesterone preferentially over the older formulations. I think we need more randomized trials of these formulations that are now in more common use, especially looking at breast density, mammographic breast density, to see if there is less suggestion of a future risk in breast cancer based on the change in mammographic breast density. Whether or not there is going to be another large scale trial of the magnitude of the Women's Health Initiative, which would be, if you take women in early menopause, in order to have similar numbers of health outcomes and similar robust power to look at health outcomes, it would have to be at least 40, 50,000 women being randomized in their 50s and followed for seven, eight years. I think it's really unclear whether such a trial could be mounted. Would be extremely expensive. And also because of the rapid changes in formulations over time, there would be the similar risk that the results might become obsolete by the time the results were available, as you're suggesting is the case with the conjugated estrogen and mpa. But let's keep in mind that even though the WHI was testing the most common formulations at that time in the early 1990s, it did put an end to a practice of prescribing hormone therapy among women in later menopause for the purpose of preventing strokes and heart attacks and cognitive decline, which actually were found in the WHI to be adversely affected by hormone therapy. And women were not getting the benefits for quality of life that many of them didn't have once they were in their late 60s, 70s, they were not having any hot flashes, night sweats, disruption, disrupted sleep related to these symptoms. So they weren't getting the benefits and they were getting these adverse outcomes. So it's important to acknowledge that the WHI did put an end to what was an unfavorable practice. The problem was it was over extrapolated. The results were extrapolated to women in early menopause taking hormone therapy for the hot flashes, night sweats. It's really important for women to understand that the WHI results results are really not intended to discourage a woman who's having disrupted sleep, very severe significant symptoms, to discourage her from seeking help and seeking hormone therapy as one of her options for treatment. And in her specific case in early menopause and generally good health, the benefits are likely to outweigh the risk. That's the really key message that women in early menopause pause should take these symptoms seriously, make sure they find a clinician who will take these symptoms seriously and discuss their options, their treatment options, review with them the pros and cons. And if they are not finding that clinician, they need to go outside their current system and find a clinician who can help them to do that because there are many clinicians out there who are knowledgeable in menopause management, knowledgeable in hormone therapy, decision making, making who can help them to make the best choice for themselves.

Joanne, what was the reference you gave for women to go and look for finding a provider near them where they enter their zip code? What was the name of that again?

Menopause.org website of the North American Menopause Society. And they can go to the find a certified menopause practitioner tab and it will give them an opportunity to put in the their zip code and then we'll tell them which clinicians within 5 miles, 10 miles have the expertise in menopause management and hormone therapy and other treatments.

Well, I could continue talking with you for hours and extract so much more insight. There's so many other topics. We didn't. We could talk about vitamin D for another few hours.

That could be another. That could be another.

There's a whole lot of discussion. Yeah. I'll conclude with two things, I guess one, one is just I still remain somewhat sad because I think there's a lost generation of women. I think there's 20 years of women who entered menopause who were denied HRT due to the ignorance of their physicians and the irresponsibility of the media. And I look at women like my mother and my mother in law who were entering menopause just as the WHI was coming to its conclusion and who suffered unnecessarily and I don't know how many millions of women suffered unnecessarily. I think you're right. I think the pendulum is swinging, and I'd like to believe that there aren't women that are suffering that way today. The other point I'd make is I really have always respected you and continue to do so because I feel like you're one of the few people who was such an important part of the WHI who has been able to look back at that and acknowledge its limitations. And I think your thinking seems to at least me through your writing, to have evolved over time. I don't think that's a property that is necessarily inherent to every everyone at your position. So I really applaud you for that, and I think that you're doing more good today by speaking out on the limitations of the WHI than you probably even did by taking part in the whi. So thank you for that, and thank you for joining me today.

Well, thank you, Peter. I've enjoyed talking with you and I hope that these messages are helpful to your audience.

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