#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.

31:03In 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 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.

31:38So what was the understanding of the pathophysiology of the relationship between estradiol or estriol even, or maybe it's estriol, it would deem 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 study said suggested that both estrogen plus progestin and estrogen alone would be associated with increased risk of breast cancer.

32:28But there were many, many observational studies suggesting that hormone therapies associated to increase 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 allusion there.

33:26So 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 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.

34:14And 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 Now what was really surprising as I mentioned, although there was this increase, 2530 % increase in risk of breast cancer seen with estrogen plus progestin. 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.

35:30And certainly will not apply to the combination of estrogen plus progestin. So that's interesting. 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 in a lone trial because in the estrogen plus progestin trial, you can't disentangle, it was given a command pill.

36:24Every 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 medroxy progesterone acetate. And of course, the question has been raised with other types of progestigen, 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 increase in breast cancer with that particular formulation of a progestigen. 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 progestagen on breast cancer risk.

37:26So probably the most prudent cautious approach is to assume that at least with longer duration of treatment with estrogen and 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 plus P arm, so the C E E plus MPA arm was stopped early, correct? At 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.

38:13And an overall unfavorable risk -benefit ratio is 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 plus P group in the first, second, third year relative to the final year. Do you recall what those numbers were? To drop out rate is actually substantial in all hormone therapy trials. It's a combination of people do drop out of all trials because it requires a lot of effort to take a medication this not being prescribed for your health, it's just part of a study.

38:58You 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 attack. Udorus, and we're taking estrogen plus progestin, some of them continue to have some vaginal bleeding, and you know, 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, a fatigue will set in in any randomized trial.

39:42Our 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 planned to be about nine years. Over eight years. I mean, I guess we'll never know what it would have shown it 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.

40:27The relative risk difference in the group that was CE E 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 CE plus MPA have a 25 % higher risk of breast cancer during this 5 .2 year period. The absolute risk increase was 0 .1%. It was a difference of one case per thousand. Exactly. My mirror shows me correctly. The women in the placebo group were getting breast cancer at an incidence of four cases per thousand women. The women in the CE plus MPA group were getting it at an incidence of five cases per thousand.

41:08and 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 like - Fill out your 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.

41:43I'm embarrassed to admit I don't even recall this 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.

42:34And that was a positive thing. That was a positive change in clinical practice because the WHOI showed that when hormone therapy is used for prevention of chronic disease purposes in women who have average ages 63 and women in mid to later menopause on average, the risk outweighed 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.

43:23And 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 bothersome, distressing hot flashes, night sweats, to improve their quality of life, especially generally healthy women and early menopause, who have such low absolute rates of adverse events. Now, as you say, in the WHOI, 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.

44:17However, 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 and FDA approved indication of treatment of hot flashes and night sweats among women in early manopause who had even lower absolute risk 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.

45:20I 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 you know most aren't, they can't reiterate what you just said. The only thing that they seem to understand. And by extension, the only thing that their patients seem to be led to believe, you know, really the enduring legacy of the WHO 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 inaccuracies in that that are so inaccurate that they're almost a parody, right?

46:03And 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 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.

46:52One 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 WHO? 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.

47:35And 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 increased at a post -menopausal, 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 WHOI, 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 madroxy progesterone acetate.

48:26It 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 WHOI 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.

49:14So really diametrically opposite effects of the combination with the Medroxy Prudesteroan acetate of the estrogen with the Medroxy Prudesteroan 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 menopausit, 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.

50:08This 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 usually there would not be a fatal form of cancer, a diagnosis. Overall, we did not see any significant increase in total cancer, total invasive 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 seem to be at least borderline reduced.

51:01So I think the clinical message and the message for the public is 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 lay 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's clinician may think that they really should consider hormone therapy.

51:52That's the women's decision and you respect it. However, other women, let's say, will say that they wanna take hormone therapy even though they know that there may be XY 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 it is very important that women be able to help make that decision together with their clinician that they share in that decision -make it. I don't disagree with any of that.

52:39I 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, almost a fear mode of saying, oh my God, no way I want, you know, HRT, it's gonna 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.

53:20Because 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 they're women who really want HRT, but they can't find physicians who will 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.

53:57I 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 her mother developed breast cancer while she was on the hormones, whether or not it was directly due to the hormones. So she's 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.

54:39So 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 risks 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 WHO in the early 2000s, the pendulum was in the opposite direction that hormone therapy is bad for all women.

55:32And 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 moderate to severe or bothers some 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.

56:15Not very exciting, so maybe that's why it's not the take the media had. But I play the what if game, which is how to 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 of 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 -onvillope calculation based on the assumption that somewhere between four and five million women probably missed out on HRT in the last 23 years, 22, 23 years as a result of the study, which saved, mean it reduced about 4 ,500 cases of breast cancer.

56:54There's benefit to that. But it 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 by about 1 .5 % in absolute terms. That's remarkable. Yes, there was the benefit for hip fracture and there were benefits for 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.

57:39So 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. So 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.

58:44And 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 an irrespective of their risk of osteoporotic fracture, who had a clearly 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 of the quality of life benefits.

59:35We haven't talked about age differences. I think 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 risk, the risk of having adverse events on hormone therapy lower in the younger women, women, and early menopause. But also, 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 her disease and heart attack rate compared to the women on placebo.

1:00:25there was a signal there for benefit, also a signal there for favorable outcomes in terms of all cause mortality. So overall, there 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 his direct to me. 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.

1:01:20And women should not shy away from the use of hormone therapy and should discuss the option, weigh the benefits and risk carefully with their health care 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 Medical Society has website menapause .org, and they can find the tab for find a healthcare professional, a certified healthcare professional with training and 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 discuss hormone therapy with patients.

1:02:08But 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 anti -depressant medications, SSRIs, SNRIs, some of the GABA pentanoid medications. These medications have been found to be quite effective, 40 -50 % reduction in hot flashes and night sweats with these medications.

1:03:03And there's a new medication that may be approved by the FDA barely soon that 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 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.

1:03:49So the incidence of fracture saved is about 1 .5%, and the mortality of that, once she reaches 65, the one -year mortality, depending on the series, is 15 to 30%. 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 Manipause. And we did see that the younger women, the women who were in their 50s taking either estrogen alone or estrogen plus progestin had signals for about 30 percent 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 of all cause mortality was not quite statistically significant.

1:04:57So 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 was 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, timing is everything when it comes to the all Because mortality results, their favorable signals for the hormone therapy, the women earlier in menopause, age 50 to 59 in the study, white, 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.

1:05:51That is a little different than what I was asking. I don't think the 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 paramanopause 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.

1:06:26And 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 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.

1:07:06And 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. 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 NAL for all -cause mortality. there was no 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.

1:07:50But 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 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 their 60s, 70s even longer.

1:08:39And 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 or breast cancer or other estrogen sensitive cancers. So that's right. So we're selecting for health, your 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.

1:09:21But I think there would be concern that the risk would outweigh the benefits. Because keep in mind the WHOI showed an increased risk of stroke with both estrogen alone and estrogen plus progestin 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 is going for that duration. But do you think we'll ever get another bite at the apple to use kind of better practices?

1:10:06I mean, CE 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 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 coded 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 WHOI are less relevant today given that the drugs that were tested aren't the drugs that are in mass adoption.

1:10:49Do you think it's likely we will 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 toward the transdermal estradiol and the micronized progesterone, these FDA approved bioidentical formulations of hormone therapy as opposed to the oral congeal estrogen medroxy progesterone acetate.

1:11:35I 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, you know, terms of clinical outcomes such as heart attack 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, foreclodding, and cardio metabolic 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.

1:12:40Whether 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 manopause and ordered, 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 risks 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.

1:13:35But let's keep in mind that even Even though the WHO 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 which actually were found in the WHO 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 disrupted sleep related to these symptoms.

1:14:22They weren't getting the benefits and they were getting these adverse outcomes. So, it's important to acknowledge that the WHOI 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 and eye sweats. It's really important for women to understand that the WHOI results are really not intended to discourage a woman who's having disruptive 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.

1:15:14That's the really key message that women in early menopause 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 and then a posmanagement knowledgeable in hormone therapy decisions. 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 the zip code?

1:16:00What 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 their zip code and then we'll tell them which clinicians within five miles, 10 miles, I 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.

1:16:39There's a whole lot of discussion. Yeah, I'll conclude with two things. I guess 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 WHO 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.

1:17:12And 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 WHO 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 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 WHO than you probably even did by taking part in the WHO.

1:17:48So 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. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, We've created a membership program that allows us to bring you more in -depth exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the price of the subscription. Now, for that end, membership benefits include a bunch of things. One, totally kick ass comprehensive podcast show notes that detail every topic paper person thing we discuss on each episode.

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