Podcast Episode 9: Beyond the WHI: what evidence-based research really tells us about the use of HRT with Professor Robert Langer
20 years on from the infamous Women’s Health Initiative (WHI) study, misinformation regarding the safety and efficacy of HRT continues to circulate. Though current evidence-based research suggests using HRT can in fact lead to positive long term health outcomes, fear and mistrust remains prevalent in certain clinical contexts. To set the record straight and discuss what we really know about use of HRT in the treatment of the perimenopause and menopause, host Lauren Redfern is joined by esteemed clinical researcher and scientist Professor Robert Langer. Professor Langer is Professor Emeritus in Family and Preventive Medicine at the University of California in San Diego and was the Principal Investigator for the entire primary study period from 1993 through 2005 of the WHI. Drawing upon his expert knowledge obtained during both the WHI study period and beyond, Professor Langer helps to explain how and why speculation and mistrust regarding HRT has grown and explains what evidence-based findings tell us today about the use of HRT.
Lauren Redfern [00:00:06] Welcome to the podcast for The Newson Health Menopause Society, a multi-disciplinary collective of interested professionals passionate about improving hormone health across the world. The society exists to educate and inspire others to raise the standard of menopause care and access to treatment, to facilitate research, collaborations across specialities and countries, and to provide expert advice and guidance to our associates. The ultimate aim of The Newson Health Menopause Society is to improve the lives and future health of women and all who experience the perimenopause and menopause. I’m Lauren Redfern. I’m a medical anthropologist and I’ve been exploring the experiences of those using testosterone as part of their HRT treatment. In this podcast series, I’m going to be talking to guests from a variety of different disciplines in order to share knowledge and ultimately improve our understanding of the perimenopause and menopause.
Lauren Redfern [00:01:05] In our very first podcast episode, I asked Newson Health Menopause Society founder Louise Newson a question which was, ‘why menopause?’ Her response was one of two parts. Speaking about the transformative nature of perimenopausal and menopausal treatment, Louise explained that in her opinion, there are few arenas of healthcare where, as a consulting clinician, you’re able to see such a drastic and vast improvement in the reporting of debilitating symptoms from patients after the introduction of treatment, which in the case of perimenopause and menopause, would most likely be HRT. Louise also noted an inspirational lecture she attended, one that was delivered by our guest for today, Professor Robert Langer. Louise explained how after leaving that particular lecture, she felt inspired and moved to be part of something important, to be part of something, to use her own words, transformational.
Lauren Redfern [00:02:02] To provide a little context Professor Langer has over 30 years of experience consulting in and studying the relationships between hormonal therapies and a variety of different conditions, including cardiovascular disease, breast cancer, cognitive function and dementia, osteoporosis, and colon cancer. He has not only authored hundreds of papers detailing the relevant correlations between our hormonal health and the development of chronic conditions, he’s also acted as a principal investigator for game-changing national and international clinical trials. Professor Langer’s work importantly, however, is evidence based. His expertise has helped to address and challenge not only the mistrust but the misinformation that so often surrounds conversations on HRT. So with that little introduction, I’d like to welcome Professor Langer to the podcast. Obviously, I’ve introduced your work a little bit, but I wondered if we might start actually with you just introducing yourself to everybody listening and telling us a bit more about the work that you do.
Professor Robert Langer [00:02:57] Well, thank you very much, Lauren. I’m really pleased to be invited to participate in this activity. I have spent most of my career trying to see how we might improve health as women age and in fact, as both women and men age. Although I would say about three quarters of my work has focused on postmenopausal women’s health. I was the principal investigator for the Women’s Health Initiative, Vanguard Clinical Centre at the University of California, San Diego, throughout the entire primary study period, 1993 to 2005. So have quite a bit of background in that landmark study. Prior to that, I was one of the investigators for the first ever major clinical trial of hormone replacement therapy in postmenopausal women. The PEPI Trial, postmenopausal estrogen progestins interventions trial that was conducted about five years prior to the WHI. So I come at this from having been an investigator in some of the landmark studies in the field. I am currently the principal scientist and medical director of the Jackson Hole Center for Preventive Medicine in Jackson, Wyoming. I’m also an Emeritus Professor of family medicine and public health at the University of California, San Diego. And I am a member of the Board of Trustees of the International Menopause Society, as well as member of the Board of the Newson Health Menopause Society.
Lauren Redfern [00:04:34] You mentioned the WHI there, and I wondered if we could actually just for those listening who might not be familiar, just talk a little bit about the importance of that and obviously your role really leading on that trial.
Professor Robert Langer [00:04:48] Well, the Women’s Health Initiative, or WHI is to this day, the largest ever clinical trial of its kind. It involved a total of about 60,000 women in three overlapping studies. But for our discussion today, we’re focused mostly on about 30,000 women who participated in the hormone replacement trials. And those trials, again in the WHI are the largest studies of hormone replacement that have ever been conducted and probably ever will be conducted. The goal of those studies was really quite a leap of faith. It was based on lots of prior information from studies that were mostly what we call observational. In other words, not really strictly scientific tests, but just looking at the experience of women who had taken hormones and not taken hormones. And these were generally women who started hormones, as women typically do, right around the time of menopause. And those observational studies then followed those women for quite a number of years, some of them already prior to the start of the WHI – as much as 10,15 years or so. And almost uniformly, those studies showed that women who started taking hormones around the time of menopause had better overall health and in particular were protected against some of the major chronic diseases that women face, including heart disease and fractures related to osteoporosis. Some of the studies also suggested that there was protection against dementia and also protection against some bowel cancers. So based on that information but looking at the fact that when the study was designed in the early 1990s, the baby boom generation of women were about to go through menopause. The U.S. National Institutes of Health decided to commission a study, the WHI, that would see whether what we had found in early menopausal women would actually play out to be similar protection for women who were quite a bit older when they started hormone replacement, so that it might be kind of a uniform preventive strategy for women after menopause. And that was the fundamental concept of the Women’s Health Initiative with things that we had seen pretty consistently, almost to the point where there was no need to test them further to be good in younger menopausal women would also hold true for women who started many years after menopause as much as 10, 12 years after menopause. And so by design, the Women’s Health Initiative didn’t test what we thought we already knew, but rather it enrolled women who were selected to be, on average, at least a decade past menopause or more. So the average age in the study was 63 years old, and on average the women were 12 years postmenopausal. 70% of the women were between the ages of 60 and all the way up to 79 when they started this study.
Lauren Redfern [00:08:13] There’s so much I want to pick your brain about, and I want to come back specifically to those associations that you mentioned about the beneficial impact of HRT on factors such as cardiovascular disease, osteoporosis, fractures. But just to spend a bit of time briefly on that and the evidence base there for starting hormonal treatments later, postmenopausal, would you talk us through a little bit about the difference in those findings and why starting HRT, perhaps younger in the perimenopausal phase, is seen as more beneficial as opposed to starting later in life?
Professor Robert Langer [00:08:47] So the reason it was thought that we might test benefits for women who were well past menopause came primarily from what we knew about studies of heart disease, where in general studies looking at people with heart disease risk factors showed a kind of a stepwise gradient where the greater the burden of risk factors, the greater the benefit of the intervention. Now, for the diseases that we were trying to prevent, you know, certainly heart disease, which is the major killer of women worldwide, it seems like the older you get, the greater your burden of risk factors. Age itself is a risk factor. But then a lot of the other risk factors also tend to accelerate with age, like change in body weight, change in handling of blood sugar, risk of diabetes, change in cholesterol levels. So the idea was if this stuff worked well for people who had minimal risk, it might work even that much better for people with a much higher burden of risk factors.
Lauren Redfern [00:09:58] And in terms of findings that you came out from that, what were you able to deduce?
Professor Robert Langer [00:10:02] Well, in fact, contrary to our hope and expectation, the results of the Women’s Health Initiative hormone trials very clearly demonstrated that starting later was not helpful. If anything, it was neutral. And the older a woman got – the further she got from menopause – the greater the potential harm, particularly for heart disease. In terms of some of the other factors like protection against fracture, HRT still did well at later ages, but at the expense of potential harm in cardiovascular disease. So the conclusion from the clinical trials was that it is not to be recommended for women who are well past menopause. Because the overall downside, the potential harms likely outweigh the protection. But what we learnt further in the WHI and consistent with all of the studies that went before, as well as the studies that have come since, is that starting around the time of menopause, or in perimenopause, and even all the way up to about ten years after menopause continues to be beneficial for most women. It’s not an absolute hard cut-off if you’re ten years to the day after menopause, but something around that time, the switch goes from benefit to risk. And so one of the other remarkable contributions of the Women’s Health Initiative, together with another similar study that was conducted in women who already had heart disease testing some of the same things is that we learnt that there is a background of atherosclerosis. I know that’s a big word to throw around, but of cholesterol deposits in the major arteries that supply the heart, that seems to change over time with the lowering of estrogen levels after menopause. And so what happens is that over several years and again, probably reaching a critical threshold around ten years after menopause, the deposits in those critical blood vessels get so clouded over with some inflammatory stimulants and other things that generally don’t accumulate when there’s a lot of estrogen around. So that after that period of time, when you reintroduce estrogen, you can actually trigger some unroofing of these cholesterol deposits that can cause heart attacks. On the other hand, if a woman is continuing to have reasonable amounts of estrogen coursing through her arteries after menopause, as she might, if she is taking hormone replacement therapy or menopausal hormone therapy, then that back- up of cholesterol tends not to happen and that danger does not occur.
Lauren Redfern [00:13:37] I mean, this was fascinating for me, actually, because I read the paper you published last year, I think it was titled The Role of Medications in Successful Ageing. And you presented in there actually the percentage of deaths accounted in women over the age of 50. And I was really surprised actually that 45% of deaths, I think you said, is due to cardiovascular disease, making it the leading cause of death for women in mid and later life. And you do go on to highlight that good level of evidence that there is though, for the beneficial associations of HRT in reducing risk or improving outcomes when it comes to cardiovascular health in women. But specifically this. Is that correct? Starting before the age of – I believe it was 60. And I just wanted to clarify that of those ages.
Professor Robert Langer [00:14:18] Yes, you’re entirely correct. So, you know, overall, the balance of benefit versus risk seems to change around the age of 60. And that’s really just kind of shorthand for about ten years after menopause. Since in most developed countries, the average age of menopause is around 51 or 52 years old. And as I mentioned earlier, it’s not a hard and fast rule. It’s not, you know, ten years to the day after your last period, but rather it’s around that time. And there is sort of this soft progression of changes in the body over that time. It’s also, I think valuable to mention, I outlined what we believe now happens in the coronary arteries related to the changes with low amounts of estrogen in the system. There are estrogen receptors in almost all key organ systems in a woman’s body, and many of those same kinds of changes happen in other parts of the body also. So that, you know, the decline in estrogen levels sets women up for some more rapid changes, say in bone, for example, where she begins to rapidly lose bone density, which then leads to osteoporosis and the linked risk of fracture with brittle or thin bones. Similarly, there are estrogen receptors in the central nervous system, and we believe that there may be some impacts there as well for lower levels of estrogen. And in the studies that preceded the WHI, those observational studies, again, there was strong and consistent evidence that women who stayed on hormones for many years past menopause had lower rates of dementia and other thinking issues in later life. The WHI had a sub study to look at that, but it was restricted only to women who were age 65 and older when they entered the study. And just as for the heart attack risk, that was probably too late. The damage was probably already done. But fascinatingly in the WHI, looking at 18 year post study follow up data, there was again a reduction in deaths related to dementias and those kinds of cognitive problems, which again puts the WHI consistent with the literature that preceded it.
Lauren Redfern [00:17:13] I mean, that’s fascinating. And it is something that you highlight in that paper as well as specifically, I mean, I wanted to touch on both of those the role of a possible beneficial association between HRT and fractures and osteoporosis, which I think we are becoming more familiar with. It’s becoming more a part of the conversation about benefits of HRT, but this link between possible benefits with development of dementia, I mean, that’s fascinating. And I just wondered if you could talk us through a little bit as to why we think there may be a beneficial association. Is it to do with these estrogen receptors that are thought to exist within the nervous system and brain?
Professor Robert Langer [00:17:48] Well, we don’t know as much as we would like to about that. There is speculation in a number of areas. One is that it may be related to protecting the neurons in the brain, in the central nervous system, because estrogen has been shown in animal models and in more detailed lab bench experiments to be protective of neurons in the central nervous system. Obviously, we can’t do those kinds of experiments in living, breathing women, so we don’t really have as much of an idea as we would like about an underlying mechanism. But there is consistent biology that would suggest that to be the case. The other possibility that we have probably clearer evidence for is that just as estrogen protects against damage in major organs like the heart by preventing cholesterol deposits, maintaining better circulation, we also know that estrogen has an almost immediate kind of a salutary effect on blood flow in blood vessels. And so it may be that some of what we’re seeing in terms of protection in the central nervous system is simply due to maintaining better circulation in the brain over time.
Lauren Redfern [00:19:17] And part of the reason I wanted to touch on these positive associations that you outline in this paper is because I think, as I mentioned in the beginning in this introduction, that there is still a lot of misinformation when it comes to the outcomes from certain clinical trials, specifically around breast cancer and heart disease, which we’ve touched on a little bit. But obviously I wanted, if possible, to address some of those associations and misinformation that continues to circulate regarding that relationship between HRT and the development of breast cancer. And if you could provide a bit more information on that as to where that stems from and also what the evidence is telling us currently.
Professor Robert Langer [00:20:01] I think that’s an absolutely critical question because, in fact, the reason that most women and many physicians have stayed away from hormone replacement since the WHI first reported results in 2002, going on 20 years this summer, is because of the fear of breast cancer – a very, very real fear and for most women, probably the thing that they fear the most. So it’s critical to understand what the WHI actually found for breast cancer. First off, even though the headlines blared that hormone replacement caused breast cancer, in fact, that was not statistically true. The finding for that did not meet the standard tests that we use for statistical significance, which is usually when we would draw a conclusion and further, when results were published a few years later, based on collecting all of the information that was available before we asked women in the study to stop taking the study medication and using the kinds of adjustments accounting for other breast cancer risk factors that we typically do when we do a complete analysis of data like this, even with that, in the only paper that’s actually published those results again, there was no statistically significant finding of an increase in breast cancer in that first part of this study that ended. And it’s important I qualify that, too. So that first part of the study, the one that triggered all of the international headlines, was testing estrogen as conjugated equine estrogen, sometimes known as Premarin. And for women who had a uterus to protect, a progestin, and in this case, it was medroxyprogesterone acetate, sometimes known as Provera. And that was the only medication that was tested in that part of the study. One of the issues has been that those results, as frightening as they ended up being, were then quickly generalised to all other treatments without equivalent information. And that’s something we can come back to, but to stay on this main point here, that finding, again, not statistically significant, was really what triggered the tremendous march away from HRT or MHT. Now, two years later, the second part of the hormone studies in the WHI that was being conducted in women who had had a hysterectomy before they joined the study, so didn’t need that second medication, the medroxyprogesterone acetate, that study found exactly the opposite effect. Instead of increasing breast cancer, that study with just conjugated equine estrogen alone, showed a reduction in breast cancer over time, that was statistically significant. So it suggests to us that the difference is actually the progestin. And we know that all progestins are not alike in the breast. We know that the medroxyprogesterone acetate, in fact, is – of the progestins that we use in women – the one that is probably the most inflammatory towards the breast tissue and thereby could cause some increase in breast density and potentially trigger more looking for breast cancers. Now, the reason that that’s important in thinking about the WHI data is twofold: one is that other progestins or progestogens may not have that effect, and two, is that the finding of increased breast cancer in the WHI CEE plus MPAR was starting at about three years into the study. We know from lots of research that it takes something between seven and nine years for a breast cancer to go from the earliest initiated cell to a size where it’s clinically detectable. So that means that the breast cancers that were seen in the WHI were probably not caused by the medication that the women took in the WHI but they may have been discovered earlier because of that effect of increasing breast density, which triggers the search with more repeat mammograms and breast ultrasounds and things like that for breast cancers. And so these may have been pre-existing breast cancers that were discovered earlier as a result of these women having been put on this very potent progestin in the WHI study.
Lauren Redfern [00:25:46] It’s really interesting to hear you note the progesterone as opposed to the estrogen. And I think that that’s often I found, even in my own research, that people are still quite surprised by that, that there is this sort of association with the estrogen component as being related to development of breast cancer.
Professor Robert Langer [00:26:02] Well, just to underscore that, it’s critical to understand that the estrogen alone part of the WHI did not show any increase. It showed a statistically significant decrease in breast cancer. And just as I pointed out that there are differences in progestogens, so too there are differences in estrogens. And it’s possible that the estrogen that we tested in the WHI is more likely to cause protection reduction than other estrogens might be. And that has to do with some differences in chemical composition between the estrogens, but we don’t have equivalent data for any other estrogens.
Lauren Redfern [00:26:53] So obviously we’ve seen and it’s referenced in your paper that there can be a beneficial protective effect from use of HRT on the development of osteoporosis and fractures in later life. Obviously, we outlined a little bit that starting HRT later and the possible not so great effects that that would have on cardiovascular health, when it comes to the development of osteoporosis for somebody later in life if they’ve not used HRT, is there any evidence, or could you talk us through the evidence really? Is it similar to suggest that it would not show to be beneficial if started later, that it’s only got that beneficial impact on bone health if started sort of earlier?
Professor Robert Langer [00:27:36] No. In fact, the results show clearly that HRT is beneficial against fractures basically at any point, but with the downside of potential adverse effects in other organ systems, particularly for heart attacks and even more probably for strokes. That’s not to say that there aren’t circumstances where a woman beyond ten years after menopause might not be safely started on HRT. A well-informed physician who is actively conducting practice in this field might in fact do that. I do in my practice in some rare circumstances, and the fracture protection does accrue at any point. Of course, the longer a woman has gone past menopause, if she hasn’t had anything else to protect her bones, and if she is one of the high percentage of women who does lose bone density after menopause, then, you know, she’s starting from a higher risk point. But fracture prevention does happen at any age.
Lauren Redfern [00:28:52] Well, it’s fascinating. And I suppose it comes down to that of working with your clinician, where possible, to be able to find an outcome that works best for the patient in their circumstances. Something I’ve started doing with ending in this podcast is just asking guests like yourself that have kindly joined me to talk about such fascinating topics because I could honestly talk about your work for hours, it’s just if you have any take home messages to anybody listening, anything that you’d like to emphasise because we’ve covered quite a lot, but I wonder if there’s anything in particular you’d really like to pull out and emphasise from the points we’ve discussed?
Professor Robert Langer [00:29:21] Yes, I think it bears tremendous emphasis because there is so much popular press and to some degree medical literature to the contrary, that the WHI did not show a statistically significant harm from breast cancer and that fear of breast cancer with HRT is, to a large degree, unfounded and certainly hugely blown out of proportion. So women should not think that HRT is out of the realm of possibility because of a fear of breast cancer. That’s just not true. And I think the other very important point is that for women starting the way that we typically would start women on HRT, around the time of menopause for treatment of menopausal symptoms like hot flashes, night sweats and irritability and other things from the dramatically fluctuating levels of estrogen that happen as the body is starting to shut down its production, women who start then and have good reasons not to stop are likely to experience better health in the long term. And that is something that, again, has not really been in the popular consciousness since 2002 with that first misleading report from WHI.
Lauren Redfern [00:31:06] And I am hopeful as well that the work that you’re doing and continuing to publish is helping us get there. So I want to thank you so much for spending this time chatting with me, and I hope that you’ll come back because there’s so much more that we can talk about.
Professor Robert Langer [00:31:17] Well, I really appreciate the opportunity to participate in this effort, Lauren, and I thank you very much for having me as a guest. I’d be happy to come back.
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