What Happened to HRT? The Women's Health Initiative Deep Dive

This week we tell you what the Women's Health Initiative actually studied, why the hormone therapy trial was stopped, and how the headlines shaped menopause care for decades.

The Women's Health Initiative was the study that made a generation of women toss their hormone therapy in the trash. Co-hosts Erin Stein and Dr. Gillian Goddard dig into one of the largest and most comprehensive studies of women's health ever done: more than 160,000 women, multiple clinical trials, an observational study, and millions of stored specimens that researchers are still mining today. We break down what was tested (hormone therapy, low-fat diets, and calcium plus vitamin D), and why it was never about treating menopause symptoms.

We explain why the hormone therapy trial stopped, share the real numbers behind the breast cancer headlines, and talk about what the real data. We also cover the lasting fallout, including a generation of women whose menopause symptoms went untreated, and what all of this says about how we fund and study women's health. 

References:

Facts about the Women’s Health Initiative: https://www.nhlbi.nih.gov/science/womens-health-initiative-whi

The Baseline Monograph for the Women’s Health Initiative explains study design and procedures, and all the components: https://www.whi.org/doc/WHI-Baseline-Monograph-All-Sections.pdf

For one critique of the study’s design: https://www.sciencedirect.com/science/article/pii/S0015028205034229

2005. Klaiber, E.L., Vogel, W., Rako, S. A critique of the Women’s Health Initiative hormone therapy study. Fertility and Sterility. DOI: 10.1016/j.fertnstert.2005.08.010.

We take a moment to remind you that while this is a medical discussion, it is not providing a diagnosis or treatment or any medical advice. The only way to get a diagnosis, treatment or medical advice for your particular condition is through a discussion with your doctor.

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Visit www.thesavvypatient.com/podcast for episode transcripts.

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Get your copy of The Hormone Loop by Dr. Gillian Goddard wherever books are sold.

This episode was produced and edited by Erin Stein. Music: “All We Live For (instrumental)” by Wolfclub licensed through Audiio.com. Intro and outro edited, and video created, by Ian Mayer. The Savvy Patient logo by Amanda Spielman.

TRANSCRIPT

Gillian Goddard: Hello and welcome to The Savvy Patient.

Erin Stein: Hi everyone. We're going to do something different today.

Gillian Goddard: Gonna be kind of like a history lesson.

Erin Stein: We're doing it because I thought it would be interesting. 

Gillian Goddard: Ha ha ha.

Erin Stein: You may or may not disagree with my interest in it. But we're going to talk about the Women’s Health Initiative.

Gillian Goddard: Yes, what it is, what it isn't.

Erin Stein: And you've probably heard of it because it's talked about all the time.

Gillian Goddard: But no one ever gets into the details. People don't understand necessarily how it started, what it was, what it became, which is something completely different from how it started out.

Erin Stein: And that it keeps going in many ways. 

Gillian Goddard: It does. It does.

Erin Stein: It's important and interesting. Which again, you may not agree with me, but it's such a key foundational study for women's health in general. And it gets constantly talked about. And probably how you've heard about it, is the controversial finding that someone made at the end of the first part of it about hormone therapy and its risks and we will obviously talk about that. But I think it's worth just talking about the study itself because it was… First of all, it was huge.

Gillian Goddard: Huge and kind of the first of its kind.

Erin Stein: Still largest and most comprehensive for women's health and interestingly enough, for minority women's health.

Gillian Goddard: Yes, that's true.

Erin Stein: They made a point to include women of different backgrounds and I did not realize that until I was doing this little deep dive. And I think that's fascinating as well because they didn't want to just study white women, which was nice that they thought about that back in the nineties.

Gillian Goddard: It was nice. The other thing that I think is really interesting about the Women’s Health Initiative is anytime you read research, especially if you're reading things like review articles or meta-analyses, which are sort of the types of data that we often like to rely on when we talk about how our bodies work and what kinds of interventions might affect our bodies. So anytime you're talking about women's health, the Women’s Health Initiative study is often a lion's share of the data that's included in those meta-analyses because there's just so much data. And this data that's come out of this study has been sliced, diced, and published kind of every which way.

Erin Stein: I'm just going to start with some facts that I'm going to throw at you and you're not gonna remember, but I still think it's interesting that this was conceived in the early nineties, in 1991 and Congress appropriated funds in ninety-two and they started enrolling women in the fall of 1993 and they enrolled women through the end of 1998. And this was a multi-institute group of scientists developing this study; this wasn't like one doctor or scientist said, ‘I want to do this thing.’ It was a whole giant group of…

Gillian Goddard: Yeah, a consortium.

Erin Stein: That's a good word. It was a consortium of National Institute of Health Scientists, but also many other scientists. And they sought information from the public and ideas, but the goal was to study postmenopausal health in women, specifically cardiovascular disease, breast and colorectal cancer, and osteoporotic fractures.

Gillian Goddard: Yep. I think that that's really important. People think that the Women’s Health Initiative study was a study of how well hormone therapy treats symptoms, but it was not about symptom management at all. And to be enrolled, you didn't have to have symptoms. You just had to be a woman within a certain age group, actually.

Erin Stein: Yes, and it was not perimenopausal women.

Gillian Goddard: No, it was not. It was largely women who were many years past menopause.

Erin Stein: Yes, fifties, sixties, seventies.

Gillian Goddard: The average age was in the sixties.

Erin Stein: Yeah. And there were several smaller studies done before, which fed into what they decided to look at. That's something that is common, which is why one study doesn't mean much, but when there's multiple studies and then you do a bigger study based on what you found in those smaller studies, that's how this all works.

Gillian Goddard: Yep.

Erin Stein: And they were gonna study different preventative therapies and how those impacted overall health. So there's an alphabet soup of different organizations that were involved. There were nine advisory committees, a steering committee, there was a data and safety monitoring board. Like, this was a huge deal, and many, many people worked on it and were involved,

Gillian Goddard: Yes. Yep.

Erin Stein: And there was a lot of oversight.

Gillian Goddard: It's interesting because some of these are things that all studies have. So all studies of pharmaceuticals. Anytime you're giving people drugs, those studies have a data and safety monitoring board. And all studies, even retrospective studies require IRB approval, which is the institutional review board, which is basically to make sure that you're conducting your research ethically.

Erin Stein: Yes.

Gillian Goddard: So obviously this had much more than that, but yep.

Erin Stein: This was a larger scale of that, so here's why this is such a big deal. They enrolled 161,809 women.

Gillian Goddard: And not all of those women were part of the randomized trial that sort of began. 

Erin Stein: I'm gonna get to that next, Gillian!

Gillian Goddard: Sorry!

Erin Stein: Those were the overall participants, and as we said, this was the largest and most comprehensive set of women's studies, largest study of minority women, and at the time the participant group closely mimicked the proportions of the US population at the time. So the number of Black women in the study echoed the number of Black women living in the US at the time. Again, this was the ’90s, it wouldn't be the same as today. But what I didn't realize until I was looking at it is that as you were just about to say, this was not one thing. This was clinical trials and observational studies. 

Gillian Goddard: Yes, that's correct.

Erin Stein: And the clinical trial had two parts. Well, actually, kinda three, right?

Gillian Goddard: Technically kind of three. Yeah.

Erin Stein: And within one of those even, two, you know, we'll do… okay, we'll just get into it. Listen, there's a lot of details. 

Gillian Goddard: There is. There is.

Erin Stein: So the clinical trial portion of this had 68,133 women.

Gillian Goddard: Which is wild.

Erin Stein: Yeah. All aged fifty to seventy nine years.

Gillian Goddard: At enrollment, I just wanna point that out. So you could enroll in the clinical trial at the age of seventy nine. And I think that that's really important.

Erin Stein: And it's important to say they were postmenopausal.

Gillian Goddard: Yes, yes, a hundred percent. Part of the criteria.

Erin Stein: That is particularly relevant when we get to the problems with the conclusions they came to.

Gillian Goddard: Yes, yes, exactly, exactly. But they were kind of divvied up in all these different clinical trials, right?

Erin Stein: Yes. So I'll go into those numbers because I just think it's helpful to hear all these details to comprehend what this actually was. 

Gillian Goddard: The vastness of this.

Erin Stein: The vastness, exactly. So the clinical trial portion was testing three preventions. Hormones…

Gillian Goddard: Yep, that's the one we talk about all the time.

Erin Stein: Yes. A low fat diet, and calcium and vitamin D supplementation—taking them together. So for the diet they had 48,836 women enrolled to adjust their eating pattern ;so random assignment, some of them adjusted to a low-fat eating pattern and some just did what they were doing. In the diet studies specifically, they were looking at breast cancer, colorectal cancer, and coronary heart disease. They wanted to see if the diet affected any of that.

Gillian Goddard: Yep.

Erin Stein: Then a second portion, 27,347 women, were in a study of hormone therapy.

Gillian Goddard: Yes.

Erin Stein: Now, in this study, they separated those women into two groups. Some had had hysterectomies, so they did not have a uterus, and some still had their uterus, and they essentially treated those two groups as two separate studies within this study.

Gillian Goddard: Right. That's right. And at the time hysterectomy was a much more common treatment for all kinds of Lady Troubles.

Erin Stein: Lady Troubles. Thank you. With the hormone therapy trials, they were looking at coronary heart disease primarily,

Gillian Goddard: Mm-hmm.

Erin Stein: And then they were looking at hip and other fractures.

Gillian Goddard: Yep.

Erin Stein: And then they were looking at breast cancer. It was not the primary thing they were studying.

Gillian Goddard: And the reason they were looking at breast cancer was because They already kind of knew that women who took hormone therapy had a slight uptick in breast cancer risk, and so they were looking to quantify it. But again, I think it's really important to point out they were not looking at symptoms and how effective hormone therapy was for managing symptoms. And the reason they were not looking at that is because they already knew that. That had already been adjudicated, so to speak, in the literature. There were already several studies that showed that hormone therapy was an effective treatment for menopausal symptoms.

Erin Stein: Yes. And we always talk about this, but these studies were randomized and double blinded trials. So they were taking a placebo or they were taking the hormones and they didn't know which they had.

Gillian Goddard: Yes. And the people giving them didn't know either. The investigators didn't know which they were receiving. And the all the hormone therapy was provided by a single pharmaceutical company, Wyeth Pharmaceuticals and they all got the same—there was no customization in this in this study. So the women without a uterus got conjugated equine estrogen or a placebo, without progesterone. And the women with a uterus got Prempro, which is a combination of conjugated equine estrogen and medroxyprogesterone. And these were all oral. These were all pills. Which was the standard of care at the time.

Erin Stein: Yes, and so if you were getting the placebo, you would also get a pill. It just didn't have any of these things in it.

Gillian Goddard: Exactly.

Erin Stein: Why don't you explain why those with the uterus got the progesterone element and post-hysterectomy participants did not?

Gillian Goddard: The thinking at the time, and kind of our current thinking we can talk about later, but the thinking at the time was that estrogen was the active ingredient here. Estrogen was the thing that was going to potentially prevent heart disease. It was the thing that was going to potentially prevent hip fractures. And so they really were interested in the impact of the estrogen. And women without a uterus can take estrogen alone. Women with a uterus should not take estrogen alone because it can cause an overgrowth of the uterine lining, which can increase the risk for endometrial cancer. And so they were given the progesterone to protect the uterine lining. They didn't think that that was going to be the piece that was going to have these effects. They thought that it was sort of there because you had to have it.

Erin Stein: They were studying the estrogen, but they needed the progesterone for safety.

Gillian Goddard: Exactly. Exactly.

Erin Stein: So those two were the initial clinical studies. And then they took 36,000 of those women from those two groups randomized at their one-year anniversary, and then did a double-blind comparison of taking elemental calcium plus vitamin D daily versus taking a placebo. And they were really studying fractures and colorectal cancer secondarily. So that is a lot that they were studying, and they were following up with these women. Every three years, four years, five years, it depends on what outcomes they were looking at, but they followed up with them for years, is the point. This was not a short six-month study or even one year. They repeatedly followed up with these women. And so I think that's interesting because when you are looking at the data, there's a big difference between going from fifty to fifty five and going from seventy nine to eighty four with health outcomes, okay?

Gillian Goddard: A hundred percent. Yes.

Erin Stein: I think your age would be a factor, is I guess what I am saying.

Gillian Goddard: And that was kind of on purpose because some of these things that they wanted to look at are things that don't happen to women in their fifties very often. Talking about cardiovascular disease primarily. But hip fractures too. And those things do happen more as we age. And so, to some degree, the reason they set up this study the way they did was to be a little bit of a shortcut to increase the number of events they expected to see and reduce the amount of time that they needed to follow people, even though they ended up following them for a very, very, very long time.

Erin Stein: Yes. Some other details that I thought was interesting to know is how they gathered the information. Because they were rigorous about it, as they should be with this big a study and this much staff the participants did do some self-reporting, obviously on their demographics and their medical history, their diet, behavioral factors. But if they were taking medication, they would bring the pill bottles in and those dosages and medications were examined directly.

Gillian Goddard: That is typical protocol in studies.

Erin Stein: That's actually reassuring. it is.

Gillian Goddard: It is. They even do pill counts in clinical trials to see how many doses of the study medication people are missing.

Erin Stein: That's good. Then for the dieting study, they did four-day food records with as we've discussed before, only a 24-hour recall required so that people could remember what they had actually eaten. But then they did a ton of clinical measurements, and this is why this is such an important data set that we collected. They took blood serum, plasma, they got how do you say that? Hemo-?

Gillian Goddard: Hematocrit.

Erin Stein: Hematocrit, white blood cell count, platelet count; they did ECGs, pelvic exams, pap smears, and endometrial aspiration, which I don't like the sound of.

Gillian Goddard: So basically they use this little straw put it up through the opening of the cervix and they sample the endometrial cells. It's also sometimes referred to as an endometrial biopsy and it is not the most pleasant experience as one might imagine.

Erin Stein: Yes, so that or an ultrasound was done, and they did x-rays and urine samples, and they also did cognitive assessments for women in the hormone trial. That is a lot.

Gillian Goddard: Yes they did. Yes, they did.

Erin Stein: That is a lot of data that they repeatedly got every one to three years from all these participants.

Gillian Goddard: Yes.

Erin Stein: So that is why A, the study was so important, but B, I did not necessarily realize this, people are still doing new studies using the same data. As you referenced earlier, slicing and dicing it, but they collected 5.3 million specimens.

Gillian Goddard: You can go back and test the blood samples do new assays on the blood samples. So check for new things. You can do new staining on the tissues that were collected. You can subject the imaging to new analysis, including—this is an area where imaging in general is an area where medicine has really adopted AI. So you can actually go back and not just use the information that they already had, but use the cells and tissue that they collected and do new studies on it. And this is something that's done in medicine all the time. It's just, you have to have one of these repositories with all of this stuff.

Erin Stein: Many people are still proposing new studies and analyses today. And with all this information, over twenty-six hundred papers have been published, studies and analyses using this data. And the website says they're still collecting data and you can still create new studies by reaching out to the volunteers from the study.

Gillian Goddard: Yep.

Erin Stein: Pretty amazing.

Gillian Goddard: That is true. However, the funding was cut by the current administration and so there is less funding to continue the data collection, but the data's all still there and if you can get funding to do it, you can still do all kinds of things.

Erin Stein: We went through all the clinical trials. There was also an observational study of 93, 676 women.

Gillian Goddard: Just kind of seeing naturally what was happening to them and how things were changing as they were aging.

Erin Stein: Yeah, so frequent check ins on their overall health, right?

Gillian Goddard: Yep. Yep. All the participants in the randomized trials, then when the randomized trials ended, got put into the observational trial.

Erin Stein: Right.

Gillian Goddard: So if you were in the hormone therapy trial, and we'll talk about what happened in that trial in just a minute, but if you were in that trial when those trials ended, you got automatically put into the observational moving forward.

Erin Stein: So this was a huge study with many, many factors going on in all parts of it.

Gillian Goddard: In our current climate around women's health and women's health research, it's hard to appreciate now, more than thirty years later, a movement was going on at this time to put resources into studying women's health. So the Women’s Health Initiative study started enrolling patients the same year that it first became required to include women in studies that received funding from the NIH, nineteen ninety-three. Which is why what happened is kind of so tragic because it had such a long term effect on how we study women.

Erin Stein: Yes. And so all of this background is to say this was a great thing. This was a really important thing. It continues to be important that we did it and continue to do it. The Women’s Health Initiative was not a bad study. However…

Gillian Goddard: However.

Erin Stein: Some human elements. How do you wanna describe what happened with the hormone trial?

Gillian Goddard: Yeah, so there was this safety data monitoring board and what their job is, is to get the big global view of all the data and look for signals that suggest that the interventions might not be safe.

Erin Stein: Right. And they reviewed that every year during these clinical trials.

Gillian Goddard: Yes and that is common in clinical trials, particularly clinical trials of medications. There are always people kind of high up looking at the data, they're really looking for two things. Looking for signals that the intervention might not be safe, and looking for signals that the intervention might be more effective more quickly than we thought and we can already come to conclusions, then we can stop looking.

Erin Stein: Mm-hmm.

Gillian Goddard: And so what happened in the Women’s Health Initiative study is that in the study of women with an intact uterus, they started to see an uptick in cardiovascular events. And I think that's important because that is not what the headlines were yelling about.

Erin Stein: Yeah.

Gillian Goddard: But it is why the study was stopped. The study was stopped because there was an uptick in cardiovascular events that was statistically significant in the group receiving hormone therapy. The uptick in cardiovascular events was statistically different between the group that got hormone therapy and the group that got placebo. This uptick in cardiovascular disease was not seen in the group of women who were just getting estrogen who'd had hysterectomies. And so they actually let that trial continue. It was big news when they stopped the trial. It was like on every, national news program. It was all over the place. About a year later they publish the data. But in the meantime, oftentimes what happens is different levels of data come out over time because as they're working on the data, they start presenting it at different meetings. They release press releases about it, all before they actually publish the big overarching study. And what was getting talked about in the news media was actually not the cardiovascular disease, but this small increase in breast cancer risk between the two groups. And that is not how they were talking about it. They were not talking about it as a small increase. They were talking about it as though it were catastrophic. The effect of that was really, I talk about this often, en masse women were throwing their hormone replacement in the garbage, like coast to coast.

Erin Stein: And what was the actual data? I mean, what were the actual numbers? how many people showed incidences of breast cancer?

Gillian Goddard: So when you dive down into it, it is roughly the difference between five in a thousand cases versus four in a thousand cases. So four in a thousand women receiving the placebo developed breast cancer, five in a thousand women receiving the Prempro developed breast cancer. So really, really tiny, but a 25% relative increase, and that was what was making headlines.

Erin Stein: That's why percentages are dangerous. 

Gillian Goddard: Yes, this is why statistics can be dangerous.

Erin Stein: When you hear, well, one extra woman, you know, you don't want any extra women. But also my question would be how many of those women had a family history of breast cancer? There are other factors to look at. 

Gillian Goddard: Yeah. Yeah.

Erin Stein: You can't draw that automatic conclusion even if the data were more significant than it was.

Gillian Goddard: Yeah. But when you're talking about one extra woman out of a thousand… It's not a very big increase, is the first thing. The other thing to remember is that we are now just talking about the potential risks and there was no discussion in all of this conversation about the potential benefit.

Erin Stein: Right. They were actually studying benefits, not risks.

Gillian Goddard: That's correct. They were only monitoring breast cancer cases because they had seen this signal of this slight uptick in previous studies.

Erin Stein: And again, I would wanna know if that extra woman in those thousand women was on the older end ff the scale.

Gillian Goddard: Yeah. And people have since done lots of different sub analyses because when the study came out, the headlines in the press for like general audiences was all about breast cancer risk, but the conversation—and when this study came out, I was not yet in med school, but I was about to be—the conversation among experts was already focused on where the problems with the study may have been because this was an unexpected outcome. And anytime you have an unexpected outcome that's not consistent with the previous data you have to go back and explore what was different about this study. And what was different about this study was the age of the women who were enrolled. Because these women were not given hormone therapy to treat menopausal symptoms. They were given hormone therapy under the idea that it would prevent cardiovascular disease and osteoporotic. By the way, it did prevent hip fractures. Just as an aside, it very clearly positively affected bone density. And so when that's why you're giving it and you get this unexpected result, that is not the same as women who are taking hormone therapy to manage their symptoms. And may be happy to take this risk depending on the severity of their symptoms, because every conversation about a treatment should be about the risks versus the benefits. 

Erin Stein: Yes.

Gillian Goddard: And since the benefit they were looking for was not there, they stopped the study.

Erin Stein: Again, they stopped the study because of cardiovascular concerns.

Gillian Goddard: Yes. Correct.

Erin Stein: Not breast cancer concerns. And yet, all the headlines on the media and certain experts really latched onto that breast cancer element and presented the data in a way that made it sound like a much bigger deal than it was and also as if it was a conclusive cause and effect relationship.

Gillian Goddard: Correct. Correct.

Erin Stein: And that was not the case.

Gillian Goddard: Then what happened, and I think it's important to understand this too, is now the group doing the data monitoring and safety, they're all keyed up, right? So they're watching this other group of women like a hawk. They start analyzing the data more often and so they actually saw a non-statistically significant uptick in the incidence of stroke in the group of women who did not have a uterus. And they had some discussion about stopping the study, decided not to stop it, and then came back I think it was six months later and said, actually no, we're just gonna stop it. We're just gonna stop this study. So when you do these studies you actually put in some preset thresholds at which you will stop the study. So you say ‘if we see X, we will stop the study.’ They actually stopped the study in the women who did not have uteruses who were just taking estrogen without any of the data meeting any of their preset metrics. They just got spooked. and those women did not have an increased risk in heart disease. They had a very small increased risk of stroke and again the same kind of around the same magnitude of increased risk of breast cancer, but not as big as the small increase they had seen and not until women had been taking hormone therapy for more than five years. And that five year number is important.

Erin Stein: They were looking at cardiovascular disease and one of the critiques I pulled up said they were also weren't necessarily screening as thoroughly as they could have, perhaps, for example, like plaque already starting to build up.

Gillian Goddard: Yeah. Yeah.

Erin Stein: You know, early signs of cardiovascular disease. These women might have entered the study with that already pre-existing. They did not screen for that. And so that's another complication here. 

Gillian Goddard: Yep. That's correct.

Erin Stein: Again, it’s why it's always difficult with these things to say this caused that, because you really usually can't say that. But especially with this many women, with this many individual factors and health history that was not all screened for, and different ages, again, our overall health changes a lot in our later decades, from decade to decade. 

Gillian Goddard: Yes it does. Yes it does.

Erin Stein: That's a major factor. So all of that is to say, this was a groundbreaking huge study and then some unfortunate headlines overstated some conclusions that were not really conclusions they could be making. Fair?

Gillian Goddard: Yeah, fair, totally fair. And it is difficult to overstate the chilling effect that this study and these particular outcomes and the way they were reported had on research into women's health, conversation about menopause. It is virtually impossible to overstate how detrimental this outcome and the reporting about this outcome was. We're still feeling it. for sure. A hundred percent.

Erin Stein: Yeah, it created a panic. It created a panic. And breast cancer is still a scary thing, but as I talked about with my own experience, it's a lot less scary than it used to be. It was quite a bit of a boogeyman back in the day. You were terrified to get breast cancer because treatments weren't great, outcomes weren't great, we were not catching it early and able to treat it early. It was very scary for a long time to get it. And so the last thing any woman wanted to get was breast cancer.

Gillian Goddard: Even though heart disease then and now was much more likely to be the thing that women died from.

Erin Stein: Yes, again, please listen to our episode about your heart health, because it is so important. But breast cancer is the villain. It was the scary, bad guy that everyone panicked about and wanted to avoid. And as much as there's this push now that estrogen is good and we all need more estrogen. Slather it on your face, stick it everywhere, take it in a pill. There were books coming out saying estrogen was evil and bad and you should never take estrogen. 

Gillian Goddard: Yeah. Yeah. Yep.

Erin Stein: The pendulum swung back to the dark ages and we are clawing our way back out essentially.

Gillian Goddard: Well, we're experiencing an overcorrection and maybe someday we'll come back to the middle ground would be my assessment of this current situation.

Erin Stein: Well, yes, but we're always preaching middle ground here.

Gillian Goddard: This is true. This is true. One of the things that is good that came out of all of this is that they developed new formulations of estrogen. At this time, conjugated equine estrogen, which is basically estrogen that is collected from the urine of pregnant horses. 

Erin Stein: Fun fact.

Gillian Goddard: Fun fact. It was what most people were taking and so it wasn't weird that they were using that form of estrogen at that time. That form of estrogen is still available. It's still available as pills, in patch form. But one of the direct effects of this study was the development of synthetic estradiol that is bioidentical to the estrogen that our bodies make and so I think that one of the benefits was that it led to some innovation in this area, even though women didn't largely benefit from that innovation until more recently.

Erin Stein: Yeah, that's another point to make. This study was done in the nineties, largely. What they were given is not necessarily what you are getting at your doctor today.

Gillian Goddard: Yeah, absolutely.

Erin Stein: Think that's important.

Gillian Goddard: Yeah. It is, it is important. The other thing that's important to know is that they are still looking at this specific group of women who, 30 years ago, were randomized to get estrogen or not get estrogen and looking to see what happens to them. Some of the data that we have around dementia comes from this group. And most of the data talking about the timing hypothesis, which is a theory that came out of this study, comes from creating subsets of the participants, by looking at the subgroup of women who were under the age of sixty versus the subgroup of women who were older. This data is still very useful.

Erin Stein: Explain the timing hypothesis again. I know we've talked about it before, but it's directly relevant to this.

Gillian Goddard: Yeah, the timing hypothesis was how experts started to explain the unexpected results that came out of this study. The timing hypothesis states that if you give a woman estrogen before she has developed significant cardiovascular disease, then estrogen may be preventative. But if you have this period of time where a woman does not have estrogen, and then you give her back estrogen—and the idea is that in that interim time period she may have developed some cardiovascular disease because estrogen is among premenopausal women very protective against the formation of plaque—if you give women estrogen later when they've had a big gap of time where they did not have estrogen, then it may actually be harmful. And this is where this idea came that you should be starting hormone therapy before the age of 60 or within 10 years of your last menstrual period, because it takes about 10 years to start to form plaques once your estrogen levels have dropped. People are pushing back against this now. And I think that that makes sense that this hard, fast cutoff may not be appropriate for everyone. Because it seems that it's really about whether you have personally developed signs of cardiovascular disease or not, and less about the absolute time that you have not had estrogen.

Erin Stein: Right.

Gillian Goddard: One of the things that we're seeing is a much more individualized approach to that. But that timing hypothesis came out of this data and this unexpected outcome. Now, contrary to what you will hear some people say, what we still don't know is that if you take estrogen around your last menstrual period, either start it just before or just after you would have your last menstrual period, does that reduce your risk of cardiovascular disease in the future? And the data there is really quite mixed. But we know that if you start it early it doesn't cause cardiovascular disease.

Erin Stein: So again, you need to monitor your heart health. We can't say that enough.

Gillian Goddard: Cannot.

Erin Stein: But it is personalized to you and your body and what's happening inside of it. So there is no one answer, you should take this, you should not take this. There are generalities. And then there's your specific situation. This is a prime example of you can't just say something works or doesn't work when you're 40 and the same is true when you're 60. 

Gillian Goddard: Right.

Erin Stein: Your body is changing. Yay, our bodies keep changing all the f---king time. So how it performs in a younger woman versus an older woman is probably going to be different. 

Gillian Goddard: Yeah.

Erin Stein: I feel like people don't grasp that. They're like, ‘well it's bad, so I should never take it.’ And that is the summary of what you just said. It's not bad when you're younger. Bad is probably not even a great word, but it might increase some risk when you're older. It depends.

Gillian Goddard: Right. It depends. Yeah, it depends. Whenever we talk about medication, we shouldn't just be talking about the risk. We should be talking about the potential benefits, and we should be talking about the risks and benefits of doing nothing.

Erin Stein: Correct.

Gillian Goddard: So what we know is that there was then a generation of women whose menopause symptoms were not treated as the direct effect of this study.

Erin Stein: And they're really pissed about it now.

Gillian Goddard: They are really pissed about it now. And who can blame them, by the way?

Erin Stein: Yeah.

Gillian Goddard: But there's this whole generation of women who were not adequately treated for their menopause symptoms. And you know what? There's harm in not treating those symptoms too.

Erin Stein: Yep.

Gillian Goddard: Even if it's just in quality of life. And I think we would argue that it's not just a quality of life thing, but there is harm in not treating someone's symptoms to improve their quality of life.

Erin Stein: What about the low-fat diet and the calcium/ vitamin D trials? Because we never talk about those.

Gillian Goddard: We never do. We never do. So calcium plus vitamin D reduces hip fracture if you have osteopenia or low bone mass or osteoporosis. Again, among a certain subset of these women, not necessarily all women. And I think that the diet study ended up not being statistically significant.

Erin Stein: Yeah, that was part of our low-fat diet obsession.

Gillian Goddard: Yes. Snackwell's cookies, you remember those horrible things? Yeah.

Erin Stein: Yes. Yeah. We're just gonna keep talking about Snackwell's on this podcast forever.

Gillian Goddard: It was such a thing. They were full of chemicals and sugar.

Erin Stein: They were really good. When I was younger I really enjoyed chemicals and sugar together.

Gillian Goddard: Yeah. Yeah. Yeah.

Erin Stein: Yeah, the low-fat diet, doesn't seem like anything exciting came out of that one.

Gillian Goddard: Nothing interesting came out of that.

Erin Stein: But the vitamin D and calcium, they studied that. There's a reason your doctor tells—well, is telling me to take mine.

Gillian Goddard: People are still looking for interesting ways to use this data. And so I think that it's still really important. The last and biggest takeaway is part of the reason that we got the outcome that we got was because we're trying to take shortcuts. 

Erin Stein: Explain that. How were they trying to take a shortcut?

Gillian Goddard: And I don't think they really thought about it this way. I don't think that they were like, gosh, we should like take a shortcut. I really don't think that's what was going through the people's heads when they were designing this study. It's more, you know, Monday morning quarterbacking that is making me say that. And I have the obviously the benefit of hindsight at this point.

Erin Stein: Yeah.

Gillian Goddard: But if we're saying that estrogen prevents cardiovascular disease, the real study that we should be doing to figure that out is a really complicated one that involves randomizing women when they're in their 50s and following them until there are enough events to see whether there's a difference or not. And unfortunately following them could take decades and that is why we don't have an answer to that question.

Erin Stein: Yeah.

Gillian Goddard: Same with dementia, by the way.

Erin Stein: Yeah. And that feeds into what we started with. You know, smaller studies lead to bigger studies. This was a huge study with a lot of data points looking at multiple outcomes in each part of it. And so there's a limit to how specific you can get with your conclusions, I would say. 

Gillian Goddard: Yeah. Yep.

Erin Stein: This now has spawned so many other analyses and studies and more ‘okay, let's answer that more specific question.’ That's how science works. We keep honing in.

Gillian Goddard: Yeah. It is.

Erin Stein: And asking the questions in a slightly different way and studying them in a slightly different way, and that's how we learn. Isn't that fun, everyone? Wasn't this interesting?

Gillian Goddard: It is. It is.

Erin Stein: Everyone's like, no, Erin, please stop.

Gillian Goddard: This is why I decided to go to med school was because I loved clinical trials.

Erin Stein: Yeah, well, you are a nerd.

Gillian Goddard: I am. And I'm all right with that.

Erin Stein: Yes, I thought this was a very interesting deep dive. I did not know all these details, how big it was, how broad it was, how it was really multiple clinical trials and studies over years.

Gillian Goddard: Yep.

Erin Stein: And I think it is really unfortunate that it has been reduced to this flub.

Gillian Goddard: Yes.

Erin Stein: That kind of f--ed everything up.

Gillian Goddard: Yeah, I mean look, the political climate is also different than it was in the early nineties, but we are not back to where we were in the early nineties when it comes to studying women's health. We haven't gotten back to that place of interest, to that place of funding, and it's been twenty years since the results were released of these two studies, more than twenty years. I think we're moving in that direction. In some circles, not in others.

Erin Stein: This is where we say it matters what the government is funding or not funding.

Gillian Goddard: It does.

Erin Stein: It's worth talking to your representatives. It's worth talking about this in general, which is partly why we have this podcast.

Gillian Goddard: Yep.

Erin Stein: Because we deserve better for our health.

Gillian Goddard: We do, we do. The idea that the NIH funded this giant study of women inconceivable right now.

Erin Stein: Great downer, Gillian.

Gillian Goddard: Sorry, that was such a sad note on which to end.

Erin Stein: I hope you found this interesting. If you have questions, I will put some links in the show notes if you really want to nerd out and read a lot of these details and more. but it's worth knowing a little bit more about this.

Gillian Goddard: It is worth knowing.