Feature Article
Women's health research at CHS:
A conversation with four investigators about hormone therapy research in
the post-WHI era
By Katie Saunders
How does the recently formed Women’s Health Investigator Program at
Group Health Center for Health Studies define the scope of its work?
"Anything but prostate cancer," jokes CHS Senior Investigator
Andrea LaCroix, PhD. Meanwhile, a review of the Center’s research
portfolio shows that her remark is actually quite insightful. CHS
scientists are studying a number of "equal opportunity"
conditions (diabetes, colorectal cancer, cardiovascular disease, Alzheimer’s
disease, back pain) that affect women and men in roughly equal numbers.
Many of the other subjects under investigation disproportionately affect
women, such as breast cancer, osteoporosis, domestic violence, depression,
urinary incontinence, sexually transmitted diseases, and urinary tract
infections. And, completing the Center’s portfolio are several
conditions that only impact women, such as menopause, uterine
fibroids, and ovarian cancer.
While not every investigator with work connected to women’s health is
a member of the Women’s Health Investigator Program, those who care to
define themselves as "women’s health researchers" are welcome
to join the group’s monthly meetings to share perspectives and
expertise. The composition of the group was largely determined by
"who wanted to sit down at the table," according to CHS
Assistant Investigator Diana Buist, PhD.
Members from CHS are Buist, LaCroix, Katherine Newton, PhD, and Delia
Scholes, PhD (See biographies.) The
University of Washington (UW) membership consists of
Linda LeResche, ScD, a health services researcher focusing on gender and
hormone issues related to facial pain; Jennifer Melville, MD, MPH, an OB/GYN
physician interested in the connection between urinary incontinence and
depression; and Susan Reed, MD, an OB/GYN physician whose research focuses
on menopause.
Women’s health research has been thriving at CHS since long before
the formation of the Women’s Health Investigator Program. The Center’s
first external grant, received in 1985, dealt with the long-term effects
of tubal sterilization. Twenty years later, women’s health research
accounts for $30 million in research funding over the next several years—and
this is according to a relatively restrictive definition. Much of this
funding can be traced to the CHS members of the Women’s Health
Investigator Program—Buist, LaCroix, Newton, and Scholes—who, among
them, have more than 50 years of research experience at CHS and a rich
history of collaboration.
For this article, we invited these four CHS investigators to share
their insights about research into the use of hormone therapy before and
after the Women’s Health Initiative (WHI) randomized trial of
estrogen-plus-progestin therapy was stopped in 2002. Their informal
conversation begins with Buist, LaCroix, and Newton. Scholes joins the
conversation later on.
By way of background, Buist, LaCroix, and Newton have studied hormone
therapy for more than ten years. In the mid-1990s, as part of the EnPOWER
project, the three researchers surveyed patients and providers about their
attitudes and beliefs surrounding hormone therapy, and also developed and
tested a workbook designed to help postmenopausal women make an informed
decision about short- and long-term hormone therapy use.
At the time of EnPOWER, hormone therapy was widely used to treat
menopausal symptoms, such as hot flashes and night sweats. While use of
hormone therapy for symptom relief was typically short-term, some women
took hormone therapy indefinitely in light of persuasive evidence that the
medication, through its maintenance of bone density, helped prevent
fractures. By the mid-1990s, the case for long-term use of hormone therapy
was bolstered by findings from several observational studies suggesting
that hormone therapy might protect women against heart attacks. However,
this positive message was tempered somewhat by results from other
observational studies indicating that long-term hormone therapy use might
increase a woman’s risk of developing breast cancer. Thus, according to
the weight of the evidence in the mid-1990s, long-term use of hormone
therapy appeared to be a mixed bag.
However, until 1998, all of the studies that had evaluated the
long-term effects of hormone therapy were observational. These types of
studies can be problematic because it’s impossible to fully adjust for
differences between users and non-users of hormone therapy. So, if hormone
therapy users tended to be healthier at the outset than non-users—the
so-called "healthy user bias"—results of observational studies
would be skewed in favor of hormone therapy. In contrast, a randomized
trial design means that women are assigned by chance to take hormone
therapy (or not), negating the bias inherent in observational studies.
In 1998, the Heart and Estrogen/Progestin Replacement Trial (HERS)
showed that, in the first year of hormone therapy use, postmenopausal
women with established heart disease were at a 50 percent increased risk
of recurrent coronary disease. And in 2002, the Women’s Health
Initiative (WHI) randomized trial of estrogen-plus-progestin therapy was
stopped early because the risk-benefit ratio did not justify continuing
women on combination hormone therapy. The study found that long-term
hormone therapy use among women aged 50–79 increased the risk of breast
cancer, heart attack, and stroke, and reduced the risk of colorectal
cancer and fractures.
These WHI results led to two hormone therapy "diffusion"
studies at CHS—that is, studies comparing trends in hormone therapy use
before and after release of the WHI findings in 2002. (See Newton and
Buist biographies.) And, the dark shadow cast on hormone therapy by the
HERS and WHI trials has heightened interest in Newton’s trial of
alternative therapies for menopausal symptoms (HALT). (See Newton
biography.)
Katie Saunders: What are some of your research highlights?
Katherine Newton: All three of us worked on the EnPOWER study. I
think we did a lot of really ground-breaking work as part of that study,
looking at attitudes, beliefs, and practices around hormone therapy. We
interviewed women and providers. We looked at pharmacy data. Over a series
of years, it was an extremely comprehensive look at practices around this
issue and I think it’s a really nice body of work.
Diana Buist: It seems to me like a lot of work has come from
EnPOWER. For example, some of the HALT work.
Katherine: Yes, it was EnPOWER that provided the data about
alternative therapies. That enabled us to have some important preliminary
data when we came to propose the HALT study.
Andrea LaCroix: And definitely the hormone therapy diffusion work
that you’re doing.
Katie: What prompted your interest in hormone therapy in the first
place?
Andrea: I think it was the fervor for hormone therapy treatment
that was just running rampant in the 1990s, don’t you?
Katherine: Yeah. It was highly used. There was a lot we didn’t
know about it. There was a huge impetus to get more women to take it,
which in some ways was the impetus for finding out about attitudes. Some
health care providers were vigorously encouraging women to take it and a
lot of women were really resistant and we didn't know why. The docs were very
persistent and we weren’t sure we knew the why of that either. In the
beginning, it was sort of trying to understand what was going on there.
Who was doing what and why?
Andrea: To be honest, I think it started with your [Katherine’s]
dissertation.
Katherine: Andrea was my advisor. I wanted to do something on women
and heart disease and I wanted to do something different. Finally, I came
into Andrea’s office one day and I said, "What about secondary
prevention?" That is, hormone therapy use in women who already had
had a heart attack. Andrea looked at me and said "That’s it."
Finally, we had a topic.
Katie: Ten years later, are you surprised at the state of the
knowledge about hormone therapy—that some of the observational studies
may have been wrong?
Andrea: I don’t think we thought anything was going to be bad
about hormone therapy except for what we already knew about gallbladder
disease and maybe breast cancer.
Katherine: We were a little iffy about breast cancer because those
data were a little squishy at the time.
Andrea: Until HERS came out, I don’t think we had a sense that
there was a revolution afoot.
Katherine: And people really discounted HERS for various reasons.
It was really not until WHI came out that the bomb dropped. Even then, my
read on that was that everything is in the expected direction except for
heart disease.
Andrea: And stroke—before WHI there wasn’t any evidence of either a protective effect or
increased risk.
Diana: But there had always been the thought that there’s been a
healthy user bias related to hormone therapy. That was the unquantifiable.
Andrea: Yes. You [Diana] did work on that in EnPOWER. That’s what
you wrote about: Were the long-terms users of hormone therapy different
before they ever got to be long-term users?
Katie: A recent article in The New York Times reported that
the drop-off in hormone therapy use might be bottoming out. Do you think
it’s going to start going the other way now?
Diana: Our preliminary data in the hormone therapy diffusion
project--we don’t go very far out--look as though we had a really
dramatic drop and then use started to rise again. Then our data stop.
Katherine: There’s a lot of resistance on the part of certain
members of the physician community to accept the WHI results. They’re
having a lot of trouble giving it up.
Andrea: I really think there’s a resistance-to-change element
among a lot of people. But I think that will go away after awhile. Like
the end of any fad, it takes awhile to die off. And this one was
particularly long. Just to get out on the edge a bit, there has been an
element of sexism in the growth of hormone therapy. And that came out,
much to my amazement, after the WHI data were published. There’s this
book published in the 1960’s called Forever Feminine that Wyeth
[the manufacturer of the most commonly used form of hormone therapy] paid
a doctor to write. And there was this campaign that was incredibly sexist
about women needing this medicine to be fit to live with and to stay young
and attractive. You have to stay in touch with that because a lot of the
resistance that’s coming now is coming from older men.
Katie: Do you think the resistance is coming more from male than
female providers?
Andrea: That’s a researchable question and we should look at that
in Katherine’s new grant.
Katherine: But there will always be women who have sufficient
menopausal symptoms that they will want to take hormone therapy. I run
into people in all walks of my life. When they find out what I do, they
want to talk about it. And some of them are just miserable. They’re 48
or 50 and they’re sweating in their boardroom meetings and they can’t
stand it.
Andrea: Unless we find something that works differently or better.
Katherine: So, I think there will always be those women. But the
difference now is they’re more frightened to take hormones. They want to
take it just as long as they need to, and no longer, rather than thinking
of it as a long-term thing.
Andrea: Regarding the "getting-off" issue—I think in
some ways you’re just delaying the agony. We’re studying the WHI women
who came off placebo and who came off active pharmacotherapy. They were
the same at the beginning—many of them did not have any symptoms at all—but
when they come off, if they’re on active therapy, they’re not feeling
good. So I think it actually causes you to have some estrogen withdrawal
whenever you stop it. And for some people that’s uncomfortable, too. I
think if you could figure out how to use the smallest dose needed all
along, and maybe the goal isn’t to be totally symptom free but to have
tolerable symptoms…
Katherine: Like a lot of women wouldn’t mind if they were warm,
as long as they weren’t sweating. But we don’t know if it works like
that. Whether your hot flash is your hot flash, or whether you can
modulate parts of it. It’s never been looked at that way.
Katie: Hormone therapy was one of the therapies for osteoporosis
prevention. What’s happening on that front after the WHI?
Andrea: I think right now the big tension in the field is whether
all women need to take medicines to prevent fractures in later life. That’s
what the drug companies would have you believe.
Delia Scholes (who has now joined the conversation): It’s sort of
like, what should women do now?
Andrea: There’s a lot of trying to capitalize on the desire not
to use hormone therapy. Again, who is at risk for the untoward effects of
medicine being practiced without the evidence of long-term treatment
effects? We are—the women are. One of our roles as researchers is
to constantly say "Where’s the evidence for that?" and
"What harm may be we be doing unknowingly?" I see a lot of our
work and our satisfaction coming from advocating for women to make
informed choices. And, when they don’t have the evidence to make
informed choices, researchers like us are saying "Don’t necessarily
push women to do things that may be hurting them." Where’s the
evidence for most of what’s being done in fracture prevention at the
moment? There’s good evidence for a few things and lots of
extrapolation.
Delia: And lots of assumptions underlying it that women need
"something."
Andrea: Women are a huge market. And our health consciousness in
America makes us even more of a huge market. Part of our role is to
advocate for women not to be misused.
Katie: Informed decision-making is a common theme of a lot of your
research. Do you think it’s best that information come directly from the
doctor or should the information be disseminated directly to women?
Delia: There’s increasing evidence in research that
patient-oriented activation strategies are increasingly important and need
to be implemented and evaluated.
Katie: What’s the best way to implement them?
Andrea: The hormone therapy workbook worked really well. This
really just encouraged a more informed partnership between women and
doctors. Doctors loved it because they didn’t have to go through and
explain all this stuff. I don’t think we know all the ways. The Internet
could be a great way eventually.
Delia: In our system, MyGroupHealth has a lot of potential
for interventions that are patient-oriented. I think providers respond
well to not having all the onus be on them to disseminate information. I
don’t think they feel circumvented or threatened when patients are
directly informed.
Katherine: I think at the delivery system level, they’re starting
to understand that one of the ways to make changes that they want to see
made is through directly accessing patients. There’s this huge statin
and ace-inhibitor initiative and they’ve started doing some direct
mailing. The response they’re getting is huge. They’re amazed,
actually, that this might be the cheapest and most efficient way to get
people to think about it. I think this is a fascinating approach that’s
been way under-utilized, and in a managed care kind of situation is
readily available as an approach you can use to inform people.
Andrea: And that’s why we picked that approach in the EnPOWER
intervention phase. We wanted to reach the most people we could in the
cheapest way. In my kid’s generation, the Internet might be the way
rather than through the mail. For my grandmother’s generation, the
Internet will probably never be the way.
Diana: And there’s always the mass media.
Delia: As Diana says, mass media dissemination has been shown to
have effects if it’s done well, even though it’s untargeted. All you
have to do, if you reach a lot of people, is to increase a small amount of
response, and it’s a large effect. From the standpoint of reaching women
with mass media for, say, STD prevention, that’s one option that we
haven’t pursued in this country. It’s regrettable, because they have
found that some mass media campaigns have had pretty big effects on HIV
prevention and condom use in other countries.
Diana: Just look at WHI in contrast to HERS in response to who’s
gone off hormone therapy. [A recent article in the Annals of Internal
Medicine reported that WHI had a bigger impact on hormone therapy use,
in part because of wider media coverage]. Katherine and I were talking
about another study in which the funders expressed a concern about taking
women off hormones without their providers’ explicit written consent.
Katherine’s comment was that we know from EnPOWER that half of the women
are already making these decisions on their own. So, women, and probably
men as well, make healthcare decisions in the absence of their providers
anyway. Things that come out in mass media have an opportunity to both
hurt and benefit women.
Katherine: If you look at the rate in which women went off hormone
therapy, you know they weren’t talking to their providers. It would have
been physically impossible for the system to have absorbed that many
conversations in any way—email, phone visits, whatever. It would have
been a physical impossibility in that one or two month period when rates
just plummeted for that to have been happening with provider
conversations.
Andrea: It’s patronizing to think that women need permission from
their doctor to act upon their own health. If you believe that has to be
the way it is, that’s a patronizing viewpoint.
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