What Now for Women Who Benefit from Hormone Replacement Therapy (HRT)? A New Study and Condescending Headlines May Be Wrong
How the System Discounts Patients, Especially Women
The news just keeps getting worse
for the millions of women taking Premarin, Prempro, or other forms of hormone
replacement therapy (HRT). Last summer, the Women's Health Initiative bombshell
linked Prempro with an increased risk of cancer and debunked the medical dogma
of half a century that these hormones reduced cardiac risk (1).
Since then, new studies have revealed more HRT risks: heart attacks, strokes,
blood clots, pulmonary emboli, invasive breast cancer, and Alzheimer's disease
(2-3C).
But where does that leave the women who clearly
benefit from HRT? Whose hot flashes, night sweats, or other menopausal symptoms
are severe, even disabling? In March 2003, insult was added to injury for
these women by a new study showing that their improvement with HRT wasn't
real, but a placebo response. Pure suggestion.
It's difficult enough these days for women reliant
on HRT to decide whether they should continue it, so it's particularly important
to clarify whether these drugs help their symptoms at all.
HRT: "Delusions of Feeling Better?"
The revelation that HRT doesn't work emanated from
a New England Journal of Medicine study so important, it was announced
two months before its formal publication (4).
The study's conclusion: HRT doesn't work any better than placebo.
The pre-published study prompted headlines announcing
that, madam, your reduced hot flashes, improved mood and skin texture from
HRT are all in your head. These condescending dispatches -- epitomized by
the New York Times' "Delusions of Feeling Better (5)"
-- took me back.
In the 1950s, that's precisely what doctors
(predominantly male) told our grandmothers about their menopausal symptoms
-- that their hot flashes and irritable moods were all in their heads. But
then, suddenly, we had a treatment that worked -- HRT -- which replaced grandma's
sagging hormone production. Almost miraculously, grandma's symptoms went away.
Golly, maybe they weren't in grandma's head after all. A Long Legacy of Discounting Women
PMS (premenstrual syndrome) was another example.
My first job out of internship in 1972 was at a college student health center,
and almost every day, a young woman came in complaining about PMS-like symptoms.
But we didn't call it PMS because the name didn't exist. Medical dogma dictated
that these symptoms were psychosomatic. Of course, the dogma was set by males.
But as one woman after another related almost
identical symptoms, it struck me as unlikely that neurosis or mass hysteria
could explain the phenomenon. My patients didn't seem neurotic or stupid,
and their reports were so consistent that they had to be real. Besides, with
the major shifts in hormone levels before and during menstruation, mood changes
didn't seem farfetched. And they weren't: today, PMS is an accepted reality.
For more than half a century, we were sure that
depressive neurosis was entirely psychological. It was in patients' heads,
and most of these patients were women. Then Prozac arrived in 1988, and it
made life-long depressive neuroses vanish almost overnight. Sometimes, just
tiny doses (2.5 or 5 mg) were enough.
Suddenly, depressive neuroses weren't psychological
after all, but at least partially, and sometimes entirely, the result of inadequate
serotonin levels in the brain. Today, the diagnosis of depressive neurosis
no longer exists. It has been replaced by dysthymic disorder, a very real
disorder with biological and psychological components.
The tendency of male doctors to discount the
experiences of women goes back even further. A hundred years ago, most doctors
didn't believe multiple sclerosis was real. The symptoms were too variable.
They came and went, shifting in intensity. Doctors called it "the faker's
disease." Some type of hysteria, obviously, because MS mainly affected
women. But as our diagnostic abilities and tests improved, we learned that
MS, regrettably, stems from degeneration of neurons in the central nervous
system, and we're still seeking a cure for this vicious physical disease. The WHI Findings: Some Doctors Disagree
The new HRT study in the New England Journal
offered a new twist: your menopausal symptoms are real, madam, but your response
to HRT is imaginary.
But is this really true? I'm no great advocate
of mainstream medicine's use of HRT. For years I've urged doctors to use the
lowest, safest doses of Premarin and Prempro while the drug industry and doctors
were recommending doses 100%-400% higher. In Over
Dose: The Case Against The Drug Companies, I also advocated using
other brands of estrogen and progesterone that are human identical, because
hormones in Premarin and Prempro are not (6).
And I warned about the link between HRT and cancer a year before the Women's
Health Initiative (WHI) hit last year. I wasn't prophetic -- there'd been
many previous studies showing increased risks of cancer with HRT (7-12),
but these had been ignored.
Yet, I've never doubted that HRT relieves menopausal
symptoms. I've known too many women whose severe hot flashes evaporated with
HRT, returned with a vengeance when HRT was stopped, then disappeared again
when HRT was restarted. Such patterns of response, especially when repeated
in many people, are considered fairly reliable scientific proof.
I've know women who tried clonidine, Valium,
Prozac, and all kinds of other drugs without relief, but did great on HRT.
If these women were so delusional, suggestive, and prone to placebo responses,
why didn't these other drugs provide the same delusions of relief?
I'm not the only doctor skeptical of the NEJM
study. "Any healthcare provider who has treated postmenopausal women
over the past twenty-five years knows that the clear benefit of individualized
hormone replacement therapy to quality of life is indisputable," Dr.
Alan Altman of the Harvard Medical School told the Los Angeles Times following
the article's prepublication in March (13).
Indeed, as if distancing itself from the WHI
findings, the NEJM carried an accompanying editorial that dissented. Deborah
Grady, M.D., a respected expert, stated that "vasomotor symptoms occur
in about two-thirds of women and are very distressing in 10 to 20 percent.
Hot flashes are not deadly, but they can be very disabling." And while
other therapies are sometimes helpful, Dr. Grady added, "systemic hormone
therapy is the most effective treatment (14)."
Other experts agreed. "I think women are
being overly frightened, almost intimidated, by data that doesn't quite justify
the level of fear," Dr. Wulf Utian, executive director of the North American
Menopause Society, an organization of menopause specialists, told the Los
Angeles Times in early April (15). "For
younger, peri-menopausal or early menopausal women, who are most likely to
have severe hot flashes, the level of risk [with HRT] is much less."
"We hear from women who have these severe,
flaming hot flashes, who can't get through the day the way they need to,"
said Cynthia Pearson, executive director of the National Women's Health Network,
a consumer advocacy organization in Washington DC. "Hormone replacement
therapy is the only real alternative (15)."
"We ought to absolutely inform our patients
about the risks of hormones," said Dr. Isaac Schiff, chief of obstetrics
and gynecology at Massachusetts General Hospital and the chairman of the American
College of Obstetrics and Gynecology's hormone therapy task force, told the
New York Times after another worrisome study in August 2003. "But
it would be an equal disservice to say that no hormones ought to be used.
Anyone who says that has not spoken to a symptomatic patient who feels a lot
better on treatment (15A)."
The Reliability and Limits of Clinical Studies
Dr. Marcie Richardson, a gynecologist at Harvard
Vanguard Medical Associates in Boston, told the New York Times in
March 2003. "I've seen lots of women who either stopped cold turkey or
who tapered and who come in and say, `I can't think' or `I can't sleep' or
`I can't be focused.' It's hard for me to understand the results in this context."
She added, "I saw a woman this week who said, `I don't care if it causes
cancer.' She just feels so much better." Dr. Richardson concluded, "What
that's got to mean from my perspective is that the people who feel better
is a subset of women. I'm not seeing randomized women who are enrolled in
a study (16)."
That's precisely right. Although we hold clinical
studies in high esteem, the fact is that clinical studies often do not reflect
the real world. The subjects who volunteer for clinical studies are often
non-representative of everyday office patients. The measures of effectiveness
used in clinical studies are often far different from the realities of everyday
medical practice.
Moreover, the results of clinical studies often reflect averages derived from the highly varying responses of hundreds or thousands of individuals. Averages often obscure reality. Averages are useful for indicating trends, but they do not reflect the actual experiences of individuals. For these and many other reasons, experts have long asserted that the findings of clinical studies must be applied with caution to individual patients:
JAMA 2000: "Clinicians must recognize that patients are rarely identical to the average study patient (17)."
New England Journal of Medicine 2001: "Frequently, the patients enrolled in clinical trials do not match the population of patients receiving care... (18)."
Indeed, one of the great flaws in mainstream
medicine today is that we take clinical studies too seriously, believing every
study's every word while ignoring the direct experiences of our own patients.
We treat clinical studies like gospel, while dismissing the input of intelligent,
educated patients.
So what can we say about this WHI study stating
that HRT doesn't work? We shouldn't dismiss the findings altogether, but neither
should we embrace them. It's just one study. Previous studies have shown that
HRT works. Why should this new study utterly discount them? Sure, women should
avoid HRT when other, safer solutions work. We already knew that. But when
HRT works for women who haven't benefited from other alternatives, we shouldn't
discount this either.
What the Study Actually Said, And Why the Media Got It Wrong
There's another lesson from this new WHI study:
Read studies carefully! Too often, doctors are content with studies' abstracts,
handy summaries, but which sometimes skip very important findings. The abstract
of NEJM study was misleading. It stated: "In this trial in postmenopausal
women, estrogen plus progestin did not have a clinically meaningful effect
on health-related quality of life (4)."
But the study itself said something entirely different:
"We examined the effects of estrogen plus progestin on the relief of symptoms among all women who reported moderate-to-severe vasomotor symptoms at base line (1072 women in the estrogen-plus-progestin group and 974 women in the placebo group). At the one year follow-up, 76.7 percent of the women in the estrogen-plus-progestin group had improvement in the severity of hot flashes, as compared with 51.7 percent of the women in the placebo group (P<0.001); 71.0 percent of the women in the estrogen-plus-progestin group had improvement in the severity of night sweats, as compared with 52.8 percent of the women in the placebo group (P<0.001)."
These results are highly significant. The bottom
line: For the women who actually reported substantial hot flashes, the treatment
worked very well indeed.
So what was all the fuss about? Why were the
headlines so negative? Maybe the real lesson of this study is: Health
editors and writers must read the entire studies before publishing sensationalistic
stories that are alarming or condescending to millions of women! Better
yet, read the editorials that often accompany important new studies. These
editorials, written by respected experts, often provide much needed perspective.
As I say in just about every article in the
MedicationSense E-Letter, you have to inform yourself. You cannot, unfortunately,
always rely on doctors alone to interpret how medical findings might affect
you individually. Studies are important, but your individual experience is
the most important study of all. Treatment decisions should always be made
with your doctor's guidance, of course, but also with your history and input
as part of the equation.
So Now What?
No one disagrees anymore that it is better for
women to avoid or stop HRT -- if they can. But what about women whose symptoms
flare when HRT is stopped and other therapies don't work?
For years I've been saying that the dosages
of Premarin and Prempro are too strong for millions of women. Most of the
recent studies focus on the 0.625 mg of estrogens in these drugs, but for
decades until 2000, the standard one-size-fits-all starting estrogen dose
in Premarin -- one of the most prescribed drugs ever -- was 1.25 mg, 100%
higher. How much extra harm was done? No one knows.
Even the 0.625 mg estrogen dosage in Premarin
and Prempro were unnecessarily strong for millions of women. We've known for
more than a decade that 0.3 mg was all that may women needed, but it was never
the manufacturer's recommended starting dose with Premarin, and Prempro was
never offered with this lower estrogen dose.
Hormones are among the many drugs I've long
advocated starting low and, if necessary, increasing the dose very gradually,
so that no woman receives more medication than she actually needs. This is
very important, because most medication side effects are dose-related, a function
of the doses rather than the drugs themselves.
In her May 2003 editorial, Dr. Grady advised:
"Women who choose to take estrogen should [be started with] a low dose
and gradually increase it until symptoms are adequately controlled (14)."
Indeed, if we'd been using this "start-low go-slow" approach all
along, rather than prescribing double and quadruple doses indiscriminately
decades after studies showed that low doses worked (19-30), these recent studies
might have turned out differently.
Even the FDA has finally gotten the message.
Commissioner Mark McClellan recently said: "Our recommendation is that
if you [and your doctor] choose to use hormone therapy for hot flashes or
vaginal dryness, or if you prefer it to other treatments to prevent thin bones,
take the lowest dose for the least duration required to provide relief (31)."
But it was the FDA that originally approved these hormones at much higher
initial doses, and the agency still commits the same mistake with many new
drugs. I've debated Dr. Robert Temple, the FDA's top authority on medications,
about this several times, and I'm scheduled to do so again in March in Miami.
So perhaps they are finally taking notice.
Meanwhile, treatment decisions can be made with
greater precision than ever today. Jeffrey Baker, M.D., of the Immanuel Clinic
in Springdale, AR, orders hormone level testing for his patients: "Variables
in patient size, drug metabolism capacity, and intrinsic hormone requirements
all call for individualized therapy. We think nothing of monitoring many treatments
like insulin or thyroid hormones; why not use routinely available testing
to verify women's hormone levels and ratios?" Dr. Baker also prefers
using natural, bio-identical hormones in a ratio similar to women's intrinsic
hormones. Whether these hormones are safer than Premarin or Prempro isn't
known, mainly because natural hormones aren't patentable, nor particularly
profitable, so they don't command the financial clout required to run large
studies like the Women's Health Initiative.
For women wanting to discontinue HRT, hormone
doses may have to be lowered gradually. Dropping from 0.625 to 0.3 mg then
to discontinuation works for many women, but others may need a more gradual
approach. A newer, 0.45 mg dose makes this easier. Some women may need to
use an every-other-day schedule to make reductions even more gradual, for
example 0.625 mg on even days and 0.45 mg on odd ones, or a 0.45/0.3 mg schedule.
That's why it's so important for women and their doctors to be fully informed
about the low-dose alternatives, so that they can make these decisions together
(do not adjust doses or drugs yourself).
For women taking combination hormones, several
studies suggest that the progesterone component may be the greater risk factor.
Therefore, reducing or stopping the progestin might be considered before trying
the same with the estrogen component.
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NOTE TO READERS: The purpose of this E-Letter is solely informational and educational. Theinformation herein should not be considered to be a substitute forthe direct medical advice of your doctor, nor is it meant to encourage the diagnosis or treatment of any illness, disease, or other medical problem by laypersons. If you are under a physician's care for any condition, he or she can advise you whether the information in this E-Letter is suitable for you. Readers should not make any changes in drugs, doses, or any other aspects of their medical treatment unless specifically directed to do so by their own doctors.
If you have questions about your medications or medical care, Dr. Cohen is available for consultation at his office or by telephone.
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