Jay S. Cohen M.D.       http://medicationsense.com      1337 Camino Del Mar   Suite C       Del Mar, CA 92014       Phone: 858.345.1760       Fax: 858.509.8944


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.

References
1. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principle results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
2. Lacey, JV, Mink, PJ, Lubin, JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002;288:334-341.
3. Shumaker, SA, Legault, C, Thal, W, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative memory study. JAMA 2003;289:2651-2662.
3A. Manson, J, Hsia, J, Johnson, KC, et al. Estrogen plus progestin and the risk of coronary heart disease. New England Journal of Medicine 2003;349:523-534.
3B. Herrington, DM, Howard, TD. From presumed benefit potential harm -- hormone therapy and heart disease. New England Journal of Medicine 2003;349:519-521.
3C. Beral, V, et al. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419-427.
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5. Delusions of feeling better. Editorial. New York Times, Mar. 19, 2003:A28.
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15A. Duenwald, M. First Year of Hormone Treatment Is Found to Raise Risk of Heart Attack. New York Times, August 7, 2003:nytimes.com.
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29. Utian WH, Burry KA, Archer DF, et al. Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients. American Journal of Obstetrics and Gynecology 1999;18:71-79.
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Dickinson, JG. FDA Opens Hormone Therapy Info Campaign. Dickinson's FDA Webview, 09/09/2003:fdaweb.com





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