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by Patricia Yarberry Allen, MD | bio

As a physician, I am often asked why recommendations concerning hormone therapy seem to be in flux, changing year-to-year based on new studies and research.

An article published Sunday in The New York Times Magazine probes that same question and provides an essential analysis of what writer Gary Taubes refers to as the “elusive search for truth in medicine.”

The balanced article starts with a review of the history of hormone therapy research and recommendations. It uses the HRT story to illustrate the differences between epidemiological studies, which are observational — such as the 1985 Nurses Health Study, which touted the benefits of taking estrogen — and randomized-controlled clinical trials — such as the Heart and Estrogen-progestin Replacement Study of 1998 and, later, the Women’s Health Initiative, which concluded that HRT constituted a potential health risk for postmenopausal women.

Even that wasn’t the final word, however, as a study published in The New England Journal of Medicine in June indicated that women who have had hysterectomies may see some heart benefits if they take estrogen, but only if taken early in the menopausal transition (and it should still only be taken by women who need help managing severe symptoms). Taubes writes:

Many explanations have been offered to make sense of the here-today-gone-tomorrow nature of medical wisdom — what we are advised with confidence one year is reversed the next — but the simplest one is that it is the natural rhythm of science. An observation leads to a hypothesis. The hypothesis (last year’s advice) is tested, and it fails this year’s test, which is always the most likely outcome in any scientific endeavor. There are, after all, an infinite number of wrong hypotheses for every right one, and so the odds are always against any particular hypothesis being true, no matter how obvious or vitally important it might seem.

In the case of H.R.T., as with most issues of diet, lifestyle and disease, the hypotheses begin their transformation into public-health recommendations only after they’ve received the requisite support from a field of research known as epidemiology. This science evolved over the last 250 years to make sense of epidemics — hence the name — and infectious diseases. Since the 1950s, it has been used to identify, or at least to try to identify, the causes of the common chronic diseases that befall us, particularly heart disease and cancer. In the process, the perception of what epidemiologic research can legitimately accomplish — by the public, the press and perhaps by many epidemiologists themselves — may have run far ahead of the reality. The case of hormone-replacement therapy for post-menopausal women is just one of the cautionary tales in the annals of epidemiology. It’s a particularly glaring example of the difficulties of trying to establish reliable knowledge in any scientific field with research tools that themselves may be unreliable.

Epidemiological studies can be very effective over long periods of time. One example Taubes cites is the discovery that cholera is caused by contaminated water. But it’s much more complicated when we’re looking for subtle causes.

The article provides an incredibly important overview of the epidemiological studies on which HRT research was based. And Taubes goes a step further than most writings on this subject by offering several detailed explanations for the discrepancy between clinical trial results and those of the Nurses’ Health Study and other observational studies:

In the third explanation, the clinical trials and the observational studies both got the right answer, but they asked different questions. Here the relevant facts are that the women who took H.R.T. in the observational studies were mostly younger women going through menopause. Most of the women enrolled in the clinical trials were far beyond menopause. The average age of the women in the W.H.I. trial was 63 and in HERS it was 67. The primary goal of these clinical trials was to test the hypothesis that H.R.T. prevented heart disease. Older women have a higher risk of heart disease, and so by enrolling women in their 60s and 70s, the researchers didn’t have to wait nearly as long to see if estrogen protected against heart disease as they would have if they only enrolled women in their 50s.

This means the clinical trials were asking what happens when older women were given H.R.T. years after menopause. The observational studies asked whether H.R.T. prevented heart disease when taken by younger women near the onset of menopause. A different question. The answer, according to Stampfer, Willett and their colleagues, is that estrogen protects those younger women — perhaps because their arteries are still healthy — while it induces heart attacks in the older women whose arteries are not. “It does seem clear now,” Willett says, “that the observational studies got it all right. The W.H.I. also got it right for the question they asked: what happens if you start taking hormones many years after menopause? But that is not the question that most women have cared about.”

It’s such a good overview, and readers will learn a lot as to how we use epidemiological studies.

Press, patients and doctors all need to understand that medicine and science are not static.

Indeed, the Wall Street Journal yesterday reported on a new study that attempts to explain why HRT may not be helpful in preventing heart disease in some women. The abstract of the study, published in the October issue of the journal Nature Medicine, is available online.

“Researchers at University of Texas Southwestern Medical Center in Dallas have discovered that a compound related to cholesterol can block the hormone estrogen from performing functions in blood vessels that keep them healthy and free of disease that can lead to heart attacks,” writes Ron Winslow in the WSJ.

The culprit identified by the Texas team is a molecule called 27-hydroxycholesterol, or 27HC, a byproduct created as the body processes cholesterol. The researchers found in experiments in mice that 27HC and estrogen target the same receptors in blood vessels.

When estrogen is present in normal amounts and 27HC levels are low — as is typically the case in women before they enter menopause — the hormone successfully latches onto the receptors, triggering actions that protect the heart, the researchers found. But when estrogen falls, as it does during menopause, 27HC is able to beat the hormone to the targeted receptors and block its beneficial effects.

JoAnn Manson, one of the WHI principal investigators and chief of preventive medicine at Harvard University-affiliated Brigham and Women’s Hospital in Boston, told the WSJ that the new findings provide “intriguing” insight into the results of the WHI study. One of the WHI’s findings was that women with high cholesterol had worse outcomes while taking HRT than those with low cholesterol.

“Their overall finding ties together very nicely with the clinical-trial results,” Manson said. “This could help fit pieces of the puzzle together.”

And all of us concerned with the health and well-being of menopausal and postmenopausal women will keep looking for the other puzzle pieces.

* * * * *
Dr. Patricia Yarberry Allen,
director of the New York Menopause Center, is a gynecologist affiliated
with New York-Presbyterian Hospital and a board certified fellow of the
American College of Obstetrics and Gynecology.
Have a question about sex, women’s health or the menopausal transition? Write to [email protected].

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