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Thu 23 Aug 2007 12:00 AM

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The risk-benefit tightrope

Women must balance heart disease protection and breast cancer risk when considering hormone therapy.

It was a shock several years ago when results from a large, government-funded study called the Women's Health Initiative (WHI) showed that postmenopausal women who took hormones were more likely to have heart problems than those who didn't. Previous research had pointed to both risks and benefits from hormone therapy.

The risks? Stroke, blood clots in the veins that could potentially travel to the lungs (pulmonary emboli), and most of all, breast cancer - all were more likely with hormone therapy.

Re-examination of the WHI results provides more evidence that the timing of hormone therapy is critical.

But on the benefit side of the equation, there were several factors: A lower risk for colon cancer, protection against broken bones, relief from a variety of postmenopausal symptoms like hot flushes and night sweats - and protection against heart disease.

Since heart disease is by far the most common cause of both death and disability in women, protection against heart disease was vitally important.

But the 2002 WHI results threw the risk-benefit balancing act out of alignment. It seemed that hormone therapy increased the risk for both the most feared disease, breast cancer, and the most common one, heart disease.

By the end of 2002, the use of hormone therapy by women had plummeted by 38%, and in 2003, 20 million fewer prescriptions for hormone therapy were written. The era of widespread use of hormones by postmenopausal women was declared over.

Heart disease: Is it in the timing?

Over the past several years, a more nuanced view of the heart disease risk from hormone therapy has emerged. Of course, it was never a secret, but researchers reconsidering the WHI results have pointed out that the average age of the women at the start of the study was 63. That means many of them started taking hormones a decade after they stopped menstruating. The usual practice is to start hormone therapy at the time of menopause when menopausal symptoms begin. For American women, on average, menopause occurs at age 51. Some experts argued that the WHI results were likely true for women in their 60s and 70s and could be misleading if applied to younger women entering menopause.

That's a plausible argument, given our growing understanding of the biology of atherosclerosis. The precursors of atherosclerotic plaques start developing when people are in their 20s and 30s, but it takes decades for the plaques to grow and fully form. In women, oestrogen seems to slow that process down, which is why women tend to get symptomatic coronary disease at a later age than men.

But after menopause, when oestrogen levels wane, women begin to "catch up," and atherosclerotic plaques start to form. Once plaques form, the effect of oestrogen is no longer beneficial.

Why is that? Atherosclerotic plaques are pools of cholesterol, fat-laden foam cells, and inflammatory molecules covered by a thin, fibrous cap. If that cap breaks open, the "gunk" inside spills into the bloodstream, which causes blood clots to form. If clots block the flow of blood to the heart muscle, the result is a heart attack. Oestrogen makes established plaques more likely to rupture by stirring up the inflammatory factors inside. So starting older women on hormone therapy after they have atherosclerotic plaques may be quite risky, whereas it might be protective in younger women whose arteries are still relatively plaque-free.

Results from studies like the Nurses' Health Study - which are simply observational, following the participants for many years - bear this out. The women in those studies have tended to start hormone therapy closer to menopause. Some results have linked hormone therapy to steep declines of almost 50% in heart disease risk.
Re-examination of the WHI results provides more evidence that the timing of hormone therapy is critical. In the April 4, 2007, issue of the Journal of the American Medical Association, the WHI investigators reported that an analysis of their data grouping women by age and years since menopause showed that those who started hormone therapy closer to menopause had a reduced risk of heart disease. But the results didn't meet their criterion for statistical significance, which means they could have occurred by chance. The stroke risk was elevated regardless of how long ago a woman experienced menopause.

The breast cancer risk

The 2002 Women’s Health Initiative results threw the risk-benefit balancing act out of alignment.

But just as investigators were sorting out the subtleties of the heart disease risk, big news about the breast cancer risk from hormones stomped its way into the headlines.

Researchers reported that after years of steady increases, breast cancer incidence (the number of new cases diagnosed) reversed and began to decline in 2003 - the very year that postmenopausal hormone prescriptions dropped off sharply because of the WHI results. In a more complete report published in the April 19, 2007, issue of the New England Journal of Medicine, they noted that the decrease was only among women who were 50 and older - in other words, in those who might have stopped taking postmenopausal hormones. What's more, the decrease was more pronounced for oestrogen-sensitive tumours - and those are the tumours most likely to be affected by the oestrogen in hormone therapy.

It will take more research to figure out all the reasons for the decline. We may be seeing fewer cases of breast cancer because mammography rates are down, so it's a matter of fewer cases of breast cancer being detected, not fewer cases of breast cancer. Moreover, the women who stopped taking hormones may be among those not getting mammograms as often because they figure they no longer need to be quite so vigilant about getting screened for breast cancer. Another big question is whether breast cancer incidence really could change so quickly in response to women quitting hormones. Breast cancer is usually viewed as a condition that develops slowly. The researchers who reported the decline in incidence think it's possible, pointing to anecdotal evidence of breast tumours regressing after discontinuation of hormone therapy.

There are other unanswered questions about hormone therapy and breast cancer. For example, the WHI reported that the risk of breast cancer for women taking oestrogen-only pills declined, which suggests that the progestin part of hormone therapy may be the main cause of the previously demonstrated association between hormone therapy and breast cancer. (Progestin was added to protect against uterine cancer.)

It's not clear whether the timing of hormones might influence breast cancer risk the way it does heart disease risk. WHI investigators hope to report data in 2007 about how long it takes for breast cancer risk to return to normal after women stop taking hormones.

The bottom line - for now

Hormone therapy does reduce the risk of colon cancer, fractures from osteoporosis, and, depending on the timing, perhaps also heart disease.

There are, however, other ways to reduce these risks (exercising regularly, for starters) that don't carry hormone therapy's "baggage": breast cancer, blood clots, and stroke.

Most experts we've consulted say the weight of all the current evidence argues for women taking postmenopausal hormones only for relief of menopausal symptoms and for the shortest time possible.

That's been the prevailing opinion for a number of years. What has changed since 2002 is that women in their first 10 years or so of menopause don't have to add heart disease to the list of risks they are taking with hormone therapy.

This article is provided courtesy of Harvard Medical International. © 2007 President and Fellows of Harvard College.

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