Hormone therapy: The risk-benefit tightrope

Content provided by the Faculty of the Harvard Medical School

Women must balance heart disease protection and breast cancer risk.

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.

But on the benefit side of the equation were a lower risk for colon cancer, protection against broken bones, relief from a variety of postmenopausal symptoms like hot flashes and night sweats — and protection against heart disease. And since heart disease is by far the most common cause of both death and disability in women, protection against heart disease was 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 all 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, estrogen 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 estrogen levels wane, women begin to "catch up," and atherosclerotic plaques start to form. Once plaques form, the effect of estrogen 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. Estrogen 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.


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Which of the following is one of the changes your may experience during menopause?