A bit of history
In 1991, the NIH started two large studies, called the Women’s Health Initiative, or WHI. One study looked at postmenopausal women taking estrogen plus progestins (Prempro) for control of hot flashes and night sweats. The other study looked at postmenopausal women who have had a hysterectomy and were taking estrogen (Premarin) for control of these symptoms.
In 2002, one WHI study was halted because the women taking Prempro had more heart attacks than the ones who did not. At the time, this caused great confusion among women and great surprise among physicians. No wonder: A 1985 Harvard study (the Nurses Health Study) showed that hormone use lowered heart attack risk by 50%. Several other studies, albeit smaller, showed cardiac and cholesterol profile benefits.
As if to confirm the bad results of the first WHI study, the second one—of women taking Premarin—was halted in 2004 because of increased incidence of strokes.
A second look
A recent reanalysis of combined data of both WHI studies (a total of 27,347 women) has recently been published (JAMA, vol. 297, pp. 1465-1477, 2007). The basic finding can be summarized with the old adage: Timing is all.
- Women who started taking hormones within 10 years after reaching menopause had an 11% lower risk of heart attacks.
- Women who started taking hormones within 10-19 years after reaching menopause had a 22% higher risk of heart attacks.
- Women who started taking the hormones 20 or more years after menopause had a 71% higher risk.
- All women taking hormone therapy had a slight increase of breast cancer risk.
The news is actually better than it looks. Most women who use hormonal therapy do it within 5-10 years of reaching menopause; so in terms of absolute numbers, most women can safely use the hormones.
To take or not to take, that is the question
- The risk of breast cancer is slight, and there is no additional risk if you limit the hormone treatment to 4 years.
- There is evidence, from the WHI studies and from other studies, that hormonal therapy reduces osteoporosis and the incidence of hip fractures.
- Changes in lifestyle, like diet and exercise, have a much stronger beneficial effect on cardiac risk and osteoporosis than hormonal therapy. It is also much more pleasant, and it is risk-free.
- In the final analysis, you will have to decide if your symptoms are severe enough to justify hormonal therapy.
The new analysis did not make hormone therapy kosher for prevention of cardiac disease. For that, the best modality, as I mentioned, is a healthy diet plus physical activity. And if drugs are indicated, there are far more effective ones the estrogen.
Why the conflicting results?
There is an apparent paradox here: Same studies, same set of data, yet the original analyses were so alarming that they caused both trials to be halted.
The answer is quite enlightening in terms of trial design, and in terms of public understanding of the complexity of clinical trials.
The mean age of women entering the WHI trials was 63. Women reach menopause by and large between the ages of 45 and 55, with a mean age of about 50. Therefore, most women in the study received the hormone therapy, on average, 13 years after reaching menopause. That put them at a higher risk of cardiac disease. In fact, of the 27,347 participants in the WHI studies, only 3,425 women were under age 55. The beneficial effects that the drug had on the younger women were simply swamped by the deleterious effects it had on the older women, who made up the large majority (87.5%) of the study population. Only the subsequent analysis of the timing of therapy with respect to the onset of menopause could have uncovered this fact.