Postmenopausal Hormone Therapy and the Risk of Mortality
Grodstein and colleagues compared each of 3637 deaths with 10 live control subjects in the Nurses’ Health Study. After adjusting for variables (such as smoking), current postmenopausal hormone users had a 37% reduced risk of mortality (RR = 0.63; CI = 0.56-0.70) compared to never users. With increasing duration of use, however, the risk of dying, although still reduced, was less (after 10 or more years of use: RR = 0.80; CI = 0.67-0.96). This was because in the Nurses’ Health Study, there was an increase in breast cancer mortality among long-term users. The major impact of hormone therapy was due to protection against coronary heart disease. The effect was still present after adjusting for dietary factors, alcohol intake, vitamin or aspirin use, and exercise. A reliable estimate of death because of stroke was not possible because of the small number of stroke deaths. (Grodstein F, et al. N Engl J Med 1997;336:1769-1775.)
COMMENT BY LEON SPEROFF, MD
When this latest report from the Nurses’ Health study was received by the media, I was afraid that the breast cancer effect would be highlighted, and that is exactly what happened. And by the way, I hope it aggravates you as much as it aggravates me when the N Engl J Med and JAMA release reports to the media before you and I have even received our journals. This catering to the media places us in the position of responding to patients (and even journalists) without having read the reporthardly a position in which it is possible to be effective (or even to be able to avoid being embarrassed).
Remember that this report on mortality reflects the Nurses’ Health Study, and the increased risk of breast cancer in long-term users of postmenopausal hormone therapy in the Nurses’ Health Study is more than balanced by many studies with negative conclusions. As good as the Nurses’ Health Study is, it is still an observational study subject to biases that can only be escaped in a large, randomized clinical trial. Indeed, in my own analysis of the Nurses’ Health Study, I conclude that the current users of hormone therapy are critically different compared to the non-users. They have several characteristics that can contribute to an increased risk of breast cancer (more benign breast disease, more mammograms, and most importantly, fewer pregnancies and more nulliparous women). Therefore, we should not view the Nurses’ Health Study data on risk of breast cancer as definitive, but we must await the results of the Women’s Health Initiative, the large, ongoing clinical trial. Even in the Nurses’ Health Study, the risk of death from breast cancer was reduced (as demonstrated in many other studies), probably because breast cancer in hormone users is more differentiated and detected earlier.
Can we take some good news from this latest Nurses’ Health Study report? A very important message in this report is the lack of evidence indicating that the addition of a progestin attenuates estrogen’s beneficial effect. In fact, the relative risk of death for current users of estrogen and progestin was even lower than that in users of estrogen alone. In addition, no association with hormone use was found with the risk of cancer death from ovarian cancer, pancreatic cancer, or brain cancer. Indeed, the overall risk of cancer death was reduced, probably because of hormone protection against colorectal cancer.
The evidence from the Nurses’ Health Study indicates that protection for mortality is maintained for only 3-4 years after discontinuation of hormone use. Maximal protection against fractures and coronary heart disease requires very long-term treatment. Of course, the fears regarding breast cancer are an obstacle to such long-term therapy. It is important to provide a balanced picture to our patients. It is totally appropriate to say that whereas some studies have found an increased risk of breast cancer with long-term, postmenopausal use of hormones, many have not. This disagreement means there is no definitive evidence, and furthermore, this lack of agreement means to me that there is unlikely to be a major impact of long-term hormone therapy on the risk of breast cancerotherwise, we would have agreement and consistency among the more than 40 observational studies on this issue.
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