In 2002 some scientists published a paper (see ref at end of this article) which said taking hormones after menopause increased risks of heart problems, breast cancer, stroke and blood clots. The news media were quick to exclaim to the world that: BIG BAD HORMONES WERE NOT GOOD FOR YOU.
This caused quite a stir and many physicians advised patients to stop taking their hormone drugs which contained estrogen and progesterone. This is too bad because the conclusions of the Woman’s Health Initiative (WHI) scientist were wrong for the following reasons:
THEY USED THE WRONG CONFIDENCE INTERVAL TO DETERMINE STATISTICAL SIGNIFICANCE
In their first paper, the one in 2002 that caused most of the problems, the WHI authors used a measurement of variation called the nominal 95% confidence interval and they should have used an adjusted 95% confidence interval. Confidence intervals (CIs) are used in tests for statistical significance.
Nominal CIs can be used when a single outcome or result is being tested but in the WHI studies there were multiple outcomes being tested, so they should have used CIs which are adjusted to take into consideration the possible error introduced by multiple testing. Nominal CIs are smaller than adjusted CIs, so when they are used incorrectly they make numbers look significant when they are not.
For example: The relative risk (RR) and nominal CI for risk of breast cancer was 1.26 (1.0-1.59) which is barely significant ; however, when the correct adjusted CI is used (0.83-1.92) we see that it includes the no effect level of 1.0 and would be judged as not significant. This incorrect use of nominal CIs was used throughout the paper.
Such incorrect use of statistical techniques should have disqualified this paper from publication.
ACTUAL AND RELATIVE RISKS
One of the biggest contributions to inaccuracies and exaggerations in these studies is the failure to state and emphasize that the actual or absolute risks are small. How can this be? It is really very simple as I have explained in my two earlier Blogs entitled: What is the truth about health risks? and How to understand blog graphs.
The bottom line is you can have very small actual risks accompanied by very large relative risks. Since the relative risk numbers are large they are the ones that show up in the news media. If the small actual risk numbers were released no one would pay any attention to them.
For more comparisons between relative and actual risk see the table below. Remember these claimed increased risks were not significant in the first place so they don’t count.
FAILURE TO EXAMINE THEIR DATA CAREFULLY
A good example of this lack of attention was their failure to see that the apparent increased risk of heart disease and breast cancer during a critical time (yr 5) was not caused by an increased number of women with these diseases but a chance decrease in the number of women in the placebo control group. There was no real or significant increase in risk in heart disease or breast cancer but these mistakes were the main reason for stopping the study.
Increases and decreases in risks may occur by chance or there may be some underlying cause. The proper statistical analysis tells us whether these differences are real or just due to chance. All too often in these kinds of studies the authors will make statements like: The risk of breast cancer was increased by hormone treatment. Then they add: although the increase was not significant. In other words the differences could have occurred by chance and there is no real increase. The only part of the above which is published in the press is: Breast Cancer Risks Increased by Hormone Treatment. The headline should have been: Breast Cancer Risks Not Increased by Hormone Treatment.
In a subsequent more detailed paper on the effects of hormone treatment these authors indicate that no significant increased risks of breast cancer were observed (Chlebowski et al 2003). This revised conclusion was not announced by the news media and no retraction of the original incorrect conclusions was made. Most doctors and researchers either do not know of this correction or choose to ignore it.
THE WOMEN IN THE STUDY WERE TOO OLD WHEN THE STUDY BEGAN
The WHI studies used data from women who were 12-15 years past menopause before they started taking hormones. This means these women were without their normal levels of estrogen and progesterone long enough to bring about changes in various bodily functions which are the precursors of disease. For instance, ovarian hormones are important for maintaining the blood vascular system in good shape. Once vascular disease has begun as a result of menopause hormone treatment is not likely to reverse the effects. Proper bone strength is maintained by estrogen and when it is no longer secreted at menopause bones begin to lose calcium and the first stages of osteoporosis begin. Most reproductive scientists believe that post menopausal hormones should be used as preventives not corrective therapy.
WHI STUDIES WERE NOT REALLY DOUBLE BLIND
The best way to do a clinical study of this kind is to do it so that neither the participants nor the doctors know who is getting the drug and who is getting the placebo. This was supposed to be one of the strengths of the WHI studies; unfortunately, the women did not remain blind and as many as 45% of them were not only told what group they were in but also given warnings about the possibility of increased risks for heart disease, breast cancer etc. This destroys the credibility of such a study and when this happen the entire study should have been stopped because of these flaws.
ESTROGEN ALONE DID NOT INCREASE RISK OF BREAST CANCER
The WHI investigators also evaluated disease outcomes in women who took estrogen alone as a post-menopausal treatment. The authors concluded that estrogen alone did not increase the risk of breast cancer or heart disease and decreased the risks of hip fracture. They also concluded that estrogen alone did increase the risk of stroke. These four papers, most of which were published in 2006, suffer from the same problems and bad sciences as outlined above. They are loaded with extreme variability in the treated and control groups which were not taken into consideration. Once again, they used the wrong measure of variability to test for significance, and called the increase risk of stroke to be significant when it was not. In addition, these estrogen only studies have all of the other problems discussed for the estrogen plus progestin studies.
CONCLUSIONS
Most people, including physicians, do not realize that the conclusions in the original 2002 paper were incorrect. Although the WHI investigators indicate in their later papers that no increased risks were found, they fail to point out clearly that their conclusions were incorrect in 2002 and that the study should not have been stopped. Little has been said in the popular media. No retraction, no admission that the WHI study should have been continued, no attempt to set the record straight. So most women and many physicians keep plodding along believing hormones increase risks for these diseases, when they don’t.
REFERENCES
Chlebowski RT et al (2003) Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA 289: 3243
Writing Group for the Women’s Health Initiative Investigators. (2002) Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women’s Health Initiative Randomized Controlled Trial. JAMA:288:321-333.
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