Position StatementsWomen’s Health Initiative & HT (2007)
Women’s Health Initiative and Estrogen/Estrogen Progestin Therapy For Prevention of Chronic Illness After Menopause
This document is the updated statement of the Society for Menstrual Cycle Research with regard to the Women’s Health Initiative (WHI) research on estrogen therapies to prevent chronic illness after menopause. A paper analyzing the evolving professional response to WHI was presented at the Society’s meeting in June, 2007. Drafts of the update were written and reviewed by a committee of interested members and the Board of Directors. The basic conclusions of the Society’s 2003 position statement remain: WHI provided strong evidence that hormone therapies are not safe and effective for prevention of chronic illness, and that menopause is not an estrogen deficiency disease. However, this updated statement adds a critique of an increasingly heard criticism, the estrogen “timing hypothesis,” which asserts that the WHI research results are limited to older postmenopausal women and that younger women would derive positive benefits from hormone use. This hypothesis has little experimental confirmation and should not be the basis for professional decision-making.
WHI is a program of research to investigate prevention and control of chronic illnesses among postmenopausal women and includes a number of experimental, observational, and intervention studies. As part of the WHI program, a pair of randomized, controlled clinical trials evaluated whether hormone therapies are a safe and effective strategy for prevention of illness, especially of heart disease, in postmenopausal women. One trial, the Estrogen plus Progestin trial (EPT) included women who had not had pelvic surgery; the other (Estrogen Therapy, or ET) included hysterectomized women. Although both trials were ended prematurely because of ethical concerns regarding the safety of study participants, the results collected before the studies ended have had a major impact on professional practice and have been the object of much professional discussion and debate.
Prior to WHI, many in the medical community had advocated use of hormones for disease prevention notwithstanding a lack of experimental data pertaining to this, based on weaker kinds of evidence and their professional judgment. However, WHI provided strong clinical trial evidence, using the hormones that were most commonly prescribed in the USA at the time of the study, that neither estrogen alone nor in combination with a progestin prevents heart disease, and, in addition, when several outcomes were considered together, overall harm outweighed overall benefit. Some conditions such as urinary incontinence and Alzheimer’s disease which were considered by some professionals to be a consequence of menopause turned out to be worse rather than better among hormone users. Risk of stroke, which was hypothesized by some to be reduced by hormones, again was increased rather than decreased. Some professionals had previously asserted that hormones increased a woman’s general feeling of well-being, and, again, this turned out not to be the case for women who did not have symptoms like hot flashes. Although hormones effectively reduce hot flash frequency and intensity, when hormone users stopped taking hormones, hot flushes were more of a problem for some than when the study began.
The conviction that hormones prevent disease relied on the idea that menopause is a disease state, in which estrogen deficiency creates vulnerability to a wide range of illnesses, including heart, bone, and brain disease. The WHI results therefore also supported SMCR’s position that menopause is a normal phase of a woman’s life and not an estrogen deficiency disease that requires hormone “replacement” to prevent serious chronic illnesses.
While many professionals accepted the results of the study, a variety of criticisms have also been made. An important recent development has been the hypothesis that WHI did not observe significant disease prevention because the research participants were too old. The idea is that hormone therapy must be begun soon after menopause (or even in perimenopause) in order to be effective for disease prevention; if women begin hormone therapy many years after menopause, it is already too late to be helpful and, because of incipient development of disease, can be actually harmful. This idea is being generalized to a variety of chronic illnesses of old age, including heart and brain disease.
The Society regards the credence given this emerging estrogen “timing hypothesis” with alarm. Some professional groups have already incorporated this possibility into their recommendations (for example, the North American Menopause Society) and many professional articles cite it. Yet the research supporting the hypothesis is not strong data, and often is not even acceptable as reliable data, when considered by the normal standards used by researchers. For example, conclusions are drawn from data that are not statistically significant (that is, they could have occurred by random chance) or research that is underpowered (that is, there aren’t enough subjects to draw an accurate conclusion). Conclusions are drawn from markers of disease rather than from disease outcomes. Research data inconsistent with the hypothesis are not considered, for example, studies suggesting that younger women also have negative health effects from hormones. Data are inaccurately over-interpreted; for example, assuming that an observation in younger women will continue to be found as they age. Conclusions are drawn based on possible positive coronary artery outcomes while not simultaneously taking into account negative cardiovascular effects such as stroke and serious blood clots. Further, the WHI study participants in fact reflected the demographic of hormone users when the study was started.
Ironically, WHI showed that a set of hypotheses based on weak data, no matter how firmly believed, can turn out to be inaccurate when clinical trial data are collected. We believe that this lesson of WHI should be remembered. The estrogen “timing hypothesis” is just that—it requires testing in a large, controlled trial with power to detect diseases themselves, not just markers for disease. It is premature to give credence to the idea that younger women react differently to hormone therapy. We believe that it is the continued belief in the underlying idea that menopause is an estrogen-deficiency disease, rather than strong evidence, that has led to the hypothesis that hormone therapy immediately after menopause will prevent a broad variety of diseases. This must be proven.
SMCR, like the WHI researchers, the FDA, and others, believes that hormones should not be used for disease prevention; short-term use to treat distressing symptoms like menopausal hot flashes is warranted and effective but should be with the lowest dose and for the shortest time. SMCR, like the American Heart Association and others, concurs that for midlife and older women, as for men, engaging in regular physical activity, maintaining a normal weight, eating a well-balanced healthy diet and avoiding cigarettes are the first lines of defense in maintaining health. We believe that continued research on the normal course of menopause and on the etiology and best treatment for menopause-related distress is needed, as is continued research on lifestyle and other interventions for disease prevention.
SMCR also believes that avoiding harm should be a primary consideration in preventive health and in research on preventive health. Even if it were true that hormone therapy could prevent heart and other chronic diseases, a prevention tool that requires medicating large numbers of women for long periods of time relative to the number of women who will benefit, is not effective prevention. This is especially true if the medication in question carries risks of serious outcomes like strokes and blood clots. While risks are not large enough to preclude treating symptomatic women, these medications are inappropriate in a prevention tool. Further, research on EPT and ET for menopausal women has repeatedly caused harm to study participants, in WHI and in previous studies.
Menopause is not a disease causing heart disease but a normal phase of an adult woman’s life.
Contact: Paula S. Derry, Ph.D., 410 433-7356, Paula.Derry[at]gmail.com
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