Position StatementsWomen’s Health Initiative & HRT (2003)
Women’s Health Initiative & HRT
RESPONSES TO THE WOMEN’S HEALTH INITIATIVE AND EMERGING RANDOMIZED CONTROLLED TRIAL DATA ON “HRT”
The Society for Menstrual Cycle Research (SMCR), a multi-disciplinary feminist organization promoting accurate and woman-centered science relating to women’s reproductive lives, herewith goes on record regarding the Women’s Health Initiative Estrogen Plus Progestin Arm and other recent controlled trial data. This statement is centered on four important issues.
- The WHI Estrogen plus Progestin trial has produced Level 1 evidence that was previously unavailable.
- These data strongly support SMCR’s position that menopause is a normal phase of all women’s lives and not an estrogen deficiency state that requires hormone “replacement” to prevent serious chronic diseases.
- Integration of previous epidemiological data on menopausal women’s risks for cardiovascular disease with the new WHI data suggests that 59-79% of women’s risks for heart attack and stroke can be eliminated by positive lifestyles and socioeconomic biases in the observational studies.
- More research is needed prospectively documenting women’s health and experiences through the menopause transition (perimenopause) in multicultural populations—funding for the Study of Women Across the Nation needs to be maintained. More research is also needed into the etiology and management of hot flashes/night sweats and other changes that are distressing for some women during the menopause transition and following menopause.
Each of these major points is discussed in more detail below.
1. WHI Estrogen plus Progestin Arm is important science
First, the Women’s Health Initiative Study of Estrogen and Progestin is a well conducted, powered and conceived controlled clinical trial (1). The discontinued Estrogen plus Progestin arm is one portion of a larger study that is also testing the effectiveness of estrogen alone versus placebo and low fat diet related to breast cancer and calcium with vitamin D for osteoporosis. With the screening, enrollment and completion by 16,608 women of 5.2 years of this trial, the National Institutes of Health has accomplished the largest such study that has ever been or will likely ever be performed.
Many thought leaders in women’s health are finding it hard to accept the results of the E plus P arm of the WHI. To adopt these initial WHI results requires change of a strong and carefully constructed but erroneous paradigm about menopause (2). There are many criticisms of WHI—they all arise from the discomfort caused by a paradigm shift. Some of the more prevalent of these criticisms will be addressed here.
This is not “just one study” which implies that it is the only study showing these results. A recent meta-analysis shows that several randomized, placebo-controlled trials did not show heart disease benefit from estrogen alone or estrogen plus progestin (3). This meta-analysis also confirms the increased stroke, breast cancer and pulmonary embolism negative effects and hip fracture and colon cancer positive effects of ovarian hormone therapy (3). Rather it was the first adequately powered trial to test the primary prevention heart disease with hormone therapy.
Some have implied that the increased risks for breast cancer, thrombosis, stroke and coronary artery diseases are caused by the very low dose of medroxyprogesterone that was combined with the daily conjugated equine estrogen. This inference is made because the Estrogen Only arm of the WHI study is still ongoing. However, that sub-study enrolled only 10,700 women and has not yet accumulated adequate experiences to have power to answer the primary question. In addition, because it has now been shown that the risk for breast cancer is significantly decreased in women who have had a hysterectomy (4) estrogen treatment without progestin, which characterizes therapy for women after hysterectomy, starts with a lower underlying risk for breast cancer.
It is of note that the participants in both the estrogen only and the E Plus P arms were issued periodic warnings that excess cardiovascular risks were occurring in those receiving hormonal versus placebo therapy (under instructions from the Data Safety and Monitoring Board).
Other critics have said that the batches of conjugated equine estrogen were faulty and not well absorbed. That is unlikely to be true given the careful, routine monitoring of the pharmacology of trial drugs. Another criticism is that participating women whose age averaged 63 already had osteoporosis or heart disease and therefore that this was not a primary prevention trial. The ages of women were carefully chosen to represent the ages of women who have been routinely offered “HRT” in the United States. Although some women may have had lower than ideal bone density or microscopic vascular disease, they had not fractured and only 7.7% had clinical vascular disease at study entry.
One common initial criticism of the WHI was that it had ignored issues that were important to women such as psychological health and memory. Within nine months after this arm’s discontinuation results of quality of life and dementia sub-studies were also published. Health-related quality of life results showed that there were no significant and clinically important changes in quality of life on E plus P compared with placebo except in the few women ages 50-54 with moderate-to-severe vasomotor symptoms at baseline (5)
Cognition and dementia results showed a significant doubling of the risk for dementia on E plus P over placebo after adjustment for important covariates (6). And the progression of cognitive decline with increasing age was not interrupted by E plus P treatment (7).
A statistical criticism of the WHI is that the increased breast cancer risk is not really a significant finding because the lower bound of the 95% confidence intervals is 1.0. However, for complex but defensible statistical reasons this is a statistically significant result. A further criticism is that the breast cancers documented in the hormone arm were undoubtedly present at some microscopic level at the beginning of the trial. That may well be true given the slow growth rate for most breast cancers. In addition, the women, in a subgroup analysis (not yet formally reported) who had previously used ovarian hormone therapy were at much higher risk for breast cancer than those who had never previously used it. Neither of these observations invalidates the result that those asymptomatic, healthy women randomized to E plus P experienced an increase in breast cancer compared with placebo-treated women, some of whom had also previously used ovarian hormone therapy.
2. WHI results confirm that menopause is not an estrogen deficiency state
The results of the randomized double blind placebo-controlled trial of Estrogen Plus Progestin showed that asymptomatic women on ovarian hormone therapy experienced significantly more serious diseases during the five years of this trial than did women on the placebo (1). These risks included an excess of blood clots (increased 211%), cardiovascular disease (increased by 29%), breast cancer (increased 26%) and strokes (increased by 41%). This means that it is healthier to be an asymptomatic menopausal woman who doesn’t take E plus P than one who does. Although the absolute numbers of women experiencing these serious health conditions was small, no excess risk is acceptable in treatment of a normal phase of life in healthy women.
In its 14th biannual meeting in June, 2001, a year before any WHI results were available, The Society for Menstrual Cycle Research urged a change in language and attitudes related to estrogen and progestin therapy. The SMCR adopted a resolution stating “Whereas menopause is a normal phase of every woman’s life and not an estrogen deficiency condition . . .” the term “Hormone Replacement Therapy (HRT)” should no longer be used.” Instead the SMCR strongly urged that menopausal treatment with estrogen and progestin or progesterone be called “Ovarian Hormone Therapy (OHT).”
For the record, we note that current members of the SMCR Board of Directors, while acting as individual scientists (8-10) have questioned the belief that OHT is effective for heart disease and that menopause is deficiency state (2). Sister organizations such as the National Women’s Health Network effectively lobbied for the WHI trial.
The SMCR’s original philosophical and now science-based position, however, does not mean that symptomatic women who are one year beyond their final menstrual flow and therefore menopausal might not benefit from therapy with estrogen plus progestin. The WHI did not test this question. However there are strong data that OHT is effective for hot flashes and night sweats.
3. WHI highlights the key role that lifestyle plays in heart disease prevention
Observational, epidemiological studies of thousands of women have repeatedly shown that estrogen plus progestin use is associated with a decreased risk for coronary heart disease that averages approximately 30-50% (11). However, the participants in these studies who took hormone therapy were healthier than those who did not (“the healthy cohort bias”). They were more likely to be of normal weight, to be physically active, and less likely to have abnormal blood cholesterol and lipid levels, high blood pressure or diabetes. In some studies OHT taking women were of higher educational or socioeconomic status or had more access to medical care. OHT users who continued on therapy were adherent to taking it. This “compliance bias” has been shown to be associated with better health even in those assigned to placebo treatments (12).
With the results of the WHI E plus P arm hormone therapy increased heart disease risk by 29%. Therefore, the healthier lifestyle of previous hormone users in epidemiological studies overcame this increased risk plus providing the previously documented decreased risk. Together these data inform us that menopausal women’s risk for heart disease can be decreased by 59-79% through simple healthy behaviors such as regular walking, eating sensibly and not smoking, as well as by obtaining appropriate treatment for high blood pressure, abnormal lipids or diabetes if they are documented.
A recent meta-analysis has also examined the results of all trials of estrogen or E plus P treatment and estrogen alone (3). These authors summarized results of all available randomized controlled trials including over 20,000 women for up to 4.9 years to say that negative health outcomes exceeded positive ones in one per 230 50-59 year old women and in 1 per 150 women aged 60-69 years (3).
4. Research on the Menopausal Transition and Hot Flashes is still needed
The WHI E plus P arm has documented that the average, asymptomatic menopausal woman does not need ovarian hormone therapy for heart disease prevention or enhancement of well being. However, a portion of women are highly symptomatic in the years after menopause and during the long and hormonally chaotic menopausal transition (13-16). The NIH-funded Study of Women Across the Nation (SWAN) has currently accomplished a major task in enrolling and documenting midlife women from many ethnic and cultural backgrounds (17). However, their important prospective work still lies ahead. Key scientific questions must be answered through the continuation and appropriate funding of this important study.
Many women, hearing the media reports of adverse effects of E plus P therapy from the WHI study have abruptly discontinued ovarian hormone therapy that they were taking for symptomatic relief of night sweats and hot flashes. It is important the experiences of women abruptly stopping OHT be documented.
The second major area in which physiological and randomized, double blind placebo-controlled research is urgently needed is to understand and effectively manage night sweats and hot flash symptoms (collectively called vasomotor symptoms, VMS). These occur in both the menopausal transition (when estrogen levels are chaotic but tend to be high and not low (18;19) and in women during the early years after menopause. VMS are not “nuisance” experiences but rather are deeply disturbing to some women. They have been linked to increased risks for osteoporosis, sleep disturbances (with associated musculoskeletal disabilities and possible cardiovascular risks) as well metabolic changes such as insulin resistance.
VMS are extremely important to study in women with treated breast cancer. VMS are probably more common and more severe in women who have breast cancer than in other women. These women’s breast cancer treatments (such as chemotherapy, tamoxifen and aromatase inhibitors) increase their risk for VMS. Furthermore, based on the results of the E plus P arm of WHI it is likely that taking estrogen with progestin therapy will increase risks of breast cancer recurrence as well as incidence. However, ovarian hormone therapy is the most effective known treatment for VMS. Some alternatives such as paced respiration (20) and Mind Body Therapy (21) decrease VMS significantly more than placebo. Many pharmaceutical alternatives are either ineffective or have serious side effects or both.
In summary, much more research continues to be needed to understand the physiological and experiential changes of women during the menopausal transition. Some women are highly symptomatic either during the years before or the years after menopause. More research is needed especially to understand the physiology and treatment of VMS in general, and in particular in the subset of women with breast cancer.
Draft written by Jerilynn C. Prior BA, MD, FRCPC (2002/10, revised 2003/06) for the Society for Menstrual Cycle Research with revisions by and approval of the SMCR at their semi-annual business meeting, June, 2003, and by the Board of Directors of SMCR.
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