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MedGenMed. 2004; 6(3): 65.
Published online Aug 9, 2004.
PMCID: PMC1435607

The Women's Health Initiative 2004 - Review and Critique

John A Goldman, MD, FACP, FACR, FASLMS

Abstract

The Women's Health Initiative (WHI) was designed to define the risks and benefits of interventions, notably hormone therapy, to potentially prevent heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women. On the basis of results from the study and their interpretation by the lead investigators, guidelines for the use of hormone therapy in postmenopausal women have changed. This article reviews the published results from the WHI and their various interpretations. The author argues that the WHI investigators and the journals reporting the initial and follow-up studies from the hormone therapy arms of WHI did not put the data into clinical perspective appropriately. It was not emphasized that the WHI participants were older postmenopausal women, for example, and that women with menopausal symptoms were dissuaded from entering the study. The reports also undervalued the fracture data. Those responsible for publishing the WHI data did not allow an in-depth critique of the study, did not ensure that the shortcomings of the study and the implications of the exclusion and inclusion criteria were clearly emphasized, and did not take the responsibility of ensuring discourse and critique of the studies in their editorials and letters to the editors. What was presented by the WHI authors in July 2002 changes with each new publication from the group, and this author suggests it has undermined the credibility of the research and of the medical community as a whole.

Background

Health (NIH) -- specifically, the National Heart, Lung and Blood Institute (NHLBI). The aim of the study was to define the risks and benefits of interventions to reduce the risk of heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women.[1-3] For the study as a whole, 373,092 women were screened, and 161,809 aged 50 to 79 years were enrolled in either an observational study or clinical trials of low dietary fat vs self-selected diet, estrogen and progesterone therapy (HT) or estrogen therapy alone (ET) vs placebo, or calcium and vitamin D supplementation vs placebo. The larger of the 2 studies evaluating postmenopausal hormone therapy randomized nonhysterectomized women to estrogen plus progestin (0.625 mg conjugated equine estrogens [CEE] + 2.5 mg medroxyprogesterone acetate (MPA), Prempro, N = 8506 women) or placebo (N = 8102 women). Monitoring of these subjects began in the fall of 1997 and was scheduled to last until 2005. However, the Data Safety Monitoring Board (DSMB) terminated the HT arm of the WHI early when a predetermined threshold of excess cases of breast cancer was reached.[4] The smaller hormone study involved 10,739 women who had undergone hysterectomy; they were randomized to receive estrogen alone (0.625 CEE, Premarin) or placebo. The ET arm was terminated March 2, 2004 -- also early -- because of increased risk of stroke. Of note is that the DSMB did not recommend termination of this study; rather, the NIH directly decided to terminate the study.

Termination of the HT and ET Arms of the WHI

Both arms of the hormone therapy component of the WHI were terminated early: HT WHI after 5.2 years, and ET WHI after nearly 7 years. As reported in the July 17, 2002 JAMA[1] and in an NIH news release,[4] the DSMB recommended that the trial of HT vs placebo be stopped because the risks outweighed the benefits. The statistical data collected indicated that in addition to an increase in breast cancer cases, the global index statistic supported the finding that the risks exceeded the benefits.[2] Of note is that the global index, which is a combination of the monitored outcomes of coronary heart disease (CHD), stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death due to other causes, has never been independently validated. The WHI investigators had set out to determine whether the global index would demonstrate an overall benefit despite the expectation of increased breast cancer.[2) This was not the case. There were no differences in mortality or cause of death reported between the treatment and placebo groups.[1]

Initial analysis of the outcomes for women on placebo and women on HT indicated that for every 10,000 women taking HT there would be 8 more cases of breast cancer, 7 more cardiac events, 8 more strokes, 18 more cases of venous thromboembolism, 6 fewer cases of colorectal cancer, 5 fewer hip fractures, and 19 more women with an increased global index per year. In addition, 23 more cases of dementia per 10,000 women per year were predicted on the basis of data reported in May 2003.[5-7] In August 2003, the estimated number of cardiac events was revised downward from 7 to 6 more cases per 10,000 women on HT per year.[8] The initial HT WHI analysis[1] also revealed a 34% reduction in hip and in vertebral fractures, a 23% reduction in other osteoporotic fractures, and a 24% decrease in total fractures, but only the hip fracture data (and not the other fracture data) were included in the global index. The HT WHI fracture data were reported independently in October 2003.[9]

The termination of the ET arm on March 2, 2004 will now be weighed against the earlier data and an attempt made to explain the seemingly paradoxical differences in risks found between the 2 arms of the WHI. ((Table 1)).[1,10,11] Whereas HT was associated with an increase in CHD and breast cancer within 5 years, during 7 years there were no increases in CHD or breast cancer associated with ET. Both ET and HT were associated with an increase in strokes and deep venous thromboembolism (DVT) and a decrease in hip fractures. HT was found to increase dementia and/or mild cognitive impairment, and there was a trend for increases in these same measures with ET. There was neither an increase in risk of mortality with ET nor global index risk, but there was an increase in colorectal cancer in the treated older age group (age 70 to 79 years). The separate outcomes results and analysis of this arm are just beginning to be published.[11-16]

Table 1
Comparisons of the Outcomes of the Women's Health Initiative -- Estrogen Plus Progestin vs Estrogen-Alone Study Arms [1,11]

Comparisons

WHI was a well-done study, but the statistics used to analyze the data are complex. The data in the WHI were compared using hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportional hazard analyses. Cumulative HRs were estimated by the Kaplan-Meier method for each designated outcome. The WHI used 2 CIs: the traditional or nominal confidence interval (nCI), which is comparable to CIs reported in most other hormone therapy studies, and the adjusted confidence interval (aCI) to acknowledge multiple testing issues, which was calculated using group sequential methods and the Bonferroni correction for the multiple secondary outcomes. Percentages and outcomes in the published papers, such as the number of events per 10,000 women per year, were calculated using the published WHI data sheets if they were not directly stated in the papers.

Coronary Heart Disease

CHD was a primary outcome. Further analysis of the risk of CHD in the HT WHI arm was adjudicated centrally, and when reported in August 2003, the CHD risk was decreased from 7 (as reported in July 2002) to 6 per 10,000 women per year.[8] There was a significant increased risk for CHD in the first year and a smaller, non-statistically significant increase in subsequent years. However, it was also noted that there was a trend toward decreasing relative risk over time that was statistically significant (z score = minus 2.36 [P = .02]). CHD risk actually increased in the placebo group by Year 6, which leads to an apparent although not statistically valid risk reduction with HT.[8] The HR for CHD was smaller for women in early menopause (< 10 years since menopause) as compared with older postmenopausal women (HR = 0.89), but this was not significant. The authors stated that the low number of events during the course of the study, the decreased adherence to the study medications over time, and the fact that the results were confined to women at risk for their first coronary event should warrant caution with respect to interpretation of the CHD data.[8] The HRs for adverse CHD events with time since menopause did not show an increased risk, but rather a decreased risk[8] ((Table 2)). Notably, in the 2003 publication, the CHD data were stated to be nonsignificant after the first year. In addition, as was found for the Heart and Estrogen/progestin Replacement Study (HERS) trial, in the WHI the women on HT who used both statins and HT did not have an increased risk of CHD.[17,18]

Table 2
Declining Risk of Coronary Heart Disease According to Year of Follow-up for Women's Health Initiative Estrogen plus Progestin Risk of Coronary Heart Disease study.[8]

The media attention that accompanied the release of the results of the HT arm of the WHI to physicians and the public should have been repeated when the new CHD data were released. That there was a significant trend for decreasing relative risk is an important point -- one that has not been emphasized to treating physicians. The ET arm of the WHI shows a mild, nonsignificant, early increase in CHD; however, no increase in CHD was observed for the treatment group in total, and in fact there was a decrease with ET in the younger age group (age 50 to 59 years; HR = 0.56, nCI = 0.30- 1.03).[11]

(Table 3) illustrates some of the contrasting results of the 2 WHI studies regarding CHD. Note the increase in CHD in the HT WHI study and the decrease in the ET WHI. Note also that (Table 2) compares the HT WHI cardiovascular study details vs the ET WHI general paper.[8,11] Other authors have used data comparing both general papers.[8,11,19] The release of further cardiovascular data from the ET WHI is necessary for a more comprehensive analysis and comparison. Perhaps then we will be able to explain the paradoxical outcomes in the ET and HT arms.

Table 3
Coronary Outcomes Among Women in the Estrogen Plus Progestin and Estrogen Alone Women's Health Initiative[8,11]

The WHI authors also reported that the results of the ET arm did not support those of earlier observational trials that found ET to be protective for CHD; yet, if one looks at the data presented in the article, there is a decrease for the women in the younger age group (50 to 59) who were randomized to ET.[11] It may be that the authors will address this in future articles. Fasting lipids were measured in 8.6 % of the ET WHI participants. The women in the treatment group had a greater decrease in low-density lipoprotein cholesterol (-13.7% vs -1.0%, P < .001), a larger increase in high-density lipoprotein cholesterol (15.1% vs 1.1%, P < .001), comparable reductions in total cholesterol, and a comparable increase in triglycerides (25% vs 3%, P < .001). The systolic blood pressure, but not the diastolic blood pressure, was elevated by a mean of 1.1 mm Hg, with standard error 0.4 mm Hg. The initial data from the ET WHI also show a modest benefit of ET, as noted by the authors, with a decrease in CHD at 7 years for the entire group. Remember, there was a nonsignificant decrease in CHD after 6 years with HT, although it was neither hyped nor heralded by the WHI investigators or the publishing journals.

Published at the same time as the HT WHI cardiovascular data in the same issue of The New England Journal of Medicine (NEJM) was an article reporting no progression in coronary atherosclerosis by quantitative coronary angiography during therapy with 17beta-estradiol alone or 17beta-estradiol with medroxyprogesterone acetate, which are different hormone preparations from those used in the WHI.[20] The latter article's authors, the Women's Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial (WELL-HART) Research Group, monitored 226 postmenopausal women in a controlled study and found no evidence of reducing atherosclerosis with hormone therapy, but neither was there an adverse effect. (No comment was made on plaque stability or thrombosis, as noted in the editorial by Herrington[21]). Notably, these patients with established coronary artery disease were all taking HMG-CoA reductase inhibitors along with the 17beta-estradiol.[18] Because there was no increase in CHD in the participants of the WHI who were on statins -- a finding that was also reported in HERS -- this might suggest that the use of cardioprotective therapy such as statins or low-dose aspirin should be considered as an adjunct therapy to HT in patients with risk factors for CHD. The HT WHI authors note that HT seemed to have "less adverse coronary effect on women who were taking statins," but further remarked that until clinical trials are done, there are not enough data to support this recommendation.[8] The data on statin use are only briefly noted for those with CHD and are not discussed for the other participants in this paper.[8] This is an area where evidence-based medicine needs to be developed, but for the present the clinician will need to make a decision on a case-by-case basis.

There are other noteworthy facts about the WHI: There was a high dropout rate -- 42% in the HT group and 38% in the placebo group. In addition, the number of subjects in many of the subgroups was small (although it should be noted that, compared with other studies, the numbers in some subgroups are sizable), and there were a number of comparisons made between the subgroups, with approximately 36 tests for interaction. In the ET arm, 53.8% of the participants dropped out by stopping their medicines.[11] The authors caution that these factors can have an effect on the statistical data and thus, the data should be interpreted with caution.[1,8] In particular, Bailer[22] notes that the loss to follow-up affected the ratios of loss of patients to follow-up to the number patients with a cardiac event. The ratio is 57:99 in WELL-HART and 541:335 in WHI, so that completion of follow-up for 57 missing subjects in WELL-HART or 541 missing subjects in WHI might add enough endpoints to alter the findings.[22] The WHI involved 16,608 women at 40 participating centers with as many as 12,000 independent treating physicians. This study was a gigantic undertaking, and a high dropout rate would not be surprising; indeed, the investigators should be given major credit for keeping as many participants as they did. Even the subanalyses of the WHI represent large studies when compared with other hormone studies. The patients who were lost to follow-up may also simulate the on/off nature of estrogen usage in the real world.

Kleerekoper[23] has advised that we be cautious with our interpretations of the cardiovascular data collected in WHI. Why did the study confirm previous observational studies for the risk of breast cancer and thrombosis but not the bulk of the cardiovascular studies? He emphasizes the need for careful experimentation and observation to see the effect of estrogen on the cardiovascular system rather than taking the WHI as the last word.[23] The release of the ET WHI data showing no increase or decrease in CHD seems to lend support to this point.[10,11] The ET WHI study does not show an increase in CHD -- does this mean that progestin added to CEE can increase the risk? There was a large decrease in the risk for CHD in the younger age group (50 to 59 years) with an HR of 0.56 -- does this vindicate the earlier observational trials that showed cardioprotection with HT or ET? A full report of the ET WHI cardiovascular endpoints should help us to answer these questions.

In addition, it must be noted that the WHI studies used a single type and dose of estrogen, namely 0.625 mg CEE supplied by Wyeth Pharmaceuticals. Would similar results occur with other hormonal products? Another question one ought to consider is whether a patient without an intact uterus has different risk factors for CHD.[24] The ET WHI authors offer possible explanations for the difference in outcomes in the HT and ET arms, including the presence of progestin, different baseline risk factors in the populations of the HT and ET WHI studies, duration of intervention, follow-up time, and the role of chance.

Grodstein, Clarkson, and Manson[25] have suggested there may be a variety of explanations for the difference found between randomized trials and observational trials. The studies may have methodologic differences, including confounding ("healthy user") bias, compliance bias, and incomplete capture of early clinical events. There may be different biologic effects that depend on formulation and dose of the hormone regimen; or differences in characteristics of the study population, including endogenous estrogen level, time since menopause, and stage of monitored endpoint such as atherosclerosis. The WHI data diverge from observational studies with respect to CHD, but with breast cancer there is concurrence between the WHI and observational studies. The WHI showed an increase in CHD with HT, HERS showed the same risk as placebo with HT, and observational trials showed a decrease in CHD with HT. And, the WHI ET showed no increase in CHD.

It has been suggested that different hormone regimens may have yielded a different outcome and that using HT earlier, ie, in younger menopause (on average the women in the WHI were 10 years postmenopausal) and before coronary atherosclerosis is established, would not have led to an increase in CHD. It has been stated that by design the WHI was 10-fold underpowered to show cardioprotection by estrogen and progestin.[26] Thus, observational trials that have shown cardioprotection are the only reliable guides for now until randomized clinical trials are done.[26] Clarkson and Appt[27] have considered the question of whether progestins, such as MPA, attenuate ET's beneficial cardiovascular effects. Their conclusions are that, currently, experimental, clinical, and observational data do not find that progestins attenuate the cardiovascular benefits of estrogen.[27] This kind of information also needs to be considered by the clinician who ultimately makes the therapeutic decisions.

In light of the fact that the trial enrolled more than 166,000 participants and that a total of at least 24 articles are predicted to come out of the WHI, we must keep in mind that the meaning of the results presented in the individual papers on cardiovascular risks cannot be fully appreciated and interpreted until we get a complete view of the whole study. What if a detailed profile of risk factors for the patients participating in the HT and ET arms differs from what we have deduced on the basis of what has been published so far in terms of conclusions regarding who is at risk? This is something that physicians and patients who are earnestly trying to make long-term clinical decisions may have to confront. The WHI observational study, which was also published in JAMA,[28] suggests that use or nonuse of HT was less important as a predictor of cardiovascular risk than were baseline levels of either CRP or IL-6. This article thus gives us a different view and perspective. Another observational WHI study[29] indicates depressive symptoms are significantly related to increased risks of cardiovascular disease (CVD) death and all-cause mortality, even when controlling for CVD risk factors. Taking antidepressant medications did not alter the depression-associated risks. This clearly emphasizes the role of depression and highlights this as another CVD risk factor to treat. This study is curious, however, because antidepressants did not alter the associated risks; perhaps other factors of therapy may affect the outcome, such as type of antidepressant or dose or even timing of therapy. Also the type of depression may need to be clarified.

Menopausal Symptoms

Despite the well-known symptoms of menopause, which are often the major reason to initiate HT and ET, the WHI did not report on menopausal symptoms in the initial July 2002 article.[1] This is an important point, because control of vasomotor symptoms may be a significant benefit for thousands per 10,000 women per year, especially younger women in early menopause. Vasomotor symptoms occur in about two thirds of menopausal women and are distressing in 10% to 20%.[30] Most have hot flashes for 6 months up to 2 years, although they can last for ≥10 years.[31] Because data on menopausal symptoms were not included in the first article, we did not have that information to discuss with our patients. If the data had been reported, there is little doubt that the number of women now taking and benefitting from hormone therapy would be substantially higher. This omission was partially rectified in May 2003, when the authors for the HT WHI published the article "Effects of Estrogen plus Progestin on Health-Related Quality of Life" in NEJM.[32] The authors conclude that HT does not have a meaningful effect on health-related quality of life compared with placebo. However, they analyzed the whole population of 16,608 women for only the first year; a smaller subgroup of 1511 women, 8.6% of the total study population, was randomly chosen for further evaluation at 3 years.

Nowhere in this article does it state the number of women who were not enrolled in the study because of severe menopausal symptoms. For the HT arm of the study (as well as for the ET arm), there was a 3-month washout period before therapy (ie, HT or placebo) was initiated. Women in this washout group who had moderate to severe menopausal symptoms were discouraged from participating in the WHI study. This obviously excluded women who may have had the greatest benefit from HT and furthermore may have skewed the data such that the conclusion would be that HT had "no meaningful effect on health-related quality of life."[32]

In the total group of 16,608 participants, after the first year, there were favorable improvements in those on HT for bodily pain and role limitations due to physical problems and sleep disturbance ((Table 4)). The authors note these were small improvements and were not maintained after 3 years in the smaller group. There was a lot of discussion in the article about the "smallest increment of change" being the smallest benefit or harm to an individual person as measured by a particular instrument. It is of interest that this "smallest increment of change" was not used in the initial WHI article.[1] And, in the NEJM article regarding quality of life,[32] the authors do not express their data in terms of the familiar "number of events per 10,000 women per year." In fact, it is unclear from the NEJM article how the data could be placed in these terms, which calls into question the standardization of the WHI writing groups.

Table 4
Estrogen Plus Progestin Arm of the Women's Health Initiative -- Changes in Quality of Life in Change in Estrogen Plus Progestin Minus Change in Placebo [32]

In an editorial accompanying the article, Deborah Grady, MD, MPH, emphasizes that postmenopausal hormones should be used only to treat symptoms.[30] She acknowledges that the WHI was not designed to test the effects of hormones on vasomotor and other menopausal symptoms. She proposed that because only 12% of the participants reported symptoms at baseline, the symptoms must not have been so severe that the participants were not willing to be randomly assigned to placebo. She does not address the enrollment process, in which women with menopausal symptoms were actually discouraged from joining this study.

In a subgroup analysis also presented in the NEJM article, 2 groups were evaluated: one group consisted of early menopausal women aged 50 to 59 for whom there were substantial differences from the other participants with respect to the effect of HT on vasomotor symptoms. When women in this age group who entered the study with moderate-to-severe vasomotor symptoms at baseline were evaluated (1072 women in the HT group and 974 in the placebo group), the analysis revealed statistically significant improvement with HT for hot flashes (76.7% in the HT group and 51.7 % in the placebo group, P < .001) and night sweats (71% in the HT group and 52.8 % in placebo, P < .001). The second subgroup evaluated consisted of women 50 to 54 years old (574 total women). After 1 year, those receiving HT experienced improvement in sleep disturbance (P < .02), and there was a trend toward improvement in social functioning (P < .06) and satisfaction with sex (P < .06).

The majority of the participants in the WHI study were much older, and the authors[32] note that the conclusions drawn on the basis of the total participant results may not be applicable to those younger women who believed they needed hormones and would not have undergone randomization. The authors also conclude that the small improvements in physical functioning, bodily pain, and sleep disturbance were noted only in the first year, although they did not assess these endpoints in the entire population in the third year. They further state that these improvements did not outweigh the small numbers of heart attacks, strokes, blood clots, and breast cancers noted in the earlier WHI report,[1] but as the data are presented so differently in the 2 reports, this is a difficult comparison to make and judge. As the outcomes are at odds with the goals of a prevention study for which prevention is supposed to be essentially risk free, this would be an argument against the use of HT. However, to compare with previous data in the WHI, outcomes in the NEJM article should be enumerated in number of events per 10,000 women per year.

As an aside, another twist is that a recent study has shown that MPA antagonizes the beneficial effects of estradiol (E2) in ovariectomized pigtail macaques (Macaca nemestrina) whereas progesterone (P4) does not.[33] E2 alone increased female sexual initiation rates. P4 did not inhibit sexual behavior but MPA did. Both MPA and P4 did counteract the effects of E2 on anxiety. There was also an increase in aggression with MPA. Thus, there is concern that HT with MPA may have a negative effect on sexuality and anxiety and serious side effects with aggression. Quality-of-life measures in the WHI HT were mainly subjective, whereas these are objective measures. It will be interesting to compare the WHI HT and ET arms with respect to "health-related quality of life" to see whether there is difference.[32]

Cancer

According to a press release, the DSMB halted the HT WHI study principally because the risk for invasive breast cancer had become significantly higher in the HT group compared with the placebo group.[1,4](Table 5) summarizes the cancer data and shows an increase in invasive breast cancer, a decrease in colorectal cancer, and no change in endometrial and total cancer. The criteria to stop the HT WHI for breast cancer were apparently pre-arranged using O'Brien-Flemming boundaries.[2] This suggests that the DSMB planned to stop the study once the risk of breast cancer confirmed the findings of previous case control and historical studies. Thus, it seems that although this study was planned to last for 8 years, hypothetical scenarios of the WHI trial were constructed at the time of design to see whether the DSMB would or would not recommend stopping a given study component of the clinical trial. Under this framework, it could be that the study originally intended to last 8 years could be shortened, even though the risk of breast cancer is thought to take longer than 8 years to manifest.[3] The WHI investigators had hypothesized that the global index would outweigh the expected risk of breast cancer. But as mentioned above, the global index has not been independently validated. So, was it appropriate to use? And, was it appropriate to give equal weighting to each of the adverse and beneficial outcomes? That an increase in breast cancer did not occur during the time period studied in the ET arm of the WHI ((Table 6)) should also lead to questioning the difference of HT vs ET and to further questioning of both outcomes.

Table 5
Cancer and the Estrogen Plus Progestin Women's Health Initiative[1]
Table 6
Cancer and the Estrogen-Alone Arm of the Women's Health Initiative[11]

The study on the influence of HT on breast cancer and mammography yielded important results for clinicians to be aware of and raised some major questions.[34] There was a statistical increase in total breast cancer (HR =1.24; P < .001), invasive breast cancer (HR = 1.24; P = .003), and a nonsignificant trend in "in situ" breast cancer (HR = 1.18; P = .09). The difference became prominent after 4 years, but when a sensitivity analysis in adherent participants was evaluated and the nonadherent participants excluded, the risk for invasive breast cancer increased, and this increase became apparent after 3 years (HR = 1.49; P < .001).

The mammograms for those on HT were substantially abnormal in the first year (9.4% vs 5.4 %, P < .001 HT vs placebo) and even more so in younger women age (50 to 59 years; 8.8% vs 5.9 %, P < .001). These differences continued, so that by the end of the study, 31.5% of those on HT had at least 1 abnormal mammogram compared with 21.2 % of the placebo group (P < .001). Difficulty in interpreting the mammograms may have led to later discovery of breast tumors, allowing them to grow more, have more positive nodes, and be diagnosed at a more advanced stage. The invasive breast cancers with HT were larger than those in the placebo group, 1.7 cm vs 1.5 cm (P = .04), respectively. The HT invasive breast cancers were more likely to have positive lymph nodes (25.9% vs 15.8%, respectively; P = .3). The tumors in the women on HT were in a more advanced stage than those in the women on placebo (Surveillance, Epidemiology, and End Results [SEER] stage regional/metastatic 25.4% vs 16.0% respectively; P = .04). This study was well done and well reported, but it is disappointing that the results in relation to the global index were not discussed and that the data on the number of events per 10,000 women per year were not provided.

An important point to note from this study is that it may be more difficult to detect cancers in women on HT because they will have denser breasts. The finding of increased abnormal mammograms in women on HT should stimulate physicians to use more scrutiny in such patients. In addition, although it will increase cost, follow-up mammograms will no doubt be required more frequently. Of note is that a mammography study is ongoing; the information gained from this research should be helpful to physicians.

Because the WHI study included older participants, the breast cancer risk would be higher, and perhaps breast cancer would be apparent earlier (detection at 3 vs 4 years) in those who took HT before entering the WHI study, and these participants may have been at greater risk compared with those who never used menopausal hormone therapy. However, although there was a trend for difference, it was not significant: < 5 years prior use, HR = 1.09 vs > 5 years prior use, HR = 2.27; weighted P = .15.

Finally, the implication that the breast cancer risk may be greater with use of HT than with ET will need to be examined once the ET WHI breast cancer data are published.

Estrogen as a Carcinogen

The listing, December 11, 2002, by The National Institute of Environmental Health Sciences of estrogen therapy as a carcinogen in their National Toxicology Program, Tenth Report on Carcinogens (RoC), is worth mentioning.[35] The RoC is probably not familiar to most practicing physicians, and many may not even be aware of the National Toxicity Program. The data from the WHI are not referenced in this report. Conjugated estrogens have been on the list for 10 years, but steroidal estrogens were added December 11, 2002. Some of the medications we use, such as azathioprine and cyclophosphamide, are on the list, whereas others, such as the carcinogen methotrexate, are not. An agent is added to this list on the basis of results from a variety of studies (conducted mostly before 2000), and the requirement is that the agent has been shown to be carcinogenic in humans. The impact of this list, which now contains 228 substances "known" or "reasonably anticipated" to pose a cancer risk, on prescribing is not known at this time.

Whether or not physicians are aware of the RoC, they were certainly aware of the risk of breast cancer associated with HT and ET before the WHI results and aware that this risk influences patient acceptance of HT and ET. The impact of the HT WHI has been to emphasize this risk, although the ET WHI may lead to a questioning of it. It will be important to see the complete cancer outcome studies of both the HT WHI and ET WHI arms.

Breast Cancer and Menopausal Symptoms

The difficult problem of treating menopausal symptoms in women with breast cancer was addressed in the HABITS (Hormone replacement therapy breast cancer diagnosis – is it safe?) study.[36] This trial evaluated the use of HT for menopausal symptoms in women who had a history of breast cancer. But on December 17, 2003, the report of the data monitoring committee (DMC) of the HABITS study prompted the steering committee to stop the trial and advise all patients on HT to stop treatment because of an increase in recurrent breast cancer.[36] The study had planned to evaluate 1300 women to determine whether it was safe to use a 2-year HT treatment program for menopausal symptoms in women with previously treated breast cancer. Only 434 women had been randomized by September 2003. The investigators found an unacceptable risk for women exposed to HT after finding 26 new breast cancer events in the HT group and 7 in the non-HT group. This study had been initiated because earlier observational studies had suggested that HT does not increase recurrent risk. Chlebowski and Col's comments on this study's findings suggest that the HABITS investigators have found that even short-term use of HT poses an unacceptably high risk in patients with previous breast cancer.[37] They called for research to find therapy for the difficult problem of menopausal symptoms. This is an important point. An implication of the WHI trial is also that research into alternatives for therapy to treat menopausal symptoms is necessary. For now, the North American Menopause Society has published a comprehensive review of therapies for the treatment of menopausal symptoms that physicians should find useful.[31]

Osteoporosis and Fractures

The initial report from the HT WHI presented data showing a decrease in hip fractures of 5 per 10,000 per year in women on HT and a decrease in 47 per 10,000 per year in all other fractures measured.[1,9] There was a decrease in hip fractures by 34%, clinical vertebral fractures by 34%, other osteoporotic fractures by 23%, and total fractures by 24 % ((Table 7)). This is the first randomized clinical trial demonstrating that HT reduces the risk of fractures at the hip, vertebrae, and wrist. This was confirmed by the results of the ET WHI, which showed a decrease in hip fractures of 6 per 10,000 per year, a decrease in vertebral fractures of 6 per 10,000 per year, and a decrease in total fractures of 56 per 10,000 per year. There was a decrease in hip fractures by 35%, clinical vertebral fractures by 35%, and total fractures by 29% ((Table 8)).[11]

Table 7
Fracture Reduction in the Estrogen Plus Progestin Women's Health Initiative[9]
Table 8
Fracture Reduction in the Estrogen-Alone Women's Health Initiative[11]

The update of the HT WHI in the October 2003 JAMA[9] reported that 733 women (8.6%) in the estrogen-plus-progestin group and 896 women (11.1%) in the placebo group experienced a fracture (HR = 0.76; 95%; CI = 0.69-0.83). The hip and clinical vertebral fractures were significantly reduced by 34% and total osteoporotic fractures by 24%. When stratifying the women by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, bone mineral density (BMD), or summary fracture risk score, the effect did not differ.

The fractures included for the outcomes in both the HT and ET arms of the WHI included hip, wrist/lower arm, clinical vertebral, and total fractures. For the HT arm, only the hip fractures were centrally adjudicated, and the agreement between local and central adjudication was 94%. All other fractures at clinical centers where BMD was not measured were locally adjudicated, and adjudicators were blinded to treatment assignment. There were 52 hip fractures in the HT group and 73 in the placebo group. There were 189 lower arm/wrist fractures in the HT group and 245 in the placebo group; there were 41 clinical vertebral fractures in the HT group and 60 in the placebo group. Using the familiar number of events per 10,000 women per year, the fracture rates per 10,000 person-years in the HT and placebo groups, respectively, were as follows: hip fracture, 11 and 16 (5 fewer per 10,000 women per year with HT); wrist/lower arm, 44 and 62 (18 fewer per 10,000 women per year); clinical vertebral, 11 and 17 (6 fewer per 10,000 women per year); and total fractures, 152 and 199 (47 fewer per 10,000 women per year). The ET arm of the study also showed that ET decreased hip fractures.[9,11] The total fracture data from both studies ought to be compared.[9,11]

For the HT arm, the BMD was measured in only 1024 women at the spine and hip at 3 centers using Hologic dual x-ray absorptiometry (DXA) machines.[9] According to World Health Organization criteria, only 4% of women in the HT group and 6% of women in the placebo group were considered to have osteoporosis at the total hip. This confirms that the study was basically an osteoporosis prevention study. Total hip BMD increased 3.7% after 3 years of treatment compared with 0.14% in the placebo group (P < .001).[9]

Risk factors for fracture were combined in a summary fracture risk score, and it was found that HT reduced fractures to a similar degree in women who were considered at low, medium, and high risk of fracture. In addition, an osteoporosis global index was developed by the WHI authors using a modification of a summary FRACTURE Index risk score developed by Black and colleagues.[38] Black and colleagues used the Study of Osteoporosis Fractures (SOF) data to develop a simple clinical algorithm fracture risk index based on 7 risk factors -- age, fractures after age 50, mother had a hip fracture after age 50, weight < 125 pounds, currently a smoker, the need to use one's arms to assist oneself in standing up from a chair, and the DXA BMD T-score. The FRACTURE Index was based on fracture risk factors in 7782 women age 65 and older from SOF and was validated in 7575 women age 75 and older from the EPIDOS study.[38] The index used in the WHI analyses does not include BMD (except for the 1024 participants), the rising-from-the-chair factor, or maternal hip fracture after age 50, and instead uses maternal hip fracture after age 40; that is, it is a modified osteoporosis global index -- one that has not been independently validated.[9] The HR for the modified osteoporosis global index was subdivided into tertiles across the fracture risk scales. It was similar across the tertiles of the fracture risk scale "(lowest fracture risk tertile, HR, 1.20; 95% CI, 0.93-1.58; middle tertile, HR, 1.23; 95% CI, 1.04-1.46; highest tertile, HR, 1.03; 95% CI, 0.88-1.24) (P for interaction = .54)."[9] Thus, even among women who were considered at high risk of fracture, the HR for the WHI osteoporosis global index did not indicate net benefit.

In the initial July 2002 report of the HT WHI, no data were presented on death from hip fractures,[1] nor were such data provided in the HT WHI fracture paper.[9] When this omission was raised in a letter to the editor of JAMA in response to the July 2002 report,[39] no reply to this point was offered by the HT WHI authors; nor, it seems, did the JAMA editorial staff require that the authors reply. The letter by Goodson pointed out that the overall mortality for the HT group was still lower than that for the placebo group (0.52% per year vs 0.53% per year, although this difference was not statistically significant). He further points out that mortality due to colon cancer is greater than that due to breast cancer and that the 6-month mortality for hip fracture is greater than the 10-year mortality for stage 1 breast cancer. This would suggest that the mortality from improvement in colon cancer and hip fracture would offset the increase in mortality from breast cancer.[40,41] He wrote that this might contradict both the need for early discontinuation of the study and the WHI conclusion that "the absolute numbers of excess [adverse] outcomes [due to HT] would increase..." if the study continued. By allowing the WHI response to ignore this point, the editors of the JAMA "letters to the editor" section effectively contributed to its downplay.

The WHI authors[9] concluded that the results imply that the benefit of fracture reduction does not outweigh the risks of CVD and breast cancer, even in women at higher risk of fracture. Yet, the authors did not discuss the mortality or morbidity of those identified with hip fractures, or of those with vertebral fractures, or any of the fractures. This may have been because of the low numbers; nonetheless, it should have been discussed. The authors admit that although BMD and prevalent vertebral fractures are strong predictors of future fracture, data were not collected for all women in the trial; hence, they were unable to identify a group of women with severe osteoporosis for whom the benefits of HT might exceed the risks. The mortality of the women with hip and the other fractures should have been enumerated no matter what the data showed.

Osteoporosis remains largely underdiagnosed and undertreated, and the HT WHI, as reported, underemphasizes the importance of fractures. Although patients are routinely screened for risk factors associated with heart attack, stroke, and breast cancer, prevention and treatment of osteoporosis are often overlooked. The incidence of osteoporotic fractures in women is far greater than the incidence of heart attacks, strokes, and breast cancer combined. There are 3 times more osteoporotic fractures than heart attacks, 6 times more osteoporotic fractures than strokes, and 8 times more osteoporotic fractures than breast cancer.[42-44] The data collection and conclusions of the WHI undervalue the seriousness of osteoporosis and fractures.

Memory

The Women's Health Initiative Memory Study (WHIMS) has reported results for both the HT and ET arms.[12-15] The WHIMS data were collected for the older WHI volunteers, 65- to 79-year old participants in the WHI. Increased risks of probable dementia (PD) and mild cognitive impairment (MCI) were found in both the HT and ET arms of this trial. MCI was not prevented by use of HT or ET.

Dementia increased with HT (HR = 2.05, [P = .01]), with an additional 23 cases of dementia per 10,000 women per year; PD began to increase within the first year, with an HR = 2.05 for 5 years.[12] MCI began within 2 years, but the risk was low, with HR = 1.07 in 5 years. The 5-year HR was 1.37 for the combination of PD and MCI, both of which began by at least 2 years.

Global cognitive function was evaluated using the mean Modified Mini-Mental State Examination (3MSE) score. For this test, higher scores reflect better cognitive functioning.[13] The 3MSE scores began to diverge after 2 years, with an increase of 0.149 (0.21) units per year in the HT group compared with 0.213 (0.020) units in placebo (P = 0.3).[13] Even when adherence data were censored, the results still marginally favored the placebo (P = .008). Declines in the 3MSE score ≥ 2 standard deviations (ie, ≥ 8 units) occurred in 6.7% of the HT group and 4.8% of the placebo.

ET did not reduce either dementia or MCI and increased the risk of both endpoints combined[14] (see footnote. The incidence of PD was calculated to be 37 vs 25 per 10,000 person-years (HR = 1.49) for ET vs placebo and 45 vs 22 per 10,000 person-years (HR=2.05) for HT vs placebo. The authors also pooled the results for HT and ET. The calculated incidence of PD is 41 vs 23 per 10,000 person years (HR = 1.76) for the combination of HT plus ET vs placebo. For the combined outcomes, PD plus MCI, vs placebo, the calculated incidence is 110 vs 78 per 10,000 person-years (HR = 1.41).

The 3MSE scores for ET, HT, and placebo groups initially increased through the first 3 to 5 years, with greater increases reported for the placebo groups. During the ET trial, which had longer follow-up, the initial increases in mean 3MSE score decreased; the placebo group had a higher score, and differences between ET and placebo emerged after 2 years.[15] When the trials were censored by the first occurrence of nonadherence, the mean differences were lower for the 3MSE score for the treatment groups: ET, 0.25 (0.14) (P = .07); HT, 0.14 (0.10) (P = .17); and for the treatment groups combined, 0.19 (0.8) (P = .02). The differences in scores between the trials were not statistically significant (P = .51).

The possibility that HT or ET is associated with increase in vascular disease in the brain and thus dementia has been discussed. [14] The WHIMS data are complex and no doubt difficult for the average physician to process.(Table 9)is a simplification of the data. It is difficult to extract data in the references 12 and 14 and place them in this table, but this is my best interpretation of the data in the figures, tables and text. Thus, if one subtracts the numbers to come up with the overall number per 10,000 person years for PD, one gets 12 more for ET, 23 more for HT, and 18 more for the combination of ET + HT. For the composite endpoint of PD + MCI, the increase in number per 10,000 per year is 34 for ET, 22 for HT, and 46 for ET + HT. These numbers of events per 10,000 person-years are much larger than those for the other risk factors we are used to, such as CHD, DVT, or breast cancer. However, it should be noted that the analysis uses data for WHI participants 65 years of age and older and that the number of events is also high in the placebo groups.

Table 9
Incidence of Endpoint by Treatment Assignment for Probable Dementia (PD) and Mild Cognitive Impairment (MCI)[12,14]

Stroke

The relationship to the increase in dementia may be related to the increase in stroke. The initial JAMA report[1] indicated there were 8 more strokes per 10,000 person-years in the HT arm compared with placebo. When the WHI HT analysis on stroke was analyzed in detail, there were 151 strokes (1.8%) in the HT group and 107 (1.3%) in the placebo group.[16] Of the strokes, there were 79.8% ischemic strokes and 14.8 % hemorrhagic strokes. The HR for all stroke subtypes combined was 1.31 (nominal 95 % CI = 1.02-1.68). The Bonferroni aCI was (0.93-1.84) with an HR for ischemic stroke of 1.44 (aCI = 1.09-1.90), and the HR for hemorrhagic stroke was 0.82 (aCI = 0.43-1.56). The Kaplan-Meier cumulative hazard of all strokes begins to diverge after 1.5 years.

As a whole, the HT group had a 31% increase in total stroke risk. The HR for HT was 1.31 (95 % CI = 1.02-1.68) and, after adjustment for adherence, increased to 1.50 (95% CI = 1-08-2.08). The increased risk for all strokes attributed to HT was present in all subgroups. The HT WHI group had a baseline of 5% CVD, indicating basically healthy women. Although the total WHI looked at an older menopause group, even the youngest subset of the group (50 to 59 years) with hot flashes showed no difference compared with the whole HT WHI group.

This increase in stroke was also seen in the ET arm at 12 per 10,000 person-years, which crossed the statistical monitoring boundary for adverse effect. The HR was 1.39 (nCI = 1.10-1.77 and aCI = 0.97-1.99). The increase in stroke was not unexpected, as the risk of stroke with HT and ET was known even before the WHI results were published. Although mentioned in the initial HT WHI article[1] and the initial ET WHI article,[11] the number per 10,000 person-years did not appear in the HT WHI stroke analysis.[16] The authors fail to provide a clear message about the clinical approach to this risk factor, as a multivariate analysis did not show significant interaction with use of aspirin, nonsteroidal drugs. or statins. There was an increase in risk associated with black race,, current cigarette smoking, high systolic blood pressure or diastolic blood pressure, left ventricular hypertrophy, diabetes, higher white blood cell counts, and higher hematocrit levels. Reduced risk was associated with vitamin C supplements and physical activity consisting of moderate to strenuous activity 4 or more times per week. There was no increase with prior use of oral contraceptives. There was no increase in stroke in those who had probable dementia in this study, but this has been suggested in other studies. Small, undetected cerebrovascular events may have occurred in the HT group but could not be determined as associated with probable dementia.

Osteoarthritis

The effect of HT on osteoarthritis was overlooked in the WHI study. Studies have shown that patients on ET had less worsening of osteoarthritis radiographic scores, with a moderate but not statistically significant effect in one study and a statistically significant effect with long-term ET in another study.[45,46] This beneficial effect has also been seen experimentally in cynomolgus monkeys.[47] A review of this topic indicates there is clear evidence that cartilage can be influenced by estrogen, and epidemiologic studies suggest that estrogen can be beneficial, but this must be weighed by the potential for adverse health effects.[48] At either lower or higher than normal concentration, estrogen potentially induces a negative effect on chondrocytes and initiates cartilage damage through a chondrocyte-cartilage interaction, which leads to either cartilage homeostasis and maintenance or cartilage degradation. Some of this can occur through growth factors, cytokines, or adhesion molecules. Thus, ET or its withdrawal may have a major implication for patients with osteoarthritis or for those who are at risk for osteoarthritis who decide to discontinue HT or ET: Would those who discontinue HT or ET be at increased risk for developing osteoarthritis or exacerbation of their osteoarthritis?

Summary Critique and Recommendations

The release of the results of the WHI study generated a tremendous outflow of hyperbole and conjecture in the media, and yet the conclusions are far from clear. Even this author's comments have been updated because the data have changed.[49,50] Although the safety of patients participating in the WHI governed the DSMB decision to terminate the HT arm -- and the NIH's decision (not the DSMB's) to terminate the ET arm -- the risk to present and future patients whose therapy changed because of these conclusions remains largely unaddressed. Was the basis for terminating the study truly valid? Was the statistical analysis of the results (and the generated confidence intervals) accurate enough? Were the benefits of fracture prevention discounted by the authors, or were the results just underpowered? Why was relief from menopausal symptoms for the full cohort not included in the planning of this study? This is a late and not early menopause study. However, this fact was not apparent until the article published May 16, 2003 stated that only 1 in 6 women were within 5 years of menopause.[32] This makes a world of difference to patients and treating physicians; it should have been emphasized earlier and should continue to be emphasized with the same vigor as the initial report. The ACOG news release of 4 May 2004 points out "the high quality [of the] WHI studies was not served well by the manner is which the results were released."[24]

The style of writing and developing the data change from one article to another. This calls into question the standardization of the WHI writing groups. Use of the number of women with an event per 10,000 women per year is helpful in understanding and comparing the data, but it must be given consistently in the projected 24 additional articles to come out of this study. In addition, the global index perspective has been omitted from many follow-up studies recently published. The fracture data are presented as 5 fewer hip fractures per 10,000 women per year, but the quality-of-life report discusses the data as the smallest increment of change.[9,32] The detailed report on the breast cancer data never mentions the global index or number per 10,000 per year.[34] This is not helpful; we ought to be able to compare data from one report to another to better understand how the data relate. By way of example, data from the National Highway Traffic Safety Administration indicate the number of motor vehicle accidents per 10,000 women drivers (ages 55 to 64 years) per year is 271.9 and the number of fatalities is 1.113 per 10,000 drivers per year.[51]

It would have been helpful to be able to define the subgroups of women in the WHI who were truly at risk to take HT and ET, so the clinician would be able to comfortably decide which patients could be treated with safety. At this point, the WHI emphasizes HT and ET should not be used for prevention of disease, but the guidelines as to when to use it for treatment of symptoms are not presented. The WHI did not include symptomatic women; this is a major shortcoming with respect to relevance of the data for clinical practice. The WHI set out to study a prevention population with minimal symptoms with a forced age distribution. The acceptable risks in this specific age population for a prevention intervention were exceeded by preset criteria. Are these preset criteria germane to younger menopause? Probably not, but they are being used widely by clinicians as if they were.

ACOG emphasizes that the results of the HT WHI and ET WHI need to be considered with balance and that hormone therapy (HT or ET) needs to be used at the "right time and for appropriate reasons."[24] Their recommendations are that women use HT and ET for the shortest possible time in the smallest effective dose; that they visit their physician regularly, at least once a year, to determine whether the treatment can be discontinued (or the dose decreased); and that they have annual breast examinations and periodic mammograms -- every 1 to 2 years during the 40s and annually after that.[24] In August 2002, ACOG developed and published a paper to try to guide women with questions and answers about how to approach hormone therapy. Although these data are old in terms of the continuous reports published by the WHI, the responses are still germane today.[52]

Clearly, long-term therapy should not be used to prevent disease, but the data do not preclude the use of HT and ET for appropriate duration for such valid indications as hot flashes and vaginal dryness or discomfort.[52] Local lubricants or local estrogen can help genital atrophy, and alternative therapy such as selective serotonin-reuptake inhibitors and clonidine, for example, may be helpful if HT or ET cannot be used. Lowering the dose of HT or ET, tapering the frequency, or doing both may be appropriate. Some women may choose to continue HT or ET, and this can be justified as long as they understand the risks, benefits, and alternatives and follow the ACOG recommendations stated above.

The WHI report clarifies some of the risks and some of the benefits of HT and ET. However, by excluding information on menopausal symptoms, seeming to discount the significance of osteoporotic fractures, and not addressing the potential effect on osteoarthritis, the study does not provide enough information for patients and physicians to base their decisions. This can undermine public trust in scientific reporting and, more immediately, physician trust. Further WHI analyses continue to clarify what we knew, or think we knew, on July 17, 2002. As the data from the ET WHI trial are published, will our perspective of results and conclusions change?

We await release of additional information from the HT arm of the WHI and from the ET arm to help us better understand the true magnitude of risk and benefits of HT and ET and to help us better individualize treatment recommendations for our patients. Many of the conclusions depend on the WHI global index. But is this a validated instrument? Should each of the adverse and beneficial events be given equal weight? The 7-factor osteoporosis global index was validated in the original study by Black and colleagues[38] as a FRACTURE Index, but it was modified as the osteoporosis global index for the WHI study,[9] and this modification has not been validated.

The WHI study is cited as an example that highlights the limitations of observational studies. Is it such an example? Some previous data from observational trials such as breast cancer and DVT risks were affirmed. We have an excellent opportunity to investigate how and why some observational trials are valid and what may help distinguish those trials that are from those that are not.

Presentation of data to the medical and nonmedical community must be made as clearly as possible. In a study with multiple publications, the data should be presented in comparable format from report to report, and the host journal and the authors have a responsibility to consider the data and implications in clinical context and to invite critique and discourse. When articles are released that may call for paradigm shifts in clinical approaches, full evaluation, dissection, and clarification ought to be the rule. The conclusions drawn from the WHI will have a long-term influence on the care of our patients. Indeed, there has been a paradigm shift in how physicians treat patients. As the saying goes, "reality often astonishes theory," but in the case of the WHI one might ask, Is the reality suggested by the WHI authors real? It is extremely important for the credibility of both medical research and patient care that the conclusions be valid.

Acknowledgments

I thank Michael Kleerekoper, MD, for his helpful suggestions regarding the manuscript. I also thank Victor Silverman, MD, for reviewing the manuscript.

Footnotes

The article by Shumaker and colleagues[14] reporting these data is confusing to read because the tables and figures denote data on Estrogen Alone "or" or "and" Estrogen Plus Progestin. The last columns of the tables are labeled Estrogen Alone "or" Estrogen Plus Progestin and the figures' part B say Estrogen Alone "and" Estrogen Plus Progestin.

References

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