The Backlash Against the WHI: Myths and Facts About Menopause Hormone Therapy

Since the initial results of the Women's Health Initiative (WHI) were published last July, defenders of menopause hormone therapy have claimed that the study's conclusions are faulty because of flaws in the design of the trial. This backlash is based on a number of myths being propagated by spokespeople for Wyeth, which manufactures Premarin, as well as by other hormone defenders in the ob-gyn community.

The fundamental theme throughout this misinformation is that the women in the WHI were not "normal" and did not represent typical patients. In response, Adriane Fugh-Berman, MD, an assistant professor at George Washington University School of Medicine. and Tony Scialli, MD, a professor at Georgetown University Hospital, enumerate the most common backlash myths about the WHI findings and provide the facts refuting them.

Myth: The women in the WHI were too old. There were too few women who were close to the onset of menopause/in their 50s.
Fact: A third of the women—a total of 5,702—were in their 50s. In fact, the WHI is the largest randomized controlled trial ever done of women in this age group.

Myth: Women enrolled in the WHI weren 't having menopausal symptoms, so they were different from normal women of their age.
Fact: This argument implies that women who are near or at menopause who don't experience hot flashes are not normal. In fact, many women either have no menopausal symptoms or experience symptoms that aren't bothersome. Even among women taking hormones, only a minority say they started taking them because of hot flashes. ^{1, 2}

It is true that many women with significant menopausal symptoms (especially those with hot flashes) were excluded from the WHI; this is because assigning them to placebo would have denied them effective therapy. Hormone defenders have used this fact to argue— inaccurately—that there had to be a relatively small number of women in the trial who were close to menopause (see previous myth). ³

Despite this exclusion, some WHI participants experienced hot flashes. At the start of the trial, 12 percent of the women enrolled reported experiencing moderate-to-severe hot flashes or night sweats. It is possible that these women were willing to risk being assigned placebo because their hot flashes and night sweats did not seriously bother them.⁴ Among that 12 percent, 1,072 were assigned to the combined hormone group and 974 to placebo. ⁵

Myth: The women in the WHI had preexisting cardiovascular disease, and that's why the hormones didn't protect them.
Fact: Every woman enrolled in the trial was screened for cardiovascular disease before the study started and was found to be healthy. Proponents of this myth claim that, test results to the contrary, the women in the WHI weren't actually healthy - that they had underlying cardiovascular disease that had not progressed far enough to be detected by the screening tests.¹ It is quite likely that some women in the trial did, indeed, have underlying cardiovascular disease, but there is no rationale for assuming that more of those women were in the treatment group than in the control group. One of the strengths of a randomized clinical trial with an adequately large sample size is that it minimizes or eliminates the effects of this kind of unknown variable.

This argument is also being used to support the newest hormone marketing theory: that women who start taking hormones even earlier—before menopause— will get a cardiovascular benefit from the drugs. Proponents of this theory claim that estrogen does prevent cardiovascular disease if a woman starts taking it before even an undetectable sign of the disease develops. This is very similar to the argument that estrogen would prevent heart disease in healthy women, despite an earlier study (the HERS trial) finding no benefit for the group originally believed to benefit most from hormone therapy: women with heart disease. After the HERS trial, hormone defenders countered its negative findings by suggesting that the arteries of women who had previously suffered cardiac events were too far gone to respond to estrogen. They argued then that hormones would still protect healthy women from developing cardiovascular disease. Now they're saying essentially the same thing, but they're claiming that the only women healthy enough to benefit are those who haven't yet reached menopause.

Myth: Most risks of hormone, therapy found in the WHI weren't statistically significant. If the trial had gone on longer, the risks might have become significant or they might not have, but because the trial was stopped too early, we'll never know.
Fact: The part of the WHI that was stopped—the estrogen-progestin combination— was stopped because its risks reached the level that independent experts agreed were not acceptable for the safety of the women enrolled. These experts served on the trial's safety monitoring board and established the safety criteria before the trial started. They set predetermined criteria for specific health problems that women might experience, such as breast cancer, as well as for the overall harm caused by the total effect of all the problems that might be experienced. They made the decision to stop WHFs combined hormone arm because it crossed the statistical boundaries for breast cancer and for overall harm.

Myth: The women in the WHI were sicker than women in the general population.
Fact: Like most people who enroll in clinical trials designed to study disease prevention, the women in the WHI were probably healthier than the general population. This phenomenon is so well documented that it has a name: the "healthy volunteer effect."^6-7 Moreover, because this trial was designed to test the effect of hormones on healthy women, women with detectable illness were excluded. Predictably, rates of cardiovascular disease in both the estrogen- progestin and placebo groups were lower than in the general population.

Myth: So many women dropped out of the trial that the results cannot be reliably interpreted.
Fact: Only 3.5 percent of women actually left the trial, a very low rate for clinical trials. What the myth-makers are talking about is the discontinuation rate—women who continued to participate in the trial but stopped taking the pills assigned to them. Had the discontinuation rate in one group been significantly different than in another, it could have been difficult to interpret the results. But this was not the case in the WHI. Discontinuation rates were similar between groups: 42 percent for the estrogen-progestin group and 38 percent for the placebo group. Additionally, it's worth noting that this rate is perhaps even lower than the rate among women who use hormones in regular life, outside any clinical trial. A large study of almost 30,000 women using hormones found that more than half had stopped taking their pills as prescribed after one year.8 Among women over 65, 62 percent discontinued hormone therapy within a year: and among women aged 50-55, 48 percent had stopped after that time.^8-9

Myth: The WHI results apply only to the specific combination of drugs that were given in the arm of the study that was stopped. Estrogen taken alone and different versions of combination therapies will prevent disease without the risks.
Fact: The WHI tested conjugated equine estrogen and medroxyprogesterone acetate. These drugs were chosen because they were by far the most widely used by women in the U.S. and because this combination was the one that previous studies had suggested might be able to prevent heart disease. It's possible, although not likely, that the WHI results will not hold true for estrogen alone or for other estrogen-progestin combinations, but women should demand proof before acting on another unfounded theory. An important lesson of the WHI is not to prescribe unproven drugs to healthy women, but rather to wait until there is supporting evidence from prospective randomized trials. Drug companies and doctors who want to promote other formulations for menopausal hormone therapy should be required to perform such trials with disease endpoints.

Although the estrogen-only arm of the WHI has not been stopped, its continuation should not be interpreted as proof of either effectiveness or lack of harm. There is no basis for concluding that estrogen alone is safer or more effective than combined hormone regimens. In fact, what little we know about risks to women in the estrogen-only arm is not reassuring; WHI participants have already received a letter saying there was an increased risk of cardiovascular events in the estrogen-only group as well as the combined hormone group after years one and two of the trial. But because the estrogen-only group is smaller than the combined hormone group—even if the same dangers are there—it will take longer for the number of adverse events to reach the statistical level of risk necessary to stop the trial.

REFERENCES

1. Salamone LM, Pressman AR, Seeley DG, Cauley JA. "Estrogen Replacement Therapy. A Survey of Older Women's Attitudes." Archives of Internal Medicine June 24 1996; 156(12): 1293-1297.

2. Ettinger B, Pressman A, Silver P. "Effect of Age on Reasons for Initiation and Discontinuation of Hormone Replacement Therapy." Menopause Winter 1999; 6(4): 282-289.

3. Speroff L "WHI Trial Arm with E/P Finds an Increase in Breast Cancer." Ob-Gyn Clinical Alert (American Health Consultants, Atlanta) 2002; 19(4): 25-28.

4. Grady D. "Postmenopausal Hormones— Therapy for Symptoms Only." New England Journal of Medicine May 2003; 348(19).

5. Hays J, Ockena JK, Brunner RL et al. "Effects of Estrogen Plus Progestin on Health-Related Quality of Life." New England Journal of Medicine May 2003; 348(19).

6. Lindsted KD, Fraser GE, Steinkohl M, Beeson WL "Healthy Volunteer Effect in a Cohort Study: Temporal Resolution in the Adventist Health Study." Journal of Clinical Epidemiology July 1996; 49(7): 783-790.

7. Froom P, Melamed S, Kristal-Boneh E, Benbassat J, Ribak J. "Healthy Volunteer Effect in Industrial Workers" Journal of Clinical Epidemiology August 1999; 52(8): 731-735.

8. Faulkner DL, Young C, Hutchins D, McCollam JS. "Patient Noncompliance with Hormone Replacement Therapy: a Nationwide Estimate Using a Large Prescription Claims Database." Menopause Winter 1998; 5(4): 226-229.

9. Ettinger B, Pressman A, Silver P. "Effect of Age on Reasons for Initiation and Discontinuation of Hormone Replacement Therapy." Menopause Winter 1999; 6(4): 282-289.