The Women's Health Initiative (WHI) was one of the largest, most ambitious randomized clinical trials in history. Because it was so massive, the results of the WHI have influenced patients and prescribers for nearly 20 years. The Women's Health Initiative has fundamentally changed the way healthcare practitioners treat menopause.
Chances are you've heard or read about the WHI. But many healthcare providers haven't read the report, written by the team of researchers who worked on the study. If we take a closer look at the study results and actually read what they say, we may start to see a different picture of what the study says . . . and doesn't say.
Let's dive into "Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women Principal Results From the Women's Health Initiative Randomized Controlled Trial."(1) The study report was published by the WHI Writing Group in JAMA in July, 2002.
Let's examine the words the research team used and see if we can figure out exactly what they mean, in context.
"26% increase [in breast cancer]"(Women's Health Initiative Writing Group)
The 26% increase (38 vs 30 per 10 000 person-years) observed in the estrogen plus progestin group almost reached nominal statistical significance . . . (emphasis added)
Researchers stopped the WHI in 2002, before it was completed. A perceived increase in breast cancer in the treatment group led to the stopping of the study. In other words, women taking hormone replacement showed a higher risk of breast cancer than women not taking hormones.
Note that the 26% increase cited in this paragraph was an increase in relative risk. Although a 26% increase seems dramatic, the absolute increase in breast cancer cases was much more modest.
"(38 vs. 30 per 10 000 person-years) " (Women's Health Initiative Writing Group)
The incidence of breast cancer went from 30 cases per 10,000 women in one year to 38 cases per 10,000 women in one year. Raw data showed that 124 women (out of a total of 8102 women) not taking hormones developed breast cancer. In contrast, 166 women (out of 8506) taking hormones developed the disease.
"almost reached nominal statistical significance" (WHI Writing Group)
A single word in this quote changes the results of the entire study. But this word has been largely forgotten in the chaos that surrounded the trial.
Statistical significance in this case indicates whether the increase in breast cancer is likely due to the treatment (hormones) or is higher by chance. Researchers explicitly state that the increase in breast cancer "almost" reached statistical significance. That's the same as saying it "did not" reach statistical significance.
By using the word "almost," the WHI writing group admitted that there was a very small increase in breast cancer risk, which could have been a result of chance, rather than a result of the hormone treatment.
"CEE [conjugated equine estrogen] + MPA [medroxyprogesterone acetate]"
This trial tested only 1 drug regimen, CEE, 0.625 mg/d, plus MPA, 2.5 mg/d, in postmenopausal women with an intact uterus. The results do not necessarily apply to lower dosages of these drugs, to other formulations of oral estrogens and progestins, or to estrogens and progestins administered through the transdermal route. (emphasis added)
The patients recruited for the Women's Health Initiative were give one of three treatments:
- Women in the treatment arm with an intact uterus (who had not had a hysterectomy) received CEE (conjugated equine estrogens) along with MPA (medroxyprogesterone acetate).
- The protocol gave hysterectomized women in the treatment arm (those without a uterus) only CEE (conjugated equine estrogens).
- Women in the non-treatment arm received placebo tablets.
Study researchers gave patients a combination of hormones that was the gold standard menopause treatment when the study began. At the time, there were very few alternatives to these two hormones.
"results do not necessarily apply . . ." (WHI Writing Group)
The WHI Writing Group explicitly states that the results of their study should NOT be applied to other doses, formulations, or dosage forms of estrogens and progestins. In spite of this statement, the FDA and several physician groups have done exactly the opposite of what the Writing Group recommends.
The FDA has placed a "Black Box Warning" on any and all hormones intended to treat menopause. The warning includes any and all other formulations and dosage forms of estrogens and progestins. It's even applied to hormones that are not the same as those used in the WHI, even though the WHI report doesn't support that conclusion. The warning explicitly cites the results of the Women's Health Initiative as the primary reason prescribers need to be wary of any hormone replacement therapy.
"unopposed estrogen" (WHI Writing Group)
a statistically significant lower cumulative breast cancer incidence of 0.27% was seen in the CEE group (n = 151) compared with 0.35% in the placebo group (n = 199)
"Principal Results From the Women's Health Initiative" doesn't cover it substantially. But researchers prescribed unopposed estrogen (CEE) to women who had had a hysterectomy. Later analysis of this "estrogen only" treatment group showed that women taking only CEE had a significantly lower rate of breast cancer than women taking CEE + MPA. (2)
The results of the CEE group showed "a statistically significant lower cumulative breast cancer incidence." While this estrogen only component of the study doesn't conclusively prove anything, it does drop some strong hints.
Perhaps the estrogen (CEE) given to women in the trial was not the cause of the slightly increased breast cancer risk. The estrogen only arm hints that the progestin (MPA) could be a more likely culprit in increasing breast cancer risk.
"The mean (SD) age was 63.3 (7.1) years." (Women's Health Initiative Writing Group)
The Women's Health Initiative involved post-menopausal women. These women were, on average, about 63 years old. Women start menopause at an average age of 51.
This means that women in the WHI had gone, on average, a full 12 years past menopause.
None of the women in the study had symptoms of menopause like hot flashes. The reason is because hot flashes would make it much more difficult to "blind" study patients. Women who got the placebo would know within a day or two whether their hot flashes went away. Conversely, women who received active hormones would know right away that their hot flashes were getting better.
Because of this "no symptoms" limitation, the study group decided to enroll older patients, ones who had already gone past the 5-10 years of menopause when symptoms usually persist. But focusing the trial on older women created some unintended consequences.
12 years Without Hormones
The HRs for all-cause mortality tended to differ by age during the intervention and cumulative follow-up phases. Comparing younger women (aged 50-59 years) with older women (aged 70-79 years), the ratios of nominal HRs for all-cause mortality in the pooled cohort were 0.61 (95% CI, 0.43-0.87) during the intervention phase and 0.87 (95% CI, 0.76-1.00) during the cumulative 18-year follow-up, without significant heterogeneity between trials (eTable 4 in Supplement 2). Comparing hormone therapy with placebo, the HRs in the pooled cohort during the intervention phase were 0.69 (95% CI, 0.51-0.94) for women aged 50 to 59 years, 1.04 (95% CI, 0.87-1.25) for women aged 60 to 69 years, and 1.13 (95% CI, 0.94-1.36) for women aged 70 to 79 years (P value for trend by age = 0.01) (3)
This later analysis of data from the Women's Health Initiative showed that younger women, closer to the age when menopause starts, did not have an increase in cardiovascular disease. Blocked arteries and heart attacks increase as women age. Hormones did not increase the risk for heart disease when women were separated by age.
Does 12 years without hormones have a negative impact on women's hearts? The data from this study would seem to indicate that it does.
"Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women Principal Results From the Women's Health Initiative Randomized Controlled Trial" (study title)
In spite of the use of the word "healthy" in the title, we might question whether the women in the WHI truly were healthy. If we look more closely at how these women were described in the study report, again by the WHI Writing group, we see that:
- mean BMI (basal metabolic index) was 28.5 indicating women were overweight or obese
- 50% smoked, either currently or in the past
- 4.4% of the women reported having diabetes
- 12-13% had high cholesterol
- 7% took statins to reduce cholesterol
- 36% had high blood pressure
- 1.6 to 1.9% of women in the study said they a history of heart attack
Read The Women's Health Initiative For Yourself
Don't just to take my word for it. I would encourage you to read the reports on the Women's Health Initiative for yourself. Look closely at the data and the conclusions to determine what it says and what it doesn't say.
If you're a healthcare practitioner and you're interested in more of the evidence around menopause and hormone replacement therapy, I'd love to help. I've compiled a comprehensive list of references so you can take a look at the studies for yourself. Click here to get access to my menopause references.
I've provided 2 formats. One is a public PubMed bibliography. You can easily share the downloadable .pdf version with colleagues or patients who might be interested.
- Writing Group for the Women's Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA. 2002;288(3):321–333. doi:10.1001/jama.288.3.321
- LaCroix AZ, Chlebowski RT, Manson JE, et al. Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy: A Randomized Controlled Trial. JAMA. 2011;305(13):1305–1314. doi:10.1001/jama.2011.382
- Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women’s Health Initiative Randomized Trials. JAMA. 2017;318(10):927–938. doi:10.1001/jama.2017.11217
Providers: Hot Flashes vs. Fear of Hormones
Are your menopausal patients afraid hormone replacement will give them breast cancer or heart attacks? Maybe their symptoms are making them miserable, but they're still not sure. Maybe they've never even heard of the WHI, but it's influenced their fear anyway. My Simple Hormones patient education programs help you relieve your patients' fears. For a limited time, I'm offering a 60-day free trial subscription. Click the link to learn more.