The WHI and Quality of Life

Abstract & Commentary

An analysis of the effect on memory, sleeping, and mental status of daily estrogen-progestin administration to postmenopausal women, based on data from the discontinued arm of the Women’s Health Initiative (WHI), was summarized on the Internet site of the New England Journal of Medicine on March 17. The publication is scheduled for the May 8, 2003 issue of the New England Journal of Medicine, but the journal decided to release the results early "because of their importance." The data indicated no positive effects on emotional health, depressive symptoms, energy levels, memory, sleeping, or sexual satisfaction. There was a statistically significant benefit on sleep disturbance, physical functioning, and bodily pain; however, Hays and colleagues state that this was small and not clinically meaningful. An analysis restricted to the 574 women aged 50-54 who had moderate-to-severe vasomotor symptoms at baseline revealed a beneficial effect only on sleep disturbance (Hays J, et al. Accessed April 7, 2003).

Comment by Leon Speroff, MD

The message sent by the authors of this WHI analysis, and repeated by the media, is that postmenopausal hormone therapy should be used only as brief treatment for severe menopausal symptoms. The experts quoted (for example, by the New York Times) were individuals with a track record of antihormone sentiments and statements. Deborah Grady said, "There is no place for this treatment in women who are not having hot flashes." JoAnn Manson of Harvard and the Nurses’ Health Study said that the new results dispel the myth that hormone therapy improves the quality of life.

Do the editors of the New England Journal of Medicine really believe they are performing a service by releasing this information in this manner? The media report and seek quotes emphasizing the most negative possibility. The New York Times article was titled "Hormone Therapy Is Now Said to Lack Benefits." Clinicians cannot respond with knowledge and authority because the detailed results were not readily available for analysis. Of course, patients ultimately pay the price for what is, in my view, an unconscionable act on the part of this respected medical journal. Did it make me sign up for the New York Times web site? Yes! Does it score points for the New England Journal in its competition with other leading medical journals? Yes! Does it make clinicians angry? Yes! Does it harm patients? Yes!

Why is it possible that the reported WHI results do not apply to the majority of women for whom we prescribe hormone therapy? Remember that the participants in the WHI had an average age of 67 and were 18 years distant from their menopause. The WHI investigators like to point out that the group of women in their early 50s in the WHI presented similar findings. However, women with significant menopausal symptoms were excluded from the study to avoid an exceedingly high drop-out rate in the placebo group. Women who had been on hormone therapy (about 25% of the participants) and then underwent a 3-month "washout" period and experienced menopausal symptoms were discouraged from participation (about 12.5% of the participants reported vasomotor symptoms upon entry but were willing to be assigned to placebo, and, therefore, their symptoms were unlikely to have had a major disturbing effect). This exclusion means that only a small number of women in the WHI were close to their age of menopause (about 16.5% of the participants were less than 5 years since their menopause). The analysis of women aged 50-54 was based on about 250 women in the treated group and 225 in the placebo group. The WHI was a study of elderly women who were not representative of the population receiving hormone therapy. In addition, the inclusion and exclusion criteria of a randomized trial often produce a relatively homogenous study group. Is it possible that this group had a quality of life unlikely to be affected by hormone therapy?

There are 10 WHI publications in preparation and another 16 scheduled. Unfortunately, we face the prospect of repetitive political journalism with predictable media reporting. The burden will be great for clinicians and patients.

I believe a theme has emerged from the epidemiologic confusion of the last few years: It takes healthy tissue to allow effective responses to estrogen and to maintain health. Experimental evidence in monkeys and women indicates that as endothelial cells become involved with atherosclerosis and neurons become affected with the pathologic process of Alzheimer’s, beneficial responses to estrogen diminish.1-3 Maximal benefit, therefore, requires early onset of treatment near the time of the menopause, a principle of treatment that has not been tested by the WHI.

I do not believe the WHI results negate long-term postmenopausal hormone therapy in selected individuals. The most effective and appropriate method to help in decision-making is to identify the specific goals and objectives of the individual patient. For one patient, the goal may be protection against fractures, for another, prevention of Alzheimer’s disease, and for another, relief from menopausal symptoms. Once identified, choices from the multiple available treatment options can be reviewed. This is at least an annual process, incorporating new knowledge as it appears. Approached in this fashion, the terms "short-term" and "long-term," and the imposition of time limits for therapy become meaningless. Clinician and patient together make a periodic, appropriate clinical judgment that is directed to accomplishing the individual patient’s goals.

Dr. Speroff is Professor of Obstetrics and Gynecology at Oregon Health Sciences University in Portland.


1. Herrington DM, et al. Arterioscl Thromb Vasc Biol. 2001;21:1955-1961.

2. Mikkola TS, Clarkson TB. Cardiovasc Res. 2002;53: 605-619.

3. Zandi PP, et al. JAMA. 2002;288:2123-2129.