Clinical Review

Update on menopause: An expert’s insight on pivotal studies

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Confusion about what to do—on the part of both physicians and patients—may be the greatest consequence of recent studies.


The past 2 years have witnessed a flurry of scientific publications on menopause and related therapies, particularly use of the sex steroid hormones. In turn, attitudes about menopause and hormone therapy have changed. Perhaps the greatest consequence of all the attention is the confusion about what to do, on the part of both provider and patient.

Many organizations responded with considered, evidence-based, practical guidelines. The most detailed and practice-oriented of these guidelines is the North American Menopause Society’s (NAMS’s) September 2003 Position Statement on use of estrogen and progestogen in peri- and postmenopausal women ( Even as this Update on Menopause is being written, the report of the terminated estrogen-only arm of the Women’s Health Initiative (WHI) is in press and may further change clinical practice. NAMS will present an updated report on all these developments at the 2004 scientific meeting in Washington, DC, October 6 to 9, 2004. In the interim, the current recommendations hold, and the following publications are of clinical relevance.

WHIHigher levels of exercise reduce breast cancer risk

McTiernan A, Kooperberg C, White E, et al. Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women’s Health Initiative Cohort Study. JAMA. 2003;290:1331–1336.

The risk of breast cancer in postmenopausal women who exercised moderately for only a few hours a week was reduced by 18% compared with inactive women—and risk was reduced more in women who exercised moderately but for considerably more hours per week.

A total of 74,171 postmenopausal women aged 50 to 79, with no history of breast cancer, were enrolled. At a mean follow-up of 4.7 years, an increasing total current physical activity score was associated with a statistically significant reduced risk for breast cancer (P = .03 for trend). The women in whom the 18% (95% confidence interval [CI], 0.68-0.97) reduced risk of breast cancer was observed exercised the equivalent of 1.25 to 2.5 hours per week of brisk walking (5.1-10.0 metabolic hours). Women who exercised the equivalent of 10 or more hours of brisk walking per week had slightly greater reductions.

The greatest benefit was in women with a body mass index (BMI) below 24.1, but benefits were seen in women with BMIs ranging from 24.1 to 28.4. In evaluating the effect of previous strenuous-intensity exercise, a statistically significant decreased risk of breast cancer was seen for women who had engaged in strenuous exercise at age 35 (relative risk [RR], 0.86; 95% CI, 0.78-0.95); no significant associations were found for strenuous exercise at ages 18 or 50.

Modest protection, but encourage exercise anyway

This large, prospective cohort study performed in the mid-1990s strengthens the growing body of evidence that higher levels of physical activity afford modest protection against breast cancer. Recreational physical activity appears to be associated with reduced risk for breast cancer in postmenopausal women; longer exercise durations showed only slightly greater reduction in risk.

The strengths of this study are its large numbers, prospective nature, and detailed reporting of breast cancer outcomes. Limitations include possible confounders such as prior oral contraceptive use, and use of self-administered questionnaires to estimate physical activity.

One very important question is raised by this study: Given the low increase in absolute risk of breast cancer reported by the WHI with estrogen plus progestin1—which barely reached statistical significance (total breast cancer RR, 1.24; 95% CI, 1.02-1.50)—and given the statement in the McTiernan study that “the reduced risk associated with increased levels of total physical activity was seen across all the categories of these variables” (including current or past use, or no previous use of hormone therapy), does the reduction of incidence with physical activity in hormone therapy users lower the level of risk to non-significance or to that of nonexercisers in the placebo group? The answer cannot be determined from this report, but it would be illuminating.

These findings are preliminary, and confirming studies are needed. There is little harm in encouraging women to exercise, however.

1. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA. 2003;289:3243-3253.

WHIEstrogen-progestin has no significant effect on gynecologic cancers

Anderson GL, Judd HL, Kaunitz AM, et al, for the Women’s Health Initiative Investigators. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women’s Health Initiative randomized trial. JAMA. 2003;290:1739–1748.

Continuous combined estrogen plus progestin therapy (EPT) does not have a statistically significant effect on either ovarian or endometrial cancer compared with placebo, according to this report.


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