BMJ  2007;334:860-861 (28 April), doi:10.1136/bmj.39188.594282.80

Editorials

Postmenopausal hormone therapy

Symptoms should be treated with lowest effective dose of hormone therapy for the shortest time possible

In March 2007, the North American Menopause Society (NAMS) published an updated position statement on the use of hormone therapy in postmenopausal women.¹ NAMS recommends hormone therapy, which is a highly effective treatment for hot flushes and vaginal atrophy,² as first line treatment for women with moderate to severe symptoms. It is also effective for preventing osteoporotic fractures,^{3 4} but NAMS recommends that hormone therapy for this purpose should be weighed against potential harm and that other approved preventive treatments such as bisphosphonates should be considered. These recommendations are clear, simple, and based on solid evidence from many randomised controlled trials.

However, NAMS recommendations are less clear in several other areas. For example, after clearly stating that hormone therapy increases risk of venous thromboembolic events and stroke, no advice is provided about how clinicians and patients should use this information. Similarly, NAMS notes that risk of breast cancer is increased in women who use oestrogen plus progestin for five years or more, but no recommendation is given about its use in women at high risk of breast cancer. The statement also notes that treatment with hormone therapy in women over 65 years increases risk for dementia,^{5 6} and that no evidence is available regarding effects on dementia from clinical trials in younger women, but there is no clear statement that hormone therapy should not be used to prevent dementia.

NAMS published a position statement on use of postmenopausal hormone therapy in 2004, and since then no large randomised trials have been published that would require revision of guidelines. What then has changed since the earlier statement? The main changes in the new position statement reflect the belief of NAMS panelists that, if used during or shortly after the menopause, hormone therapy may not increase risk of coronary heart disease. Evidence to support this "timing hypothesis" comes from studies of castrated animals and post hoc analyses of observational studies, but primarily rests on subgroup analyses of data from the two women's health initiative randomised trials.⁷ Analyses that pooled data from the women's health initiative trial of oestrogen alone and of oestrogen plus progestin show no clear difference in risk for coronary heart disease associated with use of hormone therapy in women in their 50s compared with older women. However, women treated with hormone therapy within 10 years of the menopause seemed to have a reduced risk of heart disease (hazard ratio 0.76, 95% confidence interval 0.50 to 1.16), whereas those who had undergone the menopause more than 20 years ago had an increased risk (1.28, 1.03 to 1.58; P value for interaction 0.02). These data are not entirely convincing, as about 137 comparisons were performed, and several statistically significant findings would be expected to occur by chance. The "timing hypothesis" will probably never be directly confirmed or refuted, because the low absolute rate of coronary heart disease among perimenopausal women would require many thousands of perimenopausal and early postmenopausal women to be randomised to treatment or placebo for more than a decade. Even if the timing hypothesis is true, little evidence exists that other risks of hormone therapy vary with time since menopause.⁷ Finally, the timing hypothesis has little impact on clinical care. Even if we reject the timing hypothesis and assume that the overall risks documented in the women's health initiative trials apply to younger women, the absolute risk associated with taking hormone therapy for a few years to treat menopausal symptoms is low, and worth the benefit of symptom relief.

The NAMS position statement is not an evidence based guideline as defined by the UK National Institute for Health and Clinical Excellence⁸ or the US Preventive Services Task Force.⁹ A search of Medline (but not other databases) was performed, but data were not systematically abstracted or synthesised. References are provided in a bibliography, but it is not possible to determine which studies were used to support specific recommendations. NAMS uses a consensus process, in which selected experts are given recent references and asked to provide their opinions. The position statement is based on agreement among at least two thirds of the panel—more a majority than a consensus. NAMS is to be congratulated for providing financial disclosures of panel members, but these are extensive.

Another worrying aspect of the 2007 NAMS position statement is that it suggests that use of postmenopausal hormone therapy is complicated. While some details are unclear or complex, the basic approach to using postmenopausal hormone therapy is clear and simple: treat bothersome menopausal symptoms with the lowest effective dose of hormone therapy for the shortest time possible and do not use it to prevent disease.

¹ University of California, San Francisco and San Francisco VA Medical Center, San Francisco, CA 94115, USA, ² Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego School of Medicine, San Diego, California, 92093, USA

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Competing interests: DG has received research support from Berlex, Bionovo, Eli Lilly, and Pfizer. EB-C has received research support from NIH, Amgen, Lilly, Merck, Wyeth, Proctor and Gamble, Roche, and GlaxoSmithKline.

Provenance and peer review: Commissioned; not externally peer reviewed.

References

1. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of the North American Menopause Society. Menopause 2007;14:1-17.[CrossRef][ISI][Medline]
2. Nelson HD, Haney E, Humphrey L, Miller J, Nedrow A, Nicolaidis C, et al. Management of menopause-related symptoms. Evidence Report/Technol Assessment No 120. Rockville, MD: Agency for Healthcare Research and Quality, 2005. www.ahrq.gov/clinic/epcsums/menosum.htm
3. 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;288:321-33.[Abstract/Free Full Text]
4. Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The women's health initiative randomized controlled trial. JAMA 2004;291:1701-12.[Abstract/Free Full Text]
5. Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women. JAMA 2004;291:2947-58.[Abstract/Free Full Text]
6. Shumaker SA, Legault C, Thal L, Wallace RB, Ockene JK, Hendrix SL, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the women's health initiative memory study: a randomized controlled trial. JAMA 2003;289:2651-62.[Abstract/Free Full Text]
7. Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465-77.[Abstract/Free Full Text]
8. National Institute for Health and Clinical Excellence. The guidelines manual. London: National Institute for Health and Clinical Excellence, 2006.
9. Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, et al. Current methods of the U.S. Preventive Services Task Force: a review of the process. Am J Prev Med 2001;20:21-35.[ISI][Medline]

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