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Hormone therapy offers no benefit on central nervous system outcomes
New WHI information leads to more questions on role of hormone therapy
Expect more questions from patients about hormone therapy (HT) with the publication of three reports from the Women’s Health Initiative (WHI), the largest randomized controlled trial conducted to date on the drug therapy.
The studies examine the impact of hormone therapy on central nervous function, using the daily regimen of 0.625 mg conjugated estrogens and 2.5 mg medroxyprogesterone acetate (Prempro, Wyeth Pharmaceuticals, Collegeville, PA) or placebo. The research suggests that use of the combined estrogen and progestin regimen is associated with increased risk of dementia and stroke and offers no improvement in cognitive function.1-3
How should clinicians integrate this information in their daily practice? In an accompanying editorial to the three studies, Kristine Yaffe, MD, an assistant professor in the department of psychiatry, neurology, and epidemiology at the University of California, San Francisco, concludes that HT should be prescribed only for temporary use to treat menopausal symptoms.4
Research results on the estrogen-alone sub-study are expected in about two years, says Stephen Rapp, PhD, professor of psychiatry and behavioral medicine at Winston-Salem, NC-based Wake Forest University, who served as lead author on the cognitive function study.
"During that time, we will also continue to follow the women in the estrogen plus progestin sub-study to examine the effects of hormone therapy termination on cognition and incident dementia and mild cognitive impairment," he states.
Until more information is available from both the estrogen plus progestin arm and the estrogen-only arm, women should talk with their health care providers about hormone therapy and the benefits and possible risks involved, advises the Washington, DC-based Association of Reproductive Health Professionals (ARHP).
Take a closer look
Two of the new publications are drawn from the WHI Memory Study (WHIMS), which specifically looked at women age 65 and older in the WHI trial. Women in the WHIMS study, like women in the larger WHI study, stopped taking the estrogen plus progestin therapy in July 2002 when it was found that the risks for developing breast cancer, strokes, and cardiovascular disease outweighed the benefits that were studied.5 At that time, not all of the memory study data have been analyzed, and the dementia risk had not been established.
In the first publication, researchers found that 40 of 2,229 women receiving HT and 21 of 2,303 women on placebo aged 65 or older were diagnosed as having probable dementia. This translated into a significant hazard ratio of 2.05 after an average of 4.05 years of follow-up.1 Effects of therapy on mild cognitive impairment did not differ between the groups. Translated to a population of 10,000 women taking the combined hormone therapy, there would be an additional 23 cases of dementia per year, researchers conclude.
In the other publication, researchers looked at global cognitive function including concentration, language, memory, and abstract reasoning. In this area, women taking the estrogen plus progestin therapy performed slightly worse than the placebo group.3
In a separate study, which looked at the entire population of women enrolled in the estrogen plus progestin arm of the WHI, researchers found that 151 of 8,506 (1.8%) women taking HT and 107 of 8,102 (1.3%) women on placebo had strokes, representing a 31% increased risk of combined ischemic and hemorrhagic stroke among users of HT.2 Hormone therapy increased risk only of ischemic stroke, findings indicate. The number of strokes was increased in women on HT of all ages, including those ages 50-59.
Weigh benefits, risks
How will you incorporate this new information into your current practice? The ARHP, in a statement issued following publication of the studies, points out the WHIMS study evaluated women who were an average age of 71 at enrollment, far past the average age for women experiencing menopause, which is 51.
Hormone therapy has never been indicated to prevent or treat dementia; it was approved by the Food and Drug Administration only to relieve uncomfortable changes such as hot flashes, night sweats, and vaginal dryness associated with menopause and to prevent osteoporosis, uses unrelated to the focus of the WHIMS research, the organization points out.
"This large randomized trial only emphasizes the need for additional studies on the effects of gonadal steroids. The presumption that data from the WHI apply to all women and to all regimens of HT remains to be established," states a comment from the Washington, DC-based American Society for Reproductive Medicine.
Keep in mind that another recent report6 from the WHI found some quality-of-life improvement in symptomatic women who used HT, points out Anita Nelson, MD, professor in the obstetrics and gynecology department at the University of California in Los Angeles (UCLA) and medical director of the women’s health care clinic and nurse practitioner program at Harbor-UCLA Medical Center in Torrance.
In that report, among women ages 50-54 with moderate-to-severe vasomotor symptoms at base line, estrogen and progestin improved vasomotor symptoms and resulted in a small benefit in terms of sleep disturbance but no benefit in terms of the other quality-of-life outcomes.6
This improvement was unexpected, since the WHI study excluded women who were experiencing severe hot flashes and who would have been precisely the women in whom estrogen’s benefits would be most obvious, Nelson observes.
Some have suggested that, in light of findings from WHI, helping patients make decisions regarding hormone therapy has become more complicated than ever. Others, including Andrew Kaunitz, MD, professor and assistant chair in the obstetrics and gynecology department at the University of Florida Health Science Center/Jacksonville and director of menopausal services at the Medicus Women’s Center, see this situation differently. He points out that the WHI research, along with findings regarding HT risks and benefits, have clarified that the one clear indication for prescribing hormone therapy is to treat menopausal symptoms.
Kaunitz believes that systemic HT remains the most effective therapy clinicians have available to treat vasomotor symptoms and related insomnia; likewise, vaginal estrogen represents the best therapy available to address dryness and discomfort associated with genital atrophy in menopausal women. In contrast, HT has no role in the prevention or treatment of heart disease, he says.
"Regarding subsequent cognitive function, the impact of HT prescribed to perimenopausal and early menopausal women remains uncertain," he states. "Given the WHIMS findings, however, we can be confident that in elderly women, use of combination HT does not enhance cognitive function and should not be used for the purpose of preventing dementia."
1. Shumaker SA, Legault C, Rapp SR, 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; 289:2,651-2,662.
2. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women. The Women’s Health Initiative: A randomized controlled trial. JAMA 2003; 289:2,673-2,684.
3. Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women. The Women’s Health Initiative Memory Study: A randomized controlled trial. JAMA 2003; 289:2,663-2,672.
4. Yaffe K. Hormone therapy and the brain. Déjà vu all over again? JAMA 2003; 289:2,717-2,719.
5. 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; 288:321-333.
6. Hays J, Ockene JK, Brunner RL, et al. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003; 348:1,839-1,854.
The Washington, DC-based Association of Reproductive Health Professionals (ARHP) has developed a web-based Hormone Therapy Resource Center (www.arhp.org/hormonetherapy/). The site is designed for health care providers and the general public and is updated daily to include the latest news and research on hormone therapy.
New data link hormone therapy, breast cancer
Just-published papers in the June 25, 2003, Journal of the American Medical Association add to heightened concern regarding hormone therapy (HT). In the first paper, which draws from the Women's Health Initiative, researchers report the incidence of total and invasive breast cancer was increased significantly in the estrogen plus progestin group compared with the placebo group. Invasive breast cancers in the two groups were similar in histology and grade, but were larger and at more advanced stages in the estrogen plus progestin group, state the researchers. In the second paper, a population-based case control study focusing on long-term use of HT among older women, results indicate that combination estrogen/progestin HT poses an increase in breast cancer risk, regardless of the pattern of progestin use. Read the September 2003 issue of Contraceptive Technology Update for an analysis of these findings.