In sharp contrast to prevailing hypotheses, taking combination hormone replacement actually doubles a woman’s risk of developing dementia, including Alzheimer's disease, when the therapy is begun at age 65 or older, according to a study in today’s Journal of the American Medical Association. Hormone replacement also did not prevent mild cognitive impairment in trial participants.
Evidence from earlier studies suggested that hormone replacement would decrease the risk of dementia. Although prospective observational trials have not shown any benefit, a meta-analysis of 14 epidemiologic studies suggested that estrogen could cut AD risk by half.
The Women's Health Initiative Memory Study assessed combination therapy's effect on risk in a large randomized, double-blind, placebo-controlled trial with nearly 4,500 participants aged 65 or older. Sally A. Shumaker, Wake Forest University Health Sciences, Winston-Salem, North Carolina, and colleagues report that overall, 61 trial participants were diagnosed with probable dementia. Of those, 40 (66 percent) were receiving estrogen and progestin, while 21 (34 percent) were taking placebo. About half of the cases in each group were classified as AD.
The results did not change significantly even after the investigators controlled for baseline dementia rates, adherence, use of statins and nonsteroidal antiinflammatory drugs, socioeconomic and educational status, and prior hormone use.
The study is an ancillary to the larger hormone therapy trials within the Women’s Health Initiative (WHI) that were halted last summer because the participants were found to be at greater risk for heart disease, stroke, pulmonary embolism, and breast cancer (see ARF related news story). It is possible that small strokes contributed to the increased risk of AD in this trial, the researchers write. The present study also comes hard on the heels of an analysis of the WHI study published earlier this month, which found that, contrary to prior studies and general expectation, combined estrogen-progestin therapy does not improve health-related quality of life (Hays et al., 2003).
The absolute risk of dementia is still small, the researchers point out. The increased risk of HRT would increase the number of cases by 23 for every 10,000 women. Even so, the authors conclude: "Estrogen plus progestin should not be prescribed with the expectation that it will enhance cognitive performance in postmenopausal women. When considered in conjunction with the WHI results reported earlier, the WHIMS estrogen plus progestin data reinforce the conclusion that the risks of estrogen plus progestin outweigh the benefits."
Participants in the trial took a combination of estrogen and progestin. The effect on risk may be different in women taking only estrogen, rather than the combination, the researchers suggest. That trial is still in progress.—Apoorva Mandavilli
- Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE, Patterson RE, Aragaki AK, Shumaker SA, Brzyski RG, LaCroix AZ, Granek IA, Valanis BG, . Effects of estrogen plus progestin on health-related quality of life. N Engl J Med. 2003 May 8;348(19):1839-54. PubMed.
- Zandi PP, Breitner JC. Estrogen replacement and risk of Alzheimer disease. JAMA. 2003 Mar 5;289(9):1100-2. PubMed.
- Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J, . 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 May 28;289(20):2651-62. PubMed.