Basically, the results from over 4,500 women studied in the WHI and WHIMS studies conclude independently that combination hormone replacement therapy (CHRT) holds no efficacy in protecting women from Alzheimer's when the hormones are begun at age 65 or older. Taken together with last year's report that CHRT does not protect against atherosclerosis, there is now no indication for CHRT as prevention of any illness. Indeed, in the NHLBI studies and in one of the new WHI studies, side effects (clotting and Alzheimer's, respectively) were increased in the group of women taking CHRT.

More than 80 percent of women on CHRT are under 65, however, and it remains unclear whether hormones begun perimenopausally might be more effective than those begun many years later: Certainly this result emerged from the Cache County study (Zandi et al., 2002). More importantly, it is worth noting that virtually all of the basic and early clinical literature suggesting that hormones protected against Alzheimer's utilized unopposed,...  Read more

Basically, the results from over 4,500 women studied in the WHI and WHIMS studies conclude independently that combination hormone replacement therapy (CHRT) holds no efficacy in protecting women from Alzheimer's when the hormones are begun at age 65 or older. Taken together with last year's report that CHRT does not protect against atherosclerosis, there is now no indication for CHRT as prevention of any illness. Indeed, in the NHLBI studies and in one of the new WHI studies, side effects (clotting and Alzheimer's, respectively) were increased in the group of women taking CHRT.

More than 80 percent of women on CHRT are under 65, however, and it remains unclear whether hormones begun perimenopausally might be more effective than those begun many years later: Certainly this result emerged from the Cache County study (Zandi et al., 2002). More importantly, it is worth noting that virtually all of the basic and early clinical literature suggesting that hormones protected against Alzheimer's utilized unopposed, estrogen-only formulations. The estrogen-only protocol is now only available to women who have had hysterectomies, since uterine cancer rates can increase. An arm of the WHI testing unopposed estrogen replacement continues in women who have had hysterectomies, and results are expected in 2005. Biologically, progestins antagonize many of the effects of estrogens, giving plausibility to the hypothesis that progestins may be "undoing" any good effects of estrogens.

If the estrogen-only study shows benefit, the effort to identify brain-specific SERMs (selective estrogen receptor modulators) will be bolstered, in an effort to provide the protective effects without the side effects on reproductive tissues. If unopposed estrogens are not protective against Alzheimer's, or if a protective window is not identified, enthusiasm for this proposed strategy will be very difficult to sustain.

View all comments by Samuel Gandy

I'd like to follow up on Sam Gandy's comment regarding the antagonistic effect of progestins on the estrogenic effect on memory. While the results from the WHI trial on unopposed estrogen will report more definitive answers, we published in 2000 observational results from the Kame Project showing mean change scores in performance on the Cognitive Abilities Screening Instrument (CASI) over two years among 837 women of +0.79 (sem=.19) for women who were never on hormone replacement therapy; +1.68 (sem=.36) for unopposed estrogen users (p=.04) and -0.41 (sem=.50) for current estrogen-progestin users (p=.02). These figures were adjusted for age, education, language spoken at the interview (Japanese/English), surgical menopause and baseline CASI score. These earlier results support a modest beneficial effect of current unopposed estrogen use on rate of cognitive change, and a modest detrimental effect of combined estrogen-progestin use relative to women who have never taken hormone replacement. This was the first observational study to examine potential differences in combined...  Read more

I'd like to follow up on Sam Gandy's comment regarding the antagonistic effect of progestins on the estrogenic effect on memory. While the results from the WHI trial on unopposed estrogen will report more definitive answers, we published in 2000 observational results from the Kame Project showing mean change scores in performance on the Cognitive Abilities Screening Instrument (CASI) over two years among 837 women of +0.79 (sem=.19) for women who were never on hormone replacement therapy; +1.68 (sem=.36) for unopposed estrogen users (p=.04) and -0.41 (sem=.50) for current estrogen-progestin users (p=.02). These figures were adjusted for age, education, language spoken at the interview (Japanese/English), surgical menopause and baseline CASI score. These earlier results support a modest beneficial effect of current unopposed estrogen use on rate of cognitive change, and a modest detrimental effect of combined estrogen-progestin use relative to women who have never taken hormone replacement. This was the first observational study to examine potential differences in combined therapy versus unopposed estrogen only. In this study, all women receiving combined therapy were on medroxyprogesterone acetate. In addition to studies of unopposed estrogen, other formulations of combined therapy should be examined.

References:
Rice MM, Borenstein Graves A, McCurry SM, Gibbons LE, Bowen JD, McCormick WC, Larson EB. Postmenopausal estrogen and estrogen-progestin use and 2-year rate of cognitive change in a cohort of older Japanese American women. Arch Intern Med 2000;160:1641-9. Abstract Schumaker SA et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women's Health Initiative Memory Study. JAMA 2003;289:2651-62.Abstract

View all comments by Amy Borenstein