Early HRT Use Linked to Reduced Risk of Alzheimer's Disease, All-Cause Dementia

Caroline Cassels

May 04, 2007

May 4, 2007 (Boston) — New research from the Women's Health Initiative Memory Study (WHIMS) links use of hormone replacement therapy (HRT) before the age of 65 years to a reduced risk of all-cause dementia and Alzheimer's disease (AD) in women.

However, investigators warn these findings should be interpreted with caution and, at this point, have no clinical implications or indicate a need to modify current HRT guidelines.

Here at the American Academy of Neurology 59th Annual Meeting, researchers presented an analysis that showed early HRT use was associated with a 46% overall reduction in dementia risk and a 64% reduction in AD.

"These findings are observational and have implications in terms of informing some of the research that needs to be done to determine the long-term cognitive outcomes of early HRT usage. But they do not inform clinical practice," said Victor Henderson, MD, from Stanford University in Palo Alto, California.

"The current recommendations to use hormone replacement therapy for the treatment of moderate to severe vasomotor symptoms associated with menopause at low doses and for a shorter duration are still appropriate," he added.

HRT Doubled Dementia Risk in Older Women

WHIMS is an ancillary study of the Women's Health Initiative (WHI), a large randomized, placebo-controlled trial designed to look at the impact of estrogen alone or estrogen plus progestin (E + P) on a number of health outcomes, including breast cancer and cardiovascular disease, in postmenopausal women with and without hysterectomy.

In 2002, the WHI was halted prematurely because preliminary results showed individuals receiving active treatment had an increased risk for breast cancer and cardiovascular disease compared with placebo.

Similarly, WHIMS included 2 studies that looked at cognitive outcomes and HRT in women over 65 years old. The first included approximately 4000 subjects who received E + P vs placebo, while the second study compared treatment with estrogen alone vs placebo in about 3000 women.

At an average 5-year follow-up, both the E + P and the estrogen-alone trials showed conjugated estrogens, with or without progesterone, increased dementia risk when therapy was initiated after age 65 years. In the E + P trial the risk doubled, while in the estrogen-alone trial there was about a 50% increased risk.

Dr. Henderson noted that prior hormone therapy use during these trials did not influence the results of on-trial treatment. "Adverse outcomes applied to both women who had used hormones in the past and those who didn't," he said.

Cognitive Impact in Younger Women Unclear

However, he added, the relationship between HRT use and AD and dementia in younger postmenopausal women subjects remained unclear.

To better understand this relationship, investigators analyzed data provided by 7153 WHIMS participants who provided information on prior hormone exposure at initial study enrollment.

Subjects included women aged 65 to 79 years without dementia. In total, there were 2228 in the prior-users group and 4925 subjects reporting no prior use. The study's primary outcomes were baseline modified Mini-Mental State Examination (MMSE) and incident dementia.

According to Dr. Henderson, there were some differences between prior HRT users and nonusers. Those who reported past HRT use tended to be slightly older, have a higher BMI, and, although the numbers were small, had a slightly increased history of stroke and transient ischemic attack (TIA).

The study's final analysis was based on 106 women who developed dementia during the WHIMS follow-up period — 22 of whom reported prior HRT use and 84 with no HRT history before age 65 years.

Reduction in All-Cause Dementia

The results suggest the overall reduction in risk for all-cause dementia in women who took HRT before age 65 years was about 46%, which was statistically significant, said Dr. Henderson. For AD alone, the reduction in incidence was 64%. For other causes of dementia, it was approximately 30%, a result that was not statistically significant.

In the estrogen-alone study, average baseline MMSE scores were 94.95 for prior HRT users vs 94.93 for nonusers. However, this was not the case in the E + P trial. Although this finding in the estrogen-alone group was statistically significant and tended to favor prior HRT users, it is unlikely to be clinically relevant, said Dr. Henderson.

If, in fact, the protective effect of early HRT use is real, there is no indication from this study of optimal age of initiation or duration of therapy, he said.

Intriguing Results

Asked to comment on the results, Kristine Yaffe, MD, chief of geriatric psychiatry at the University of California, San Francisco–affiliated Veterans Affairs Medical Center, said the area of late cognitive outcomes related to early HRT use is still a viable and important area of interest but agreed that the study's findings, although intriguing, cannot be translated into clinical practice.

"You have to be very careful when you're looking at a big trial like this conducting post hoc, nonrandomized analyses. That being said, I think there's a lot of interesting biological evidence from animal models suggesting estrogen at an earlier stage may be beneficial, and therefore these study results are intriguing, because they seem to support that evidence," Dr. Yaffe told Medscape.

However, she added, based on the WHI findings, as well as the WHIMS trial results, a large randomized controlled trial using conventional HRT would be unethical.

"I think we're going to have to look the possibility of using some of the selective estrogen-receptor modulators, or so-called designer estrogens, in trials to help us answer some of the outstanding questions about the effect of HRT on cognitive and other outcomes," she said.

American Academy of Neurology 59th Annual Meeting: Abstract S31.004. April 28 – May 5, 2007.


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