Alzheimer’s Patients Fail to Improve in Estrogen Trial
abstract & commentary
Source: Mulnard RA, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: A randomized controlled trial. JAMA 2000;283:1007-1015.
The hypothesis that estrogen replacement therapy can be used as a treatment for Alzheimer’s disease (AD) was supported by the results of several small, open-label pilot studies over the past decade. No large-scale or well-controlled prospective trials examining estrogen’s effects on cognition in AD patients had been carried out until the Alzheimer’s Disease Cooperative Study Group initiated a randomized, double-blind trial in hysterectomized AD patients in 1995. This group now reports that estrogen treatment for a period of one year is no better than placebo in maintaining the cognitive status and daily functioning of female AD patients.
One hundred twenty hysterectomized women with mild to moderate AD participated in this trial. The study was restricted to women who had undergone hysterectomies to permit the use of estrogen unopposed by progesterone over a one-year period. Participants ranged in age from 56-91 years and had Minimental State Exam (MMSE) scores between 12 and 28. The three-armed design compared daily use of 0.625 mg and 1.25 mg of conjugated equine estrogen (premarin) to placebo. Women who had been previously treated with estrogen were admitted into the study. The primary outcome measure was the seven-point Clinical Global Impression of Change score. A variety of secondary outcome measures were used to assess changes in cognition, mood, and activities of daily living.
A total of 97 participants completed one year of treatment. At one year, there were no significant positive differences on either the primary or the secondary outcome measures between the estrogen-treated patients and those who received placebo. One secondary measure, the Clinical Dementia Rating Scale, actually indicated a marginally greater decline in the estrogen-treated group. At two and six months of treatment, patients receiving 0.625 of estrogen did score higher on the MMSE, but they did not show comparable performance advantages on any of the other tests used. In supplemental analyses, no significant difference was observed between patients receiving the low- and high-dose estrogen regimes. Mulnard and colleagues conclude that estrogen is not of benefit in the primary treatment of AD, but further studies are needed to examine its potential use in the prevention of AD.
Commentary
This well-designed trial took more than four years to complete. Although fewer patients completed the study than were originally planned, the lack of a trend toward statistical significance on any of the one-year outcome measures argues against the negative results being a function of sample size. There were some possible biases introduced by the study’s inclusion criteria. The inclusion of AD patients who had been previously treated with estrogen was pragmatically necessary but could be potentially problematic if it selected out a group of patients who developed AD despite receiving hormonal treatment. Likewise, the inclusion of women with relatively advanced dementia may have adversely affected the results, since estrogen receptors occur in highest concentration in areas of the brain such as the amygdala and hippocampus that are presumably affected much earlier in the course of AD. It is conceivable that other benefits of estrogen accrue early in the disease process, or with longer treatment times, than were used in this study. In the latter part of the study, patients receiving donepezil were permitted to participate, and no detailed analysis of the results stratified by donepezil status was presented in the published manuscript. Nevertheless, it is undeniable that the largest prospective study to date addressing the value of estrogen replacement therapy in treatment of patients with AD has failed to show significant benefits.
Several retrospective epidemiologic studies have indicated that estrogen replacement therapy may reduce the risk of AD when initiated during the postmenopausal period. There is still considerable reason for optimism that the putative preventative effects of estrogen will be borne out in the prospective studies that are currently ongoing. The lack of apparent benefits of unopposed estrogen therapy in this one-year study does not preclude it possibly being of value as an adjunct treatment for AD. An ongoing study is examining whether estrogen boosts the beneficial effects of cholinesterase therapy, an effect previously observed in retrospective studies and which is mechanistically plausible based on estrogen’s known biological effects. —nrr
The use of estrogen in the treatment of Alzheimer’s disease:
a. is warranted based on the results of a recent double-blind treatment trial.
b. is possible in hysterectomized women only.
c. has clear benefits for cognition after one year of high-dose therapy.
d. has comparable effects to placebo irrespective of dosage.
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