Cognitive effects of estrogens in women with cardiac disease: what we do not know.

Clinical skill in the early detection of cognitive loss in the aging population has grown, and interest in the prevention of age-associated memory impairment and frank dementia is a major initiative in medical research (1). Concerns about cognitive consequences of many diseases as a source of major disability have a growing urgency, particularly regarding women, who live longer than men, survive with more chronic diseases, and continue to work at older ages. To address women’s health issues, clinical trials have been conducted to examine the effects of estrogens on the heart (2,3), breast (3,4), and brain (5,6); however, results have been disappointing. One of the first studies to report results, the Heart and Estrogen/progestin Replacement Study (HERS), found no difference in cardiac outcomes over a 4-year period in women randomly assigned to conjugated estrogen plus medroxyprogesterone acetate or to placebo, although in the first year there were more cardiac events in the estrogen group (2). In this issue of the Journal, Grady et al. (7) describe an “add-on” study that assessed cognitive function in a subset of HERS participants at the end of the treatment period using a mental status test and five other cognitive outcomes. No benefit was observed on any measure, and small but statistically significant differences were observed on a measure of verbal fluency, with lower scores in the hormone replacement therapy group. Given that hormone therapy demonstrated similar trends on coronary outcomes in these same at-risk women, these results may not be surprising. Several studies have demonstrated the effects of coronary disease on cognitive function (8,9), and the apparent minimal effect of treatment may have been due to pre-existing disease. However, the study used only post-treatment assessment, and thus whether hormone therapy or pre-existing disease is the cause cannot be determined. The design permitted only evaluation of group differences, which could be due to baseline variables, and not true change. Furthermore, treatment differences in cardiac outcomes may have affected post-treatment cognitive testing via a wide range of peripheral and central mechanisms. The presence of a specific apolipoprotein E genotype (E4) has been associated with an attenuated effect on change in both cognitive and cardiac measures (10). Since the HERS cohort was selected for the presence of cardiac disease, a sample associated with a higher prevalence of the E4 allele, cognitive observation may have been confounded. Estrogenic mechanisms that may prevent observable benefit in cardiac or cognitive outcomes include prothrombotic and proinflammatory effects, which may lead to challenge of the central nervous system. Mechanisms that have been proposed to account for potential benefit include favorable effects on lipids, reduction of ischemia, and protection of cholinergic neurons. These mechanisms model prevention of disease and may depend on initiation of treatment in the presence of an intact nervous system. Multicenter trials involving patients with Alzheimer’s disease have also failed to demonstrate a benefit of estrogens on cognitive or clinical outcome measures, and it has been suggested that estrogenic benefits in Alzheimer’s disease may not be observable as symptomatic relief in the presence of disease, but only in prevention of disease (6). Such are the limitations of so-called “add-on” studies, which attempt to address a secondary question in a trial designed to assess a different outcome. In the case of primary prevention, which typically involves a relatively unselected population, multiple outcomes may be addressed by determining or assuming equivalence at baseline (e.g., absence of an outcome or a risk factor). In secondary prevention trials, identifying the presence of a disease or risk factor for one condition may confound the distribution of another condition, and unless it is directly assessed, it will be difficult to interpret results. In addition, features designed to assess the primary outcome may not be ideal for assessing a secondary measure. This is particularly true for assessing cognition, as in the study by Grady et al. (7), which would require longer observation periods and older subjects. The challenge presented by this report is determining if these results can be generalized beyond those with coronary heart disease. A recent trial that examined the effect of estradiol on the secondary prevention of cerebrovascular disease reported no benefit in stroke reduction (5). However, this trial will examine the effects of estrogen on dementia and cognitive decline, and these results may help to define the universality of the findings. Am J Med. 2002;113:612– 613. From the Taub Institute for Alzheimer’s Disease Research (MS, KB), and the Gertrude H. Sergievsky Center (MS, KB, DJ), Department of Neurology, College of Physicians and Surgeons of Columbia University, New York, New York. Requests for reprints should be addressed to Mary Sano, PhD, Clinical Neuropsychology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, Box 16, New York, New York 10032, or sanomar@sergievsky.cpmc.columbia.edu.