ABSTRACT
Results of recent clinical studies have challenged our previously held view that estrogen therapy (ET) promotes neurological health and prevents or ameliorates Alzheimer’s disease (AD). A major question emerging from these studies is how can there be such disparity between the basic science and epidemiological data which show that estrogen can protect neurons against degenerative insults and reduce the risk of AD and the recent data from the Women’s Health Initiative Memory Study (WHIMS) trial and the trial of estrogen treatment for AD which show that hormone therapy (HT) in the WHIMS and estrogen treatment in women with existing AD showed no benefit and even a potential deleterious effect of the interventions? Which set of data is correct? The proposition put forth in this review is that both sets of data are correct and that two major factors determine the efficacy of ET or HT. First is the time at which ET is initiated. The data indicate that initiation of therapy early in menopause, in a healthy
neuron state, reduces the risk of AD, whereas ET initiated after the disease has developed or decades following menopause, is without benefit. Second, ET is not the same as HT and the type of progestin used determines the outcome of the therapeutic intervention. Insights into estrogen and progestin mechanisms of action in the brain provide a framework for understanding the paradox of estrogen benefit in prevention of AD vs. the lack of benefit in treatment trials and in trials when HT is instituted years following the menopause. On the basis of estrogen-inducible mechanisms, which have been elucidated in healthy neuron model systems, it would be predicted that ET could be highly efficacious in preventing neurodegenerative diseases by promoting neuronal defense and memory mechanisms. The mechanisms of estrogen action also predict that ET would be an ineffective strategy for reversing the pathology of AD. Factors affecting the efficacy of ET, such as duration of estrogen deficiency, age, the hormonal status when ET or HT is begun, and the type of progestin used in hormone combination therapy, are considered. The issue of when to intervene with ET or HT, whether during perimenopause or following menopause, is also discussed. Finally, an estrogen-advantage hypothesis is put forth, which provides a unifying mechanism of estrogen action with implications for both the benefits and the risks of ET.
