Neurobiological Consequences of Long-Term Estrogen Therapy

Postmenopausal women demonstrate an increased incidence of Alzheimer’s disease (AD). Epidemiological evidence suggests that estrogen replacement therapy (ERT) may reduce the risk or delay the onset of AD, yet recent clinical trials found no cognitive benefits of ERT in women with mild to moderate AD. This review suggests that the timing of estrogen administration may explain these conflicting results. Chronic administration has neurobiological consequences that can affect neural and immune function, but a therapy designed to mimic the natural cycle of fluctuating hormones may more effectively slow the progression of AD in postmenopausal women. KEYWORDS—estrogen; Alzheimer’s disease; luteinizing hormone (LH); immune; neuroprotection Postmenopausal women demonstrate an increased incidence of Alzheimer’s disease (AD), and many researchers have considered whether this heightened risk is linked to their low menopausal levels of the hormone estrogen. Indeed, epidemiological evidence suggests that postmenopausal estrogen replacement therapy (ERT) may reduce the risk and delay the onset of AD. Moreover, animal studies demonstrate that estrogen has beneficial effects on brain cell survival and cognition. Despite these positive indications, however, recent clinical trials found no benefits of ERT on cognitive function in women with mild to moderate AD (for a review, see Hogervorst, Williams, Budge, Riedel, & Jolles, 2000). In this review, we attempt to reconcile these conflicting findings, highlighting a potential misunderstanding of estrogen’s action in the brain.