Estrogen Bows to a New Master: The Role of Gonadotropins in Alzheimer Pathogenesis

Epidemiological data showing a predisposition of women to develop Alzheimer disease (AD) led many researchers to investigate the role of sex steroids, namely estrogen, in disease pathogenesis. Although there is circumstantial support for the role of estrogen, the unexpected results of the Women's Health Initiative (WHI) Memory Study, which reported an increase in the risk for probable dementia and impaired cognitive performance in postmenopausal women treated with a combination of estrogen and progestin, have raised serious questions regarding the protective effects of estrogen. Although explanations for these surprising results vary greatly, the WHI Memory Study cannot be correctly interpreted without a complete investigation of the effects of the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis on the aging brain. Certain hormones of the HPG axis, namely, the gonadotropins (luteinizing hormone and follicle-stimulating hormone), are not only involved in regulating reproductive function via a complex feedback loop but are also known to cross the blood-brain barrier. We propose that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a potentially primary causative factor for the development of AD. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, AD. On this basis, we suggest that the results of the WHI Memory Study are not only predictable but also avoidable by therapeutically targeting the gonadotropins instead of the sex steroids.