Age-related changes in neuroprotection: is estrogen pro-inflammatory for the reproductive senescent brain?

Estrogen replacement therapy (ERT) is widely prescribed to postmenopausal women for relief from the adverse vasomotor effects of menopause, to reduce bone loss, to improve cardiovascular health, and to protect against metabolic disorders. However, there is now greater awareness of the increased risk to benefit ratio from the recently concluded Women's Health Initiative Memory Study (WHIMS), which reported that ERT increased the risk of cognitive impairment and dementia in elderly women. Studies from the experimental literature indicate that while estrogen is neuroprotective in many instances, estrogen replacement can be deleterious in some cases. These differences may be partly due to the age and species of the experimental model. The majority of the experimental data comes from studies where the age or endocrine status of the animal model is not comparable to that of menopausal or postmenopausal women, such as those in the WHIMS study. In this review, we will focus on age-related changes in estrogen's neuroprotective effects and evidence that reproductive senescence-related changes in the blood-brain barrier and the immune system may result in deleterious consequences for ERT.