Estradiol and progesterone are two steroid hormones that target a variety of organ systems, including the heart, the bone and the brain. With respect to the latter, a large volume of basic science studies support the neuroprotective role of estradiol and/or progesterone. In fact, the results of such studies prompted the assessment of these hormones as protective agents against such disorders as Alzheimer's disease, stroke and traumatic brain injury. Interestingly, results from the Women's Health Initiative (WHI) yielded results that appeared to be inconsistent with the data derived from in vitro and in vivo models. However, we argue that the results from the basic science studies were not inconsistent with the clinical trials, but rather, are consistent with, and may even have predicted, the results from the WHI. To illustrate this point, we review here certain in vivo paradigms that have been used to assess the protective effects of estrogens and progesterone, and describe how the results from these animal models point to the importance of the type of hormone, the age of the subjects and the method of hormone administration, in determining whether or not hormones are neuroprotective. KeywordsEstrogens; Progestins; Neuroprotection; Alzheimer's disease; Animal Models; Review INTRODUCTIONThe U.S. Census Bureau estimates that by 2010, the population of women between 45 and 64 years old will reach approximately 42 million, a marked increase from the value reported for 2000 (approx. 32 million) (U.S. Census Bureau. Projected population of the United States, by Age and Sex: 200 to 2050. www.census.gov/ipc/www/usinterimproj/Internet release date: March 18, 2004). This increasing number of women will consequently need to make decisions about the use of hormone therapy to treat not only menopausal symptoms, but potentially, to maintain a healthy brain. And though numerous basic science studies, epidemiological studies and some clinical trials have supported the potential benefit of hormone therapy in reducing the incidence of age-associated brain dysfunction (including reducing the risk for Alzheimer's disease), recent results from the Women's Health Initiative (WHI) have suggested the contrary and left the field unsettled as to the future of hormone therapy. For example, caveats of the WHI (particularly the WHI memory study, WHIMS) include the possibility that both the age of the subjects and the duration of post-menopausal hormone deprivation diminish the protective brain response to steroid hormones. Additionally, the type of hormone (for example, While it is clear that a better understanding of the neurobiology of gonadal steroid hormones and their receptors is needed, it is equally important that we interpret the basic science studies appropriately, and understand their limitations if we are to apply the results from these studies towards the design of the next large-scale clinical trial or in fact, implement safer and more effective ways of treating the menopause and the post-menopausal period. To this end,...