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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 …