Mechanisms of progesterone-induced neuroprotection

Gonadal steroid hormones such as estrogen and progesterone can no longer be considered strictly within the confines of reproductive function, and with respect to their anatomic targets, extrahypothalamic structures within the brain such as the cerebral cortex have revealed themselves to be important targets. As such, it may come as no surprise that the decline in such hormones, which occurs after the menopause or ovariectomy, can result in neuronal dysfunction. Although estrogen has been shown to help restore the deficits consequent to ovariectomy, it is important to consider that ovariectomy, like the menopause, results in the precipitous loss of not only estrogen but of progesterone as well. As such, the loss of progesterone may contribute to the deficits observed after ovariectomy or the increased risk for Alzheimer's disease seen after the menopause. Indeed, recent evidence supports the neuroprotective potential of progesterone itself. Here, we review the current understanding of some of the diverse mechanisms by which progesterone may reduce neuronal vulnerability to toxic insults relevant to age and age-associated diseases such as Alzheimer's disease. Further, we comment on the need to carefully consider the various preparations of progestins that are currently available and argue that "not all progestins are created equal," at least when it comes to influences on neuroprotection and other extrahypothalamic brain functions.