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Estrogen-based therapies often include a progestin to antagonize tumorigenic effects of estrogens in the uterus. While much has been learned about the functional and neuroprotective effects of estrogens in the brain, far less is known about the effects of progestins, particularly specific progestins like progesterone and medroxy-progesterone acetate, used either alone or in combination with estrogenic therapies. In this chapter, Pike and Carroll review many of the effects on cell survival and function, first of estrogens, and then of progestins. While not all progestins are alike, the authors find that prolonged exposure to progestins often will decrease the protective effects of estradiol on cell survival and function. Evidence suggests that a cyclical regimen of estradiol and progesterone may be most efficacious. Ultimately, the development of neural selective estrogen receptor modulators (SERMs) with the potential to circumvent the need for, and hence the negative neural consequences of, progesterone will be an important advance to estrogen-based therapies.