Research strategy for studying females in mouse models of AD. To determine how reproductive aging alters AD-related measures in females, an appropriate strategy is comparing gonadectomized to intact mice. Intact females can be separated into estrogen dominant* (E2: proestrous, estrous) or progesterone dominant** (P4: metestrous, diestrous) stages of the reproductive cycle since these hormones can have opposing effects in the brain. To determine whether hormone replacement alters AD-related measures in females, an appropriate strategy is comparing vehicle- versus hormone-treated mice that have all undergone gonadectomy to simulate human reproductive aging. E2 is estradiol, the most biologically active estrogen in the mammalian reproductive cycle.