The overall goal of this grant is to elucidate the mechanisms by which aging leads to a functional loss of the preovulatory gonadotropin surge and a cessation of estrous cycles in middle-aged female rats. The integrity of the reproductive function depends upon coordinated interactions between the neuroendocrine system and the ovary. In particular, the preovulatory surge of luteinizing hormone (LH), which is induced by the positive feedback actions of estradiol (E2) and progesterone (P), is essential for ovulation to occur. However, in the female rat, reproductive aging is characterized by a gradual loss of regular ovulatory cycles, diminished fertility, and the decline in the preovulatory LH surge magnitude. The decline in LH surge profiles in middle-aged female rats is associated with decreased positive feedback response to E2 stimulation, altered patterns of hypothalamic neurotransmitter gene expression, attenuated rise in plasma P on proestrous afternoon, and decreased activation of hypothalamic gonadotropin releasing hormone neurons which provide the central neural drive to the reproductive axis. Together, these findings suggest that neural changes may contribute to attenuated LH surges and the eventual loss of regular estrous cycles in aging female rats. This grant proposes to (a) reveal patterns of central neuronal activity and neurochemistry mediating the loss of the functional preovulatory LH surge and the cessation of estrous cyclicity in middle-aged rats, and (b) assess the ability of acute exogenous P administration to augment LH secretion and restore central neuronal activity and neurochemistry mediating preovulatory LH surge secretion. Findings from these studies will provide new insight into the role of altered central neural function upon the onset of reproductive senescence. Furthermore, the proposed projects will use a natural, progressive model of aging with which to study changes in neural function in the female rat during a critical period of reproductive transition, and should provide a useful model in which to examine the dynamic interactions among the hypothalamus, pituitary, and ovary.
