Female mammals cease exhibiting reproductive cycles early in their lifespan. The events surrounding the aged-related loss in estrous cyclicity have been well characterized in laboratory rats. Whereas alterations at all levels of the hypothalamic-pituitary-ovarian axis contribute to the loss of fertility, the hypothalamus appears to be the major site of deficit in this species. Aged-related changes at the hypothalamic level result in alterations in LHRH neurosecretion and the subsequent loss of the preovulatory LH surge. Due to the early onset of reproductive decline, the aging female rat provides an important model for the study of age-related alteration in a neuroendocrine axis without serious concern about indirect effects from age related alterations in other systems. In addition, identification of the deficits responsible for altered LHRH neurosecretion in aging females will provide important information about the regulation of normal reproductive cycles which, at present, remains inadequately understood. Whereas the ovary appears to be the primary site of deficit in human menopause, several lines of evidence suggest neural involvement as well. Moreover, alteration in hypothalamic signals might contribute to the accelerated depletion of ovarian follicles during the perimenopausal period. The function of LHRH neurons in middle-aged females is the focus of the proposed studies. Immunocytochemical localization of Fos will be used to test the hypothesis that fewer LHRH neurons are activated during an LH surge in aging animals (Experiment 1). In situ hybridization will be used to test the hypothesis that the increase in LHRH gene expression observed in young animals in conjunction with the LH surge are significantly diminished in aging animals. (Experiment 2). Comparisons of data from the young and aging animals in these studies should enable identification of specific subgroups of LHRH neurons that are both essential for the LH surge and functioning submaximally in aging animals. A second series of studies will utilize experimental manipulations to determine the relative contributions of deficits in excitatory stimulation (Experiment 3) or enhancement of inhibitory influences (Experiment 3) to the age-related deficit in the regulation of LH secretion. Understanding the nature of the disturbance in LHRH neurosecretion in aging female rats may provide valuable insights for the treatment of infertility.
