Alterations in the hypothalamic-pituitary-ovarian axis are apparent early in the lifespan of female mammals. In laboratory rats, regular estrous cycles cease at 8-12 months of age, yet the average lifespan of the species is approximately 24 months. The primary site of the deficitis that lead to reproductive senescence in female rats appears to be the hypothalamus. Much interest has centered, in particular, on alterations in luteinizing hormone releasing hormone (LHRH) neurosecretion. Understanding the nature of the hypothalamic changes that contribute to reproductive decline in the species is important from two perspectives. First, because reproductive decline occurs so early in the lifespan, the specific events that contribute to senescence of a system can be studied without major concern for indirect influences from age-related alterations in other systems. Second, because impairment of LHRH neurosecretion is considered by many to play a major role in the loss of reproductive function, the model becomes particularly interesting. Many questions surround the neural modulation of LHRH secretion, and the aging female rat exhibits perturbations within the system. Therefore, characterization of the hypothalamic alterations that occur in middle aged (MA) females will yield important information about the modulation of LHRH neurosecretion in young cycling animals. Whereas the ovary appears to be the primary site of deficit in human menopausae, alterations at the hypothalamic level certainly could contribute to the loss of ovarian function. The series of experiments in the present proposal will examine the LHRH system, patterns of LHRH neurosecretion, and specific neurochemical factors implicated in the control of LHRH neurosecretion in aging females. The first experiment will combine in vivo (push pull perfusion and measurement of pulsatile LH release) and in vitro (superfusion) methods to both directly and indirectly assess LHRH neurosecretion in aging females. Intraventricular infusions will be employed in the 2nd experiment in an attempt to alter specific systems known to influence LHRH release in order to determine which of these excitatory or inhibitory influences might contribute to reproductive senescence. An immunocytochemical approach will be taken in a 3rd experiment. The LHRH system and several other sytems implicated in the neural modulation of LHRH release will be examined on the afternoon of proestrus in order to identify differences that exist in MA and young females and could contribute to the age-related alterations in LH secretion.
