NEUROENDOCRINE CONCOMITANTS OF REPRODUCTIVE AGING

Depletion of ovarian follicles is often thought to be the determining factor in female reproductive aging. However, increasing evidence sugg ests that neural and neuroendocrine changes play important causative r oles in the decline of regular reproductive cycles leading to the meno pause. A blunting or suppression in the daily pattern of secretion of several neuroendocrine hormones has been documented in aging laborator y animals and humans. Investigators have designed experiments to test whether these changes reflect multiple unrelated changes in the regula tion of each of these hormones, or whether these alterations result fr om a fundamental change in the time-keeping mechanism that underlie th ese patterns of hormone secretion. Oscillations that occur approximate ly every 24 h are a hallmark of most living organisms. These cycles pr ovide the organism with the capability of coordinating events that occ ur at higher (hourly) and lower (weekly or monthly) frequencies within an individual organism, and with the capability of synchronizing thes e events with the external environment. In mammals, the hypothalamic s uprachiasmatic nucleus is thought to be a master oscillator that regul ates most circadian rhythms in mammals. Perturbations in temporal orga nization occur during aging and influence multiple physiological syste ms, including reproductive cyclicity in females. Thus, the question fo r neuroendocrinologists is: Do changes in the cyclic pattern of hormon e secretion reflect a change in the master oscillator, and do these ch anges play a role in female reproductive aging? Data from our laborato ry demonstrate that the timing of the preovulatory and steroid-induced luteinizing hormone (LH) surge changes during middle-age in rats. Thi s change correlates with changes in the diurnal pattern of activity or gene expression of several neurotransmitters, including norepinephrin e, serotonin, and beta-endorphin. These neurotransmitters regulate the release of gonadotropin-releasing hormone from the hypothalamus. More recent findings show that changes in the integrity of the suprachiasm atic nucleus, or inputs and/or outputs of this neural pacemaker, may u nderlie changes in the pattern of activity of these neurotransmitters: 1) The circadian pattern of metabolism of the neural substrate, as me asured by local cerebral glucose utilization, is blunted and phase adv anced in aging animals; and 2) Transplantation of fetal suprachiasmati c tissue partially restores the diurnal rhythm in cFos expression of t he aging host to that observed in the suprachiasmatic nucleus of young animals. These data strongly suggest that changes in neural time-keep ing mechanisms may contribute to changes in the patterns of LH secreti on that, in turn, may contribute to age-related deterioration of ovari an function.