Neuroendocrine concomitants of reproductive aging

Depletion of ovarian follicles is often thought to be the determining factor in female reproductive aging. However, increasing evidence suggests that neural and neuroendocrine changes play important causative roles in the decline of regular reproductive cycles leading to the menopause. A blunting or suppression in the daily pattern of secretion of several neuroendocrine hormones has been documented in aging laboratory animals and humans. Investigators have designed experiments to test whether these changes reflect multiple unrelated changes in the regulation of each of these hormones, or whether these alterations result from a fundamental change in the time-keeping mechanism that underlie these patterns of hormone secretion. Oscillations that occur approximately every 24 h are a hallmark of most living organisms. These cycles provide the organism with the capability of coordinating events that occur at higher (hourly) and lower (weekly or monthly) frequencies within an individual organism, and with the capability of synchronizing these events with the external environment. In mammals, the hypothalamic suprachiasmatic nucleus is thought to be a master oscillator that regulates most circadian rhythms in mammals. Perturbations in temporal organization occur during aging and influence multiple physiological systems, including reproductive cyclicity in females. Thus, the question for neuroendocrinologists is: Do changes in the cyclic pattern of hormone secretion reflect a change in the master oscillator, and do these changes play a role in female reproductive aging? Data from our laboratory demonstrate that the timing of the preovulatory and steroid-induced luteinizing hormone (LH) surge changes during middle-age in rats. This change correlates with changes in the diurmal pattern of activity or gene expression of several neurotransmitters, including norepinephrine, 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 suprachiasmatic nucleus, or inputs and/or outputs of this neural pacemaker, may underlie changes in the pattern of activity of these neurotransmitters: 1) The circadian pattern of metabolism of the neural substrate, as measured by local cerebral glucose utilization, is blunted and phase advanced in aging animals; and 2) Transplantation of fetal suprachiasmatic tissue partially restores the diurnal rhythm in cFos expression of the aging host to that observed in the suprachiasmatic nucleus of young animals. These data strongly suggest that changes in neural time-keeping mechanisms may contribute to changes in the patterns of LH secretion that, in turn, may contribute to age-related deterioration of ovarian function.