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.