Clocks and the black box: Circadian influences on gonadotropin-releasing hormone secretion

Although the mechanisms underlying hypothalamic surge secretion of gonadotropin-releasing hormone (GnRH) in rodent models have remained enduring mysteries in the field of neuroendocrinology, the identities of two fundamental constituents are clear. Elevated ovarian oestrogen, in conjunction with circadian signals, combine to elicit GnRH surges that are confined to the afternoon of the proestrus phase. The phenomenon of oestrogen positive feedback, although extensively investigated, is not completely understood, and may involve the actions of this steroid directly on GnRH perikarya, as well as on the activity of neuronal afferents. Additionally, whereas many studies have focused upon regulation of GnRH surge secretion by the neuroanatomical biological clock, the suprachiasmatic nucleus, it remains unclear why this daily signal is capable of stimulating surges only in the presence of oestrogen. This review re-examines multiple models of circadian control of reproductive neurosecretion, armed with the recent characterisation of the intracellular transcriptional feedback loops that comprise the circadian clock, and attempts to evaluate previous studies on this topic within the context of these new discoveries. Recent advances reveal the presence of oscillating circadian clocks throughout the central nervous system and periphery, including the anterior pituitary and hypothalamus, raising the possibility that synchrony between multiple cellular clocks may be involved in GnRH surge generation. Current studies are reviewed that demonstrate the necessity of functional clock oscillations in generating GnRH pulsatile secretion in vitro, suggesting that a GnRH-specific intracellular circadian clock may underlie GnRH surges as well. Multiple possible steroidal and neuronal contributions to GnRH surge generation are discussed, in addition to how these signals of disparate origin may be integrated at the cellular level to initiate this crucial reproductive event.