Autoshortloop feedback regulation of pulsatile gonadotropin-releasing hormone (GnRH) secretion by its metabolite,...

Given the central role of the decapeptide gonadotropin-releasing hormone (GnRH) in reproductive function, our long-term objective is to delineate the underlying mechanism regulating these reproductive processes. The outcome of GnRH secretion is in part dependent on the proteolytic metabolism of this decapeptide. In contrast to the belief that the metabolism of GnRH serves only as a degradative process that removes excess GnRH, we have shown that a metabolite of the decapeptide, GnRH-(1-5), can directly regulate GnRH gene expression and reproductive behavior. To further characterize the effect of GnRH-(1-5) on GnRH neuronal function, we determined whether GnRH-(1-5) can directly regulate GnRH secretion and pulsatility using an in vitro perifusion system. We compared the effect of GnRH-(1-5) on GnRH secretion in the immortalized GnRH neuron (GT1-7 cell line), whole rat hypothalamic explant, and enzymatically dispersed rat hypothalamic cells. Tissue preparations were perifused continuously for 9 h during which a 3-h challenge with GnRH-(1-5) was administered (4-6 h). The results show that treatment with GnRH-(1-5) increased (p < 0.05) the mean GnRH secretion and the amplitude of the pulses but not the pulse frequency. The present study supports the notion that GnRH-(1-5) is functionally capable of regulating the reproductive neuroendocrine system.