The secretion of Gonadotropin-releasing Hormone (GnRH) involves activation of N-methyl-D-aspartate (NMDA) receptors. Here, we show that pulsatile GnRH secretion from hypothalamic explants is suppressed by 1-5GnRH, an endogenous breakdown product of GnRH, while 2-10GnRH has no effect. GnRH secretion evoked by NMDA is selectively inhibited by 1-5GnRH and this effect is similar to that of AP-5, a competitive antagonist at NMDA receptors. In addition, 1-5GnRH accounts for a dose-related inhibition of tritiated glutamate binding to hypothalamic membrane preparations. Using GnRH secretion as a model of NMDA-receptor controlled system, the effect of different peptides has been studied. Growth Hormone Releasing Factor (GRF), Insulin-like Growth Factor-I (IGF-I) and Proinsulin result in inhibition of GnRH secretion. Bioactive subproducts of those peptides (1-29GRF, 4-701GF-I and insulin) do not show any effect, suggesting that their classical receptors are not involved. In contrast, GnRH secretion is inhibited by other subproducts (1-37GRF, 1-31GF-I and C-peptide) all terminating in a glutamate residue. These subproducts selectively suppress the NMDA-evoked secretion of GnRH. Protease inhibitors prevent the inhibitory effects of IGF-I on GnRH secretion. This, breakdown products of different peptide hormones are possible endogenous antagonists at NMDA receptors. This effect could account for an autocrine or paracrine limitation of NMDA-receptor-mediated secretion of peptides.