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Early Prepubertal Ontogeny of Pulsatile Gonadotropin-Releasing Hormone (GnRH) Secretion: I. Inhibitory Autofeedback Control through Prolyl Endopeptidase Degradation of GnRH¹

Developmental Neuroendocrinology Unit (M.C.L., E.V., A.G., G.P., J.P.B.), Division of Ambulatory Pediatrics and Adolescent Medicine, Department of Pediatrics, University of Liège, C.H.U. Sart Tilman, B-4000 Liège, Belgium; Eurogentec (M.L.), B-4000 Liège, Belgium; and Department of Pharmacology (S.W.), The Mount Sinai Medical Center, New York, New York 10029-6574

Address all correspondence and requests for reprints to: Jean-Pierre Bourguignon, M.D., Ph.D., Division of Pediatric and Adolescent Medicine, C.H.U. Sart Tilman, B-4000 Liège, Belgium. E-mail: Jean-Pierre.Bourguignon{at}chu.ulg.ac.be

GnRH_[1–5], a subproduct resulting from degradation of GnRH by prolyl endopeptidase (PEP) and endopeptidase 24.15 (EP24.15) was known to account for an inhibitory autofeedback of GnRH secretion through an effect at the N-methyl-D-aspartate (NMDA) receptors. This study aimed at determining the possible role of such a mechanism in the early developmental changes in frequency of pulsatile GnRH secretion. Using retrochiasmatic explants from fetal male rats (day 20–21 of gestation), no GnRH pulses could be observed in vitro, whereas pulses occurred at a mean interval of 86 min from the day of birth onwards. This interval decreased steadily until day 25 (39 min), during the period preceding the onset of puberty. Based on GnRH_[1–10] or GnRH_[1–9] degradation and GnRH_[1–5] generation after incubation with hypothalamic extracts, EP24.15 activity did not change with age, whereas PEP activity was maximal at days 5–10 and decreased subsequently until day 50. These changes were consistent with the ontogenetic variations in PEP messenger RNAs (mRNAs) quantitated using RT-PCR. Using fetal explants, the NMDA-evoked release of GnRH was potentiated in a dose-dependent manner by bacitracin, a competitive PEP inhibitor and the desensitization to the NMDA effect was prevented using 2 mM of bacitracin. At day 5, a higher bacitracin concentration of 20 mM was required for a similar effect. Pulsatile GnRH secretion from fetal explants was not caused to occur using bacitracin or Fmoc-Prolyl-Pyrrolidine-2-nitrile (Fmoc-Pro-PyrrCN), a noncompetitive PEP inhibitor. At postnatal days 5 and 15, a significant acceleration of pulsatility was obtained using 1 µM of Fmoc-Pro-PyrrCN or 2 mM of bacitracin. At 25 and 50 days, a lower bacitracin concentration of 20 µM was effective as well in increasing the frequency of GnRH pulsatility. We conclude that the GnRH inhibitory autofeedback resulting from degradation of the peptide is operational in the fetal hypothalamus but does not explain the absence of pulsatile GnRH secretion at that early age. After birth, PEP activity is high and may account for the low frequency of pulsatility. The potency of that effect decreases before the onset of puberty and may contribute to the acceleration of GnRH pulsatility.

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