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Amino Acid Neurotransmission and Initiation of Puberty: Evidence from Nonketotic Hyperglycinemia in a Female Infant and Gonadotropin-Releasing Hormone Secretion by Rat Hypothalamic Explants¹

Division of Pediatric and Adolescent Medicine, Department of Pediatrics, Centre Hospitalier Universitaire Sart Tilman, University of Liege (J.P.B., A.G.), Liege; and the Divisions of Genetic and Metabolic Diseases (J.J.), and Neonatology and Endocrinology (F.d.Z.), Department of Pediatrics, University of Leuven, Leuven, Belgium

Address all correspondence and requests for reprints to: Prof. J. P. Bourguignon, Division of Pediatric and Adolescent Medicine, University of Liege, Centre Hospitalier Universitaire Sart Tilman, B-4000 Liege, Belgium.

The pulse frequency of hypothalamic GnRH secretion increases at the onset of puberty. In rodents and primates, this process involves facilitatory and inhibitory effects mediated through hypothalamic N-methyl-D-aspartic acid (NMDA) and -aminobutyric acid (GABA) receptors, respectively. Precocious puberty was observed in an 11-month-old girl with nonketotic hyperglycinemia. This was thought to result from the effect of high concentrations of glycine (112 µmol/L in cerebrospinal fluid; normal, 3–12) acting on NMDA receptors as a coagonist of glutamate. Regression of pubertal development during anticonvulsive treatment with GABA agonists (loreclezole and vigabatrin) suggested that the stimulatory effects of glycine could be overcome by GABA receptor-mediated inhibition. These two hypotheses were tested in the in vitro model of the explanted hypothalamus from infantile (15-day-old) male rats. Glycine concentrations of 1–10 µmol/L increased the pulse frequency of GnRH secretion. This acceleration was prevented by 7-chlorokynurenic acid, a glycine antagonist at the NMDA receptor complex, and by the GABA agonist loreclezole. In addition, loreclezole and vigabatrin suppressed the developmental increase in the frequency of pulsatile GnRH secretion. The observation of precocious puberty in an infant with hyperglycinemia followed by pubertal regression during GABA agonist therapy and the in vitro findings in hypothalamic explants suggest that stimulatory inputs mediated through NMDA receptors and inhibitory inputs through GABA receptors are involved in the initiation of puberty.

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