Sustained Intermittent Release of Gonadotropin-Releasing Hormone in the Prepubertal Male Rhesus Monkey Induced by N-Methyl-DL-Aspartic Acid

Abstract

The purpose of the present study was to determine whether gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus of the prepubertal monkey may be prematurely provoked into producing a sustained train of intermittent GnRH release. N-methyl-DL-aspartic acid (NMA), an analog of the putative excitatory neurotransmitter aspartate, was used to stimulate the hypothalamus. In order to utilize pituitary luteinizing hormone (LH) secretion as a bioassay of hypothalamic GnRH release, juvenile males were castrated and the responsiveness of their gonadotrophs to GnRH was enhanced prior to the study with a chronic intermittent intravenous infusion of the synthetic decapeptide (0.1 µg/min for 3 min every hour). Treatment with this regimen of GnRH, which appears to provide the pituitary gonadotrophs with a hypophysiotropic stimulus similar to that produced by the hypothalamus of castrated adults, elicited a pattern of pulsatile LH secretion in prepubertal animals similar to that observed in the open-loop situation in adults. This episodic pattern of LH release was sustained without decrement following termination of GnRH priming and initiation of an intermittent intravenous infusion of NMA (4.5–6.5 mg NMA/kg body weight/pulse, administered over 1 min) delivered at a frequency of 1 pulse/1 h for 50 h. In contrast, an intermittent infusion of the vehicle employed to administer NMA (saline) failed to maintain LH secretion. Administration of the same dose of NMA at a slower frequency of 1 pulse/2 h for 52 h, while also sustaining LH secretion without decrement, resulted in an exaggeration in the LH response. Since it has been previously established that NMA-induced release of LH is mediated by hypothalamic GnRH, these results demonstrate that in the monkey GnRH neurons possess the potential for sustaining an adult-like pattern of intermittent GnRH release well before the onset of puberty. The foregoing findings are discussed in the context of current understanding of the neuroendocrine mechanisms underlying the prepubertal hiatus in gonadotropin secretion in primates.

Increased hypothalamic GPR54 signaling: A potential mechanism for initiation of puberty in primates

“…injections of an NMDA receptor agonist elicited a sustained train of hypothalamic GnRH discharges at this stage of development (23). In striking contrast to GnRH release, GnRH gene expression and GnRH peptide content in the hypothalamus are maintained during juvenile development in the monkey (24,25).…”

KISS1R: Hallmarks of an Effective Regulator of the Neuroendocrine Axis

“…In the rhesus monkey (Macaca mulatta), the responsiveness of pituitary gonadotropes to GnRH stimulation is clearly enhanced by a preceding chronic pulsatile infusion of GnRH [63]. This important observation led Plant and colleagues [64,65,66,67,68]to employ a standard GnRH priming protocol in their studies where gonadotropin secretion is measured in response to various factors. Studies have also been conducted in men exhibiting gonadotropin deficiency, and in the absence of any pituitary defects it has been reported that GnRH priming improves gonadotropin secretion [69,70].…”

Effect of Estrogen on Hypothalamic Transforming Growth Factor Alpha and Gonadotropin-Releasing Hormone Gene Expression in the Female Rhesus Monkey

“…That reaugmentation of pulsatile GnRH release at the time of puberty is unrelated to any maturational changes of the GnRH neurons themselves is suggested by the findings that the hypothalamic contents of immunoactive GnRH, bioactive GnRH and the messenger RNA (mRNA) coding for the decapeptide in prepubertal monkeys are similar to those in adults [2, 3, 4]. Moreover, repetitive hourly stimulation of the GnRH neuronal system of juvenile monkeys by N-methyl- D -aspartate, a glutamate receptor agonist, results in the immediate activation of an adult-like pattern of pulsatile GnRH release [5, 6]. The latter result suggests that initiation of the pubertal enhancement of pulsatile GnRH release in primates is determined by developmental changes in an ‘upstream’ input to the neurons responsible for the secretion of this hypophysiotropic factor.…”