Acute N-Methyl-<i>D,L</i>-Aspartate Administration Stimulates the Luteinizing Hormone Releasing Hormone Pulse Generator in the Ovine Fetus

Abstract

To assess whether fetal luteinizing hormone releasing hormone (LH-RH) neurosecretory neurons have the capacity to respond to an exogenous stimulus, a synthetic excitatory amino acid analogue, N-methyl-D-L-aspartate (NMDA; 15 mg/kg), was given rapidly intravenously to 8 chronically catheterized fetuses (130–142 days of gestation; term 147 ± 3 days). All 8 fetuses exhibited a rise in plasma ovine luteinizing hormone (oLH) and ovine follicle-stimulating hormone (oFSH) within 5 min. The mean maximal increments of oLH (2.25 ± 0.36 ng/ml) and oFSH (1.21 ± 0.32 ng/ml) were significantly greater than in 6 normal saline-injected controls (oLH p < 0.0002; oFSH p < 0.03). The secretion of ovine prolactin (oPRL) and ovine growth hormone (oGH) was unaffected. LH-RH (5 μg) evoked a greater oLH response (p < 0.0009) and a greater oFSH response (p < 0.03) than NMDA (n = 6). Desensitization of the fetal gonadotrope by a potent LH-RH agonist, D-Trp⁶Pro⁹NEt-LH-RH (10 μg/day i.v. × 4 days), abolished the fetal oLH and the oFSH response to NMDA (n = 5). Moreover, D,L-2-amino-5-phosphonovalerate, a specific competitive antagonist for the NMDA receptor, completely inhibited the fetal oLH and oFSH response to NMDA, whereas D-L-2-amino-5-phosphonovalerate alone did not affect the plasma oLH or oFSH levels, the gonadotropin response to LH-RH, or the release of oGH or oPRL (n = 3). In primary ovine fetal pituitary cell cultures, NMDA (10^–10 to 10^–6 M) had no effect on oLH, oFSH, oGH, or oPRL secretion, whereas LH-RH stimulated oLH (10^–8 M; p < 0.0004) and oFSH (10^–8 M; p < 0.0001) release, evidence that NMDA did not have a direct pituitary effect. The results suggest that NMDA induces oLH and oFSH secretion by stimulation of the fetal LH-RH pulse generator and is mediated by central NMDA receptors. Fetal LH and FSH secretion and the response to LH-RH decrease in late gestation in the ovine and human fetus. The relative importance of sex steroid dependent and sex steroid independent central nervous system inhibition in this developmental change is unclear. It appears that central neural inhibition in addition to sex steroid negative feedback contributes to the decrease in fetal gonadotropin concentrations in late gestation. NMDA did not affect fetal oGH or oPRL secretion.

Early stage development of the glycine‐1 re‐uptake inhibitor SCH 900435: central nervous system effects compared with placebo in healthy men

“…The results for FSH did not reach statistical significance in the visual effects study, for reasons that are not entirely clear, but testosterone concentrations in this study decreased similarly to the SAD study.Literature on the relationship between NMDA receptor stimulation and FSH, LH or testosterone production in humans is sparse, and most studies show no clear association [33,34] or contradict the present findings [35]. In preclinical experiments, an increase of FSH was found [36,37]. The testosterone reductions found in this study are compatible with the diminished gonadotrophic hormone concentrations, particularly of LH.…”

The Neuroendocrinology of Human Puberty Revisited

“…Plant et al [42]induced puberty in the prepubertal male rhesus monkey by repetitive intravenous injections of N -methyl-D,L-aspartate (NMDA); in both prepubertal and pubertal female rhesus monkeys, NMDA administered centrally induced the release of LHRH [43]. Parenthetically, NMDA administration acutely stimulates the LHRH pulse generator in the ovine foetus, providing additional evidence of NMDA receptors on foetal LHRH neurons and the functional capacity of the foetal pulse generator [44]. NMDA receptor blockers inhibit the action of glutamatergic neurons on the hypothalamic pulse generator [reviewed in 19, 25].…”

Initiation of Puberty in Heifers

“…6 In sheep, it has been demonstrated that the CNS-stimulated reduction in gonadotropin release that occurs in late gestation is mediated through inhibition of N-methyl-dl-aspartate receptors, which have been demonstrated to be stimulatory to the gonadotropin-releasing hormone (GnRH) pulse generator nucleus in the fetal hypothalamus. 7 Postnatally, mean plasma LH concentrations reach a maximum around 3 months of age, then slowly decline before again rising and culminating in ovulation typically around 10-11 months of age. 8 This early transient increase in circulating concentration of LH is associated with early follicular development and is thought to regulate the timing of puberty.…”