Acute N-methyl-D,L-aspartate administration stimulates the luteinizing hormone releasing hormone pulse generator in the ovine fetus

To assess whether fetal luteinizing hormone releasing hormone (LH-RH) neuro secretory 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 fetus es (130-142 days of gestation; term 147 +/- 3 days). All 8 fetuses exhibite d a rise in plasma ovine luteinizing hormone (oLH) and ovine follicle-stimu lating hormone (oFSH) within 5 min. The mean maximal increments of oLH (2.2 5 +/- 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. LHRH (5 mu g) 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-Trp(6)Pro(9)NEt-LH-RH (10 mu g/day i.v. x 4 days), abolished the fetal oLH and the oFSH response to NMD A (n = 5). Moreover, D,L-2-amino-5-phosphonovalerate, a specific competitiv e antagonist for the NMDA receptor, completely inhibited the fetal oLH and oFSH response to NMDA, whereas D-L-2-amino-5-phosphonovalerate alone did no t 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 ce ll 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 oF SH (10-8 M; p < 0.0001) release, evidence that NMDA did not have a direct p ituitary effect. The results suggest that NM DA induces oLH and oFSH secret ion by stimulation of the fetal LH-RH pulse generator and is mediated by ce ntral 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 impor tance 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 cont ributes to the decrease in fetal gonadotropin concentrations in late gestat ion. NMDA did not affect feta I oGH or oPRL secretion.