Effects ofN-Methyl-D,L-Aspartic Acid on Luteinizing Hormone Secretion in Normal Mice and in Hypogonadal Mice with Fetal Preoptic Area Implants*

Abstract

Many aspects of reproductive function are corrected in hypogonadal mice with preoptic area grafts (HPG/POA). Gonadotropin release and gonadal development are dependent on the presence of GnRH cells within the grafts and GnRH innervation of the median eminence. This study examined the effect of a known modulator of GnRH secretion, N-methyl-D,L-aspartic acid (NMA), in adult normal and HPG/POA male and female mice. All HPG/POA males had significant testicular development after graft surgery, and most HPG/POA females were in constant vaginal estrus and showed ovarian and uterine development; a few also demonstrated ovulatory cyclicity after pregnancies initiated by reflex ovulation. Groups of normal and HPG/POA males that were intact (INT) or castrated (CX) 7 days before testing were challenged with saline, NMA (20 mg/kg), and GnRH (100 ng/0.1 ml). Sequential blood samples from awake animals were obtained via intracardiac catheters for evaluation of plasma LH. There were significant increases in plasma LH after NMA challenge in normal INT [n = 15; 0 min, 0.26 +/- 0.02 (mean +/- SE); 10 min, 1.20 +/- 0.10 ng/ml; P less than 0.05] and normal CX (n = 13; 0 min, 0.36 +/- 0.06, 10 min, 3.25 +/- 0.27). Plasma LH secretion in response to NMA was significantly correlated (r = 0.786; P less than 0.001) with plasma LH release after the GnRH challenge in normal males. In contrast, only 3 of 17 HPG/POA (1 INT and 2 CX) showed increased circulating LH after NMA challenge, despite heightened pituitary sensitivity to GnRH. Normal and HPG/POA female mice were ovariectomized (OX) or OX and estrogen primed (OXE2) 7 days before testing. Intact cycling normal and cycling HPG/POA mice were tested in estrus (EST). There was a greater response to NMA in normal OX (n = 8; 0 min, 0.39 +/- 0.02; 10 min, 1.44 +/- 0.28) than in OXE2 (n = 13; 0 min, 0.29 +/- 0.01; 10 min, 0.52 +/- 0.07) despite similar gonadotroph sensitivity to GnRH. There was also a significant increase in plasma LH in response to NMA in HPG/POA-OX (n = 7; 0 min, 0.50 +/- 0.10; 10 min, 1.62 +/- 0.22) and HPG/POA-OXE2 (n = 12; 0 min, 0.39 +/- 0.04; 10 min, 1.31 +/- 0.26). Plasma LH levels after NMA treatment were significantly correlated with responses to GnRH in female HPG/POA (r = 0.58; P less than 0.03), but not in normal females. Neither normal-EST nor HPG/POA-EST had increased LH release after NMA challenge, perhaps due to the low gonadotroph sensitivity in this state.(ABSTRACT TRUNCATED AT 400 WORDS)