Effects of N-methyl-D,L-aspartic acid on luteinizing hormone secretion in normal mice and in hypogonadal mice with fetal preoptic area implants.
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)
Saitoh
Y
Y
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029.
Silverman
A J
AJ
Gibson
M J
MJ
D000818:Animals; D002369:Castration; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D016332:Fetal Tissue Transplantation; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006066:Gonads / Q000473:pathology; D007006:Hypogonadism / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000494:pharmacology*; D009929:Organ Size; D011301:Preoptic Area / Q000196:embryology*; D012016:Reference Values
D004967:Estrogens; D007987:Gonadotropin-Releasing Hormone; D016202:N-Methylaspartate; D007986:Luteinizing Hormone