LUTEINIZING-HORMONE RESPONSE TO N-METHYL-D, L-ASPARTIC ACID IN THE PRESENCE OF PHYSIOLOGICAL ESTRADIOL CONCENTRATIONS - INFLUENCE OF AGE AND THE OVARY

We have previously reported that the pituitary of intra-atrially cannu lated old female c57BL/6J mice is as capable of responding to a GnRH c hallenge as is that of young females (10). We have observed elevated l uteinizing hormone (LH) levels in ovariectomized (OVX) intra-atrially cannulated mice. Sustained physiologic levels of estradiol (E(2)) for 6 days suppressed circulating LH to intact levels. However, in that mo del, a bolus of E(2) following E(2) priming was unable to elicit an LH surge (Joshi et al., unpublished findings). The present studies were designed to examine: first, whether GnRH neurons are competent to rele ase GnRH in the presence of tonic physiologic levels of E(2) and, seco nd, whether either age or the ovary can influence GnRH neuronal respon siveness. The N-methyl-D, L-aspartic acid (NMA)-evoked GnRH response w as assessed indirectly by measuring LH in two groups of OVX c57BL/6J m ice: short-term OVX (S-OVX) (1 week) mice were either prepubertal (5 w eeks), postpubertal (10 weeks), young (5 months), middle aged (12 mont hs), or old (24 months). Long-term OVX (L-OVX) mice were either young (5 months), or old (24 months) and OVX at puberty; middle-aged L-OVX m ice were OVX at 8 months and examined at 12 months of age. Animals wer e administered physiologic levels of E(2) by subcutaneous silastic cap sule for 1 week before testing. LH secretion was inhibited by E(2) in S-OVX mice of all ages. In no case did NMA overcome this inhibition in E, primed S-OVX females. E, also inhibited LH secretion in L-OVX mice of all ages, but NMA was able to overcome the E(2) inhibition of LH s ecretion in L-OVX mice (young: 0.5 +/- 0.1, 0.84 +/- 0.19 ng/ml, first and second challenge, respectively; middle-aged: 0.46 +/- 0.1, 1.08 /- 0.16 ng/ml; and old: 1.44 +/- 0.19, 0.99 +/- 0.27 ng/ml). This last effect was independent of animal maturity at the time of OVX or anima l age at the time of experiment. These findings suggest that although the ovaries in the 24-month-old S-OVX mice had not produced enough E(2 ) to alter the vaginal cytology for 2 +/- 0.5 months before the experi ment, the ovarian modulation of the inhibitory effect of E(2) on NMA-i nduced LH secretion was still present. The nature of the ovarian facto r(s) modulating this effect is unknown. These results demonstrate that in the intra-atrially cannulated female c57BL/6J mouse, the negative feedback effect of E(2) on hypothalamic GnRH release predominates and prevents the induction of an LH surge by a bolus of E(2). The ability of E(2) to inhibit the NMA response is mediated by the length of time between removal of the ovary end initiation of estrogen replacement, a nd this effect is independent of age.