Although the excitatory amino acid, N-methyl-DE-aspartate (NMA), is generally thought to stimulate LH release, we have previously reported that NMA inhibits LH secretion in the adult ovariectomized (OVX) rhesus monkey. The objectives of this study were: (1) to compare the effect of NMA on LH in the OVX monkey before and after replacement with ovarian steroids, and (2) to evaluate the LH response to NMA in the intact female monkey during three phases of the menstrual cycle. Three hourly injections of NMA (45 mg i.v.) were given to OVX monkeys (OVX; n = 12) and to OVX animals treated for 4 days with estradiol alone (OVX + E; n = 4) or with estradiol plus progesterone (OVX + E/P; n = 5). Replacement with ovarian steroids prevented the NMA-induced decrease in LH: mean ( ± SE) areas under the LH curve (expressed as a percentage of the 3-hour baseline preinjection control) during the 3-hour NMA treatment period were as follows: OVX,-26.6% ± 2.4; OVX + E, +69.6% ± 33.9; OVX + E/P, + 161.5% ± 59.3 (p < 0.001 vs. OVX). Three hourly NMA (45 mg i.v.) injections were also given to monkeys in the early to mid-follicular phase (n = 5), the late follicular phase (n = 6) and the luteal phase (n = 11). NMA significantly increased LH in the luteal phase: control, 11.5 ± 2.1; peak LH response, 19.8 ± 2.1 (p < 0.005). A small response was observed in the late follicular phase (control, 8.3 ± 0.8; peak LH response, 10.2 ± 1.1; p < 0.05), while no significant response was seen in the early follicular phase. NMA significantly increased cortisol in all groups and no difference was found in regard to the presence or absence of ovarian steroids or to the phase of the menstrual cycle. We conclude that gonadal steroids are required for the excitatory action of NMA on LH secretion in the adult animal. The similar cortisol responses following NMA in all OVX monkeys, whether untreated or replaced with ovarian steroids, and in cyclic animals suggest that activation of the corticotropin-releasing hormone β-endorphin pathway, which in the OVX appears to be responsible for the inhibition of LH, is counteracted in the presence of ovarian steroids.