The effect of acute intravenous injection of 400mg cimetidine, a histamine H2-receptor antagonist, on prolactin (PRL) secretion was investigated in women with normal menstrual cycles (n = 12) and normoprolactinemic secondary amenorrhea (n = 10). In addition, the PRL response to cimetidine was also examined in women with puerperal (n = 10) and idiopathic (n = 10) hyperprolactinemia. The administration of cimetidine provoked a rapid rise in plasma PRL in both normal and amenorrheic women, with peak values occurring at 10-15 minutes, followed by a return toward the baseline by 2 hours. The PRL response was significantly greater (p less than 0.001) in normal women [mean (+/- SE) basal vs. peak values: 15.3 +/- 1.5 vs. 124.6 +/- 10.3 ng/ml (p less than 0.001)] than in amenorrheic women [13.5 +/- 1.3 vs. 71.7 +/- 7.2 ng/ml (p less than 0.001)]. There were no significant changes in plasma LH or FSH levels in any group. The cimetidine injection caused a remarkable increase in plasma PRL in women with puerperal hyperprolactinemia [110.8 +/- 31.1 vs. 288.8 +/- 39.6 ng/ml (p less than 0.001)], while the PRL response was diminished or absent in women with idiopathic hyperprolactinemia [103.3 +/- 19.3 vs. 122.9 +/- 14.6 ng/ml (p greater than 0.1)]. The mean incremental PRL response was 1.6 times greater than that observed in normal women. These results suggest that histamine may exert an inhibitory effect on PRL secretion through H2-receptors and that an altered central histaminergic tone may be involved in amenorrheic or pathological hyperprolactinemic state.