Central Nervous System-Mediated Stimulation of Prolactin Secretion by Cimetidine, a Histamine H2- Receptor Antagonist: Impaired Responsiveness in Patients with Prolactin-Secreting Tumors and Idiopathic Hyperprolactinemia*

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Abstract
Studies were performed to elucidate the mechanism by which cimetidine, a histamine H2-receptor antagonist, stimulates PRL release and to determine whether altered responsiveness exists in patients with PRL-secreting tumors and idiopathic hyperprolactinemia. The iv injection of cimetidine (300 mg) resulted in an acute rise of plasma PRL in all normal subjects, with peak values occurring at 7.5 or 15 min, followed by a return toward baseline. Responses were greater in females than in males and tended to be increased during the luteal phase of the menstrual cycle. A similar stimulatory effect on PRL secretion was demonstrated in unanesthetized, unrestrained rats. Cimetidine did not, however, stimulate PRL release or impair the PRL-suppressive effects of dopamine in primary monolayer cultures of dispersed rat adenohypophyseal cells. Diphenhydramine, a histamine H1-receptor antagonist, did not suppress the PRL response to cimetidine. Enhancement of dopaminergic tone peripherally (with L-dopa) but not centrally (with L-dopa plus carbidopa) suppressed the response to cimetidine. Neither cimetidine nor TRH stimulated PRL secretion in subjects pretreated with metoclopramide. Cimetidine stimulation of PRL was unaltered by cyproheptadine or naloxone. These data indicate that the effects of cimetidine occur within the central nervous system and suggest that they result from an inhibition of a histamine H2-receptor-mediated pathway which is independent of dopaminergic pathways. Cimetidine stimulation of PRL was unimpaired in normal postpartum women, indicating that hyperprolactinemia per se does not affect the response. However, 21 of 27 patients with PRL-secreting tumors exhibited impaired or absent response to cimetidine, and transsphenoidal adenomectomy failed to restore their response to normal even when basal PRL levels returned to the normal range. Diminished or absent PRL responses were observed in all 5 patients with idiopathic hyperprolactinemia. The results suggest the presence of altered central nervous system histaminergic tone in a majority of patients with PRLsecreting tumors which is independent of hyperprolactinemia, and that a similar defect is present in patients with idiopathic hyperprolactinemia. The potential contribution of this abnormality to the pathogenesis of these disorders remains to be clarified.