Functional Studies of Dopamine Control of Prolactin Secretion in Normal Women and Women with Hyperprolactinemic Pituitary Microadenoma*

Abstract

Functional studies of the dopamine-PRL system in the control of the secretory activity of the lactotrope were conducted in 8 normal cycling women during the early follicular phase of the cycle and in 14 hyperprolactinemic patients with pituitary microadenoma (prolactinoma). Dynamic changes in PRL release in response to dopamine infusion and a dopamine receptor antagonist [metoclopramide (MCP)], singly and in combination, were determined and compared between normal women and prolactinoma patients. Our data show that the degree of dopamine inhibition of PRL (via 4–h infusion) in prolactinoma patients was significantly greater in terms of both the absolute PRL decrement and the rate of PRL decline compared to normal women. A strong positive correlation (r = 0.964) was found between basal PRL levels and the magnitude of PRL decline during dopamine infusion. In contrast, the rebound PRL release above basal levels after dopamine withdrawal was significantly smaller in prolactinoma patients than in normal women. In response to MCP alone, prolactinoma patients exhibited only one eighth the PRL increment observed in normal women; however, once substantial inhibition of PRL release was achieved in prolactinoma patients (via dopamine infusion), the dopamine receptor antagonistic function of MCP (interposed during the third hour of dopamine infusion) was restored. In normal women, the consequence of this dopamine-dopamine antagonist interaction on PRL release was manifested by a significant reduction in the magnitude of PRL release due to MCP and a significant increase in the rate as well as the magnitude of PRL release upon dopamine withdrawal when compared with the response to either experiment alone. Thus, the sensitivity of the normal lactotrope to dopamine inhibition changed markedly when its action was interrupted by the dopamine-receptor antagonist. The rate of PRL rise after dopamine withdrawal in prolactinoma patients was similarly increased, but the magnitude of PRL increments was smaller. These observations provide the first functional evidence that hypothalamic dopamine in humans constitutes a major PRL-inhibiting hormone, and the inhibitory function of dopamine on lactotrope PRL release is a tightly punctuated system. Further, the adenoma lactotrope appears to be capable of recognizing both dopamine and its antagonist, implying functionally intact dopamine receptors; however, reduced receptor-binding affinity for dopamine cannot be excluded. The hypersecretion of PRL in prolactinoma patients is causally related, at least in part, to a relative local deficiency of dopamine at the receptor site of the adenoma lactotrope.