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 PRLinhibiting 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. (J Clin Endocrinol Metab 50: 994, 1980) 'HAT the tuberoinfundibular dopamine system functions as a hypothalamic PRL inhibitor by a direct action on the lactotrope dopamine receptor, delivered by way of the hypophyseal portal system, is unequivocally established in the rat (1-4). Preliminary data in humans also implicate hypothalamic dopamine as a major inhibitor of PRL secretion (5-9). However, f...

Catecholamines and Pituitary Function

“…contain few secretory granules [36,37], As the administration of DA ago nists induces a considerable increase in the number of PRL-containing granules in pa tients with prolactinomas [38], it could be hypothesized that the restoration of the PRL response to TRH during 0.1 pg/kg-min DA infusion is functionally related to the pre vious inhibition of PRL release and the con sequent storage of PRL granules as TRHrcleasable PRL pool. This view is strength ened by the positive linear correlation be tween the DA-induced reduction in serum PRL levels and the PRL rise after TRH administration in our patients and it is in line with previous findings that both DA-agonist administration [39,40] and high-dose DA infusion [16] restore the PRL response to DA-antagonists in hyperprolactinemic sub jects.…”

“…Several studies showed that PRL levels are reduced [13][14][15] and the PRL re sponse to DA antagonists restored by DA infusion in hyperprolactinemic patients, sug gesting that reduced DA delivery to the PRLsecreting pituitary cells is responsible for their hypersecretory status [16]. More recent ly, however, a relative PRL insensitivity to a low-dose DA infusion rate has been reported in patients with PRL-secreting pituitary tu mors and the physiological significance of previous studies which employed large infu sion doses of DA has been seriously ques tioned [17].…”

“…More recent ly, however, a relative PRL insensitivity to a low-dose DA infusion rate has been reported in patients with PRL-secreting pituitary tu mors and the physiological significance of previous studies which employed large infu sion doses of DA has been seriously ques tioned [17]. As, however, no data are avail able on DA levels in the pituitary portal plexus in man, there is doubt as to whether the 0.02-8 pg/kg-min DA doses infused to datc [10][11][12][16][17][18] are those required tocorrectly evaluate PRL sensitivity to physiologi cal DA inhibition in hyperprolactinemic pa tients. In nonhuman primates, a DA infusion rate of 0.1 pg/kg-min is needed to produce peripheral plasma DA concentrations similar to those measured in their hypophysial portal plasma and to normalize PRL serum concen trations after pituitary stalk transection [19].…”

Catecholamines and Pituitary Function

“…The same AMPT dose was not fol lowed, however, by any significant rise in serum PRL in women with hyperprolacti nemia, either due to the presence of a pitu itary microadenoma or 'idiopathic'. The ab sence of PRL response to a DA-depleting drug in prolactinoma patients well agrees with the reported abnormalities of PRL dy namics after DA-antagonist administration in subjects with PRL-secreting pituitary tumors [31,38,39], whilst the presence of similar behavior in women with 'idiopathic' hyperprolactinemia suggests that there are similar defects in the tuberoinfundibular DA inhibition of PRL release either in 'idiopath ic' or in tumoral forms of hyperprolactinemia [40], although the possibility that patients without radiological signs of pituitary tumors may harbor a microadenoma too small to be radiologically detected cannot be excluded.…”

“…Functional studies have suggested, in this condition, a relative DA deficiency at the PRL-secreting cells and a relative DA excess at the Gn-RH secreting terminals in the me dial basal hypothalamus [21,31,32]. This view is well in accordance with the observa tions of several authors on augmented DA turnover in the lateral zone of the median eminence in hyperprolactinemic animals [13,14,33,34],…”