Defective Central Nervous System Dopaminergic Function in Rats with Estrogen-Induced Pituitary Tumors, as Assessed by Plasma Prolactin Concentrations*

Publisher Website
Google Scholar
Abstract
Mature cycling female rats were each injected at 3-week intervals with 2 mg estradiol valerate (EV) in sesame oil. Controls received an equivalent volume of sesame oil. The administration of EV induced, at first, hyperplasia and then, 10 weeks after the first EV injection, adenomatous changes in the pituitary gland. Concurrently, there was a striking rise in plasma PRL concentrations, which reached values of about 2 μg/ml at 25 weeks. Acute administration of nomifensine (NOM), an indirectly acting dopamine (DA) agonist, to EV-injected rats suppressed baseline PRL levels at 1 week but failed to significantly decrease PRL levels at 4, 7, 10, and 25 weeks. Unlike NOM, bromocriptine, a direct DA agonist, strikingly reduced baseline PRL levels in EV-injected rats 1,10, and 25 weeks after the first EV injection. The administration of domperidone (DOM), a potent blocker of DA receptors, inconsistently increased plasma PRL at 1 week and was ineffective at the following time intervals. Since both NOM and DOM are drugs probing selective aspects of central nervous system (CNS)-DA neurotransmission, it may be inferred from the foregoing that the latter was defective in EV-injected rats. In keeping with such a view, light and electron microscopic examinations of the hypothalamus revealed the existence in EV-injected rats of pathological changes in the arcuate nucleus region. In addition, measurement of DA in the median eminence of diluent- and EV-injected rats showed in the latter the presence of progressively reduced DA concentrations. The possibility of a mechanical obstruction of the portal vessels due to the presence of suprasellar extensions of the pituitary tumors was excluded by the observation that ether, a neuroactive stimulus, further enhanced plasma PRL titers in EV-injected rats at times when they were unresponsive to NOM and DOM. Similarly, the competence of TRH in further stimulating PRL secretion 4 and 10 weeks after the first EV injection denoted that failure of DOM to increase baseline PRL levels was not due to the inability of a maximally stimulated pituitary to make a further secretory response. Finally, the administration of FK 33–824, a potent analog of met-enkephalin, probably acting via inhibition of CNS-DA neurotransmission, increased baseline PRL levels 1 week, but not 7 weeks, after the first EV injection. These data suggest that rats with primary estrogen-induced PRL-secreting tumors have a defect in CNS-DA neurotransmission, a condition which has been postulated to also occur in human subjects bearing a prolactinoma.