Oestrogen-Induced Hyperprolactinaemia in the Rat: Reduced Concentrations of Hypothalamic Dopamine and the Effects of Bromocriptine

Abstract

The induction of hyperprolactinaemia in the male rat following chronic oestrogen administration over 3 months was shown to result in a highly significant reduction in hypothalamic dopamine (DA) concentration as well as significant reductions in hypothalamic noradrenaline (NA) and serotonin (5-HT). Significant increases in hypothalamic DA synthesis were found 4 days after a single dose of oestrogen but not after 3 months' chronic treatment. However, after the latter treatment there was a reduction in the ratio of the level of DA to its acidic metabolites in the hypothalami of the rats.When small doses of the ergot bromocriptlne were chronically administered to oestrogen-treated rats a significant return towards normal concentrations was noted for serum prolactin and the hypothalamic catecholamines but 5-HT was suppressed even further. An acute dose of bromocriptine given to rats which had been chronically administered oestrogen caused a complete reversal of hyperprolactinaemia and a small increase in hypothalamic DA levels.The suppressive effects of chronic oestrogen treatment on hypothalamic monoamines in intact rats was not observed in hypophysectomized rats. In hypophysectomized rats after chronic oestrogen treatment hypothalamic DA concentration was not significantly different from that of normal controls while both NA and 5-HT were significantly elevated.In this investigation oestrogen-induced hyperprolactinaemia was found to relate to hypothalamic DA but not to NA or 5-HT. In normal and oestrogen-treated rats there was found to ,be a highly significant correlation between serum prolactin and hypothalamic DA concentration. The data indicate that the reduction in hypothalamic DA is primarily due to the hyperprolactinaemia and not to a direct action of oestrogen on the brain.This study raises the possibility that reduced hypothalamic DA concentrations may be related to the degenerative hypothalamic lesions seen in chronically oestrogen-treated rats and that these lesions may be an effect of prolactin rather than oestrogen as proposed previously.

Loss of Hypothalamic Dopaminergic Control of Prolactin Secretion in the Hyperprolactinaemic Rat

“…1 reduction (P < 0·05) of hypothalamic DA concentrations from already very low levels was caused by the administration of MIT. The fall to approximately 50 % of the levels of the saline controls is similar to the changes in the hypothalamus of normal control rats after MIT (Smythe et al 1979) but, due to the lower basal level, is indicative of a lower turnover rate for hypothalamic DA in the E 2 -treated rats as noted previously (Smythe and Brandstater 1980). It is notable that one of the animals excluded from the study due to an out of range anterior pituitary gland weight (105 mg) was examined further and found to have a concentration of DA in the hypothalamus of 0·2 pmol/mg which is the lowest we have ever recorded.…”

“…When circulating prolactin levels are raised in the rat 3-5 days following oestrogen (E 2 ) administration there is a significant increase in median eminence DA turnover and an increased prolactin release from the pituitary in response to tyrosine hydroxylase inhibition with IX-methyl-tyrosine (Eikenburg et al 1977). However, we have recently presented evidence that this initial response to increased prolactin secretion is not maintained following chronic hyperprolactinaemia induced by E2 treatment in the rat (Smythe and Brandstater 1980). After treatment for 3 months with E 2 , when anterior pituitary weight is increased fourfold and serum prolactin is increased nearly 100-fold, median eminence DA concentrations are highly significantly reduced and there is no change in DA turnover detectable following tyrosine hydroxylase inhibition (Smythe and Brandstater 1980).…”

“…Anterior pituitary glands were dissected out and weighed immediately. Because interpretation of earlier studies was complicated by a wide range in response to E2 indicated by a spread of pituitary weights in rats receiving high doses of E2 (Smythe and Brandstater 1980), in the present investigation a larger number of animals than was required was treated with high dose E2 and only those (13 out of 17) with anterior pituitary weights in the range 20-50 mg were used. Other animals having heavier or lighter pituitaries, with the one exception noted later, were discarded.…”

“…The hypothalamic samples were rapidly dissected as previously described (Smythe et at. 1979;Smythe and Brandstater 1980). The tissue block was approximately a 2-mm cube in order to ensure that the full extent of the arcuate nucleus and median eminence was obtained (Monroe et al 1972;Amback and Palkovits 1979) and the mean wet weight of the samples was 1l·5±0·5 (s.e.)…”

“…However, we have recently presented evidence that this initial response to increased prolactin secretion is not maintained following chronic hyperprolactinaemia induced by E2 treatment in the rat (Smythe and Brandstater 1980). After treatment for 3 months with E 2 , when anterior pituitary weight is increased fourfold and serum prolactin is increased nearly 100-fold, median eminence DA concentrations are highly significantly reduced and there is no change in DA turnover detectable following tyrosine hydroxylase inhibition (Smythe and Brandstater 1980). Furthermore, this latter study indicated that there was a lack of prolactin response to inhibition of brain DA synthesis in these animals.…”