Sustained oestrogen-induced hyperprolactinaemia results from a pituitary defect

Abstract

Pituitary enlargement and hyperprolactinaemia were induced in male rats by a single subcutaneous injection of 2 mg oestradiol benzoate in oil. Two months after treatment, when oestrogen levels were normal, serial blood samples for determination of plasma concentrations of prolactin were obtained from undisturbed animals through an indwelling right atrial cannula which had been implanted 7-10 days before. Basal concentrations of prolactin were obtained in treated and control rats, and responses of prolactin to intravenous injections of thyrotrophin releasing hormone (TRH), apomorphine, butaclamol and fenfluramine were measured. Sustained hyperprolactinaemia with pituitary hyperplasia was achieved in only 20% of animals. Responses of prolactin to TRH were the same in control, oestrogen-treated hyperprolactinaemic and non-hyperprolactinaemic rats, indicating normal pituitary responsiveness to one prolactin releasing factor. Complete suppression of prolactin concentrations by apomorphine occurred in hyperprolactinaemic animals, whereas no suppression could be demonstrated in animals with normal (low) basal prolactin levels, indicating good responsiveness of hyperplastic pituitary glands to dopamine inhibition. Dopamine receptor blockade by butaclamol resulted in a vigorous prolactin response in animals with sustained hyperprolactinaemia, indicating that dopaminergic prolactin inhibitory mechanisms remain qualitatively intact, but the response was quantitatively less than in controls, suggesting insufficient hypothalamic release of dopamine. Responses of prolactin to certain doses of fenfluramine were completely abolished in hyperprolactinaemic animals, indicating diminished sensitivity to serotoninergic prolactin releasing factor mechanisms. Prolactin releasing factor unresponsiveness and relative insufficiency of dopaminergic activity could be regarded as physiologically appropriate responses to chronic hyperprolactinaemia. Thus oestrogen-induced chronic hyperprolactinaemia appears to be entirely of pituitary origin.

Hypothalamic Monoaminergic Activity and Pituitary Function in Male Rats with Estrogen-Induced Pituitary Hyperplasia

“…The present studies indicate that 5-HT is not involved in the early stages of estrogen-induced hyperprolactinemia. Fur thermore, earlier studies showed that fenfluramine, an agent that releases endogenous 5-HT and stimulates PRL, has no effect on PRL in animals with estrogen-induced pi tuitary hyperplasia [43], suggesting that 5-HT does not con tribute to hyperprolactinemia.…”

Responses to prolactin secretagogues in oestrogen-treated rats suggest that the defect in prolactin regulation produced by oestrogen is at the level of the pituitary gland

“…It has also been shown that high doses of oestrogen cause structural alterations in the hypothalamus (Brawer, Naftolin, Martin & Sonnenschein, 1978;Casanueva et al 1982;Sarkar, Gottschall & Meites, 1982) and some pharmacological studies implicate damage to dopamine inhibitory tuberoinfundibular neurones (Casanueva et al 1982) while bioassayable hypothalamic prolactin-releasing activity is increased (Nakagawa, Obara & Tashiro, 1980); findings which suggest a hypothalamic site of action for oestro¬ gen. Conversely, we have reported previously that hypothalamic dopaminergic neurones function appropriately to suppress prolactin secretion, and serotoninergic neurones, which enhance prolactin secretion, are suppressed in animals with chronic oestrogen-induced pituitary hyperplasia (Willoughby, Pederick, Jervois & Menadue, 1983). In that study, animals were examined 8 weeks after oestrogen treatment when oestrogen levels were no longer increased.…”

Evidence for a Permanent Decline in Tuberoinfundibular Dopaminergic Neuronal Function after Chronic Estrogen Treatment Is Terminated in Fischer 344 Rats

“…Deficient hypothalamic dopaminergic regulation of PRL release during long-term E2 treatment has already been reported [5,6,8,13,14,20,22,24]. Two laboratories showed that the E2-induced TIDA decline was reversed when chronic E2 treatment was terminated in Long-Evans female or F344 male rats [6,13,14].…”

“…APO, a dopaminergic agonist, when given at a low dose (0.01 mg/kg), did not sig nificantly decrease serum PRL in control rats, but de creased PRL levels in rats after E2 withdrawal, which sug gests that animals previously treated with E2 are at least as sensitive to APO as OVX controls. Others, using different chronic E2 treatment models, have also observed that DA agonists can inhibit PRL secretion [8,22,24], Injection of MOR, a drug that decreasesTIDA neuronal activity, signif icantly raised PRL only in OVX controls and not in the E2-treated animals. The loss of PRL response to MOR in E2-treated animals is possibly due to reduced activity of TIDA neurons and is particularly significant since long term treatment increases hypothalamic opiate binding sites [23].…”

“…Short-term estrogen treatment (days) increases TIDA neu ronal activity via the estrogen-induced increase in prolactin (PRL) secretion [6,12]. Long-term administration (2 weeks or longer) of estrogen depresses TIDA neuronal function [5,6,8,20,22,24] by mechanisms which remain to be clari fied. The decline in TIDA neuronal function during long term estrogen may release the PRL-secreting cells of the an-1 Aided in part by NIH grant AG00416 from the National Insti tute on Aging; we wish to thank Victoria Kingsbury for typing this manuscript.…”