3,4-Dihydroxyphenylalanine (Dopa) accumulation and dopamine (DA) and noradrenaline levels were measured in the median eminence (ME) of Fisher 344-derived inbred male rats. These animals had been treated with Silastic capsules containing 8-9 mg diethylstilbestrol (DES) or with empty capsules for 3, 7,14, or 30 days and had the pellets removed 22 days before killing. In an additional group of rats, the DES pellets were continuously present until killing. Blood was collected before treatment was started, at pellet removal, 2 days before killing, and at killing. All rats received 50 mg/kg hydroxybenzylhydrazine (NSD-1015), an l-aromatic amino acid decarboxylase inhibitor, iv 30 min before killing, and the subsequent accumulation of Dopa provided an indirect measure of DA synthesis. Treatment with DES for 7, 14, or 30 days produced an elevation of circulating PRL. Although this elevation of PRL levels was substantially reduced after pellet removal, this parameter was still elevated in the 30-day DES-treated rats at the time of killing. Pituitary levels of PRL and PRL secretion in vitro were elevated in both the 14- and the 30-day DES-treated rats. Rats treated continuously with DES had markedly elevated circulating PRL levels, and the pituitary content and in vitro release of this hormone were also enhanced. DA synthesis, as evidenced by the accumulation of Dopa after NSD-1015 treatment, was significantly elevated in the ME of rats treated with DES for 14 or 30 days while the concentration of DA was reduced in the 30-day treated rats. DA synthesis in the ME was not different from controls in rats treated continuously with DES, although DA levels were markedly suppressed. Pituitary weights were elevated, and BWs were reduced in rats continuously treated with DES. Pituitary weights were also elevated in rats treated with DES for 30 days although not as much as in rats treated continuously with DES. A progressive reduction in seminal vesicles and testes weights was observed with longer periods of DES treatment. Testosterone levels were suppressed in rats treated continuously with DES. In a second study in which rats received DES pellets for 2 months and then the pellets were removed for 4 months, 1 mg bromocriptine sc markedly suppressed the elevated levels of circulating PRL. Collectively, these results show that 14 to 30 days of DES treatment are sufficient to induce PRL-secreting adenohypophysial tumors in adult male rats, although considerable involution of the tumor appears to occur after pellet removal. This involution may not occur after 2 months of DES treatment. Our findings suggest that the tuberoinfundibular DA (TIDA) system responds dramatically to the DES-induced elevation of PRL but can do so only after removal of the DES pellet. The enhanced function of the TIDA neurons after pellet removal may be a factor in the subsequent involution of the tumor, and the suppression by DES of the normal increase in the activity of the TIDA neurons may be involved in the initial proliferation of the PRL-secreting cells.
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