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The effects of antioestrogens on the oestrogen receptor

1979; Pergamon Press; Volume: 11; Issue: 1 Linguagem: Inglês

10.1016/0022-4731(79)90314-5

1878-2353

Thomas S. Ruh, Lawrence J. Baudendistel, William F. Nicholson, Mary F. Ruh,

Menopause: Health Impacts and Treatments

Abstract In order to probe the source of the antagonistic properties of triphenylethylene antioestrogens in oestrogen induced uterine growth, we have studied both low- and high-affinity antioestrogens. In in vitro competition studies H-1285 was shown to have about 1100% the affinity for the oestrogen receptor when compared with 17-β-oestradiol (E2) (100%) which is in sharp contrast to H-1067 and U-11, 100A (UA) which have 25 and 4% binding affinities, respectively. H-1285 and H-1067 both caused an increase in uterine DNA and wet weight, but were impeded oestrogens. H-1285 and H-1067 were also antioestrogenic because they inhibited the E2-induced DNA and wet weight responses. The in vivo nuclear and cytoplasmic oestrogen receptor responses to UA, H-1067 and H-1285 were also investigated and compared to the E2 response. All antioestrogens studied caused a prolonged nuclear retention of the oestrogen receptor, in contrast to the rapid uptake followed by a rapid deletion seen with E2. H-1285 receptor complexes, however, displayed a delayed uptake, which did not reach maximal nuclear levels until 24 h. Cytoplasmic oestrogen receptor replenishment with E2 was immediate and rapid. All the antioestrogens studied demonstrated delayed and slow receptor replenishment, about 25% the E2 induced rate. E2 injected at 48 h subsequent to an injection of H-1285 caused a rapid 1-h nuclear translocation of the oestrogen receptor followed by a complete nuclear “fallout” of receptor, a phenomenon previously seen only with oestrogens. No salt-resistant oestrogen receptor complex was measurable with a high-affinity antioestrogen H-1285 or with low affinity antioestrogens, H-1067, UA or enclomiphene during 1–12 h, but the salt-resistant form was seen with E2 and diethylstilboestrol at 1–6 h. All of the oestrogen responses (wet weight, protein content, DNA and protein synthesis) exhibited the same increase at 24 h whether single 5 μg E2 or H-1285 injections were administered. However, by 48 and 72 h, H-1285 consistently gave higher responses than did E2. E2 administered at 48 h subsequent to a previous E2 injection caused a dramatic increase in oestrogenic responses, in contrast to E2 given subsequent to H-1285 which caused only a slight increase in these responses. These data demonstrate the ability of H-1285 to inhibit oestrogen induced uterine responses.