TIME-RELATED EFFECTS OF EN-CLOMIPHENE UPON CENTRAL AND PERIPHERAL OESTROGEN TARGET TISSUES AND CYTOPLASMIC RECEPTORS

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Abstract
The temporal effects of the oestrogen antagonist en-clomiphene were studied in the 3 week ovariectomized rat for up to 24 days after a single dose of 0·5 or 50 mg/kg. Cytosol binding of [3H]oestradiol was measured in central and peripheral target tissues. One day after treatment both doses of en-clomiphene decreased binding of [3H]oestradiol to similar levels within tissues. In brain cytosols binding of [3H]oestradiol returned to expected control values by 16 days with the exception of the hypothalamic cytosol after treatment with 50 mg/kg which, paradoxically, achieved control levels by 8 days. However, a single-point saturation assay was inadequate for the measurement of high-affinity oestrogen receptors in brain tissue. Uterine binding of [3H]oestradiol returned to control levels by 2 and 16 days after treatment with 0·5 and 50 mg/kg respectively. Replenishment of [3H]oestradiol binding was slower in pituitary cytosol and was achieved by 8 and 24 days after treatment with 0·5 and 50 mg/kg respectively. En-clomiphene was uterotrophic; the maximal increase was at 4 days and 1 day after 0·5 and 50 mg/kg and was sustained, albeit at a lower level, for 4 and 8 days respectively. En-clomiphene at 50 mg/kg increased total uterine DNA 2 days after treatment. Small dose-related sustained increases in weight of uterine luminal fluid were also observed. En-clomiphene had no effect upon serum FSH. Serum LH was decreased only on day 8 after treatment. Serum prolactin was increased to a similar level by both doses of en-clomiphene; however, the maximum was achieved 2 and 16 days after treatment with 0·5 and 50 mg/kg respectively. Rats were tested for sexual receptivity after 50 mg/kg en-clomiphene and increases were detected between 7 and 9 days of treatment. Progesterone facilitated this effect only on days 8 and 9. En-clomiphene produced dose-related falls in food intake and body weight, the latter remaining below the weights of control rats throughout the period studied. It is apparent that the temporal effects of en-clomiphene upon cytoplasmic [3H]oestradiol binding are diverse, replenishment of binding being dependent upon the dose and the tissue examined. In addition, the changes in biological activity as measured by uterine and neuroendocrine effects also appear temporally unrelated to each other and to the binding of [3H]oestradiol. Thus further studies are necessary to elucidate possible differences in tissue oestrogen receptor mechanisms and the mode of action of the oestrogen antagonists.