Biology of Reproduction, Vol 15, 381-389, Copyright © 1976 by Society for the Study of Reproduction

Dissimilar Effects of Antiestrogens Upon Estrogen Receptors in Responsive Tissues of Male and Female Rats

¹ Department of Endocrinology, Medical College of Georgia, Augusta, Georgia 30902

This study was designed to evaluate and compare the effectiveness with which several antiestrogenic compounds can compete for and regulate the biogenesis of cytosol estrogen receptors in the anterior pituitary, hypothalamus and uterus of the rat. In all three tissues, the order of decreasing ability to compete with 17-estradiol for specific binding sites at equilibrium was: dimethylstilbestrol>CI-628>MER-25. Differences were found, however, in the amount of competition encountered from cytosol of one tissue to that of another. CI-628 administration to ovariectomized rats caused extensive depletion of anterior pituitary and uterine cytoplasmic receptor by translocation to the nucleus, but did not result in subsequent receptor replenishment. CI-628 had no significant effect on intracellular distribution of hypothalamic receptors in the same animals. Injection of MER-25 was followed by a moderate amount of depletion and a short, but significant, phase of replenishment in the uterus and anterior pituitary; as with CI-628, MER-25 had no effect on hypothalamic receptors. Dimethylstilbestrol was intermediate between MER-25 and 17-estradiol in effecting depletion in uterus and pituitary, but was a very potent inducer of replenishment. In the hypothalamus, dimethylstilbestrol was even more active than 17-estradiol in causing depletion and replenishment of receptors. In the anterior pituitary and hypothalamus of the castrate adult male rat, dimethylstilbestrol was far less active in promoting depletion and replenishment than in the female. MER-25 led to a small gradual decrease in male pituitary cytosol receptor content without subsequent replenishment, and was ineffective in the hypothalamus. The pituitary of the male responded similarly to that of the female following CI-628 administration; the male hypothalamus, however, did manifest some receptor depletion and eventual replenishment, in contrast to the lack of response in the female. Protein synthesis, cytoplasmic protein content and cytoplasmic receptor activity were measured and compared by gel filtration analysis of samples obtained 5 h after administration of 17-estradiol, CI-628 or dimethylstilbestrol. The effects of 17-estradiol and dimethylstilbestrol were similar, while those of CI-628 were less pronounced. The results indicate that some, but not all, antiestrogens may be antagonistic by virtue of their ability to block receptor replenishment and render the tissue subsequently insensitive. This effect, however, is tissue-specific and sex-specific, and may involve multiple or different mechanisms. In addition, our findings caution that in vitro analysis of receptor interactions may lead to erroneous deductions about the in vivo loci of antiestrogen action.