Differential Effects of Estrogens in Tissues: A Comparison of Estrogen Receptor in Rabbit Uterus and Vagina*

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Abstract
Reports of the preferential activity of some estrogens (e.g. estriol and ethynyl estradiol) in either uterus or vagina has prompted this study comparing the physicochemical characteristics of the cytoplasmic estrogen receptor (ER) in immature rabbit uterus and vagina in an effort to discover differences which might be exploited in developing tissue-selective estrogen Pharmaceuticals. We determined the ratio of association constants (RAC; where RAC = 100% for estradiol) for a number of competitors for ER in the rabbit uterus and vagina. Some of these compounds are reported by others to be selectively vaginotropic or uterotropic in mice. The ratio of the RAC of a competitor in the vagina to the RAC of a competitor in the uterus was close to 1 for most compounds tested, indicating that none of these compounds bound vaginal ER preferentially. In contrast, two compounds (ethynyl estradiol and ethynyl 8α-estradiol), which are reported to be preferentially uterotropic in mice, bound uterine ER more strongly than vaginal ER. Physicochemical characterization by polyacrylamide gel electrophoresis (at differeing gel concentrations to measure ER molecular size and electrophoretic mobility) and by sucrose gradient analysis showed rabbit uterine and vaginal ERs to be essentially identical, as did a comparison of estradiol-binding affinities. Significant estradiol dehydrogenase activity is present in uterine cytosol from mature rabbits, but very little activity is present in vaginal cytosol from mature or immature rabbits or uterine cytosol from immature rabbits. We conclude that any differential effects of estrogens in the rabbit are not based on ER differences, and we suggest that differential effects of estrogens may be related to differences in pharmacokinetic parameters or in the interaction of estrogen with the nucleus. (Endocrinology106: 1345, 1980)