Comparative Dynamic Studies on the Biological Responses to Estriol and 17β-Estradiol in the Fetal Uterus of Guinea Pig: Relationship to Circulating Estrogen Concentrations*

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Abstract
This study compares the kinetics of biological responses to estriol (E3) and 17β-estradiol (E2) treatment (uterotrophic effect and uterine progesterone receptor stimulation) in the fetal uterus of guinea pig. A single sc administration of 1 mg/kg of E2 or E3 to pregnant guinea pigs provokes a slight early uterotrophic effect in the fetus after 3 h for E3 and 6 h for E2 (26% increase for both in relation to controls) and a late uterotrophic effect that is maximal 2 days after treatment with both E2 and E3 (80% increase). This second phase of the uterotrophic effect is of shorter duration in E3-treated animals (return to control values after 7 days) than in E2-treated animals (maintain maximal values 7 days after treatment). The same treatment provokes a stimulation of uterine progesterone receptor that is detectable sooner for E3-treated (3 h) than for E2-treated animals (6 h) and that is maximal between 15 h and 24 h after hormone administration (10-fold increase in relation to controls). The maximal uterine wet weight and concentration of uterine progesterone receptor attained after a single injection of either E3 or E2 are the same as those found after three daily injections of either hormone. This uterotrophic effect was not accompanied by an increase in DNA content. Both E3 and E2 are capable of translocating estrogen receptor from the cytosol into the nucleus, but E3 causes this transfer more rapidly (1 h) than E2 (3–6 h). After translocation, E3-receptor complex is rapidly released by the nucleus, but the levels still remain significantly higher than control values up to 24 h. In contrast, low levels of E2-receptor complex remain in the nucleus for at least 7 days after a single administration of E2. The appearance of the two biological responses is related to the time of estrogen receptor translocation by both E3 and E2, whereas only the prolonged uterotrophic effect can be correlated with the persistence of estrogen receptor in the nucleus, since a dissociation of the disappearance curves of the two responses is observed after E2 administration. The similar responses to E3 and E2, as well as their different kinetic patterns, can be explained by the concentrations of the hormones in the fetal plasma and by their relatively slow clearance from the circulation: although both hormones remain at sufficiently high levels for enough time to provoke the maximal late uterotrophic effect, the E3 levels between 3 and 7 days after treatment are not sufficient to maintain the E3-receptor complex in the nucleus. Thus, in the fetal guinea pig uterus, E3 when maintained at persistent and high levels elicits estrogenic responses similar to E2.

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