Interaction of estradiol and estriol with uterine estrogen receptor in vivo and in excised uteri or cell suspensions at 37 C: noncooperative estradiol binding and absence of estriol inhibition of estradiol-induced receptor activation and transformation.

The partial agonist and antagonist properties of estriol (E3) have been related to the brief nuclear retention of receptor-E3 complexes and to the lower affinity of E3 for the receptor compared to estradiol (E2). More recently, it was proposed that the partial agonist/antagonist activity of E3 may be due to its ability to eliminate positive cooperative binding of [3H]E2 to cytosolic estrogen receptor. In this model, positive cooperativity is related to receptor activation and transformation. We first examined the long term effects of E3 on E2 action in vivo. Mature ovariectomized rats were treated for 16 days with E2, E3, or mixtures of these two substances delivered through Alzet pumps at a constant hourly rate (E2, 0.04 microgram; E3, 0.4 and 0.04 microgram; E2 and E3, 0.04 and 0.4 microgram). The effects of E3 on uterine growth, induction of progesterone receptor synthesis, and activation (nuclear binding) of estrogen receptor suggest that when given continuously, E3 acts as a full agonist and does not inhibit E2 action. Furthermore, incubation of uteri at 37 C with [3H]E2 in the presence of a 1- to 20-fold molar excess of nonradioactive E3 did not alter the subcellular distribution of receptor-[3H]E2 complexes (80% nuclear and 20% cytosolic), demonstrating that E3 does not inhibit E2-induced receptor activation (i.e. the increased nuclear binding of receptor). Similarly, 4S to 5S transformation of [3H]E2-labeled estrogen receptor in intact uteri was not inhibited by E3. Equilibrium binding of [3H]E2 to uterine cell suspensions at physiological temperature (37 C) was noncooperative; nonradioactive E3 did not alter the affinity of the estrogen receptor for [3H]E2; Dixon plot analysis indicates that E3 is a purely competitive inhibitor of [3H]E2 binding. This, in conjunction with the lower affinity of the receptor for E3 than for E2, adequately explains the agonistic-antagonistic properties of E3.(ABSTRACT TRUNCATED AT 250 WORDS)