Rat Uterine Growth and Induction of Progesterone Receptor without Estrogen Receptor Translocation*

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Abstract
The rat uterus responds to estradiol (E2) and E2 benzoate [E2B] stimulation with an increase in progesterone receptor production and with growth. These responses were also elicited to varying degrees by a series of estrogenic (ICI 77,949 [trans-1-(4-hydroxyphenyl)-1,2-diphenyl-but-2-ene] and ICI 47,699 [cis-1-(p-dimethylaminoethoxyphenyl)-1,2-diphenyl-2-ethylethylene]) and antiestrogenic triphenylethylene derivatives [tamoxifen (TAM), 4-hydroxy-TAM) (4-OH-TAM and 4-CH3-TAM]. These compounds have a range of affinities for the estrogen receptor (ER) and are able to compete with [3H]E2 binding in the uterus in vivo. Within 1-2 h of a s.c. injection of high affinity ligands (E2, E2B and 4-OH-TAM), there was a decrease in cytosol ER. This decrease was also observed with TAM, which is metabolized to 4-OH-TAM in vivo. There was no decrease in cytosolic ER in animals treated with low affinity compounds (ICI 77,949, ICI 47,699 and 4-CH3-TAM) at any time before the onset of an estrogen response. The nuclear ER increased after administration of a high affinity ligand (E2), as measured by exchange assay, but no increase in nuclear ER was observed after administration of low affinity ligands (ICI 77,949 and 4-CH3-TAM), although estrogenic responses were produced. A functional model was suggested to explain ER-mediated events in the rat uterus that supports the recent proposal that unoccupied ER is located in the nuclear compartment. In this model, the majority of unoccupied ER may reside in the nucleus in vivo; when the cells are disrupted in vitro, the unoccupied receptor or dissociation of low affinity ligand-ER complex causes unoccupied receptor to fall out of the nucleus and to be incorporated into the cytosolic fraction. The high affinity ligand-ER complexes are retained in the nucleus. The apparent translocation of the ER from the cytoplasm to the nucleus may be an artifact. The data may reflect differential extraction of unoccupied receptors from the nucleus rather than transfer of receptor complexes to the nucleus.