Estrogen‐receptor binding: Relationship to estrogen‐induced responses

The relationship between nuclear binding of the receptor‐estrogen complex (R·E) and estrogenic responses was examined. Nuclear‐bound R·E was measured by the [ ³ H] estradiol exchange assay, which permits the quantification of R·E as a function of either endogenous or nonlabeled estrogen. The quantity of nuclear R'E fluctuated as a function of blood levels of estrogen during the estrous cycle in the rat. This indicates that the accumulation of the R'E complex by the nucleus of uterine cells may be of physiologic significance and under the control of endogenous estrogen.

Immature rats received a single injection of estradiol (E ₂ ) or estriol (E ₃ ) and the following parameters were measured: accumulation and retention of the estrogen receptor by the nucleus of uterine cells; incorporation of [ ¹⁴ C] glucose into CO ₂ , lipid, protein, and RNA; RNA polymerase activity; water imbibition; and increased dry weight. All early uterotropic responses (0–3 hr) that were measured were equally stimulated by E ₁ and E ₃ . However, E ₃ failed to stimulate true uterine growth (increased dry weight 24 hr after injection), whereas E ₂ produced a significant stimulation of true uterine growth. These data suggest that the R·E complex is capable of stimulating early uterotropic events, regardless of which estrogen is present. To produce true uterine growth, however, the R·E complex must be retained in the nucleus for long periods of time.

The mechanism of action of nonsteroidal estrogen antagonists was also investigated. Nafoxidine, CI‐628, or clomiphene was injected either alone or in combination with estradiol, and the uterine weight and cytoplasmic estrogen‐receptor content were determined. All antagonists were clearly uterotropic and not antagonistic at 24 hr after Injection. These data demonstrate that nonsteroldal estrogen antagonists are antagonists not because they compete for cytoplasmic estrogen receptors to produce a complex that is a poor stimulator of growth, but because they fail to stimulate the replenishment of the receptor.