Modulation of rat uterine steroid hormone receptors by estrogen and antiestrogen.
The effect of sc injections (25 microgram) of estradiol benzoate, monohydroxytamoxifen [1-(4 beta-dimethylaminoethoxyphenyl)1-(4-hydroxyphenyl)-2-phenylbut-1-ene] and tamoxifen [trans-1-(4 beta-dimethylaminoethoxyphenyl)1,2-diphenylbut-1-ene] every 12 h on uterine wet weight, DNA, and cytoplasmic estrogen and progesterone receptor levels has been studied in the immature rat for up to 90 h. Estradiol benzoate produced a 4-fold rise in uterine wet weight, with a doubling of uterine DNA within 48 h. Tamoxifen and monohydroxytamoxifen doubled uterine weight, with a small rise in uterine DNA. Cytoplasmic estrogen receptor levels were reduced within 24 h by all treatments. Estradiol benzoate and monohydroxytamoxifen produced a maximal rise in nuclear estrogen receptor levels within 8 h, followed by a rapid decline to control levels within 80 h. Tamoxifen produced a slower rise in nuclear estrogen receptor levels and never reached the levels achieved by estradiol or monohydroxytamoxifen. The level of nuclear tamoxifen-estrogen receptor complexes slowly decreased with time. In each case, the cytoplasmic progesterone receptor levels increased as nuclear estrogen receptor levels decreased. Cycloheximide (5 microgram/2 h for 8 h before and 20 h after the first estrogen or antiestrogen injection) was used to determine the effect of protein synthesis inhibition on the hormone receptor profiles. Progesterone receptor synthesis was inhibited by cycloheximide. Cycloheximide did not affect translocation, but produced a rapid decrease in nuclear estrogen receptor levels. The results suggest that without the continual translocation of estrogen receptors from the cytoplasm, the antiestrogen-estrogen receptor levels in the nuclear compartment decrease because of destruction or processing. The nuclear antiestrogen-estrogen receptor pool is therefore not static but dynamic. High affinity ligand-estrogen receptor complexes are readily processed in the nucleus to effect progesterone receptor synthesis in the cytoplasm; however, this series of biochemical reactions is only secondary to the fundamental events essential for cell division. After an initial increase in cytoplasmic steroid receptor synthesis by estrogen or antiestrogen, there is a gradual reduction in total cytoplasmic and nuclear estrogen receptor complexes in response to continual nuclear stimulation. This reduction, in turn, reduces progesterone receptor synthesis.
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D007700:Kinetics; D009929:Organ Size / Q000187:drug effects; D011397:Promegestone / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D011987:Receptors, Steroid / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism*
D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; D004247:DNA; D003513:Cycloheximide; D011397:Promegestone