Stilbestrols and stilbestrol derivatives: Estrogenic potency and temporal relationships between estrogen receptor binding and uterine growth

This study analyzes some of the differences between the estrogenic potencies of two homo logous stilbestrols, the potent estiogen diethylstilbestrol (DES) and the weak estrogen dimethylstilbestrol (DMS). The action of these compounds and their corresponding dimethyl ethers is compared in terms of the duration of their interaction with the estrogen receptor in immature rat uterus and the time-course of responses elicited in this tissue. Dose-response curves of 3-day uterotrophic assays indicate that etherification of DMS, which is only weakly uterotrophic, converts it into a compound, DMS-(OMe)₂, that has enhanced uterotrophic activity, while etherification of the more active estrogen, DES, diminishes its potency. Only at high doses is DES-(OMe)₂ as effective a uterotrophic agent as DES. After a single injection, DMS (20 μg) and DES (10 μg) both rapidly translocate estrogen receptor from the cytoplasmic to the nuclear compartment, but while uterine weight (by 24 h) and nuclear receptor levels (by 6 h) rapidly return to control levels after DMS, they remain elevated for a more prolonged period after DES. Likewise, DMS stimulates only an early (2 h) wave of uterine deoxyglucose phosphorylation. In contrast to DMS, DMS-(OMe)₂ (20 μg) shows a gradual movement of receptor to the nucleus after 1 h, with moderate but above control levels of receptor being maintained for at least 36-48 h. This retention of nuclear receptor correlates with prolonged elevation of uterine weight (beyond 60 h) and stimulation of deoxyglucose metabolism (beyond 24 h). Likewise a high (10 μg) dose of DES-(OMe)₂ evokes a slower but more protracted elevation of nuclear receptor levels, and a more prolonged elevation of uterine weight than does DES (10 μg). The weak activity of DMS appears to be due to its short duration of interaction with receptor, and conversion to the methyl ether prolongs nuclear receptor occupancy and increases its biological potency. DES is potent because it is itself long-acting. Methylation of DES further extends its period of nuclear receptor occupancy; this increases its duration of action at high doses, but reduces its potency at low doses.