The role of 2-methoxyestrone in estrogen action

The plasma and tissue concentrations of 2-methoxyestrone (2-MeOE 1) and 2-hydroxyestrone (2-OHE 1) were measured in immature rats. The plasma levels of 2-MeOE 1 were found to be high at birth and to decrease through puberty, when the low levels found in the adult rats were achieved. 2-OHE 1 was undetectable in the plasma and brain, and barely detectable in the uterus and liver. 2-MeOE 1 was undetectable in the brain and uterus, but high in the liver. The affinity of 2-MeOE 1 and 2-OHE 1 for rat α-fetoprotein was found to be low, while the affinity of estradiol, estrone, 4-hydroxyestrone, and 4-fluoroestradiol was high. This data suggests that 2-OHE 1 and 2-MeOE 1 would be available to estrogen target tissues in the fetal and neonatal rat. Although these metabolites lack uterotropic activity they are capable of acting in the liver. It is suggested that the plasma 2-MeOE 1 of neonatal rats acts as a prohormone capable of stimulating the liver and other estrogen target tissues which possess demethylating enzymes. It is pointed out that unlike estradiol the non-steroidal estrogens such as diethylstibestrol (DES) lack the ability to form two sets of catechol and guaicol metabolites, i.e. “C-2” and “C-4” metabolites with their different biological characteristics are not formed by DES.