Temporal actions of 16 alpha-hydroxyestrone in the rat: comparisons of lordosis dynamics with other estrogen metabolites and between sexes.

16 alpha-Hydroxyesterone (16OHE1), a metabolite of estradiol (E2) and precursor of estriol (E3), binds to the estrogen receptor (ER) with low affinity (3% of E2), but is estrogenic in both in vitro and in vivo systems. This metabolite is able to bind in a non-dissociable manner to the ER. We examined these properties in vivo by assessing the temporal dynamics of estrogen metabolite action in the rat brain, using lordosis score (LS) to manual stimulation as a serial bioassay of estrogen effect. Male and female castrate Fisher rats were implanted with osmotic minipumps containing either vehicle, E2, 16OHE1, or E3. 16OHE1-induced LS was delayed in onset in both sexes relative to E2 and E3. Male LS reached a similar plateau for all metabolites, whereas female LS reached an initial LS plateau similar in amplitude to the male plateau. Over the next several days, female LS increased to reach a secondary plateau of higher amplitude, which persisted until pump removal. Upon pump removal, E2- and E3-stimulated LS fell to baseline quickly in both sexes, whereas 16OHE1-stimulated LS in males demonstrated a prolongation of maximal LS for 6 days following pump removal. These results suggest that 16OHE1 is estrogenic in the brains of both sexes. The delay of onset of LS with 16OHE1 is consistent with its poor ER affinity. Females were able to augment LS with prolonged exposure to all metabolites, while males could not. The ability of 16OHE1 to maintain maximal LS in the male long after its withdrawal is consistent with its ability to bind non-dissociably to the ER and promote prolonged estrogenic activation. However, females do not exhibit this response, suggesting a sex specificity in the dynamics of ligand-receptor action in the rat brain.