Lupeol, the major compound of the dichloromethane extract of Millettia macrophylla Benth (Fabaceae), displays estrogenic effects in ovariectomized rats.

The present work deals with the assessment of the in vitro and in vivo estrogenic effects of the triterpenoids (lupenone, lupeol, and stigmastenone) isolated from Millettia macrophylla extract. The in vitro estrogenicity was performed by a reporter gene assay and estrogen receptor- (ER) target gene expression, whereas the in vivo estrogenicity was evaluated by a 3-day uterotrophic assay in ovariectomized rats. As results, lupenone and lupeol did not transactivate ER as well as ER of human embryonic kidney 293T (HEK293T) cells. However, lupeol seems to be antagonistic to estrogen (E2) only in HEK293T-ER (10(-9) and 10(-8)M). Furthermore, lupeol slightly upregulated GREB1 gene expression at the concentration of 1M, suggesting a weak activation of endogenous ER. In vivo, only lupeol at a dose of 1mg/kg significantly increased the uterine wet weight (p<0.05), uterine (p<0.05), and vaginal (p<0.01) epithelial heights. The concomitant administration of lupeol (1mg/kg) with a pure antiestrogen fulvestrant abrogated its effects only in the vagina, whereas in combination with E2, lupeol exhibited a significant antiestrogen-like effect in uterine wet weight and synergistic effects on endometrium. Lupeol has estrogenic effects that is partly through ERs transcriptional activity and does involve alternative mechanisms that are still to be uncovered.