In vitro metabolism of gestodene in target organs: formation of A-ring reduced derivatives with oestrogenic activity

Gestodene (13 beta -ethyl-17 alpha -ethynyl-17 beta -hydroxy-4,5-gonadien-3 -one), the most potent progestin ever synthesized, stimulates breast cancer cell growth through an oestrogen receptor-mediated mechanism, and its use in hormonal contraception has been associated with side effects attributabl e to oestrogenic actions. These observations have remained controversial, s ince gestodene does not bind to the oestrogen receptor or exert oestrogen-l ike activities. Recently, we have demonstrated that non-phenolic gestodene derivatives interact with oestrogen receptors and induce oestrogenic effect s in cell expression systems. To assess whether gestodene is biotransformed to metabolites with intrinsic oestrogenic potency, [H-3]- and [C-14]-label led gestodene were incubated in vitro with rat anterior pituitary, hypothal amus and ventral prostate homogenates under different experimental conditio ns. The most remarkable finding was the isolation and identification of 3 b eta ,5 alpha -tetrahydrogestodene and 3 alpha ,5 alpha -tetrahydrogestodene as metabolic conversion products of gestodene, presumably with 5 alpha -di hydrogestodene as intermediate. The overall results seem to indicate that t he weak oestrogenic effects attributable to gestodene could be mediated by its tetrahydro metabolites. (C) 2001 Published by Elsevier Science B.V.