MOLECULAR MECHANISMS OF THE ANTIHORMONAL AND ANTIIMPLANTATION EFFECTSOF NORETHISTERONE AND ITS A-RING REDUCED METABOLITES

Norethisterone (NET) has been used as a contragestational postcoital a gent. It is biotransformed to 5 alpha dihydro-NET (5 alpha-NET) and 3 beta,5 alpha tetrahydro-NET (3 beta,5 alpha-NET) in target tissues. Th e participation of these metabolites in NET effects is unknown. We hav e examined the antiimplantation and antiprogestational effects of NET and its metabolites, in adult mated female rabbits, by assessing the n umber of implantation sites and the expression products of the uterogl obin (UTG) gene in the uterus, and by comparing them with those of RU- 486 and estradiol. Steroids were daily administered s.c, at several do ses for 7 consecutive days, starting 24 hr after coitus. To assure tha t fertilization occurred in all animals, the presence of early pregnan cy factor was determined. The results demonstrated that high doses (5 mg/kg) of NET reduced both implantation and the expression of the UTG gene. On the other hand, lower doses (1.5 mg/kg) of 5 alpha-NET produc ed an antiimplantation effect and suppressed UTG synthesis and its mRN A. These effects were similar to those of RU-486. At lower doses (1 mg /kg), both estradiol and the estrogenic metabolite 3 beta,5 alpha-NET were also effective in inhibiting implantation and UTG gene expression . The overall results suggest that NET metabolites exert antiimplantat ion and antiprogestational effects through their interaction with prog esterone and estrogen receptors, and provide an explanation for the mo lecular mechanisms involved in the postcoital contraceptive action of NET. (C) 1995 Wiley-Liss, Inc.