The estrogen-like effects of norethisterone (NET) seem to be mediated by the interaction of 3 beta 5 alpha- and 3 alpha 5 alpha-tetrahydronorethisterone (3 beta 5 alpha- and 3 alpha 5 alpha-NET, respectively) with the estrogen receptor. Considering that the in vitro uterine contractile response to serotonin (5-HT) is specifically dependent on estrogen, the aim of the present study was to investigate whether NET and its A-ring reduced metabolites administered in vivo to ovariectomized rats induce uterine sensitivity to 5-HT in vitro. The administration of 3 beta NET in vivo, which is the NET metabolite with the highest affinity for the estrogen receptor, induced a maximal contractile response to serotonin similar to that of 17 beta-estradiol treatment. The other metabolites induced less uterine activity. According to the effective dose 50, the order of estrogenic potency was 17 beta-estradiol > 3 beta 5 alpha NET > 3 alpha 5 alpha NET > NET > 5 alpha NET. The estrogenic effect of 3 beta 5 alpha- and 3 alpha 5 alpha NET may be exerted through their interaction with the estrogen receptor, whereas NET and 5 alpha NET, which do not bind to the estrogen receptor and display a minor estrogenic activity, require prior bioconversion to 3 beta 5 alpha NET and perhaps to 3 alpha 5 alpha NET. The A-ring reduced metabolites of NET, mainly the 3 beta 5 alpha NET, may be exerting estrogenic responses and modulating uterine activity when administered in vivo.