Estrogenic actions of norethisterone and its A-Ring reduced metabolites: induction of in vitro uterine sensitivity to serotonin

RESUMO

The estrogen-like effects of norethisterone (NET) seem to be mediated by the interaction of 3ß5alpha- and 3alpha-5alpha-tetrahydronorethisterone (3ß5alpha- and 3alpha5alpha-NET, respectively) with the estrogen receptor. Considering that the in vitro uterine contractile response to sertonin (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 sentivity to 5-HT in vitro. The administration of 3ßNET in vivo, wich is the NET metabolite with the highes affinity for the estrogen receptor, induced a maximal contractile response to serotonin similar to that of 17ß-estradiol treatment. The other metabolites induced less uterine activity. According to the effective dose 50, the order of estrogenic potency was 17ß-estradiol>3ß5alphaNET>3alpha5alphaNET>NET>5alphaNET. The estrogenic effect of 3ß5alpha- and 3alpha5alphaNET may be exerted throug their interaction with the estrogen receptor, whereas NET and 5alphaNET, which do not bind to the estrogen receptor and display a minor estrogenic activity, require prior bioconversion to 3ß5alpha NET. The A-ring reduced metabolites of NET, mainly the 3ß5alphaNET, may be exerting estrogenic responses and modulation uterine activity when administered in vivo