ESTROGENIC AND PROGESTAGENIC ACTIVITIES COEXISTING IN STEROIDAL DRUGS- QUANTITATIVE-EVALUATION BY IN-VITRO BIOASSAYS WITH HUMAN-CELLS

The progestin-specific stimulation of alkaline phosphatase (AP) activi ty in cells of the T47D human breast cancer line was applied to the de velopment of a sensitive microtiter plate bioassay for the quantitativ e evaluation of progestagenic and antiprogestagenic potencies of natur al and synthetic compounds. Some of the steroids tested (viz. progeste rone, medroxyprogesterone acetate, norethynodrel) behaved as full-agon ists, capable of inducing AP activities to the same maximal levels (eq ual efficacy), while others (norethindrone, gestrinone, R5020, norgest rel, Org OD 14 and its 4-ene metabolite) behaved as partial agonists, eliciting lower maximal effects. Efficacy, EC(50) values (concentratio ns at which they induce one-half of the maximal response) and ''slope factors'' serve to characterize agonistic effects. Relative progestage nic potencies among the full-agonists were evaluated by comparing EC,o concentrations. Several 19-nor synthetic progestins (norethynodrel, n orethindrone, Org OD 14 and its 4-ene isomer, dl-norgestrel, levo-norg estrel, RU2323), but none of the tested progestins with the pregnane s tructure, showed intrinsic estrogenic activity, as evaluated by using a similar in vitro bioassay based on a previously reported estrogen-sp ecific induction of AP in human endometrial adenocarcinoma cells of th e Ishikawa Var-1 line. Maximal estrogenic effects of all the tested pr ogestins with dual activity were as high as those of estradiol. Howeve r, these compounds widely varied in their EC(50) values for estrogenic activity. Consequently, the in vitro bioassays can reveal differences in the ratio of progestagenic and estrogenic activities intrinsic to these compounds. The reduced capability of the partial agonists to exe rt progestagenic on AP expression may reflect an impeded, receptor-med iated action, a mechanism that would also account for their inhibitory effects on the induction of AP activity by full agonists. Partial pro gestagenic agonists were able to reduce the efficacy of a full agonist to their own partial maximal activity.