BIOLOGICAL MECHANISMS UNDERLYING RU-486 CLINICAL EFFECTS - INHIBITION OF ENDOMETRIAL STROMAL CELL TISSUE FACTOR CONTENT

Despite the pronounced hemorrhagic effects of RU 486 administration on luteal phase and early gestational endometrium, no information is available on the effect of RU 486 on endometrial hemostatic potential. The expression of endometrial stromal cell tissue factor (TF), the primary initiator of hemostasis, has been shown to be progestationally regulated in vivo and in vitro. To evaluate the effects of RU 486 on progestin-enhanced TF expression, confluent stromal cell cultures derived from proliferative phase endometria were exposed to vehicle control, 10(-8) mol/L estradiol (E(2)), 10(-6) mol/L dexamethasone, 10(-7) mol/L medroxyprogesterone acetate (MPA), E(2) plus MPA, E(2) plus 10(-6) mol/L progesterone (P), or 10(-6) mol/L RU 486 alone or with E(2) plus MPA or E(2) plus P for 3-4 days. Compared to the vehicle control, E(2), dexamethasone, and RU 486 alone had no effect on the content of immunoreactive and functionally active TF protein, whereas MPA increased and the combination of E(2) and MPA further increased TF protein content. Similarly, E(2) and P enhanced the stromal cell TF content. These progestin effects were blocked by RU 486. Similar results were obtained for steady state TF messenger ribonucleic acid (mRNA) levels. Possible RU 486-mediated reversal of progestin-enhanced stromal cell TF expression was assessed by incubating confluent cultures in E(2) plus MPA for 3-10 days to enhance TF content, then washing the cultures and reexposing them to either E(2) plus MPA or to RU 486 alone or with E(2) plus MPA for 3, 4, or 7 days. Exposure to RU 486 alone or with E(2) plus MPA greatly reduced levels of stromal cell TF protein and mRNA expression compared to those in cultures maintained in E(2) plus MPA. These findings demonstrate that RU 486 not only blocks but also reverses in vitro progestin-enhanced stromal cell TF protein and mRNA expression, suggesting an additional mechanism for RU 486-induced menses and early abortion.