BIOLOGICAL MECHANISMS UNDERLYING RU-486 CLINICAL EFFECTS - INHIBITIONOF 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 ava ilable on the effect of RU 486 on endometrial hemostatic potential. Th e expression of endometrial stromal cell tissue factor (TF), the prima ry initiator of hemostasis, has been shown to be progestationally regu lated in vivo and in vitro. To evaluate the effects of RU 486 on proge stin-enhanced TF expression, confluent stromal cell cultures derived f rom 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 MP A 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 immuno reactive 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 pro gestin effects were blocked by RU 486. Similar results were obtained f or steady state TF messenger ribonucleic acid (mRNA) levels. Possible RU 486-mediated reversal of progestin-enhanced stromal cell TF express ion was assessed by incubating confluent cultures in E(2) plus MPA for 3-10 days to enhance TF content, then washing the cultures and reexpo sing 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 M PA greatly reduced levels of stromal cell TF protein and mRNA expressi on compared to those in cultures maintained in E(2) plus MPA. These fi ndings demonstrate that RU 486 not only blocks but also reverses in vi tro progestin-enhanced stromal cell TF protein and mRNA expression, su ggesting an additional mechanism for RU 486-induced menses and early a bortion.