Biological mechanisms underlying the clinical effects of RU 486: modulation of cultured endometrial stromal cell plasminogen activator and plasminogen activator inhibitor expression.
The abortifacient and menstrual effects of the potent antiprogestin, RU 486, are associated with both endometrial hemorrhage and extracellular matrix (ECM) degradation. Such processes reflect reduced perivascular decidual cell hemostatic and increased ECM-degrading protease activity. Therefore, we assessed the effects of RU 486 administration on the expression of immunoreactive (ir) endometrial stromal cell urokinase-type (uPA) and tissue-type (tPA) plasminogen activator and their activities as well as levels of ir type 1 plasminogen activator inhibitor (PAI-1) using a well characterized in vitro model of decidualization. Thus, confluent stromal cell cultures were exposed to vehicle control, 10(-8) mol/L estradiol (E2), 10(-7)-10(-8) mol/L medroxyprogesterone acetate (MPA), E2 plus MPA, or 10(-6)-10(-7) mol/L RU 486 alone or in combination with MPA or E2 plus MPA for 3-4 days. Compared to the vehicle control, E2 and RU 486 used alone had no effect on levels of ir PAI-1, uPA, or tPA or on PA activity in the conditioned medium. In contrast, MPA and E2 plus MPA decreased ir uPA and tPA levels and their corresponding activities, whereas MPA increased, and E2 plus MPA further increased ir PAI-1 release. These effects of progestin were blocked by a log higher concentration of RU 486. Similar results were obtained for steady state PAI-1 messenger ribonucleic acid levels. To determine if RU 486 reversed progestin-inhibited stromal cell uPA and tPA release and progestin-enhanced PAI-1 expression, confluent cultures were exposed to 10(-8) mol/L E2 plus 10(-7) mol/L MPA for 10 days, washed, and reexposed to E2 plus MPA, steroid-free medium, or RU 486 for 3-5 or 9-11 days. Compared with cultures maintained in E2 plus MPA for 3-5 days, withdrawal to a steroid-free medium failed to affect stromal cell ir PAI-1, uPA, or tPA levels. In contrast, exposure to RU 486 for 3-5 days increased ir uPA and tPA levels 5- to 8-fold (P < 0.02) while reducing PAI-1 levels by 85% (P < 0.04). By 9-11 days of treatment, steroid withdrawal and RU 486 exerted similar effects on ir PAI-1, tPA, and uPA levels. Comparable results were obtained for PAI-1, uPA, and tPA steady state messenger ribonucleic acid levels. These findings indicate that RU 486 blocks and reverses progestin-inhibited PA expression, suggesting a mechanism for RU 486-induced endometrial hemorrhage and ECM dissolution.
Lockwood
C J
CJ
Department of Obstetrics, Gynecology, and Reproductive Science, Mount Sinai School of Medicine, New York, New York 10029, USA.
Krikun
G
G
Papp
C
C
Aigner
S
S
Schatz
F
F
D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004717:Endometrium / Q000166:cytology / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D010960:Plasminogen Activators / Q000235:genetics / Q000378:metabolism*; D015849:Plasminogen Inactivators / Q000378:metabolism*; D011372:Progestins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D015849:Plasminogen Inactivators; D011372:Progestins; D012333:RNA, Messenger; D015735:Mifepristone; D004958:Estradiol; D003907:Dexamethasone; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator