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Submitted on May 25, 2006
Accepted on September 11, 2006
Departments of Obstetrics and Gynecologyand Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, Faculty of Clinical Medicine, Mannheim Institute of Clinical Pharmacology, University of Heidelberg, Mannheim, Germanyand Medicine/Experimental Medicine, AstraZeneca R&D, S48183 Molndal, Sweden
Context. Progesterone (P4) inhibits human granulosa/luteal cell apoptosis by an unknown mechanism.
Objective. To assess the role of the nuclear progesterone receptor (PGR) and progesterone receptor membrane component 1 (PGMC1) in mediating P4's anti-apoptotic action in human granulosa/luteal cells.
Design, Setting and Patients. In vitro laboratory studies were designed in which human granulosa/luteal cells were harvested from IVF patients from 2004-2006.
Main Outcome Measured. Apoptosis was assessed by TUNEL assays and DNA staining. Protein expression was observed by Western blot and immunocytochemistry.
Results. PGR was detected in 20% of the human granulosa/luteal cells and 25 and 50 µM RU486 induced 
70% of the cells to undergo apoptosis. Five µM RU486 neither induced apoptosis nor attenuated the anti-apoptotic action of 1 µM P4. PGRMC1 and its binding partner, Plasminogen Activator Inhibitor RNA Binding Protein-1 (PAIRBP1) were detected human granulosa/luteal cells. Antibodies to either PGRMC1 or PAIRBP1 completely attenuated P4's action.
Conclusions. PGR does not exclusively mediate P4's action because: 1) 5 µM RU486 should have been able to override the anti-apoptotic action of 1 µM P4, since RU486 binds to the PGR at a greater affinity than P4, 2) 25 and 50 µM RU 486 induce 3 to 4 times more cells to undergo apoptosis than express PGR, 3) P4 must be continuously present to prevent apoptosis, which implies a rapid, possibly membrane-initiated mechanism of action, 4) expression and blocking antibody studies suggest that PGRMC1 and PAIRBP1 account in part for P4's action in human granulosa/luteal cells.
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