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Progesterone Regulation of Human Granulosa/Luteal Cell Viability by an RU486-Independent Mechanism

Departments of Obstetrics and Gynecology (L.E., J.J.P.) and Cell Biology (J.J.P.), University of Connecticut Health Center, Farmington, Connecticut 06030; Faculty of Clinical Medicine (R.L., M.W.), Mannheim Institute of Clinical Pharmacology, University of Heidelberg, D-68135 Mannheim, Germany; and Medicine/Experimental Medicine (M.W.), AstraZeneca R&D, S-48183 Molndal, Sweden

Address all correspondence and requests for reprints to: John J. Peluso, Ph.D., Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030. E-mail: peloso{at}nsoz.uchc.edu.

Context: Progesterone (P4) inhibits human granulosa/luteal cell apoptosis by an unknown mechanism.

Objective: Our objective was to assess the role of the nuclear P4 receptor (PGR) and PGR membrane component 1 (PGRMC1) in mediating P4’s antiapoptotic 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 in vitro fertilization patients from 2004–2006.

Main Outcome Measure: Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling 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 at least 70% of the cells to undergo apoptosis. Five micromolar RU486 neither induced apoptosis nor attenuated the antiapoptotic action of 1 µM P4. PGRMC1 and its binding partner, plasminogen activator inhibitor RNA-binding protein-1 (PAIRBP1), were detected in 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 antiapoptotic action of 1 µM P4 because RU486 binds to the PGR at a greater affinity than P4; 2) 25 and 50 µM RU486 induce three to four 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; and 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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