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Progesterone-receptor antagonists and statins decrease de novo cholesterol synthesis and increase apoptosis in rat and human periovulatory granulosa cells in vitro

Journal article
Authors Emilia Rung
P. Anders Friberg
Linus Ruijin Shao
D. G. Joakim Larsson
Eva Ch. Nielsen
Per-Arne Svensson
Björn Carlsson
Lena M S Carlsson
Håkan Billig
Published in Biology of reproduction
Volume 72
Issue 3
Pages 538-45
ISSN 0006-3363 (Print)
Publication year 2005
Published at Institute of Internal Medicine, Dept of Body Composition and Metabolism
Institute of Physiology and Pharmacology, Dept of Physiology
Pages 538-45
Language en
Keywords Animals, Apoptosis/drug effects/*physiology, Cell Survival/physiology, Cholesterol/*biosynthesis, Estrenes/pharmacology, Female, Furans/pharmacology, Gene Expression Profiling, Gene Expression Regulation, Granulosa Cells/drug effects/*metabolism, Hormone Antagonists/pharmacology, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology, Mifepristone/pharmacology, Oligonucleotide Array Sequence Analysis, Ovulation/*physiology, Rats, Rats, Sprague-Dawley, Receptors, Progesterone/antagonists & inhibitors/*metabolism, Signal Transduction/physiology
Subject categories Medical and Health Sciences, Physiology


Progesterone-receptor (PR) stimulation promotes survival in rat and human periovulatory granulosa cells. To investigate the mechanisms involved, periovulatory rat granulosa cells were incubated in vitro with or without the PR-antagonist Org 31710. Org 31710 caused the expected increase in apoptosis, and expression profiling using cDNA microarray analysis revealed regulation of several groups of genes with functional and/or metabolic connections. This regulation included decreased expression of genes involved in follicular rupture, increased stress responses, decreased angiogenesis, and decreased cholesterol synthesis. A decreased cholesterol synthesis was verified in experiments with both rat and human periovulatory granulosa cells treated with the PR-antagonists Org 31710 or RU 486 by measuring incorporation of [14C]acetate into cholesterol, cholesterol ester, and progesterone. Correspondingly, specific inhibition of cholesterol synthesis in periovulatory rat granulosa cells using 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (lovastatin, mevastatin, or simvastatin) increased apoptosis, measured as DNA fragmentation and caspase-3/7 activity. The increase in apoptosis caused by simvastatin was reversed by addition of the cholesterol synthesis-intermediary mevalonic acid. These results show that PR antagonists reduce cholesterol synthesis in periovulatory granulosa cells and that cholesterol synthesis is important for granulosa cell survival.

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