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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 Vitro¹

Department of Physiology and Pharmacology³ Research Centre for Endocrinology and Metabolism, Department of Internal Medicine,⁴ Göteborg University, SE-40530 Göteborg, Sweden

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.

¹ Supported by grants 10380, 11295, 13141, and 13550 from the Swedish MRC and by grants from the Assar Gabrielsson Foundation, the Hjalmar Svensson Foundation, the Ollie and Elof Ericsson Foundation, the Lundberg Foundation, the Eva and Oscar Ahrén Research Foundation, Stockholm and Swegene, Sweden.

² Correspondence: Håkan Billig, Department of Physiology, Göteborg University, P.O. Box 434, SE-40530 Göteborg, Sweden. FAX: 46 0 31 7733531; hakan.billig{at}fysiologi.gu.se

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