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1
,2
* Department of Physiology and Experimental Medicine, The George Washington University School of Medical and Health Sciences, Washington, DC 20037, USA;
Department of Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany; and
Departments of Chemistry and Biochemistry and Cell Biology, Rice University, Houston, TX 77251-1892, USA.
1Correspondence: Female Health Care Research, Schering AG, Muellerstrasse 170-178, 13342 Berlin, Germany. E-mail: bernhard.lindenthal{at}schering.de
Theresumption of meiosis is regulated by meiosis-preventing and
meiosis-activating substances in testes and ovaries. Certain
C29 precursors of cholesterol are present at elevated
levels in gonadal tissue, but the mechanism by which these
meiosis-activating sterols (MAS) accumulate has remained an unresolved
question. Here we report that progestins alter cholesterol synthesis in
HepG2 cells and rat testes to increase levels of major MAS (FF-MAS and
T-MAS). These C29 sterols accumulated as a result of
inhibition of 
24-reduction and 4
-demethylation. Progesterone,
pregnenolone, and 17-OH-pregnenolone were potent inhibitors of
24-reduction in an in vitro cell assay and led to the
accumulation of desmosterol, a 5,24 sterol precursor of cholesterol.
A markedly different effect was observed for 17-OH-progesterone,
which caused the accumulation of sterols associated with inhibition of
4-demethylation. The flux of 13C-acetate into
lathosterol and cholesterol was decreased by progestins as measured by
isotopomer spectral analysis, whereas newly synthesized MAS
accumulated. The combined evidence that MAS concentrations can be
regulated by physiological levels of progestins and their specific
combination provides a plausible explanation for the elevated
concentration of MAS in gonads and suggests a new role for progestins
in fertility.—Lindenthal, B., Holleran, A. L., Aldaghlas, T. A., Ruan, B., Schroepfer, G. J., Jr., Wilson, W. K., and
Kelleher, J. K. Progestins block cholesterol synthesis to produce
meiosis-activating sterols.
Key Words: progesterone • 17-hydroxyprogesterone • cholesterol precursors • GC-MS • isotopomer spectral analysis • HepG2 cells
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