Progestins block cholesterol synthesis to produce meiosis-activating sterols.
The resumption 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 Delta24-reduction and 4alpha-demethylation. Progesterone, pregnenolone, and 17alpha-OH-pregnenolone were potent inhibitors of Delta24-reduction in an in vitro cell assay and led to the accumulation of desmosterol, a Delta5,24 sterol precursor of cholesterol. A markedly different effect was observed for 17alpha-OH-progesterone, which caused the accumulation of sterols associated with inhibition of 4alpha-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.
Department of Physiology and Experimental Medicine, The George Washington University School of Medical and Health Sciences, Washington, DC 20037, USA. bernard.lindenthal@schering.de
B
B
Lindenthal
A L
AL
Holleran
T A
TA
Aldaghlas
B
B
Ruan
G J
GJ
Schroepfer
W K
WK
Wilson
J K
JK
Kelleher
D000818:Animals; D001835:Body Weight; D002775:Cholestadienols / Q000378:metabolism / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis* / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D006801:Humans; D006908:Hydroxyprogesterones / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008540:Meiosis / Q000502:physiology; D008825:Miconazole / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D011372:Progestins / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013057:Spectrum Analysis; D013261:Sterols / Q000096:biosynthesis*; D013629:Tamoxifen / Q000494:pharmacology; D013737:Testis / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002775:Cholestadienols; D004965:Estrogen Antagonists; D006908:Hydroxyprogesterones; D011372:Progestins; D013261:Sterols; D013629:Tamoxifen; D015735:Mifepristone; D008825:Miconazole; D002784:Cholesterol