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Progestins block cholesterol synthesis to produce meiosis-activating sterols

B Lindenthal1, A L Holleran, T A Aldaghlas

  • 1Department of Physiology and Experimental Medicine, The George Washington University School of Medical and Health Sciences, Washington, DC 20037, USA. bernard.lindenthal@schering.de

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|March 22, 2001
PubMed

Insights

Progestins regulate meiosis-activating sterols (MAS) by altering cholesterol synthesis in gonadal tissues. This discovery explains elevated MAS levels and suggests a novel role for progestins in fertility.

Area of Science:

  • Reproductive Biology
  • Sterol Metabolism
  • Biochemistry

Background:

  • Meiosis resumption is controlled by meiosis-preventing and activating substances in gonads.
  • The mechanism behind the accumulation of meiosis-activating sterols (MAS), C29 cholesterol precursors, in gonadal tissue is not fully understood.

Purpose of the Study:

  • To investigate how progestins influence cholesterol synthesis and MAS accumulation.
  • To elucidate the specific enzymatic pathways affected by progestins in relation to MAS production.

Main Methods:

  • Utilized HepG2 cells and rat testes models.
  • Employed in vitro cell assays and isotopomer spectral analysis with 13C-acetate.
  • Measured alterations in cholesterol synthesis pathways, including Delta24-reduction and 4alpha-demethylation.

Main Results:

  • Progestins, including progesterone, pregnenolone, and 17alpha-OH-pregnenolone, increase levels of major MAS (FF-MAS and T-MAS) by inhibiting Delta24-reduction.
  • 17alpha-OH-progesterone specifically inhibits 4alpha-demethylation, leading to sterol accumulation.
  • Progestins reduced the flux of 13C-acetate into lathosterol and cholesterol while newly synthesized MAS accumulated.

Conclusions:

  • Physiological levels of progestins can regulate MAS concentrations in gonads.
  • This regulation provides a plausible explanation for elevated MAS levels in gonadal tissues.
  • Progestins may play a novel role in regulating fertility through their effects on sterol metabolism.

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