Progestins block cholesterol synthesis to produce meiosis‐activating sterols

Abstract

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.

Changes in the Activities of Hydroxysteroid Dehydrogenases in Porcine Oocytes during Meiotic Maturation In Vitro.

“…I t h a s a l s o be e n demonstrated that progestins increase the level of these sterols in HepG2 cells in vitro [14]. In the p resent study, metab olic ab ilitie s of some progestins were determined to alter in porcine oocytes with maturation, suggesting a possibility that such progestins may interact with MASs for maturation in porcine oocytes.…”

Sterols in spermatogenesis and sperm maturation

“…, 6.1-49 ppm) ( 9 ). Another group demonstrated a 4-fold increase of T-MAS in the rat testis during puberty ( 10 ). No other sterol precursor has shown comparable changes in testis during puberty, implying the important role of T-MAS in spermatogenesis.…”

Boots for Achilles: Progesterone's Reduction of Cholesterol Is a Second-Order Adaptation

“…This movement of sterols from the plasma membrane to the endoplasmic reticulum is required for cholesterol biosynthesis (Metherall et al 1996); thus, progesterone's impediment of LDL-derived cholesterol movement in turn impedes cholesterol biosynthesis. Consistent with the disruption of cholesterol production pathways, treating tissue with progesterone leads to an accumulation of sterol precursors (Lindenhall et al 2001). At the organismic level, exogenous progesterone has been shown to reduce HDL cholesterol both when administered through progestin-only oral contraceptives (Wynn and Niththyananthan 1982) and when administered through hormone-replacement therapies in postmenopausal women (LamonFava et al 2006).…”

“…Progesterone has been shown to inhibit the esterification of cholesterol derived from low-density lipoproteins (LDLs), preventing its delivery to cellular enzymes (Metherall et al 1996). Treatment of cholesterol with progesterone also causes the accumulation of sterol precursors, implying that cholesterol production pathways are disrupted (Lindenhall et al 2001). Indeed, progesterone disrupts pathways involved in both cholesterol biosynthesis and the processing of LDLderived cholesterol (Lindenhall et al 2001).…”

“…Treatment of cholesterol with progesterone also causes the accumulation of sterol precursors, implying that cholesterol production pathways are disrupted (Lindenhall et al 2001). Indeed, progesterone disrupts pathways involved in both cholesterol biosynthesis and the processing of LDLderived cholesterol (Lindenhall et al 2001).…”