Vastatins have a distinct effect on sterol synthesis and progesterone secretion in human granulosa cells in vitro.
Lovastatin and simvastatin are strong inhibitors of cholesterol synthesis in cultured human granulosa cells, as measured within 6 days after isolation, with IC50-values of respectively 27.0 and 18.2 nM obtained after 3.5 hours of incubation with the drugs. Pravastatin is a much weaker inhibitor of cholesterol synthesis (IC50-value of 977.8 nM) in these cells. Under these conditions inhibition of cholesterol synthesis had no influence on progesterone secretion into the medium which was probably due to the presence of large cholesterol pools in the cells. To deplete these pools, granulosa cells were cultured for 7 days after which the culture medium was changed into medium supplemented with 20% lipoprotein-depleted serum to deprive the cells of exogenous cholesterol. Additionally, 30 mIU of follicle-stimulating hormone and luteinizing hormone per ml were added to stimulate the progesterone production and secretion, thereby decreasing the cholesteryl ester pools. After 48 h of incubation, culture was continued without hormones for another two days. Thereafter, the cells were preincubated for 24 h without or with 1 microM of lovastatin, simvastatin or pravastatin in medium containing lipoprotein-deficient serum and the above-mentioned hormones. This period is followed by incubation for another 24 h in the presence of [14C]acetate after which cells and media were collected for determination of 14C-labelled sterols synthesized and progesterone secreted into the media. Now, lovastatin and simvastatin, which strongly inhibited sterol synthesis, significantly attenuated the secretion of progesterone. One microM of pravastatin had no significant effect on sterol synthesis nor on progesterone secretion. When the latter experiment was performed under conditions in which exogenous cholesterol was provided in the form of human low density lipoproteins, no influence of the vastatins on progesterone secretion was observed. So under conditions in which the cholesterol pools were decreased, lovastatin and simvastatin attenuated the progesterone secretion, whereas pravastatin did not. When pools were filled by exogenous cholesterol, no effect on progesterone secretion by either of the drugs was observed.
van Vliet
A K
AK
Gaubius Laboratory TNO-PG, Leiden, The Netherlands.
van Thiel
G C
GC
Naaktgeboren
N
N
Cohen
L H
LH
D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D003470:Culture Media; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D006107:Granulosa Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology*; D011374:Progesterone / Q000378:metabolism*; D019821:Simvastatin
D003470:Culture Media; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011374:Progesterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin