The HMG-CoA reductase inhibitor simvastatin suppresses human testicular testosterone synthesis in vitro by a selective inhibitory effect on 17-ketosteroid-oxidoreductase enzyme activity.
In concentrations probably exceeding those achieved in vivo, the cholesterol lowering compound simvastatin was found to suppress the synthesis of the androgens androstenediol and testosterone in vitro by human testicular homogenates. It was demonstrated that simvastatin in addition to its known inhibitory effect on HMG-CoA reductase activity, also affects the later steps of testicular steroidogenesis by selectively inhibiting the 17-ketosteroid-oxidoreductase catalyzed conversion of dehydroepiandrosterone and androstenedione to androstenediol and testosterone respectively. There was no effect of simvastatin on the Cytochrome P-450-dependent microsomal enzymes. Although in doses conventionally used in the treatment of hypercholesterolemia, simvastatin does not affect testicular steroidogenesis, at higher doses--especially when inadvertently administered during early pregnancy--adverse effects on normal testosterone biosynthesis and thereby fetal development should be considered.
Smals
A G
AG
Department of Medicine, University of Nijmegen, The Netherlands.
Weusten
J J
JJ
Benraad
T J
TJ
Kloppenborg
P W
PW
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000368:Aged; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D010088:Oxidoreductases / Q000378:metabolism*; D011471:Prostatic Neoplasms; D019821:Simvastatin; D013256:Steroids / Q000096:biosynthesis; D013737:Testis / Q000187:drug effects / Q000378:metabolism*; D013739:Testosterone / Q000096:biosynthesis*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013256:Steroids; D013739:Testosterone; D008148:Lovastatin; D019821:Simvastatin; D010088:Oxidoreductases; D015067:17-Hydroxysteroid Dehydrogenases; D006903:Hydroxymethylglutaryl CoA Reductases