Statin drugs markedly inhibit testosterone production by rat Leydig cells in vitro: implications for men.
Statin drugs lower blood cholesterol by inhibiting hepatic 3-hydroxy-3-methylglutaryl-Coenzyme-A reductase. Statins are known to inhibit sterol production in the testis, but effect of statins on testosterone production has not been studied critically in vitro and clinical data are controversial. We measured 18-h testosterone production in vitro, using highly purified rat Leydig cells exposed to atorvastatin, mevastatin, or simvastatin and also determined if statin-induced inhibition of testosterone production could be bypassed with substrate distal to cholesterol. Statins had no effect on testosterone production during culture without LH. However, with 10ng/mL LH, testosterone production was ≥12-fold higher and markedly inhibited (-40%) by ≥0.3μM statin. Leydig cells provided sub-saturating pregnenolone or progesterone to bypass the site of statin action, maintained LH-stimulated testosterone production at or above amounts observed with LH stimulation and no statin. Pregnenolone resulted in greater testosterone production, but LH responsiveness was lost. With progesterone, LH responsiveness was maintained.
United States Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Toxicology Assessment Division, Reproductive Toxicology Facility, Durham, NC 27713, United States. Electronic address: klinefelter.gary@epa.gov.
G R
GR
Klinefelter
United States Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Toxicology Assessment Division, Reproductive Toxicology Facility, Durham, NC 27713, United States.
J W
JW
Laskey
Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, CO 80523-1683, United States.
R P
RP
Amann
D000818:Animals; D002478:Cells, Cultured; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism; D007986:Luteinizing Hormone / Q000494:pharmacology; D008297:Male; D011284:Pregnenolone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013739:Testosterone; D011374:Progesterone; D011284:Pregnenolone; D007986:Luteinizing Hormone
Isolated Leydig cells; LH-stimulation; Progestin; Statins; Testosterone production