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Statin Drugs Markedly Inhibit Testosterone Production by Rat Leydig Cells In Vitro: Implications for Men
Klinefelter, G., J. Laskey, AND R. Amann. Statin Drugs Markedly Inhibit Testosterone Production by Rat Leydig Cells In Vitro: Implications for Men. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 45:52-58, (2014).
Statin drugs lower blood cholesterol by inhibiting hepatic 3-hydroxy-3-methylglutaryl-Coenzyme-A reductase. During drug development it was shown that statins inhibit production of cholesterol in the testis. We evaluated testosterone production in vitro, using highly purified rat Leydig cells exposed to atorvastatin, mevastatin, or simvastatin and determined if statin-induced inhibition of testosterone production could be bypassed with substrate distal to cholesterol. Statins had no effect on testosterone produced during culture without LH. However, with 10 ng/mL LH, testosterone production was ≥12-fold higher and was markedly inhibited by each statin (-40%). Inhibition concentration (IC50) values were 0.002, 0.085, and 0.048 μM, respectively. When Leydig cells were provided with sub-saturating (0.5 μM) pregnenolone or progesterone to bypass the site of statin action, LH-stimulated inhibition was maintained at or above levels observed with LH stimulation and no statin. Pregnenolone resulted in greater testosterone production, but LH responsiveness was lost. With progesterone, LH responsiveness was maintained.
Statin drugs are prevalent in the environment as an estimated 9 billion pills are disposed of into the waste water or trash annually. The mean predicted concentraion of simvastatin alone has been estimated at 1.2 ug/L. In addition to this 'indirect' exposure, many men are exposed directly via daily drug administration. The cumulative risk attributed to these exposures warrants clarification. We found that statins markedly compromise the ability of the rat Leydig cell to respond to LH stimulation. The IC50 for this inhibition is less than 2X what human Leydig cells might be exposed to following direct exposure. As such, it is reasonable to conclude that statin exposure might be contributing to the putative decline in semen quality and the increasing incidence of low testosterone in men. We found that the deleterious effect of statins on testosterone production could be effectively bypassed with subtrate distal to the site of ation (e.g. progestin).
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
TOXICOLOGY ASSESSMENT DIVISION
REPRODUCTIVE TOXICOLOGY BRANCH