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A risk of prolonged acetaminophen use
The analgesic acetaminophen is one of the most commonly used medications worldwide. Although it has a good safety profile, previous human studies have found an association between the use of acetaminophen in pregnancy and cryptorchidism in male offspring. Now, van den Driesche et al. confirmed and refined this observation in a xenograft model using human fetal testicular tissue. The authors found that a single therapeutic dose of acetaminophen had no effect on testicular development, but continued dosing of acetaminophen for a week at clinically relevant doses reduced fetal testosterone and markers of androgen exposure. Further work will be needed to determine a safe dose and duration of acetaminophen exposure, but the current findings suggest a need for caution.
Abstract
Most common male reproductive disorders are linked to lower testosterone exposure in fetal life, although the factors responsible for suppressing fetal testosterone remain largely unknown. Protracted use of acetaminophen during pregnancy is associated with increased risk of cryptorchidism in sons, but effects on fetal testosterone production have not been demonstrated. We used a validated xenograft model to expose human fetal testes to clinically relevant doses and regimens of acetaminophen. Exposure to a therapeutic dose of acetaminophen for 7 days significantly reduced plasma testosterone (45% reduction; P = 0.025) and seminal vesicle weight (a biomarker of androgen exposure; 18% reduction; P = 0.005) in castrate host mice bearing human fetal testis xenografts, whereas acetaminophen exposure for just 1 day did not alter either parameter. Plasma acetaminophen concentrations (at 1 hour after the final dose) in exposed host mice were substantially below those reported in humans after a therapeutic oral dose. Subsequent in utero exposure studies in rats indicated that the acetaminophen-induced reduction in testosterone likely results from reduced expression of key steroidogenic enzymes (Cyp11a1, Cyp17a1). Our results suggest that protracted use of acetaminophen (1 week) may suppress fetal testosterone production, which could have adverse consequences. Further studies are required to establish the dose-response and treatment-duration relationships to delineate the maximum dose and treatment period without this adverse effect.
- Copyright © 2015, American Association for the Advancement of Science
