There's been epidemiological evidence pointing in this direction for years, but more direct evidence, from a xenograft model, has now been reported.
Pregnant women are being advised to see their doctor if they need to take paracetamol for more than a day, after researchers found in an animal study that prolonged use of the analgesic reduced the production of testosterone.1Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model
Four previous studies have linked the use of paracetamol in pregnancy with an increased risk of cryptorchidism in male babies, but a causal effect has not been shown because it is not possible to test the association in women. To overcome this, researchers from the University of Edinburgh developed an animal model using castrated mice, into which they grafted human testicular tissue. These grafts have been shown to mimic how the developing testes grow and function in pregnancy.
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.Paracetamol, aspirin and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent
Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat
Context: Masculinization depends on the fetal testis. Exposure of the human fetus during pregnancy to paracetamol or/and to other mild-analgesics is associated with an increased risk of cryptorchidism. [. . .]
Results: Indomethacin and aspirin stimulated testosterone production, particularly by the younger testes (8–9 GW vs 10–12 GW). Paracetamol, AM404 and ketoconazole decreased INSL3 levels. Aspirin stimulated, whereas ketoconazole inhibited AMH production. PGE2 levels were inhibited by paracetamol, and aspirin in the 7–12 GW testes, and by indomethacin but only in 7–9.86 GW old testes. The inhibitory trends seen for PGD2 were not statistically significant.
Conclusions: Analgesics at concentrations relevant to human exposure cause endocrine disturbances in the fetal testis. We suggest that the fetal human testis displays slight critical age windows for sensitivity to direct exposure to aspirin, indomethacin and paracetamol. The analgesic-induced inhibition of INSL3 may be the mechanism by which analgesics increase the risk of cryptorchidism. Greater caution is required concerning consumption of analgesics during pregnancy.
BACKGROUND More than half of pregnant women in the Western world report intake of mild analgesics, and some of these drugs have been associated with anti-androgenic effects in animal experiments. Intrauterine exposure to anti-androgens is suspected to contribute to the recent increase in male reproductive problems, and many of the anti-androgenic compounds are like the mild analgesics potent inhibitors of prostaglandin synthesis. Therefore, it appears imperative to further investigate the potential endocrine disrupting properties of mild analgesics. [. . .]
RESULTS In the Danish birth cohort, the use of mild analgesics was dose-dependently associated with congenital cryptorchidism. In particular, use during the second trimester increased the risk. This risk was further increased after the simultaneous use of different analgesics. The association was not found in the Finnish birth cohort.
[. . .] Our results suggest that intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders.
It is widely accepted that androgens are required for normal abdominal translocation of the testes (Boisen et al., 2004; Swan et al., 2005; Tomiyama et al., 2005; Scott et al., 2009). Therefore, a particular strength of this study is the use of two complementary rat models to support the contention that the association between analgesic use and cryptorchidism seen in our cohort study may result from a reduction in androgen production. Intrauterine exposure to paracetamol, with a lowest dose of 150 mg/kg/day, resulted in a decrease in fetal testosterone-dependent AGDi comparable with effects seen after exposure to known anti-androgenic compounds such as phthalates (Borch et al., 2006), which have PG inhibitory properties similar to those of mild analgesics (D. M. Kristensen et al., submitted for publication). Since this is only three times the dose recommended for humans of 50 mg/kg/day, further work is needed to determined the no adverse effect level.
Comparative wholesale statistics from the five Nordic countries show an increase of 15–42% in the total consumption of analgesics and anti-inflammatory drugs (including antirheumatics) in the period 1978–1988. Denmark had the highest total consumption (112 DDD/1000 inhab/day in 1988) and Norway had the lowest (61 DDD/1000 inhab/day). Iceland and Finland, with the highest increases in total consumption (45% and 35%), overtook Norway in the early to mid 1980's. Division of total consumption into subgroups showed that Denmark had the highest consumption of analgesics (90 DDDs) and that Finland and Iceland had the lowest figure. The latter countries, however, had the highest consumption of non-steroidal anti-inflammatory drugs (NSAID), 35 and 30 DDDs, respectively, in 1988. The increase in NSAID consumption was 57% in Finland and 54% in Iceland, while Denmark had only an 18% increase. The new NSAIDs introduced in the 1970's appear to have increased the overall consumption of pain relievers in the Nordic countries, especially in Finland and Iceland.