Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.

doi:10.1210/jc.2013-2531

Paper

Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.

Published Sep 12, 2013 · S. Mazaud-Guittot, Christophe Nicolas Nicolaz, C. Desdoits-Lethimonier

The Journal of clinical endocrinology and metabolism

Q1 SJR score

149

Citations

4

Influential Citations

Full textSemantic Scholar

Abstract

CONTEXT Masculinization depends on the fetal testis. Exposure of the human fetus during pregnancy to paracetamol and/or to other mild analgesics is associated with an increased risk of cryptorchidism. OBJECTIVE We aimed to determine whether mild analgesics disrupted the morphology and endocrine function of the human testis. DESIGN We used an in vitro system based on the culture of human fetal testes exposed or not to paracetamol, its metabolite N-(4-hydroxyphenyl)-arachidonoylethanolamide (AM404), aspirin, indomethacin, and ketoconazole at 10(-4) to 10(-7) M. SETTING The study was conducted at the University of Rennes I. PATIENTS/PARTICIPANTS Human fetal testes were from pregnant women after induced abortion, between 7 and 12 weeks of gestation (GW). MAIN OUTCOME MEASURES Testosterone (RIA), anti-Müllerian hormone (ELISA), insulin-like factor 3 (RIA), and prostaglandin (PG) D2 and PGE2 (ELISA) were assayed in the medium. Testicular cells were counted using histology and image analysis. The possible nuclear receptor-mediated activities of the analgesics were investigated using reporter cell lines expressing estrogen, androgen, and peroxisome proliferator-activated γ receptors. RESULTS Indomethacin and aspirin stimulated testosterone production, particularly by the younger testes (8-9 GW vs 10-12 GW). Paracetamol, AM404, and ketoconazole decreased insulin-like factor 3 levels. Aspirin stimulated whereas ketoconazole inhibited AMH production. PGE2 levels were inhibited by paracetamol and aspirin in the 7 to 12 GW testes and by indomethacin but only in 7 to 9.86 GW 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.

In Vitro Study

Rigorous Journal

Highly Cited

Study Snapshot

Analgesics like paracetamol, aspirin, and indomethacin can disrupt fetal testis function, potentially increasing the risk of cryptorchidism, and caution is advised during pregnancy.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Sign up to use Study Snapshot

Consensus is limited without an account. Create an account or sign in to get more searches and use the Study Snapshot.

Create an account

Paper

Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.

Sign up to use Study Snapshot

References

Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro.

Mild analgesics, paracetamol, aspirin, and indomethacin, can cause multiple endocrine disturbances in adult human testis in vitro, with variations in their effects depending on the drug, dose, and duration of exposure.

International geographic correlation study of the prevalence of disorders of male reproductive health.

Testicular cancer, hypospadias, cryptorchidism, and low sperm concentration show positive correlations and negative correlations, with stronger correlations observed outside Europe.

Paracetamol and opioid pathways: a pilot randomized clinical trial

Naloxone does not inhibit paracetamol antinociception, suggesting no significant opioid system involvement in its mechanism of action.

Prostaglandins, Masculinization and Its Disorders: Effects of Fetal Exposure of the Rat to the Cyclooxygenase Inhibitor- Indomethacin

Indomethacin exposure during the fetal masculinization programming window in rats does not affect testosterone production or masculinization, suggesting a species difference.

Diethylstilboestrol Exposure Does Not Reduce Testosterone Production in Human Fetal Testis Xenografts

Human fetal testis exposure to diethylstilboestrol does not impair testosterone production, suggesting minimal risk to masculinization of the human fetus.

Citations

Role of the Endocannabinoid System in Gonadal Development: Implications for Endocrine Disruption and Reproductive Toxicity.

The endocannabinoid system plays a crucial role in reproductive development, and endocrine-disrupting chemicals like phthalates may interfere with its signaling, potentially leading to reproductive abnormalities like Testicular Dysgenesis Syndrome.

Overuse of analgesics can affect the fertility biomarker Anti-Müllerian Hormone in females. A translational study.

Frequent use of over-the-counter analgesics in females with medication overuse headaches can repress Anti-Müllerian Hormone levels, potentially through disruption of granulosa cell proliferation.

Modulation of adipogenesis and lipogenesis by indomethacin and pantoprazole.

Indomethacin and pantoprazole may have obesogenic effects through different mechanisms, and further in vivo and epidemiological studies are needed to confirm their potential to cause obesity.

The Possible Protective Role of N-acetylcysteine against Testicular Toxicity Induced by Paracetamol Overdose in Adult Male Rats

N-acetylcysteine (NAC) effectively lowers testicular toxicity caused by paracetamol overdose in adult male rats, restoring normal testicular function and testosterone levels.

Effects of major analgesics on male fertility: A systematic literature review

Paracetamol and ibuprofen may cause harmful endocrine and seminal changes in male fertility, while aspirin's effects on fertility remain unclear.

Arachidonic Acid Pathways and Male Fertility: A Systematic Review

Targeting arachidonic acid pathways could be an attractive strategy for improving male fertility, as PGE agonists show potential in improving sperm function and semen parameters.

Developmental toxicity window of fetal testicular injury in offspring mice induced by prenatal amoxicillin exposure at different time, doses and courses.

Prenatal amoxicillin exposure during late pregnancy and high doses can cause severe fetal testicular damage, with the mechanism being inhibition of AKT and ERK signaling pathways.