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A new study conducted by Inserm researchers at Irset (Institute of Research in Environmental and Occupational Health)[1] shows that ibuprofen is liable to cause disruptions in the hormone system in the human foetal testis, with possible implications for the development of the male urogenital tract. This drug suppresses the production of various testicular hormones, including testosterone, which controls the primary and secondary sex characteristics and the descent of the testes. These effects are obtained at doses similar to the standard dosage. These results are published in Scientific Reports.

Ibuprofen, which can be obtained without prescription, is one of the drugs most commonly consumed by pregnant women. Although nearly one woman in ten reports having taken ibuprofen during her pregnancy, studies indicate that in reality up to 3 in 10 have self-medicated with it.

Epidemiological studies conducted in recent years have shown a link between taking analgesics during pregnancy and the occurrence of adverse effects in the child (low birthweight, asthma, premature birth etc.). Other research combining epidemiology, in utero experimentation in rats and ex vivo on rat and human organs, undertaken at Irset in collaboration with Danish researchers from the University of Copenhagen, showed that paracetamol and aspirin could disrupt the endocrine system of the foetal testis, resulting in an increased risk of failure of the testes to descend (cryptorchidism). Only the effects of ibuprofen had not yet been tested.

To do that, the Irset researchers – with the support of colleagues at Rennes University Hospital and the University of Copenhagen, researchers from Laberca (Laboratory for the Study of Residues and Contaminants in Food) in Nantes, and Scots colleagues from MRC Edinburgh – conducted two series of tests to study the effects of ibuprofen on the human foetal testis. In the first series of studies, the testes were cultured; in the second, they were grafted onto mice[2]. The effects of ibuprofen were studied over periods corresponding to the 1^st and 2^nd trimesters of pregnancy.

When testes corresponding to the 1^st trimester of pregnancy were exposed to ibuprofen, there was a sharp drop in testosterone production by the Leydig cells. During the same period (up to 12 weeks of development), the researchers observed for the first time that ibuprofen also affected the production of antimüllerian hormone by the Sertoli cells. This hormone plays a key role in genital tract masculinisation.

Moreover, expression of the genes needed for the germ cells, the progenitors of spermatozoa, to function is considerably reduced in the presence of ibuprofen.

Finally, production of prostaglandin E2 (known to be produced by the testes, and known to be involved in many biological processes) and the corresponding genes are also inhibited by the presence of ibuprofen at the same developmental age.

All these effects are observed very early in the first trimester, and none of them is found in tests conducted during the second trimester.

For Bernard Jégou, Inserm Research Director and coordinator of this study, and Séverine Mazaud-Guittot, Inserm Research Fellow, the conclusions of this work, which was supported by the French National Agency of Medicine and Health Products Safety (ANSM), are to be taken seriously: “There is a well-defined window of sensitivity during the 1^st trimester of foetal development during which ibuprofen seems to present a risk for the future genital and reproductive system of the child. All the indications point to the need for great prudence regarding the use of this drug during the 1^st trimester of pregnancy. Furthermore, if we now take the body of available data into account, it seems that taking several analgesics during pregnancy represents an even greater danger for the hormonal balance of the male foetus.”

[2] Xenografting is the transplantation of cells or organ fragments from one living organism (e.g. human cells) into the body of another species (here the mouse) in order to understand their development.

[1] Institute of Research in Environmental and Occupational Health; Inserm; French School of Public Health (EHESP), University of Rennes 1.

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