Using mild painkillers in pregnancy appears to raise the risk of cryptorchidism (undescended testicles) in baby boys, new EU-funded research suggests. The findings offer an explanation of why cryptorchidism, which is the biggest risk factor for poor semen quality and testicular cancer in later life, is becoming more common.

The study is published online in the journal Human Reproduction. EU support for the work came from the DEER ('Developmental effects of environment on reproductive health') and CONTAMED ('Contaminant mixtures and human reproductive health - novel strategies for health impact and risk assessment of endocrine disrupters') projects, which each received EUR 3.5 million under the Environment Theme of the Seventh Framework Programme (FP7).

Rates of cryptorchidism are on the rise; in Denmark, just 1.8% of newborn boys were affected in 1959-1961, but by 1997-2001 that figure had risen to 8.5%. Studies in rats have suggested that cryptorchidism may be caused by a lack of male sex hormones during a particular period of pregnancy. So-called endocrine disruptors, molecules that interfere with or block the action of hormones, are thought to be behind the problem. However, tracking down these endocrine disruptors has proven difficult. Some studies have pointed to certain common painkillers, namely aspirin, paracetamol and ibruprofen, which may reduce testosterone production and could act as endocrine disruptors.

In this study, the scientists set out to study the influence of mild analgesics on male reproductive disorders in both humans and rats.

For the human part of the study, the scientists quizzed over 2,000 pregnant women in Denmark and Finland on their use of medication during pregnancy. The baby boys were examined at birth by paediatricians who looked for signs of cryptorchidism and graded any cases found according to their severity.

The results were clear; women who had used more than one kind of painkiller at the same time were seven times more likely to give birth to a son with some form of cryptorchidism than a woman who had not taken painkillers.

The second trimester appears to be a particularly sensitive time; taking any painkiller during this time more than doubled the risk of cryptorchidism, and taking more than one kind of painkiller during the second trimester increased the risk 16-fold.

Studies in rats confirmed that analgesics do indeed disrupt the production of androgens, resulting in a lack of testosterone during the period of pregnancy when the male sex organs are formed. According to the researchers, mild analgesics effectively halved testosterone levels in the testes of unborn rats.

The findings are important because around half of pregnant women in Europe and the US report taking mild painkillers, usually paracetamol.

"If exposure to endocrine disruptors is the mechanism behind the increasing reproductive problems among young men in the western world, this research suggests that particular attention should be paid to the use of mild analgesics during pregnancy, as this could be a major reason for the problems," commented Dr Henrik Leffers of the Rigshospitalet in Copenhagen, Denmark, who led the research.

"A single paracetamol tablet (500 mg) contains more endocrine disruptor potency than the combined exposure to the ten most prevalent of the currently known environmental endocrine disruptors during the whole pregnancy," Dr Leffers added.

"In fact, a single tablet will, for most women, be at least a doubling of the exposure to the known endocrine disruptors during the pregnancy and that dose comes on a single day, not spread out over nine months as with the environmental endocrine disruptors. Thus, for women using mild analgesics during the pregnancy, the mild analgesics will be by far the largest exposure to endocrine disruptors."

The team note that more research is needed into this issue; for their part, they will continue to monitor the boys born during the study, who are now entering puberty.

On the issue of whether pregnant women should take painkillers or not, Dr Leffers says: "As biologists this is not something we can advise women about. So we recommend that pregnant women seek advice from their physician before using mild analgesics and in general follow the advice to use as little medicine during pregnancy as possible."

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