A new study is hinting that a common over-the-counter painkiller, ibuprofen, may be linked to a male reproductive disorder. While the study uses a pretty small sample of male subjects, it's backed up by a set of consistent experiments from isolated cells, and earlier studies had hinted there might be something strange here.

The good news is that the problems required multiple weeks of constant ibuprofen use, so there's no indication that handling the odd muscle ache or hangover with ibuprofen will cause problems. The bad news is that ibuprofen is one of a large class of related drugs that includes aspirin, and the likelihood that other drugs will have similar effects is high.

NSAIDs

Ibuprofen belongs to a group of drugs called non-steroidal anti-inflammatories, or NSAIDs. This group includes aspirin, and it generally works by blocking the production of hormone-like signaling molecules called prostaglandins, thereby cutting down on pain and inflammation.

Aspirin was known to cause stomach problems but was thought to be otherwise safe. Still, the stomach issues were enough to induce pharmaceutical companies to design more specific NSAIDs like Vioxx and Celebrex. These ultimately revealed an underlying risk of heart complications that turned out to be common among NSAIDs, including aspirin.

Meanwhile, other studies were turning up a set of unrelated issues with the reproductive system. Epidemiological studies have shown that NSAID exposure during pregnancy was associated with reduced testosterone and congenital malformations; another study showed a drop in a testosterone metabolite among men who were taking ibuprofen regularly.

To take these hints beyond correlational studies, a large international team set up a small clinical trial. How small? There are more authors on the paper—19 of them—than the 14 male subjects in the experimental group. The experimental group received ibuprofen twice a day for a total of six weeks and was tested for hormone levels at two and six weeks.

Over that time, there were no significant changes in the testosterone levels found in the blood of the subjects. But there were indications that something was off. Tissue in the male brain senses the level of testosterone and, if it's too low, produces luteinizing hormone, which stimulates the testes to make more. In the men receiving ibuprofen, levels of luteinizing hormone were up, and the ratio of testosterone to luteinizing hormone dropped. The effect was apparent at two weeks and became more pronounced after six weeks of ibuprofen use.

This suggests that the body compensated for reduced levels of testosterone by revving the entire system up.

Compensation

Clinically, this condition is called "compensated hypogonadism"—"hypogonadism" because the body probably isn't producing testosterone at the appropriate rate, and "compensated" because other hormones have kicked in and gotten testosterone levels to increase. And, while testosterone levels are normal during compensated hypogonadism, it's not a good condition to have. The condition has been associated with an increased probability of reproductive, cognitive, and physical problems, as well as general mortality.

On its own, a study this small would be little more than a call to do more detailed studies. But the authors have done a thorough job of following up on their results. They obtained testes tissue samples from organ donors and prostate cancer patients, and they've tested how these respond to ibuprofen; the researchers did the same with testicular cell lines. The samples showed that applying ibuprofen triggered a dose-dependent drop in the production of testosterone within 48 hours. (In culture, there are no cells to produce luteinizing hormone to compensate.) The researchers found that a number of genes involved in steroid synthesis were affected by ibuprofen.

This study also looked at a couple of other hormones produced by the testes and found that they, too, were reduced by ibuprofen. One thing that seems unscathed was the production of sperm, as genes involved in that process appeared unaffected within the timeframe examined by the researchers. (Longer term, lower testosterone would affect this, too.) A few other groups of genes involved in different testicular processes were also unaffected. This suggests that any effect of NSAIDs is specific to certain processes, rather than generally suppressing activity in the cells of the testes.

Again, it's important to emphasize this was a really small study that required two weeks of constant ibuprofen use before there was any indication that something was out of the ordinary. The consistency of the results, however, as well as the earlier epidemiological results, suggest that there might really be an issue here. And the problem is not likely to be ibuprofen-specific, as most NSAIDs work through similar mechanisms.

PNAS, 2017. DOI: 10.1073/pnas.1715035115 (About DOIs).