Common drugs linked to sex drive

Fetuses and newborns exposed to some common anti-inflammatory drugs may be at risk for lasting changes in brain structure that can affect adult sexual behavior, according to a new study involving rats.

While researchers emphasize that the results might not apply in humans, some scientists say they raise the possibility that during a vulnerable window in pregnancy and infancy, these drugs could alter developing human brains, too.

Known as COX-2 inhibitors, this class of anti-inflammatories includes aspirin, acetaminophen, ibuprofen and indomethacin.

Most of these drugs bear warnings about use during pregnancy, noting possible fetal side effects that include bleeding and liver problems. But many of the medicines are used by pregnant women, and some researchers say the effects disclosed by the study, which were previously unknown, are troubling.

“Until we know more, we should be cautious about giving COX-2 inhibitors to pregnant women,” said one of the authors, Margaret McCarthy, a neuroscientist at the University of Maryland School of Medicine.

The study, which appears in the latest issue of Nature Neuroscience, looked at two COX-2 inhibitors, aspirin and indomethacin, which is also known as Indocin. In male rats exposed in utero to the drugs, adult sexual behavior decreased markedly.

This was particularly true for indomethacin, a powerful prescription anti-inflammatory. As adults, the group treated with the drug showed no sexual interest in females.

McCarthy and her co-author, University of Maryland School of Medicine neuroscientist Stuart Amateau, also fed aspirin to pregnant rats during the final week of gestation and the first week of breast-feeding.

As adults, male offspring of the aspirin-exposed females initially showed little sexual interest in females. But the effect of aspirin was much weaker than indomethacin — over several sessions, the males’ indifference dissipated, and the aspirin group eventually showed the same sexual behavior as the non-aspirin group.

The researchers also found that the drugs permanently changed the structure of a small brain region known as the preoptic area, which seems to play a key role in sexual behavior.

“What’s amazing about what we observed is it’s a permanent change in the synaptic structure,” McCarthy said.

Other scientists praised the research. “It’s a very fine study. It comes at the question from several different angles,” said Arthur Arnold, a University of California, Los Angeles neurobiologist.

But he and others expressed caution about human implications. The study “doesn’t give us any specific information about the effects on human development,” said Arnold, who has studied sex differences in the brain for three decades.

He focused more on the paper’s scientific significance than on its human implications. Researchers have known for decades that during pregnancy testosterone and other hormones act on a baby’s brain to make it more male or female. But they didn’t understand how this happens.

The results provide important new details about this process. McCarthy and Amateau found that during pregnancy, testosterone and other hormones increase the amount of an enzyme called cyclooxygenase-2 (COX-2). COX-2 in turn increases a hormone called prostaglandin, which boosts the number of excitatory nerve connections in the preoptic area of the brain.

“This is the first time in any species that this pathway has been discovered. It opens up a whole new line of investigation,” Arnold said. “Indications are, pretty much the same thing is happening in human brains.”

COX-2 and prostaglandin also play a key role in causing inflammation and pain, which is why COX-2 inhibitors work well for treating ailments such as arthritis and fever.

In general, these drugs are seen as relatively safe. But the paper raises the possibility that in humans COX-2 inhibitors might alter the development of the preoptic area during pregnancy or early infancy.

While the study examined only two COX-2 inhibitors, McCarthy noted that all such drugs affect the same pathway. “They all act on the COX enzymes,” she said.

If COX-2 inhibitors alter the developing human brain, McCarthy and others say, the drugs are more likely to decrease male sexual interest than change sexual orientation.

“People might jump to the conclusion, `This might make my child gay,’ ” said Melissa Hines, a neuroscientist at City University in London. “That’s an overreaction.”

McCarthy and others agreed that indomethacin was more likely to cause problems than aspirin.

“If anyone is taking indomethacin during pregnancy, I would raise more serious questions about that,” Arnold said.

The drug is used regularly during pregnancy. Like many COX-2 inhibitors, it can help forestall premature labor, according to Dr. Frank Witter, a Johns Hopkins University obstetrician and pharmacologist. He said indomethacin is “fairly widely used” for this purpose.

Some researchers expressed doubt that the rat experiments have much relevance for the study of human sexual development. “Humans are much less a product of their hormones than rats. Socialization is also extremely important,” Hines said.

Even if COX-2 inhibitors cause serious changes in the developing human brain, researchers may have a hard time proving the link. The key problem is the decades-long gap between cause and effect — maternal use of anti-inflammatories and the subsequent sexual behavior of adult offspring.

Hines is looking for early evidence of this connection. After hearing McCarthy speak last year, she decided to examine data from an ongoing study of almost 15,000 British women and their children.

Hines will look into whether aspirin use during pregnancy correlates with subsequent, sex-specific behavior of male children.