More! Female! Mice!

Photo-Illustration: The Cut. Photo: JacobStudio/Getty Images/iStockphoto

Today in gender biases you didn’t know existed: Many drug trials on mice and rats (i.e., most drug trials) are conducted only on males of the species. Historically, researchers have claimed that the short reproductive cycles of female rodents (which repeat every four to five days) could throw off the reliability of their findings. Yes, even in the animal kingdom, females are considered too hormonal to take seriously.

By skipping over females, researchers may be missing important information about how hormonal shifts could interact with our medicines, said Dr. Rebecca Shansky, a neuroscientist and associate professor at Northeastern University. “The excuse that I would hear over and over again is that the estrous cycle” — the mouse version of a menstrual cycle — “would just make the data too complicated,” she explained. Dr. Shansky has been studying the implications of excluding female mice from trials for years, and her 2019 article in the journal Science helped ignite conversation around it.

“Some researchers would say that because one day the animals have high levels of estrogen and the next day they have low levels of estrogen, you couldn’t possibly understand anything about the brain or physiology or the effects of the drug in a drug trial,” she added. But of course, males of any species, be they mice or men, have hormones too. “Male mice and rats [also] have lots of fluctuating hormones, but there’s such a myopic focus on female hormones,” said Dr. Shansky. “It comes from longstanding gender stereotypes that essentially, male is the norm and female is deviation from that.”

Not using female mice has real-world implications, one famous example being with the sleep drug Ambien. It was tested on male animals and then on human men in clinical trials, but once it was widely prescribed, it proved to be much more potent in women because the female body metabolized it slower. “Normally, you would take Ambien so you can go to sleep, and you’d hope that by the time you wake up in the morning it would be out of your system,” explained Dr. Shansky. But that wasn’t happening in women — they would take the Ambien, go to bed, wake up, and then still feel the effects well into the morning. In fact, across many kinds of medications, women are much more likely to suffer side effects because of testing biases. (Today, the FDA recommends that women be prescribed lower doses of Ambien than men.)

Things are finally changing on the research front, but slowly. In 2016, mandates were brought by the U.S. National Institute of Health and the Canadian Institutes of Health Research to include both sexes “equitably” in animal trials. While many researchers have since updated their methods to meet those requirements, there are still a lot of gray areas, said Dr. Shansky. For instance, even if a research team applied for NIH funding on the basis that both sexes will be included in a study, their funding wouldn’t necessarily be pulled if they subsequently decided to only use male rodents instead. “You don’t have to do exactly what you say you’re going to do in the grant proposal,” explained Dr. Shansky. Another loophole: A lab might be basing their research on previous studies done only on males. “So they say, ‘We should continue it only in males because that’s the foundation of this research,’ and then the work in females is just a side project.”

Still, Dr. Shansky said this is not a call for women to refuse treatment or distrust medical advice. Instead, she said that women should feel emboldened to speak up and let their physicians know when drugs aren’t working for them, or create problematic side effects. “Often, women aren’t believed when they go to the doctor and explain that they have abnormal symptoms. If you feel that a drug is not doing what it’s supposed to do, speak to your doctor and communicate your experience,” she said.

More! Female! Mice!