In one of her first research studies, Deborah Clegg, professor of biomedical science at Cedars-Sinai Hospital in Los Angeles, asked what she thought was a stupid question.
“We asked the question, is a male fat cell the same as a female fat cell?” she says. She wasn’t expecting much. But when the results came back, she found that the male and the female cell looked completely different.
And differences don’t stop at the cellular level. Men and women produce estrogen and testosterone in different amounts, they metabolize drugs differently, they have different healthy body fat ranges, just to name a few. But when it comes to biological research, scientists too often treat male and female cells, organs, and bodies the same. According to Clegg, researchers often design experiments with an assumption that “one size fits all.”
“Even something as simple as looking at a cell — currently, I would say 98 percent of the researchers do not pay any attention to where that cell came from and whether that’s a male cell or a female cell,” noted Clegg. Most animal studies never use female animals. And even when biologically female subjects are used in studies, the researchers don’t pay attention to where they are in their menstrual cycles, or whether they’re pre or postmenopausal, which causes differences in hormone levels that could contribute to study results.
According to Clegg, that’s just bad study design. Because most researchers aren’t looking at these differences, they don’t have a good understanding of the ways that gender and hormones affect the results of tests and experiments. But bad study design isn’t the only result of leaving female subjects out of studies. It can also lead to bad therapies and bad clinical outcomes.
But bad study design isn’t the only result of leaving female subjects out of studies.
Pain, for example, is processed and perceived differently in the male and female body. Research in mice has shown that male and female rodents process pain through different cells in the spinal cord, but the majority of pain research only uses male subjects, which means therapies aren’t targeted to the different way that the female body experiences pain.
Data from drug studies is often analyzed without looking at sex differences, which means that the researchers don’t know if the drug will be processed differently in women. The sleep aid Ambien, for example, was found to linger longer in women’s bodies than men’s — but the difference wasn’t studied and the dosage wasn’t adjusted for women until years after the drug had hit the market and complaints from female patients suffering ill-effects caught the attention of the FDA.
“When I’m given a drug I’d like to know, number one, has this been tested in women? And number two, has it been tested in pre and postmenopausal women?” said Clegg. “I want it to be nuanced to me… because we just do one size fits all [testing], we haven’t been adequately dosing or taking care of people.”
Clegg, along with a group of other scientists, published an essay in the scientific journal Cell Metabolism in August 2016 calling attention to this issue. The essay also aimed to draw attention to new National Institute of Health (NIH) requirements for the inclusion of female subjects in studies.
In the late 1980s, the NIH required that any research that they funded include women participants in clinical trials. However, that requirement did not apply to research on diseases and drugs in non-human models.
But this year, new rules seeking to correct these imbalances were implemented to require that pre-clinical research use female cells and animals, as well. Scientists will also have to include sex as a variable for analysis of their results. That means that any researcher who submitted a funding request to the NIH after January 2016 will be penalized for not providing a clear outline of their plans to include sex differences in their study. Science is slow, and it will take some time for the results of these new rules to show up in the scientific literature and in patient care, but it’s a step in the right direction.
Clegg says that there’s a simple reason that most scientists haven’t been taking sex differences into account — it’s hard. It means paying attention to hormone levels, performing additional statistical analyses, and teasing out the differences between male and female biology in ways that they haven’t had to before. But now that the NIH requirements are stricter, scientists who want funding from the NIH are going to have to learn how.
“People don’t know how to do it,” she said. “Just including females, that’s fine, but that’s not going to tell you across a female cycle. Maybe there’s an influence when estrogen is high, or an influence of the drug when estrogens are low. How you begin to peel away what the contribution of the hormones are is really not super easy. It’s going to be a learning curve.”