According to data recently released by the Food and Drug Administration, women report more adverse drug reactions than do men. While this finding could be due to greater reporting of side effects by women, it also may have something to do with the longstanding bias against using female animals in preclinical medical research.
A 2010 study found a pronounced bias in the use of male-over-female animals in eight out of 10 biological fields. In neuroscience, for example, studies including only male animals outnumbered those including only female animals 5.5 to 1. Even when examining disorders, like depression and anxiety, that are more frequently diagnosed in women than in men, researchers often use only male animals. Surprisingly, this sex bias in preclinical studies has worsened over the last 50 years—despite the fact that women now make up more than half of the participants in clinical trials.
Last month, Janine Clayton and Francis Collins wrote in an editorial in Nature that the National Institutes of Health (NIH) plan to address the issue of sex bias in research animals. Starting in October 2014, the NIH will require investigators "to report their plans for the balance of male and female cells and animals in preclinical studies in all future applications, unless sex-specific inclusion is unwarranted, based on rigorously defined exceptions." They also plan to release training materials to NIH staff and grantees about how to design and evaluate experiments that may show sex differences.
Why don't investigators include both male and female animals in all studies already? There are several answers to that question. Some scientists fear that hormone fluctuations in female animals associated with their oestrus cycle can make data more variable and difficult to interpret—although this claim was debunked in a recent meta-analysis. Scientists also like being able to compare new data with previously collected data, which again, have mostly been collected from male animals.
There are also logistical concerns. In some types of experiments, the inclusion of female animals will require using a higher number of animals overall because animals of each sex will need to be analyzed separately. It is unclear if the cost of these additional animals will be addressed by the NIH. Interestingly, while the meta-analysis did not find higher variability in female animals than in male animals, it did find increased variability in mice housed in groups compared to mice housed alone. Because male mice housed together fight but females do not, most labs house males individually and females in groups. Moving these female mice to single cages would substantially increase the animal care costs for many labs. Ideally, this won't be an issue for the majority of studies where experimenters can just decrease the number of males included when they increase the number of females, but it could add a hefty cost to some labs.
According to the editorial, the NIH will also push researchers to include both male and female cell lines in their studies. This may be the most difficult change for researchers. Most cell lines are completely unique because they are cancer-derived and originate from a single individual. For example, there is no male version of the famous female HeLa cells, the first immortal cell line in history. Since many labs use only one or two cell lines for their studies, it will be interesting to see how this recommendation is implemented.
Increasing the representation of female animals and cells in biological studies just makes sense both intuitively and scientifically, both because of what we know and what we don't. We know, for example, that male and female animals differ in how they metabolize some drugs. There are likely many additional sex differences that will be discovered by routinely including female animals in biological studies. Hopefully, increasing sex parity in research animals also will increase the number of preclinical findings that are replicable in clinical trials.