Use of male mice skews drug research against women, study finds

Male animal bias is unjustified and can lead to drugs that work less well for women

The male mind is rational and orderly while the female one is complicated and hormonal. It is a stereotype that has skewed decades of neuroscience research towards using almost exclusively male mice and other laboratory animals, according to a new study.

Scientists have typically justified excluding female animals from experiments even when studying conditions that are more likely to affect women on the basis that fluctuating hormones would render the results uninterpretable. However, according to Rebecca Shansky, a neuroscientist at Northeastern University, in Boston, it is entirely unjustified by scientific evidence, which shows that, if anything, the hormones and behaviour of male rodents are less stable than those of females.

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Shansky is calling for stricter requirements to include animals of both sexes in research, saying the failure to do so has led to the development of drugs that work less well in women.

Rebecca Shansky of Northeastern University in Boston. Photograph: Glanzman, Adam

People like to think theyre being objective and uninfluenced by stereotypes but there are some unconscious biases that have been applied to how we think about using female animals as research subjects that should be looked at by scientists, she said.

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The male bias is seen across all fields of pre-clinical research, but one of the starkest areas is neuroscience, in which male animals outnumber females by nearly six to one. And considering the brain through a male lens has had public health implications, according to Shanskys article, published in the journal Science.

In one recent example, the sleeping drug Ambien, which had been tested in male animals and then men in clinical trials, was later shown to be far more potent in women because it was metabolised more slowly in the female body. Across all drugs, women tended to suffer more adverse side effects and overdoses.

Major depression and post-traumatic stress disorder are twice as prevalent in women, but tests designed to mimic their symptoms in rodents are typically developed and validated in males. Shanskys work shows male and female rodents can behave differently in such experiments, which could provide new insights into these conditions.

Recent research has challenged the reasoning behind using almost exclusively male animals, with one analysis of nearly 300 neuroscience studies revealing that data collected from female mice was not more variable than that from males in fact, for some measures, the reverse was true.

Female rodents have a four- to five-day reproductive cycle, during which oestrogen and progesterone increase roughly fourfold. However, male mice housed together establish a dominance hierarchy in which the circulating testosterone levels in the dominant males are, on average, five times as high as the subordinates.

This evidence has led the US National Institutes of Health and the Canadian Institutes of Health Research to introduce mandates in 2016 to include both sexes in research. However, major UK funders such as the Wellcome Trust and the Medical Research Council have yet to introduce any similar requirements. Now that the US and Canada have made these mandates its time for Europe to step up, said Shansky.

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She is also concerned about the approach taken by some research teams in the US which incorporate both sexes in experiments by working things out in males first and then repeating it in females. It perpetuates the dated, sexist and scientifically inaccurate idea that male brains are a standard from which female brains deviate, she said.

Ironically, Shansky said, the ways in which the male and female brains differ may have remained under-investigated due to a backlash against the idea of there being meaningful differences between the male and female brain.

Theres a concern that research that shows sex differences in the brain will be weaponised by misogynists or used to justify and promote inequality, she said. Its up to scientists to make sure that the message of those studies is not conveyed in a comparative way that adds any value. It doesnt have to be a competition, its not about being better, its just about saying this is how things works.

Theres nothing anti-feminist about saying the neurobiology in the female brain might be different.

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