Why scientists use more male than female mice – 08/17/2023 – Science

If you’ve ever taken a drug, you’ve already benefited from animal research. But ten years ago, if you read a scientific report of a study involving mice or rats, it probably only used male animals.

This means that, even today, if you are a woman and you use a drug that has only been tested on male subjects, we don’t know how that treatment will affect you.

Scientists have long assumed that female subjects would respond the same way as males in experiments. Today, that situation is changing. More and more studies are using animals of both sexes in tests. As a consequence, new knowledge is emerging about relevant sex differences.

For example, there is a growing body of evidence showing complex differences in rodent brains related to the size, shape, and connection of nerve cells.

Not surprisingly, research is increasingly showing sex differences in human medical issues. For example, women are twice as likely to be diagnosed with depression as men, and gender differences are also clear in people’s response to antidepressants.

Women have a stronger response than men to selective serotonin reuptake inhibitors (SSRIs), while men have a better response to tricyclic-type antidepressants.

Adverse reactions

Excluding females from experiments for so long had worrying consequences for women’s health.

One example is adverse drug reactions—which are the unintended consequences of taking a drug, such as nausea, headaches, seizures, and heart problems.

Women typically have twice the risk of adverse drug reactions (although men are at greater risk for some types of side effects).

One reason is that women, on average, are smaller than men, but the recommended dosage for many drugs is based on them.

For example, women who take beta-blockers, which are used to treat heart problems, have higher concentrations of the drug in their blood.

This is not just because the same amount of drug in a smaller volume of blood will result in a higher concentration. Due to sex hormones and different enzyme activity, women also metabolize many drugs differently.

Why were females excluded?

In science, we like to reduce variability as much as possible, to be more confident that any change in an animal or human is due to the experiment we’ve done.

Females were largely excluded from guinea pig and human trials because of their menstrual cycle. Fluctuating hormone levels make data difficult to interpret, results more variable, and research more expensive.

While men have the same sex steroid hormones, female hormone levels rise and fall. This can affect brain function, behavior and response to medication.

However, the estrous cycle in rodents (analogous to the menstrual cycle in humans) is much shorter than in women, lasting only four or five days. Research over the past decade has shown that, as a result, the behavior of female rodents is not as variable.

In part, the prioritization of men in clinical trials has also occurred because women of childbearing age can be pregnant and not yet know it. The thalidomide tragedy fueled this mentality.

Thalidomide was developed in the 1950s as a sedative and became a popular treatment for morning sickness — but the drug had not been tested in pregnant animals or humans.

Doctors soon realized that thalidomide was linked to developmental abnormalities in children born to mothers taking the drug. But it was too late for the estimated 10,000 children worldwide born with underdeveloped arms and legs and other birth defects.

Things are getting better?

There is a growing field of research studying the interaction between medications and the menstrual cycle, pregnancy, and hormonal contraception.

For example, some anti-epileptic drugs can reduce the effectiveness of hormonal contraception, while contraception can reduce the effectiveness of some anti-epileptic drugs in controlling seizures.

But given the many years that women have been excluded from studies, there’s still a lot we don’t know.

In the United States, the inclusion of women in clinical trials only became mandatory by law in the 1990s. About 30 years later, surveys show that approximately half of the participants in trials funded by the National Institutes of Health (NIH, the American agency for medical research) is currently women.

There are also evolving initiatives to integrate biological sex (genetically defined) and gender (a person’s self-identity) into the design, analysis, and reporting of clinical trials.

Many scientific journals are banding together in an effort to publish only studies that have considered sex in the process from start to finish.

Meanwhile, it took a long time for female mice to become part of the research.

In 2014, the NIH, one of the largest funders of medical research in the world, announced that all grant requests must include a balance of cells and male and female subjects. This policy has since been adopted by major research funders in other countries, such as Canada and the European Union.

Changes take time. It usually takes 10 to 15 years for a new drug to be developed, although timeframes vary widely. In addition, there are clinical trials, which can take a long time depending on the difficulty of recruiting participants.

We are heading towards an era of personalized medicine, where drugs can be prescribed based on an individual diagnosis, with targeted interventions based on understanding how an individual patient’s genomes (DNA instruction set) affect response to treatment.

But women will miss out on many of the benefits if we don’t understand exactly how the medication they are prescribed affects them.

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Sarah Bailey is Professor of Neuropharmacology at the University of Bath, UK.

This article was originally published on The Conversation and is reprinted here under a Creative Commons license. Click here to read the original english version.