If you have ever had to take a medication in your life, you can consider yourself one of the beneficiaries of scientific research conducted on laboratory animals (usually mice or rats). But you probably don’t know that just a decade ago, this type of work relied almost entirely on the use of male animals.
However, in recent years there is increasing evidence, collected in studies of animals of both sexes, indicating that there are complex differences in the brains of rodents depending on whether we consider male or female individuals. These differences are related not only to size or shape, but also to the way nerve cells are connected to each other.
This is potentially problematic because scientists have long assumed that women responded the same as men during the clinical trial phases that are essential to developing and obtaining marketing approval for new drugs.
However, this may not always be the case and therefore we may not know all the effects on women of drugs developed and tested exclusively on male animals.
Scientists interested in specific human health problems are increasingly identifying gender differences. This means that women are twice as likely as men to be diagnosed with depression during their lifetime. However, they also react differently to antidepressants than men: Selective serotonin reuptake inhibitors (SSRIs) trigger a stronger reaction in women, while men respond better to tricyclic antidepressants (“classic” antidepressants).
Never accept
The long exclusion of female animals from medical research has had worrying consequences for women’s health. A good example of such consequences are adverse drug reactions, i.e. unwanted effects that occur after taking an active ingredient (nausea, headaches, heart problems, etc.).
The risk of experiencing such side effects is estimated to be twice as high in women as in men (although they themselves have an increased risk of certain specific side effects). One reason for this is that although women are on average smaller than men, the recommended dosage of many medications is based on male characteristics.
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Women who take beta-blockers (drugs used to treat heart problems) have higher levels of these molecules in their blood than men. One might think that this is because taking the same amount of drug in a smaller volume of blood mechanically results in an increase in concentration, but that is not the only reason. In fact, women metabolize many medications differently than men, due to different levels of sex hormones and enzyme activities.
Why were women excluded from the trials?
During their experiments (whether on animals or humans), scientists want to reduce variability as much as possible. This allows them to assume with sufficient certainty that changes they observe in the test subjects are actually the result of their interventions.
For this reason, women have largely been excluded from clinical trials based on their menstrual cycle. While sex steroid hormone levels do not fluctuate in men, they rise and fall in women. These fluctuations can affect brain function, behavior, and response to medications. They increase the variability of results and complicate the interpretation of experimental data, which increases research costs.
However, things are a little different in rodents: their estrous cycle (the period between ovulations) is shorter than that of women and only lasts four to five days. Research over the last decade has shown that this was the case during this period [le comportement des rats femelles n’est pas plus variable]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962440/ accordingly.
Another reason for establishing clinical trials with a focus on men: the fact that some of the women of childbearing age who could have participated could have been pregnant without their knowledge, which could have had consequences for their fetus. The thalidomide tragedy increased this fear. Thalidomide was developed in the 1950s as a sedative and later became a popular treatment for morning sickness in some pregnant women – but the drug has not been tested on pregnant females (let alone animals).
Doctors quickly discovered that children born to mothers who took thalidomide had serious developmental disabilities. But it was already too late: it is estimated that around 10,000 babies worldwide were born with severely stunted arms and legs and other birth defects.
Is it getting better?
The area of research analyzing the interactions between medications and the menstrual cycle, changes during pregnancy and the use of hormonal contraceptives is in full development.
We now know that not only can certain antiepileptic drugs reduce the effectiveness of hormonal contraceptives, but also that hormonal contraceptives themselves can reduce the effectiveness of certain antiepileptic drugs. Unfortunately, there are still many unknowns as women have been excluded from clinical trials for many years.
In the United States, the law required women to be included in clinical trials in the 1990s. Thirty years later, the impact of this decision is felt: almost half of the participants in clinical trials conducted by the National Institutes of Health (NIH – the American medical research agency) are now women.
Today, many scientific journals take the approach of only publishing clinical research studies whose design, data analysis and dissemination of results take gender into account. Guidelines are also evolving to include not only biological sex (defined genetically) but also gender (personal identity).
The integration of female rodents into the research landscape is progressing more slowly. In 2014, the NIH, one of the largest funders of medical research on the planet, announced that all scientists applying for grants must consider gender parity in their projects. and female (or cells from males and females). Major donors from other countries – such as Canada or the European Commission – have now adopted the same position.
Change takes time. This is particularly explained by the duration of research and development: Although this can vary considerably, it is generally assumed that the development of a new drug takes 10 to 15 years. Next come clinical trials, which can also take a long time depending on the difficulty of recruiting the necessary participants.
We are heading towards an era of personalized medicine, in which medicines can be prescribed as part of targeted interventions, following a diagnosis made precisely for each individual according to their genome (the set of genetic instructions that they carry) and the treatment so as closely as possible, as these personal characteristics can influence the response. If we don’t understand exactly how the medications prescribed to women actually work, they risk missing out on the many benefits of these new approaches…