Shedding light on biomedical research and clinical trials : how researcher bias endangers women’s health

Women’s health is a varied and complex subject, with a long and often perilous history. It is closely linked to the continued development of women’s rights and the education surrounding them. Sexual and reproductive health including topics such as from menstruation, pregnancy, menopause and hormones, to domestic violence and mental health, to sex education and adverse drug reactions, the history of women as patients has been marked by discrimination problems.The fight for an equitable approach to healthcare and the inclusion of women in drug research and validation processes goes hand in hand with feminism and the fight for women’s rights.

Until the 1990s, most health research was conducted primarily by men, on men

A hypothesis that could explain this surprising and discriminating choice would be the following : if you study men, you will obtain the basics of biology, and this will probably apply to women [1]. Historically, it was assumed that there were no fundamental differences between men’s and women’s bodies, aside from height, weight, and reproductive organs. On the contrary, women were seen as “little men”. The Greek philosopher Aristotle described women’s bodies as those of “mutilated males.” His ideas influenced Western medical thought.

Another hypothesis to justify the fact that women were voluntarily excluded from most clinical trials would be that the scientists feared that the inclusion of women in the trials would harm their reproductive health but also and probably above all because they considered that hormonal fluctuations, which are part of the female menstrual cycle, would cause greater variability of results and were too difficult to manage and interpret in experiments. It was therefore a question of choosing the easy way to the detriment of the rigor recommended by the scientific method.

Additionally, the assumption that using only one gender would reduce variation in trial results, which has been shown to be false later on [2], meant that the research did not incorporate female animals either (as shown in the graph below).

Researchers have therefore for centuries assumed that the results of exclusively male studies could be extrapolated to women. This bias has prevented more rapid progress in the detection and treatment of many diseases. It is also partly responsible for the poor translation and reproducibility of preclinical research into the clinic and has a particularly significant impact on women’s health.

For example, a study published in June 2020 in the journal Biology of Sex Differences shows that for the same dosage of the 86 identified products approved in the United States (antidepressants, cardiovascular and anticonvulsant drugs, analgesics, etc.) 90% of women experience more serious side effects — nausea, migraine, hallucinations, cardiac abnormalities, etc. The single dosage, based on that of a man, therefore does not correspond to the majority of women [4].

What do we know about biological differences between the sexes ?

“Sex” is a biological trait, generally defined in mammals by the complement of sex chromosomes (X and Y), with “XX” defining a female individual and “XY” male. Sex represents one of the most evolutionarily conserved biological differences. Yet it is one of the most underappreciated differences in biomedical research. Although many factors can influence an outcome, sex is a fundamental variable and is responsible for differences in many anatomical, physiological, and biological functions.

Over the past decades, the scientific literature has reported an impressive number of studies showing differences between the sexes in terms of pathological risks, treatment effectiveness and disease outcomes. Below are some notable examples of differences observed between men and women.

• In neurology, women are at higher risk of developing Alzheimer’s disease than men (2/3 of patients in Europe are women) and they are twice as likely to suffer from major depressive disorder (MDD) than men, with probably more severe or atypical symptoms, and a comorbid anxiety disorder [5]. Men have almost 7 times more gray matter and women ten times more white matter [6]. These neuroanatomical variations clearly highlight potential differences between women and men in any brain-related disorder, such as schizophrenia or anxiety, and could also explain why pain perception and reactivity are sex dependent [7].
• Cardiovascular diseases usually develop 7 to 10 years later in women and do not present the same clinical symptoms as those described in men [8]. Initially described as male disorders, they are today, surprisingly, the leading cause of death among women. There are many publications on cardiovascular differences between the sexes, some even showing that the structure of the heart of women is different from that of men : two of the four main valves of the heart — the tricuspid and mitral valves — are different, as are the electrical tracks, the anatomy of arteries and veins, and even cellular composition [9].

The list of sex differences is still long, greatly highlighting the need to better explore and understand them to provide appropriate care. These differences are explained not only by genetics and physiology but also by behavior (lifestyle, smoking, physical activity, etc.).

Women and laboratory animals, same cause (or almost)?

To explain the incredibly high failure rate in clinical translation of research findings (ranging from 80 to 99%), scientists focus more on subjective biases like flawed statistical analyzes or experimental designs, instead of rectifying the long-standing problem of the predominance of one sex in their studies, what is more, in animal models, therefore far removed from human genetics and physiology.

Indeed, the way scientists approach the experimental design of animal studies is primarily driven by the replacement, reduction, and refinement (3R) framework, dating back to 1960 [10]. The reduction element, which aims to use as few animals as possible, has led to an environment in which researchers explore a very narrow testing space, neglect many variables, and then extrapolate the results to a broader scenario. It is not uncommon to study a single genetic background, a single age and/or a single sex and interpret the result as generalizable. If we take a step back, knowing that research discoveries for a given sex cannot necessarily translate to the other, how can we imagine that scientific discoveries on animals, with even more obvious physiological differences than between men and women, will be relevant to humans ? From this point of view, we can really wonder what makes researchers so attached to animal experimentation. It makes sense that moving away from gender bias would only be truly beneficial if biomedical research also moves away from animal-method bias [11].

In the era of “personalized medicine”, focusing on subpopulations of patients would improve drug development and medical care.

Biomedical and clinical research is experiencing considerable progress thanks to the development of new cutting-edge technologies such as organs-on-a-chip and artificial intelligence, the latter of which can be combined and based on patient data, and patient. Precision medicine is increasingly recognized as a new therapeutic approach of reference in the world of researchers and clinicians. Given these major technological advances, it seems insane that sex, the most obvious biological variable in humans, has been largely neglected in biomedical research.

Between 2014 and 2016, funding agencies, notablyNational Institutes of Health (NIH) of the United States, the European Commission (EC) and the Canadian Institutes of Health Research (CIHR), have taken steps to integrate gender throughout the research process [12].

It is also important to note that the number of research studies including sex has increased significantly in most biological disciplines, and that researchers and clinicians are increasingly recognizing the need to take this variable into account. This article, published in 2022 in the journalNature Reviews Molecular Cell Biology, entitled “Let’s talk about (biological) sex”, is addressed to researchers and begins with this : “You have spent years studying your beloved protein. You created mouse models, found a phenotype, and treated it with a drug. You even used human cells to confirm the observed mechanism. But a prestigious journal rejected your manuscript because you didn’t include women. Here’s why you shouldn’t blame them » [13].

Even though male bias has decreased, studies involving subjects of both sexes do not include sex-based analysis in the experimental method, demonstrating that there is still a need for awareness, education and advocacy to consider sex as a biological variable.