Mind the gap

Several studies show that female subjects are underrepresented in medical research. How do you explain this phenomenon?

Katharina Crepaz: In medicine there is the “normal patient”: young, male, white, without disabilities, six feet tall and weighing 80 kilograms. Anyone who deviates from this supposed norm, such as women and minorities, is underrepresented. Women, in particular, are considered “difficult” study subjects for two reasons: first because of their menstrual cycle, which involves hormonal fluctuations that must be taken into account in studies, and second because of the possibility of pregnancy. Drug testing, in fact, could affect a fetus.

Giacomo Strapazzon: The female subject is more complex to study because of hormonal fluctuations related to the menstrual cycle. When you want to conduct the study on a physiologically homogeneous sample, it is much easier to do it with male subjects. To standardize the physiological condition of the participants would require inhibiting the menstrual cycle, but then potentially interesting information would be lost.

But is the complexity of female physiology really a good reason not to include women in research?

Katharina Crepaz: This is an excuse behind which the real – economic – reasons are hidden. Of course, conducting studies on women is more time-consuming and expensive if factors such as cycle fluctuations have to be taken into account, but this is not a valid reason for excluding female subjects from research. Health policy must ensure adequate care for all population groups, regardless of economic factors, and therefore appropriate guidelines must be implemented for medical research as well.

Giacomo Strapazzon: I confirm the need to have to economize on resources. However, the inclusion of one or both sexes also depends on the research question being asked. In some cases it may make sense to study only one. Sometimes, for example when one does not expect to find differences between the two sexes, one may choose to conduct a preliminary study on the easiest subjects to study, i.e., the male subjects, and then, if one has interesting results, deepen the research by including the female subjects as well. In other cases, however, including female subjects in the study is imperative, such as when you are testing treatments intended for women.

Ms. Crepaz, in your studies, you deal with the social determinants of health. We said that the hormonal component makes the study of female physiology complex. But are there other factors that negatively affect women’s opportunities to be included in clinical trials and which could impair access to good healthcare?

Katharina Crepaz: Hormones, as well as age and hereditary factors, are among the biological determinants of a person’s health and social factors can play an equally important role in the ability to access appropriate care. These include, for example, the biases of health care providers. Studies show that women’s pain is classified as less severe than men’s and that, often, their physical complaints are misdiagnosed as psychological.

Why is it important to include women in clinical trials, as well as to analyze the results by sex? And what are the risks of not including women in health-related research?

Giacomo Strapazzon: Excluding women a priori forces us to assume that results obtained from male-only research are also good for female subjects. This, however, is not always true, partly because of those hormonal differences we have already mentioned. In women, for example, cardiovascular risk increases significantly after menopause. Therefore, to know the role played by biological gender on the occurrence of certain diseases and to develop guidelines to prevent them and treatments to counteract them, we need to study subjects of both sexes. More generally, we can say that to evaluate the effectiveness of a treatment, it should be tested in the population for which it is intended.

Katharina Crepaz: I would add that women represent half of the world’s population. To exclude such a large segment of the population from studies is not only irresponsible and it would mean not having a scientifically valid basis for treatments. We know that drugs often work differently in women and that dosing must be adapted to the different physiology of the two sexes. Conducting studies only on the “normal patient,” that is, the male patient, could therefore have fatal consequences for women’s health. Moreover, women often have different symptoms. Thanks to awareness campaigns about heart attack, most people know that pain in the left side of the chest radiating to the arm is a warning sign. However, women experience other symptoms, such as severe pain between the shoulder blades. These signs are not associated with a heart attack or are recognized too late.

In her book “Invisibles. How our world ignores women in every field. Data in hand.” Caroline Criado Perez claims that some scientists say recruiting female participants is difficult. How do you respond to those who make this claim?

Katharina Crepaz: There are different population groups that are relatively difficult to reach: when it comes to participating in studies, it is women and people with migrant backgrounds, while when it comes to participating in prevention measures, it is men. However, this fact should not be used as a justification for excluding certain groups from research and medical care. What should be done is to create specific offers for each of them.

Giacomo Strapazzon: I would not say that women are always more difficult subjects to reach, but it may be true when certain cultural barriers come into play, as in the case of women of the Muslim faith. In that case, conducting certain tests can be complicated as they may force participants to go far beyond their comfort zone.

Public institutions in various countries, such as the National Institutes of Health in the United States, have issued regulations mandating the inclusion of female subjects in clinical trials. Similar provisions are provided by associations such as the German Society of Epidemiology, which obliges its researchers to justify the inclusion of subjects of only one sex in studies that might affect them both. What is the situation in Italy?

Giacomo Strapazzon: Italy is also going in the same direction as other countries. The same ethics committees that have to approve research projects promote the inclusion of both sexes.

Katharina Crepaz: In addition, in 2022, the European Union introduced regulations that make a representative distribution of gender and age groups mandatory in clinical trials. In Italy, in particular, in 2023, the Istituto Superiore di Sanità issued guidelines for fair medical research from the perspective of both biological gender, that is, the sex of the individual, and social gender. An important step in the right direction.

Addressing a more specific issue, a recent scientific publication reports, although women have been climbing mountains since the advent of modern mountaineering, most studies on human physiology at high altitudes have been conducted on male subjects. Why is that?

Katharina Crepaz: I think this always has to do with the complexity of studies that take into account the female cycle. Also, the topic of the menstrual cycle and menstruation is still taboo; even today, it makes the news that female athletes talk about how menstruation affects their performance and which, at least, is happening more and more often. Also, fortunately, in sports science it is becoming more and more common to consciously work with the menstrual cycle, through trainings prepared with it in mind. I hope these approaches will bring the taboo of the female cycle into the social spotlight.

Giacomo Strapazzon: There is also to say that, for a long time, mountaineering was mostly practiced by men. In a study we conducted simulating avalanche burials, the majority of the sample were male subjects. That's because we had recruited participants from among ski mountaineers, members of mountain rescue, slope rescue and mountain guides, all activities still practiced more often by men than by women. The scenario, however, is changing.

In this regard, Eurac Research’s Institute for Emergency Medicine has initiated a project that aims to study female physiology at high altitudes. Mr. Strapazzon, can you tell us a little bit about that?

Giacomo Strapazzon: Seventy years after the conquest of K2, the Italian Alpine Club has promoted an initiative in which eight female mountaineers are involved in climbing this peak. Here at the Institute for Emergency Medicine we will study the physiology of the female mountaineers, before and after the expedition. Last March, the eight female climbers conducted preliminary tests at the terraXcube, Eurac Research’s extreme environment simulator. During these tests, the participants’ cardiovascular, respiratory and brain function were evaluated. The same tests will also be undertaken in August, once the mountaineers are back from the expedition. The goal is to accumulate data on the physiological processes underlying women’s acclimatization to extreme altitudes.

What impact might this study have on the lives of those who do not live at high altitudes and do not climb mountains?

Giacomo Strapazzon: At high altitude, the amount of oxygen able to reach body tissues decreases. This is a condition known as “hypoxia” and can be shared by those who mountaineer at high altitudes and those who suffer from particular pathological conditions. Investigating the body’s response to oxygen deficiency can, therefore, come in handy in the care of patients admitted to intensive and sub-intensive care units.