Women have been underrepresented in clinical trials for many decades, but their life expectancy exceeds that of men. How come? Researchers at the University of Cologne show that there are knowledge gaps for all genders. In the future, gender-sensitive medicine can contribute to the precise treatment of every person.

By Eva Schissler

It is one of the classic examples to describe gender-sensitive medicine: When women have a heart attack, they often do not show the ›typical‹ symptoms, but may experience nausea and pain in the abdominal area. »This is what happened to my grandmother,« said Professor Dr Alexander Quaas. The grandmother’s family doctor sent her home with her abdominal pain – a suspected gastrointestinal infection. Two days later, she died as a result of an undetected heart attack. »I was in the early semesters of my medical degree at the time and it took me years to understand what had happened,« said Quaas. Today, he is deputy director of the Department of Pathology at University Hospital Cologne and head of the Department of Gastrointestinal Diseases. He is still interested in gender differences in illness and health.

Together with Professor Dr Elke Kalbe, head of the Department of Medical Psychology – Neuropsychology & Gender Studies, he has founded a working group focussing on the topic of ›Sex, Gender and Diversity in Medical Research‹. On the one hand, the working group responds to the great interest of students and early-career researchers in gender issues. On the other hand, it lobbies for a better consideration of gender differences in research. The government of North Rhine-Westphalia also regards this as an important field: In April 2023, it founded the lighthouse project ›Gendermedizin.NRW‹, to which Quaas and Kalbe from Cologne also contribute as part of the steering committee.

Elke Kalbe is also Vice-Dean for Academic Development and Equal Opportunities at the Faculty of Medicine. But for her, gender issues in medical research are not a question of politics, but of science. »Gender equality in academia is an important and legitimate concern, but our work focuses on precision medicine,« said the neuroscientist. She has observed that already the word ›gender‹ tends to arouse emotions and is all too often dismissed as ›women’s stuff‹. »Unfortunately, resentment about one topic often leads to scepticism or a lack of interest in the other.«

Kalbe regards gender, like age, as an important determinant of health and illness. However, she believes that it has not been sufficiently taken into account in medicine – much less so than age. In her field of neurodegenerative diseases, differences have been described, but they are still poorly understood. For example, men are about one and a half times more likely to develop Parkinson’s disease than women. In this disease, the cells that produce the neurotransmitter dopamine deteriorate, which typically affects both the motor and non-motor systems. However, although more men suffer from it, the disease attacks women’s cognitive strengths, i.e. their verbal memory, particularly severely. More boys and men also suffer from other disorders that arise from imbalances of the dopaminergic system, such as attention deficit hyperactivity disorder (ADHD). Depression, on the other hand, statistically affects more women. »The underlying mechanisms of these gender-specific differences, which form the basis of targeted therapies, must be given much more attention in the future,« said Elke Kalbe.

The problem of the standardized body

In many cases, scientists still disagree on whether differences are due to biological, physiological or social factors. »Illness and health are always embedded in a psycho-social context,« said Kalbe. This context includes the fact that women generally have a healthier diet and are more likely to take advantage of preventive health care services. They seek medical help earlier if they have problems. Their life expectancy exceeds that of men in almost every country in the world. But such lifestyle factors are not enough to explain many of the differences.

Often, the available data is insufficient: In the past, most clinical trials were conducted exclusively on young male volunteers. Like the heart attack example, this ›gender knowledge gap‹ is one of the most frequent criticisms raised against medical research. This gap is not the result of deliberate discrimination, but rather due to supposedly practical reasons: In women, drugs work differently depending on hormone levels during the menstrual cycle – a variable that would have to be controlled in a trial. In addition, pregnancy would have to be ruled out in participants.

This lack of knowledge affects how diseases are treated. As a cancer researcher, Alexander Quaas is interested in differences in the immune systems of men and women: »More women suffer from autoimmune diseases. And in women, the menstrual cycle has an effect on immune response. This can affect how well vaccinations work, for example.« He and other researchers also suspect that cancer drugs work differently in men and women. »It has been shown that a standard chemotherapeutic agent, 5-FU, which was approved back in the 1960s, is metabolized differently by men and women,« said Quaas. »Men eliminate more 5-FU via the kidneys. As a result, women are exposed to a higher level of toxicity with more side effects, but their cancer is not treated any better.«

The relatively new therapeutic approach of so-called checkpoint inhibitors, which activate the T cells of our immune system against cancer, is also showing initial indications of gender-specific differences. Quaas: »There are observations that these drugs work differently in women than in men and that women could benefit from additional chemotherapy.«

Similar risks, different precautions

However, the much-criticized gender knowledge gap can also work to men’s disadvantage, as another example from cancer research shows. Gynaecologist Professor Dr Rita Schmutzler heads the Center for Hereditary Breast and Ovarian Cancer at University Hospital Cologne and has been researching these types of cancer for decades.

Breast cancer is by far the most common type of cancer in women. The risk factors are not always hereditary, but carriers of mutations in certain genes, such as BRCA1 and BRCA2, have a significantly increased risk of developing the disease. Prevention and screening programmes, in whose development Schmutzler has played a key role, therefore test for these gene variants.

However, Schmutzler attributes the great success of these programmes not only to scientific progress: »Prevention also depends on the initiative of those affected. In the case of breast cancer, the self-help and support groups are very committed and have worked early on to create awareness.« The example shows that largely women-specific diseases can even play a pioneering role in research, care and prevention.

What breast cancer is for women, prostate cancer is for men. It is similarly widespread, and in a similar number of cases caused by a genetic predisposition. However, in terms of prevention and care, this type of cancer is nowhere near the level of breast cancer. »We gynaecologists are now advising urologists, and the breast cancer support groups are helping prostate cancer patients. They are working together to lobby for similar prevention and care concepts to be established for men as well.«

New training standards

Next year, new Licensing Regulations for Physicians (Approbationsordnung) are due to come into force in Germany, which will take gender-sensitive medicine into account for the first time. According to Elke Kalbe, many prospective doctors are interested in the topic: »Students and doctoral candidates are calling for gender issues to be given greater consideration.« Moreover, it is not just about differences between men and women, but about the entire gender spectrum as well as questions of diversity. The data available on gender-diverse people is particularly scarce – also because there are no mandatory data collection standards in clinical trials. A group within the ›Sex, Gender and Diversity in Medical Research‹ working group is looking into this question and analysing what standards and methods already exist. Gynaecologist Rita Schmutzler is also convinced: »We have to pay particular attention to gender minorities because the lack of data often means that decisions have to be made on a case-by-case basis and require particularly careful consideration.«

Questions relating to sex, gender and diversity are significant in many areas of medical care and research. More and more chairs and institutes are being established across Germany, and funding organizations are calling for greater consideration of these issues in clinical trials. But Quaas and Kalbe don’t think the topic has really caught on yet. It is still mostly younger doctors and more women who are interested in this field. »The new licensing regulations will change many things because it is crucial for gender medicine to be structurally integrated into degree programmes,« said Kalbe. The lecture series ›Gender Medicine‹ at the Faculty is already packed every semester – an important precondition for achieving equality in medical care in the future.

‘Sex, Gender and Diversity in Medical Research’ working group
The working group at the Faculty of Medicine is concerned with gender differences in health and illness as well as the care situation of minorities who are discriminated against based on characteristics such as ethnicity, religion, physical impairment or sexual orientation. Through research in this field, the working group aims to contribute to the precision medicine of the future. It also promotes cooperation between academics on campus, develops joint third-party funded projects and provides students with an overview of possible contacts for doctoral supervision and other academic work.

GENDERMEDIZIN.NRW
The lighthouse brings together experts from various research fields and organizations (research institutes, university hospitals, universities, networks) in North Rhine-Westphalia to exchange ideas and network. Other lighthouses focus on clinical research and clinical trials, digital medicine and artificial intelligence, ageing research, biohybrid medicine, and climate and health.