A story from 1904 by Isaac Singer takes place in a rural Jewish village where a young woman called Yentl disguises herself as a man to escape the expectations of that time, attend Jewish school and study the Talmud. “Being just like a man has historically been a price women have had to pay for equality”, wrote Bernardine Healy in an article published on the New England Journal of Medicine in 1991. She shed light for the first time on the different clinical management of coronary heart disease for both genders, whereby women received a lower number of diagnostic and treatment interventions compared to men under the same conditions, thus pointing to a discriminatory clinical and treatment approach. Additionally, there was little or no women’s representation in trials, starting from animal models. The article, which described “the Yentl syndrome”, was a starting point to strengthen gender medicine.
Increasing evidence demonstrates that the presence of significant differences between men and women can impact the health and ill state of each individual. Studying the impact of such differences- both biological (defined by the sex), financial and cultural (defined by the gender) ones- which can be identified at the onset, during prognosis, in the response to drugs and in the side effects and survival to the main groups of illnesses, reflects the definition of gender-specific medicine by the World Health Organisation. Many years on after the famous article by the American cardiologist that highlighted the different management of coronary heart disease for the two genders, cardiovascular diseases are still viewed as a men’s issue, while they are the main cause of death in women, explains Alessandra Carè, director of the Reference Centre for Gender Medicine of the Italian National Institute of Health (ISS). “On the contrary, conditions that are considered to be impacting only women actually affect men as well but with different incidence and symptoms. For this reason gender-specific medicine aims to collect the data needed to better tailor the treatments to each patient based on indicators that are more and more appropriate. Some mistakenly think of it as women’s medicine but it is everybody’s medicine and the sex and gender variables are essential to head towards truly practising so-called precision medicine”.
Any male or female specificities should be taken into account during all the stages required to get from bench to bedside – Alessandra Carè
“We refer to it as gender-specific medicine because gender medicine does not exist and when we talk about gender medicine as its own thing it seems as though it’s a medical specialty. We should help the scientific community, patients and citizens understand that the approach of gender-specific medicine is cross-sectional and it involves all specialties,” says Giovannella Baggio, the president of the National Centre for Health and Gender Medicine Studies, who is already teaching the first gender medicine professorship in Italy. “In 2012 the director of my department became passionate about gender medicine and decided to create a professorship for it, which I covered for five years. It was the very beginning so it made sense to do that. Gender medicine needed to be launched. Today it would be a mistake to create separate professorships for gender medicine and to continue side lining the field as if it were a branch of medicine. Gender-specific medicine is a cross-sectional dimension that should be adapted, taught and practiced in all medical specialties”.
Some mistakenly think of it as women’s medicine but it is everybody’s medicine and it is the way to head towards truly practicing so-called precision medicine. – Alessandra Carè
Steps forward
“Gender is getting more and more attention all over the world, as a series of new protocols and recommendations made in the United States and Canada demonstrate,” continues Alessandra Carè. “Any male or female specificities should be taken into account during all the stages required to get from bench to bedside. In terms of preclinical studies, in the United States the Food and Drug Administration and the National Institutes of Health have been recommending a correct planning of animal models for a while, as they are currently indispensible to study the efficacy of treatments. However, today the majority of studies includes animals of just one sex due to organisational and financial reasons”.
The approach of gender-specific medicine is cross-sectional and it involves all specialties. – Giovannella Baggio
The approval of law n. 3/2018, which introduced a focus on gender-based differences in clinical practice, research, prevention, diagnosis and care, was the essential step for Italy, explains Carè. Its four main objectives are: to review clinical routes (thus prevention, diagnosis, treatment and rehabilitation), research and innovation, training (of the new healthcare workers and as professional self-development) and communication. “We are beginning an important phase,” adds Baggio, “we are the only country in the world with a law on gender medicine. Everybody’s watching us. I think we have a national and international responsibility”.
Following the approval of the law, the Reference Centre for Gender Medicine of the ISS and the Ministry of Health, in collaboration with a team of regional coordinators and the support of the Italian National Agency for Regional Health Services, the Italian Medicines Agency and the IRCCSs (Research Based Institutes), created an intervention Plan that outlines the main actions to take to ensure the start of gender medicine awareness raising programs throughout the country, says the director of the Centre. Furthermore, in September last year the ISS instituted the National Gender Medicine Observatory, which is meant to monitor the promotion and application of actions in support of gender medicine as outlined in the Plan. Finally, we should point out, adds Carè, that there is an Italian network of collaborations taking place in the gender medicine context that has been there for a while and is progressively growing. It includes the Reference Centre for Gender Medicine of the ISS, the Italian Health and Gender Group, the National Centre for Health and Gender Medicine Studies, the National Federation of the Orders of Surgeons and Dentists and many scientific societies.
What are we referring to when we talk about differences?
There are many examples. The most known one is myocardial infarction, the leading cause of death in women, explains Giovannella Baggio. “Myocardial infarction in women is diagnosed late because the symptoms differ from the ones presented by men. Men and women have different symptoms, lesions, pharmacological (and prevention) needs, just like for any other condition. Women display a few symptoms during an episode of myocardial infarction. They might not have any pain and feel a light stomachache, tiredness and a bit of dyspnoea. Therefore they tend to ask for help later because they don’t realise these are heart related symptoms. Additionally, when they turn up at the A&E they are not treated as emergency cases, which is something even more serious. Some women were even admitted to the gastroenterology ward and their first exam was a gastroscopy because they reported pain to the higher part of the stomach area. This obvious delay in diagnosis must be corrected so it is necessary to rewrite the diagnostic and treatment protocols for many conditions.
There are other shocking examples in the oncology context. One is colon cancer. Women predominantly suffer from ascending colon cancer while men are largely affected by descending colon cancer. The results of the faecal occult blood test become positive much later on for ascending colon cancer so the mortality of women is greater because diagnoses happen late”.
Gender-specific medicine also means paying attention to men for those pathologies that are completely neglected in men, such as osteoporosis and depression, because they are historically associated to women, explains Baggio. “The onset of the former, for example, is roughly ten years later in men compared to women and in more serious cases, after a fracture, men have a much higher mortality rate. Depression is undoubtedly more common in women, but we don’t have the tools to diagnose it in men and we know that suicide rates are five to seven times higher in men than in women. Were any of these men diagnosed with depression? Gender-based medicine aims to fill the knowledge gaps on the different gender-specific symptoms, it starts a conversation about balance, fairness, a scientific discussion of great significance that enables you to better understand the physiopathology of certain conditions and makes it easier to find gender-based pharmacology”.
Gender stratification
Men and women do not get sick in the same way. The incidence and prevalence of conditions differ between the two sexes therefore so does their impact in terms of use of healthcare resources, states Eliana Ferroni, Medical Manager of Hygiene, Epidemiology and Public Health at the Epidemiology Service of the Veneto Region. “A stratified analysis of the population affected by chronic conditions, which was conducted in Veneto, showed that women have a greater impact- in terms of support complexity thus the consumption of healthcare resources- in heart failure and dementia, while men tend to absorb more healthcare resources in diabetes and chronic obstructive bronchopneumopathy. In Italy the oldest population group is predominantly made of women; they live longer than men- according to the ISTAT (Italian National Institute of Statistics) in 2019 women had a life expectancy of 85.3 years compared to 81 years for men, but these 4 “additional” years are often lived with disabilities. A recent study, published on The Lancet Healthy Longevity, based on data collected in OECD countries confirms that even though women live longer than men they are exposed to a greater risk of developing chronic illnesses that impact significantly their health and quality of life. Furthermore women spend more years in solitude and with lower incomes.” Even though there are significant differences between the sexes, adds Ferroni, the use of gender as a variable is not always appropriate in epidemiological studies and results are often presented with all-encompassing figures that include both men and women, which does not allow for potential differences to emerge. “Gender should not just be taken into account when presenting results but also during the planning stage of the trial. This is a very important aspect, particularly in the context of pharmacoepidemiological studies, which assess the efficacy and safety of drug treatments. However, women are underrepresented in randomised clinical studies: the percentage of women enrolled in phase III clinical trials rarely goes over 20 per cent, which means that in some cases the approval of drugs is based on the outcomes obtained in a predominantly male population.
Gender stratification is also important to better assess the health conditions of the population. – Eliana Ferroni
The research experience on Covid-19 confirms this data as well. A recent study, published on Nature Communications, analysed the Covid-19 related clinical trials that were registered on the American database ClinicalTrials.gov under the gender differences profile. 66.7 per cent of the group of studies does not mention sex/gender in the registration and only 4 per cent of the trials include it as a variable. The absence of data stratified by gender also emerges in the publications of randomised controlled trials on the efficacy and safety of drugs for Covid-19: only 17.8 per cent provide information stratified by sex or analysis divided by subgroups. It is therefore necessary to invest more resources to promote a culture that pays more attention to the female dimension in the context of pharmacological trials, also in light of the recent progress made in pharmacogenomics and personalised treatments.
Gender should not just be taken into account when presenting results but also during the planning stage of the trial. – Eliana Ferroni
Gender stratification is also important to better assess the health conditions of the population. If a condition affects one sex more than the other it might be appropriate to use different tools to reduce its incidence. There are numerous examples of gender-based preventative interventions that turned out to be very effective, such as those linked to adopting a healthy lifestyle. For this reason it would be ideal if the upcoming Regional Prevention Plans associated to the 2020-2025 Italian National Prevention Plan focused more on gender, also by developing stratified indicators to assess interventions. Finally, it would be important to implement the gender-based approach to data stratification, also in the context of outcome assessment programs, such as the Italian National Program for Outcomes and the Bersaglio Project.
The recently formed Health and Gender Medicine workgroup of the Italian Association of Epidemiology was created with the aim to create awareness on the importance of gender difference in the epidemiological context. I am the coordinator of the group, together with Cristina Mangia, who is planning to activate different research lines, particularly in prevention, environmental epidemiology and health and vaccination inequality”.
We are facing an ethical step for medicine; if we don’t do it, it means that we don’t practice science-based medicine. – Giovannella Baggio
Prospects
During the press conference on “Practical ideas to create a type of healthcare that pays attention to sex and gender-based difference” organised by Senator Paola Boldrini, MP Speranza emphasised that “it is important to redesign the whole SSN using the gender medicine lens”. This prospect “gives those of us working in this area a level of responsibility” comments Alessandra Carè, and adds, “the Minister understood and committed to the importance of gender-based policies. On various occasions he emphasised that the inclusion of sex and gender variables is an essential basis to head towards true precision medicine”. This approach doesn’t just have the power to make healthcare policymaking more equal, it has the duty to do it, adds Baggio. “Gender-specific medicine isn’t an invention or a new discovery. Gender-specific medicine takes on a scientific- thus ethical- potency. We are facing an ethical step for medicine; if we don’t do it, it means that we don’t practice science-based medicine.
Universities play a crucial role in students’ education and training, but medical associations and scientific societies should take action as well: they are the ones writing new guidelines. Furthermore pharmaceutical companies should no longer do nothing when presented with guidelines that were written way too long ago and regulatory agencies should no longer accept data from studies that involved a percentage of women ranging from 0 to 20 per cent. The attendees of gender-based difference trainings are predominantly female doctors and this just does not make sense. This is a 360-degree revolution that involves the entire National Health Service, universities, medical associations, scientific societies, regulatory agencies, admission facilities and pharmaceutical companies. It is an absolute revolution and many parties need to get a handle of the situation.”
Edited by Giada Savini
Health and gender medicine
What are the prospects outlined in the Regional Prevention Plans?
Prevention, in combination with research, diagnosis and treatment, represents one of the main areas where, according to the Plan for the Application and Diffusion of Gender Medicine, healthcare interventions should be modified adopting a gender medicine approach. Similarly, the 2020-2025 Italian National Prevention Plan (PNP) highlights the need to adapt interventions that promote health and prevention by paying attention to gender aspects. The PNP is a unique document of healthcare programs as it indicates the key strategy and the health macro-objectives that are then implemented at the regional level through the Regional Prevention Plans (PRPs). Therefore the PNP and the PRPs provide “governance and guidelines by promoting the link and the integration between the actions outlined by the laws, the regulations and the sector-specific plans”. The 2020-2025 PNP also introduces two important new elements:
- On one hand the investment in creating action plans for all the Regions (“predefined” Programs that are binding for all the Regions), which are based on efficacy data, good practices that are established and documented, and recommended strategies, both nationally and internationally;
- On the other hand the recommendation to adopt a more impactful approach to fighting health inequality- including gender inequality- with the invite to “utilise scientific data and the available and verified methods and tools, in order to ensure that fair actions are taken”.
Furthermore, the 2020-2025 PNP, in continuity with the past, outlines a system of actions for the promotion of health and prevention that support citizens through each life phase, with interventions designed for the “cycle of life”, thus tailored to the specific needs of the individual based on their age. In this sense gender differences might also develop and change over time, because they are linked to age. Furthermore, the younger population groups present specific health needs: chronic conditions are not very common yet, while there are differences between individuals and also between men and women- that are evident from their birth- in terms of their exposure and vulnerability to risk factors linked to preventable chronic conditions such as cardiovascular diseases and tumours.
To summarise, the 2020-2025 PNP identifies gender approach as a strategic element for public health and recognises the importance of gender-based biological and sociocultural differences, with the goal to improve the clinical appropriateness of interventions for prevention and to promote equality and fairness in healthcare. Regions are now facing the real challenge: all Regions had to define the so-called Regional Health and Fairness Profiles- inclusive of gender aspects- by 31 August 2021, processing data on the health status of the regional population. Additionally, the Regions created the 2021-2025 PRPs indicating the regional actions- tailored to specific contexts- to be taken in order to reach the national strategic objectives. After the ex-ante assessment conducted by the Ministry of Health, the Italian Regions will have to approve the 2021-2025 PRPs by the end of the year, implementing the principles and indications of the PNP.
In the public health context paying attention to gender turns into a strategic regional choice that, in line with the Plan for the Application and Diffusion of Gender Medicine, requires the following elements- also in the prevention area:
- Monitoring and assessing the gender specific preventative interventions outlined in the PRPs;
- Training all the socio-healthcare workers involved in the PRPs on the gender approach and on the bio-psychosocial mechanisms that underpin differences between men and women in terms of their exposition and vulnerability to risk factors for conditions and also in terms of the health issues and social consequences linked to experiencing the illness;
- Consultations taking place in the context of university research, study and training- and at the regional level as well- so that gender-specific research/action plans can also be created in the sector dedicated to promoting health and prevention;
- Overall, more attention paid to gender medicine and its health implications by regional management, healthcare workers and citizens as well.
Finally, it is essential that the link between the activities associated to the implementation of the Plan for the Application and Diffusion of Gender Medicine, and the activities linked to the now upcoming 2021-2025 PRPs, is guaranteed regionally.
Lilia Biscaglia
Area Promoting Health and Prevention
The Lazio Region*
*The author expresses personal opinions that might not necessarily reflect those held by the institutions she works for.
© 