Author: Emilie Théberge, MSc. Medical Genetics, Clinical Research Coordinator (University of British Columbia/Vancouver General Hospital) Editors: Romina Garcia de leon & Shayda Swann (Blog Co-coordinators).
Published: December 30th, 2022.
Note: Biological sex (i.e. female, male) is not the same as gender (i.e. woman, man, nonbinary, Two-Spirit, etc.), which is a social construct. Throughout this blog post, the cited literature considers the term “women” to equate to cisgender females, and the term “men” to cisgender males. This post’s cited conclusions of sex differences are under researched in reference to transgender and non-binary individuals, as well as those with non-conforming gender identities. Read more
When does stress overwhelm the body to the point that it causes a state of mental and/or physical illness with an accelerating feedback loop? If the cause of stress is unremovable, how can we adapt and find hope?
A large-scale wildfire may cause short-term (acute) stress to someone nearby, but there is also a defined endpoint when the fire is put out and no longer a threat. However, there can be long-term (chronic) consequences to one’s lungs and the local environmental ecosystem This wildfire metaphor may be translated to the acute and chronic mental and physiological adaptations caused by stressful events. Everyone has different thresholds of stress tolerance based on their lived experiences and biological (genetic) susceptibility to how their bodies manifest this stress.
Despite being half of the world’s population, I am shocked at how little research in psychiatric and neuroscience is dedicated to studying sex differences and women’s health. Approximately one in four Canadians were estimated to have depression in 2021 – and across borders, depression rates are consistently reported twice as high in women (20%) than in men (10%). How much of this is attributed to biological sex differences? Do the physical manifestations of mental stress and depression differ between the sexes? I decided to explore these ideas in my thesis.
This recently published article on the “immunometabolic theory of depression” piqued my interest. Most literature on depression focuses on dysfunction within the brain, ignoring the context of its link to the cardiovascular and metabolic systems. Recent genetics literature on depression has pointed towards genes and molecular pathways that implicate the immune system, specifically chronic-low-grade inflammation, as a key driver of depression. The brain controls the perception of stress, and the heart reacts to it. Chronic low-grade inflammation is a result of this system staying “on” too long after the perceived threat has passed.
Depression is a systemic and whole-body concern that can affect our cardiovascular system. I developed a keen interest in exploring these connections when working with patients who believed that stress triggered their cardiovascular disease onset. Heart disease does not occur overnight. Chest pain to the point of a heart attack comes from a complex interaction of metabolic and immune factors that build up over time from imbalances in the body (i.e. from stress). This can manifest as plaque in the large blood vessels with coronary artery disease or dysfunction of the smallest blood vessels with microvascular dysfunction. Traditional risk factors such as high cholesterol, diabetes, high blood pressure, smoking, and obesity, may also have different effects between men and women.
In my thesis, I studied a sample of over 16,000 people from the Canadian Longitudinal Study on Aging (CLSA) cohort of 50,000 people and found sex differences in the genetic and cardiometabolic risk factors associated with depression. Women with a history of clinical depression were at higher odds of having comorbid histories of heart disease, diabetes, hypothyroidism (which results in slower metabolism), and a higher “genetic risk score” for depression. However, men with depression did not show significant relationships with these conditions, in comparison to men without depression. Among men, high blood pressure was a significant risk factor, while high genetic risk was not. Younger age and lower annual income contributed the most to my statistical models for both sexes.
Depression is not just in the head, it’s a whole-body dysfunction to cope with stress. In consultation with your primary health care provider, you can make a habit of checking on your body through regular health examinations and seeking support for your mental health. Mental and physical health are interconnected, and gradual mental and physical decline in our youth have the potential to snowball into early life-threatening heart disease. It is imperative that we talk about the individual and collective actions that we can take to treat depression, especially in this post-COVID era. This can take place in our friend groups, families, and workplaces – as we think about long-term solutions instead of “quick fixes.”
https://womenshealthresearchcluster.com/wp-content/uploads/2024/11/2.png9001600caordahttps://womenshealthresearchcluster.com/wp-content/uploads/2024/08/WHRC-logo.pngcaorda2022-12-30 10:00:272025-02-07 18:22:04Sex Differences and the Brain-heart Connection
Author: Avril Metcalfe-Roach, PhD student, University of British Columbia | Editors: Negin Nia and Arrthy Thayaparan (Blog Coordinators)
Published: November 12th, 2021
If you had to build your own house from scratch, what supplies would you bring to the job? High-quality building materials would certainly make the house much more durable, and having a diverse array of tools on hand will make construction much easier.
Joe, on the other hand, brought just four zip ties and a wrench and is probably in for a tough time. If you live in a hot climate, you might consider installing air conditioning; in cold climates, good insulation and a heater will help you avoid freezing during the winter. In any case, putting love and effort into the home helps ensure that it keeps you comfortable for many years.
Similarly, the food we eat directly impacts every facet of our health. The links between diet, obesity, and cardiovascular disease are well known. However, more research indicates that dietary habits also directly impact issues like cancer, mentalhealth, and even neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. Healthy eating can also indirectly reduce disease burden by ensuring that your body has the tools it needs to heal and combat infection.
So, how do different foods actually exert these effects?
Each food, of course, has a different nutritional profile and will provide your body with different tools. We can anticipate what tools we will need and provide them before problems arise. For example, people who menstruate require more iron in their diets, and oral contraceptive use can lower the absorption of multiple vitamins and minerals.
Humans also have a little problem: we’re more complex than our genetics allow. While our bodies directly absorb and create many nutrients, a lot of essential nutrients are created solely by the 100 trillion bacteria living in our intestines. In exchange for some energy and a warm place to call home, these beneficial bacteria help to prevent other harmful bacteria from infecting the gut. This keeps our gut tissue working properly, and produces vitamins and other compounds that can leave the gut and promote health throughout the body. For example, certain types of fiber are broken down by bacteria into molecules that enter the bloodstream and help to reduce inflammation.
Even the ‘happy’ chemical, serotonin, is mostly produced in the gut. Like us, each type of bacteria has its own nutritional requirements that mostly revolve around fiber-rich foods such as fruits and whole grains. By eating a variety of nutrient-dense foods, we foster a gut environment full of healthy, anti-inflammatory bacteria that in turn keep us healthy.
What type of diets are sustainable and have health benefits?
Dietary research is progressing at a staggering rate, and it can be overwhelming to stay up to date. When the research is clarified, however, certain dietary patterns emerge that are consistently linked with specific health outcomes.
The Mediterranean diet, which promotes plant-based foods, fish, and healthy oils, while limiting red meat and other animal products, is perhaps the best-studied healthy diet in the world. It has been associated with lower rates of cardiovascular disease, obesity, glucose sensitivity and diabetes, and overall mortality.
Most food groups are conserved between the two diets; crucially, however, the MIND diet also promotes brain-healthy berries and leafy greens, while restricting pro-inflammatory sugary, fried, and processed food. These latter foods are becoming increasingly common, especially in North America; some research suggests that their overconsumption can even negate some of the health benefits normally associated with the Mediterranean diet.
We recently investigated the MIND diet in a group of individuals with Parkinson’s disease, where we assessed their normal dietary intake and assigned a score based on how closely their intake resembled the MIND diet. Female participants had higher scores on average, indicating closer MIND diet resemblance. Participants with high scores developed Parkinson’s disease significantly later than those with low scores; unexpectedly, this association was especially strong in the female participants, where dietary habits accounted for up to 17 years’ difference in disease onset. Interestingly, the MIND diet accounted for only 10 years in men, and the Mediterranean diet accounted for 10 years with no apparent sex differences.
How do these diets work exactly?
While the complexity of these diets means that it is difficult to know exactly how they work, a sizable amount of research has zeroed in on our microscopic friends as a key factor. Brain-healthy diets help anti-inflammatory bacteria to thrive, which may help to limit inflammation in the brain. Regulation of the immune system is known to be partially sex-specific – for example, women are more prone to autoimmune disease, where the immune system attacks healthy body tissue – and these differences might impact how effective the diets are against neurodegeneration. Indeed, women make up only 1/3 of all Parkinson’s disease cases.
While our findings here are only correlational, they highlight the importance of including sex as a factor in further research. With a strong enough framework, everyone can design a house that will keep them happy and healthy for a lifetime.
https://womenshealthresearchcluster.com/wp-content/uploads/2024/11/website_-_the_gut-brain_connection_why_biological_sex_may_matter.jpg9001600caordahttps://womenshealthresearchcluster.com/wp-content/uploads/2024/08/WHRC-logo.pngcaorda2021-11-12 11:23:002025-02-07 18:22:08The Gut-Brain Connection: Why Biological Sex May Matter
Authors: Maria Tokuyama, PhD, Assistant Professor at UBC Microbiology & Immunology; Joshua Mao, University of California Berkeley, Summer Intern at the Tokuyama Lab, UBC Microbiology & Immunology | Editors: Negin Nia and Arrthy Thayaparan (Blog Coordinators)
Published: September 10th, 2021
Since March 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has drastically changed our lives and has killed over four million people worldwide. Although people of all ages and sex get COVID-19, a striking observation is that the number of female COVID-19 deaths were half of what was seen in males. Data analysis from New York City Health found that of all death cases 38.2% were female and 61.8% were male. So what are the factors that contribute to this sex difference in COVID-19 outcomes? Several research studies have shown that differences in immune response and metabolism during disease may partly explain the worse outcomes in males than females. Here, we will summarize the key takeaways from those studies.
The immune system is largely divided into two parts: the innate and adaptive immune system. The innate immune system is the body’s first line of defence against infection. It is able to recognize danger within minutes and rapidly fire inflammatory factors called cytokines and chemokines to recruit immune cells to sites of infection and set off alarms to engage the adaptive immune system. The adaptive immune response takes about five to seven days to fully kick-in, but once activated, it is very specific to the invading pathogen and provides long-term memory responses that can be quickly recalled to fight future infections by the same pathogen. The adaptive arm of the immune system is what is provided by vaccinations. During viral infection, both the innate and adaptive immune responses work together to fight the infection. Ultimately, the magnitude and quality of the immune response dictate disease outcomes.
Male patients show increased activation of the innate immune response.
In a study published by Yale in August 2020, researchers compared immune responses between female and male hospitalized COVID-19 patients, who were not taking anti-inflammatory drugs. They found that male patients had higher amounts of key inflammatory molecules, interleukin 8 (IL-8) and 18 (IL-18), in their blood compared to female patients, despite having similar amounts of SARS-CoV-2 RNA. In addition, male patients had a higher amount of a type of innate immune cells called non-classical monocytes. These findings are supported by another study that reported worsening health conditions in males due to SARS-CoV-2 infection was related to increased innate immune activation. Although the immune response is intended to fight the infection, over activation of the innate immune response can lead to tissue damage and may be one explanation for why males have worse outcomes than females in COVID-19.
Female patients have a stronger adaptive immune response.
The two major players of the adaptive immune responses are B cells and T cells. B cells make virus-specific antibodies that bind to the virus and prevent the virus from infecting cells. T cells recognize cells that are infected and destroy them to prevent further spread of the virus. T cells also help B cells make more antibodies and strengthen the immune response.
From the same Yale study, researchers found no difference in the amount of antibodies against SARS-CoV-2 between male and female COVID-19 hospitalized patients. However, female patients had a higher amount of fully activated T cells than males. This means that female patients are better able to control the infection through their T cells, and the weaker T cell response in males may be another reason for worse outcomes with COVID-19.
Kynurenic acid levels correlate with deteriorating disease in males.
The metabolism regulates the immune system through metabolites, which are small molecules that are produced through chemical reactions in the body. A study published in July 2021 found that a higher amount of a key metabolite called kynurenic acid (KA) produced from kynurenine was related to higher innate immune responses in both female and male COVID-19 patients, but this association was more pronounced in males. Male patients with worse COVID-19 had a higher ratio of kynurenic acid to kynurenine (KA:K), which also seemed to predict higher innate immune responses and lower amounts of activated T cells. A higher Body Mass Index and increased age were associated with worsening disease in male COVID-19 patients. Overall, the metabolic status of individuals seems to contribute to disease outcomes, where certain amounts of KA predicted over activation of the innate immune response and worse disease in males.
Different levels of sex hormones in COVID-19 patients.
Estradiol and estrone are major and minor female sex hormones, and testosterone is a major male sex hormone. Sex hormones can affect many aspects of the immune system and are important to consider. A preprint article, that has not yet been peer-reviewed, reported that both male and female COVID-19 patients have higher levels of estradiol and estrone compared to healthy individuals. However, only male COVID-19 patients had decreased testosterone levels. Whether lower testosterone levels in male patients results in worse disease is not known, but it will be an important factor to monitor moving forward.
Concluding remarks:
A wide range of disease outcomes have been observed in COVID-19 including a major difference between males and females. These studies highlight key sex differences in SARS-CoV-2 infection that affect severity of COVID-19 including differences in the coordination between the innate and adaptive immune response, metabolism and potentially, sex hormones. These differences between sexes may be important factors that explain why fewer females have died from COVID-19 than males.
Bibliography
“Worldometer Coronavirus Death Toll.” Worldometer, 2020, https://www.worldometers.info/coronavirus/coronavirus-death-toll/. (Accessed 1 August 2021).
Takahashi, Takehiro et al. “Sex differences in immune responses that underlie COVID-19 disease outcomes.” Nature. 2020 Dec;588(7837):315-320.
Petrey, Aaron C, et al. “Summary of Cytokine release syndrome in COVID-19: Innate immune, vascular, and platelet pathogenic factors differ in severity of disease and sex.” J Leukoc Biol. 2021 Jan;109(1):55-56.
Cai, Yuping, et al. “Kynurenic acid may underlie sex-specific immune responses to COVID-19.” Sci Signal. 2021 Jul 6;14(690):eabf8483.
Schroeder, Maria, et al. “Sex hormone and metabolic dysregulation are associated with critical illness in male Covid-19 patients.” MedRxiv, 2020, https://www.medrxiv.org/content/10.1101/2020.05.07.20073817. (Accessed September 2021).
https://womenshealthresearchcluster.com/wp-content/uploads/2024/11/ornate_frame_social_media_graphic_1.png800800caordahttps://womenshealthresearchcluster.com/wp-content/uploads/2024/08/WHRC-logo.pngcaorda2021-09-10 11:52:122025-02-07 18:22:09COVID-19 Differences Between Men and Women
Authors: Arrthy Thayaparan and Alex Lukey (Blog Coordinators)
Published: June 4th, 2021
Interviewee: Dr. Robert-Paul Juster, PhD, University of Montreal
For this month’s Behind the Science feature, we spoke with Dr. Rober-Paul Juster, an assistant research professor in the department of psychiatry and addiction at the University of Montreal.
As Dr. Juster is a proud member and advocate for research with the LGBTQ2S+ community, we discussed the challenges faced by this community in the sciences. In honour of Pride month, we hope that these discussions bring to light the challenges faced by queer and gender diverse communities.
Additionally, we talked about Dr. Juster’s work on sex and gender research to understand the effects of stress and adversity. He is currently conducting an ongoing survey of COVID-19 that focuses on sex and gender. If you are interested in learning more or participating in his work, check this link out.
But without further ado, we introduce Dr. Juster…
How did you get into the sex and gender research field?
The first scientific project that I was involved in looked at sex differences in cognition, which was something I was learning in a class at the time. Then I remembered learning about gender roles, masculinity, and femininity in another class. I just sort of put them all together and was particularly interested in the LGBTQ2S+ community. I ignored these interests a bit during my master’s. But then, in my PhD, I had the opportunity again to revisit and look into them further.
I’m a gay man. So I think the best research often has a personal meaning to the person. I think we can debate whether that makes us purely objective, but I think I had a real desire to contribute to the community and engage in activism through my science. So I think that was always sort of there in my mind, that I wanted to be involved through science. And it so happened that that’s probably been one of the most interesting and fruitful parts of my career so far.
Why is it important to have research that focuses on and includes diverse communities like the LGBTQ2S+ community?
That’s a great question. I think underrepresentation is something that we talk about not just in the field of sex and gender. More broadly, there is still so little research tat has been done with consideration of women. I’ve always felt a real alliance with women, in particular. I think gay men and heterosexual cisgender women have a pretty interesting alliance. My dedication to advancing research and especially health research among the LGBTQ2S+ community is really focused on the desire to really represent better. I think representation is really the most important thing for my research.
Is there enough representation of the LGBTQ2S+ community within the sciences?
I don’t think so, especially for trans and/or non-binary people. I think there’s not a sufficient amount of representation. It’s something new as an ally, I can do my best to lend my interest and my research focus to these and other underrepresented communities. But I feel like so many areas that have not received sufficient representation in science and health research are often the ignored people of those communities.
So I think there is a slowly growing number of people from the LGBTQ2S+ community represented in academia and in STEM. But I think there’s always more that’s needed.
I think we talk a lot about equity, diversity and inclusion. More needs to be done to really be aware of that reality and to be sensitive to the fact that even though you’re an ally with an identity that is also marginalized, you can never truly understand the experiences of every subgroup that you’re interested in.
That’s been an interesting process for me of humility, being really humble and always being aware of the realities of other groups that have not received the same representation. Nor the same privileges. As a white cisgender male, I have a lot of privileges that I think a lot of other groups don’t and it’s important to acknowledge that.
When working with diverse communities, there’s always the potential to create harm when conducting research. How can that harm be mitigated?
Even researchers with the best possible intentions can go into research among a group and not identify their real needs. I think particularly for the transgender and/or gender non-binary communities, there’s been a lot of research that has focused on the origins of difference. Same thing for sexual minorities to try and identify brain regions that are different. This inquiry aims to explain why people are gay or why they’re trans.
I mean, human beings are curious, and we want to identify the causes of things. But I’m not sure that that research really speaks to any sort of direct needs of the community. Being mindful about what is important to the communities that you want to study and serve is really the essential thing. We can have all kinds of great ideas about research that would be great among the communities that we’re interested in, but it just doesn’t speak to their needs.
And that’s potentially damaging, because there’s no investment of taxpayers dollars to an issue that might not actually be pertinent to the communities that you’re studying. So I think it’s so important to be engaged in participatory research and to really be attentive to the needs of the community and being able to adjust research accordingly.
Can you explain your research to us?
My research aims to understand how men, women, and gender diverse people each have unique health and wellness needs. Beyond binary sex or any kind of focus on categories of groups of people, my work is really focused on the nuance within sex. So trying to identify how things, like sexual orientation, sex hormones, gender roles, or combinations and social economics in relation to your gender, all relates to your health and well-being.
I’m also really interested in groups that are exposed to different forms of stress and can develop inspiring resilience. What are the things that they do to help minimize their stress? What are the factors that contribute to their protection or resilience to certain conditions? I want to spend my career answering those questions
So studying the LGBTQIA2S+ community, for me, is fascinating because there’s so much gender diversity, and just so much lived experience that is mixed with adversity and resilience. It provides a really strong lens from which to identify how people can become quite tough in terms of facing problems in the future.
Any last thoughts you’d like to share?
Studying sex and gender research is much more complicated than it seems. Each and every different group combines with other factors like social economics, geography, age, race, and ethnicity, that collectively influence people’s health. We have a tendency, I think the general public and scientists sort of silo off different groups of people. But the bottom line is that every individual has multiple identities that can protect them, but can also affect their health in negative ways, based on stigma and inequalities. The take home message is that allowing groups and subgroups to really express their lived experiences. It’s so important to be attentive, sensitive and engaged to find ways to be an ally.
You know a lot of the time, people will talk about the transgender community and they’ll be like, ‘Well, you know, [transgender people] only represents one to two per cent.’ That’s still a substantial number of people. And I think there’s a tendency for a lot of the general public, as well as scientists, to sort of dismiss that if it’s a small group of people, then it’s not really going to affect everyone else. But I really argue that you’re all connected. It’s so important to be able to represent all these different groups and to learn from them. Because I think a lot of people that are underrepresented and have been marginalized, engage in very unique and very powerful coping responses that make them resilient. Being able to understand those mechanisms is actually kind of a hopeful message for all.
And this applies for the rest of society as well. It doesn’t just become about doom and gloom and how society stigmatizes you and your poor health, but more about how you navigate these issues that we’re trying to slowly fix as society progresses, so that we can work on those different factors in the future. In the context of COVID-19, different groups within the LGBTQ2S+ community are engaging in different coping strategies. And while for instance, trans and non-binary people are dealing with a lot of mental health problems, like so many other people they’re also engaging in seeking social supports in virtual ways. In any kind of situation where there’s adversity, people that have faced adversity for reasons of their identity are going to engage in ways that the rest of society can learn from.
https://womenshealthresearchcluster.com/wp-content/uploads/2024/11/unnamed.jpeg597578caordahttps://womenshealthresearchcluster.com/wp-content/uploads/2024/08/WHRC-logo.pngcaorda2021-06-04 10:42:432025-02-07 18:22:09Behind The Science With Dr. Robert-Paul Juster
Authors: Arrthy Thayaparan and Alex Lukey (Blog Coordinators)
Published: May 21st, 2021
What do eight percent of pregnant women from around the world, including the likes of Beyoncé and Kim Kardashian, have in common? Complications due to high blood pressure.
Known as the ‘silent killer’ due to its ability to go undetected, high blood pressure is often misdiagnosed and treated less in women than in men, said Professor Angela Maas director of the Netherlands Women’s Cardiac Health Program.
For middle-aged women, symptoms such as hot flashes and heart palpitations, are often attributed to menopause. This mislabelling puts women at risk for serious heart conditions that could be avoided.
“A woman’s life provides clues that you need to start early with prevention. We have to assess female patients differently to men, and not just ask about high cholesterol,” said Professor Maas in a recent article with Science Daily.
But before understanding how high blood pressure can be better diagnosed and supported in women, we need to know exactly what high blood pressure is.
What is high blood pressure?
Also known as hypertension, high blood pressure happens when the blood vessels that carry blood around the body constrict, narrowing the blood’s space to pass. This constriction causes damage as blood pushes against the walls of the vessels. High blood pressure also makes the heart work harder to pump blood around the body.
The risk of untreated high blood pressure impacts almost every system in the body. As blood vessels around the body accumulate damage, they become weaker and less elastic. The organs that vessels bring blood to can become damaged over time, leading to the risk of multiple diseases. High blood pressure contributes to many life-threatening conditions such as heart disease, stroke and kidney damage.
Why might high blood pressure be dismissed in women?
Until the onset of menopause, women are at lower risk for hypertension than men due to the protective effects of estrogen on blood vessels.
Here is the list of potential symptoms of menopause that may mask signs of high blood pressure
Palpitations
Hot flushes
Headaches
Chest pain
Tiredness
Sleeping disturbances
According to Professor Maas, there are several subgroups of women that can be identified as high-risk before it is too late.
“High blood pressure during pregnancy is a warning sign that hypertension may develop when a woman enters menopause … If blood pressure is not addressed when women are in their 40s or 50s, they will have problems in their 70s when hypertension is more difficult to treat,” she said.
How do I know if I have high blood pressure?
It is essential to know what your baseline blood pressure numbers are to track changes over time.
You can take your blood pressure at most pharmacies. Taking your blood pressure outside of the doctor’s office may give a more accurate measure of blood pressure since many people feel nervous in appointments, potentially leading to an artificial increase in blood pressure.
Hypertension Canada Guidelines state that if your systolic blood pressure (top number) is more than 135 or diastolic blood pressure (bottom number) is more than 85, you may have high blood pressure.
If you are concerned that you have high blood pressure, you should talk to your primary care doctor or nurse practitioner.
How can women be safeguarded from hypertension?
Dr. Maas and her team authored a publication for the European Society of Cardiology with recommendations on how to help middle-aged women prevent heart problems due to high blood pressure.
They stress the importance of a healthy lifestyle and diet, especially in women who are at higher risks of high blood pressure during pregnancy and women who have type 2 diabetes.
But most importantly, the need for collaboration between cardiologists, gynecologists, and endocrinologists is needed to provide women with the best care.
Dr. Maas notes that women need to work as a team with their doctors to watch for signs and symptoms of high blood pressure.
“Women can help their doctors prevent heart problems and make earlier diagnoses by mentioning issues like complicated pregnancies and early menopause and monitoring their own blood pressure.”
Photo by Hush Naidoo on Unsplash
https://womenshealthresearchcluster.com/wp-content/uploads/2024/11/hush-naidoo-pa0uoltkwao-unsplash-scaled.jpg8001200caordahttps://womenshealthresearchcluster.com/wp-content/uploads/2024/08/WHRC-logo.pngcaorda2021-05-21 11:16:282025-02-07 18:22:10High Blood Pressure: Misunderstood in Women and Not Just for Men
Author: Dr. Luzia Troebinger, Post-Doctoral Fellow, University College London – Clinical Psychopharmacology Unit | Editors: Alex Lukey and Arrthy Thayaparan (Blog Coordinators)
Published: April 8th, 2021
What’s your worst memory? If I offered you a pill that could erase it, would you take it? Or let’s rephrase the question: How bad would your worst memory have to be to take that pill? What if you couldn’t leave your house without reliving this memory? You might think this scenario is exaggerated, but for people suffering from post-traumatic stress disorder (PTSD), this might be a daily reality. For many people with PTSD, the impact on quality of life is so severe that they would not hesitate to take that pill.
Research suggests that women are twice as likely to develop PTSD, even though rates of trauma exposure are higher in men.[1-3] The reason for this disparity is complicated and dependent on environmental and biological factors.[4] With regard to biological factors, the role of sex hormones in the context of stress and fear memory has become a primary target for research in this area.[5-7]
Studying fear memories in the laboratory can help improve our understanding of the mechanisms involved in PTSD. In the lab, a ‘fear memory’ is first established through a learnt association between a neutral and an adverse stimulus (e.g. a tone paired with an electric shock). This is similar to what happens in PTSD: a previously neutral stimulus becomes associated with the traumatic event. Extinction learning refers to the process of suppressing or reversing that learnt association. This is typically accomplished through repeated exposure to the neutral but not the adverse stimulus. Finally, extinction recall refers to how well this ‘extinction memory’ is remembered when confronted with the neutral stimulus later in time.
Fear extinction plays an important role in exposure therapy, a type of behavioural treatment commonly prescribed in PTSD.[8-10] Briefly, this type of therapy involves repeated exposure to trauma-related memories in a safe context. Just as in the laboratory models, the idea is that repeated exposure will result in the ‘extinction’ of learnt associations between environmental stimuli and the traumatic event. Although this type of treatment is effective for many people, it has limitations.
Try to think about your worst memory again. Now imagine doing this over and over again. Not exactly pleasant, is it?
There is a host of factors that influence if exposure therapy will benefit an individual. One aspect that might be highly relevant for women is the level of sex hormones at the time of treatment.
Evidence from rodent studies suggests that low estrogen levels in females are associated with poor extinction recall. These findings also seem to translate to studies in human subjects, with extinction recall being worse during low-estrogen stages of the menstrual cycle.[5,11] Moreover, the suppression of the body’s natural estrogen through the administration of hormone-based contraceptives has also been found to impair extinction recall.[12] This is an issue because impaired extinction recall could render exposure therapy ineffective or even counter-productive. If patients go through the difficult process of recalling traumatic memories without an understanding that doing so is safe and effective, they may lose motivation to continue treatment.
What are the possible implications of this in a clinical context? Timing could be a crucial factor in prescribing exposure therapy in naturally cycling women. Also, women with chronically low estrogen levels may benefit from pairing exposure therapy with pharmacological interventions. For instance, a recent study in rodents has shown that a certain type of blood pressure drug could reverse the adverse effects of low estrogen on extinction recall, possibly by making up for low-estrogen-related deficits in the regulation of the physiological stress response.[13]
Another approach to dealing with intrusive, distressing trauma memories is to reduce their impact near the time they are formed. This could be achieved by using pharmacological treatments to prevent traumatic memories from being further strengthened. As with exposure therapy, the case can be made that such treatments should take sex into account.
Previous research suggests that high progesterone levels at the time of trauma exposure could contribute to a strengthening of the traumatic memory, resulting in the type of intrusive, ‘flashback’ memories associated with PTSD.[14] Another study found that women who had been exposed to sexual assault had differing levels of PTSD depending on if they received hormone-based emergency contraceptives and what hormone the contraceptive contained. [15] One of two types of emergency contraceptives was administered, with one containing both synthetic estrogen and progestin (Ogestrel), while the other drug contained a synthetic progestin-only (Plan B). Interestingly, the women who took Ogestrel reported fewer intrusive memories than those who took Plan B. This might point to a combined effect of estrogen and progesterone on the formation of trauma memories. In any case, these studies highlight the importance of considering sex in the development of pharmacological treatments intended for use in the immediate aftermath of a trauma.
Given this research, why are we not prescribing treatments – behavioural or pharmacological – in a sex-specific way?
Treatments need to be well-studied before they can be used in clinical practice. Particularly in the case of pharmacological interventions, this process can be lengthy, costly and complex. The reality of research is that resources are limited, and drug studies are expensive. Testing for the influence of the menstrual cycle phase would increase the sample size required and would also put further demand on resources by necessitating the acquisition, storage, and analysis of biological samples for rigorous testing of hormone levels. At this time, there is a need for more evidence regarding hormonal influences on PTSD treatments. With the emergence of funding opportunities dedicated to the field of women’s health, there is hope that this will change. What is clear from the evidence is that there are hormonal influences on the development of PTSD. By including sex differences, we are presented with an opportunity to drastically improve the treatment of mental health disorders.
About the author
Dr. Luzia Troebinger currently works as a postdoctoral research fellow in Professor Sunjeev Kamboj’s group at University College London’s Clinical Psychopharmacology Unit. Her research focuses on both behavioural and pharmacological approaches to the treatment of PTSD and is funded by the Sir Bobby Charlton Foundation.
Twitter: @UCL_SBCF
Bibliography
1. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994;51(1):8-19. doi: 10.1001/archpsyc.1994.03950010008002 [published Online First: 1994/01/01]
2. Breslau N. Gender differences in trauma and posttraumatic stress disorder. J Gend Specif Med 2002;5(1):34-40. [published Online First: 2002/02/28]
3. Kessler RC, Sonnega A, Bromet E, et al. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 1995;52(12):1048-60. doi: 10.1001/archpsyc.1995.03950240066012 [published Online First: 1995/12/01]
4. Christiansen DM, Berke ET. Gender- and Sex-Based Contributors to Sex Differences in PTSD. Curr Psychiatry Rep 2020;22(4):19. doi: 10.1007/s11920-020-1140-y [published Online First: 2020/03/04]
5. Milad MR, Zeidan MA, Contero A, et al. The influence of gonadal hormones on conditioned fear extinction in healthy humans. Neuroscience 2010;168(3):652-8. doi: 10.1016/j.neuroscience.2010.04.030 [published Online First: 2010/04/24]
6. Maeng LY, Milad MR. Sex differences in anxiety disorders: Interactions between fear, stress, and gonadal hormones. Horm Behav 2015;76:106-17. doi: 10.1016/j.yhbeh.2015.04.002 [published Online First: 2015/04/19]
7. Goel N, Workman JL, Lee TT, et al. Sex differences in the HPA axis. Compr Physiol 2014;4(3):1121-55. doi: 10.1002/cphy.c130054 [published Online First: 2014/06/20]
8. Foa EB, McLean CP. The Efficacy of Exposure Therapy for Anxiety-Related Disorders and Its Underlying Mechanisms: The Case of OCD and PTSD. Annu Rev Clin Psychol 2016;12:1-28. doi: 10.1146/annurev-clinpsy-021815-093533 [published Online First: 2015/11/14]
9. Kothgassner OD, Goreis A, Kafka JX, et al. Virtual reality exposure therapy for posttraumatic stress disorder (PTSD): a meta-analysis. Eur J Psychotraumatol 2019;10(1):1654782. doi: 10.1080/20008198.2019.1654782 [published Online First: 2019/09/07]
10. Steenkamp MM, Litz BT, Hoge CW, et al. Psychotherapy for Military-Related PTSD: A Review of Randomized Clinical Trials. JAMA 2015;314(5):489-500. doi: 10.1001/jama.2015.8370 [published Online First: 2015/08/05]
11. Wegerer M, Kerschbaum H, Blechert J, et al. Low levels of estradiol are associated with elevated conditioned responding during fear extinction and with intrusive memories in daily life. Neurobiol Learn Mem 2014;116:145-54. doi: 10.1016/j.nlm.2014.10.001 [published Online First: 2014/12/03]
12. Graham BM, Milad MR. Blockade of estrogen by hormonal contraceptives impairs fear extinction in female rats and women. Biol Psychiatry 2013;73(4):371-8. doi: 10.1016/j.biopsych.2012.09.018 [published Online First: 2012/11/20]
13. Parrish JN, Bertholomey ML, Pang HW, et al. Estradiol modulation of the renin-angiotensin system and the regulation of fear extinction. Transl Psychiatry 2019;9(1):36. doi: 10.1038/s41398-019-0374-0 [published Online First: 2019/01/31]
14. Ney LJ, Gogos A, Ken Hsu CM, et al. An alternative theory for hormone effects on sex differences in PTSD: The role of heightened sex hormones during trauma. Psychoneuroendocrinology 2019;109:104416. doi: 10.1016/j.psyneuen.2019.104416 [published Online First: 2019/09/01]
15. Ferree NK, Wheeler M, Cahill L. The influence of emergency contraception on post-traumatic stress symptoms following sexual assault. J Forensic Nurs 2012;8(3):122-30. doi: 10.1111/j.1939-3938.2012.01134.x [published Online First: 2012/08/29]
https://womenshealthresearchcluster.com/wp-content/uploads/2024/11/luzia_blog_copy.png10801080caordahttps://womenshealthresearchcluster.com/wp-content/uploads/2024/08/WHRC-logo.pngcaorda2021-04-08 17:07:102025-02-07 18:22:10Learning to Forget: Making the Case for Sex-Specific Approaches to the Treatment of PTSD
Author: Elise Wiley, Ph.D. Student, McMaster University | Editors: Alex Lukey and Arrthy Thayaparan (Blog Coordinators)
Published: March 19th, 2021
There is a growing body of research focused on the biological differences between males and females in pharmaceuticals, risk factors, pathology, severity, and prognosis of different diseases [1]. In contrast to this large body of evidence related to sex-based differences, we know far less about how gender impacts the risk of disease. For example, how does the risk for stroke or heart attack differ in a heterosexual man versus a transgender non-binary individual? While more research is accounting for sex differences, this is not the case for gender identity. The lack of sex and gender considerations are causing a significant gap in knowledge for many health conditions.
Stroke is a leading cause of disability and death worldwide [2]. Over the past 20 years, there has been a growing body of literature showing that exercise-based interventions are beneficial in improving physiological and psychosocial health markers in individuals with stroke [3]. However, the extent to which sex-and gender-based considerations were implemented into exercise trials in individuals with stroke has not been previously reviewed.
In this blog post, I will share results from a study that I conducted, which aimed to examine the extent to which stroke researchers include sex-and gender-based considerations in their exercise trials. In this study, we surveyed publications of exercise trials in stroke and applied the Sex and Gender Equity in Research (SAGER) tool as a framework to determine whether sex and gender considerations were implemented in each section of a study (i.e., introduction, study design/methods, results and discussion) [4]. We were also interested in examining whether the incorporation of sex- and gender-based considerations had increased since the publication of the SAGER guidelines in 2016.
I will preface the summary of the results by stating that we have a long way to go in addressing sex-and gender-based considerations in exercise-based trials in individuals with stroke. Over the past ten years, sex-and gender-based considerations have gained recognition for their importance in health research. This is thanks to the pioneer Canadian researchers in the field of sex and gender research who advocated for more inclusive research practices. Unsurprisingly, before 2016, the vast majority of stroke and exercise studies did not include any sex or gender considerations in any section of the research article. After 2016, we found a slight increase in the proportion of studies incorporating sex-based considerations since the publication of the SAGER guidelines. However, we also noted that researchers continued to use terminology related to “sex” and “gender” interchangeably.
Of note, there were no exercise-based studies in stroke that included gender-based considerations. While this is unsurprising, I do wonder why we, as researchers in the field of exercise and stroke, have neglected gender in our studies? Is it that there isn’t enough awareness of the available gender-based resources to guide its inclusion or assessment? Or is the reason more deep-seated? It is important to acknowledge that it is indeed challenging to incorporate gender-based considerations into research studies when self-reported gender measures are unavailable, and there is no firm consensus on how various constructs of gender are to be measured [5].
We hope that our research findings will serve as a call to action for researchers in the field of exercise and stroke to acknowledge the opportunities that lie ahead in being able to address the knowledge gaps related to sex-and gender-based considerations in exercise trials in individuals with stroke. We must continue to reinforce the idea that although sex and gender are interrelated, they are not interchangeable. I urge researchers to consult the resources that I’ve provided to ensure that their participants are being addressed properly. It may also be that there is a greater onus on journal editors to ensure that, at minimum, authors submitting to their journal are incorporating proper sex and gender terminology.
As an advocate for sex and gender implementation in health research, the findings from this work suggest that we have a long way to go, but the positive trend is encouraging. I am optimistic for the years to come and continue to be inspired by my fellow researchers who advocate for enhanced sex and gender implementation in health research.
References
1. Melloni Chiara, Berger Jeffrey S., Wang Tracy Y., et al. Representation of Women in Randomized Clinical Trials of Cardiovascular Disease Prevention. Circulation: Cardiovascular Quality and Outcomes. 2010;3(2):135-142. doi:10.1161/CIRCOUTCOMES.110.868307
2. Campbell BCV, De Silva DA, Macleod MR, et al. Ischaemic stroke. Nature Reviews Disease Primers. 2019;5(1):1-22. doi:10.1038/s41572-019-0118-8
3. Saunders DH, Sanderson M, Hayes S, et al. Physical fitness training for stroke patients. Cochrane Database of Systematic Reviews. 2020;(3). doi:10.1002/14651858.CD003316.pub7
4. Heidari S, Babor TF, De Castro P, Tort S, Curno M. Sex and Gender Equity in Research: rationale for the SAGER guidelines and recommended use. Research Integrity and Peer Review. 2016;1(1):2. doi:10.1186/s41073-016-0007-6
5. Lacasse A, Pagé MG, Choinière M, et al. Conducting gender-based analysis of existing databases when self-reported gender data are unavailable: the GENDER Index in a working population. Can J Public Health. 2020;111(2):155-168. doi:10.17269/s41997-019-00277-2
6. Government of Canada CI of HR. IGH Learning – CIHR. Published September 2, 2015. Accessed February 25, 2021. https://cihr-irsc.gc.ca/e/49347.html
7. Government of Canada CI of HR. Gender-Based Analysis Plus (GBA+) at CIHR – CIHR. Published May 15, 2018. Accessed June 5, 2020. https://cihr-irsc.gc.ca/e/50968.html
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Authors: Jolande Fooken, Xiuyun Wu, & Doris Chow | Editors: Alex Lukey and Arrthy Thayaparan (Blog Coordinators)
Published: November 12th, 2020
In recent years more scientists have advocated an increased focus on the role of sex and gender differences in neuroscience research. Specifically, it is important to study sex-related mechanisms in the brain and how they affect sensory processing and motor behaviour.
Considering that historically most research included only male participants, research standards are trending in the right direction. Today, researchers are strongly encouraged to take sex and gender into consideration for their research. However, is it enough to simply collect the same number of male and female participants or should we think about sex as a scientifically relevant and meaningful variable?
Missed Opportunities in Present Research
A recent study by Mathew and colleagues investigated the effect of sex as a biological variable on hand-eye coordination and processing by the brain, led us to reconsider how sensory and motor neuroscience currently take sex differences into account.[1] It’s true that researchers pay greater attention to sex and gender balance in their research than in the past. However, we still know very little about how visuomotor function might vary between people of different sex and gender.
Driven by that very question, Mathew and colleagues decided to analyze how the ability to manually track a moving target varies between self-reported male and females.[1] Whereas the general research question could fill a large gap in our current literature, the authors missed their chance to make a significant contribution and advance our knowledge about the importance of sex as a biological variable.
The study, entitled “Sex Differences in Visuomotor Tracking”, was published in July 2020 in Scientific Reports and could potentially reach a high impact in the field. Yet, this study has several gaps, which we will later discuss, that are not sufficiently addressed in the paper. Therefore, the conclusions drawn should raise red flags as they may mislead some readers and future research. In the following, we will comment on three major points that scientists—interested in sex differences in behavioural neuroscience—should take into account
1. Sex differences are no afterthought
We are living in a time where there are vast amounts of data being used for scientific research. Often scientists publish a subset of the full dataset that was collected, reporting only those measures that address the current research question. At the same time, there may be additional information about the participants, such as age, handedness, or biological sex not included in the analysis. Therefore, it is very tempting to later re-analyze the data to look for differences across various variables. Such differences are exactly what Mathew and colleagues reported.
The authors analyzed data from a manual-tracking baseline task that usually preceded the main experiment in their lab. Manual tracking is a common task in sensorimotor research, in which participants move a joystick to align a visual cursor with a moving target. Typically, experiments aim to investigate how participants adapt their visuomotor control to changes in the visual scene. In the study by Mathew et al., the baseline task required participants to track the moving target as closely and accurately as possible. The authors observed differences between female and male participants: females tracked the unpredictably moving target with a larger time lag than their male counterparts.
These findings should spark interest in any curious scientist. However, there is also a problem: the authors did not have an a priori hypothesis (reasoning based on inference before the study, rather than evidence) about the role of biological sex with respect to visuomotor tracking. Instead, they performed their analyses after the fact. Accordingly, several factors that may influence the role of sex and gender on the results were not controlled for.
One factor that may have skewed the results of this study is video-gaming, an activity more common among males.[2, 3] Video game experience most likely influences participants’ ability to accurately use a joystick to track a moving target. Additionally, general personality traits could explain the observed individual differences in manual tracking behaviour. For example, risk-averse individuals may track the target with a higher time lag to be able to adjust their hand movements more precisely to sudden changes of target motion. All of this is of course speculative. The study was not designed to study sex differences and therefore cannot answer if visuomotor tracking truly differs between males and females.
2. The battle of the sexes: what is a male advantage?
Some readers may cringe when they read that Mathew and colleagues wrote that they found, “a clear male advantage in hand tracking accuracy”. The study shows differences, yes, but an advantage? Tracking a target as fast as possible does not necessarily translate to advantages in everyday life in which timing is often relevant.
Imagine getting into a car with someone who is trying to follow the car in front as closely as possible—keeping a larger distance may in fact be the safer option. Driving and many other naturalistic scenarios may require us to choose a tracking behaviour that differs from a pure distance minimization. To study optimal visuomotor behaviour we need to first define normative models that allow us to evaluate a decision or judgement.[4] What is the goal of the actor? What does it mean to be successful in a task? What is the error we should aim to minimize?
In motor control, there may be some tasks in which action accuracy is easy to judge. For example, how well a person can throw a ball can be measured in the distance the ball has travelled. However, when we change the definition of success, we also change our measure of accuracy. For daily activities, it may be relatively easy to judge success, but in basic sensorimotor research, it is less clear.
Thus, optimal performance during manual tracking can be defined in different ways: it may be optimal to track a moving target as closely as possible or to track it as smoothly as possible and thereby reduce overall movement cost. Defining optimal task performance is key to understanding individual strategies when solving any given task. Only then can we draw conclusions about so-called advantages.
3. Males are different from females, now what?
For a moment let’s assume that, despite all the weaknesses in the study by Mathew et al., that we have pointed out, that there is a difference between male and female participants during visuomotor tracking. What does that mean?
First, we should aim to investigate where such a difference originates. Mathew and colleagues conclude that males may rely on “faster decisional processes dynamically linking visual information of the target with forthcoming hand actions”.[1] However, some of these proposed processes, such as visual processing and early visual brain regions have relatively fixed time scales.
So the question that arises is at what stage of the decision process do differences occur? Does the transformation from visual information into motor commands take longer in female participants? Why? Does this difference change with experience or training? Or are there other factors, such as knowledge about motor uncertainty, that influence visuomotor tracking? Again, we simply don’t know yet and we need more carefully designed research to find these answers.
Another important question that we should ask ourselves is what the implications of the observed differences are. For example, visuomotor control has become very important in the medical field, where robotic devices enable complicated brain surgeries. Are such devices tailored to an average operator? Should we design different devices for female neurosurgeons as compared to males? Is there an actual physiological difference between males and females or are we just measuring differences along a spectrum of individual performance variability? At this time we do not have concrete answers to these questions. So, until we have better answers to the questions of how these differences arise, it may be harmful to make sweeping statements of sex-based advantages.
We have the opportunity to study sex differences in sensory and motor neuroscience in a meaningful and thorough way. Let’s not report sex differences as an afterthought, but instead study biological sex as an interesting and important factor at the centre of our research agenda.
REFERENCES
1. Mathew, J., Masson, G. S., & Danion, F. R. (2020). Sex differences in visuomotor tracking. Scientific reports, 10(1), 1-12. https://doi.org/10.1038/s41598-020-68069-0
2. Terlecki, M.S., Newcombe, N.S. (2005). How Important Is the Digital Divide? The Relation of Computer and Videogame Usage to Gender Differences in Mental Rotation Ability. Sex Roles, 53, 433–441. https://doi.org/10.1007/s11199-005-6765-0
3. Quaiser-Pohl, C., Geiser, C., & Lehmann, W. (2006). The relationship between computer-game preference, gender, and mental-rotation ability. Personality and Individual Differences, 40(3), 609-619. https://doi.org/10.1016/j.paid.2005.07.015
4. Körding, K. (2007). Decision theory: what” should” the nervous system do?. Science, 318(5850), 606-610. https://doi.org/10.1126/science.1142998
Images courtesy Joel Staveley, Jehoots and Photologic on Unsplash
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Author: Jennifer Williams, PhD Candidate, McMaster University | Twitter: @jennyswilliams
The importance of integrating sex/gender in health research has been evident in the calls for action by researchers, funding organizations, and peer-reviewed journals alike. Especially in the midst of the global COVID-19 pandemic, this remains at the forefront of study design, illuminated recently by the first of the Women’s Health Research Cluster blogs. Over the past few years as a graduate trainee, I have been involved in research projects either integrating sex-based differences or examining female-specific conditions to fill gaps evident in cardiovascular research. Mentored by leaders in the field, much of my passion for sex/gender research has also been directed to supporting education of undergraduate and graduate trainees through mentorship, teaching, and volunteering with the CIHR Institute of Gender and Health Trainee Network.
However, in reflecting on my research journey, it occurred to me that many trainees may be presently searching for resources and a network of colleagues considering these important questions. As the upcoming semester approaches, my hope is that this blog will serve as a useful guide to explore sex/gender in your future research studies, whether you’re an early integrator (like me) or an advanced champion (like many of my mentors). By no means is this an exhaustive list, so I encourage you to continue the conversation by sharing your favourite resource on Twitter with the #sexandgender.
Getting Started
What is Sex? What is Gender? When I started to ask myself these questions, I found the following definitions and infographic on the CIHR website helpful in finding the answers. Furthermore, this video (3min) provided me with an explanation about why learning about sex/gender is important.
The CIHR Institute of Gender and Health curates an excellent list of resources for researchers to consider when integrating sex/gender into research. Check out their guide here, which is updated frequently with new resources and published studies.
Training Modules
The following training courses/modules served as a foundation for developing my understanding of sex/gender in health research.
In addition to the training modules provided by CIHR, this video (5min) is a helpful resource for understanding what grant reviewers are looking for in assessing your integration of sex/gender into your research study design. This video, alongside a resource for reviewers, entitled “Key considerations for the appropriate integration of sex and gender in research”, can provide insight into what makes a strong research design, and hopefully a successful grant application.
What are Researchers Saying? Research Articles & Guideline Documents
The following article about the Sex and Gender Equity in Research (SAGER) guidelines are recommended for all researchers to review and include in their research study designs. Find out more here (Table 1 includes a comprehensive checklist of considerations).
Strategies have also been well detailed by the following articles:
Journal Clubs: One of the most impactful ways I’ve found for integrating sex/gender into discussions within my lab is in suggesting journal articles during journal club gatherings. Here’s an extensive list of articles curated by the NIH and a list of articles from the CIHR here.
Championing Sex/Gender Research: Organizations to Get Involved With
Become a Sex and Gender Champion on collaborative research initiatives with CIHR. Similarly, consider joining the Institute of Gender and Health Trainee Network as a trainee mentee or Faculty mentor, and spearhead local initiatives at your institution with the support of this network. You can subscribe to the trainee network’s newsletter here.
Finally, look for mentors and collaborators who are experienced in exploring sex and gender in research. If exploring women’s health, the Women’s Health Research Cluster directory is useful for connecting with individuals from across Canada, but primarily in BC, and similar for this directory in Ontario.
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Have a resource to share not on this list? Continue the conversation by sharing your favourite resource on Twitter with the #sexandgender.
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Authors: Bonnie H. Lee (BSc, PhD student) and Liisa A.M. Galea (PhD, Graduate Program in Neuroscience, Department of Psychology. Djavad Mowafaghian Centre for Brain Health, University of British Columbia)
Every day we learn more about the novel coronavirus (severed acute respiratory syndrome coronavirus 2: SARS-CoV-2). During these early months of the worldwide outbreak, it has become apparent that although men and women may be similarly susceptible to the virus, males are more likely to become severely ill developing the disease, known as COVID-19 that comes from SARS-CoV-2, and worse, have a higher mortality rate. Both biological (sex) and environmental (let’s loosely think of this as gender) factors likely contribute to this sex bias, although most of our focus here will be on the biological contributions.
A research group from China analyzed data from 1099 early cases of COVID-19, including 37 of the first death cases from Wuhan city, and found that in addition to older age and higher number of underlying health conditions, male sex was associated with higher disease severity and mortality rate in patients with COVID-19. Of the 37 death cases, 70.3% were males.
According to Italy’s National Health Institute, 58% of the confirmed novel coronavirus cases, and 70% of the reported deaths from COVID-19 were males. These numbers are consistent with those from China. To date, 25 countries have made data relating to COVID-19 publicly available, but only 6 of them provided the data about both confirmed cases and deaths, broken down by sex: China, France, Germany, Iran, Italy, and South Korea. Through a collaborative effort, CNN and Global Health 50/50 have created a live tracker of the sex-disaggregated data. In order to continue assessing the important differences between males and females regarding COVID-19, it is necessary for all countries to collect and publish their data broken down by sex. Only in this way can we leverage knowledge on sex differences to aid in the discovery of new treatments.
So why is disease severity and mortality rate worse in males than females?
Two ways to approach the sex differences seen with COVID-19 are to examine factors that may cause males to be at greater risk of becoming severely ill with COVID-19 and examine factors that may cause female to be more resilient to becoming severely ill with COVID-19. Both perspectives are needed to understand the differences in mortality rates. In addition, although biological factors like genetics and sex hormones are important to examine, environmental and gendered factors may also contribute to the difference in COVID-19 disease severity and mortality rate between males and females.
Note that the term “sex” is used as a biological variable, defined by the physiological characteristics that define males and females (such as chromosomes, reproductive organs, and sex hormone levels), which is distinct from gender, which involves what a given society may deem appropriate behaviours and activities and/or gender identity (see definitions). It is also important to be aware of the intersectionality between sex and gender.
Biological Factors
Males and females differ in their innate and adaptive immune responses. Typically, females present with stronger immunological responses and are more resistant to virus infections compared to males. Genetically, females possess two X chromosomes whereas males possess one X and one Y sex chromosome, and these chromosomes are present in every cell throughout the body. Interestingly, literature shows that the X chromosome contains many genes that regulate immune function, and it is suggested that because males have fewer of these genes, they are at greater risk of developing certain immune-related diseases. A recent analysis indicates that females had a greater (high range) antibody response when in the severe stage of COVID-19 compared to males. These early analyses suggest some biological component to the sex differences in COIVD-19 responses. Time will tell, with further data, whether this finding is replicated, and whether this effect is seen across age groups.
Sex hormones play an important role in the regulation of the development and function of the immune system. Estrogens, which are produced at higher levels in females, can act by binding to estrogen receptors. Given that estrogen receptors are widely expressed in most cells of the immune system, it is not surprising that estradiol, the most potent form of the estrogens, modulates the functional activity of innate immune cells, and influences downstream adaptive immune responses. On the other hand, androgens, which are at higher levels in males suppress immune cell activity, resulting in inhibited immune reactivity and inflammation. Thus, it is possible that estrogens and androgens play a role in COVID-19 but given that the sex differences are seen in older age groups, which includes postmenopausal females, this suggests that levels of sex hormones can not be the only factor.
Research has identified the angiotensin-converting enzyme 2 (ACE2) as a receptor that is present in many areas of the body including the lungs and nose for the novel coronavirus (Hamming et al., 2004; Xu et al., 2020; Zhou et al., 2020). Data extracted from healthy human lung transplant donors revealed that male donors had higher ACE2-expressing cell ratio, more widespread distribution of ACE2, and a greater variety of different types of cells expressing ACE2, compared to female donors. This suggests that once in contact with the novel coronavirus, the virus has more opportunity to bind with receptors in males compared to females, thus making it easier for the virus to duplicate and potentially cause worse disease outcomes in males. However, we would like to caution that this study only included 8 donors, and only 2 of them were male, and that it will be important in future studies to replicate these intriguing findings. Other research has shown sex differences in ACE2 activity in kidneys, with greater activity in males compared to females that was not dependent on chromosomal sex, but rather 17β-estradiol. Further studies are beginning to bear fruit using gene by sex analyses to examine candidates to combat viral transfer – one such candidate is Muc4, in which expression gives an advantage to female mice but not male mice in viral loads following infection from SARVS-COV.
A study that analyzed lung tissue samples found that smokers (including current and former smokers) had higher ACE2 gene expression compared to non-smokers, even after adjusting for age, sex, and race. More males have reported a history of smoking compared to females according to the WHO, suggesting that males may be predisposed with a higher expression of ACE2 from smoking. In China, sex differences in smoking levels are very high (50% of males and 2% of females are smokers), but the sex difference in Italy is not as profound (28% of males and 19% of females are smokers). Given that both countries show sex differences in mortality from COVID-19 this suggests that sex differences in smoking may contribute but not completely account for the sex differences in mortality rates.
On a related note, it is known that preexisting health conditions confers greater risk for developing a severe case of COVID-19. A report recently released by the Centre for Disease Control and Prevention shows that approximately 80% of ICU and 70% of hospitalized COVID-19 patients in the United States of America reported having at least one underlying health condition. Commonly reported conditions include smoking, lung disease, heart disease, and diabetes. Some of these conditions (mainly lung and heart diseases) are found to be more prevalent among males compared to females. Sex differences in the prevalence of preexisting health conditions may also play a role in the findings that males have a greater morality risk than females from COVID-19.
Environmental Factors
Environmental factors play an impactful role in exposure and infection from viruses. For instance, practicing proper hand hygiene is a crucial for preventing contraction of the novel coronavirus. Curiously, an epidemiological investigation conducted in 2018 found that female participants had significantly greater hand hygiene knowledge compared to their male counterparts. In addition, research shows that females seem to wash their hands more often, use soap more often, and wash their hands for a longer period of time compared to males. And although anecdotal, a recent survey from February 2020 suggests that 65% of females were washing their hands (and keeping surfaces clean) compared to 52% of men surveyed due to coronavirus concerns.
The presence of these different risk and protective factors in males and females may, at least in part, explain the sex differences observed in the disease severity and mortality rate of COVID-19. Moving forward, it remains crucial for research to include and analyze both sexes in their data, so we can further understand the mechanisms driving these sex differences and to propel effective treatments forward for both sexes. It also emphases that the reasons for these sex differences span multiple disciplines and domains and that it will take a concerted effort among a number of different areas of research to fully understand all the factors that contribute to COVID-19 mortality (e.g. social, implementation science, compliance, inflammation, lifestyle choices).
Summary of risk and protective factors in males (blue) and females (pink relating to COVID-19 disease severity and mortality rate.
Lastly, it is important to remember that although mortality from COVID-19 affects men more than women, COVID-19 can affect anyone. Although some may feel as though our risk of becoming sick from the virus is low, there are many younger patients that can have COVID19, and even “mild” symptoms can be devastating. We all need to be doing our part to protect those around us and in the greater community. Let’s continue to wash our hands with soap, stay home, practice physical distancing, and be kind to one another in these trying times.
Bibliography
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Borchgrevink CP, Cha J, Kim S. Hand Washing Practices in a College Town Environment. Journal of Environmental Health. 2013;75(8):7.
Bouman A, Heineman MJ, Faas MM. Sex hormones and the immune response in humans. Hum Reprod Update. 2005;11(4):411-423. doi:10.1093/humupd/dmi008
Cai G. Bulk and single-cell transcriptomics identify tobacco-use disparity in lung gene expression of ACE2, the receptor of 2019-nCov. medRxiv. February 2020:2020.02.05.20020107. doi:10.1101/2020.02.05.20020107
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